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https://openalex.org/W2945618938
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http://www.scielo.br/pdf/coluna/v15n4/1808-1851-coluna-15-04-00290.pdf
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English
| null |
RELAÇÃO ENTRE QUALIDADE DE VIDA E OSTEÓLISE EM TORNO DE PARAFUSOS PEDICULARES LOMBARES
| null | 2,016
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cc-by
| 6,147
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CORRELACIÓN ENTRE CALIDAD DE VIDA Y OSTEÓLISIS ALREDEDOR DE TORNILLOS
PEDICULARES LUMBARES Marcelo Italo Risso Neto1
, Sylvio Mistro Neto2, Roberto Rossanez2, Guilherme Rebechi Zuiani1, Ivan Guidolin Veiga2, Wagner Pasqualini2,
Marcos Antônio Tebet2, Augusto Celso Scarparo Amato Filho3, Elcio Landim1, Paulo Tadeu Maia Cavali1 1. Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Orthopedics and Traumatology Department, Spinal Surgery Department, Campinas, SP, Braz
e Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil. e Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil. 2. Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas da Unicamp, Orthopedics and Traumatology Department, Spinal Surgery Department
Campinas, SP, Brazil. C
(
C
)
C ê
é
C
S e Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil. 2. Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas da Unicamp, Orthopedics and Traumatology Department, Spinal Surgery Department,
Campinas, SP, Brazil. p
,
,
,
2. Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas da Unicamp, Orthopedics and Traumatology Departmen
Campinas, SP, Brazil. Campinas, SP, Brazil. 3. Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas da Unicamp, Radiology Department, Campinas, SP, Brazil. Original Article/Artigo Original/Artículo Original Original Article/Artigo Original/Artículo Original RESUMO Objetivo: Avaliar se a presença de osteólise em torno dos parafusos pediculares influencia a qualidade de vida de pacientes submetidos
à artrodese posterolateral da coluna lombossacral. Métodos: Estudo retrospectivo com pacientes submetidos à artrodese posterolateral
lombar ou lombossacral por doença espinal degenerativa. Foram realizadas tomografias computadorizadas dos segmentos operados em
intervalos de 45, 90, 180 e 360 dias de pós-operatório. Nesses exames, foi pesquisado a presença de um halo radiolucente peri-implante,
que foi considerado presente quando maior que 1 mm no corte coronal. Concomitantemente à realização dos exames de TC foi aplicado o
questionário Oswestry Disability Index (ODI) para avaliar o grau de incapacidade dos pacientes. Resultados: Foram avaliados 38 pacientes e
14 (36,84%) deles apresentavam algum grau de osteólise ao redor de pelo menos um parafuso pedicular ao final do seguimento. Dos 242
parafusos analisados, 27 (11,15%) apresentaram osteólise no corte coronal da TC, sendo a maioria dessas ocorrências no nível mais distal
do segmento com artrodese. Não se observou relação da presença dessa osteólise com a qualidade de vida dos pacientes. A qualidade de
vida tem melhora significativa quando se compara o resultado pré-operatório com os resultados pós-operatórios nos diversos momentos de
aplicação do ODI. Essa melhora no ODI mantém a linearidade de melhora com o passar do tempo. Conclusão: Não há relação da presença
da osteólise peri-implante com a qualidade de vida dos pacientes submetidos à artrodese lombar ou lombossacral posterolateral no período
de seguimento até os 360 dias. A qualidade de vida pós-operatória tem melhora significativa quando comparada ao momento pré-operatório. Descritores: Osteólise; Fusão vertebral; Qualidade de vida; Pseudoartrose; Coluna vertebral. ABSTRACT Objective: To evaluate whether the presence of osteolysis around the pedicle screws affects the quality of life of patients who underwent
posterolateral arthrodesis of the lumbosacral spine. Methods: A retrospective study of patients undergoing lumbar posterolateral or lum-
bosacral arthrodesis due to spinal degenerative disease. CT scans of the operated segments were performed at intervals of 45, 90, 180,
and 360 postoperatively. In these tests, the presence of a peri-implant radiolucent halo was investigated, which was considered present
when greater than 1mm in the coronal section. Concurrently with the completion of CT scans, the participants completed the questionnaire
Oswestry Disability Index (ODI) to assess the degree of disability of the patients. Results: A total of 38 patients were evaluated, and 14
(36.84%) of them showed some degree of osteolysis around at least one pedicle screw at the end of follow-up. Of the 242 analyzed screws,
27 (11.15%) had osteolysis in the CT coronal section, with the majority of these occurrences located at the most distal level segment of
the arthrodesis. There was no correlation between the presence of the osteolysis to the quality of life of patients. The quality of life has
significantly improved when comparing the preoperative results with the postoperative results at different times of application of ODI. This
improvement in ODI maintains linearity over time. Conclusion: There is no correlation between the presence of peri-implant osteolysis to the
quality of life of patients undergoing lumbar or posterolateral lumbosacral arthrodesis in the follow-up period up to 360 days. The quality
of life in postoperative has significantly improvement when compared to the preoperative period. Keywords: Osteolysis; Spine fusion; Quality of life; Pseudarthrosis; Spine. RELAÇÃO ENTRE QUALIDADE DE VIDA E OSTEÓLISE EM TORNO DE PARAFUSOS
PEDICULARES LOMBARES CORRELACIÓN ENTRE CALIDAD DE VIDA Y OSTEÓLISIS ALREDEDOR DE TORNILLOS
PEDICULARES LUMBARES Study conducted by the Spine Surgery Group of the Department of Orthopedics and Traumatology of the Faculdade de Ciências Médicas da UNICAMP, Campinas, SP, Brazil.
Correspondence: Depto. de Ortopedia e Traumatologia, Área de Cirurgia da Coluna, Faculdade de Ciências Médicas - UNICAMP. Rua Tessália Vieira de Camargo, 126, Cidade Universitária “Zeferino Vaz”,
Campinas, SP, Brazil. 13083-887. mrisso@mpc.com.br, sylvio.mistro@gmail.com METHOD (Figure 1A) The software Arya
Pixeon© version 1.5.5 was used, and sections with thickness of 3 mm. All the patients agreed to and signed the Informed consent
Form (ICF), which was approved by the Institutional Review Board
of the Universidade Estadual de Campinas, SP, Brazil, under number
856/2009. For the statistical analysis, the software SPSS 20.0 (SPSS,
Inc., Chicago, IL, USA) was used, and a level of significance of 5%
was used for the tests. This is a retrospective analysis study of patients submitted to
surgical treatment of the vertebral spine, with lumbar or lumbosacral
posterolateral arthrodesis instrumented with pedicle screws. The study
was conducted from 2010 to 2013 at a tertiary public hospital. Patients
aged between 20 and 85 years were included, of both sexes, with a
history of degenerative disease of the lumbosacral spine, who had
already undergone conservative treatment without improvement in
the symptoms. Patients were excluded who had a history of vertebral
spine tumor, congenital deformities, a previous history of surgical
procedure to the lumbosacral spine, and patients who did not agree
to the research terms and did not sign the Informed Consent Form
(ICF). The patients responded to the Oswestry Disability Index in the
preoperative period, and at 45, 90, 180 and 360 postoperative days. The ODI questionnaire was always applied by an orthopedic surgeon
who was trained and familiar with it. The questionnaire consists of
10 questions with six statements in each, to identify limitations when
performing nine activities of daily living, and in the patient’s sex life. The final score expresses the degree of disability, as a percentage,
classifying it as minimal, moderate, severe, very severe and bed-bound
or exaggerating the symptoms, as shown in annex 1. At the time of
application of the questionnaire, except during the preoperative period,
computed tomography exams were taken of the lumbosacral spine. Lumbar arthrodesis has been indicated as one of the treatment
alternatives in selected cases of degenerative diseases of the verte-
bral spine with instability, including scoliosis, spondylolisthesis, and
narrowing of the lumbar canal,2,3 proving efficient, when properly
indicated, and resulting in an improvement in the pain and other
disabilities generated by these pathologies.1-4 Lumbar arthrodeses can be performed via the anterior, posterior,
or posterolateral approaches, or a combination of these. RESUMEN Objetivo: Evaluar si la presencia de osteólisis alrededor de los tornillos pediculares afecta la calidad de vida de los pacientes que fueron
sometidos a artrodesis posterolateral de la columna lumbosacra. Métodos: Estudio retrospectivo de pacientes sometidos a artrodesis lumbar
posterolateral o lumbosacra debido a enfermedad degenerativa de la columna vertebral. Se realizaron tomografías computarizadas de los
segmentos operados en intervalos de 45, 90, 180 y 360 días después de la cirugía. En estas pruebas, fue investigada la presencia de un
halo radiotransparente alrededor del implante, que se consideró presente cuando era mayor que 1 mm en corte coronal. Simultáneamente http://dx.doi.org/10.1590/S1808-185120161504147749 Received on 03/27/2015, accepted on 07/13/2016. Coluna/Columna. 2016;15(4):290-4 CORRELATION BETWEEN QUALITY OF LIFE AND OSTEOLYSIS AROUND LUMBAR PEDICLE SCREWS 291 con la realización de las tomografías se aplicó el cuestionario Oswestry Disability Index (ODI) para evaluar el grado de discapacidad de
los pacientes. Resultados: Se evaluaron 38 pacientes y 14 (36,84%) de ellos tenían algún grado de osteólisis alrededor de al menos un
tornillo pedicular al final del seguimiento. De los 242 tornillos analizados, 27 (11,15%) tenían osteólisis en el corte coronal de la tomografía,
estando la mayoría de estas ocurrencias, en el nivel más distal de la artrodesis. No hubo correlación entre la presencia de la osteólisis a
la calidad de vida de los pacientes. La calidad de vida ha mejorado de manera significativa al comparar los resultados preoperatorios con
los resultados postoperatorios en sus distintos momentos del ODI. Esta mejora en el ODI mantiene linealidad de mejoría con el tiempo. Conclusión: No existe correlación entre la presencia de osteólisis alrededor del implante a la calidad de vida de los pacientes sometidos
a artrodesis posterolateral lumbar o lumbosacra en el período de seguimiento de hasta 360 días. La calidad de vida postoperatoria ha
mejorado significativamente en comparación con el período preoperatorio. Descriptores: Osteólisis; Fusión vertebral; Calidad de vida; Seudoartrosis; Columna vertebral. Coluna/Columna. 2016;15(4):290-4 METHOD Images were used in
the coronal and sagittal planes, so that the image in the coronal plane,
used for the evaluation of osteolysis, reflected the image of the screw
oriented perpendicularly to the vertebra. (Figure 1A) The software Arya
Pixeon© version 1.5.5 was used, and sections with thickness of 3 mm. All the patients agreed to and signed the Informed consent
Form (ICF), which was approved by the Institutional Review Board
of the Universidade Estadual de Campinas, SP, Brazil, under number
856/2009. For the statistical analysis, the software SPSS 20.0 (SPSS,
Inc., Chicago, IL, USA) was used, and a level of significance of 5%
was used for the tests. INTRODUCTION health professionals to evaluate and better understand the patients’
expectations and anxieties in the period prior to the proposed treat-
ment, and during the recovery phase.21 One such questionnaire is the
“Oswestry Disability Index” (ODI).27 Low back pain or chronic lumbociatalgia, defined as pain lasting
more than three months, is the second biggest cause of visits to
the doctor and the main cause of absence from work in the USA. It
affects 5% to 8% of the general population, and is reported by 19% of
the economically active population, generating costs of more than a
hundred billion dollars each year.1,2 There is a wide spectrum of treat-
ments available for patients with chronic low back pain resulting from
degenerative changes to the vertebral spine, including conservative
and surgical alternatives.2 y
y
(
)
The aim of this study is to evaluate the presence of osteolysis
around each of the pedicle screws used in surgical arthrodesis pro-
cedures and the time to its occurrence during the first postoperative
year, and to correlate this finding with the levels of disability of patients
during their evolution, through the application of the ODI. METHOD The benefits
of the posterolateral approach include its relative ease of execution
and the fact that most surgeons are familiar with it, the possibility of
direct decompression of the neural elements, and the high fusion
rates, which are optimized with the use of pedicle instrumentation,
increasing the rigidity of the system.5-9 g
g
y
y
Pedicle screw loosening is cited in various studies as one of the
complications of vertebral spine surgeries.10-13 This phenomenon can
be observed by the presence of a radiolucent halo, indicating peri-
implant osteolysis around the pedicle screw, in the coronal sections of
the computed tomography. The presence of this halo is a suggestive
sign of pseudoarthrosis.8,14-16 Its incidence varies between 0.6% and
25%.8 Schatzker et al.17 describe the histological finding resulting from
micromovements in the bone-implant interface, such as the presence
of a fibrous peri-implant tissue, which has a radiological image cor-
responding to a halo. The sensitivity of the finding of a radiolucent
halo for the diagnosis of pseudoarthrosis is 93% and the specificity is
92%.16 It is known that fusion failure of the arthrodesis can be a source
of pain, according to some authors, but there are few reports in the
literature, and there is no definitive conclusion as to whether there is
a direct relationship between the presence of a radiolucent halo and
one of the unfavorable clinical outcomes, such as the presence of
postoperative pain.8,18 Quality of life refers to the dimensions of life
that can be affected by diseases or their treatment.19 It is known that
low back pain has a direct negative impact on the patient’s quality of
life, and that it is a condition commonly associated with severe pain
and great physical, social and psychological disability,20-22 leading to
deficits four times greater when compared to the general population,
after adjusting for age and comorbidities.23 The exams were evaluated by an experienced radiologist who did not
have information about the patient’s disorders or their clinical informa-
tion, in order to identify the presence of osteolysis. The observation of
a peri-implant radiolucent line greater than 1 mm in the coronal slice
of the tomography was considered positive for the presence of oste-
olysis,12 as shown in Figure 1. The computed tomography exams were
performed using a 64-channel multislice device. METHOD Low back pain and lumbociatalgia are commonly the result of disc
disease, which may manifest as intersomatic arthrosis, protrusion and
disc extrusion. The degenerative cascade, associated with lesions
of the anatomical structures, vertebral instability and narrowing of
the canal and intervertebral foramina, generates an environment that
could lead to low back pain and radiculopathies.2,3 This is a retrospective analysis study of patients submitted to
surgical treatment of the vertebral spine, with lumbar or lumbosacral
posterolateral arthrodesis instrumented with pedicle screws. The study
was conducted from 2010 to 2013 at a tertiary public hospital. Patients
aged between 20 and 85 years were included, of both sexes, with a
history of degenerative disease of the lumbosacral spine, who had
already undergone conservative treatment without improvement in
the symptoms. Patients were excluded who had a history of vertebral
spine tumor, congenital deformities, a previous history of surgical
procedure to the lumbosacral spine, and patients who did not agree
to the research terms and did not sign the Informed Consent Form
(ICF). The patients responded to the Oswestry Disability Index in the
preoperative period, and at 45, 90, 180 and 360 postoperative days. The ODI questionnaire was always applied by an orthopedic surgeon
who was trained and familiar with it. The questionnaire consists of
10 questions with six statements in each, to identify limitations when
performing nine activities of daily living, and in the patient’s sex life. The final score expresses the degree of disability, as a percentage,
classifying it as minimal, moderate, severe, very severe and bed-bound
or exaggerating the symptoms, as shown in annex 1. At the time of
application of the questionnaire, except during the preoperative period,
computed tomography exams were taken of the lumbosacral spine. The exams were evaluated by an experienced radiologist who did not
have information about the patient’s disorders or their clinical informa-
tion, in order to identify the presence of osteolysis. The observation of
a peri-implant radiolucent line greater than 1 mm in the coronal slice
of the tomography was considered positive for the presence of oste-
olysis,12 as shown in Figure 1. The computed tomography exams were
performed using a 64-channel multislice device. Images were used in
the coronal and sagittal planes, so that the image in the coronal plane,
used for the evaluation of osteolysis, reflected the image of the screw
oriented perpendicularly to the vertebra. Table 1. General patient data. At the end of these 360 days of follow-up, 14 (36.84%) patients
presented osteolysis in the computed tomography. The levels of
arthrodesis of these patients are shown in Table 2; in the majority of
cases, the radiological signal was observed at 90 postoperative days. A total of 242 screws were evaluated, and osteolysis was found
in 27 (11.15%) as shown in Table 3. At the end of these 360 days of follow-up, 14 (36.84%) patients
presented osteolysis in the computed tomography. The levels of
arthrodesis of these patients are shown in Table 2; in the majority of
cases, the radiological signal was observed at 90 postoperative days. g
g
p
p
y
A total of 242 screws were evaluated, and osteolysis was found
in 27 (11.15%) as shown in Table 3. (
)
The absolute majority of the screws with osteolysis were those
of the more distal level of the area of arthrodesis; 12 patients in
S1, two patients in L5, and one patient in L2 (this patient also
represented osteolysis in the more distal level) as shown in Table 4. Table 3. Total number of screws evaluated and screws with osteolysis. Screws n(%)
242 (100)
Screws with osteolysis n (%)
27 (11.15)
Table 4. Location of the screws with osteolysis. Screws with osteolysis n(%)
27 (100)
Screws with osteolysis in S1 n (%)
20 (74.1)
Screws with osteolysis in L5 n (%)
6 (22.2)
Screws with osteolysis in L2 n (%)
1 (3.7) Table 3. Total number of screws evaluated and screws with osteolysis. Table 5 presents a comparison between the Oswestry Disability
Index score, recorded as a percentage, and the presence of oste-
olysis in the various evaluation times. It is observed that the levels of
disability are very similar in the osteolysis group and the group that
did not present this finding. p
g
Looking closely at Table 6, we see that the index of disability
presented, on average, difference only between the different
evaluation times during the first year of postoperative follow-up,
independently of the presence or absence of osteolysis (p < 0.001). This finding demonstrates a gradual improvement in the ODI during
the evaluation period. The osteolysis did not statistically influence
the disability scores of the ODI (p=0.559). Table 1. General patient data. y
(p
)
Table 7 shows that there is an improvement in the disability index,
with statistical significance, when comparing the preoperative result
with the other evaluation periods. However, there is no statistical
significance when the improvement in ODI is compared among
the other evaluation times, in the different postoperative periods. Table 5. Comparison of ODI with osteolysis in the evaluation times. Table 5. Comparison of ODI with osteolysis in the evaluation times. Time (days)
Osteolysis
No
Yes
Mean
SD
N
Mean
SD
N
Preoperative
56.4
14.9
22
54.9
18.9
13
45
25.8
23.1
22
30.4
13.8
13
90
24.7
19.2
22
32.1
17.9
14
180
21.3
19.1
23
22.0
16.8
14
360
17.5
15.5
23
22.4
18.8
14 RESULTS j
g
g
Quality of life questionnaires are a feasible, effective and routinely
used tool for monitoring the evolution of patients in treatment with
pathologies of the vertebral spine.24-26 These questionnaires also help The study involved 38 patients; 20 male and 18 female, with a mean
age of 51.02 years and median age of 51 years, as shown in Table 1. 292 Figure 1. A and B Example of the measurement of osteolysis in the CT. Coro-
nal section (1 A) perpendicular to the long axis of the screw (1 B). The arrows
show the area of osteolysis and the distance “d” is the measurement used to
quantify the halo. d
A
B d
A McAfee et al.32 report, in a study of 526 pedicle screws, that there was
no loosening. Essens et al.10 describe a rate of 0.81% of loosening in
617 treated patients. That study also presented a literature review that
showed a loosening frequency of between 0.6% and 11%. However,
these studies with low screw loosening rates do not describe, in detail,
the radiological methods or criteria used to identify the loosening. In three other studies with better detailed radiological methodology,
loosening rates of 18%, 21% and 27% were demonstrated.15,29,33 B g
Our study showed that of the 242 pedicle screws analyzed, 27
(11.15%) presented signs of loosening, as shown by the tomographic
finding of a radiolucent halo larger than 1 mm in the coronal section,
described here as osteolysis. These data coincide with the averages
described in the literature on the theme. The fact that the highest B Figure 1. A and B Example of the measurement of osteolysis in the CT. Coro-
nal section (1 A) perpendicular to the long axis of the screw (1 B). The arrows
show the area of osteolysis and the distance “d” is the measurement used to
quantify the halo. Table 2. Patients with osteolysis in up to 360 days of follow-up. Levels submitted to
arthrodesis
Level(s) with
osteolysis
Patient 1
L3-S1
S1
Patient 2
L2-L5
L5
Patient 3
L4-S1
S1
Patient 4
L1-S1
S1
Patient 5
L3-S1
S1
Patient 6
L3-S1
S1
Patient 7
L3-S1
S1
Patient 8
L3-S1
S1
Patient 9
L1-S1
S1
Patient 10
L4-S1
S1
Patient 11
L2-S1
S1 and L2
Patient 12
L5-S1
S1
Patient 13
L3-S1
S1
Patient 14
L4-L5
L5
Table 3. Total number of screws evaluated and screws with osteolysis. Coluna/Columna. 2016;15(4):290-4 RESULTS Screws n(%)
242 (100)
Screws with osteolysis n (%)
27 (11.15)
Table 4. Location of the screws with osteolysis. Screws with osteolysis n(%)
27 (100)
Screws with osteolysis in S1 n (%)
20 (74.1)
Screws with osteolysis in L5 n (%)
6 (22.2)
Screws with osteolysis in L2 n (%)
1 (3.7)
Table 5. Comparison of ODI with osteolysis in the evaluation times. Time (days)
Osteolysis
No
Yes
Mean
SD
N
Mean
SD
N
Preoperative
56.4
14.9
22
54.9
18.9
13
45
25.8
23.1
22
30.4
13.8
13
90
24.7
19.2
22
32.1
17.9
14
180
21.3
19.1
23
22.0
16.8
14
360
17.5
15.5
23
22.4
18.8
14
Table 6. Comparison of ODI with osteolysis, evaluation time, and both. Variable
Factor
Test statistic
gl
p
Oswestry
Osteolysis
0.34
1
0.559
Evaluation time
133.35
4
<0.001
Osteolysis and Time
4.57
4
0.334 Table 2. Patients with osteolysis in up to 360 days of follow-up. Levels submitted to
arthrodesis
Level(s) with
osteolysis
Patient 1
L3-S1
S1
Patient 2
L2-L5
L5
Patient 3
L4-S1
S1
Patient 4
L1-S1
S1
Patient 5
L3-S1
S1
Patient 6
L3-S1
S1
Patient 7
L3-S1
S1
Patient 8
L3-S1
S1
Patient 9
L1-S1
S1
Patient 10
L4-S1
S1
Patient 11
L2-S1
S1 and L2
Patient 12
L5-S1
S1
Patient 13
L3-S1
S1
Patient 14
L4-L5
L5 Table 2. Patients with osteolysis in up to 360 days of follow-up. Table 1. General patient data. Variable
(N = 38)
Sex, n (%)
Female
18 (47.4)
Male
20 (52.6)
Age (years)
mean (DP)
51 (12.4)
median (min/max)
51 (28/84) DISCUSSION Variable
Time
Comparison
Mean
difference or
percentage
Standard
error
gl
p
CI (95%)
Lower
Upper
Oswestry Disability
Index
All the evaluation
times
Preoperative - 45 days
28.35
2.77
1
<0.001
20.58
36.11
Preoperative - 90 days
27.83
3.43
1
<0.001
18.21
37.44
Preoperative - 180 days
33.86
3.79
1
<0.001
23.22
44.50
Preoperative - 360 days
36.07
4.02
1
<0.001
24.79
47.34
45 days - 90 days
-0.52
2.68
1
>0.999
-8.04
6.99
45 days - 180 days
5.51
3.40
1
>0.999
-4.02
15.05
45 days - 360 days
7.72
3.78
1
0.412
-2.89
18.33
90 days - 180 days
6.04
2.65
1
0.228
-1.41
13.48
90 days - 360 days
8.24
3.37
1
0.145
-1.22
17.71
180 days - 360 days
2.21
2.64
1
>0.999
-5.19
9.61 incidence of osteolysis was found at the distal level, especially in
S1, is explained by the high mechanical demand placed on the
lumbosacral junction, a region with biomechanical particularities
that make fusion of the arthrodesis difficult, with known high rates
of pseudoarthrosis, which is a separate subject of discussion in the
field of spinal surgery, as described Harimaya et al.14 In this study, we noted an improvement in quality of life in the
postoperative period, independently of the presence of osteolysis
around the pedicle screws. This improvement in quality of life scores
had statistical significance only when the preoperative results were
compared with any other postoperative evaluation times. When the
quality of life was compared between the different evaluation times in
the postoperative period, there was no statistically significant difference. The aim of our study was to correlate osteolysis of the screws,
which represents a sign of instability in the area of arthrodesis, with
the quality of life of these patients. It would be expected that patients
with this radiological sign of loosening of the implant would present
greater pain, resulting in a consequent worsening of the quality of life
scores. However, this hypothesis was not confirmed, as the patients
without signs of loosening of the implant presented similar quality of
life scores to those with this sign. This finding is in accordance with
the findings published by Kim et al.8 who evaluated the prevalence of
loosening of the screws and its clinical significance in a study with 24
women submitted to surgery of the vertebral spine due to stenosis. DISCUSSION The use of pedicle screws as a means of stabilization of the
spine gained popularity in Europe in the 1980s, through the work of
Roy-Camille et al.28 and became the most prevalent form of spinal
fixation in North America in the 1990s. The transpedicle technique
enables a rigid, segmental fixation of the vertebral spine under various
conditions of spondylolisthesis, tumor, post-traumatic instability, multiple
laminectomies, and degenerative arthritis.10 Despite the efficacy of the
pedicle screws used in the treatment of various pathologies of the
vertebral spine, it is not free of complications.14,26,29-31 One of these
is loosening of the screw. However, data on this outcome are very
varied in the literature, probably due to the different study designs. Table 6. Comparison of ODI with osteolysis, evaluation time, and both. Variable
Factor
Test statistic
gl
p
Oswestry
Osteolysis
0.34
1
0.559
Evaluation time
133.35
4
<0.001
Osteolysis and Time
4.57
4
0.334 omparison of ODI with osteolysis, evaluation time, and both is loosening of the screw. However, data on this outcome are very
varied in the literature, probably due to the different study designs. CORRELATION BETWEEN QUALITY OF LIFE AND OSTEOLYSIS AROUND LUMBAR PEDICLE SCREWS 293 Table 7. Comparison of ODI between the various patient evaluation times. CONCLUSION This study demonstrated that in patients submitted to surgical
procedures with posterolateral arthrodesis, using pedicle screws for
the treatment of degenerative disease of the vertebral lumbosacral
spine, the presence of osteolysis around these pedicle screws did
not result in worsening disability in the patients, evaluated by the ODI. Further studies are necessary to understand the real significance of
this radiological signal. All the authors declare no potential conflict of interest concerning
this article. CONTRIBUTIONS OF THE AUTHORS: Each author made an individual and significant contribution to the development of the manuscript. MIRN, RR and SMN
were the main contributors to the writing of the manuscript. GRZ, IGV and PTMC performed the surgical procedures. MIRN, RR and SMN followed up the patients
and gathered clinical data. ACSAF performed the radiological interpretation of the exams. MIRN and GRZ evaluated the data from the statistical analysis. RR, SMN
and MIRN carried out the bibliographic review. EL, PTMC, WP, MAT and MIRN reviewed the manuscript and contributed to the intellectual concept of the study. DISCUSSION Those authors came to the conclusion that the real significance of
the phenomenon of osteolysis is not fully understood, but that it did
not have any significance in the clinical evolution of the patient. Wu et
al.,12 in a study with 126 patients and 658 screws analyzed, came to
the conclusion that loosening of the screw may be asymptomatic in its
presentation, and that it presents an opportunity for bone integration
in future follow-up. Tokuhashi et al.16 concluded that approximately
two thirds of the radiolucent zones around the implants disappear
with time, and that these are not necessarily diagnostic findings of
pseudoarthrosis. On the other hand, it is emphasized that when this
zone of radiolucency remains for more than two years after surgery,
there is a high risk of the occurrence of pseudoarthrosis. The improvement in quality of life, measured through the ODI,
following a surgical spinal procedure in patients with degenerative
disease, is well known in the literature.26 Carreon et al.34 in an extensive
literature review, showed that patients with degenerative disc disease
or spondylolisthesis submitted to surgical treatment had considerable
improvements in postoperative ODI. In another study, Carreon et al.25
observed that patients with worse preoperative ODI scores had more
significant improvements during postoperative follow-up. Coluna/Columna. 2016;15(4):290-4 CONTRIBUTIONS OF THE AUTHORS: Each author made an individual and significant contribution to the development of the manuscript. MIRN, RR and SMN
were the main contributors to the writing of the manuscript. GRZ, IGV and PTMC performed the surgical procedures. MIRN, RR and SMN followed up the patients
and gathered clinical data. ACSAF performed the radiological interpretation of the exams. MIRN and GRZ evaluated the data from the statistical analysis. RR, SMN
and MIRN carried out the bibliographic review. EL, PTMC, WP, MAT and MIRN reviewed the manuscript and contributed to the intellectual concept of the study. surgery to nonoperative care for treatment of chronic back pain. Spine (Phila Pa 1976).
2007;32(7):816-23.
5. Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes
it? Spine (Phila Pa 1976). 2006;31(18):2151-61.
6. Kwon BK, Vaccaro AR, Grauer JN, Beiner J. Indications, techniques, and outcomes of
posterior surgery for chronic low back pain. Orthop Clin North Am. 2003;34(2):297-308.
7. Lu WW, Zhu Q, Holmes AD, Luk KD, Zhong S, Leong JC. Loosening of sacral screw
fixation under in vitro fatigue loading. J Orthop Res. 2000;18(5):808-14. 5. Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes
it? Spine (Phila Pa 1976). 2006;31(18):2151-61. 1. Phillips FM, Slosar PJ, Youssef JA, Andersson G, Papatheofanis F. Lumbar spine fusion
for chronic low back pain due to degenerative disc disease: a systematic review. Spine
(Phila Pa 1976). 2013;38(7):E409-22.
2. Lykissas MG, Aichmair A. Current concepts on spinal arthrodesis in degenerative
disorders of the lumbar spine. World J Clin Cases. 2013;1(1):4-12.
3. Herkowitz HN, Garfin SR, Eismont FJ, Bell GR, Balderston RA. Rothman simeone the
spine. 6th ed. Philadelphia: Saunders; 2011.
4. Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain. Spine (Phila Pa 1976).
2007;32(7):816-23. 6. Kwon BK, Vaccaro AR, Grauer JN, Beiner J. Indications, techniques, and outcomes of
posterior surgery for chronic low back pain. Orthop Clin North Am. 2003;34(2):297-308. 7. Lu WW, Zhu Q, Holmes AD, Luk KD, Zhong S, Leong JC. Loosening of sacral screw
fixation under in vitro fatigue loading. J Orthop Res. 2000;18(5):808-14. REFERENCES 2012;16(3):238-47. y
p
y
25. Roy-Camille R, Saillant G, Mazel C. Internal fixation of the lumbar spine with pedicle
screw plating. Clin Orthop Relat Res. 1986;(203):7-17 of 84 patients. J Neurosurg Spine. 2012;16(3):238-47. 26. Winter RB. Complications after transpedicular stabilization of the spine. Spine (Phila
Pa 1976). 1995;20(16):1847-8. 12. Wu JC, Huang WC, Tsai HW, Ko CC, Wu CL, Tu TH, Cheng H. Pedicle screw loose-
ning in dynamic stabilization: incidence, risk, and outcome in 126 patients. Neurosurg
Focus. 2011;31(4):E9. 27. Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976). 2000;25(22):2940-52. 13. Aghayev E, Zullig N, Diel P, Dietrich D, Benneker LM. Development and validation of a
quantitative method to assess pedicle screw loosening in posterior spine instrumentation
on plain radiographs. Eur Spine J. 2014;23(3):689-94. 28. McAfee PC, Weiland DJ, Carlow JJ. Survivorship analysis of pedicle spinal instrumen-
tation. Spine (Phila Pa 1976). 1991;16(Suppl 8):S422-7. 14. Harimaya K, Mishiro T, Lenke LG, Bridwell KH, Koester LA, Sides BA. Etiology and
revision surgical strategies in failed lumbosacral fixation of adult spinal deformity
constructs. Spine (Phila Pa 1976). 2011;36(20):1701-10. 29. Bechara AHS; Zuiani GR, Risso MIN, Cavali PTM, Veiga IG, Paqualini W et al. Evolução
dos questionários Oswestry 2.0 e do componente físico (PCS) do SF-36 durante o pri-
meiro ano de pós-operatório de artrodese da coluna lombar em doenças degenerativas. Coluna/Columna. 2013;12(2):128-32. p
;
15. Pihlajämaki H, Myllynen P, Böstman O. Complications of transpedicular lumbosacral
fixation for non-traumatic disorders. J Bone Joint Surg Br. 1997;79(2):183-9. 30. Kang SH, Cho YJ, Kim YB, Park SW. Pullout strength after expandable polymethylme-
thacrylate transpedicular screw augmentation for pedicle screw loosening. J Korean
Neurosurg Soc. 2015;57(4):229-34. 16. Tokuhashi Y, Matsuzaki H, Oda H, Uei H. Clinical course and significance of the clear
zone around the pedicle screws in the lumbar degenerative disease. Spine (Phila Pa
1976). 2008;33(8):903-8. g
31. Kang SH, Cho YJ, Kim YB, Park SW. Pullout strength after expandable polymethylme-
thacrylate transpedicular screw augmentation for pedicle screw loosening. J Korean
Neurosurg Soc. 2015;57(4):229-34. )
;
( )
17. Schatzker J, Horne JG, Sumner-Smith G. The effect of movement on the holding power
of screws in bone. Clin Orthop Relat Res. 1975;(111):257-62. 18. Tokuhashi Y, Ajiro Y, Umezawa N. Follow-up of patients with delayed union after pos-
terior fusion with pedicle screw fixation. Spine (Phila Pa 1976). 2008;33(7):786-91. 32. Ohlin A, Karlsson M, Düppe H, Hasserius R, Redlund-Johnell I. REFERENCES 1. Phillips FM, Slosar PJ, Youssef JA, Andersson G, Papatheofanis F. Lumbar spine fusion
for chronic low back pain due to degenerative disc disease: a systematic review. Spine
(Phila Pa 1976). 2013;38(7):E409-22. 1. Phillips FM, Slosar PJ, Youssef JA, Andersson G, Papatheofanis F. Lumbar spine fusion
for chronic low back pain due to degenerative disc disease: a systematic review. Spine
(Phila Pa 1976). 2013;38(7):E409-22. 2. Lykissas MG, Aichmair A. Current concepts on spinal arthrodesis in degenerative
disorders of the lumbar spine. World J Clin Cases. 2013;1(1):4-12. 3. Herkowitz HN, Garfin SR, Eismont FJ, Bell GR, Balderston RA. Rothman simeone the
spine. 6th ed. Philadelphia: Saunders; 2011. p
p
;
4. Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion Coluna/Columna. 2016;15(4):290-4 294 patients following selected types of lumbar spinal surgery: a pilot study. Health Qual
Life Outcomes. 2007;5:71. 8. Sandén B, Olerud C, Petrén-Mallmin M, Johansson C, Larsson S. The significance of
radiolucent zones surrounding pedicle screws. Definition of screw loosening in spinal
instrumentation. J Bone Joint Surg Br. 2004;86(3):457-61. patients following selected types of lumbar spinal surgery: a pilot study. Health Qual
Life Outcomes. 2007;5:71. 22. Otani K, Kikuchi S, Yabuki S, Igarashi T, Nikaido T, Watanabe K, Konno S. Lumbar spinal
stenosis has a negative impact on quality of life compared with other comorbidities: an
epidemiological cross-sectional study of 1862 community-dwelling individuals. Scienti-
ficWorldJournal. 2013;2013:1-9. Disponível em: http://dx.doi.org/10.1155/2013/590652 g
9. Carreon LY, Glassman SD, Djurasovic M, Dimar JR, Johnson JR, Puno RM, et al. Are
preoperative health-related quality of life scores predictive of clinical outcomes after
lumbar fusion? Spine (Phila Pa 1976). 2009;34(7):725-30. ficWorldJournal. 2013;2013:1-9. Disponível em: http://dx.doi.org/10.1 p
10. Esses SI, Sachs BL, Dreyzin V. Complications associated with the technique of pe-
dicle screw fixation. A selected survey of ABS members. Spine (Phila Pa 1976). 1993;18(15):2231-8. p
p
g
23. Battié MC, Jones CA, Schopflocher DP, Hu RW. Health-related quality of life and
comorbidities associated with lumbar spinal stenosis. Spine J. 2012;12(3):189-95. 24. Davidson M, Keating JL. A comparison of five low back disability questionnaire
reliability and responsiveness. Phys Ther. 2002;82(1):8-24. 24. Davidson M, Keating JL. A comparison of five low back d
reliability and responsiveness Phys Ther 2002;82(1):8 24 11. Nakashima H, Yukawa Y, Imagama S, Kanemura T, Kamiya M, Yanase M, et al. Compli-
cations of cervical pedicle screw fixation for nontraumatic lesions: a multicenter study
of 84 patients. J Neurosurg Spine. REFERENCES Complications after
transpedicular stabilization of the spine. A survivorship analysis of 163 cases. Spine
(Phila Pa 1976). 1994;19(24):2774-9. 19. Jansson KA, Németh G, Granath F, Jönsson B, Blomqvist P. Health-related quality of
life in patients before and after surgery for a herniated lumbar disc. J Bone Joint Surg
Br. 2005;87(7):959-64. 33. Soini J, Laine T, Pohjolainen T, Hurri H, Alaranta H. Spondylodesis augmented by
transpedicular fixation in the treatment of olisthetic and degenerative conditions of
the lumbar spine. Clin Orthop Relat Res. 1993;(297):111-6. 20. Sirvanci M, Bhatia M, Ganiyusufoglu KA, Duran C, Tezer M, Ozturk C, et al. Degenerative
lumbar spinal stenosis: correlation with Oswestry Disability Index and MR imaging. Eur Spine J. 2008;17(5):679-85 34. Carreon LY, Glassman SD, Howard J. Fusion and nonsurgical treatment for symptomatic
lumbar degenerative disease: a systematic review of Oswestry Disability Index and
MOS Short Form-36 outcomes. Spine J. 2008;8(5):747-55. 21. Saban KL, Penckofer SM, Androwich I, Bryant FB. Health-related quality of life of Annex 1. Presentation of the Oswestry Disability Index. Coluna/Columna. 2016;15(4):290-4
Oswestry Disability Index 2.0
Takes into consideration how far the problem in the back (or legs) has affected the day-to-day activities in the following areas
1- intensity of the pain
6- standing
2- personal care
7- sleep
3- lifting heavy objects
8- sex life
4- walking
9- social life
5- sitting
10- travel
Interpretation of the results of the Oswestry Index
0% - 20% :
minimal disability
21% - 40%:
moderate disability
41% - 60%:
severe disability
61% - 80% :
very severe disability
81% - 100%:
bed-ridden or exaggerating the symptoms Oswestry Disability Index 2.0
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https://openalex.org/W4317514617
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Young-Adult Social Outcomes of Attention-Deficit/Hyperactivity Disorder
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The Journal of clinical psychiatry/The journal of clinical psychiatry
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cc-by
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Riglin, L., Todd, A., Blakey, R., Shakeshaft, A., Stergiakouli , E.,
Davey Smith, G., Tilling, K. M., & Thapar, A. (2023). Young-Adult
Social Outcomes of Attention-Deficit/Hyperactivity Disorder. Journal of
Clinical Psychiatry, 84(2), Article 22m14379. https://doi.org/10.4088/jcp.22m14379 Peer reviewed version
License (if available):
CC BY
Link to published version (if available):
10.4088/jcp.22m14379 Peer reviewed version
License (if available):
CC BY
Link to published version (if available):
10.4088/jcp.22m14379 Link to publication record on the Bristol Research Portal
PDF-document This is the accepted author manuscript (AAM). The final published version (version of record) is available online
via Physicians Postgraduate Press at https://doi.org/10.4088/jcp.22m14379. Please refer to any applicable terms
of use of the publisher. Riglin, L., Todd, A., Blakey, R., Shakeshaft, A., Stergiakouli , E.,
Davey Smith, G., Tilling, K. M., & Thapar, A. (2023). Young-Adult
Social Outcomes of Attention-Deficit/Hyperactivity Disorder. Journal of
Clinical Psychiatry, 84(2), Article 22m14379.
https://doi.org/10.4088/jcp.22m14379 Riglin, L., Todd, A., Blakey, R., Shakeshaft, A., Stergiakouli , E.,
Davey Smith, G., Tilling, K. M., & Thapar, A. (2023). Young-Adult
Social Outcomes of Attention-Deficit/Hyperactivity Disorder. Journal of
Clinical Psychiatry, 84(2), Article 22m14379. https://doi.org/10.4088/jcp.22m14379 University of Bristol – Bristol Research Portal
General rights This document is made available in accordance with publisher policies. Please cite only the
published version using the reference above. Full terms of use are available:
http://www.bristol.ac.uk/red/research-policy/pure/user-guides/brp-terms/ nvestigating young-adult social outcomes of attention deficit hyperactivity disorder Lucy Riglin PhD1, Andrew Todd MRCPsych1, Rachel Blakey PhD2, Amy Shakeshaft MRes1, Evie
Stergiakouli PhD2, George Davey Smith MD FRS2, Kate Tilling PhD2, Anita Thapar FRCPsych
PhD1* 1Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for
Neuropsychiatric Genetics and Genomics, Cardiff University, UK. 2Population Health Sciences
and MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. *Corresponding author. Division of Psychological Medicine and Clinical Neurosciences, Cardiff
University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ. Tel: +442920 688325. Email: thapar@cardiff.ac.uk. Conflicts of Interest. None. Acknowledgements. We are extremely grateful to all the families
who took part in this study, the midwives for their help in recruiting them, and the whole
ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical
workers, research scientists, volunteers, managers, receptionists and nurses. Funding. The UK
Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of
Bristol provide core support for ALSPAC. RB, ES, GDS and KT work in a unit that receives
funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1
and MC_UU_00011/3). This publication is the work of the authors and Lucy Riglin and Anita
Thapar will serve as guarantors for the contents of this paper. A comprehensive list of grants
funding is available on the ALSPAC website (www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The primary
outcome measures used in the paper were specifically funded by the Wellcome Trust
(204895/Z/16/Z) for age 25 data. LR, RB and AS conducted this research while funded by the
Wellcome Trust (204895/Z/16/Z) for which funding was acquired by ES, GDS, KT and AT. For (www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The primary
outcome measures used in the paper were specifically funded by the Wellcome Trust (204895/Z/16/Z) for age 25 data. LR, RB and AS conducted this research while funded by the
Wellcome Trust (204895/Z/16/Z) for which funding was acquired by ES, GDS, KT and AT. For 1 1 the purpose of Open Access, the author has applied a CC BY public copyright licence to any
Author Accepted Manuscript version arising from this submission. the purpose of Open Access, the author has applied a CC BY public copyright licence to any
Author Accepted Manuscript version arising from this submission. 2 2 Abstract Objective. Attention Deficit Hyperactivity Disorder (ADHD) is associated with a range of adverse
outcomes in adult life. However it is unclear whether the risk pathways to adverse adult
outcomes are established during childhood or whether associations are driven by concurrent
ADHD symptoms that have persisted to adulthood. Methods. We examined associations between
broadly defined child-limited (remitted) and persistent ADHD (assessed using the ADHD
subscale of the Strengths and Difficulties Questionnaire) with social outcomes (low emotional
and instrumental support, antisocial behaviour, employment, receipt of state benefits as an
indicator of socio-economic disadvantage, homelessness) at age 25 years in a UK longitudinal
population sample ALPSAC (the Avon Longitudinal Study of Parents and Children, age 25 data
collected between years 2017 and 2018): total N=6439. Results. Up to 20% of young-people
with less favourable social outcomes at age 25 had persistent ADHD. Persistent ADHD was
associated with an increased likelihood of being not in education, employment or training
(NEET: OR=3.71, 95% CI=2.06 to 6.67, p=1x10-05) and receiving state benefits (OR=2.72, 95%
CI=1.62 to 4.57, p=2x10-04) at age 25 years compared to those without ADHD. We did not find
strong evidence of associations between child-limited ADHD and social outcomes (NEET
OR=1.20, 95% CI=0.54 to 2.69, p=0.65; state benefits OR=1.38, 95% CI=0.76 to 2.51, p=0.29). Persistent ADHD associations with negative social outcomes were observed across family-of-
origin income groups, sex and were not explained by comorbidity. Conclusion. Our findings
highlight the importance of continued monitoring and management of ADHD symptoms and
related social as well as clinical outcomes across development into adulthood. Future research
is needed to identify what factors promote positive social outcomes, including effective
treatment of adult ADHD symptoms. K
d
ADHD
d l
i
i l
ALSPAC Keywords: ADHD, young-adult, persistence, social outcomes; ALSPAC. 3 3 Introduction In the UK prospective twin cohort E-risk, those with remitted ADHD showed worse
outcomes at age 18 years than those who have never had ADHD but not to the same extent as
those with persistent ADHD.17 The question of what happens to those with ADHD that remits is
clinically important: if ADHD appears to have remitted by late adolescence, should these young
people be discharged from services or continue to be monitored by adult mental health or
primary care services even if this follow-up is provided less frequently than for those with
persistent ADHD? In this study we utilise a UK longitudinal birth cohort, followed up to age 25 years to address
this question. We set out to examine the adult social outcomes at age 25 years associated with
broadly defined ADHD, differentiating those that were child-limited (remitted) and persistent. We hypothesised that those with ADHD who had remitted by age 25 years, as well as those with
persistent ADHD, would show adverse social outcomes by age 25 years. Introduction Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable neurodevelopmental
disorder with typical onset in childhood. Although most affected individuals continue to display
some ADHD symptoms and impairment after childhood, others remit before adult life.1, 2 ADHD,
whether defined categorically as a clinical disorder or as continuously distributed total
symptom scores, is associated with multiple adverse adult clinical outcomes such as depression,
anxiety, substance misuse and self-harm as well as worse social, occupational and physical
health outcomes than those who are unaffected.3-6 Many of these adversities carry great
personal, familial and societal cost. The association between ADHD and higher levels of antisocial behaviour is well established7. One meta-analysis estimated fivefold higher prevalence of people with ADHD detained in youth
prison populations (30.1%) and tenfold in adult prison populations (26.2%) across a number of
countries, compared to general population prevalence estimates at equivalent ages.8 ADHD is
also associated with an increased likelihood of not completing secondary school or attending
tertiary education,9 employment difficulties, homelessness and financial dependence on parents
or government/public assistance in adulthood.10, 11 Finally, studies also suggest an association
between ADHD and poorer quality social relationships and support in adulthood.12, 13 A variety of different research designs have been used to infer causal relationships between
ADHD and several different clinical and physical health outcomes; these include time-series
investigations of prescription data and Mendelian randomisation approaches. These studies
suggest that the relationships between ADHD and some adverse outcomes, including depression,14, 15 substance misuse, cigarette smoking, BMI and coronary artery disease16 may be 4 4 causal, arising as a direct result of ADHD. If that is the case, then vigorous and effective
support/treatment of ADHD would be crucial for preventing adverse adult outcomes. For many individuals however, the transition from child to adult mental health services disrupts
engagement with clinicians and treatment continuity. That may not be a problem if ADHD has
remitted and adverse adult outcomes primarily are influenced by concurrent ADHD symptoms. However, if ADHD symptoms in childhood lead to adversities or disadvantages (e.g. victimization, maltreatment and educational failure) across childhood and adolescence, then the
risk mechanisms leading to poor adult outcomes have already been set in place. That would
support the argument for continued monitoring of those with a history of childhood ADHD even
if ADHD symptoms have declined or remitted. One previous study supports the latter
hypothesis. Sample Of these initial pregnancies, there was a total of 14,676 foetuses, resulting in 14,062
live births and 13,988 children who were alive at 1 year of age. When the oldest children were
approximately 7 years of age, an attempt was made to bolster the initial sample with eligible
cases who had failed to join the study originally. As a result, the total sample size for data
collected after the age of seven is therefore 15,454 pregnancies, resulting in 15,589 foetuses. Of
these 14,901 were alive at 1 year of age. Part of this data was collected and managed using
REDCap electronic data capture tools hosted at the University of Bristol.21 REDCap (Research
Electronic Data Capture) is a secure, web-based software platform designed to support data
capture for research studies. Ethical approval for the study was obtained from the ALSPAC Law
and Ethics Committee and Local Research Ethics Committees. Informed consent for the use of
data collected via questionnaires and clinics was obtained from participants following the
recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological
samples has been collected in accordance with the Human Tissue Act (2004). Please note that
the study website contains details of all the data that is available through a fully searchable data
dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/. Further details of the study, measures and sample can be found elsewhere.18-20 Where families
included multiple births, we included the oldest sibling. Sample 5 We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a well-
established prospective, longitudinal UK birth cohort study.18-20 Pregnant women resident in
Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 were invited to
take part in the study. The initial number of pregnancies enrolled is 14,541 (for these at least
one questionnaire has been returned or a “Children in Focus” clinic had been attended by
19/07/99). Of these initial pregnancies, there was a total of 14,676 foetuses, resulting in 14,062
live births and 13,988 children who were alive at 1 year of age. When the oldest children were
approximately 7 years of age, an attempt was made to bolster the initial sample with eligible
cases who had failed to join the study originally. As a result, the total sample size for data
collected after the age of seven is therefore 15,454 pregnancies, resulting in 15,589 foetuses. Of
these 14,901 were alive at 1 year of age. Part of this data was collected and managed using
REDCap electronic data capture tools hosted at the University of Bristol.21 REDCap (Research
Electronic Data Capture) is a secure, web-based software platform designed to support data
capture for research studies. Ethical approval for the study was obtained from the ALSPAC Law
and Ethics Committee and Local Research Ethics Committees. Informed consent for the use of
data collected via questionnaires and clinics was obtained from participants following the
recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological
samples has been collected in accordance with the Human Tissue Act (2004). Please note that
the study website contains details of all the data that is available through a fully searchable data
dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/. Further details of the study, measures and sample can be found elsewhere.18-20 Where families
included multiple births, we included the oldest sibling. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a well-
established prospective, longitudinal UK birth cohort study.18-20 Pregnant women resident in
Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 were invited to
take part in the study. The initial number of pregnancies enrolled is 14,541 (for these at least
one questionnaire has been returned or a “Children in Focus” clinic had been attended by
19/07/99). ADHD The SDQ ADHD subscale has high validity in identifying DSM-5 ADHD
caseness. The category of broadly defined ADHD was applied to participants who scored above
the recommended SDQ cut-point for identifying ADHD diagnosis. These cut-points are ≥8 in
childhood and adolescence21 and ≥5 for self-reports at age 25 years.23 In-line with previous
work24 childhood ADHD was defined as the presence of broadly-defined ADHD at ages 7, 8, 9 or
12 and late adolescent/young-adult ADHD where participants scored above the SDQ-ADHD
subscale cut-point at ages 17 or 25. Based on these categories, individuals were categorised as
having low ADHD levels (i.e. below the SDQ cut-point in both childhood and late report at age 25 years. The SDQ ADHD subscale has high validity in identifying DSM-5 ADHD
caseness. The category of broadly defined ADHD was applied to participants who scored above
the recommended SDQ cut-point for identifying ADHD diagnosis. These cut-points are ≥8 in
childhood and adolescence21 and ≥5 for self-reports at age 25 years.23 In-line with previous
work24 childhood ADHD was defined as the presence of broadly-defined ADHD at ages 7, 8, 9 or
12 and late adolescent/young-adult ADHD where participants scored above the SDQ-ADHD
subscale cut-point at ages 17 or 25. Based on these categories, individuals were categorised as
having low ADHD levels (i.e. below the SDQ cut-point in both childhood and late adolescence/young-adulthood), child-limited ADHD (i.e. above the SDQ cut-point in childhood
but not in late adolescence/young-adulthood) or persistent ADHD (i.e. above the SDQ cut-point
in both childhood and late adolescence/young-adulthood). These groups are shown in Figure 1. Sensitivity analyses were conducted investigating “late-onset” ADHD (ADHD symptoms first
manifest after the age of 12 years) and are available on request from the author. ADHD ADHD symptoms were assessed using the 5-item ADHD subscale of the Strengths and
Difficulties Questionnaire (SDQ: possible range 0-10),22 a well-established screening measure
completed by parents about their children at approximately ages 7, 8, 9, 12 and 17, and by self- 6 report at age 25 years. The SDQ ADHD subscale has high validity in identifying DSM-5 ADHD
caseness. The category of broadly defined ADHD was applied to participants who scored above
the recommended SDQ cut-point for identifying ADHD diagnosis. These cut-points are ≥8 in
childhood and adolescence21 and ≥5 for self-reports at age 25 years.23 In-line with previous
work24 childhood ADHD was defined as the presence of broadly-defined ADHD at ages 7, 8, 9 or
12 and late adolescent/young-adult ADHD where participants scored above the SDQ-ADHD
subscale cut-point at ages 17 or 25. Based on these categories, individuals were categorised as
having low ADHD levels (i.e. below the SDQ cut-point in both childhood and late
adolescence/young-adulthood), child-limited ADHD (i.e. above the SDQ cut-point in childhood
but not in late adolescence/young-adulthood) or persistent ADHD (i.e. above the SDQ cut-point
in both childhood and late adolescence/young-adulthood). These groups are shown in Figure 1. Sensitivity analyses were conducted investigating “late-onset” ADHD (ADHD symptoms first
manifest after the age of 12 years) and are available on request from the author. report at age 25 years. The SDQ ADHD subscale has high validity in identifying DSM-5 ADHD
caseness. The category of broadly defined ADHD was applied to participants who scored above
the recommended SDQ cut-point for identifying ADHD diagnosis. These cut-points are ≥8 in
childhood and adolescence21 and ≥5 for self-reports at age 25 years.23 In-line with previous
work24 childhood ADHD was defined as the presence of broadly-defined ADHD at ages 7, 8, 9 or
12 and late adolescent/young-adult ADHD where participants scored above the SDQ-ADHD
subscale cut-point at ages 17 or 25. Based on these categories, individuals were categorised as
having low ADHD levels (i.e. below the SDQ cut-point in both childhood and late
adolescence/young-adulthood), child-limited ADHD (i.e. above the SDQ cut-point in childhood
but not in late adolescence/young-adulthood) or persistent ADHD (i.e. above the SDQ cut-point
in both childhood and late adolescence/young-adulthood). These groups are shown in Figure 1. Sensitivity analyses were conducted investigating “late-onset” ADHD (ADHD symptoms first
manifest after the age of 12 years) and are available on request from the author. report at age 25 years. Social outcomes Social outcomes were assessed based on self-reports at age 25 years. Emotional (e.g. having
someone to talk to) and instrumental support (e.g. having someone who can provide practical
support) were measured by the National Institute of Health (NIH) Toolbox Adult Social
Relationship Scales25 (possible ranges 0-32). Low support was defined as the bottom 10% for
descriptive purposes. Aggressive and non-aggressive antisocial behaviour were measured using
the Edinburgh Study of Youth Transitions and Crime26 which assessed engagement in 12
antisocial activities in the past year (possible range 0-12). Antisocial behaviour was defined as
engagement in any of the relevant anti-social activities: the aggressive (4 items) and non-
aggressive (8 items) antisocial behaviours (details available on request from the author). Not in
Education, Employment or Training (NEET) status was derived in-line with the UK Office for
National Statistics definition27 (details available on request from the author). State benefit
recipient was defined as receiving unemployment-related benefits, income support, sickness or 7 7 disability benefits, housing benefits (including council tax benefit, rent or rate rebate) or tax
credits. We included receiving state benefits as an outcome as a proxy measure of socio-
economic disadvantage. Homelessness was assessed using one item from a 27-event checklist
that asked about events experienced in the previous 12 months. Variables for sensitivity analyses Sensitivity analyses were conducted stratifying by sex and family of origin (“family”) income. Family income was measured by mother-report at approximately child age 11 years as the
average household income including social benefits each week on a 10-point scale from <£120
to ≥£800. Four income groups were generated, with lower/higher income defined based on
falling below/above the median and the lowest and highest subsequently identified as
bottom/top decile. We also examined whether associations between ADHD and age 25 social outcomes were still
present in the absence of child comorbidities. Low IQ was defined as IQ<80, measured using the
Wechsler Intelligence Scale for Children.28 Autism symptoms were measured using the parent-
rated 12-item Social Communication Disorders Checklist (SCDC)29 at ages 7 years (cut-point
≥9). Conduct problems were assessed using the parent-rated 5-item SDQ22 subscale at age 7
years (cut-point ≥4). Emotional problems were also assessed using the parent-rated 5-item
SDQ22 subscale at age 7 years (cut-point ≥5). Finally, we examined whether associations between ADHD and age 25 social outcomes were
still present in the absence of young-adult emotional problems and when excluding those with
ADHD medication use. Young-adult emotional problems were also assessed using the self-rated
5-item SDQ22 subscale at age 25 years (cut-point ≥6). Lifetime ADHD medication use 8 Analyses Analyses were conducted using multiple imputation with inverse probability weighting
(IPW/MI),30 including individuals with ADHD data available in both childhood and
adolescence/adulthood (N=6439): social outcome data were available for N=3591-3654
depending on the variable (details available on request from the author). We used logistic and
linear regression to examine associations with social outcomes, with low ADHD symptoms as
the reference group to estimate associations for child-limited and persistent ADHD. Sensitivity
analyses examined associations stratified by sex, family income, childhood comorbidities (low
IQ, autism symptoms, conduct problems and emotional problems), young-adult emotional
problems and excluding those with ADHD medication use. Sensitivity analyses based on MI
(without IPW), IPW (without MI) and complete-case analyses are available on request from the
author. Finally, sensitivity analyses using different definitions of ADHD were conducted (a)
defining childhood ADHD as having high ADHD symptoms at multiple times across 7, 8, 9 or 12
(i.e. at least twice, rather than at least once), (b) defining high ADHD symptoms at age 25 years
using the more stringent cut-point of ≥6 23 and (c) defining persistent ADHD based on the
presence of high symptoms at age 25 years only (i.e. rather than age 17 or 25 years). Sensitivity
analyses using different definitions of ADHD are also available on request from the author. Results Approximately 89% of the sample were defined as having low ADHD symptom levels, 6% as
having child-limited ADHD symptoms and 5% as having persistent symptoms. Estimated social outcome means/proportions by ADHD group are shown in Table 1. The
proportions of individuals with ADHD by outcome (e.g. of those with low emotional support, the
proportion with child-limited and persistent ADHD) are shown in Table 2: up to 20% of those
showing less favourable adult outcomes such as being NEET, receiving state benefits and being
homeless had ADHD. 9 9 As shown in Table 3, persistent ADHD was associated with lower adult emotional support and
an increased likelihood of being NEET and of receiving state benefits compared to those with
low ADHD symptoms. There was a trend for persistent ADHD to be associated with antisocial
behaviour (aggressive and non-aggressive) and homelessness; we did not find strong evidence
of association with lower instrumental support for persistent ADHD. There was also not strong
evidence of association for child-limited ADHD with any of the social outcomes at age 25 years. As shown in Table 3, persistent ADHD was associated with lower adult emotional support and
an increased likelihood of being NEET and of receiving state benefits compared to those with
low ADHD symptoms. There was a trend for persistent ADHD to be associated with antisocial
behaviour (aggressive and non-aggressive) and homelessness; we did not find strong evidence
of association with lower instrumental support for persistent ADHD. There was also not strong
evidence of association for child-limited ADHD with any of the social outcomes at age 25 years. Persistent ADHD was also associated with a higher total number of these adverse social
outcomes (defined categorically) compared to those with low ADHD symptoms (OR=2.07, 95%
CI=1.47 to 2.93, p=4x10-05), whereas evidence of association for child-limited ADHD was weaker
(OR=1.33, 95% CI=0.93 to 1.89, p=0.11). The estimated total number of these outcomes by
ADHD group are shown in Figure 2: for those with persistent ADHD, 45% were estimated to
have none of the adverse social outcomes assessed at age 25, 30% to have one and 25% to have
multiple (this was 56%, 31% and 14% respectively for those with child-limited ADHD and 63%,
26% and 11% for those with low ADHD symptoms). Sensitivity analyses Sensitivity analyses results are available on request from the author. Results Analyses stratified by sex found associations to be generally consistent across males and
females, with some evidence that associations for persistent ADHD with lower emotional
support may be driven by females and association with NEET status driven by males (although
confidence intervals overlapped). Associations stratified by family of origin income also found
associations to be generally consistent across income levels, with overlapping confidence
intervals across groups. 10 Sensitivity analyses also examined whether associations between ADHD and adult social
outcomes were still present in the absence of child comorbidities (low IQ, autism symptoms,
conduct problems and emotional problems), young-adult emotional problems and ADHD
medication use. Evidence of association between persistent ADHD and lower emotional
support, being NEET and receiving state benefits remained when excluding these child
comorbidities, young-adult emotional problems and taking ADHD medication although the
association with state benefits was somewhat attenuated when excluding those with childhood
ASD symptoms and association with lower emotional support was somewhat attenuated when
excluding those taking ADHD medication. Missing data sensitivity analyses showed a similar pattern of results across different
approaches. Finally, sensitivity analyses using different definitions of ADHD also showed a similar pattern of
results, as did those investigating “late-onset” ADHD. Discussion This study set out to examine the adult social outcomes at age 25 of ADHD symptoms across
childhood and young-adulthood in a longitudinal birth cohort, differentiating those that were
child-limited (remitted) and persistent. The findings observed did not support our hypothesis
that adults with both remitted and persistent ADHD would show adverse social outcomes by
age 25 years. While we found associations with persistent ADHD, we did not find such strong
evidence of association with child-limited ADHD. We found ADHD that persisted into young-adulthood was associated with multiple adverse
social outcomes including lower levels of emotional support and an increased likelihood of
being NEET (Not in Education, Employment or Training) and of receiving state benefits (a proxy 11 measure of socio-economic disadvantage). Approximately 20% of young people with NEET
status, receiving state benefits and who were homeless had ADHD. This pattern of associations
was present across sex, family of origin income level, and when excluding childhood
comorbidities, young-adult emotional problems and ADHD medication use. While it is beyond
the scope of this paper to investigate the mechanisms linking (persistent) ADHD to these social
outcomes, possible explanations include ADHD-related core symptoms and emotional
regulation difficulties impacting on the initiation and/or maintenance of supportive
relationships and upon educational attainment. Interestingly we did not find strong evidence of
association between persistent ADHD and lower instrumental support, which may result from a
reliance on (and therefore increase use of) others for practical support. Difficulties in ADHD-
service engagement (including during the transition from child to adult services) at a time of
formal examinations, transitions out of school and future planning may also contribute to poor
social outcomes. We also found persistent ADHD to be associated with an increased number of
these negative social outcomes even though the sample is a population-based cohort and we
defined ADHD broadly. Around 1 in 4 of this group had more than one of these negative social
outcomes. Future research needs to identify what modifiable social factors promote better
social outcomes. There also was some evidence that women with ADHD may be more likely to
have impairments in social relationships (low emotional support) and men with ADHD to have
impairments in employment/training (NEET). Further work would be needed to investigate
potentially different pathways for men and women between ADHD and social outcomes. measure of socio-economic disadvantage). Discussion Approximately 20% of young people with NEET
status, receiving state benefits and who were homeless had ADHD. This pattern of associations
was present across sex, family of origin income level, and when excluding childhood
comorbidities, young-adult emotional problems and ADHD medication use. While it is beyond
the scope of this paper to investigate the mechanisms linking (persistent) ADHD to these social
outcomes, possible explanations include ADHD-related core symptoms and emotional
regulation difficulties impacting on the initiation and/or maintenance of supportive
relationships and upon educational attainment. Interestingly we did not find strong evidence of
association between persistent ADHD and lower instrumental support, which may result from a
reliance on (and therefore increase use of) others for practical support. Difficulties in ADHD-
service engagement (including during the transition from child to adult services) at a time of
formal examinations, transitions out of school and future planning may also contribute to poor
social outcomes. We also found persistent ADHD to be associated with an increased number of
these negative social outcomes even though the sample is a population-based cohort and we
defined ADHD broadly. Around 1 in 4 of this group had more than one of these negative social
outcomes. Future research needs to identify what modifiable social factors promote better
social outcomes. There also was some evidence that women with ADHD may be more likely to
have impairments in social relationships (low emotional support) and men with ADHD to have
impairments in employment/training (NEET). Further work would be needed to investigate
potentially different pathways for men and women between ADHD and social outcomes. Our findings suggest that directing resources to supporting those with ADHD and monitoring
symptoms across adolescence and young-adulthood may be a beneficial area of focus. This age
captures a period of increasing socio-occupational, personal and financial demands, when
young people typically graduate from education into the world of further training and/or
employment. The absence of strong evidence of association between child-limited ADHD
suggests that the risk-mechanisms linking ADHD and social outcomes in young-adulthood are 12 not exclusively set in place in childhood – that effective ADHD treatment and other
interventions that reduce symptoms may help prevent adverse adult outcomes. Discussion Indeed,
previous work has found for example that stimulant medication in young people with ADHD is
associated with a decreased risk of subsequent smoking and substance use disorders in
adolescence (at 5-year follow-up)31: but that this effect may not persist into young-adulthood
(10-yearfollow-up).32 However our study design cannot differentiate whether associations with
outcomes are a causal consequence of ADHD symptoms. For example, evidence suggests that
ADHD persistence is associated with ADHD severity and a higher genetic loading than remitted
ADHD.33 Also ADHD symptom persistence into young-adulthood does not exclude the possibility
that risk mechanisms for social outcomes were set in place earlier in development for this
group. Regardless, our findings highlight the importance of ADHD monitoring and management
of ADHD symptoms across development, the transition from child to adult services and the
variability in adult social outcomes. Our findings somewhat differ from a previous UK cohort study which showed association
between remitted ADHD and life satisfaction, NEET status and criminal convictions (although
not social isolation) at the age of 18 years.17 One explanation is that our study focussed on
broadly defined ADHD whereas the previous work17 examined ADHD diagnosis, which means
that individuals who were categorised as having remitted ADHD (i.e. did not meet diagnostic
threshold at 18 years) may still have had (subthreshold) ADHD symptoms at 18.17 Such
individuals would have been categorised as having persistent ADHD symptoms in our study. It
could be that our (less common) outcomes were defined more stringently and were more
severe. Alternatively, differences could be due to follow-up period: it may be that the familial,
social, occupational and personal life events and changes that occur between ages 18 and 25
explain the apparent contrasting findings. 13 Our study findings should be considered in light of limitations. As with many longitudinal
population-based samples, ALSPAC also suffers from non-random attrition, with those who
drop out more likely to be at elevated risk of psychopathology.34, 35 We used multiple imputation
with inverse probability weighting to try to minimise the effect of missingness and findings
were consistent across different approaches. We focused on ADHD symptoms in a population
cohort and although evidence suggests that ADHD behaves as a continuously distributed trait
without clear-cut thresholds in terms of associations with adverse outcomes,36 our findings may
not be able to be generalised to clinical diagnosis or those in clinical services. Discussion Holistic age-specific 14 ADHD resources, interventions, support and services that span the lifespan may be beneficial in
addressing the range of adverse outcomes associated with ADHD, as well as core features. Mental health awareness initiatives are increasingly taking place in educational establishments,
however specific ADHD-informed interventions are indicated to anticipate and support young
people in making choices around goals for further training and/or occupational activity. Understanding individuals with ADHD and matching strengths and interests (and
acknowledging areas of challenge) with appropriate lines of work may serve to increase the
likelihood of increased enjoyment, satisfaction and longer-term engagement in meaningful
socio-occupational activity. This may in turn have positive effects on navigating supportive
relationships, emotional wellbeing and use of maladaptive coping strategies. Early identification
and specific careers guidance by resourced practitioners with increased awareness of ADHD
would support and highlight to young people with persistent symptoms the wide range of
complimentary, realistic and exciting future opportunities for their diverse skill sets. ADHD resources, interventions, support and services that span the lifespan may be beneficial in
addressing the range of adverse outcomes associated with ADHD, as well as core features. ADHD resources, interventions, support and services that span the lifespan may be beneficial in
addressing the range of adverse outcomes associated with ADHD, as well as core features. Mental health awareness initiatives are increasingly taking place in educational establishments,
however specific ADHD-informed interventions are indicated to anticipate and support young
people in making choices around goals for further training and/or occupational activity. Understanding individuals with ADHD and matching strengths and interests (and
acknowledging areas of challenge) with appropriate lines of work may serve to increase the
likelihood of increased enjoyment, satisfaction and longer-term engagement in meaningful
socio-occupational activity. This may in turn have positive effects on navigating supportive
relationships, emotional wellbeing and use of maladaptive coping strategies. Early identification
and specific careers guidance by resourced practitioners with increased awareness of ADHD
would support and highlight to young people with persistent symptoms the wide range of
complimentary, realistic and exciting future opportunities for their diverse skill sets. In conclusion, our study found ADHD that persists to young-adulthood is associated with a
range of less favourable social outcomes, including low emotional support, NEET status and
receiving state benefits (as an indicator of socio-economic disadvantage) although these
adverse outcomes were not inevitable. Strong evidence of association was not found for child-
limited ADHD. Discussion However our
prevalence rates of ADHD are not much higher than the rate of ADHD diagnosis in many
population surveys. The use of a population sample also limited our power for detecting
association with rarer outcomes such as homelessness. Finally, beyond examining young-adult
emotional problems we did not examine the potential impact of presence and treatment of
additional comorbid psychiatric disorders in adulthood. Our study findings should be considered in light of limitations. As with many longitudinal
population-based samples, ALSPAC also suffers from non-random attrition, with those who
drop out more likely to be at elevated risk of psychopathology.34, 35 We used multiple imputation
with inverse probability weighting to try to minimise the effect of missingness and findings
were consistent across different approaches. We focused on ADHD symptoms in a population
cohort and although evidence suggests that ADHD behaves as a continuously distributed trait
without clear-cut thresholds in terms of associations with adverse outcomes,36 our findings may
not be able to be generalised to clinical diagnosis or those in clinical services. However our
prevalence rates of ADHD are not much higher than the rate of ADHD diagnosis in many
population surveys. The use of a population sample also limited our power for detecting
association with rarer outcomes such as homelessness. Finally, beyond examining young-adult
emotional problems we did not examine the potential impact of presence and treatment of
additional comorbid psychiatric disorders in adulthood. Further research using alternative designs such as those that assess causal inference is needed
to test whether the associations we found are causal and work is needed to identify potentially
modifiable risk mechanisms, groups that are at highest risk and factors that promote positive
adult social outcomes. Identification of such moderating and mediating factors as well as those
relating to service disengagement is needed to be able to better address the emotional
wellbeing and social marginalisation of at-risk young people with ADHD. The effect of the
COVID-19 global pandemic on the social outcomes of young people with ADHD is also as yet
unknown: the associated additional challenges that this has posed on young people and
understanding how they can be best supported as they progress into wider society remains
vital. The funding and expansion of support for young-adults with ADHD in educational/occupational
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functional impairment beyond core ADHD features. Clinical Points •
ADHD is associated with a range of adverse outcomes in adult life, but it is unclear
whether this is driven by concurrent ADHD symptoms that have persisted to adulthood. •
ADHD is associated with a range of adverse outcomes in adult life, but it is unclear
whether this is driven by concurrent ADHD symptoms that have persisted to adulthood. •
Continued monitoring and management of ADHD into adulthood is important, including
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2016;387(10024):1240-1250. 17 Table 1. Social outcomes means/percentages by ADHD group using IPW/MI to account for
missing data
Low
Child-limited ADHD
Persistent ADHD
Emotional support
43.04 (42.58 to 43.49) 42.44 (40.47 to 44.41) 39.07 (37.09 to 41.05)
Instrumental support 39.41 (38.80 to 40.02) 40.63 (38.31 to 42.95) 38.05 (35.54 to 40.56)
Aggressive ASB
5.11% (3.87 to 6.34)
7.05% (2.17 to 11.93) 10.04% (3.28 to 16.81)
Non-aggressive ASB
13.04% (11.64 to 14.44) 12.26% (6.42 to 17.68) 19.87% (12.24 to 27.49)
NEET
5.54% (4.44 to 6.64)
6.77% (2.00 to 11.53) 18.02% (9.95 to 26.08)
State benefit recipient
7.67% (6.52 to 8.83)
10.43% (5.04 to 15.83) 18.56% (10.86 to 26.27)
Homelessness
1.63% (0.82 to 2.45)
1.57% (-1.48 to 4.62)
4.65% (-0.04 to 9.71)
N=6439. 95% confidence intervals in parentheses. Abbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse
probability weighting, NEET = Not in Education, Employment or Training. Table 2. Percentage of individuals with ADHD, by social outcome using IPW/MI to account for
missing data
Persistent ADHD
Child-limited ADHD
Low emotional support (10%)a
8.87% (5.54 to 12.20)
6.54% (3.22 to 9.85)
Low instrumental support (10%)a
5.40% (2.23 to 8.56)
5.47% (2.38 to 8.55)
Aggressive ASB (5%)
9.35% (3.27 to 15.44)
7.85% (2.57 to 13.14)
Non-aggressive ASB (13%)
7.62% (4.68 to 10.56)
5.63% (3.14 to 8.11)
NEET (6%)
14.78% (8.24 to 21.32)
6.58% (1.98 to 11.18)
State benefit recipient (8%)
13.34% (-0.66 to 27.33)
5.34% (-5.17 to 15.84)
Homelessness (2%)
12.29% (6.72 to 15.86)
7.61% (3.75 to 11.47)
N=6439. aFor continuous outcomes, low support defined as the bottom 10%. 95% confidence
intervals in parentheses. Table 1. References Social outcomes means/percentages by ADHD group using IPW/MI to account for
missing data
Low
Child-limited ADHD
Persistent ADHD
Emotional support
43.04 (42.58 to 43.49) 42.44 (40.47 to 44.41) 39.07 (37.09 to 41.05)
Instrumental support 39.41 (38.80 to 40.02) 40.63 (38.31 to 42.95) 38.05 (35.54 to 40.56)
Aggressive ASB
5.11% (3.87 to 6.34)
7.05% (2.17 to 11.93) 10.04% (3.28 to 16.81)
Non-aggressive ASB
13.04% (11.64 to 14.44) 12.26% (6.42 to 17.68) 19.87% (12.24 to 27.49)
NEET
5.54% (4.44 to 6.64)
6.77% (2.00 to 11.53) 18.02% (9.95 to 26.08)
State benefit recipient
7.67% (6.52 to 8.83)
10.43% (5.04 to 15.83) 18.56% (10.86 to 26.27)
Homelessness
1.63% (0.82 to 2.45)
1.57% (-1.48 to 4.62)
4.65% (-0.04 to 9.71)
N=6439. 95% confidence intervals in parentheses. Abbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse
probability weighting, NEET = Not in Education, Employment or Training. Table 2. Percentage of individuals with ADHD, by social outcome using IPW/MI to account for
missing data
Persistent ADHD
Child-limited ADHD
Low emotional support (10%)a
8.87% (5.54 to 12.20)
6.54% (3.22 to 9.85)
Low instrumental support (10%)a
5.40% (2.23 to 8.56)
5.47% (2.38 to 8.55)
Aggressive ASB (5%)
9.35% (3.27 to 15.44)
7.85% (2.57 to 13.14)
Non-aggressive ASB (13%)
7.62% (4.68 to 10.56)
5.63% (3.14 to 8.11)
NEET (6%)
14.78% (8.24 to 21.32)
6.58% (1.98 to 11.18)
State benefit recipient (8%)
13.34% (-0.66 to 27.33)
5.34% (-5.17 to 15.84)
Homelessness (2%)
12.29% (6.72 to 15.86)
7.61% (3.75 to 11.47)
N=6439. aFor continuous outcomes, low support defined as the bottom 10%. 95% confidence
intervals in parentheses. Table 1. Social outcomes means/percentages by ADHD group using IPW/MI to account for
missing data
Low
Child-limited ADHD
Persistent ADHD
Emotional support
43.04 (42.58 to 43.49) 42.44 (40.47 to 44.41) 39.07 (37.09 to 41.05)
Instrumental support 39.41 (38.80 to 40.02) 40.63 (38.31 to 42.95) 38.05 (35.54 to 40.56)
Aggressive ASB
5.11% (3.87 to 6.34)
7.05% (2.17 to 11.93) 10.04% (3.28 to 16.81)
Non-aggressive ASB
13.04% (11.64 to 14.44) 12.26% (6.42 to 17.68) 19.87% (12.24 to 27.49)
NEET
5.54% (4.44 to 6.64)
6.77% (2.00 to 11.53) 18.02% (9.95 to 26.08)
State benefit recipient
7.67% (6.52 to 8.83)
10.43% (5.04 to 15.83) 18.56% (10.86 to 26.27)
Homelessness
1.63% (0.82 to 2.45)
1.57% (-1.48 to 4.62)
4.65% (-0.04 to 9.71)
N=6439. 95% confidence intervals in parentheses. References Abbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse
probability weighting, NEET = Not in Education, Employment or Training. Table 2. Percentage of individuals with ADHD, by social outcome using IPW/MI to account for
missing data
Persistent ADHD
Child-limited ADHD
Low emotional support (10%)a
8.87% (5.54 to 12.20)
6.54% (3.22 to 9.85)
Low instrumental support (10%)a
5.40% (2.23 to 8.56)
5.47% (2.38 to 8.55)
Aggressive ASB (5%)
9.35% (3.27 to 15.44)
7.85% (2.57 to 13.14)
Non-aggressive ASB (13%)
7.62% (4.68 to 10.56)
5.63% (3.14 to 8.11)
NEET (6%)
14.78% (8.24 to 21.32)
6.58% (1.98 to 11.18)
State benefit recipient (8%)
13.34% (-0.66 to 27.33)
5.34% (-5.17 to 15.84)
Homelessness (2%)
12.29% (6.72 to 15.86)
7.61% (3.75 to 11.47)
N=6439. aFor continuous outcomes, low support defined as the bottom 10%. 95% confidence
intervals in parentheses. Table 1. Social outcomes means/percentages by ADHD group using IPW/MI to account for
missing data
Low
Child-limited ADHD
Persistent ADHD
Emotional support
43.04 (42.58 to 43.49) 42.44 (40.47 to 44.41) 39.07 (37.09 to 41.05)
Instrumental support 39.41 (38.80 to 40.02) 40.63 (38.31 to 42.95) 38.05 (35.54 to 40.56)
Aggressive ASB
5.11% (3.87 to 6.34)
7.05% (2.17 to 11.93) 10.04% (3.28 to 16.81)
Non-aggressive ASB
13.04% (11.64 to 14.44) 12.26% (6.42 to 17.68) 19.87% (12.24 to 27.49)
NEET
5.54% (4.44 to 6.64)
6.77% (2.00 to 11.53) 18.02% (9.95 to 26.08)
State benefit recipient
7.67% (6.52 to 8.83)
10.43% (5.04 to 15.83) 18.56% (10.86 to 26.27)
Homelessness
1.63% (0.82 to 2.45)
1.57% (-1.48 to 4.62)
4.65% (-0.04 to 9.71)
N=6439. 95% confidence intervals in parentheses. Abbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse
probability weighting, NEET = Not in Education, Employment or Training. Table 2. Percentage of individuals with ADHD, by social outcome using IPW/MI to account for
missing data
Persistent ADHD
Child-limited ADHD
Low emotional support (10%)a
8.87% (5.54 to 12.20)
6.54% (3.22 to 9.85)
Low instrumental support (10%)a
5.40% (2.23 to 8.56)
5.47% (2.38 to 8.55)
Aggressive ASB (5%)
9.35% (3.27 to 15.44)
7.85% (2.57 to 13.14)
Non-aggressive ASB (13%)
7.62% (4.68 to 10.56)
5.63% (3.14 to 8.11)
NEET (6%)
14.78% (8.24 to 21.32)
6.58% (1.98 to 11.18)
State benefit recipient (8%)
13.34% (-0.66 to 27.33)
5.34% (-5.17 to 15.84)
Homelessness (2%)
12.29% (6.72 to 15.86)
7.61% (3.75 to 11.47)
N=6439. aFor continuous outcomes, low support defined as the bottom 10%. 95% confidence
intervals in parentheses. References 18 bbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse probability weighting, NEET = Not in Education, Employment or Training. probability weighting, NEET = Not in Education, Employment or Training. Table 3. Associations between ADHD group and social outcomes using IPW/MI to account for
missing data
Child-limited ADHD
Persistent ADHD
Emotional support
RC=-0.60 (-2.59 to 1.39), p=0.56
RC=-3.97 (-5.94 to -1.99), p=9x10-05
Instrumental support
RC=1.22 (-1.13 to 3.57), p=0.31
RC=-1.36 (-3.87 to 1.15), p=0.29
Aggressive ASB
OR=1.38 (0.65 to 2.93), p=0.40
OR=2.02 (0.95 to 4.30), p=0.07
Non-aggressive ASB
OR=0.92 (0.56 to 1.53), p=0.76
OR=1.64 (1.01 to 2.67), p=0.05
NEET
OR=1.20 (0.54 to 2.69), p=0.65
OR=3.71 (2.06 to 6.67), p=1x10-05
State benefit recipient
OR=1.38 (0.76 to 2.51), p=0.29
OR=2.72 (1.62 to 4.57), p=2x10-04
Homelessness
OR=0.74 (0.08 to 6.50), p=0.79
OR=2.81 (0.86 to 9.12), p=0.09
N=6439. Reference group = low ADHD group. 95% confidence intervals in parentheses. Abbreviations: ASB = antisocial behaviour, IPW/MI = multiple imputation with inverse
probability weighting, NEET = Not in Education, Employment or Training, OR = odds ratio, RC = Table 3. Associations between ADHD group and social outcomes using IPW/MI to account for
missing data 19 Figure 1. ADHD groups for primary analyses 20 Figure 2. Total number of social outcomes by ADHD group using IPW/MI to account for missing Figure 2. Total number of social outcomes by ADHD group using IPW/MI to account for missing Figure 2. Total number of social outcomes by ADHD group using IPW/MI to account
data
Abbreviations: IPW/MI = multiple imputation with inverse probability weighting Figure 2. Total number of social outcomes by ADHD group using IPW/MI to account for missing
data
Abbreviations: IPW/MI = multiple imputation with inverse probability weighting Abbreviations: IPW/MI = multiple imputation with inverse probability weighting 21
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https://zenodo.org/records/7203332/files/EJAR11110.pdf
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ФАКТОРЫ, ВЛИЯЮЩИЕ НА КАЧЕСТВЕННЫЕ ПОКАЗАТЕЛИ ГОТОВОЙ ОДЕЖДЫ
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Широкое
распространение
получило
оборудование
для
выполнения
операций
внутрипроцессной
и
окончательной
влажно-тепловой
обработки
с
микропроцессорным
управлением режимами обработки. С
помощью
таких
оборудований
обеспечивается
улучшение
условий
труда
и
культуру
производства. Расширился
ассортимент
клеевых
прокладочных материалов для одежды,
соединение
которых
с
основными
деталями
осуществляется
на
оборудовании проходного типа в отделе
влажно-тепловой обработки. Широко
стала
применяться
сварка
для
обработки различных видов одежды. В
настоящее
время
значительно
улучшилось
качества
технологии
изготовления одежды, основанные на
накопленном
предприятиями
практическом
опыте
работы
с
иностранными фирмами и внедрённых
научных разработках. Поэтому возникла
необходимость
в
обновлении
и
пополнении
сведений
по
вопросам
обработки швейных изделий, особенно
верхней одежде [2]. Качество готовой одежды связано с
качеством
выполнения
соединений
деталей
одежды. В
процессе
эксплуатации
одежда
подвергается
различного
рода
механическими
воздействиями: сжатию, растяжению,
кручению изгибу и т д Поэтому уже в
качество
ниточных
соединений
приведено в схеме-1. При выполнении машинных работ
в
процессе
изготовления
одежды
необходимо
соблюдать
общие
технические условия к выполнению
машинных
работ. Для
оценки,
показателей
качества
ниточных
соединений деталей одежды в основном
применяют
технические
и
эвристические методы. Эвристическими
методами
оцениваются
показатели
эмоционального,
психологического,
эргономического
воздействия
на
человека. Наиболее используемым в
швейной
промышленности
является
органолептический
метод
для
оценивания
показателей,
который
основан на оценке качества с помощью
органов
чувств
человека. Органолептический метод применяется
при оценке эстетических показателей
качества
ниточных
соединений:
ровноты линии строчки, целостности
строчки, плотности затяжки стежков,
симметричности деталей [4,5]. Для оценки показателей качества
ниточных
соединений
также
применяются
технические
методы
оценки
-
измерительный,
регистрационный и расчетный. В процессе образования стежков на
качество ниточных соединений влияют
различные
факторы. Эти
факторы
можно разделить на пять групп: 1 – вид
переплетения и структура стежка; 2 – EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz приемов,
машины-полуавтоматы,
автоматизированные
и
роботизированные машины. Широкое
распространение
получило
оборудование
для
выполнения
операций
внутрипроцессной
и
окончательной
влажно-тепловой
обработки
с
микропроцессорным
управлением режимами обработки. С
помощью
таких
оборудований
обеспечивается
улучшение
условий
труда
и
культуру
производства. Расширился
ассортимент
клеевых
прокладочных материалов для одежды,
соединение
которых
с
основными
деталями
осуществляется
на
оборудовании проходного типа в отделе
влажно-тепловой обработки. Широко
стала
применяться
сварка
для
обработки различных видов одежды. В
настоящее
время
значительно
улучшилось
качества
технологии
изготовления одежды, основанные на
накопленном
предприятиями
практическом
опыте
работы
с
иностранными фирмами и внедрённых
научных разработках. Поэтому возникла
необходимость
в
обновлении
и
пополнении
сведений
по
вопросам
обработки швейных изделий, особенно
верхней одежде [2]. Эвристическими
методами
оцениваются
показатели
эмоционального,
психологического,
эргономического
воздействия
на
человека. УДК. 687.0
ФАК
Нутфу
Научный
Бух
ARTICLE INFO
Received: 01st October 2022
Accepted: 05th October 2022
Online: 15th October 2022
KEY WORDS
показатели
качества,
соединения деталей одежды,
клеевое соединения, сварное
соединения,
влажно-
тепловая
обработка,
технические методы оценки,
волокнистый состав ткани. В статье изучены методы повышения качества
готовой
одежды,
влияющие
факторы
при
технологическом процессе изготовления швейных
изделий. Рассмотрены виды соединения деталей
одежды, обеспечивающие прочности, надежности,
долговечности швов и красивый внешний вид изделия;
посмотрены качество клеевых соединений а также
основные задачи влажно-тепловой обработки —
придание готовым изделиям товарного вида, формы,
обеспечивающей хорошую посадку изделий на фигурах
потребителей в соответствии с образцами моделей. Основу технологии изготовления
швейных
изделий
составляют
различные способы соединения деталей
одежды – ниточные, клеевой, сварной, а
также влажно-тепловая обработка. На
качественных показателей соединений
деталей одежды влияет ряд факторов:
свойства
материалов,
режимы
обработки,
технологические
характеристики
применяемого
оборудования
для
технологического
процесса и др [1]. Современный
рынок
швейных
изделий для населения предоставляет
просто огромное количество моделей,
расцветок и текстильных материалов. Но при прочих равных, при наличии
такого
выбора,
подобрать
то,
что
нужного - это тоже иногда проблема. Как
минимум, потому, что качественной
одежды не так уж и много, а цена далеко
не
всегда
гарантирует
это
самое,
пресловутое качество. Нам известна, что одежда является
один из основных предметов первой
необходимости
для
человека. Она
выполняет утилитарную и эстетическую
функции, покрывает тело человека и
защищает
его
от
неблагоприятных
воздействий внешней среды. Благодаря
одежде человек способен сравнительно
легко
переносить
различные
климатические
условия,
физико-
механические, химические воздействия
и др. Требования к ней разнообразны и
многочисленны. В последнее время все больше
уделяется
внимания
совершенствованию
способов
соединения деталей одежды, их влажно-
тепловой
обработке
в
связи
с
появлением
широкого
ассортимента
новых
материалов
с
различным
волокнистым составом и свойствами. Произошла
корректировка
режимов
машинной
и
влажно-тепловой
обработки материалов. Появилось новое
швейное
оборудование
с
автоматизацией
вспомогательных В последнее время все больше
уделяется
внимания
совершенствованию
способов
соединения деталей одежды, их влажно-
тепловой
обработке
в
связи
с
появлением
широкого
ассортимента
новых
материалов
с
различным
волокнистым составом и свойствами. Произошла
корректировка
режимов
машинной
и
влажно-тепловой
обработки материалов. Появилось новое
швейное
оборудование
с
автоматизацией
вспомогательных Volume 2 Issue 11, October 2022 ISSN 2181-2020
Page 570 Volume 2 Issue 11, October 2022 Volume 2 Issue 11, October 2022 ISSN 2181-2020 ISSN 2181-2020 Page 570 EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz
приемов,
машины-полуавтоматы,
автоматизированные
и
роботизированные машины. Наиболее используемым в
швейной
промышленности
является
органолептический
метод
для
оценивания
показателей,
который
основан на оценке качества с помощью
органов
чувств
человека. Органолептический метод применяется
при оценке эстетических показателей
качества
ниточных
соединений:
ровноты линии строчки, целостности
строчки, плотности затяжки стежков,
симметричности деталей [4,5]. Для оценки показателей качества
ниточных
соединений
также
применяются
технические
методы
оценки
-
измерительный,
регистрационный и расчетный. Качество готовой одежды связано с
качеством
выполнения
соединений
деталей
одежды. В
процессе
эксплуатации
одежда
подвергается
различного
рода
механическими
воздействиями: сжатию, растяжению,
кручению, изгибу и т. д. Поэтому уже в
процессе
проектирования
модели
необходимо
выбрать
такой
вид
соединения деталей одежды, который
обеспечивал бы прочность, надежность
и долговечность швов также красивый
внешний вид готовой одежде [3]. К
й В процессе образования стежков на
качество ниточных соединений влияют
различные
факторы. Эти
факторы
можно разделить на пять групп: 1 – вид
переплетения и структура стежка; 2 –
вид и свойства материала; 3 – вид и
свойства ниток; – технологические
режимы пошива; 5 – параметры швов[6]. Качество
ниточных
соединений
определяется
целым
комплексом
показателей. Эти показатели можно
разделить на пять групп, эти показатели Volume 2 Issue 11, October 2022 ISSN 2181-2020 Volume 2 Issue 11, October 2022 ISSN 2181-2020 Page 571 www.in-academy.uz вдоль строчки в значительной степени
определяется видом ниток, структурой
материала,
режимами
стачивания. Внешний вид соединений зависит от размерных параметров и структуры
стежков в строчках, ровноты строчек,
степени затяжки стежков, целостности
строчки. й Клеевые
соединения
широко
применяются
при
изготовлении
швейных изделий особенно верхней
одежде. Несмотря на то, что их доля в
общей
трудоёмкости
изготовления верхней одежды невелика, для придания
формоустойчивости деталям, многие из
них дублируются. Доля трудоёмкости
изготовления
верхней
одежды
приведены в таблице. Volume 2 Issue 11, October 2022 ISSN 2181-2020 ISSN 2181-2020 Page 572 EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz EURASIAN JOURNAL OF ACADEMIC RESEARCH Таблица
Трудоёмкость изготовления верхней одежды
Швейное изделие в
примере
Удельный вес операции, %
ниточная
технология
влажно-
тепловая
обработка
клеевая
технология
Женское пальто из
шерстяной ткани
Мужской пиджак из
шерстяной ткани
Мужская сорочка
51,8
40,0
66,0
13,3
33,3
4,4
6,3
8,7
4,4 охлаждении скрепляет их. Наиболее
качественное соединение получается
при образовании равномерной клеевой
прослойки[7]. Склеивание происходит за счёт
расплавления клея, помещённого между
текстильными
материалами,
под
воздействием температуры и давления. При
нагревании
под
давлением
термопластичный клей переходит в
вязкотекучее состояние, проникает в
материалы на некоторую глубину и при С развитием познаний человека об
окружающем его мире используются
натуральные
клейкие
вещества,
примеры этих веществ приведены в
схеме-2. Схема-2. Виды натуральных клейких веществ
Между
продолжительностью
Основные параметры влияющие на
свойства
клеевых
соединений
в
й
й
НАТУРАЛЬНЫЕ КЛЕЙКИЕ ВЕЩЕСТВА
яичный
белок
мука
сера
смола
каучук
деготь
крахмал
пчелиный
воск Схема-2. Виды натуральных клейких веществ
Между
продолжительностью
нагревания склеиваемых материалов и
температурой
существует
обратная
зависимость. Чем выше температура
рабочих
прессующих
органов,
тем
меньше продолжительность перевода
клея в вязкотекучее состояние. Основные параметры влияющие на
свойства
клеевых
соединений
в
производстве
швейных
изделий
приведены в схеме-3. Они зависят от
вида клея, вида материала и от вида
используемое
оборудование
для
дублирования. НАТУРАЛЬНЫЕ КЛЕЙКИЕ ВЕЩЕСТВА
яичный
белок
мука
сера
смола
каучук
деготь
крахмал
пчелиный
воск Схема-2. Виды натуральных клейких веществ
НАТУРАЛЬНЫЕ КЛЕЙКИЕ ВЕЩЕСТВА
яичный
белок
мука
сера
смола
каучук
деготь
крахмал
пчелиный
воск Схема-2. Виды натуральных клейких веществ Схема-2. Виды натуральных клейких веществ Основные параметры влияющие на
свойства
клеевых
соединений
в
производстве
швейных
изделий
приведены в схеме-3. Они зависят от
вида клея, вида материала и от вида
используемое
оборудование
для
дублирования. Основные параметры влияющие на
свойства
клеевых
соединений
в
производстве
швейных
изделий
приведены в схеме-3. www.in-academy.uz Они зависят от
вида клея, вида материала и от вида
используемое
оборудование
для
дублирования. Между
продолжительностью
нагревания склеиваемых материалов и
температурой
существует
обратная
зависимость. Чем выше температура
рабочих
прессующих
органов,
тем
меньше продолжительность перевода
клея в вязкотекучее состояние. Volume 2 Issue 11, October 2022 ISSN 2181-2020 Volume 2 Issue 11, October 2022 ISSN 2181-2020 Page 573 EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz
Схема-3. Основные параметры, влияющие на свойства клеевых соединений
Выбранная температура рабочих
ганов
оборудования
для
блирования
должна
обеспечивать
ранение
свойств
соединяемых
териалов, цвета красителя, исключать
рушение
отделочных
препаратов. потребительские
свойства. Для
синтетических материалов характерны
такие свойства как легкость, красивый
внешний
вид,
несминаемость,
водостойкость,
невысокая
цена,
легкость ухода. Влажно-тепловая обработка (ВТО)
СВОЙСТВА
КЛЕЕВЫХ
СОЕДИНЕНИЙ
Температура
Давление
Продолжи
тельность сжатия
и нагревания
Влажность
текстильного
материала СВОЙСТВА
КЛЕЕВЫХ
СОЕДИНЕНИЙ Схема-3. Основные параметры, влияющие на свойства клеевых соединений
Выбранная температура рабочих
анов
оборудования
для
лирования
должна
обеспечивать
ранение
свойств
соединяемых
териалов, цвета красителя, исключать
потребительские
свойства. Для
синтетических материалов характерны
такие свойства как легкость, красивый
внешний
вид,
несминаемость,
водостойкость,
невысокая
цена,
легкость ухода. Выбранная температура рабочих
органов
оборудования
для
дублирования
должна
обеспечивать
сохранение
свойств
соединяемых
материалов, цвета красителя, исключать
разрушение
отделочных
препаратов. Если
температура
рабочих
органов
оборудования
ниже
требуемой,
то
увеличение
продолжительности
и
давления прессования не приведет к
размягчению
клея. Превышение
температуры
сопровождается
проникновением
клея
на
лицевую
сторону
основного
материала
и
термоклеевого
прокладочного
материала. у
д
Влажно-тепловая обработка (ВТО)
наряду
с
ниточной
и
клеевой
технологиями
является
важнейшим
технологическим
процессом
при
изготовлении одежды. Она позволяет
получать
такие
эффекты,
которые
недостижимы
другими
известными
способами,
и
является
логическим
завершением
конструкторских
и
технологических решений получения
изделия высокого качества. Назначение
ВТО – придание швейным изделиям
требуемой пространственной формы и
красивого товарного вида, который
достигается путем устранения заминов,
помятостей,
лас
(местного
блеска),
утонения краев деталей (борт, край
воротника
…),
разутюживания
и
заутюживания швов и т. д. Развитие производства швейных
изделий особенно верхней одежды,
улучшение
ее
ассортимента
и
увеличение объемов выпуска тесно
связано
с
увеличением
доли
синтетических волокон в сырьевом
балансе. Химические волокна в общем
балансе мирового производства волокон
всех видов составляют 48,2 %, из них
37,3
%
–
синтетические
волокна,
главным
образом
полиэфирные,
полиамидные
и
полиакрилонитрильные. UIF = 8.1 | SJIF = 5.685 полуфабрикат - Р, МРа; количество
внесенной в него влаги - W, %; и время
обработки - t, сек. Числовые значения -
называемые параметрами, определяют
режимы ВТО и зависят от волокнистого
состава обрабатываемой ткани, вида
выполняемых операций и применяемого
оборудования для ВТО[8]. система взаимодействия средств труда и
предметов
труда,
приводящая
к
получению
готового
изделия. Качественная одежда имеет больший
запас прочности, она не теряет форму
после первых стирок и не вытягивается
при носке, не покрывается моментально
катышками и у нее не топорщиться
молния. Все
это
завысить
от
правильного выбора технологических
обработок
одежды
-
от
ниточных
соединений, клеевых соединений и в
большем объеме от влажно-тепловой
обработки изделия. полуфабрикат - Р, МРа; количество
внесенной в него влаги - W, %; и время
обработки - t, сек. Числовые значения -
называемые параметрами, определяют
режимы ВТО и зависят от волокнистого
состава обрабатываемой ткани, вида
выполняемых операций и применяемого
оборудования для ВТО[8]. Технологический
процесс
изготовления швейного изделия – это References: 1. Ebersol, J. A. & Field, M. L. From reader to reading teacher: Issues and strategies for second
language classrooms. New York: Cambridge University Press. (1997).P 37 1. Ebersol, J. A. & Field, M. L. From reader to reading teacher: Issues and strategies for second
language classrooms. New York: Cambridge University Press. (1997).P 37 2. Alderson, J. C. Reading in a foreign language: A reading problem or a language problem? In
J.C. Alderson & A.H. Urquhart (Eds.), Reading in a foreign language (1984). (pp.1-27). New York:
Longman. 2. Alderson, J. C. Reading in a foreign language: A reading problem or a language problem? In
J.C. Alderson & A.H. Urquhart (Eds.), Reading in a foreign language (1984). (pp.1-27). New York:
Longman. 3. Alderson, J. C. & Luckman, Y. Cognition and reading: cognitive levels as embodied in test
questions. Reading in a Foreign Language 5 (2), (1989).253-70. 3. Alderson, J. C. & Luckman, Y. Cognition and reading: cognitive levels as embodied in test
questions. Reading in a Foreign Language 5 (2), (1989).253-70. 4. Alderson, J. C. Assessing Reading. Cambridge: Cambridge University Press. (200 on, J. C. Assessing Reading. Cambridge: Cambridge University Press. (2000).p 19 5. Afflerbach, from reader to reading teacher: Issues and strategies for second language
classrooms. New York: Cambridge University Press 2007. p 268 5. Afflerbach, from reader to reading teacher: Issues and strategies for second language
classrooms. New York: Cambridge University Press 2007. p 268 6. Geva, E. Facilitating reading comprehension through flowcharting. Reading Research
Quarterly, 18, (1983)384-405. 6. Geva, E. Facilitating reading comprehension through flowcharting. Reading Research
Quarterly, 18, (1983)384-405. 7. Grabe, W. Current development in second language reading research. TESOL Quarterly, 25,
3, (1991) (p. 378) 7. Grabe, W. Current development in second language reading research. TESOL Quarterly, 25,
3, (1991) (p. 378) 8. Gough, P. One second of reading. In Kavanagh, J., Mattingly, I. (Eds.), Language by ear and by
eye: The relationships between speech and reading (1982). Cambridge: MIT Press. pp. 331-335
9. Goodman, K. S. Reading: A psycholinguistic guessing game. In Ruddell, R., Ruddell, M., Singer,
H. (Eds.), Theoretical models and processes of reading Newark: International Reading
Association. (1976). (pp. 497-508). 8. Gough, P. One second of reading. In Kavanagh, J., Mattingly, I. (Eds.), Language by ear and by
eye: The relationships between speech and reading (1982). Cambridge: MIT Press. pp. 331-335
9. Goodman, K. S. Reading: A psycholinguistic guessing game. www.in-academy.uz Синтетические
волокна в текстильных материалах
позволяют
улучшить
их При
производстве
швейных
изделий,
основное
влияние
на
изменение
свойств
материала
в
процессе ВТО и его деформационную
способность оказывают такие факторы,
как
температура
гладильной
поверхности - Т,
0С; давление
на Volume 2 Issue 11, October 2022 ISSN 2181-2020 Page 574 EURASIAN JOURN
Innovative Ac
UIF = 8.1 | SJIF = 5.685
полуфабрикат - Р, МРа; количество
внесенной в него влаги - W, %; и время
обработки - t, сек. Числовые значения -
называемые параметрами, определяют
режимы ВТО и зависят от волокнистого
состава обрабатываемой ткани, вида
выполняемых операций и применяемого
оборудования для ВТО[8]. Технологические
процессы
изготовления
швейных
изделий
являются
основой
швейного
производства и включают в себя всю
совокупность операций по обработке и
соединению
деталей
и
узлов
в
определенной
технологической
последовательности [9-10]. Технологический
процесс
изготовления швейного изделия – это URNAL OF ACADEMIC RESEARCH
ve Academy Research Support Center
www.in-academy.uz
во
мя
я -
ют
ого
да
ого
сы
ий
ого
сю
е и
в
ой
система взаимодействия средств труда и
предметов
труда,
приводящая
к
получению
готового
изделия. Качественная одежда имеет больший
запас прочности, она не теряет форму
после первых стирок и не вытягивается
при носке, не покрывается моментально
катышками и у нее не топорщиться
молния. Все
это
завысить
от
правильного выбора технологических
обработок
одежды
-
от
ниточных
соединений, клеевых соединений и в
большем объеме от влажно-тепловой
обработки изделия. EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz
рикат - Р, МРа; количество
й в него влаги - W, %; и время
и - t, сек. Числовые значения -
мые параметрами, определяют
ВТО и зависят от волокнистого
обрабатываемой ткани, вида
емых операций и применяемого
ания для ВТО[8]. нологические
процессы
ения
швейных
изделий
основой
швейного
ства и включают в себя всю
ость операций по обработке и
ию
деталей
и
узлов
в
нной
технологической
ательности [9-10]. нологический
процесс
система взаимодействия средств труда и
предметов
труда,
приводящая
к
получению
готового
изделия. Качественная одежда имеет больший
запас прочности, она не теряет форму
после первых стирок и не вытягивается
при носке, не покрывается моментально
катышками и у нее не топорщиться
молния. Все
это
завысить
от
правильного выбора технологических
обработок
одежды
-
от
ниточных
соединений, клеевых соединений и в
большем объеме от влажно-тепловой
обработки изделия. EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz EURASIAN JOURNAL OF ACADEMIC RESEARCH
Innovative Academy Research Support Center
UIF = 8.1 | SJIF = 5.685
www.in-academy.uz L OF ACADEMIC RESEARCH
emy Research Support Center
www.in-academy.uz
система взаимодействия средств труда и
предметов
труда,
приводящая
к
получению
готового
изделия. Качественная одежда имеет больший
запас прочности, она не теряет форму
после первых стирок и не вытягивается
при носке, не покрывается моментально
катышками и у нее не топорщиться
молния. Все
это
завысить
от
правильного выбора технологических
обработок
одежды
-
от
ниточных
соединений, клеевых соединений и в
большем объеме от влажно-тепловой
обработки изделия. References: In Ruddell, R., Ruddell, M., Singer,
H. (Eds.), Theoretical models and processes of reading Newark: International Reading
Association. (1976). (pp. 497-508). 10. Hamdan, J., & Diab, T.Using L1 in testing reading comprehension in English. Journal of
the Educational Research Centre, Qatar University (1997) 6, 12, 1-19 10. Hamdan, J., & Diab, T.Using L1 in testing reading comprehension in English. Journal of
the Educational Research Centre, Qatar University (1997) 6, 12, 1-19 11. Huang, S. H. Assessing the relationship between referential understanding and academic
reading comprehension among EFL college students. (2005). p276 11. Huang, S. H. Assessing the relationship between referential understanding and academic
reading comprehension among EFL college students. (2005). p276 Volume 2 Issue 11, October 2022 ISSN 2181-2020
Page 575 Volume 2 Issue 11, October 2022 ISSN 2181-2020 ISSN 2181-2020 Page 575
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https://openalex.org/W4386860688
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https://www.researchsquare.com/article/rs-3313718/latest.pdf
|
English
| null |
Transcriptome Analysis Identified Dichogamy Regulation Networks in Alpinia mutica
|
Research Square (Research Square)
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cc-by
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Research Article Keywords: Dichogamy, Sex transition, Flowering plant, Regulation mechanism, RNA-seq
Posted Date: September 19th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-3313718/v1
License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Page 1/23 Abstract In the sexual reproduction of flowering plants, outcrossing has natural advantages in heredity, and is the
reproduction method used by most flowering plants. Dichogamy, accompanied by flower sex transition or
differential maturation, promotes outcrossing and reduces selfing and interference with male and female
functions, impacting the diversity and evolution of flowering plants significantly. However, due to a
chronic lack of available research materials, the regulatory mechanism of dichogamy, an important
reproductive trait that has been of great interest since Darwin's time, remains unknown. Fortunately,
Aplinia mutica, a species of wild ginger that has two sexes within the same population and achieve
dichogamy through sex transition, provides superb research material. In this study, differential expression
gene analysis and group screening were conducted to identify the underlying causes and potential
regulatory networks that may be involved in the flower sex transition and the maturity of two sex organs,
anther, and stigma. Our findings revealed that genes such as MYB-TFs, NAC-TFs, FLA11, KSC6, NADPH,
PP1CG2, and VTC2; plant hormones such as jasmonic acid (JA), auxin, and brassinosteroids (BR);
environmental factors such as light and temperature; and many other factors, such as phosphorylation
and other biological processes, may all affect the sex transition process of A. mutica. the regulation of
sex transition and dichogamy is a complex process. Since the regulatory mechanism of dichogamy has
been an important open question for a long time, our study has made a novel contribution by identifying
and examining its transcriptional regulation in plants at the molecular level. This finding holds immense
importance for further investigations in this area. Introduction Sexual reproduction has been the driving force behind the evolution of angiosperms. Sex expression and
conversion determine the mating mode of sexual reproduction of flowering plants (angiosperms),
determine the inheritance of plant genetic material, play a crucial role in the evolution of angiosperms,
and then influence the evolution and diversity pattern of the entire biological realm (Barrett, 2003;
Campbell & Kessler, 2013). The diversity of the mating system is one of the characteristics of flowering
plants (Barrett, 2002), most angiosperms are bisexual flowers, which express both male and female,
allowing them to engage in both selfing and outcrossing. Outcrossing has become the preferred mode of
reproduction for most angiosperms due to its advantages in genetic diversity and progeny fitness
(Goodwillie et al., 2005), while selfing is mostly considered to play a role in ensuring reproduction under
conditions of limited pollination(Zhou et al., 2012). Therefore, how to promote outcrossing is one of the
core issues in the evolution of flowering plant reproductive system (Lloyd & Webb, 1986; Sargent & Otto,
2004). A direct method is to turn bisexual into unisexual (dioecy)(Renner & Ricklefs, 1995). In addition,
self-incompatibility (SI) can be used to prevent the generation of selfing (Wright et al., 2013), or the
functions of male and female organs (stigma and anther) can be separated in space(heterogamy) and
time(dichogamy) to reduce the probability of self-pollination(Bertin & Newman, 1993; Glover & Barrett,
1986). In hermaphrodite flower plants, the sex transition of flowers is one of the key processes to achieve
dichogamy and this study focuses on this process. Page 2/23 Page 2/23 Surprisingly, there is a group of plants that perfectly combines dichogamy, herkogamy, and dioecy
through sex transition. Flexistyly - reported in Alpinia kwangsiensis of Zingiberaceae in 2001 (Li, 2002; Li
et al,. (Li, 2002; Li et al., 2001). Dichogamy represents the temporal separation of male and female
functions in plant individuals or populations, unlike most dichogamy species, which only have one type:
protandry (PA, male first) or protogyny (PG, female first) (Lloyd & Webb, 1986), A. Kwangsiensis has both
PA and PG phenotypes and is classified as heterodichogamy (Gleeson, 1982; Li et al., 2001), In the early
flowering stage, PG stigma first matures to receive pollen and exercise female function, while PA anther
first matures to release pollen and exercise male function. Introduction After half the flowering period, the PG anther
matures to release pollen, transitioning from female to male, while the PA stigma matures to receive
pollen, transitioning from male to female. This is the dichogamy characteristic caused by the difference
in maturity time between males and females and the sex transition. At the same time, when the flower is
in the female stage, the stigma will bend downward and move towards the pollinating insect's visiting
channel, while in the male stage, the stigma will bend upward and move away from the pollinating
insect's visiting channel. This is the herkogamy feature brought about by the sigma bending motion. In
addition, the proportion of the two phenotypes in the population is 1:1, which conforms to Gregor
Mendel's law. Due to the separation of the male and female stages of the two phenotypes, the population
shows the characteristics of dioecy (Li, 2002; Li et al., 2001). The combination of these reproductive
characteristics greatly promotes outcrossing, minimizing interference between selfing and male and
female function. Surprisingly, there is a group of plants that perfectly combines dichogamy, herkogamy, and dioecy
through sex transition. Flexistyly - reported in Alpinia kwangsiensis of Zingiberaceae in 2001 (Li, 2002; Li
et al,. (Li, 2002; Li et al., 2001). Dichogamy represents the temporal separation of male and female
functions in plant individuals or populations, unlike most dichogamy species, which only have one type:
protandry (PA, male first) or protogyny (PG, female first) (Lloyd & Webb, 1986), A. Kwangsiensis has both
PA and PG phenotypes and is classified as heterodichogamy (Gleeson, 1982; Li et al., 2001), In the early
flowering stage, PG stigma first matures to receive pollen and exercise female function, while PA anther
first matures to release pollen and exercise male function. After half the flowering period, the PG anther
matures to release pollen, transitioning from female to male, while the PA stigma matures to receive
pollen, transitioning from male to female. This is the dichogamy characteristic caused by the difference
in maturity time between males and females and the sex transition. At the same time, when the flower is
in the female stage, the stigma will bend downward and move towards the pollinating insect's visiting
channel, while in the male stage, the stigma will bend upward and move away from the pollinating
insect's visiting channel. This is the herkogamy feature brought about by the sigma bending motion. Introduction In
addition, the proportion of the two phenotypes in the population is 1:1, which conforms to Gregor
Mendel's law. Due to the separation of the male and female stages of the two phenotypes, the population
shows the characteristics of dioecy (Li, 2002; Li et al., 2001). The combination of these reproductive
characteristics greatly promotes outcrossing, minimizing interference between selfing and male and
female function. In addition to its reproductive significance, the greatest value of this unique reproductive strategy lies in
providing good materials for the study of rapid sex transition, sex expression control, floral organ
movement, and the regulatory mechanisms of dichogamy in plants. Dichogamy, as a reproductive
strategy widely existing in flowering plants (Bertin, 1993), is an indispensable part of studying the
diversity of flowering plant reproductive systems. Since the Darwin’s time(Darwin, 1877), researchers have
conducted many explorations into its adaptive significance in ecology and evolution (Bertin & Newman,
1993; Lloyd & Webb, 1986). However, due to the fact that most dichogamy species only have one
phenotype, it is difficult to conduct a detailed comparative analysis, and some species with two-sex
phenotypes are both rare and mostly tall trees, making it difficult to compare and analyze. Therefore,
unlike the reproductive strategies of SI, dioecy, and herkogamy, which have already been analyzed, the
regulatory mechanism of dichogamy remains a mystery more than 100 years later. The sex transition
during flowering, as one of the key processes of dichogamy, also lacks relevant research on its regulatory
mechanism. In addition, many scholars believe that the heterodichogamy with PA and PG phenotypes
may be controlled by a pair of alleles. The PA type is expressed in individuals who are homozygous
recessive (gg), while the PG type is exhibited in individuals who are either heterozygous dominant (Gg) or
homozygous dominant (GG), It may be one of the pathways for the transformation of monoecy into
dioecy(Pannell & Verdu, 2006; Pendleton et al., 2000; Renner, 2001). In summary, A Kwangsiensis and its
relatives, as perennial herbs with flexistyly, provide an excellent opportunity to expand our understanding
of the diversity of sexual reproduction system of flowering plants, including dichogamy, herkogamy, and
dioecy, especially dichogamy and its core regulation of sex transition in the process. Page 3/23 Page 3/23 In this study, due to the difficulty in collecting wild populations of A. kwangsiensis, we selected a closely
related species, A. Introduction mutica, which exhibits a similar gender transition pattern (flexistyly) as the research
material. We present 46 transcriptome datasets pertaining to A. mutica, these datasets encompass a
range of timings, phenotypes, and tissues. Subsequently, comparative analyses and differential gene
screening were performed to identify potential target genes associated with sex transition and maturation
of male and female organ differences during dichogamy. These findings provide important targets and
basic data for future studies of dichogamy and deepen our understanding of the diversity of
angiosperms' mating systems. In this study, due to the difficulty in collecting wild populatio
related species, A. mutica, which exhibits a similar gender t
material. We present 46 transcriptome datasets pertaining t
range of timings, phenotypes, and tissues. Subsequently, co
screening were performed to identify potential target genes
of male and female organ differences during dichogamy. T
basic data for future studies of dichogamy and deepen our
angiosperms' mating systems. Plant Materials Plant Materials The A. mutica used in this study was planted by ourselves in the nursery of Xishuangbanna Tropical
Botanical Garden, Chinese Academy of Sciences (101°25′E, 21°41′N), and was observed and sampled
from July to August 2020.The flexistyly of A. mutica involves the dichogamy of both male and female
sex organs. Therefore, based on the flowering dynamics of A. mutica, we collected anthers and stigmas
of PA type and PG type at 4 time points: 6:00, 9:00, 12:00, and 15:00, respectively, each group of samples
contained 3 biological replicates. All samples were collected and frozen in liquid nitrogen and stored in a
− 80 ℃ ultra-low temperature refrigerator. While collecting molecular samples, we observed and recorded
the dichogamy of A. mutica in detail. RNA-Seq Subsequently, we extracted and performed RNA sequencing 3µg of total RNA per sample was used as input material for the RNA sample preparation. Beads with
oligo (dT) were used to isolate poly(A) mRNA from total RNA. RNA sequencing libraries were constructed
from these mRNA using the TruSeq RNA Sample Preparation Kit (Illumina, San Diego, USA). Briefly, the
Elution 2-Frag-Prime (94°C for 8 minutes, 4°C hold) was used to elute, fragment, and prime the mRNA
with Elute, Prime, Fragment Mix (Illumina). First-strand cDNA synthesis was performed with First Strand
Master Mix and SuperScript II mix (ratio: 1ul SuperScript II/7ul First Strand Master Mix) (Invitrogen). The
second strand was synthesized with Second Strand Master Mix (Illumina) and Ampure XP beads
(Illumina) were used to separate the double-stranded (ds) cDNA from the 2nd strand reaction mix. After
end repair and the addition of a 3’-dA overhang, the cDNA was ligated to Illumina PE adapter oligo mix
(Illumina) and size-selected for 350 ± 20 bp fragments by gel purification. After 15 cycles of PCR
amplification, the 350 bp paired-end libraries were sequenced using the paired-end sequencing module
(150 bp at each end) of the Illumina HiSeq 4000 platform. These raw reads were stored in fastq format, and processed through Trimmomatic (Version 0.32)(Bolger
et al., 2014). This step removed reads containing adapter, reads containing poly-N and low-quality reads
from the raw data and yielded clean data for downstream analyses. Page 4/23 Page 4/23 DEGs Identification in Different Types of Anther and Stigma of A. mutica To investigate the transcriptional network's impact on dichogamy during sex transition, we utilized
transcriptome data from A. mutica across four observation periods (6:00, 9:00, 12:00, and 15:00). Through quantification of gene expression and analysis of differential expression in various groups, we
identified differentially expressed genes (DEGs). These DEGs included genes with differing phenotypes at
the same time and in the same tissue, genes with the same phenotype at the same time but in different
tissues, and genes with the same phenotype but at different times in the same tissues, the grouping is
shown in Fig. 1c, d, and Table. S3. The corresponding trimmed clean reads were aligned to the related reference genome employing
TopHat2(Kim et al., 2013) software with default settings. Calculations of gene expression levels were
conducted using Cufflinks v2.2.1(Trapnell et al., 2014). Subsequently, we extracted and performed RNA sequencing Fragments per kilobase of exon per million
fragments mapped (FPKM) were used to normalize RNA-seq fragment counts and estimate the relative
abundance of each gene. The DEGs were decided based on a P-value < 0.05 and at least a 2-fold change
between the two FPKMs (adj. P-value ≤ 0.05, | log2FC | ≥ 1). Screening of dichogamy regulation target gene sets- DEGs Analysis Next, because dichogamy of A. mutica involves both male and female functional maturation and
transition, we screened DEGs in the anther (male organ) and stigma (female organ) to identify the target
gene set associated with dichogamy in controlling A. mutica, which may result in differences between PA
and PG types. In anthers, we set 9 sets of screening conditions based on anther maturity and intersected the DEGs of
each group (Fig. 2a). Furthermore, in stigmas, we acquired the DEGs of the two phenotypic stigmas at
each time, and then took the intersection of the DEGs of the two phenotypes in different time (Fig. 2b). The genes identified in anther and stigma will be used as possible dichogamy-related target gene sets for
further analysis Screening of the dichogamy regulation target network-WGCNA Analysis Screening of the dichogamy regulation target network-WGCNA Analysis After screening the target gene sets, we intend to determine which DEGs, among many, are most
important in maintaining dichogamy, we conducted WCGNA analysis of the target gene sets of anther
and stigma. Two co-expression networks are created using the WGCNA package (version 1.72-1), which is based on
the R (version 4.2.3) environment. Genes with a maximum FPKM expression lower than 1 were filtered
based on the FPKM expression matrix for all genes, and the FPKM was then converted by log2 (FPKM +
1) for the best soft threshold screening (a.k.a Power value). The clustering modules are separated into
clusters following the computation of hierarchical clustering between genes to choose the most
important modules for various traits (refers to the four types of An, St, PG, and PA). The co-expression
network (Weight ≥ 0.30) of all modules was exported, and the DEGs of the two groups of An and St were Page 5/23 intersected with the total WGCNA expression network, and the final expression network was obtained
after screening according to the weight threshold (0.42). Two network maps were created using the
Cytoscape software (version 3.9.1), and then a regulatory network with DEGs as the core was obtained. Subsequently, we extracted and performed RNA sequencing After the final expression network is generated, we extend a node along the core node gene network for
subsequent analysis. Functional analysis of genes in the core genes network Following the above work, the genes in the anther and stigma networks were subjected to GO enrichment
analysis on tbTools (version 1.120)(Chen et al., 2020), and the corresponding protein sequences were
compared with the protein (Araport11) obtained in the TAIR database (https://www.arabidopsis.org)
using Diamond (version 2.0.14) (http://github.com/bbuchfink/diamond) software, and the possible
functions of the genes in the core network were determined. The regulatory mechanism of dichogamy
and flexistyly of A. mutica was inferred using the results of GO enrichment and the function of core
differential genes, which also includes similar studies that have been reported today. Dichogamy in A. mutica Dichogamy in A. mutica Dichogamy feature in A. mutica, as it is in its sister species A. kwangsiensis, which was the first to report
this unique sex transition (Li et al., 2001). According to earlier studies, we observed the state of
stigma(St) and anther(An) in flowers at 6:00, 9:00, 12:00, and 15:00 based on their blossoming and sex
change processes. (Fig. 1a) Both the PA and PG varieties of A. mutica had flowered by 6:00. The PA
stigma has already curved upward, away from the pollinator's flower-visiting channel, and its anther has
fractured and begun dispersing pollen. The PA is currently in the male stage. The PG stigma, on the other
hand, is located in the floral visiting channel and is bent downward, its anther securely closed and not
dispersing pollen. The PG is currently in the female stage. At 9:00, the sex of the two types remained
constant, with the PA type stigma at its lowest and the PA type pollen disperse at its highest. The PA
stigma began to descend and enter the pollination channel at 12:00. Pollinators had taken a significant
amount of pollen from the type. The PG stigma starts moving upward in the pollination channels, and the
PG anther dehiscence starts dispersing pollen. Individuals of both types are currently undergoing sex
transition. At 15:00, the PA type stigma had reached its lowest point, and pollinators had removed its
pollen. The PG stigma reached its peak, and the PG anther pollen disperse reached its peak. At this point,
both types have completed sex conversion, with PA becoming female and PG becoming male. Screening of dichogamy regulation target gene sets Screening of dichogamy regulation target gene sets By grouping and screening, the dichogamy target gene sets in anther, and stigma was screened out. In
anther, the intersection of 9 groups of screening conditions obtained 67 DGEs as target gene sets
(Fig. 2a), and in stigma, the intersection of two phenotype stigma DEGs at different times obtained 52
DEGs as target gene sets(Fig. 2b) (For more information, check Table.S4). With the help of protein sequence alignment tools Diamond v2.0.14
(http://github.com/bbuchfink/diamond), we used Arabidopsis thaliana genome as a reference for the
sequence alignment (default parameters), and annotated DEGs with A. thaliana genes description to
confirm the potential functions of the corresponding DEGs in A. mutica. Many genes related to pollen
maturation, pollen adhesion, anther maturation, cell elongation, photomorphogenesis, auxin metabolism,
BR response, and JA response were found in 67 target DEGs of anther and 52 target DEGs of stigma. (Table.1). Among them, the number of DEGs related to light signaling/response was the largest. For
example, 5 light morphogenetic genes PSEUDO-RESPONSE REGULATOR5(PRR5, 2 high light stress
response genes Am15.371 (HEAT SHOCK PROTEIN17.4, HSP17.4), Am19.246(HSP17.4) and
Am193.158(NADH dehydrogenase subunit 5-NADPH) were identified (Table. 1). In addition to the genes in
the light signaling pathway mentioned above, most of the other genes are involved in BR pathway, auxin
pathway, and JA pathway. For example, Am5.758 (MYB DOMAIN PROTEIN, MYB108, MYB78, MYB112),
Am14.1921 (ABC transporter G family member 6, ABCG6), Am21.1780 (PHYTOCHELATIN SYNTHASES 1,
PCS1) involved in pollen development, Am24.2135 (NAM, ATAF1,2, and CUC2 046, NAC046) involved in
the regulation of flower senescence. Am22.1248 (BRASSINOSTEROID INSENSITIVE 1, BRI1) and Am2.30
(BRI1 SUPPRESSOR 1, BRS1) involved in the BR pathway, and Am15.1678 (FASCICLIN-LIKE
ARABINOGALACTAN-PROTEIN 1, FLA11) involved in regulating pollen cell adhesion. Among these genes,
there are also a few genes involved in cell wall material synthesis and degradation, which may play a role
downstream of the genes related to cell elongation and stigma movement, such as Am6.468(NAC075),
Am14.1914(PROLINE-RICH EXTENSIN-LIKE RECEPTOR KINASE 13, PERK13) (Table. 1). With the help of protein sequence alignment tools Diamond v2.0.14 (
)
p
y
(
ARABINOGALACTAN-PROTEIN 1, FLA11) involved in regulating pollen cell adhesion. Among these genes,
there are also a few genes involved in cell wall material synthesis and degradation, which may play a role
downstream of the genes related to cell elongation and stigma movement, such as Am6.468(NAC075),
Am14.1914(PROLINE-RICH EXTENSIN-LIKE RECEPTOR KINASE 13, PERK13) (Table. 1). DEGs in different types of anther and stigma of A. mutica DEGs in different types of anther and stigma of A. mutica A large number of DEGs were discovered in comparison groups of different phenotypes, at the same time
and in the same tissue, and the number of DEGs peaked at 9:00 a. m. and then gradually decreased
(Fig. 1c). The number of DEGs was highest in the comparison group of the same phenotype, same time,
and different tissues, but only the number of DEGs in the PG type decreased gradually over time (Fig. 1c). Page 6/23 Page 6/23 The situation of DEGs was more unique in the comparison groups of the same phenotype, different time,
and the same tissue; the number of DEGs gradually increased over time, but the number of DEGs in the
PA type anther with the earliest pollen maturation was greater than that in the PG type (Fig. 1d). The most
obvious difference was that only PG type had the most DEGs (a small number of up-regulated genes and
a large number of down-regulated genes) during 6:00–9:00, which was significantly higher than the
number of DEGs in other groups (Fig. 1d). As a result, we hypothesized that the mechanism of
dimorphism and style bending was caused by the close correlation of these DEGs between PA and PG
types, particularly between 6:00 and 9:00. Screening of dichogamy regulation target gene sets Screening of the dichogamy regulation target network Through WGCNA analysis, we further identified the most important target genes in dichogamy. Page 7/23 Finally, we were able to isolate 15 anther core DEGs (Fig. 3c) and 5 stigma core DEGs (Fig. 3d), the anther
core DEGs are Am15.1678 (FLA11), Am193.158 (NADPH), Am2.30 (BRS1), Am3.157 (CYTOCHROME
P450 FAMILY 710 SUBFAMILY A POLYPEPTIDE 1, CYP710A1), and Am5.758 (MYB108). The core DEGs
for stigma are Am12.2672 (VITAMIN C DEFECTIVE 2, VTC2), Am17.274 (PROTEIN PHOSPHATASE 2C G
GROUP 1, PP2CG1), and Am17.286 (3-KETOACYL-COA SYNTHASE 6, KCS6), respectively. In addition, 10
and 2 uncharacterized genes, found in the stigma and anther, respectively, may be crucial for maintaining
dichogamy and flexistyly. (For more information, check Table. 1). Finally, we were able to isolate 15 anther core DEGs (Fig. 3c) and 5 stigma core DEGs (Fig. 3d), the anther
core DEGs are Am15.1678 (FLA11), Am193.158 (NADPH), Am2.30 (BRS1), Am3.157 (CYTOCHROME
P450 FAMILY 710 SUBFAMILY A POLYPEPTIDE 1, CYP710A1), and Am5.758 (MYB108). The core DEGs
for stigma are Am12.2672 (VITAMIN C DEFECTIVE 2, VTC2), Am17.274 (PROTEIN PHOSPHATASE 2C G
GROUP 1, PP2CG1), and Am17.286 (3-KETOACYL-COA SYNTHASE 6, KCS6), respectively. In addition, 10
and 2 uncharacterized genes, found in the stigma and anther, respectively, may be crucial for maintaining
dichogamy and flexistyly. (For more information, check Table. 1). In terms of expression patterns, 15 core genes in the anther showed opposite expression patterns in the
PA and PG types (Fig. 3a, b). The expression was high in the PG type at 6:00 and 9:00 and decreased at
12:00 and 15:00, while it was low in the PA type at 6:00 and 9:00 and slightly increased at 12:00 and
15:00. Other genes in the co-expression network have expression patterns similar to core genes, but there
are some differences. The majority of PG genes were highly expressed at 6:00, 9:00, and 12:00, but
decreased at 15:00. The PA type expression level peaked at 6:00, then began to fall, reaching its lowest
point at 12:00 and remaining there until 15:00. The expression pattern of core genes in stigma is slightly complex; three genes displayed different
expression trends in PA and PG types, while the other two target genes displayed the same pattern
(Fig. 3b). Screening of dichogamy regulation target gene sets The expression of gene: Am17.286 in both types was highest at 6:00 and lowest at 15:00, but
the maximum expression in PA type was lower than that in PG type, and it was down-regulated at 9:00,
earlier than 12:00 in PG type. The expression of gene: Am17.274 in both types was highest at 9:00 and
lowest at 15:00, but the maximum expression in the PA type was lower than that in the PG type. The
expression of gene: Am7.1051 in both types was opposite, with consistently low expression in the PA type
and a brief increase in the PG type between 9:00 and 12:00 (the high expression in a sample at 15:00 was
thought to be an accidental individual difference). The expression of the remaining 2 genes in both types
was the same, with high expression at 9:00, and then decreased. The expression patterns of other genes
in the co-expression network are different. Most PG type genes are low expressed at 6:00 and high
expressed at 9:00, 12:00, and 15:00, whereas the majority of PA type genes are consistently low
expressed. The differences in the core genes we screened in stigma are most pronounced between 9:00
and 12:00, which corresponds to the critical stage of A. mutica's sextransition. The expression patterns of other genes in the WCGNA network are similar (Fig.S2). In anther, genes other
than the core genes are mostly highly expressed in PG from 6:00 to 12:00, while they remain consistently
low expressed in PA. This trend is similar to core genes, but the downregulation of expression lags
behind. In stigma, genes other than the core genes are mostly highly expressed in PG from 9:00 to 12:00,
while in PA, they remain consistently low in expression. The period during which the movement direction
of stigma is reversed is the most significant difference between the two types. Functional analysis of genes in the core genes network Page 8/23
The results of GO enrichment analysis showed that nearly half of the genes in the pollen pocket's core
network are enriched in terms linked to phosphorylation and cell wall formation (Biological process), and the majority of them have phosphorylase, hydrolase, and transferase activities (Molecular function). It is
worth mentioning that the majority of these genes are engaged in cell wall formation and breakdown. Screening of dichogamy regulation target gene sets The
result of enrichment in the core network of stigma is similar to that of anthers, but what distinguishes it is
that the genes of the core network of stigma, whether BP, MF, or CC, are almost exclusively associated
with terms related to plant response to environmental stimuli, such as phosphorylation and kinase. Based
on the enrichment results, we hypothesize that phosphorylation-related genes may play a significant role
in responding to environmental stimuli (such as illumination, mechanical touch, temperature, and so on)
and regulating the synthesis and degradation of downstream cell wall substances. The genes (including
10 anther and 2 stigma uncharacterized genes) on the other core nodes were not significantly enriched
under the exact GO term, except the Am2.30 (BRS1) gene, which was enriched under the catalytic activity
(GO: 0003824) and transfer activity (GO: 0016740) terms (Fig.S4, Table. S5). This could be attributed to
the fact that most of these genes have unknown functions and have not been thoroughly studied. However, as previously indicated, other node genes radiated by core node genes are enriched for
phosphorylation and cell wall material related phrases. Discussion Our study gathered and analyzed 12 anther and 10 stigma transcripts of A. mutica in different
phenotypes and at different times, which is the first investigation of the gene expression pattern of
dichogamy, an essential plant reproductive feature, to our knowledge. These findings will aid in
identifying and interpreting core genes involved in pollen and anther maturation, pollen release, stigma
maturation, stigma movement, and dichogamy. The maturity and release of plant anther and pollen are essential for male function completion. It is also
a complex process that is influenced by a variety of elements, including external (temperature, humidity,
light, etc.) and internal (gene expression, plant hormones, etc. ). Our research begins with gene expression
in these processes. We identified many of the genes (including MYBs, ARFs NACs, CYP710A1, BRS1,
NADPH, FLA11, KCS6, and others) and their corresponding proteins play significant roles in anther and
pollen development, maturity, cracking, and pollen release. Am5.758 (MYB108) is a basic network node in our WGCNA network. MYB transcription factors play a
crucial role in the development of plants and pollen. In Arabidopsis thaliana, the MYB108 mutant’s
stamen growth, pollen fertility, and anther rupture were severely damaged. MYB108 not only directly
controls anther cracking through AUXIN RESPONSE FACTOR 17 (ARF17), but it is also controlled by
MYB21, which increases anther and pollen maturation. (Mandaokar & Browse, 2009; Xu et al., 2019). Another core gene of interest is Am15.1678(FLA11). FLAs is a glycoprotein with complex multi-domain
structure, which is involved in calcium complexation and signal transduction, affecting plant growth and
development; FLA11 is involved in the development of Secondary cell walls (SCWs) and the response to
mechanical stress; FLA3 directly regulates pollen development (Lamport & Varnai, 2013; Lopez-
Hernandez et al., 2020; Ma et al., 2022; Ma et al., 2023). The regulatory pathway that controls the
initiation and assembly of SCW in plants involves a transcription factor (TF) cascade, with the first Page 9/23 Page 9/23 master TFs being NAC transcription factors, and the MYB TFs being the second master TFs, which
directly regulate SCW synthesis genes or regulate downstream MYBs to regulate the development of
SCW(McCarthy et al., 2009; Nakano et al., 2015). In addition, the expression of these three genes is
regulated by both jasmonic acid (JA) and Auxin, and there is negative regulation between the two
pathways(Cecchetti et al., 2007). Discussion In Arabidopsis thaliana, JA directly controls anther cracking through
MYB21/24, Auxin regulates pollen release by regulating MYB108 through ARF17, excessive ARF can
inhibit anther cracking,(Song et al., 2018), and the expression of OPR3, an enzyme in the JA pathway, is
significantly upregulated in ARF mutant strains, Auxin negatively regulates JA synthesis in plants.. (Cecchetti et al., 2007). From the expression level perspective, in A. mutica, Am5.758 (MYB108) and Am15.1678 (FLA11), 2 core
genes, persistently low expressed in the PA type, initially high expressed in the PG type, and decreased in
expression from 12:00 to 15:00. This is the stage when PG type anther matures and releases pollen. The
expression trend of Am13.332 (ARF6) is consistent with core genes. These 3 genes are all in the Auxin
pathway. The expression trends of the 3 genes of the JA pathway, Am24.2135 (NAC046), Am12.2797 (12-
OXOPHYTODIENOATE REDUCTASE 1, OPR1), and Am14.1921 (JAT3), are opposite to those of the Auxin
pathway. They are initially low expressed in the PG type, upregulated after 12:00, and persistently high
expressed in the PA type (Fig.S1). This expression trend demonstrates the negative regulatory
relationship between the Auxin pathway and the JA pathway, consistent with previous studies(Cecchetti
et al., 2007), At the same time, it also indicates that the accumulation of gene expressions such as MYBs,
FLA11, and ARFs is a necessary condition for stamen maturation. In addition, Auxin has been shown to
affect the sigma movement of A. mutica(Luo et al., 2012). In addition to the Auxin and JA pathways mentioned above, sterol metabolism may also play an
important role in anther maturation. Brassinosteroids(BR) is an important sterol plant hormones, which
play an important role in the development and growth of plants, such as seed germination, rhizome
elongation and growth, photomorphogenesis, vascular bundle differentiation, tropism and reproductive
development(Mandava, 1988). Am2.30(BRS1) is an important gene in the BR signal transduction
pathway, and its phosphorylation activation energy activates the synthesis and signal transduction of BR
(Yang et al., 2011). Am3.157(CYP710A1) is an important gene in sterol metabolism and may also be
involved in BR and synthesis regulation. In A. thaliana, CYP710A1 encodes C-22 desaturase and can
synthesize stigmasterol using β-sitosterol as its precursor. CYP710A2 can act on 24-epi-campesterol and
β-sitosterol, generating BR and stigmasterol, respectively (Morikawa et al., 2006). An appropriate ratio of
β-sitosterol to campesterol may be necessary for normal plant development and sexual
reproduction(Benveniste, 2004; Schaller, 2003). Discussion In addition, light and JA may also be involved in the
regulation of the BR pathway(Martinez et al., 2018; Ren et al., 2009). The expression trend of the above
two genes and other genes(Am22.271(THESEUS1, THE1), Am20.433(THE1), Am12.837(THE1),
Am12.3425(THE1), Am18.1541(DON-GLUCOSYLTRANSFERASE 1, DOGT1), Am1.367(ROTUNDIFOLIA 3,
ROT3), Am12.454(CDG1-like 1, CDL1), Am22.2344(CDL1), Am24.1436(CDL1), Am13.93(PHYB
ACTIVATION TAGGED SUPPRESSOR 1, BAS1), Am15.2024(BRZ-INSENSITIVE-LONG HYPOCOTYLS 4,
BIL4), Am22.1464(BIL4), Am17.583(RAPID ALKALINIZATION FACTOR 23, RALF23), Am6.379(SHAGGY- Page 10/23 LIKE PROTEIN KINASE 32, SK32) of the BR pathway is similar to that of the Auxin pathway genes, and
contrary to the JA pathway genes, the BR pathway and JA pathway show antagonistic effect(Fig.S5),
which is consistent with previous studies(Ren et al., 2009) And stigma, we can't find a strong connection between the core genes identified, but there are still some
findings worth discussing. Am17.286(KCS6), a core gene identified in stigmas, encodes a key protein of
plant synchral long chain fatty acids and is an important part of a pollen coat, which is essential for
stigmas to recognize pollen (Fiebig et al., 2000; Mayfield & Preuss, 2000). This gene, which should be
highly expressed in pollen, is highly expressed in the PG stigma, 6:00–12: 00, the reason may be that the
first time when we collected, the PG stigma has matured and received a large amount of pollen from the
PA anther, thus showing the difference between the two phenotypic stigmas. However, the expression
trend of this gene in anther is consistent with that of several core genes in anther mentioned above - it is
highly expressed when anther is immature and cracking, and its expression is decreased after maturity. It
has also been shown that KCS6 can promote the elongation of cotton fiber cells(Qin et al., 2007), There
may be a link between this function and stigma's movement, but it is not clear now. We have also found
many genes involved in the JA pathway, Auxin pathway, and BR pathway in the WCGNA network of
stigma, indicating that these pathways also play a role in the regulation of stigma movement and
maturation. However, we have not found evidence to link these roles. The core genes we identified also reflect the role of environmental conditions in dichogamy regulation. Am193.158(NADPH) is a gene closely associated with the production of reactive oxygen species (ROS),
and its light response has been reported in several studies (Martin et al., 2004; Quan et al., 2022). Discussion our network also contains
many genes related to calcium ion pathways, ( Am10.991(CALCIUM DEPENDENT PROTEIN KINASE 3,
CPK3), Am15.1822(CPK3), Am13.1768(CPK3), Am14.190(CPK3), Am3.1138(CPK3), Am6.1925(CPK3),
Am6.727(CPK6), Am7.1668(CPK8), Am8.1973(CPK8) ), which are briefly highly expressed in PG and
9:00–12:00, while underexpressed in other samples which are briefly overexpressed in PG from 9:00 to
12:00, while underexpressed in other samples (Fig.S6). This trend of expression shows a difference
between calcium ions prior to the two phenotypes and is likely related to stigma maturation and
downward movement. accurate role in regulating circadian rhythm(Sancar et al., 2009). Our GO enrichment analysis of all genes
in the WCGNA network showed that both in anther and stigma, a lot of GO terms (GO:0015914,
GO:0015748, GO:0006796, GO:0006793, GO:0016310) with high q-value are related to phosphorylation,
indicating that phosphorylation may play an important role in dichogamy regulation (Fig.S4). In addition,
calcium ions play an important role in the bending of plant organs, and previous studies have shown that
calcium ions can influence stigma movement in A. mutica(Luo et al., 2011). our network also contains
many genes related to calcium ion pathways, ( Am10.991(CALCIUM DEPENDENT PROTEIN KINASE 3,
CPK3), Am15.1822(CPK3), Am13.1768(CPK3), Am14.190(CPK3), Am3.1138(CPK3), Am6.1925(CPK3),
Am6.727(CPK6), Am7.1668(CPK8), Am8.1973(CPK8) ), which are briefly highly expressed in PG and
9:00–12:00, while underexpressed in other samples which are briefly overexpressed in PG from 9:00 to
12:00, while underexpressed in other samples (Fig.S6). This trend of expression shows a difference
between calcium ions prior to the two phenotypes and is likely related to stigma maturation and
downward movement. In summary, most of the target genes we identified have been reported to play an important role in plant
sexual maturation, especially male functional maturation, indicating that our identification is reliable. Based on the above results and existing research, we summarized the regulatory network of factors that
may participate in dichogamy regulation (Fig. 4). Dichogamy is a complex character, and its functional
realization includes a series of steps such as the development, display, and maturation of male and
female sexual organs, among which the regulation of each process may affect the regulation of male
and female heterogamy, so it should have a complex regulatory mechanism. Unfortunately, our study
failed to identify a relatively fine regulatory network. Discussion Many of the genes identified in our study have been
shown to play an important role in the maturation and motility of plant sexual functions, but we believe
that they may be downstream regulated genes in dichogamy regulation, and the upstream of which still
needs to be explored (Fig.S3). Among the core genes identified by us, there are still many genes whose
functions are unknown, and their roles in dichogamy regulation are worth further exploration. At the same
time, transcriptome analysis of one species cannot directly reflect the sequence differences of PA and PG
phenotypes and the diversity of their mechanisms, thus further multi-omics analysis including
comparative genomes and validation analysis of expanded populations of more species are needed. Nevertheless, for the first time, our work has conducted targeted research on the molecular regulatory
mechanism of dichogamy and its rapid sex transition, laying an important foundation and providing an
entry point for future related researches. Discussion ROS
plays an important role in the degradation of tapetum and apoptosis of cell walls during anther
maturation, and its high expression in PG anther in the morning is consistent with previous studies. In
addition to the late cracking of PG anther, the whole anther and pollen development of PG anther may lag
behind that of PA type Am12.2672(VTC2) identified in stigma is a core gene in plant ascorbic acid(VC)
synthesis(Anisimova et al., 2021), L-ascorbate is associated with responses to growth (Pignocchi & Foyer,
2003), hormone response, flowering, and senescence(Barth et al., 2006), and various environmental
stresses, as well as ozone, strong ultraviolet radiation, high temperature, and high light intensity(Linster &
Clarke, 2008). The expression of VCT2 is proved to be light-regulated and controlled by circadian rhythm
(Aarabi & Fernie, 2023). Am17.274 (PP2CG1) encodes a putative protein phosphate 2C, whose
phosphorylation can amplify plant temperature sensing signals and enhance plant temperature response
(Lv et al., 2021). Previous studies have shown that light treatment can alter the phenotype of
dichogamy(Bi et al., 2012), Our field observations found that the flowering phenology of Lanxangia tsao-
ko significantly prolongs when experiencing low temperatures, and the maturation of anther and the
movement of stigma are also proportionally delayed (unpublished data). At present, we cannot elucidate
the specific role of environmental factors in the regulation of dichogamy, but our results also indicate that
environmental factors such as light and temperature may be very important Phosphorylation, as an important mode of post-translational covalent modification, is widely involved in
plant growth and development, stress response, and signal transduction processes, and plays an Page 11/23 Page 11/23 accurate role in regulating circadian rhythm(Sancar et al., 2009). Our GO enrichment analysis of all genes
in the WCGNA network showed that both in anther and stigma, a lot of GO terms (GO:0015914,
GO:0015748, GO:0006796, GO:0006793, GO:0016310) with high q-value are related to phosphorylation,
indicating that phosphorylation may play an important role in dichogamy regulation (Fig.S4). In addition,
calcium ions play an important role in the bending of plant organs, and previous studies have shown that
calcium ions can influence stigma movement in A. mutica(Luo et al., 2011). Data Availability All raw data of transcriptomes were deposited in National Center for Biotechnology Information ( NCBI )
under accession number PRJNA1010482. A k
l d Page 12/23 Page 12/23 Page 12/23 We thank the Xishuangbanna Tropical Botanical Garden of the Chinese Academy of Sciences fo
providing us with nurseries for planting samples and helping us in sampling. Funding
This research was supported by Joint Project between Yunnan Provincial Science and Technolo
Department and “Double First-Class” University Project of Yunnan University (grant 2019FY0030
Postgraduate Research and Innovation Foundation of Yunnan University (grant 2021Z021.)
Author information
Huang Ao-Dan and Peng Xiao-Chang contributed equally to this work. Authors and Affiliations
Yunnan Key Laboratory of Plant Reproductive Adaptation and Evolutionary Ecology and Institut
Biodiversity, School of Ecology and Environmental Science, Yunnan University, Kunming, Yunna
China. Huang Ao-Dan, Peng Xiao-Chang, Luo Pei-Wen, Zhao Jian-Li & Li Qing-Jun
Laboratory of Ecology and Evolutionary Biology, State Key Laboratory for Conservation and Util
Bio- Resources in Yunnan, Yunnan University, Kunming, Yunnan 650504, China. Zhao Jian-Li & Li Qing-Jun
Yunnan Research Institute for Local Plateau Agriculture and Industry, Kunming, Yunnan 650201
Duan Sheng-Chang & Dong Yang
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Agric
University, Kunming, Yunnan 650201, China. Duan Sheng-Chang, Xiang Gui-Sheng, Dong Yang & Wang Wei-Bin
Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Xishuangbanna, Yun
666303, China
Jiang Li-Ju
b We thank the Xishuangbanna Tropical Botanical Garden of the Chinese Academy of Sciences for
providing us with nurseries for planting samples and helping us in sampling. References 1. Aarabi, F., & Fernie, A. R. (2023). Elucidating the role of ascorbate in light signaling. Trends in Plant
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Department and “Double First-Class” University Project of Yunnan University (grant 2019FY003001.), the
Postgraduate Research and Innovation Foundation of Yunnan University (grant 2021Z021.) Page 13/23
This research was supported by Joint Project between Yunnan Provincial Science and Technology
Department and “Double First-Class” University Project of Yunnan University (grant 2019FY003001.), the
Postgraduate Research and Innovation Foundation of Yunnan University (grant 2021Z021.)
Author information
Huang Ao-Dan and Peng Xiao-Chang contributed equally to this work. Authors and Affiliations
Yunnan Key Laboratory of Plant Reproductive Adaptation and Evolutionary Ecology and Institute of
Biodiversity, School of Ecology and Environmental Science, Yunnan University, Kunming, Yunnan 650504,
China. Huang Ao-Dan, Peng Xiao-Chang, Luo Pei-Wen, Zhao Jian-Li & Li Qing-Jun
Laboratory of Ecology and Evolutionary Biology, State Key Laboratory for Conservation and Utilization of
Bio- Resources in Yunnan, Yunnan University, Kunming, Yunnan 650504, China. Zhao Jian-Li & Li Qing-Jun
Yunnan Research Institute for Local Plateau Agriculture and Industry, Kunming, Yunnan 650201, China. Duan Sheng-Chang & Dong Yang
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Agricultural
University, Kunming, Yunnan 650201, China. Duan Sheng-Chang, Xiang Gui-Sheng, Dong Yang & Wang Wei-Bin
Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Xishuangbanna, Yunnan
666303, China
Jiang Li-Ju
Contributions
The research was designed, conceived and supervised by W.W.B, P.X.C and H.A.D. W.W.B, H.A.D, P.X.C,
L.P.W, J.L.J and D.S.C collected samples, RNA isolation and DEGs identification. W.W.B, P.X.C, D.S.C, and
X.G.C analyzed subsequent data. The manuscript was drafted by H.A.D and P.X.C. All authors contributed
to the review of the manuscript before submission for publication and approved the final version. Page 13/23
The research was designed, conceived and supervised by W.W.B, P.X.C and H.A.D. W.W.B, H.A.D, P.X.C,
L.P.W, J.L.J and D.S.C collected samples, RNA isolation and DEGs identification. W.W.B, P.X.C, D.S.C, and
X.G.C analyzed subsequent data. The manuscript was drafted by H.A.D and P.X.C. All authors contributed
to the review of the manuscript before submission for publication and approved the final version. Corresponding author Corresponding author Correspondence to Peng Xiao-Chang & Wang Wei-Bin. Correspondence: qfh20m20m@163.com, wangwb@dongyang-lab.org Correspondence: qfh20m20m@163.com, wangwb@dongyang-lab.org
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154-159.https://doi. org/10.1071/bt11265 Table 1 Table. 1.Alignment of the screened target genes with the Arabidopsis database. An = anther, St = stigma,
Am Symbol = Gene numbers for A. mutica annotation, Subject ID = Gene ID of the Arabidopsis database. Page 18/23 Group
Am Symbol
Subject ID
Gene Symbol
Function Description
An
Am18.1514
AT1G04250.1
IAA17, AXR3
auxin signaling, senescence
An
Am17.2675
AT5G25890.1
IAA28, IAR2
auxin signaling, elongation
An
Am8.2205
AT3G08940.2
LHCB4.2
light signaling
An
Am10.2654
AT1G22770.1
FB, GI
light signaling
An
Am13.332
AT1G30330.1
ARF6
auxin signaling, auxin response,
elongation
An
Am8.2249
AT1G64760.1
ZET
morphology twist
An
Am14.1914
AT1G70460.1
PERK13, RHS10
elongation
An
Am12.2797
AT1G76680.1
OPR1, ATOPR1
senescence, JA signaling
An
Am4.468
AT2G30575.1
GAUT5, LGT5
Pollen tube development
An
Am3.157
AT2G34500. 1
CYP710A1
An
Am13.162
AT3G48520.1
CYP94B3
JA signaling
An
Am9.112
AT2G39660.1
BIK1
auxin signaling
An
Am242.186
AT2G45050.1
GATA2
photomorphogenesis
An
Am24.2135
AT3G04060.1
NAC046
senescence
An
Am5.758
AT3G06490.1;
MYB108, BOS1;
pollen development, senescence
AT5G49620.1;
MYB78; MYB112
AT1G48000. 1
An
Am22.1248
AT3G13380.1;
BRL3; DWF2, BRI1,
BR signaling
AT4G39400. 1;
BIN1, CBB2; BIR2
AT3G28450.1
An
Am10.730
AT3G54110.1
UCP1, PUMP1,
UCP
photomorphogenesis, light signaling
An
Am12.1139
AT3G55250.1
PSA3, PDE329
light signaling
An
Am12.1516
AT4G12800. 1
PSAL
light signaling
An
Am2.30
AT4G30610.1
BRS1, SCPL24
BR signaling An
Am14.386
AT4G34280.1
DHU1
light response
An
Am21.1780
AT5G02190.1
PCS1, EMB24,
ASP38
fertility
An
Am5.1356
AT5G02750.1
SGR9
gravity sensing
An
Am15.1678
AT5G03170.1
FLA11
Cell wall, adhesion
An
Am20.1659
AT5G04310.3
PLL12
Cell wall
An
Am12.570
AT5G50800. 1
RPG2, SWEET13
pollen development
An
Am193.158
ATCG01010.1
NDHF, NADPH
light signaling
St
Am16.1283
AT1G06040.1
BBX24, STO
light signaling
St
Am15.140
AT1G15820.1
LHCB6, CP24
light signaling
St
Am18.1550
AT1G29930.1
LHCB1.3, AB140,
CAB140, CAB1
St
Am20.2069
AT1G22770.1
FB, GI
light signaling
St
Am6.1047
AT1G50250.1
FTSH1
light signaling
St
Am17.286
AT1G68530.1
KCS6, G2, CER6,
pollen development, elongation
POP1, CUT1
St
Am17.274
AT2G33700. Table 1 1
PP2CG1
salt tolerance
St
Am6.468
AT4G29230.3
NAC075, SND4
Cell wall
St
Am14.31
AT3G22830.1
HSFA6B
Heat Stress response
St
Am15.371
AT3G46230.1
HSP17.4
heat, cold, salt,
drought and light stress response
St
Am19.246
AT3G46230.1
HSP17.4
heat, cold, salt,
drought and light stress response
St
Am13.207
AT5G52640.1
HSP81.1, HSP83,
disease resistance
HSP90.1
St
Am18.637
AT3G50310.1
AIK1, MAPKKK20,
osmotic stress response, elongation
MKKK20
St
Am10.154
AT4G14690.1
ELIP2
light signaling St
Am20.1942
AT4G30270.1
MERI5B, XTH24,
BR signaling
MERI-5, SEN4
St
Am6.2398
AT5G11260.1
HY5, TED5
ABA signaling, light response
St
Am14.1921
AT5G13580.1
JAT3, ABCG6
JA signaling, pollen development
St
Am144.28
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am17.1520
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am6.1038
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am24.2245
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am11.1564
AT5G24850.1
CRY3
light response
St
Am12.561
AT5G50260.1
CEP1
pollen development
Figures St
Am20.1942
AT4G30270.1
MERI5B, XTH24,
BR signaling
MERI-5, SEN4
St
Am6.2398
AT5G11260.1
HY5, TED5
ABA signaling, light response
St
Am14.1921
AT5G13580.1
JAT3, ABCG6
JA signaling, pollen development
St
Am144.28
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am17.1520
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am6.1038
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am24.2245
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am11.1564
AT5G24850.1
CRY3
light response
St
Am12.561
AT5G50260.1
CEP1
pollen development St
Am20.1942
AT4G30270.1
MERI5B, XTH24,
BR signaling
MERI-5, SEN4
St
Am6.2398
AT5G11260.1
HY5, TED5
ABA signaling, light response
St
Am14.1921
AT5G13580.1
JAT3, ABCG6
JA signaling, pollen development
St
Am144.28
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am17.1520
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am6.1038
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am24.2245
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am11.1564
AT5G24850.1
CRY3
light response
St
Am12.561
AT5G50260.1
CEP1
pollen development
Figures St Page 21/23
St
Am14.1921
AT5G13580.1
JAT3, ABCG6
JA signaling, pollen development
St
Am144.28
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am17.1520
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am6.1038
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am24.2245
AT5G24470.1
PRR5
photomorphogenesis, light signaling
St
Am11.1564
AT5G24850.1
CRY3
light response
St
Am12.561
AT5G50260.1
CEP1
pollen development
Figures
Figure 1
Flexistyly mode, plant photos, and overview of DGEs in A. mutica. (a) Flexistyly mode: shown the
maturation of anther(An) and the location of sigma(St) at different times in different phenotypes. (b) Figure 1 Page 21/23
Flexistyly mode, plant photos, and overview of DGEs in A. mutica. (a) Flexistyly mode: shown the
maturation of anther(An) and the location of sigma(St) at different times in different phenotypes. (b) Page 21/23 Page 21/23 Photo of A. mutica. Table 1 (c) DGEs of different phenotypes or tissues at the same time. (d) DGEs of the same
phenotypes, same tissues at different time. Figure 2 Screening of core gene set in anther and stigma. (a) Rose plot of screening conditions in anther. The
underlined green words represent the sets as non-differentially expressed genes, the black words
represent the sets as differentially expressed genes (b) Venn plot of screening conditions in stigma. Screening of core gene set in anther and stigma. (a) Rose plot of screening conditions in anther. The
underlined green words represent the sets as non-differentially expressed genes, the black words
represent the sets as differentially expressed genes (b) Venn plot of screening conditions in stigma. Figure 3
The target network and the expression trend of core genes in the network. (a) Heat map of core gene
expression trends in anther. (b) Heat map of core gene expression trends in stigma. (c) The WGCNA co-
expression network of core genes in anther. (d) The WGCNA co-expression network of core genes in
stigma. Figure 3 The target network and the expression trend of core genes in the network. (a) Heat map of core gene
expression trends in anther. (b) Heat map of core gene expression trends in stigma. (c) The WGCNA co-
expression network of core genes in anther. (d) The WGCNA co-expression network of core genes in
stigma. Page 22/23 Figure 4
Possible dichogamy regulatory pathways summarized through discussion The solid line with an arrow
represents a promoting relationship, the solid line with a vertical bar represents an antagonistic
relationship, the dotted line represents a potential but unknown regulatory relationship, the sun pattern
represents light, and the thermometer pattern represents temperature. Figure 4 Possible dichogamy regulatory pathways summarized through discussion Possible dichogamy regulatory pathways summarized through discussion The solid line with an arrow
represents a promoting relationship, the solid line with a vertical bar represents an antagonistic
relationship, the dotted line represents a potential but unknown regulatory relationship, the sun pattern
represents light, and the thermometer pattern represents temperature. Possible dichogamy regulatory pathways summarized through discussion The solid line with an arrow
represents a promoting relationship, the solid line with a vertical bar represents an antagonistic
relationship, the dotted line represents a potential but unknown regulatory relationship, the sun pattern
represents light, and the thermometer pattern represents temperature. represents a promoting relationship, the solid line with a vertical bar repres
relationship, the dotted line represents a potential but unknown regulatory
represents light, and the thermometer pattern represents temperature. Page 23/23
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English
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Exposure to 2,4-dichlorophenol, 2,4,6-trichlorophenol, pentachlorophenol and risk of thyroid cancer: a case-control study in China
|
Environmental science and pollution research international
| 2,021
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cc-by
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Exposure to 2,4-dichlorophenol, 2,4,6-trichlorophenol,
pentachlorophenol and risk of thyroid cancer: a case-
control study in China Wan-Jun Yang
Anhui Medical University
Hua-Bing Wu
Anhui Medical University
Chi Zhang
Anhui Medical University
Qi Zhong
Anhui Medical University
Ming-Jun Hu
Anhui Medical University
Jia-Liu He
Anhui Medical University
Guo-Ao Li
Anhui Medical University
Zhen-Yu Zhu
Anhui Medical University
Jin-Liang Zhu
Anhui Medical University
Huan-Huan Zhao
Anhui Medical University
Han-Shuang Zhang
Anhui Medical University
Fen Huang
(
fenh@ahmu.e
Anhui Medical University Ming-Jun Hu
Anhui Medical University Jia-Liu He
Anhui Medical University Guo-Ao Li
Anhui Medical University Zhen-Yu Zhu
Anhui Medical University Jin-Liang Zhu
Anhui Medical University Huan-Huan Zhao
Anhui Medical University Fen Huang
(
fenh@ahmu.edu.cn
)
Anhui Medical University Fen Huang
(
fenh@ahmu.edu.cn
)
Anhui Medical University Fen Huang
(
fenh@ahmu.edu.cn
)
Anhui Medical University License:
This work is licensed under a Creative Commons Attribution 4.0 International
License.
Read
Full License Research Article Page 1/26 License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read
Full License Page 2/26 Abstract Background: Thyroid cancer (TC) has inflicted huge threats to the health of mankind. Chlorophenols (CPs)
were persistent organic pollutant and can lead to adverse effects in human health, especially in thyroid. However, epidemiological studies have revealed a rare and inconsistent relationship between internal
exposure to CPs and TC risk. This study was designed to examine the association between urinary CPs and
risk of TC in Chinese population. Methods: From June 2017 to September 2019, a total of 297 histologically confirmed TC cases were recruited. Age and gender matched controls were enrolled at the same time. Gas chromatography-mass spectrometry
(GC-MS) was used to determine the levels of three CPs in urine. Conditional logistic regression models were
adopted to assess the potential association. Restricted cubic spline function was used to explore the non-liner
association. Results: After adjusting for confounding factors, multivariate analysis showed that, compared with the first
quartile, the fourth quartile concentrations of 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP)
and pentachlorophenol(PCP) were associated with TC risk [odds ratio (OR)2,4-DCP =2.28, 95%confidence
interval (CI): 1.24-4.18; OR2,4,6-TCP =3.09, 95% CI: 1.66-5.77; ORPCP =3.30, 95% CI: 1.71-6.36, respectively]. When
CPs were included in the multivariate model and restricted cubic spline function as continuous variables,
presenting significant dose-response relationships. Meanwhile, whether in the TC group with tumor diameter >
1 cm or metastatic TC, the changes of 2,4,6 TCP and PCP concentrations were positively correlated with the
risk of TC. Conclusions: Our study suggests that higher concentrations of urinary CPs are associated with increased TC
risks. Moreover, 2,4,6-TCP and PCP have certain effects on the invasiveness of thyroid cancer. Targeted public
health policies should be formulated to reduce the CPs pollution. These findings need further in-depth studies
to confirm and relevant mechanism also needed to be clarified. 1. Introduction Pentachlorophenol (PCP) was a common estrogen-like aromatic compound, which has been widely used in
insecticides, fungicides, herbicides, wood preservatives and chemical manufacturing (Cheng et al. 2015; Cui et
al. 2017). EPA estimated that 10063 kg of 2,4-DCP and 4295 kg of PCP were released into the environment in
2014 (ECCC and HC, 2016). Studies have shown that PCP levels in surface water/sediments in China increase
over time (Zheng et al. 2012). The reason is that sodium pentachlorophenol (Na-PCP) has been widely
sprayed since 1960 to control the spread of schistosomiasis, and later in China is higher than in other
countries. The annual production of pentachlorophenol reached about 3,000 tons in 2000 (Tan and Zhang
2008; Zheng et al. 2013). Chlorophenols (CPs), a class of aromatic chlorinated compound whose hydrogen atoms on the benzene ring,
was replaced by chlorine atoms, widely exists in aquatic environment, atmosphere, sediment and soil. CPs
were important raw materials in chemical production and were widely used in industry and agriculture. Among
them, 2,4-dichlorophenol (2,4-DCP) was put into mass production for pesticide production, and 2,4,6-
trichlorophenol (2,4,6-TCP) was mainly used as fungicide and dye intermediate (Zhang et al., 2018). The continuous use of CPs compounds in countries around the world suggests that it may further exacerbate
environmental pollution and pose potential risks to human health. After entering the human body, CPs can
produce a strong interference to the endocrine system, affect the synthesis and metabolism of hormones in
the body, and have a certain negative impact on the immune mechanism of the human body (Orton et al. 2009). Up to now, exposure to chlorophenols has been successively reported to be associated with the
incidence of various malignant tumors, such as gastric cancer, breast cancer, ovarian cancer and colorectal
cancer (Cheng et al. 2015; Dorgan et al. 1999; Sharma et al. 2019). The International Agency for Research on
Cancer and the U.S. Environmental Protection Agency classified PCP as a group 2B carcinogen (IARC 1999). Accumulating evidence suggests associations between CPs exposure and adverse health outcome in thyroid. Animal studies in zebra fish indicate that long-term exposure to PCP can alter thyroid hormone and mRNAs
(tshβ, trβ, dio1, dio2) in thyroid hormone pathway (Guo and Zhou 2013). Kawaguchi et al. 1. Introduction Thyroid cancer, one of the most common endocrine-related tumors originating from follicular or para-follicular
cells, constitutes a serious burden of disease worldwide due to its rapidly growing incidence (Kato and
Niebuhr, 2018). In American, the average annual percent change from 2005 through 2014 is 3.9% in both men
and women (Siegel et al. 2018). According to National Cancer Center of China, the incidence rate of thyroid
cancer in 2015 was 14.6 per 100,000, nearly three times higher than that in 2005, and it has become the fourth
most common malignant tumor among women (Zheng et al. 2019). Although most of thyroid cancer patients
with a favorable 10-year overall survival rate, above 20% of patients remain at risk of tumor recurrence for
several years after operation (Dong et al. 2019). In addition, thyroid cancer may produce numerous serious
clinical symptoms, including hoarseness, trouble breathing and swallowing, and Horner Syndrome caused by
sympathetic nerve compression (Kim et al. 2017). The increasing incidence of thyroid cancer may partly be accounted for advanced diagnostic technology,
which leads to an elevated detection rate of occult thyroid cancer (Warrick and Lengerich 2019). However, Page 3/26 Page 3/26 there is evidence that not only thyroid cancer <1cm but diameters >4cm present an obvious increasing rate
(Wang and Wang 2015). Moreover, some of the traditional risk factors for thyroid cancer still could not explain
this epidemic dynamic situation, including sex, radiation exposure, abnormal iodine intake, a family history of
thyroid disease and metabolic syndrome (Kitahara et al. 2018; Rubio et al. 2018). In view of the severe
situation of TC prevention and control, it is urgent to explore the relevant pathogenic factors of TC (Zhang et
al. 2020). The occurrence of thyroid cancer is the result of interaction between heredity and environment, so
the influence of environmental factors cannot be ignored. Chlorophenols (CPs), a class of aromatic chlorinated compound whose hydrogen atoms on the benzene ring,
was replaced by chlorine atoms, widely exists in aquatic environment, atmosphere, sediment and soil. CPs
were important raw materials in chemical production and were widely used in industry and agriculture. Among
them, 2,4-dichlorophenol (2,4-DCP) was put into mass production for pesticide production, and 2,4,6-
trichlorophenol (2,4,6-TCP) was mainly used as fungicide and dye intermediate (Zhang et al., 2018). 2.1 Study population The study participants were recruited continuously from June 2017 to September 2019 in Hefei, Anhui
Province, China. Cases were defined as patients who having a definite pathological diagnosis of thyroid
cancer, selected from Otolaryngology-Head & Neck surgery departments of First Affiliated Hospital of Anhui
Medical University, Second Affiliated Hospital of Anhui Medical University and Anhui Provincial Cancer
Hospital. Cases who suffered from severe hepatic and renal dysfunction, malignant anemia and mental
disorder were excluded. Given the abnormal thyroid hormone level in pregnancy duration, pregnant women
were also excluded from this study. Meanwhile, appropriate controls were selected from newly admitted
patients collected from non-endocrinology departments of the above three hospitals. In this study, individuals
were paired 1:1 according to gender and age (±5 years old).Controls were restricted to individuals with no
history of malignant tumors or thyroid disease verified by their biochemical test. Subjects who have receive
thyroid-related medication such as euthyrox and adrenocortical hormone were also excluded. Ultimately, a
total of 297 thyroid cancer patients comprised the case group and 297 corresponding controls were selected. This study was approved by Anhui Medical University Biomedical Ethics Committee (Approval No. 20170305)
and was in accordance with the principle of the Helsinki Declaration and its later amendments or comparable
ethical standards. Informed consent was obtained from all individual participants included in the study. Prior
to the research, subjects completed an informed consent form. 1. Introduction found that when
mice were exposed to CPs, the expression of thyroid hormone receptor 1 and brain synaptic protein I was
inhibited, leading to impaired thyroid function (Kawaguchi et al. 2008). In addition, the field epidemiological
survey (Cui et al. 2017) also indicated that the incidence of TC in community residents increased significantly
after exposure to medium and high doses of PCP. However, evidence is rather limited and divided in regard to
the effect of CPs on thyroid cancer. Whether actual exposure to CPs causes thyroid cancer remains unknown. This is the first study to investigate the effects of three chlorophenols on thyroid cancer. In this study, a 1:1
matched case-control study design was used to collect 297 TC case-controls from Anhui Provincial Cancer
Hospital, First Affiliated Hospital of Anhui Medical University, Second Affiliated Hospital of Anhui Medical
University from August 2017 to September 2019, and laboratory tests were conducted to determine the levels Page 4/26 Page 4/26 of three CPS in urine. Conditional logistic regression model and restricted cubic spline function were used to
investigate the potential association between CPS exposure and TC incidence. 2.2 Data collection Structured questionnaires were adopted to record information by trained and qualified investigators, including
socio-demographics, behavior habits, lifestyle, radioactive exposure, and family history of malignant tumor
and thyroid disease. The height (m) and weight (kg) of the participants were measured and the body mass
index (BMI) was calculated based on the formula: weight / the square of height. Clinical and pathologic
information for the cases was obtained by reviewing of medical records, including thyroid cancer subtypes,
primary tumor size, tumor metastasis (lymph node metastasis or distant metastasis), multifocality of tumors
(solitary or multifocal). Peripheral blood samples were obtained from each participant by professional nursing staff after an
overnight fast for at least 8 h. The serum was separated by centrifugal machine and stored in -80°C
refrigerator until further analysis. Serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid
stimulating hormone (TSH) was tested using electrochemiluminescence immunoassay (Cobas e411, Roche
Diagnostics, Germany). All measurements were in accordance with the instructions of experimental
instruments and kits. 2.3 Urinary CPs measurement Page 5/26 Page 5/26 Page 5/26 Considering the photolysis property of CPs, first-morning urine samples were collected by a 50ml centrifuge
tube and keep in a portable specimen box during transport to avoid any contact with direct sunlight. Then
samples were transferred to the laboratory and preserved at -80 °C refrigerator until analysis. Urine value of
CPs concentration was measured by gas chromatography-tandem mass spectrometry (GC/MS, Agilent
7890A, USA) with a HP-5MS column (30m × 0.25mm × 0.25mm, Agilent Co., USA). The procedures for
pretreatment of urine samples are as following: A 10ml urine sample was taken and 2-3 drops of concentrated
hydrochloric acid were absorbed with a glass dropper to adjust PH to acid-stage. All the samples to be tested
were uniformly added with 2,4,6-TBP (5mg/L) internal standard of 200μL and mixed. To prevent
emulsification, sodium chloride is added to the solution until saturated. In the liquid-liquid extraction step, the
n-hexane (Teida, USA) was used. We draw the n-hexane layer into another 50ml centrifuge tube and add 10
mL of n-hexane for extraction again. After that, the extract liquor of n-hexane was fully combined. In the
combined extract, 2ml 0.3 mol/L potassium carbonate solution was added, followed by 1ml acetic anhydride,
Then the mixed solution was placed in a constant temperature water bath at 65 °C for derivative reaction. 2.2 Data collection After derivatization, the sample was dehydrated with anhydrous sodium sulfate, and 1.5ml was taken in the
brown sample injection bottle to be tested. After derivatization, the sample was dehydrated with anhydrous sodium sulfate, and 1.5ml was taken in the
brown sample injection bottle to be tested. Creatinine determination is mainly used to correct the concentration of CPs in urine. Picric acid colorimetric
method was used to determine urine creatinine by Beckman DXC800 automatic biochemical analyzer. Arsenic
- cerium catalytic spectrophotometry was used to detect the level of urinary iodine (WS/T107.1-2016). - cerium catalytic spectrophotometry was used to detect the level of urinary io 2.4 Statistical analysis 2.4 Statistical analysis Statistical analysis was performed using R 3.6.3 and SPSS 23.0 software. Basic characteristics of cases and
controls were compared using two independent sample t-test for normally distributed data or Wilcoxon
signed-rank tests for skewed distribution variables, and chi-square tests were used for categorical variables. To explore the distribution of urinary CPs concentration in cases group based on different clinical pathologic
characteristics, such as tumor subtypes, maximum tumor diameter (≤1cm or ＞1cm), tumor site (unilateral or
bilateral), tumor metastasis (yes or no) and tumor multifocality (solitary or multifocal), CPs were log-
transformed and Mann-Whitney U tests was employed. We adopted conditional logistic regression models to estimate adjusted odds ratios (ORs) and 95%
confidence intervals (CIs) for thyroid cancer and CPs categorized into quartiles according to their
concentration distributions among the control group. Potential confounders were thoroughly taken into
consideration in different regression models, including, BMI (continuous), household income (≤30000CNY,
30001-59999CNY, ≥60000CNY), living conditions (live together, solitary), alcohol consumption (yes or no),
family history of thyroid disease (yes or no), family history of malignant tumor (yes or no), urinary iodine
(continuous). Linear trend p-values were derived by entering the quartiles of creatinine standardized CPs
concentrations into the models as an ordinal categorical variable. Stratified analyses were performed based
on different pathologic characteristics, including tumor subtypes, tumor diameter, tumor site, tumor
metastasis and multifocality. In order to explore the possible nonlinear relationship between CPs and thyroid cancer risk, restricted cubic
spline function model was used. The concentrations of CPs in urine after natural logarithmic conversion were Page 6/26 Page 6/26 Page 6/26 analyzed as continuous variables, entering into the restricted cubic spline function model with 3 knots
(located at the 10th, 50th and 90th percentiles) in each group, respectively. The value of chlorophenols in the
10th percentile was chosen for the reference value. In addition, the models were adjusted for BMI, household
income, living conditions, drinking, family history of thyroid disease, family history of malignant tumor and
urinary iodine. P values were two sided, and P<0.05 was defined as statistical significance. analyzed as continuous variables, entering into the restricted cubic spline function model with 3 knots
(located at the 10th, 50th and 90th percentiles) in each group, respectively. The value of chlorophenols in the
10th percentile was chosen for the reference value. 2.4 Statistical analysis In addition, the models were adjusted for BMI, household
income, living conditions, drinking, family history of thyroid disease, family history of malignant tumor and
urinary iodine. P values were two sided, and P<0.05 was defined as statistical significance. 3. Results 3.1 General demographic information and pathologic characteristics of subjects 3.1 General demographic information and pathologic characteristics of subjects Table 1 presents selected demographic and lifestyle characteristics of cases and controls, as well as clinical
pathologic characteristics. A total of 594 subjects were enrolled with age and sex matched, including 297
cases and 297 controls. Female patients accounted for 68.7% of the total cases of thyroid cancer. Compared
with the control participants, the mean BMI of cases was higher, after grouping BMI, the case group had a
higher proportion of BMI in the 24.0-27.9 group compared with the control group. In terms of family income,
living conditions and alcohol consumption, the differences between the two groups were statistically
significant (P<0.05). Additionally, subjects in cases group were apt to have a family history of thyroid disease
and malignancy than controls. For education level, smoking status, exercise frequency and history of
radiation exposure, no statistical significance was observed. 3.2 The concentration distribution of biochemical indexes in cases and controls 3.2 The concentration distribution of biochemical indexes in cases and controls The concentration distribution of biochemical indexes in case and control groups was presented in Table 2. Without creatinine correction, the median concentrations of 2,4-DCP, 2,4,6-TCP and PCP in the case group were
0.68 μ g / L, 0.36 μ g / L and 0.63 μ g / L, respectively. while those in the control group were 0.50 μ g / L, 0.24
μ g / L and 0.41 μ g / L, respectively. After creatinine correction, the median concentrations of 2,4-DCP, 2,4,6
TCP and PCP in the case group were 0.67 μ g / g, 0.34 μ g / g and 0.62 μ g / g, while those in the control group
were 0.51 μ g / g, 0.26 μ g / g and 0.39 μ g / g, respectively. It is worth noting that subjects with thyroid cancer
had higher levels of both concentration of urinary CPs and creatinine-adjusted CPs than those without thyroid
cancer. The median urinary iodine concentration was 255.76 μ g / L in the case group and 209.08 μ g / L in
the control group. The median urinary iodine concentration after creatinine correction was 297.78 μ g / g and
197.54 μ g / g, respectively. 3.3 The association between Chlorophenols and thyroid cancer 3.3 The association between Chlorophenols and thyroid cancer Results of the association of CPs exposure with the risk of thyroid cancer was presented in table 3. For 2,4-
DCP, compared with participants in the first quartile, the OR for those in the fourth quarter was 2.28 (95% CI:
1.24-4.18) with adjustment for, BMI, household income, living conditions, alcohol consumption, urinary iodine,
family history of thyroid disease and malignant tumor. After adjusting for these confounding factors, the risk
of thyroid cancer was increased by 209% (95% CI: 1.66-5.77) and 230% (95% CI: 1.71-6.36) for trichlorophenol
and pentachlorophenol, respectively. Given that papillary thyroid carcinoma accounted for 92.9% of the total
cases and was the main subtype of thyroid cancer, we performed a subgroup analysis of papillary thyroid
carcinoma patients and the results were shown in Supplementary Table 1. For PCP, the adjusted ORs in third
and fourth quartile were 2.48 (95% CI: 1.22-5.04), and 3.82 (95% CI: 1.83-7.99). Page 7/26 Page 7/26 3.4 Nonlinear association between chlorophenol exposure and thyroid cancer risk In order to clarify the relationship between three CPs and TC risk more comprehensively, the restricted cubic
spline function was used for smoothing curve fitting. The nonlinear correlation between 2,4-DCP, 2,4,6 TCP,
PCP and TC could be displayed by setting spline function nodes, and the restricted cubic spline function
model of the total population was drawn respectively. After the natural logarithmic transformation of the
concentrations of three CPs, the results showed that for 2, 4-DCP and 2,4,6 TCP, the risk of TC incidence
increased with the increase of the concentrations, and showed significant linear correlations. It can be seen
from Fig 1 that at low concentrations, the correlation between PCP and TC increases with the increase of
concentration, and decreases slightly with the further increase of concentration. Some studies have shown
that there was a significant gender difference in TC risk. Therefore, the population was divided into male and
female groups, and the restricted cubic spline models were carried out to find the difference. The associations
of 2, 4-DCP and 2,4,6 TCP with thyroid cancer risk in the male and female subgroups were consistent with the
overall population. In the male group, thyroid cancer increased with increased PCP concentration. 3.3 The association between Chlorophenols and thyroid cancer However, in
the female group, the risk of incidence first decreased with the increase of concentration, but with the further
increase of concentration, the risk of incidence of TC increased significantly (see from supplementary Fig 1). 3.5 The relationship between chlorophenols and the risk of thyroid cancer with different pathological In order to investigate the risk of 2,4-DCP, 2,4,6 TCP, PCP and TC with different tumor diameter, the tumor
diameter of TC was divided into two categories: > 1cm and ≤ 1cm, and the subgroup analysis was performed
by conditional logistic regression model. Table 4 showed a significant correlation between TC and 2,4,6 TCP
(OR = 1.68, 95% CI: 1.10-2.56) in the group with TC diameter > 1 cm, after adjusting for related confounding
factors. Compared with the first fractional concentration, the third and fourth fractional concentration of PCP
was significantly correlated with the incidence of TC with tumor diameter of > 1cm (OR = 2.86, 95% CI: 1.02-
8.00) and (OR = 3.24, 95% CI: 1.20-8.76). As shown in supplementary Fig 2, the restricted cubic spline function
was used for smoothing curve fitting to obtain the relationship between the three types of CPS and TC risk of
different tumor diameters（ > 1cm and ≤ 1cm）. 2,4-DCP at the fourth quartile concentrations increased the incidence of metastatic TC by 306% (OR = 4.06,
95%CI: 1.68-9.81). Meanwhile, 2,4,6 TCP at the third and fourth quantile concentrations were positively
correlated with the incidence of metastatic TC (OR=3.96, 95%CI: 1.53-10.24; OR=7.78, 95%CI: 2.78-21.74). Notably, urinary PCP concentration was statistically associated with the risk of thyroid cancer in both
metastatic and non-metastatic thyroid cancers (see from Table 5).Supplementary Fig 3 shows the relationship
between the three CPS and the metastatic and non-metastatic TC risks by smoothing curve fitting using the
restricted cubic spline function. Based on the location of primary tumor, it was divided into unilateral TC and bilateral TC. Supplementary
Table 2 presented that there were no significant correlations between CPs and the incidence of unilateral and
bilateral TC (P-trend > 0.05). However, in the unilateral TC subgroup, the risk of disease first increased with the
increase of PCP concentration, and then decreased with the increase of PCP concentration; In the bilateral TC Page 8/26 subgroup, the risk of morbidity increased first with the increase of 2,4,6-TCP concentration, and then
decreased with the increase of the concentration (see from supplementary Fig 4). 4. Discussion In recent years, with the development of economy, environmental pollution has become more and more
serious. CPs is an important raw material in chemical production, widely used in pesticides, herbicides and
preservatives, etc. With decades of use, CPs substances have been deposited in large quantities in the
environment and posed a great threat to human health. This study investigated the association between CPs
exposure level and thyroid cancer risk, and found that high urine concentrations of 2,4-DCP, 2,4,6-TCP and PCP
are positively correlated with the incidence of thyroid cancer. After drawing the restricted cubic spline function
and fitting the smooth curve, the results showed that the risk of thyroid cancer increased with the increase of
CPs concentration, showing a certain dose-response relationship. In the thyroid cancer group with tumor
diameter > 1 cm, the changes of 2,4,6 TCP and PCP concentrations were significantly associated with the risk
of thyroid cancer. At the same time, urinary concentrations of 2,4-DCP, 2,4,6 TCP and PCP were positively
correlated with the risk of metastatic thyroid cancer. So far, there are few studies on the correlation between CPs and TC risk at home and abroad. Cui et al. (2017)
found similar conclusions in the field study. Based on the national standard population in 2010, the
standardized rate ratio (SRR) of thyroid cancer in the total population exposed to the moderate PCP group
was 1.49, 95%CI 1.26-1.76. In addition, the SRR of thyroid cancer in women group exposed to the moderate
dose of PCP was 1.79, 95% CI: 1.60-2.01, the SRR of women in the high PCP group was 1.32, 95% CI: 1.17-
1.48. In addition, a cohort study in the United States (Ruder 2011) followed up 2122 PCP producing workers
and found that the expected standard mortality rate of thyroid cancer caused by long-term exposure to PCP
was 0.49. However, Rooney et al. (2018) did not find a significant correlation between 2,4-DCP and thyroid
disease. Similarly, Wei et al. (2016) pointed out that 2,4-DCP had no statistical effect on FT3, FT4 and TSH,
while the homolog of 2,4-DCP, 2,5-DCP, might be associated with thyroid dysfunction to some extent in their
study on CPs exposure and thyroid function in American adolescents. Therefore, the relationship between CPS
and TC is still unclear. 3.3 The association between Chlorophenols and thyroid cancer According to the number of lesions, they were divided into unifocal TC and multifocal TC. Supplementary
Table 3 showed that 2,4,6 TCP was significantly correlated with the incidence of single focal TC (OR=2.70,
95%CI: 1.20-6.05). Only in the fourth quartile of PCP concentration was observed significant association in
multifocal TC group, with OR value of 5.12 (95% CI: 1.56-16.74). In supplementary Fig 5, as PCP concentration
increased, the risk of unifocal TC showed an approximately inverted U-shaped pattern. 4. Discussion This study can fill the gaps in the research on the relationship between CPs and TC to a
certain extent, but the relevant conclusions still need to be verified in large-scale cohort studies and
experimental studies. The relationship between human exposure to CPS and increased TC risk remains unclear. A number of
experimental studies have shown that estrogen plays a key role in the pathogenesis of TC (Rubio et al. 2018;
Xue et al. 2019). Yu et al. (2014) founded that PCP showed an antagonistic effect against thyroid hormone
receptor at a concentration of 10-5 M, while 2,4,6-TCP showed an anti-estrogen effect. Yin et al. (2008) used
denaturing high performance liquid chromatography and DNA sequencing analysis methods to prove that Page 9/26 Page 9/26 Page 9/26 zebrafish exposed to 2,4,6-TCP at a rate of 5mg / L for 10 days would lead to the increase of point mutation
of p53 gene in liver genome, thus participating in the carcinogenesis process of organism by inducing point
mutation of somatic genome. Normal thyroid development depends on a balanced hormonal environment. CPS have similar molecular structure to estradiol, endowing it with the ability to bind estrogen receptor α or β,
thus exerting thyroid interference effect and destroying the normal level of estrogen, eventually leading to the
occurrence of TC. In fact, another widely accepted mechanism for causing TC is the HPT axis injury theory. The experiments on
zebrafish (Yu et al. 2014) show that PCP exposure can reduce the expression of T4 receptor mRNA in the
brain, and change the mRNA levels of deiodinase, cytoplasmic sulfur transferase and thyroxine gene in the
liver. Long term exposure to PCP will change the plasma T4 level and change the gene expression related to
thyroid hormone signal and metabolism in HPT axis, resulting in abnormal development of zebrafish. Guo et
al. (2013) verified the interfering effect of CPs on thyroid gland in vivo and in vitro experiments. The results of
in vitro experiments showed that when the rat pituitary GH3 cells were exposed to PCP at a concentration of
1.0M, they could significantly down-regulate the basal transcription and T3-induced Dio1 transcription,
indicating that PCP has antagonistic activity in vitro. In vivo experiments, PCP exposure resulted in decreased
T4 level and increased T3 level in zebrafish. 4. Discussion Meanwhile, PCP exposure significantly upregulated the mRNA
expression of genes on the HPT axis, including thyroid stimulating hormone, sodium/iodide synthase,
thyroglobulin, Dio1 and Dio2, thyroid hormone receptors, and uridine diphosphate glucuronic acid transferase. The exercise of normal thyroid function not only depends on the appropriate level of thyroid hormone, but also
requires the body to be in a normal immune state. Studies have shown that the immune system plays a
decisive role in carcinogenesis. In an animal experiment in India, white blood cells were used for cell apoptosis
and mitochondrial membrane potential analysis, and propidium iodide staining and rhodamine 123 staining
were used. The influence of DCP on cell cycle and mitochondrial membrane permeability was analyzed by
flow cytometry. The results showed that DCP reduced mitochondrial membrane potential, changed cell cycle,
and confirmed that DNA damage caused apoptosis of immune system cells (Lone et al. 2017). Nnodu et al. (2008) pointed out that CPs can reduce ATP level in the body, thereby reducing the tumor killing function of
natural killer cells and promoting the occurrence of tumors. However, relevant studies also drew different
conclusions. The results in the experiment of rats (Blakley et al. 1998) indicated that when studying the
effects of PCP on the immune function of rats, the evidence of PCP induced humoral immune injury was not
obvious, and the lymphocyte budding effect observed after PCP exposure was not related to phagocytosis or
the expression of lymphocyte surface antigen. In recent years, the relationship between thyroid disease and oxidative stress has attracted more and more
attention. Studies have shown that EEDs can destroy cellular biological energy, reduce the production of ATP,
and inhibit the complex activity of mitochondria and aerobic respiration (Al-Ghafari et al. 2019). At the same
time, the cellular redox defense system is progressively depleted by reducing sod and catalase activity and
intracellular glutathione levels. Some environmental pollutants with redox properties, such as CPs herbicides
and some aromatic compounds, can increase the content of reactive oxygen species in the body. These
environmental pollutants can catalyze the redox reaction in organism, and cause oxidative damage to
organisms. Animal experiments (Zhang et al. 2014) showed that 2,4,6-TCP can induce oxidative stress,
endoplasmic reticulum stress and cell apoptosis in vitro, which together lead to the generation of cytotoxicity Page 10/26 Page 10/26 and promote the occurrence of malignant tumors. 4. Discussion Due to the structure similar to natural hormones, CPs can
mimic the formation of hormones in vivo, interfere with the synthesis and metabolism of hormones, and then
interfere with some signal pathways and related enzyme reactions of oxidative stress response, causing
serious oxidative damage to cells. In view of the close relationship between CPs and TC, oxidative stress
should be further studied as an endogenous factor leading to increased thyroid hyperplasia. This study found that in the group with thyroid cancer diameter > 1 cm, increased concentrations of 2,4,6 TCP
and PCP were significantly associated with the risk of thyroid cancer. Urinary concentrations of 2,4-DCP, 2,4,6
TCP and PCP were positively correlated with the risk of metastatic thyroid cancer, suggesting that the high
exposure level of CPs may be related to the progression of thyroid cancer. The relationship between CPS and
the progression of thyroid cancer is not clear, but bisphenol A and polybrominated diphenyl ethers with similar
structure and endocrine disrupting effect with PCP have been confirmed to be related to the proliferation,
migration and invasion of tumor cells (Allen et al. 2016). The experimental results (Zhang et al. 2017) showed
that such endocrine disruptors could target intracellular signals involved in the development of thyroid cancer
and promote the proliferation of thyroid cells. Low dose exposure can not only produce estradiol like effect by
binding estrogen receptor α and β, but also activate AKT/mTOR pathway by binding estrogen receptor
membrane receptor, and finally affect the expression of related genes, promote the proliferation of thyroid
cancer cell BHP10-3, and enhance the invasion of thyroid adenocarcinoma. Our study has several strengths. To the best of our knowledge, this study was the first study to systematically
research the association between the exposure levels of CPs with thyroid cancer risk. As we all know, since
1960, the Na-PCP had been extensively sprayed to control the spread of snail borne schistosomiasis in China,
thus paid a heavy price for environmental pollution and become the most concerned environment problem. For the present research, we focused on the effects of non-occupational exposure to PCP and its homologues
in individual urinary sample on TC risk in Chinese population. This could provide little but valuable suggestion
for public health department in China. Availability of data and materials The datasets analyzed during the current study are available from the corresponding author on reasonable
request. 4. Discussion Then, we collected detailed information on potential confounding
factors, which were used to conduct detailed analysis in different adjusting models, and restricted cubic spline
function were used to explore the non-liner relationship. In addition, we adopted strict quality control
procedures in data collection and accurate internal standard method was added into laboratory detection to
reduce the potential of bias. Last but not least, we analyzed the relationship between the exposure levels of
CPs and the incidence of thyroid cancer with different pathological types, in order to explore the effect of CPs
on the progression of thyroid cancer. Several limitations need to be noticed. Firstly, the primary potential limitation to our study is the use of single
spot urinary PCP measurements. Although PCP has a long biological half-life and persistence characteristic,
the multiple spot urine samples may be a better reflection of long-term exposure due to the metabolism and
excretion of PCP in human body. However, this chemical of PCP was detected above 85% of samples in our
study, suggesting that PCP is continuous and ubiquitous. In addition, it has been proved that single spot
sample may be a reliable predictor for long-term exposure of PCP (Wang et al. 2016). Secondly, this study
failed to measure estrogen as a biomarker, so it was limited in the validation of the correlation between
estrogen, CPS and TC. Thirdly, most of the TC patients included in this study were PTC, and due to the
insufficient sample size of other subtypes, detailed analysis of subtypes becomes unrealistic, which also
makes the analysis not comprehensive enough. In addition, although a sequence of likely confounding Page 11/26 Page 11/26 factors was taken into consideration in conditional regression analysis, such as BMI, household income level,
living conditions, alcohol consumption, family history of thyroid disease, family history of malignant tumor
and urinary iodine, FT3, FT4 and TSH, some potential confounding variables were still out of consideration. For example, it has been demonstrated that exposure to radiation in childhood could be a vital carcinogenic
factor (Lubin et al. 2017). However, due to the long interval, the subjects could not accurately recall the
relevant information, which needed to be improved in the follow-up study. Finally, because of the nature of a
retrospective research, the ability of causal inference was limited and future prospective studies are warranted
to conclude a causal relationship. 5. Conclusion In summary, urinary concentrations of 2,4-DCP, 2,4,6-TCP and PCP were positively correlated with TC and
presented dose-response relationship. This study also found that 2,4,6-TCP and PCP had certain effects on
the invasiveness of thyroid tumor. Further studies are needed to confirm our findings, and to evaluate potential
mechanisms that might be responsible for the association between CPs exposure and TC risks. In addition,
the health department should be vigilant, not only to pay attention to the sharp rise of TC, but also to prevent
the environmental pollution of CPs. The government should formulate relevant policies as soon as possible
and do a good job in prevention and control. Ethics approval and consent to participate This study was approved by the Ethical Committee of Anhui Medical University, China. All participants signed
a written informed consent form prior to participating. Conflicts of interest The authors declares that there are no conflicts of interest. Funding Author’s contributions WJY and FH collaboratively designed the study, both making substantial intellectual contributions. WJY
analyzed the data and drafted the manuscript together with HBW, and CZ，QZ and FH revised the manuscript. MJH, GAL and ZYZ all contributed in interpreting the data. JLZ, HHZ ,HSZ and WJY all contributed in
collecting the data. WJY and HBW contributed equally. All authors read and approved the final manuscript. Funding Page 12/26 Page 12/26 Page 12/26 This work was supported by Academic Aid Project for Top Talents (Professionals) in Colleges and Universities
of Anhui Province (gxbjZD09), the Project for Anhui Province Academic Technology Leader Reserve
Candidates’ Academic Research Activities (2017H108), and the National Key Research and Development
Program (NO. 2016YFC1302605). Acknowledgements We would like to thank all the subjects who participated in this research. This work was supported by
Academic Aid Project for Top Talents (Professionals) in Colleges and Universities of Anhui Province
(gxbjZD09), the Project for Anhui Province Academic Technology Leader Reserve Candidates’ Academic
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term Exposure to Pentachlorophenol Causing Risk of Cancer - A Community Study. Asian. Pac. J. Cancer. Prev. 14(2), 811-816. https://doi.org/10.7314/apjcp.2013.14.2.811. Zheng W, Yu H, Wang X, Qu W (2012) Systematic review of pentachlorophenol occurrence in the environment
and in humans in China: not a negligible health risk due to the re-emergence of schistosomiasis. Environ Int. 42, 105-16. https://doi.org/10.1016/j.envint.2011.04.014. Zheng W, Yu H, Wang X, Qu W (2012) Systematic review of pentachlorophenol occurrence in the environment
and in humans in China: not a negligible health risk due to the re-emergence of schistosomiasis. Environ Int. 42, 105-16. https://doi.org/10.1016/j.envint.2011.04.014. Supplementary Material Page 16/26
Fig. A.1. Association between 2,4-DCP, 2,4,6-TCP, PCP and the risk of thyroid cancer in male and female
subgroups. The dose-response relationship between the concentrations of three chlorophenols after natural
logarithmic conversion and the risk of thyroid cancer in different subgroups was investigated by using
restricted cubic spline regression analysis. In the restricted cubic spline functions, three nodes were used,
which were the 10th, 50th and 90th percentiles of each urine chlorophenol concentration. The odds ratios
(solid red lines) and 95% confidence intervals (shaded areas) were estimated using the 10th percentile of the
natural logarithmic transformation for each concentration as a reference. The horizontal dotted line indicates
that each reference value of odds ratio is 1.0. The bars represented histograms of urinary chlorophenols Page 16/26 distribution among male and female participants. The model corrected for urinary iodine (continuous
variable), BMI (continuous variable), household income (categorical variable), living conditions (categorical
variable), drinking (categorical variable), family history of thyroid disease (categorical variable), and family
history of malignancy (categorical variable). distribution among male and female participants. The model corrected for urinary iodine (continuous
variable), BMI (continuous variable), household income (categorical variable), living conditions (categorical
variable), drinking (categorical variable), family history of thyroid disease (categorical variable), and family
history of malignancy (categorical variable). Similarly, the same restricted cubic spline regression analysis was used to obtain the dose-response
relationship between the natural logarithmic conversion concentrations of three chlorophenols and the risk of
different types of thyroid cancer (see from Fig. A.2.~ Fig. A.5.) Similarly, the same restricted cubic spline regression analysis was used to obtain the dose-response
relationship between the natural logarithmic conversion concentrations of three chlorophenols and the risk of
different types of thyroid cancer (see from Fig. A.2.~ Fig. A.5.) Fig. A.2. Association between three chlorophenols and the risk of thyroid cancer with different diameters. Fig. A.3. Association between three chlorophenols and the risk of thyroid cancer with different metastatic
characteristics. Fig. A.4. Association between three chlorophenols and the risk of unilateral and bilateral thyroid cancer. Fig. A.5. Association between three chlorophenols and the risk of unifocal and multifocal thyroid cancer. Tables Table 3 The association between urinary chlorophenols exposure and thyroid cancer risk * 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Free
Triiodothyronine (FT3), Free Thyroxine (FT4), Thyroid Stimulating Hormone (TSH) Figure 1 Adjusted restricted cubic splines for the relationship between ln-transformed creatinine adjusted urinary
chlorophenols and the risk of thyroid cancer. Association between the three chlorophenols and the risk of
thyroid cancer. In the restricted cubic spline analysis, three nodes were used, which were the 10th, 50th and
90th percentiles of each urine chlorophenol concentration. The odds ratios (solid red lines) and 95%
confidence intervals (shaded areas) were estimated using the 10th percentile of the natural logarithmic
transformation for each concentration as a reference. The horizontal dotted line indicates that each reference
value of odds ratio is 1.0. The bars represented histograms of urinary chlorophenols distribution among
included participants. The model corrected for urinary iodine (continuous variable), BMI (continuous variable),
household income (categorical variable), living conditions (categorical variable), drinking (categorical
variable), family history of thyroid disease (categorical variable), and family history of malignancy Figures Figure 1
Adjusted restricted cubic splines for the relationship between ln-transformed creatinine adjusted urinary
chlorophenols and the risk of thyroid cancer. Association between the three chlorophenols and the risk of
thyroid cancer. In the restricted cubic spline analysis, three nodes were used, which were the 10th, 50th and
90th percentiles of each urine chlorophenol concentration. The odds ratios (solid red lines) and 95%
confidence intervals (shaded areas) were estimated using the 10th percentile of the natural logarithmic
transformation for each concentration as a reference. The horizontal dotted line indicates that each reference
value of odds ratio is 1.0. The bars represented histograms of urinary chlorophenols distribution among
included participants. The model corrected for urinary iodine (continuous variable), BMI (continuous variable),
household income (categorical variable), living conditions (categorical variable), drinking (categorical
variable), family history of thyroid disease (categorical variable), and family history of malignancy
(categorical variable). (A) The restricted cubic spline for the association between ln-transformed urinary 2,4-
DCP and the risk of thyroid cancer. (B) The restricted cubic spline for the association between ln-transformed
urinary 2,4,6-TCP and the risk of thyroid cancer. (C) The restricted cubic spline for the association between ln-
transformed urinary PCP and the risk of thyroid cancer. Tables Table 1 Baseline characteristics and pathologic characteristics of study population Page 17/26 Page 17/26 Page 17/26 Page 17/26 Case
(N=297)
Control
(N=297)
P
Male Sex, n (%)
93(31.3)
93(31.3)
-
Age, years ± SD
46.2 ± 12.5
47.0 ± 13.2
0.452
BMI, kg/m2 ± SD
24.3 ± 3.10
23.4 ± 3.40
<0.001
BMI, kg/m2, n (%)
0.010
<18.5
6(2.0)
15(5.1)
18.5-
138(46.5)
165(55.6)
24.0-
120(40.4)
88(29.6)
>28.0
33(11.1)
29(9.8)
Education level
0.129
Junior middle school or less
174(58.6)
192(64.6)
High school or above
123(41.4)
105(35.4)
Household income, yuan/year
0.020
£30000
43(14.5)
69(23.2)
30001~
118(39.7)
112(37.7)
³60000
136(45.8)
116(39.1)
Living conditions
0.004
Live together
273(91.9)
250(84.2)
Solitary
24(9.1)
47(15.8)
Smoking status
0.099
Yes
49(16.5)
35(11.8)
No
248(83.5)
262(88.2)
Alcohol drinking
<0.001
Yes
72(24.2)
37(12.5)
No
225(75.8)
260(87.5)
Exercise, times / week
0.318
<1
196(66.0)
203(68.4)
1
53(17 8)
40(13 5) History of radiation exposure 0.165 History of radiation exposure
0.165
Yes
225(75.8)
210(70.7)
No
72(24.2)
87(29.3)
Family history of thyroid diseases
<0.001
Yes
43(14.5)
11(3.7)
No
254(85.5)
286(96.3)
Family history of malignant tumor
0.005
Yes
70(23.6)
43(14.5)
No
227(76.4)
254(85.5)
Pathology
Papillary
276(92.9)
-
follicular
7(2.4)
-
Medullary
8(2.7)
-
Poorly differentiated
6(2.0)
-
Tumor Diameter, cm
≤1.0
111(37.4)
-
>1.0
170(57.2)
-
Not available
16(5.4)
-
Unilateral or bilateral
Unilateral
188(63.3)
-
Bilateral
89(30.0)
-
Not available
20(6.7)
-
Unifocal or multifocal
Unifocal
168(56.6)
-
Multifocal
104(35.0)
-
Not available
25(8.4)
-
Metastasis
Yes
143(48.1)
-
No
147(49.5)
-
Not available
7(2.4)
- Table 2 Concentrations of chlorophenols and biochemical indexes in thyroid cancer and control groups
Object
Detections
Unit
Case(n=297)
Control(n=297)
P-
value
Median
25th–75th
Percentile
Median
25th–75th
Percentile
2,4-DCP *
μg/L
0.68
0.35-1.17
0.50
0.24-0.92
0.001
2,4,6-TCP
μg/L
0.36
0.17-0.59
0.24
0.12-0.52
0.001
PCP
μg/L
0.63
0.31-1.21
0.41
0.13-0.81
<0.001
2,4-DCP a
μg/g
0.67
0.33-1.52
0.51
0.21-1.10
0.001
2,4,6-TCP a
μg/g
0.34
0.34-0.69
0.26
0.13-0.51
0.001
PCP a
μg/g
0.62
0.62-1.28
0.39
0.17-0.95
<0.001
Iodine
μg/L
255.76
203.08-494.39
209.08
135.18-303.90
<0.001
Iodine a
μg/g
297.78
176.80-524.44
197.54
137.87-301.06
<0.001
Creatinine
g/L
1.01
0.57-1.54
1.04
0.68-1.48
0.512
FT3
pmol/L
4.68
4.32-4.94
4.68
4.28-5.20
0.454
FT4
pmol/L
16.25
14.70-16.88
16.24
14.56-17.89
0.286
TSH
uIU/mL
2.88
1.78-3.46
2.65
1.66-3.62
0.311
* 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Free
Triiodothyronine (FT3), Free Thyroxine (FT4), Thyroid Stimulating Hormone (TSH) * 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Free
Triiodothyronine (FT3), Free Thyroxine (FT4), Thyroid Stimulating Hormone (TSH) a: Urinary concentration of chlorophenols and iodine had been corrected by creatinine a: Urinary concentration of chlorophenols and iodine had been corrected by creatinine Table 3 The association between urinary chlorophenols exposure and thyroid cancer risk Page 20/26 Chlorophenols
Case
Control
Unadjusted OR (95% CI)
P-
trend
Adjusted OR
(95% CI) a
P-trend
2,4-DCP *
<0.21
46
74
1
0.013
1
0.060
0.21-
73
74
1.70(0.98-2.99)
1.80(0.94-3.44)
0.51-
80
74
1.85(1.11-3.08)
1.82(1.02-3.24)
≥1.11
98
75
2.42(1.42-4.14)
2.28(1.24-4.18)
Continuous b
297
297
1.32(1.08-1.60)
0.006
1.27(1.04-1.56)
0.021
2,4,6-TCP
<0.13
40
74
1
0.001
1
0.001
0.13-
65
74
1.62(0.98-2.65)
1.40(0.78-2.50)
0.26-
88
74
2.16(1.32-3.54)
2.52(1.39-4.54)
≥0.51
104
75
2.85(1.68-4.84)
3.09(1.66-5.77)
Continuous b
297
297
1.40(1.06-1.84)
0.016
1.52(1.12-2.08)
0.008
PCP
<0.18
38
74
1
<0.001
1
0.001
0.18-
60
74
1.82(1.05-3.18)
1.36(0.72-2.59)
0.40-
88
74
2.72(1.57-4.69)
2.46(1.30-4.64)
≥0.95
111
75
3.80(2.14-6.78)
3.30(1.71-6.36)
Continuous b
297
297
1.20(1.02-1.40)
0.025
1.24(1.06-1.46)
0.008
2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
nfidence interval (CI)
Adjusted for BMI household income level living conditions alcohol consumption family history of thyroid * 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
confidence interval (CI) * 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
confidence interval (CI) a: Adjusted for BMI, household income level, living conditions, alcohol consumption, family history of thyroid
disease, family history of malignant tumor and urinary iodine b: Odds ratio calculated for each 1 ug/g Table 4 The relationship between three chlorophenols and the risk of thyroid cancer with different diameters Page 21/26 Page 21/26 Chlorophenols
Microcarcinomas (Tumor Diameter ≤ 1
cm)
Larger Tumor Size (Tumor Diameter > 1
cm)
Case
Control
OR
a
95%CI
a
P-
value
Case
Control
OR
a
95%CI
a
P-
value
2,4-DCP *
<0.21
14
25
1
0.336
31
45
1
0.702
0.21-
32
29
2.40
(0.86-
6.60)
36
39
1.36
(0.52-
3.58)
0.51-
36
29
2.19
(0.86-
5.57)
35
42
1.48
(0.62-
3.50)
≥1.11
29
28
1.88
(0.71-
5.00)
68
43
1.70
(0.66-
4.30)
Continuous b
111
111
1.26
(0.82-
1.95)
0.283
170
170
1.24
(0.92-
1.66)
0.148
2,4,6-TCP
<0.13
18
29
1
0.422
21
42
1
0.030
0.13-
29
31
1.24
(0.50-
3.02)
31
39
0.99
(0.42-
2.32)
0.26-
33
28
1.55
(0.60-
3.98)
50
41
2.74
(1.16-
6.52)
≥0.51
31
23
2.16
(0.82-
5.74)
58
48
2.58
(1.01-
6.60)
Continuous b
111
111
1.82
(0.92-
3.60)
0.084
170
170
1.68
(1.10-
2.56)
0.016
PCP
<0.18
18
31
1
0.344
19
40
1
0.079
0.18-
31
24
1.78
(0.65-
4.87)
28
44
1.62
(0.58-
4.44)
0.40-
29
32
1.98
(0.78-
5.00)
49
36
2.86
(1.02-
8.00)
≥0.95
33
24
2.51
(0.90-
6.95)
74
50
3.24
(1.20-
8.76)
Continuous b
111
111
1.18
(0.86-
1.62)
0.294
170
170
1.24
(1.02-
1.52)
0.034
* 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
confidence interval (CI) * 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
confidence interval (CI) Page 22/26 a: Adjusted for BMI, household income level, living conditions, alcohol consumption, family history of thyroid
disease, family history of malignant tumor and urinary iodine b: Odds ratio calculated for each 1 ug/g Table 5 The association between three chlorophenols and the risk of thyroid cancer with different metastatic
characteristics Page 23/26 Chlorophenols
Non-metastatic Thyroid Carcinoma
Metastatic Thyroid Carcinoma
Case
Control
OR
a
95%CI
a
P-
value
Case
Control
OR
a
95%CI
a
P-
value
2,4-DCP *
<0.21
28
34
1
0.276
18
38
1
0.009
0.21-
46
43
1.46
(0.61-
3.49)
27
28
1.40
(0.50-
3.95)
0.51-
48
35
1.92
(0.85-
4.31)
32
38
1.42
(0.58-
3.52)
≥1.11
25
35
0.95
(0.35-
2.56)
66
39
4.06
(1.68-
9.81)
Continuous b
147
147
1.03
(0.74-
1.44)
0.864
143
143
1.80
(1.25-
2.60)
0.002
2,4,6-TCP
<0.13
25
30
1
0.310
14
41
1
0.001
0.13-
39
42
0.92
(0.41-
2.08)
23
32
2.12
(0.84-
5.38)
0.26-
46
44
1.46
(0.64-
3.34)
39
30
3.96
(1.53-
10.24)
≥0.51
37
31
1.89
(0.78-
4.62)
67
40
7.78
(2.78-
21.74)
Continuous b
147
147
1.55
(0.87-
2.76)
0.137
143
143
1.87
(1.24-
2.84)
0.003
PCP
<0.18
14
31
1
0.035
22
41
1
0.001
0.18-
33
35
2.26
(0.82-
6.22)
24
39
0.80
(0.30-
2.12)
0.40-
53
46
2.98
(1.12-
7.87)
33
25
3.15
(1.18-
8.40)
≥0.95
47
35
5.11
(1.67-
15.60)
64
38
4.27
(1.68-
10.86)
Continuous b
147
147
1.37
(0.98-
1.91)
0.060
143
143
1.26
(1.04-
1.53)
0.019
* 2,4-Dichlorophenol (2,4-DCP), 2,4,6-Trichlorophenol (2,4,6-TCP), Pentachlorophenol (PCP), Odds ratio (OR),
confidence interval (CI) a: Adjusted for BMI, household income level, living conditions, alcohol consumption, family history of thyroid
disease, family history of malignant tumor and urinary iodine b: Odds ratio calculated for each 1 ug/g b: Odds ratio calculated for each 1 ug/g b: Odds ratio calculated for each 1 ug/g Figure 1 Adjusted restricted cubic splines for the relationship between ln-transformed creatinine adjusted urinary
chlorophenols and the risk of thyroid cancer. Association between the three chlorophenols and the risk of
thyroid cancer. In the restricted cubic spline analysis, three nodes were used, which were the 10th, 50th and
90th percentiles of each urine chlorophenol concentration. The odds ratios (solid red lines) and 95%
confidence intervals (shaded areas) were estimated using the 10th percentile of the natural logarithmic
transformation for each concentration as a reference. The horizontal dotted line indicates that each reference
value of odds ratio is 1.0. The bars represented histograms of urinary chlorophenols distribution among
included participants. The model corrected for urinary iodine (continuous variable), BMI (continuous variable),
household income (categorical variable), living conditions (categorical variable), drinking (categorical
variable), family history of thyroid disease (categorical variable), and family history of malignancy
(categorical variable). (A) The restricted cubic spline for the association between ln-transformed urinary 2,4-
DCP and the risk of thyroid cancer. (B) The restricted cubic spline for the association between ln-transformed
urinary 2,4,6-TCP and the risk of thyroid cancer. (C) The restricted cubic spline for the association between ln-
transformed urinary PCP and the risk of thyroid cancer. Adjusted restricted cubic splines for the relationship between ln-transformed creatinine adjusted urinary
chlorophenols and the risk of thyroid cancer. Association between the three chlorophenols and the risk of
thyroid cancer. In the restricted cubic spline analysis, three nodes were used, which were the 10th, 50th and
90th percentiles of each urine chlorophenol concentration. The odds ratios (solid red lines) and 95%
confidence intervals (shaded areas) were estimated using the 10th percentile of the natural logarithmic
transformation for each concentration as a reference. The horizontal dotted line indicates that each reference
value of odds ratio is 1.0. The bars represented histograms of urinary chlorophenols distribution among
included participants. The model corrected for urinary iodine (continuous variable), BMI (continuous variable),
household income (categorical variable), living conditions (categorical variable), drinking (categorical
variable), family history of thyroid disease (categorical variable), and family history of malignancy
(categorical variable). (A) The restricted cubic spline for the association between ln-transformed urinary 2,4-
DCP and the risk of thyroid cancer. (B) The restricted cubic spline for the association between ln-transformed
urinary 2,4,6-TCP and the risk of thyroid cancer. (C) The restricted cubic spline for the association between ln-
transformed urinary PCP and the risk of thyroid cancer. Supplementary Files This is a list of supplementary files associated with this preprint. Click to download. Page 25/26
Fig.A.1.tif
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English
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Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican Women
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Nutrition journal
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Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Effect of calcium supplementation on bone
resorption in pregnancy and the early postpartum:
a randomized controlled trial in Mexican Women Adrienne S Ettinger1*, Héctor Lamadrid-Figueroa2, Adriana Mercado-García2, Katarzyna Kordas3, Richard J Wood4,
Karen E Peterson5, Howard Hu6, Mauricio Hernández-Avila2 and Martha M Téllez-Rojo2 * Correspondence: adrienne.ettinger@yale.edu
1Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale
Schools of Public Health and Medicine, 1 Church Street 6th floor, New
Haven, CT 06510, USA
Full list of author information is available at the end of the article Abstract Background: Calcium needs are physiologically upregulated during pregnancy and lactation to meet demands of
the developing fetus and breastfeeding infant. Maternal calcium homeostasis is maintained by hormonal adaptive
mechanisms, thus, the role of dietary calcium supplementation in altering maternal responses to fetal-infant
demand for calcium is thought to be limited. However, increased calcium absorption is directly related to
maternal calcium intake and dietary supplementation has been suggested to prevent transient bone loss
associated with childbearing. Methods: In a double-blind, randomized placebo-controlled trial, we randomly assigned 670 women in their
first trimester of pregnancy to 1,200 mg/day calcium (N = 334) or placebo (N = 336). Subjects were followed
through 1-month postpartum and the effect on urinary cross-linked N-telopeptides (NTx) of type I collagen,
a specific marker of bone resorption, was evaluated using an intent-to-treat analysis. Women with a baseline
and at least one follow-up measurement (N = 563; 84%) were included. Subsequent analyses were conducted
stratifying subjects by compliance assessed using pill counts. In random subsets of participants, bone-specific
alkaline phosphatase (BAP) (N = 100) and quantitative ultrasound (QUS) (N = 290) were also measured. Results: Calcium was associated with an overall reduction of 15.8% in urinary NTx relative to placebo (p < 0.001). Among those who consumed ≥50%, ≥67%, and ≥75% of pills, respectively, the effect was associated with 17.3%,
21.3%, and 22.1% reductions in bone resorption (all p < 0.001). There was no significant effect of calcium on
bone formation measured by BAP. However, by 1-month postpartum, those in the calcium group had significantly
lower NTx/BAP ratios than those in the placebo group (p = 0.04) indicating a net reduction in bone loss in the
supplement group by the end of follow-up. Among subjects who consumed ≥50% and ≥75% of pills, respectively,
calcium was also associated with an increase of 26.3 m/s (p = 0.03) and 59.0 m/s (p = 0.009) in radial SOS relative to
placebo by 1-month postpartum. Conclusions: Calcium administered during pregnancy and the early postpartum period, to women with intakes
around adequacy, was associated with reduced bone resorption and, thus, may constitute a practical intervention to
prevent transient skeletal loss associated with childbearing. Trial registration: ClinicalTrials.gov Identifier NCT00558623 Keywords: Bone-specific alkaline phosphatase, Calcium, Clinical trials, Lactation, Pregnancy, Quantitative ultrasound
bone speed of sound, Urinary N-telopeptide of type I collagen © 2014 Ettinger et al.; licensee BioMed Central. Study population and design First trimester pregnant women were enrolled from
January 1, 2001 to April 26, 2004 at Mexican Social
Security Institute prenatal clinics which serve a low-to-
moderate income population in Mexico City. In brief,
a total of 3,836 women were assessed for eligibility, of
whom 1,981 did not meet study eligibility criteria (preg-
nancy of no more than 14 weeks gestation; not a high-risk
pregnancy; plans to reside in Mexico City for study period;
and no other reasons for exclusion) or were not able to
be reached for contact (N = 2). When pregnant women
were screened for initial recruitment, they were excluded
if they exhibited any of the following conditions: any fac-
tor that could interfere with maternal calcium metabol-
ism, intention not to breastfeed, preeclampsia, kidney or
cardiac diseases, gestational diabetes, history of urinary
infections, family or personal history of kidney stone for-
mation, seizure disorder requiring daily medications, or
ingestion of corticosteroids. Of the remaining 1,853 eli-
gible women, 670 (36%) agreed to participate, signed in-
formed consent, and were randomly assigned to receive a
daily supplement of 1,200 mg calcium carbonate (two-600
mg tablets (Lederle, Inc.); N = 334) or placebo (N = 336)
(Figure 1). Neither participants nor study personnel were
aware of treatment group assignments and placebo tablets
were formulated to be indistinguishable from the active
treatment tablets. Biochemical markers of bone resorption (osteoclast ac-
tivity) and bone formation (osteoblast activity) have been
found change drastically during pregnancy suggesting a
physiological state of high bone turnover [12]. These
markers of bone turnover may identify changes in bone
remodeling and microarchitecture within a relatively short
time interval (several days to months) before changes in
BMD can be detected [13] and, thus, may provide insights
into mechanisms of bone loss [14]. The long-term effects
of these transient changes in maternal bone on child bone
health are not fully understood [15], but new data indicate
that maternal dietary deficiency during pregnancy may be
associated with lower peak bone mass in offspring [16,17]. p
p
g [
,
]
It is recommended that U.S. pregnant and breastfeed-
ing women over the age of 18 years consume at least
1,000 mg calcium per day [18], but these recommenda-
tions are based largely on studies in non-pregnant adults
[2]. Abstract This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated. Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Page 2 of 9 Background to populations with intakes approaching adequacy (such
as the general U.S. population). Calcium needs are physiologically-upregulated during preg-
nancy and lactation to meet the demands of the developing
fetus and breastfeeding infant for skeletal mineralization
and growth [1,2]. Maternal calcium homeostasis is main-
tained by hormonal adaptive mechanisms that control
intestinal calcium absorption, renal calcium excretion,
and mobilization of skeletal mineral stores [3,4]. The role
of dietary calcium supplementation in altering maternal
responses to fetal-infant demand for calcium is thought to
be limited; however, increased calcium absorption is dir-
ectly related to maternal calcium intake [5,6]. The objective of the present study was to evaluate the ef-
fect of dietary calcium supplementation on bone turnover
during pregnancy and the early postpartum period using a
double-blind, randomized placebo-controlled trial design. The hypothesis was that a daily supplement of 1,200 mg
calcium carbonate would decrease bone resorption over
the course of pregnancy among a relatively large sample
of women with near adequate dietary calcium intakes. Methods Pregnancy- and lactation-associated bone loss has also
been demonstrated through decreases in bone mineral
density (BMD). An estimated five percent or more of total
maternal bone mass may be mobilized [7,8], although, this
bone loss is reversible with levels rebounding to pre-
pregnancy levels after cessation of lactation [9]. There is
clear histological and biochemical evidence that the ma-
ternal skeleton undergoes increased bone resorption dur-
ing pregnancy [10,11]. Study population and design High dietary calcium intake has been shown to de-
crease bone mobilization during pregnancy [19,20] sug-
gesting that dietary calcium supplementation may be an
effective means to prevent maternal bone loss. A number
of studies have demonstrated an association with calcium
supplementation and changes in bone turnover in non-
pregnant adults [21], but data on the effects among preg-
nant women are scarce and there have been relatively few
controlled supplementation trials that have studied the
relationships directly [22]. The previously published trials
of calcium supplementation and bone turnover in preg-
nant women [23-25] have been limited by their sample
sizes and varying study designs making inferences from
their results difficult. In addition, the trials in Gambia
and China studied populations with low habitual diet-
ary calcium intakes which limit their generalizability Calcium carbonate is ~40% elemental calcium by weight
[26]; therefore, for 1,200 mg calcium carbonate, the elem-
ental calcium equivalent is: 480 mg. All treatment and
control subjects were provided with a daily supplement
of 30 mg iron (Fe) sulfate from study entry through
12 months postpartum since prenatal vitamins were not
included in the standard of care. Women were instructed
to consume Fe supplements at the mid-day “comida”
(main meal) to decrease side effects that may accompany
Fe ingestion [27]. Supplement levels were selected to meet
two criteria: ensured adequacy and safety of total dietary
intake. Doses consistent with the AI for calcium [28] and
the Recommended Dietary Allowance (RDA) for Fe [29]
to ensure normal physiologic requirements for pregnancy
and lactation [30] would be met among women in the Page 3 of 9 Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Figure 1 Study sample profile. Figure 1 Study sample profile. for loss-to-follow up and the final numbers of women
included at each stage of the analysis are detailed in
Figure 1. lower quartile of intake in our study population. Calcium
was suggested to be consumed at bedtime, rather than in
the morning, due to recent evidence (at the time of study
planning) of potentially greater effects on bone turnover
which was shown to be greater during the night than day-
time hours [31]. Given potential problems with compliance,
a split-dose regimen is not usually suggested for long-term
supplementation trials as simplified drug-dosing regimens
have been shown to improve adherence to therapy [32]. lower quartile of intake in our study population. Study population and design Calcium
was suggested to be consumed at bedtime, rather than in
the morning, due to recent evidence (at the time of study
planning) of potentially greater effects on bone turnover
which was shown to be greater during the night than day-
time hours [31]. Given potential problems with compliance,
a split-dose regimen is not usually suggested for long-term
supplementation trials as simplified drug-dosing regimens
have been shown to improve adherence to therapy [32]. The research protocol was approved by the Human
Subjects Committees of the Mexican National Institute
of Public Health, the Mexican Social Security Institute,
and participating institutions and has complied with all
federal guidelines governing the use of human subjects. All participants received a detailed explanation of the
study intent and procedures prior to signing the informed
consent. Participants were assessed at four time points: baseline
(1st trimester) prior to initiation of treatment, and after
having consumed calcium or placebo at 6 (2nd trimester)
and 8 (3rd trimester) months of gestation and 1-month
postpartum. Immediately following the baseline assess-
ment, women were instructed to consume tablets daily at
bedtime and compliance was assessed by pill count at each
follow-up visit. Women who had a baseline and at least
one follow-up measurement (calcium, N = 288; placebo,
N = 275) were defined as having completed follow-up and
included in this analysis (N = 563; 84%). The reasons Markers of bone turnover
f Urinary excretion of cross-linked N-telopeptides (NTx)
of type I collagen was measured in urine from second-
morning void collected by participants prior to each
visit. NTx is a specific marker of osteoclast activity (bone
resorption) that has been shown to be stable and resistant
to degradation in stored samples [33]. Samples were ana-
lyzed with a commercially available competitive-inhibition Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Page 4 of 9 Page 4 of 9 covariates (linear regression). A second approach was fit-
ting a by mixed-effects regression model with a random
intercept for each subject in order to adjust for imbalances
at baseline and to gain precision in treatment effect esti-
mates by including covariates. Mixed-effects models take
into account the correlation between repeated measures
on subjects over time. In addition, as mixed models are
flexible with respect to incomplete data, all subjects with
at least one follow-up measurement were included to in-
crease the study’s power. The outcome variable was nat-
ural log-transformed NTx in the 2nd and 3rd trimesters
and 1-month postpartum. Models included the following
baseline variables: treatment assignment (calcium vs. pla-
cebo), age (years), primigravidity (yes/no), NTx (nM BCE/
mM creatinine), daily calcium (g/day) and energy intake
(kcal/day), and time. We fitted a model including time*-
treatment interactions to test for heterogeneity of treatment
effects at different timepoints. To assess if breastfeeding at
1-month postpartum modified the effect of the supplement,
a cross-sectional model with an interaction term between
lactation (0,1 variable that defines whether the woman was
lactating at the time of the 1 month postpartum visit) and
supplement group was also fitted. enzyme-linked immunosorbent assay (Osteomark; Ostex
International, Seattle, Washington). NTx concentrations
were controlled for urine dilution using creatinine con-
centration and expressed as nanomoles of bone collagen
equivalents (BCE) per millimole of creatinine (nM BCE/
mM creatinine). The intra-assay CV was 8.9% (at 406 nM
BCE) and 8.7% (at 1563 nM BCE); the inter-assay CV was
8.6% (at 427 nM BCE) and 5.6% (at 1513 nM BCE). Bone-specific alkaline phosphatase (BAP) was measured
in plasma stored at −70°C from a subset of participants
(N = 100) using the Ostase® BAP immunoenzymetric assay
(Immunodiagnostic Systems Inc., Fountain Hills, AZ). BAP levels reflect the metabolic status of osteoblasts and,
thus, serve as an indicator of bone formation [34,35]. Dietary intake
l
k We also fitted a model with the NTx/BAP ratio as
the outcome variable, in the subset with both mea-
sures available (N = 100 subjects, 270 observations), to
observe if the relative levels of bone resorption-to-bone
formation changed over the course of the pregnancy and
to evaluate if this change was different between treatment
groups. All statistical analyses were performed using
STATA for Windows, version 12.0 (StataCorp LP, College
Station, Texas). Daily intakes of calcium and total energy were assessed
at each visit using a semi-quantitative food frequency
questionnaire designed to estimate usual dietary intake
over the prior month. The questionnaire was modified
and validated among women living in Mexico City [40]
and included questions specific to pregnancy such as any
additional use of dietary supplements. Statistical analysis To assess whether randomization was successful in achiev-
ing comparability, baseline characteristics were com-
pared between the calcium and placebo groups using the
Wilcoxon rank-sum (Mann–Whitney U) two-sample test
of equality. A similar comparison was performed between
those who were included in the analyses and those who
were lost to follow-up in order to assess whether selective
attrition occurred. All tests of statistical significance were
two-sided. Bone ultrasound measurement Bone speed of sound (SOS, in meters per second) was
measured at the distal radius using quantitative ultra-
sound (QUS) (Sunlight Omnisense 7000, Zicon Ltd. Petah-Tikva, Israel) in a random subset of participants
(N = 290). Dual-energy x-ray absorptiometry (DXA) is the
gold standard for measuring BMD [36], however, due to
the potential for ionizing radiation exposure to the fetus,
its use during pregnancy is inadvisable and specifically pro-
hibited by Mexican law. QUS allows for an inexpensive,
convenient, and radiation-free method by which to assess
bone quality during pregnancy and several previous epide-
miologic studies have used quantitative ultrasound to as-
sess bone changes over the course of pregnancy [37-39]. A secondary strategy was to estimate the efficacy of the
supplement by performing a dose–response analysis to
further assess the effect of the supplement by estimated
compliance. Compliance was analyzed as the proportion
of the expected number of pills taken by subjects be-
tween consecutive visits and then categorized into three
groups: ≥50% of pills consumed, ≥67% of pills consumed,
and ≥75% of pills consumed. Results Table 1 Baseline characteristics of subjects by treatment assignment and follow-up status
Treatment assignment Table 1 Baseline characteristics of subjects by treatment assignment and follow-up status aDefined as having at least one visit completed after baseline and included in final model. bp < 0.05 Wilcoxon rank-sum (Mann–Whitney U) two sample test of equality of distributions. cGeometric mean and GSD; n = 291 treated, n = 285 with placebo. aDefined as having at least one visit completed after baseline and included in final model. bp < 0.05 Wilcoxon rank-sum (Mann–Whitney U) two sample test of equality of distributions. cGeometric mean and GSD; n = 291 treated, n = 285 with placebo. Since response to treatment could depend on baseline
dietary calcium intake, we tested a dietary calcium-by-
treatment group interaction. There was no significant
interaction between dietary calcium intake (either as a
continuous variable or as quartiles) and supplement group
at baseline. However, when examining lactation status,
there was no effect of supplement in the non-lactating
women (p = 0.57) compared to a 23% reduction in lactat-
ing women (p < 0.0001), indicating that lactation is an ef-
fect modifier for the effect of calcium supplementation on
bone resorption. were 62.3 (1.7) and 62.9 (1.7) nM BCE/mM creatinine for
the calcium and placebo groups, respectively (p = 0.73). A total of 563 women (84%) had at least one follow-up
assessment and were included in the analyses. Compar-
ing those included in the analysis (placebo N = 275; cal-
cium N = 288) to those who were not included (placebo
N = 61; calcium N = 46) revealed no significant differences
by treatment assignment suggesting that those women
who remained in the study were not systematically differ-
ent than those who did not complete follow-up. Overall,
the proportion of lactating women at 1-month postpar-
tum was 89.6% and there were no differences by treatment
group (calcium, 89.9% vs. placebo, 89.3%; p = 0.8). When the effect of calcium supplementation was assessed
for women “as treated” (N = 563) using models stratified
by compliance (Table 3), we saw a dose–response effect of
calcium on NTx concentration. Among those women who
consumed ≥50% of pills, calcium was associated, on aver-
age, with a 17.3% reduction in NTx in comparison to pla-
cebo (p < 0.001). Results A total of 670 eligible women were randomized to receive
calcium supplementation (N = 334) or placebo (N = 336)
(Figure 1). Baseline characteristics were similar for the cal-
cium and placebo groups with the exception of maternal
age which was one year higher on average in controls
(26.9 years) than in the supplement group (25.9 years; p =
0.02) (Table 1). Approximately 35.4% of women were pri-
migravid and there were no significant differences by
treatment. Dietary calcium intake, also not significantly
different between treatment groups, was about 1,100 milli-
grams per day on average. Geometric mean (and geomet-
ric standard deviation (GSD)) pre-treatment NTx levels The effect of the calcium supplement on bone resorption
was evaluated using an intent-to-treat strategy. A first ap-
proach was to conduct a comparison of the log-transformed
NTx concentrations between treatment groups at each
follow-up stage, both unadjusted (t-test) and adjusting for Page 5 of 9 Page 5 of 9 Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Table 1 Baseline characteristics of subjects by treatment assignment and follow-up status
Treatment assignment
Follow-up status
Calcium
Placebo
Includeda
Not included
(N = 334)
(N = 336)
(N = 563)
(N = 107)
Variable
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Age (years)
26.9 (5.6)
25.9 (5.3)b
26.5 (5.5)
26.2 (5.3)
Education (years)
10.8 (2.9)
11.0 (3.2)
10.9 (3.1)
10.6 (2.9)
Number of pregnancies
2.0 (1.0)
2.1 (1.1)
2.1 (1.0)
2.0 (0.9)
Number of children
0.8 (0.8)
0.8 (0.9)
0.8 (0.9)
0.7 (0.7)
Number of months previous breastfeeding (cumulative lifetime)
5.6 (8.9)
6.8 (9.0)
6.4 (9.2)
5.1 (7.2)
BMI (kg/m2)
25.9 (4.1)
25.8 (3.7)
25.9 (3.9)
25.9 (3.9)
Energy intake (kcal/day)
1888 (592)
1862 (637)
1860 (613)
1951 (619)
Calcium intake (mg/day)
1108 (492)
1083 (532)
1096 (515)
1091 (497)
Hematocrit (%)
39.1 (3.3)
39.1 (3.0)
39.1 (3.2)
39.1 (2.7)
NTx (nM BCE/mM creatinine)c
62.3 (1.7)
62.9 (1.7)
62.9 (1.7)
52.2 (1.7)
aDefined as having at least one visit completed after baseline and included in final model. bp < 0.05 Wilcoxon rank-sum (Mann–Whitney U) two sample test of equality of distributions. cGeometric mean and GSD; n = 291 treated, n = 285 with placebo. Results This increased to 21.3% (p < 0.001) and
22.1% (p < 0.001) for those who consumed ≥67% of pills
and ≥75% of pills. In the unadjusted intent-to-treat analysis, calcium was
associated with average reductions of 15.1, 16.4, and
20.2% in NTx concentrations in the 2nd and 3rd trimesters,
and 1 month post-partum respectively (all p ≤0.001). The
corresponding visit-specific
covariate-adjusted
reduc-
tion estimates were 13.8, 15.6 and 19.2% (all p ≤0.001)
(Table 2). The overall covariate-adjusted average reduc-
tion in NTx concentrations relative to placebo was 15.8%
(p < 0.001). Table 2 Effect of calcium supplementation on NTX
(Log-transformed) (N = 563)
Unadjusted
Adjusteda
N
%Δb
p-value
N
%Δb
p-value
Study visit
2nd trimester
548
15.1
0.001
544
13.8
0.001
3rd trimester
517
16.4
<0.001
513
15.6
<0.001
1-month postpartum
456
20.2
<0.001
453
19.2
<0.001
Average
567
16.8
<0.001
563
15.8
<0.001
aAdjusted for baseline: age, primigravidity, NTx, and dietary calcium and total
energy intakes. bPercent reduction: 1- eβ. Table 2 Effect of calcium supplementation on NTX
(Log-transformed) (N = 563) Results of the mixed effects regression model with
treatment-by-time interactions showed a significantly
different effect of the calcium supplementation on bone
resorption at each study assessment when compared to
baseline difference between treatment groups. The re-
duction was more evident at 1-month postpartum than
in the 2nd and 3rd trimesters, but these reductions were
significant for each of the three assessments: 2nd trimes-
ter (−13.7% reduction, p = 0.002); 3rd trimester (−15.6%
reduction, p = 0.001); and 1-month postpartum: (−18.6%
reduction, p < 0.001) (Figure 2). Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Page 6 of 9 Figure 2 Effect of calcium supplementation on urinary N-telopeptides of type I collagen [NTx] (nM BCE/mM creatinine) at each trimester
during pregnancy and at 1-month postpartum (Intent-to-Treat Analysis, N = 563); adjusting for baseline variables: NTx, age, primigravidity,
dietary calcium and daily energy intake. Figure 2 Effect of calcium supplementation on urinary N-telopeptides of type I collagen [NTx] (nM BCE/mM creatinine) at each trimester
during pregnancy and at 1-month postpartum (Intent-to-Treat Analysis, N = 563); adjusting for baseline variables: NTx, age, primigravidity,
dietary calcium and daily energy intake. Results The subset of women with serum BAP measurements
(N = 100) were not significantly different than those who
did not have the measurements available (N = 463) ex-
cept for years in school (those with BAP had 0.7 more
years, on average, p = 0.04) and hematocrit (those with
BAP 0.7 percentage points higher, on average, p = 0.04). There was no significant effect of calcium on BAP alone
at any stage (p-values: 0.61, 0.20, 0.32 for 2nd trimester,
3rd trimester, and 1-month postpartum, respectively)
(data not shown). Adjusting for age, primigravidity, base-
line dietary calcium and total energy intakes, and baseline
NTx/BAP ratio, the calcium group had lower, though
not statistically significant, NTx/BAP ratio estimates at
the 2nd (−10.1%, p = 0.32) and 3rd trimester (−13.4%, p =
0.20) visits. By 1-month postpartum, those in the calcium group had statistically significant lower NTx/BAP ratios
than those in the placebo group (−21.5%, p = 0.04) indicat-
ing a greater net reduction in bone loss in the supplement
group by the end of follow-up. The subset of women with SOS available (N = 290) were
not significantly different than those who did not have the
measurements available except for years in school (those
with SOS had 0.6 more years, p = 0.01) and total energy
intake (women with SOS consumed ~190 kcal less, on
average, p < 0.001). While radial SOS decreased over the
course of pregnancy in both groups, declines in the sup-
plement group were relatively attenuated and, by 1-month
postpartum, those in the supplement group had higher,
though not significantly, radial SOS than those in the
placebo group (p = 0.13) (data not shown). Calcium was Table 3 Effect of calcium supplementationa on NTx by treatment complianceb
Average (Overall)
2nd trimester
3rd trimester
1-month postpartum
Compliance
N (Obs)
%Δc
p-value
%Δc
p-value
%Δc
p-value
%Δc
p-value
ALL
563 (1510)
15.8
<0.001
13.7
0.002
15.6
0.001
18.6
<0.001
<50%
161d (270)
11.2
0.110
10.9
0.256
10.7
0.383
12.6
0.361
≥50%
505d (1240)
17.3
<0.001
14.9
0.003
15.6
0.002
19.2
<0.001
≥67%
378 (790)
21.3
<0.001
19.0
0.005
19.2
0.001
23.0
<0.001
≥75%
267 (423)
22.1
<0.001
25.0
0.171
19.0
0.006
21.9
0.002
aAdjusted for baseline: age, primigravidity, NTx, and dietary calcium and total energy intakes. bCompliance assessed by pill count at each visit and analyzed as proportion of expected pills used between consecutive visits. cPercent reduction: 1-eβ. rcent reduction: 1 e .
umbers of subjects do not add to 563 because subjects may appear in more than one stratum due to time-varying nature of complian j
g
p
g
y
y
gy
ompliance assessed by pill count at each visit and analyzed as proportion of expected pills used between consecutive visits.
rcent reduction: 1-eβ. djusted for baseline: age, primigravidity, NTx, and dietary calcium and total energy intakes.
ompliance assessed by pill count at each visit and analyzed as proportion of expected pills used between consecutive visits bCompliance assessed by pill count at each visit and analyzed as proportion of expected pills used between consecutive vis
cPercent reduction: 1-eβ. Discussion In this randomized controlled trial, a 1,200 mg daily cal-
cium carbonate supplement administered during preg-
nancy and the early postpartum period was associated
with reductions in NTx, compared to placebo, both during
pregnancy and at one month postpartum, indicating that
dietary calcium supplementation may help to suppress
maternal bone mobilization. These effects were stronger
with increasing treatment compliance, suggesting a dose–
response effect, with a greater than 22% average overall
reduction observed among the most compliant women. These results are consistent with a previous randomized
crossover trial in a small group of women which showed
that dietary calcium supplementation reduced NTx levels
by an average of 14% when administered in the third tri-
mester of pregnancy [23]. To place the magnitude and dir-
ection of these changes into context, this is consistent
with a 28% reduction in urinary NTx observed after 1-
month of hormone replacement therapy among women
randomized to receive 0.625 mg conjugated equine estro-
gen (Premarin, Wyeth Ayerst, Philadelphia, PA) [41]. y
A limitation of our study is that we used QUS, and
not DXA, to assess bone quality in pregnant women and
this measurement was available in only about half of the
women. QUS has been demonstrated to predict fracture
risk [43] and has been widely used in epidemiologic
studies to measure bone density particularly where DXA
is not available [44] or not advisable, such as during
pregnancy [37-39] due to the potential for radiation ex-
posure to the fetus. QUS has been found to be well-
correlated with DXA at all sites measured over 7 years
of follow-up [45] and provides our study with the advan-
tage that we were able to include repeated measures of
bone density, in addition to biochemical markers of bone
turnover, over the entire course of pregnancy and the early
postpartum period. The results of this study are also consistent with the
findings of a study among 36 pregnant Chinese women
with low habitual dietary calcium intake that found cal-
cium supplementation was associated with significant
decreases in markers on bone resorption; although in
contrast to our findings, they also reported increases in
bone formation [25]. Unlike our study, calcium was pro-
vided by supplementing the “usual diet” with 45 g milk
powder (350 mg calcium) or milk powder plus 600 mg
calcium supplement (950 mg calcium). Results Table 3 Effect of calcium supplementationa on NTx by treatment complianceb dNumbers of subjects do not add to 563 because subjects may appear in more than one stratum due to time-varying nature of compliance. Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Page 7 of 9 Page 7 of 9 associated with an overall average increase of 9.05 m/s in
radial SOS relative to placebo though this difference was
not significant (p = 0.216). However, among those subjects
who consumed 50% or more of pills (N = 251), calcium
was associated with an increase of 26.3 m/s in radial SOS
relative to placebo by 1-month postpartum (p = 0.03). Among those subjects who consumed at least 75% of pills,
calcium supplementation was associated with an increase
of 59.0 m/s in radial SOS relative to placebo by 1-month
postpartum (p = 0.009). detect an effect of calcium on SOS. In addition, calcium’s
impact on bone density may differ depending on the type
of bone. We measured SOS in the distal radius, a site with
a predominance of cortical bone, and calcium may be act-
ing on bone sites where trabecular bone dominates. In a study of 125 Gambian women, supplementation
with 1,500 mg/day calcium was associated with lower
BMD measured by DXA in a subset of participants at
the distal and midshaft of the radius, but with increases
in measures of BMD in the lumbar spine and whole body
[24]. Like the Chinese study, the Gambian study also
measured the effect of calcium supplementation among
women with low dietary calcium intake. However, unlike
our study and the one by Liu et al. [25], the Gambian
study did not continue supplementation into the post-
partum period which may be partially responsible for
their findings of rebound demineralization following ces-
sation of lactation [42]. We found that the ratio of bone
resorption-to-bone formation was significantly lower in
the calcium group by 1-month postpartum suggesting that
calcium is effective in reducing net bone loss measured
after pregnancy. The observed effects at 1-month postpar-
tum were being driven by lactating women in our study
which suggests that the need for continuation of calcium
supplementation may extend into the postpartum period. Discussion In that study, diet-
ary calcium supplementation during pregnancy was asso-
ciated, in a dose-dependent manner, with greater BMD
measured by DXA at 6 weeks postpartum at the spine and
whole body (p < 0.05), but not at the hip site. Pregnancy and lactation may impact a woman’s peak
bone mass which is an important determinant of subse-
quent osteoporosis risk [46]. In addition, calcium may also
have potential benefits for child bone health [16,17,47]. The possibility that intrauterine programming of fetal
bone growth may be an important determinant of osteo-
porosis and the risk of other chronic diseases in later life
is now being considered [48]. New evidence indicates that
maternal dietary deficiencies during pregnancy may be
associated with lower peak bone mass in offspring later in
life [16,17]. In the present study, calcium was associated with sig-
nificantly higher radial SOS, a marker of bone density,
by 1-month postpartum among the most compliant sub-
jects. While the overall effect, including all subjects re-
gardless of compliance, was not statistically significant, the
direction of the effect is consistent with our hypothesis
and radial SOS measurements were available in only about
half of the subjects, thus, the study was underpowered to Average baseline dietary calcium intake for women
in our trial was within the current recommended dietary
guidelines of 1,000-1,300 mg/day for pregnant and lactating Ettinger et al. Nutrition Journal 2014, 13:116
http://www.nutritionj.com/content/13/1/116 Page 8 of 9 Page 8 of 9 women [18]. It is possible that high amounts of calcium are
needed to counterbalance the nutritional needs of the de-
veloping fetus [49]; thus, previous trials among women with
low habitual dietary calcium intakes may have been unable
to detect an effect. Bone mineralization does not depend
solely on the availability of calcium: protein, energy, and
other nutrients are also important to bone formation and
mineralization. Vitamin D is essential for calcium home-
ostatis and now recognized as an important nutrient for
bone health including modest support for maternal vita-
min D status and increased offspring bone mass among
[50]. However, this study was planned and carried out on
the basis of the 1997 IOM guidelines [28]. Vitamin D was
not specifically recommended with calcium supplementa-
tion as is currently common practice. Nonetheless, other
prior studies of calcium supplementation in adult preg-
nancy [23-25], to which we compare our results, also did
not measure or administer Vitamin D. Conclusion 1. Prentice A: Calcium in pregnancy and lactation. Annu Rev Nutr 2000,
20:249–272. In summary, dietary calcium intake likely plays a mod-
est, but important role in suppressing maternal bone
mobilization during pregnancy and the early postpartum. Calcium supplementation during pregnancy may also
reduce the risk of hypertensive disorders of pregnancy
[53,54], pre-eclampsia [55,56], and lead exposure [57]
which themselves pose risks to the mother and fetus. The risks posed by calcium supplementation at levels
approximating the upper limit of recommended daily in-
take are relatively minor [2,18] and U.S. guidelines for cal-
cium in pregnancy and lactation are based on studies in
non-pregnant adults [2]. The World Health Organization
now recognizes the importance of calcium supplementa-
tion in pregnancy [58]. Thus, dietary supplementation of
calcium intake among pregnant and lactating women
should be considered particularly in populations where
dietary calcium intake is low. 2. Hacker AN, Fung EB, King JC: Role of calcium during pregnancy: maternal
and fetal needs. Nutr Rev 2012, 70:397–409. 2. Hacker AN, Fung EB, King JC: Role of calcium during pregnancy: maternal
and fetal needs. Nutr Rev 2012, 70:397–409. 3. Kovacs CS: Calcium and bone metabolism in pregnancy and lactation. J Clin Endocrinol Metab 2001, 86:2344–2348. 4. Kovacs CS, Kronenberg HM: Maternal-fetal calcium and bone metabolism
during pregnancy, puerperium, and lactation. Endocr Rev 1997, 18:832–872. 5. Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE: Calcium homeostasis
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BCE B
ll BCE: Bone collagen equivalents; BAP: Bone-specific alkaline phosphatase;
BMD: Bone mineral density; DXA: Dual-energy x-ray absorptiometry;
QUS: Quantitative ultrasound; SOS: Speed of sound; NTx: Urinary cross-linked
N-telopeptides of type I collagen. p
g
y
p
p
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13. Pagani F, Francucci CM, Moro L: Markers of bone turnover: biochemical
and clinical perspectives. J Endocrinol Invest 2005, 28(10 Suppl):8–13. 14. Hellmeyer L, Ziller V, Anderer G, Ossendorf A, Schmidt S, Hadji P: Biochemical
markers of bone turnover during pregnancy: a longitudinal study. Exp Clin
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markers of bone turnover during pregnancy: a longitudinal study. Exp Clin
Endocrinol Diabetes 2006, 114:506–510. Acknowledgements The authors gratefully acknowledge the contribution of the American British
Cowdray Hospital in Mexico City for use of its research facilities. This work
was supported by the U.S. National Institutes of Health (NIH) [grant numbers:
P42-ES05947, R01-ES07821, R01-ES021446, P30-ES00002, and K01-ES014907]
and by México Consejo Nacional de Ciencia y Tecnología (CONACYT) (The
National Council of Science and Technology) [grant number 4150M9405]. The contents of this article are solely the responsibility of the authors and do
not necessarily represent the official views of the NIH. Authors’ contributions Study design: HH, MHA, and KEP. Study conduct: ASE, HLF, AMG, KK,
RJW, KEP, HH, MHA, MMT. Data collection: AMG, RJW. Data analysis and
interpretation: ASE, HLF, MMT. Drafting and revising manuscript content:
ASE. Approving final version of manuscript: ASE, HLF, AMG, KK, RJW, KEP,
HH, MHA, MMT. ASE, HLF, and MMT take responsibility for the integrity
of the data analysis. All authors read and approved the final manuscript. Study design: HH, MHA, and KEP. Study conduct: ASE, HLF, AMG, KK,
RJW, KEP, HH, MHA, MMT. Data collection: AMG, RJW. Data analysis and
interpretation: ASE, HLF, MMT. Drafting and revising manuscript content:
ASE. Approving final version of manuscript: ASE, HLF, AMG, KK, RJW, KEP,
HH, MHA, MMT. ASE, HLF, and MMT take responsibility for the integrity
of the data analysis. All authors read and approved the final manuscript. Received: 9 August 2014 Accepted: 11 December 2014
Published: 16 December 2014 Received: 9 August 2014 Accepted: 11 December 2014
Published: 16 December 2014 Discussion One small ran-
domized study of pregnant Brazilian adolescents with
habitually low calcium intake [51] found that 600 mg
calcium carbonate plus vitamin D3 (200 IU) resulted
in higher lumbar spine bone mass and a reduced rate of
femoral neck bone loss during lactation which is consistent
with our results. The maternal response to fetal calcium
demand may also be highly individualized and other gen-
etic, hormonal, or lifestyle factors may be involved [52]. women [18]. It is possible that high amounts of calcium are
needed to counterbalance the nutritional needs of the de-
veloping fetus [49]; thus, previous trials among women with
low habitual dietary calcium intakes may have been unable
to detect an effect. Bone mineralization does not depend
solely on the availability of calcium: protein, energy, and
other nutrients are also important to bone formation and
mineralization. Vitamin D is essential for calcium home-
ostatis and now recognized as an important nutrient for
bone health including modest support for maternal vita-
min D status and increased offspring bone mass among
[50]. However, this study was planned and carried out on
the basis of the 1997 IOM guidelines [28]. Vitamin D was
not specifically recommended with calcium supplementa-
tion as is currently common practice. Nonetheless, other
prior studies of calcium supplementation in adult preg-
nancy [23-25], to which we compare our results, also did
not measure or administer Vitamin D. One small ran-
domized study of pregnant Brazilian adolescents with
habitually low calcium intake [51] found that 600 mg
calcium carbonate plus vitamin D3 (200 IU) resulted
in higher lumbar spine bone mass and a reduced rate of
femoral neck bone loss during lactation which is consistent
with our results. The maternal response to fetal calcium
demand may also be highly individualized and other gen-
etic, hormonal, or lifestyle factors may be involved [52]. Author details 1Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale
Schools of Public Health and Medicine, 1 Church Street 6th floor, New
Haven, CT 06510, USA. 2National Institute of Public Health, Universidad 655
Colonia Santa María Ahuacatitlán, C.P. 62100 Cuernavaca, Morelos, Mexico. 3School of Social and Community Medicine, University of Bristol, Bristol,
England, UK. 4Department of Nutrition, University of Massachusetts at
Amherst, Amherst, MA, USA. 5Department of Environmental Health Sciences,
Human Nutrition Program, University of Michigan School of Public Health,
Ann Arbor, MI, USA. 6Dalla Lana School of Public Health, University of
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Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study
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Received: 13 February 2023 Revised: 14 August 2023 Accepted: 21 August 2023
1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; 2Clinical Medical Research Center of Hematology Diseases of
Guangdong Province, Guangzhou 510515, China;
3Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China;
4Bone Marrow
Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; 5Department of Hematology, Zhujiang Hospital, Southern
Medical University, Guangzhou 510280, China; 6Department of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
200125, China; 7Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; 8The First Affiliated Hospital of Soochow University,
Suzhou 215006, China; 9Hematopoietic Stem Cell Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese
Academy of Medical Sciences, Tianjin 300020, China; 10Department of Hematology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China;
11Department of Hematology, the First People’s Hospital of Chenzhou, Chenzhou 423099, China; 12Department of Hematology, the First Affiliated Hospital of Guangzhou Medical
University, Guangzhou 510120, China; 13Department of Hematology, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; 14Department of
Hematology, Peking University People’s Hospital, Beijing 100044, China and 15Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key
Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Correspondence: Yu Wang (ywyw3172@sina.com) or Qifa Liu (liuqifa628@163.com) or Li Xuan (356135708@qq.com)
These authors contributed equally: Ruoyang Shao, Yu Zhang, Jinping He, Fen Huang, and Zhiping Fan Received: 13 February 2023 Revised: 14 August 2023 Accepted: 21 August 2023 ARTICLE
OPEN
Impact of genetic patterns on sorafenib efficacy in patients with
FLT3-ITD acute myeloid leukemia undergoing allogeneic
hematopoietic stem cell transplantation: a multi-center, cohort
study
Ruoyang Shao1,2, Yu Zhang1,2, Jinping He1,2, Fen Huang1,2, Zhiping Fan1,2, Kaibo Yang1,2, Yajing Xu3, Na Xu1,2, Yi Luo4, Lan Deng5,6,
Xi Zhang
7, Jia Chen8, Mingzhe Han9, Xudong Li10, Sijian Yu1,2, Hui Liu1,2, Xinquan Liang11, Xiaodan Luo12,13, Pengcheng Shi1,2,
Zhixiang Wang1,2, Ling Jiang1,2, Xuan Zhou1,2, Ren Lin1,2, Yan Chen3, Sanfang Tu5, Jing Sun1,2, Yu Wang14✉, Qifa Liu1,2,15✉and
Li Xuan1,2✉ Ruoyang Shao1,2, Yu Zhang1,2, Jinping He1,2, Fen Huang1,2, Zhiping Fan1,2, Kaibo Yang1,2, Yajing Xu3, Na Xu1,2, Yi Luo4, Lan Deng5,6,
Xi Zhang
7, Jia Chen8, Mingzhe Han9, Xudong Li10, Sijian Yu1,2, Hui Liu1,2, Xinquan Liang11, Xiaodan Luo12,13, Pengcheng Shi1,2,
Zhixiang Wang1,2, Ling Jiang1,2, Xuan Zhou1,2, Ren Lin1,2, Yan Chen3, Sanfang Tu5, Jing Sun1,2, Yu Wang14✉, Qifa Liu1,2,15✉and
Li Xuan1,2✉ Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia
(AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this
population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML
undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four
weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and
relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and
338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2–44.7) months post-transplantation. The 3-year OS
post-transplantation was 79.6% (95% confidential interval (CI) 74.8%–84.6%) and 65.2% (95% CI 60.3%–70.6%) (Hazard ratio (HR)
0.50, 95% CI 0.37–0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR
0.33, 95% CI 0.14–0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33–0.93; P = 0.026) ELN 2017 risk subgroups. Patients with
mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, “activated signaling” and “DNA methylation” genes benefited in OS from
sorafenib maintenance, while those carrying CEBPA, “tumor suppressors” and “myeloid transcription factors” genes did not. Patients
with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of
genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the
transplantation setting. ; https://doi.org/10.1038/s41392-023-01614-1 Signal Transduction and Targeted Therapy (2023) 8:348 Signal Transduction and Targeted Therapy (2023) 8:348 Signal Transduction and Targeted Therapy Signal Transduction and Targeted Therapy Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE
OPEN
Impact of genetic patterns on sorafenib efficacy in patients with
FLT3-ITD acute myeloid leukemia undergoing allogeneic
hematopoietic stem cell transplantation: a multi-center, cohort
study
Ruoyang Shao1,2, Yu Zhang1,2, Jinping He1,2, Fen Huang1,2, Zhiping Fan1,2, Kaibo Yang1,2, Yajing Xu3, Na Xu1,2, Yi Luo4, Lan Deng5,6,
Xi Zhang
7, Jia Chen8, Mingzhe Han9, Xudong Li10, Sijian Yu1,2, Hui Liu1,2, Xinquan Liang11, Xiaodan Luo12,13, Pengcheng Shi1,2,
Zhixiang Wang1,2, Ling Jiang1,2, Xuan Zhou1,2, Ren Lin1,2, Yan Chen3, Sanfang Tu5, Jing Sun1,2, Yu Wang14✉, Qifa Liu1,2,15✉and
Li Xuan1,2✉ RESULTS
l
l Clinical and Treatment characteristics
A total of 613 patients with FLT3-ITD AML undergoing allo-HSCT
were enrolled in this study between January 2012 and June 2020,
including 441 patients from the prospective studies and 172 from
the retrospective studies (Fig. 1). There were 294 females and 319
males, with a median age at 36 years (IQR, 26–45 years). For
induction therapy, 562 patients received anthracyclines plus
cytarabine and 51 patients received other regimens. At transplan-
tation, 525 patients were in composite complete remission (CRc),
26 in partial remission (PR), and 62 in non-remission (NR). Two
hundred and fifty-one patients underwent HLA-matched sibling
donor (MSD), 42 HLA-matched unrelated donor (MUD) and 320
HLA-haploidentical donor (HID) transplants. ELN 2017 risk stratifi-
cation was available in 505 patients, including 160 patients with
favorable, 159 with intermediate and 186 with adverse risks, and
was unavailable in 108 patients because of missing FLT3-ITD AR
data. Based on sorafenib maintenance post-transplantation, 275
patients were allocated to the sorafenib group and 338 the control
group. Except pre-transplantation sorafenib, prognostic factors
such as sex, age, genetics, treatments pre-transplantation, disease
status at transplant and transplant modality were balanced
between the two groups (Table 1). The treatment and clinical
characteristics were compared between patients from prospective
and retrospective studies (Supplementary Table 1). Except cycles of
chemotherapy pre-transplantation and ELN risk, characteristics
were balanced between the prospective and retrospective cohorts
(Supplementary Table 1). In the sorafenib group, sorafenib was
initiated
at
a
median
of
45 days
(IQR,
30–115 days)
post-
transplantation. The median time of sorafenib maintenance post-
transplantation was 208 days (IQR, 144–292 days). p
FLT3-ITD AML is a group of heterogenous disease. Despite the
number, length, insertion site, allelic ratio (AR) of FLT3-ITD itself,
concomitant genetic abnormalities also influence the nature of
FLT3-ITD AML.18,23,24 For example, some studies showed that the
co-existence of NPM1 or CEBPA mutation inferred superior
prognosis, but TET2 or DNMT3A mutation predicted inferior
outcome in FLT3-ITD AML.6,25–27 Regarding the response to FLT3
inhibitors, several different FLT3 inhibitors were reported to
improve the outcomes of FLT3-ITD AML patients with mutated
NPM1,18,28,29 while their effects on patients with other genetic
patterns were less reported. A recent study by Smith et al. INTRODUCTION
FMS lik
i newly diagnosed acute myeloid leukemia (AML), including two
main types of mutation, FLT3 juxta-membrane domain internal
tandem duplication (ITD), and FLT3 tyrosine kinase domain (TKD)
point mutation.2 An ITD in FLT3 molecule inhibits the negative
regulatory function of the juxta-membrane region, resulting in
constitutive activation of the FLT3 kinase and its downstream
signaling cascades, and consequently improves survival and
proliferation of AML cells.2 While the clinical impact of FLT3-TKD
is still ambiguous, patients with FLT3-ITD positive AML face shorter FMS-like tyrosine kinase 3 (FLT3), a transmembrane ligand-
activated receptor tyrosine kinase, is usually expressed by
hematopoietic stem cells, early myeloid progenitor cells, and
early lymphoid progenitor cells.1 FLT3 plays a key role in the
regulation of proliferation, maturation and apoptosis in especially
the early stages of hematopoietic cells via multiple downstream
signaling pathways including JAK-STAT, RAS/RAF/MEK/ERK, and
PI3K/AKT.2 FLT3 is among the most frequently mutated genes in © The Author(s) 2023 N = 144
(retrospective)
N = 83
(retrospective)
N = 202
(RCT)
22 without FLT3-ITD
mutation before
transplantation
N = 736
17 duplicate
613 patients analyzed
· 6 accepted other FLT3 inhibitors
· 32 did not achieve CRc after transplantation, died
or relapsed before day 90 post-transplantation
· 85 without genomic data
N = 346
NCT03620955
(ongoing)
Xuan et al 2019
44
Xuan et al 2020
9
Xuan et al 2018
14
Fig. 1
Diagram of the study. FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication
Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 2 (RCT)
Xuan et al 2020
9 N = 202 · 6 accepted other FLT3 inhibitors
· 32 did not achieve CRc after transplantation, died
or relapsed before day 90 post-transplantation
· 85 without genomic data am of the study. FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem dupli Fig. 1
Diagram of the study. FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FMS-like tyrosine kinase 3 inte Fig. 1 To comprehensively explore the impact of concomitant genetic
patterns to sorafenib efficacy in FLT3-ITD AML patients under-
going allo-HSCT, we herein perform a multi-center, exploratory,
cohort study in patients with FLT3-ITD AML undergoing allo-HSCT. INTRODUCTION
FMS lik
i remission duration and higher relapse compared to those with
wild type FLT3.3 Therefore, allogeneic hematopoietic stem cell
transplantation (allo-HSCT) is recommended by international
consensus and guidelines for FLT3-ITD AML patients, but many
patients still undergo relapse even after allo-HSCT.4,5 In this study, we identified genetic abnormality subgroups who
benefitted or did not benefit from sorafenib maintenance post-
transplantation, and further explored the possible molecular
mechanisms of sorafenib resistance in patients carrying certain
genetic abnormalities via bioinformatic analyses and preliminary
experiments. Our results provide new insights for the optimal use
of sorafenib in FLT3-ITD AML based on concomitant genetic
patterns. Recent
years,
several
different
FLT3
inhibitors
including
sorafenib have been widely applied in FLT3-ITD AML, incorporated
with chemotherapy, as maintenance therapy, and as salvage
therapy.2,6–12 Prospective and retrospective studies including
those from our group demonstrated that administration of
sorafenib in FLT3-ITD AML patients, especially after allo-HSCT,
could reduce relapse and improve survival.9,13–20 A recent
updated report of our phase III randomized controlled trial (RCT)
showed that sorafenib maintenance post-transplantation had
long-term benefits on relapse rate and overall survival (OS) in
FLT3-ITD AML patients receiving allo-HSCT without significantly
increasing adverse events or graft-versus-host disease (GVHD).19
Sorafenib is now recommended by the AML guideline of the
National Comprehensive Cancer Network (NCCN) and ELN as post-
transplantation
maintenance
therapy
for
FLT3-ITD
AML
patients.21,22 RESULTS
l
l showed
that relapsed/refractory FLT3-mutated patients carrying DNA
methylation/hydroxymethylation mutations like DNMT3A might
benefit from gilteritinib.28 Jahn and his colleagues found that
FLT3-mutated patients carrying chromatin modifiers and spliceo-
some mutations might benefit from midostaurin.29 However,
these results were obtained in patients undergoing chemotherapy
instead of allo-HSCT.18,28,29 Also, due to differences in molecular
structure, sorafenib might also have different performance on
sensitivity compared with gilteritinib or midostaurin.30 To the best
of our knowledge, there currently lack large-scale study exploring
the impact of concomitant genetic patterns on the efficacy of
sorafenib as post-transplantation maintenance therapy in FLT3-
ITD AML patients undergoing allo-HSCT. Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 3 Table 1. Clinical and Treatment Characteristics
Characteristics
Sorafenib group (n = 275)
Control group (n = 338)
P
Sex, male/female (n%)
143 (53%)/132 (47%)
176 (52%)/162 (48%)
0.86
Age, median (IQR), years
36 (26–45)
37 (27–47)
0.24
WBC count at diagnosis, median (IQR)
53.1 (15.7–119.5)
52.9 (12.9–118.5)
0.96
Cycles of chemotherapy pre-transplant, median (IQR)
3 (3–4)
3 (3–4)
0.73
Initial induction regimens
0.25
Anthracyclines plus cytarabine
256 (93%)
306 (91%)
Others
19 (7%)
32 (9%)
Cytogenetics risk stratification (n%)
0.90
Favorable
20 (7%)
26 (8%)
Intermediate
229 (83%)
279 (83%)
Adverse
26 (9%)
33 (10%)
2017 ELN risk stratification (n%)
0.90
Favorable
77 (28%)
83 (25%)
Intermediate
84 (31%)
75 (22%)
Adverse
83 (30%)
103 (30%)
Unknown
31 (11%)
77 (23%)
Disease status at transplant (n%)
0.79
CRc
238 (87%)
287 (85%)
PR
10 (4%)
16 (5%)
NR
27 (10%)
35 (10%)
Sorafenib pre-transplant (n%)
0.028
Use
149 (54%)
153 (45%)
No use
126 (46%)
185 (55%)
Transplant modality (n%)
0.99
MSD
112 (41%)
139 (41%)
MUD
22 (8%)
20 (6%)
HID
141 (51%)
179 (53%)
WBC white blood cell, CRc composite complete remission, PR partial remission, NR non-remission, MSD HLA-matched sibling donor, MUD HLA-matched
unrelated donor, HID HLA-haploidentical donor Table 1. Clinical and Treatment Characteristics WBC white blood cell, CRc composite complete remission, PR partial remission, NR non-remission, MSD HLA-matched sibling donor, MUD HLA-matched
unrelated donor, HID HLA-haploidentical donor 74.8%–84.6%) and 65.2% (95% CI 60.3%–70.6%), (HR 0.50, 95% CI
0.37–0.69; P < 0.001) (Fig. 3a), and disease-free survival (DFS) was
75.8% (95% CI 70.8%–81.1%) and 57.5% (95% CI 52.4%–63.1%) (HR
0.48, 95% CI 0.36–0.64; P < 0.001) in the sorafenib and control
groups, respectively (Fig. 3b). RESULTS
l
l The 3-year cumulative incidence of
relapse (CIR) was 17.2% (95% CI 13.0%–22.0%) in the sorafenib
group and 31.8% (95% CI 26.9%–36.8%) (HR 0.49, 95% CI
0.35–0.69; P < 0.001) in the control group (Fig. 3c). We further
divided patients into four subgroups based on use of sorafenib
pre- and post-transplantation: non-sorafenib pre-transplantation
and post-transplantation (group A); sorafenib pre-transplantation
only (group B); sorafenib post-transplantation only (group C); and
sorafenib pre- and post-transplantation both (group D) for
subgroup analyses. Significant differences were observed in OS,
DFS, and relapse among groups A-D (Supplementary Fig. S4a–c). Group B, C and D all had superior OS, DFS and CIR compared to
group A (Supplementary Fig. S5a). Group C and D both had
superior DFS compared to group B, and Group D had superior CIR
compared to group B. No significant difference was observed
between group C and D (Supplementary Fig. S5a). Multivariate
COX analysis revealed that use of sorafenib pre- and post-
transplantation both were associated with improved OS (HR 0.73,
95% CI 0.54–0.99; P = 0.04 and HR 0.52, 95% CI 0.38–0.72;
P < 0.001, respectively), DFS (HR 0.71, 95% CI 0.54–0.94; P = 0.02
and HR 0.50, 95% CI 0.37–0.67; P < 0.001, respectively), and relapse
(HR 0.69, 95% CI 0.50–0.94; P = 0.02 and HR 0.50, 95% CI 0.35–0.70;
P < 0.001, respectively) (Table 2). Genetic landscape Genetic landscape
Of the 613 patients enrolled, Giemsa and reverse banding result
was available in 577 patients, while fluorescence in-situ hybridiza-
tion (FISH) data was available in all the patients. A total of 448
patients had a normal cytogenetics, and 165 an aberrant
cytogenetics, including 46 favorable, 508 intermediate, and 59
adverse cytogenetics. Cytogenetic abnormality patterns were
shown in Supplementary Fig. S1. For gene mutations, a total of
1285 concomitant mutations were detected. Four hundred and
ten patients (67%) harbored at least one concomitant mutation,
along with 191 (69%) and 219 (65%) in the sorafenib and control
groups, respectively. Concomitant mutations with top 5 occur-
rence were NPM1 (32%), DNMT3A (16%), TET2 (14%), CEBPA
(10%), and IDH2 (7%). The concomitant genetic patterns with ≥1%
occurrence are shown in Fig. 2. The top 20 most frequently
detected gene mutations were tested for pair-wise mutual
exclusivity and co-occurrence in patients with next generation
sequencing (NGS) data (Supplementary Figs. S2, S3). Group
Allelic ratio
ELN stratification Fig. 2
Genetic patterns of the whole population (mutation frequency ≥1%) A total of 267 patients experienced acute GVHD (aGVHD),
including 126 in the sorafenib group and 141 in the control group
(P = 0.31). The 3-year cumulative incidence of chronic GVHD
(cGVHD) was 49.8% (95% CI 43.7%–55.7%) in the sorafenib group
and 46.4% (95% CI 40.9%–51.6%) (HR 1.08, 95% CI 0.86–1.36;
P = 0.52) in the control group (Supplementary Fig. S6). other subgroups (Supplementary Fig. S7). For cytogenetic risk, the
results showed that sorafenib post-transplantation maintenance in
patients with intermediate (HR 0.57, 95% CI 0.40–0.81; P = 0.001)
and adverse (HR 0.33, 95% CI 0.13–0.82; P = 0.02) cytogenetics had
a significant benefit on OS, while patients with favorable (HR 0.15,
95% CI 0.02–1.16; P = 0.07) cytogenetics had the same trend
(Supplementary Fig. S8). pp
y
g
Based on concomitant mutations, we analyzed gene mutations in
patients with >5% occurrence and triple-mutated (co-occurring
NPM1, DNMT3A and FLT3-ITD mutations) (Fig. 4). Multivariate COX
regression results showed that patients with mutated NPM1 (HR 0.48,
95% CI 0.26–0.89; P = 0.02), DNMT3A (HR 0.36, 95% CI 0.15–0.85;
P = 0.02), and triple-mutated (HR 0.32, 95% CI 0.10–0.99; P = 0.049) in
the sorafenib group had superior OS than the control group, and
those with TET2 (HR 0.52; 95% CI 0.24–1.11; P = 0.09) and IDH1/2 (HR
0.37; 95% CI 0.12–1.15; P = 0.09) in the sorafenib group showed a
trend of improved OS. There was no significant difference in OS of
patients with CEBPA (HR 1.12; 95% CI 0.36–3.50; P = 0.85), ASXL1 (HR
0.60; 95% CI 0.11–3.35; P = 0.56), TET1 (HR 0.56; 95% CI 0.10–3.23;
P = 0.52), CD101 (HR 0.41; 95% CI 0.08–2.07; P = 0.28), EP300 (HR 0.37;
95% CI 0.08–1.78; P = 0.21), and RUNX1 (HR 0.57; 95% CI 0.14–2.39;
P = 0.44) mutations between the two groups (Fig. 4). Effects of sorafenib on survival based on Genetic patterns
Based on ELN 2017 risk stratification, the results showed that
sorafenib post-transplantation significantly improved OS in the
favorable (HR 0.33, 95% CI 0.14–0.77; P = 0.01) and adverse (HR
0.56, 95% CI 0.33–0.93; P = 0.03) risk groups but not in the
intermediate risk group (HR 0.69, 95% CI 0.39–1.23; P = 0.22) (Fig. 3d–f). Signal Transduction and Targeted Therapy (2023) 8:348 RESULTS
l
l A total of 11
pairs were statistically significant for mutual exclusivity after
adjustment for false discovery rate (FDR) (Supplementary Fig. S2). For co-occurrence, 11 pairs were significant for independent test,
but none remained significant after FDR adjustment (Supplemen-
tary Fig. S2). Survival, relapse, and GVHD Survival, relapse, and GVHD
The median follow-up was 36.5 (IQR, 25.2–44.7) months post-
transplantation. The 3-year overall survival (OS) was 79.6% (95% CI Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 4 0
5
10
Group
Allelic ratio
ELN stratification
100%
5%
2%
2%
3%
2%
5%
3%
5%
3%
2%
1%
1%
1%
1%
16%
14%
7%
5%
4%
2%
5%
5%
5%
2%
2%
3%
2%
2%
5%
2%
1%
32%
6%
5%
5%
1%
2%
1%
1%
1%
FLT3
NRAS
PTPN11
PDGFRB
KIT
KRAS
ASXL1
EZH2
MLL
BCOR
ACTR5
IRF6
KDM5A
KDM6A
MLL3
DNMT3A
TET2
IDH2
TET1
IDH1
DNMT1
RUNX1
CEBPAbi
CEBPAmono
ETV6
GATA2
DDX18
BCL6
FAM46C
WT1
TP53
PHF6
NPM1
EP300
CD101
FAT1
MYH11
SH2B3
STAG2
SRSF2
MPL
0
200
400
600
Classification
Activated signaling
Chromatin modifiers
DNA methylation
Myeloid TFs
Tr anscription
Tumor suppressors
Other
Group
Control
Sorafenib
Allelic ratio
FLT3-ITD low
FLT3-ITD high
NA
ELN stratification
Favorable
Intermediate
Adverse
NA
4 0
5
10
Group
Allelic ratio
ELN stratification
100%
5%
2%
2%
3%
2%
5%
3%
5%
3%
2%
1%
1%
1%
1%
16%
14%
7%
5%
4%
2%
5%
5%
5%
2%
2%
3%
2%
2%
5%
2%
1%
32%
6%
5%
5%
1%
2%
1%
1%
1%
FLT3
NRAS
PTPN11
PDGFRB
KIT
KRAS
ASXL1
EZH2
MLL
BCOR
ACTR5
IRF6
KDM5A
KDM6A
MLL3
DNMT3A
TET2
IDH2
TET1
IDH1
DNMT1
RUNX1
CEBPAbi
CEBPAmono
ETV6
GATA2
DDX18
BCL6
FAM46C
WT1
TP53
PHF6
NPM1
EP300
CD101
FAT1
MYH11
SH2B3
STAG2
SRSF2
MPL
0
200
400
600
Classification
Activated signaling
Chromatin modifiers
DNA methylation
Myeloid TFs
Tr anscription
Tumor suppressors
Other
Group
Control
Sorafenib
Allelic ratio
FLT3-ITD low
FLT3-ITD high
NA
ELN stratification
Favorable
Intermediate
Adverse
NA
Fig. 2
Genetic patterns of the whole population (mutation frequency ≥1%) Group
Allelic ratio
ELN stratification Subgroup analyses showed significant differences in OS
among groups A-D in patients with favorable and adverse risk, but
not in patients with intermediate risk (Supplementary Fig. S4d–f). Compared to group A, group C had superior OS in patients with
favorable (HR 0.16, 95% CI 0.04–0.71; P = 0.02) and adverse (HR
0.47, 95% CI 0.22–0.99; P = 0.05) risk, and group D had superior OS
in patients with adverse (HR 0.43, 95% CI 0.22–0.83; P = 0.01) risk
(Supplementary Fig. S5b). No significant difference was observed
among groups B, C and D in patients with favorable, intermediate,
or adverse risk (Supplementary Fig. S5b). ELN risk subgroups were
further dissected by different genetic patterns. The OS of the
sorafenib and control groups was compared in the 5 largest
genetic pattern subgroups of each ELN risk level (Supplementary
Fig. S7). Subgroup details were shown in Table S2. Except the
Adverse-Cytogenetics subgroup (HR 0.31, 95% CI 0.12–0.78;
P = 0.01) who benefitted significantly from sorafenib maintenance
post-transplantation, no significant difference was observed in g
p
g
We next explored mutations in 6 gene ontology groups
(“activated signaling”, “DNA methylation”, “transcription”, “chromatin
modifiers”, “tumor suppressor”, and “myeloid transcription factors”)
(Supplementary Table 3). The results are shown in Fig. 4. Patients
carrying mutated “activated signaling” (HR 0.20, 95% CI 0.06–0.73;
P = 0.02) and “DNA methylation” (HR 0.46, 95% CI 0.27–0.80;
P = 0.01) genes with sorafenib maintenance post-transplantation
had superior OS than those with control, and those with Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Group
Allelic ratio
ELN stratification 5 +
+
+ +++
+ +
+
+ ++
++
+ +
++ + + + +
++
++ +
+ + +++
+ ++
++ +
+
++
++
+
++
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+ + +
++
+
++
++ +
+
+
+
+
+ ++
+
+ + +
+
+
+
+
++ ++
++
+
+
+++
+
+
+
+
+
++
+
+
+
+
+
+
++
+
+ +
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
overall survival (%)
103
59
14
3
1
83
57
14
4
0
sorafenib
control
Number at risk
+
+
++
+ +
+
+ ++
++
+++++ +
+
++
+ +++
+ ++
+
+
+
+
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
++
+
+ ++ +++
+++++ +
+ ++
+
+ ++
+ +
++ + ++
+
+
++
+
+
+
++
+
++
+
+ +
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
overall survival (%)
75
54
15
3
0
84
63
12
2
1
control
Number at risk
sorafenib
0%
25%
50%
75%
100%
0
25
50
75
100
month
+ +
+
+ ++++
+ +
+
+
+
+
+
+
+
++
+ +
+++ +++
+ ++
+
+ ++
+ ++ +
+ +
+++ ++ +++ + + +++++++++++ + + ++++++
+++ + + + ++++++
+ ++ ++
+
+ +
+
+++
+++
++ + +
++ +
+++++++
++ + +++
+
+
++
+
+
++
++ +
+
+++ + + +
+ ++
+
++
++ +
+ ++
+
++
+
+
+
+
+
+
+
+
+ +
+
+
+
++
+
+ +
+
+ +
+
++
+++++
+ ++++ +
+ +
++
+ ++
+ ++
+
+++
+ +
+
+++++
+ +
++
+
+ ++++++ +
+++++
++++ +
+++ +++ +++ + + ++ +++ + +++ ++++++++ +++ +++ ++++
++++++
++
+ +++ + + ++ +++++++
+ ++ +
++++ + ++ +
+ +++
+++ +++
+
++ +
+++
+
+
++
+
++ +
+
+
+
+
+
++
++
+++
+
+
+
+ +
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
Disease−free survival (%)
338
195
57
10
2
275
199
39
8
0
sorafenib
control
Number at risk
338
195
57
10
2
275
199
39
8
0
sorafenib
control
Number at risk
+
+
+
+ ++++ + ++
+++
+
++ +
+
++
+ +
+++
+++
+ +++
+
+ ++
+ ++ +
+
+
+++ ++ +++ + ++ +++++++++++ + + +
+++++ ++++++
+ + ++++++
+ + +++ ++ +
+
+ + + +
+
++
+++
++ + +
++ +
+++++++
++ + +++
+
+
+++
++
++
+
+ ++
++ +
+
+++
+ + ++
+ +++
+
++
++ +
+ ++
++
++
+
+
+
+
+
+
+
+
+
+ +
+
+
+
++
+
+ +
+
+ +
+
++
+++
++
+ ++++
+
++
+
+++
+ ++
+ ++
+
+++
+ +
+
+++
++
+ +
++
+
+ ++++++ +
++++++
++++ +
+++ +++ +++ + + ++ +++ + +++ ++++++++ +++ +++ +++++
++++++ + ++
+ +
++ + ++ ++ +++++++
+ ++ ++
++++ + ++ +
+ +++
+++ +++
+
++ +
+++
+
+
++
+
++ +
+
+
+
+
+
+
++
++
+++
+
++
+
+ +
+
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
overall survival (%)
338
230
67
10
2
275
213
42
9
1
sorafenib
control
Number at risk
a
b
c
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
ELN intermediate
ELN adverse
e
f
+
P < 0.001
Hazard ratio 0.51, 95% CI 0.37 – 0.69
Control group
Sorafenib group
+
P < 0.001
Hazard ratio 0.48, 95% CI 0.36 – 0.65
Control group
Sorafenib group
P < 0.001
Hazard ratio 0.49, 95% CI 0.35 – 0.69
Control group
Sorafenib group
+
+
+
+
+
+
+
+
+
+
+ +
+ +
+
+
++
+
+
+
+
+ +
+
+
+
+ +
+
+
+
+
+
+ +
+
++
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
20
40
60
80
month
overall survival (%)
83
66
35
10
1
77
73
38
3
1
sorafenib
control
Number at risk
ELN favorable
d
P = 0.01
Hazard ratio 0.33, 95% CI 0.14 – 0.77
Control group
Sorafenib group
P = 0.22
Hazard ratio 0.69, 95% CI 0.39 – 1.23
Control group
Sorafenib group
P = 0.03
Hazard ratio 0.56, 95% CI 0.33 – 0.93
Control group
Sorafenib group
cumulative incidence of relapse (%)
0
25
50
75
100
0
25
50
75
100
month
0
25
50
75
100
month
0
25
50
75
100
month
0
25
50
75
100
month
0
20
40
60
80
month
g. Group
Allelic ratio
ELN stratification Overall survival of
patients with (d) favorable, (e) intermediate, and (f) adverse ELN risk in the sorafenib and control groups “transcription” genes showed the superior trend (HR 0.15, 95% CI
0.01–1.53; P = 0.11), but not those with “tumor suppressors” (HR
1.16, 95% CI 0.39–3.45; P = 0.79), “myeloid transcription factors” (HR
0.72, 95% CI 0.33–1.57; P = 0.40), and “chromatin modifiers” genes
(HR 0.63, 95% CI 0.31–1.29; P = 0.20) (Fig. 4). decreased sorafenib response, we next explored whether con-
comitant mutations associated with sorafenib sensitivity using
bulk RNA-seq data of bone marrow cells from FLT3-ITD AML
patients. A total of 197 FLT3-ITD AML patients with available RNA-
seq and mutational data was collected from the BeatAML and
TCGA-LAML datasets. Effects of sorafenib on FLT3-ITD AR Effects of sorafenib on FLT3-ITD AR
Based on FLT3-ITD AR, 471 patients obtained FLT3-ITD AR data,
with 214 FLT3-ITDhigh (AR ≥0.50) and 257 FLT3-ITDlow (AR < 0.50).4
Sorafenib maintenance post-transplantation improved
OS in
patients with FLT3-ITDhigh (HR 0.55, 95% CI 0.34–0.90; P = 0.02)
and FLT3-ITDlow (HR 0.54, 95% CI 0.32–0.92; P = 0.02) (Supplemen-
tary Fig. S9a, b). In subgroup analyses, significant difference was
found in FLT3-ITDhigh (P = 0.004) but not FLT3-ITDlow (P = 0.07)
patients among groups A-D (Supplementary Fig. S9c, d). In FLT3-
ITDhigh patients, compared to group A, group B (HR 0.48, 95% CI
0.26–0.87; P = 0.02), C (HR 0.49, 95% CI 0.26–0.94; P = 0.03) and D
(HR 0.33, 95% CI 0.16–0.65; P = 0.001) all had improved OS, while in
FLT3-ITDlow, significant difference was found in group C compared
with group A (HR 0.39, 95% CI 0.18–0.85; P = 0.02), a trend of
improved OS was also found in group D (HR 0.54, 95% CI 0.28–1.04;
P = 0.07) (Supplementary Fig. S10). No significant difference was
observed among groups B, C and D in either FLT3-ITDhigh or FLT3-
ITDlow patients (Supplementary Fig. S10). Patients were grouped according to concomitant mutations
(Supplementary Fig. S11a), and the half maximal inhibitory
concentration (IC50) of sorafenib was compared among groups
(Supplementary Fig. S11b). Interestingly, group 1 had the highest
IC50 among the 4 groups, while group 2 had the lowest, and
group 0 and group 3 had an intermediate IC50 as compared to the
other 2 groups (Supplementary Fig. S11b). Group
Allelic ratio
ELN stratification 3
Comparisons of outcomes between the sorafenib and control groups in the whole cohort and ELN risk subgroups. a Overall surviva
b disease-free survival, and c cumulative incidence of relapse in the sorafenib and control groups in the whole population. Overall survival o
patients with (d) favorable, (e) intermediate, and (f) adverse ELN risk in the sorafenib and control groups 0%
25%
50%
75%
100
overall survival (%)
contro
sorafen
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
e
+
+
+
+
+
+
+
+
+
+
+ +
+ +
+
+
++
+
+
+
+
+ +
+
+
+
+ +
+
+
+
+
+
+ +
+
++
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
20
40
60
80
month
overall survival (%)
83
66
35
10
1
77
73
38
3
1
sorafenib
control
Number at risk
ELN favorable
d
P = 0.01
Hazard ratio 0.33, 95% CI 0.14 – 0.77
Control group
Sorafenib group
0
20
40
60
80
month d Fig. 3
Comparisons of outcomes between the sorafenib and control groups in the whole cohort and ELN risk subgroups. a Overall survival,
b disease-free survival, and c cumulative incidence of relapse in the sorafenib and control groups in the whole population. Group
Allelic ratio
ELN stratification 3
Comparisons of outcomes between the sorafenib and control groups in the whole cohort and ELN risk subgroups. a Overall survival,
disease-free survival, and c cumulative incidence of relapse in the sorafenib and control groups in the whole population. Signal Transduction and Targeted Therapy (2023) 8:348 Group
Allelic ratio
ELN stratification Overall survival of
atients with (d) favorable, (e) intermediate, and (f) adverse ELN risk in the sorafenib and control groups 0%
25%
50%
75%
100%
0
25
50
75
100
month
+ +
+
+ ++++
+ +
+
+
+
+
+
+
+
++
+ +
+++ +++
+ ++
+
+ ++
+ ++ +
+ +
+++ ++ +++ + + +++++++++++ + + ++++++
+++ + + + ++++++
+ ++ ++
+
+ +
+
+++
+++
++ + +
++ +
+++++++
++ + +++
+
+
++
+
+
++
++ +
+
+++ + + +
+ ++
+
++
++ +
+ ++
+
++
+
+
+
+
+
+
+
+
+ +
+
+
+
++
+
+ +
+
+ +
+
++
+++++
+ ++++ +
+ +
++
+ ++
+ ++
+
+++
+ +
+
+++++
+ +
++
+
+ ++++++ +
+++++
++++ +
+++ +++ +++ + + ++ +++ + +++ ++++++++ +++ +++ ++++
++++++
++
+ +++ + + ++ +++++++
+ ++ +
++++ + ++ +
+ +++
+++ +++
+
++ +
+++
+
+
++
+
++ +
+
+
+
+
+
++
++
+++
+
+
+
+ +
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
Disease−free survival (%)
338
195
57
10
2
275
199
39
8
0
sorafenib
control
Number at risk
338
195
57
10
2
275
199
39
8
0
sorafenib
control
Number at risk
+
+
+
+ ++++ + ++
+++
+
++ +
+
++
+ +
+++
+++
+ +++
+
+ ++
+ ++ +
+
+
+++ ++ +++ + ++ +++++++++++ + + +
+++++ ++++++
+ + ++++++
+ + +++ ++ +
+
+ + + +
+
++
+++
++ + +
++ +
+++++++
++ + +++
+
+
+++
++
++
+
+ ++
++ +
+
+++
+ + ++
+ +++
+
++
++ +
+ ++
++
++
+
+
+
+
+
+
+
+
+
+ +
+
+
+
++
+
+ +
+
+ +
+
++
+++
++
+ ++++
+
++
+
+++
+ ++
+ ++
+
+++
+ +
+
+++
++
+ +
++
+
+ ++++++ +
++++++
++++ +
+++ +++ +++ + + ++ +++ + +++ ++++++++ +++ +++ +++++
++++++ + ++
+ +
++ + ++ ++ +++++++
+ ++ ++
++++ + ++ +
+ +++
+++ +++
+
++ +
+++
+
+
++
+
++ +
+
+
+
+
+
+
++
++
+++
+
++
+
+ +
+
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
overall survival (%)
338
230
67
10
2
275
213
42
9
1
sorafenib
control
Number at risk
a
b
c
+
P < 0.001
Hazard ratio 0.51, 95% CI 0.37 – 0.69
Control group
Sorafenib group
+
P < 0.001
Hazard ratio 0.48, 95% CI 0.36 – 0.65
Control group
Sorafenib group
P < 0.001
Hazard ratio 0.49, 95% CI 0.35 – 0.69
Control group
Sorafenib group
cumulative incidence of relapse (%)
0
25
50
75
100
month
0
25
50
75
100
month
0
25
50
75
100
month 1
b a +
+
+ +++
+ +
+
+ ++
++
+ +
++ + + + +
++
++ +
+ + +++
+ ++
++ +
+
++
++
+
++
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+ + +
++
+
++
++ +
+
+
+
+
+ ++
+
+ + +
+
+
+
+
++ ++
++
+
+
+++
+
+
+
+
+
++
+
+
+
+
+
+
++
+
+ +
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
overall survival (%)
103
59
14
3
1
83
57
14
4
0
sorafenib
control
Number at risk
+
+
++
+ +
+
+ ++
++
+++++ +
+
++
+ +++
+ ++
+
+
+
+
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
++
+
+ ++ +++
+++++ +
+ ++
+
+ ++
+ +
++ + ++
+
+
++
+
+
+
++
+
++
+
+ +
+
+
+
+
+
0%
25%
50%
75%
100%
0
25
50
75
100
month
overall survival (%)
75
54
15
3
0
84
63
12
2
1
control
Number at risk
sorafenib
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
ELN intermediate
ELN adverse
e
f
+
+
+
+
+
+
+
+
+
+
+ +
+ +
+
+
++
+
+
+
+
+ +
+
+
+
+ +
+
+
+
+
+
+ +
+
++
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
+
+
+
+
+ +
+
+ +
+
++
+
+
+ + + + + +
+ +
+++ +
++
++
+ +
++
+++ +
++ +
+ + + +
+
+
+
+
+
+
+
+
+
+
+
0%
25%
50%
75%
100%
0
20
40
60
80
month
overall survival (%)
83
66
35
10
1
77
73
38
3
1
sorafenib
control
Number at risk
ELN favorable
d
P = 0.01
Hazard ratio 0.33, 95% CI 0.14 – 0.77
Control group
Sorafenib group
P = 0.22
Hazard ratio 0.69, 95% CI 0.39 – 1.23
Control group
Sorafenib group
P = 0.03
Hazard ratio 0.56, 95% CI 0.33 – 0.93
Control group
Sorafenib group
0
25
50
75
100
0
25
50
75
100
month
0
20
40
60
80
month
Fig. Group
Allelic ratio
ELN stratification Both group 2
(P = 0.007) and group 0 (P = 0.02) had significantly lower IC 50
than group 1(Supplementary Fig. S11b). y
Since group 1 showed higher sorafenib resistance than group 2,
we next performed differential analyses between the two groups
to discover the possible mechanisms for this difference (Supple-
mentary Fig. S11c). A total of 2245 significantly differentially
expressed genes was observed, with 914 highly expressed in
group 1 and 1331 in group 2 (Supplementary Fig. S11c). Notably,
the highly expressed genes in group 1 enriched in JAK-STAT
pathway, MAPK cascade, and ERK cascade (Supplementary Fig. S11d). Similar results were also obtained in gene set variation
analysis (GSVA) (Supplementary Fig. S11e). Given that the
alternative activation of FLT3 downstream signaling like STATs,
mTOR, and MAPK was an important mechanism of sorafenib
resistance, we hypothesized that concomitant tumor suppressors
or myeloid transcription factors mutations in FLT3-ITD AML drove
sorafenib resistance via activating FLT3 downstream signaling. The association between tumor suppressor and myeloid
transcription factor mutations and sorafenib sensitivity, and the
mutational evolution of FLT3-ITD AML Since we observed association between concomitant “tumor
suppressor”, and “myeloid transcription factors” mutations and Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 6 6 Table 2. Signal Transduction and Targeted Therapy (2023) 8:348 Group
Allelic ratio
ELN stratification 4
Multivariate COX results of sorafenib maintenance post-transplantation effects on the subgroups with different ELN risk groups, FLT3-
ITD AR, and genetic patterns Fig. 4
Multivariate COX results of sorafenib maintenance post-transplantation effects on the subgroups w
ITD AR, and genetic patterns Fig. 4
Multivariate COX results of sorafenib maintenance post-transplantation effects on the subgroups with different ELN risk groups, FLT3-
ITD AR, and genetic patterns Fig. 4
Multivariate COX results of sorafenib maintenance post-transplantation effects on the subgroups with different ELN risk groups, FLT3-
ITD AR, and genetic patterns patterns. Meanwhile, we further confirmed the results of previous
retrospective
and
prospective
studies,9,14,16,20,31,32
in
which
sorafenib pre- or post-transplantation both could improve survival
in patients with FLT3-ITD AML without increasing the risk of GVHD,
especially sorafenib maintenance post-transplantation. TP53 was chosen as a representative to test this hypothesis. We
electrotransfected pLenti-CMV-TP53(R248Q)-GFP-Puro (TP53 mut),
pLenti-CMV-TP53-GFP-Puro (TP53 WT), and pLenti-CMV-GFP-Puro
(EV) into MV411 cells (Supplementary Fig. S11f). As shown by the
results of CCK-8 assay, the TP53 mut groups had significantly
higher cell viability after treated with sorafenib for 24 and 48 h
compared to the TP53 WT and EV groups (Supplementary Fig. S11g). Addition of STAT3 inhibitor significantly reduced sorafenib
resistance
in
TP53
mut
groups
of
at
both
24
and
48 h
(Supplementary Fig. S11h). Taking together, these data suggested
that TP53 mutation might drive sorafenib resistance via activating
the JAK-STAT signaling pathway in FLT3-ITD AML. The effect of FLT3 inhibitors is correlated with genetic patterns
in patients receiving chemotherapy.6,18,28,29 However, the role of
FLT3 inhibitors in different genetic patterns remains unclear. An
analysis of RCT data revealed that FLT3-ITD AML patients with all
ELN cytogenetic risk groups might benefit from midostaurin, while
another report about midostaurin reported an improved relapse
rate in the intermediate risk group only.6,33 In this study, our
results showed that sorafenib post-transplantation could improve
survival of FLT3-ITD AML patients with both favorable and adverse
risk, but did not in those with intermediate risk. The results require
to be verified by large-sample clinical studies. g
g p
y
Finally, we explored the mutational evolution of FLT3-ITD AML. The genetic patterns of patients who relapsed with NGS data at
both diagnosis and relapse were analyzed (Supplementary Fig. S12). A total of 21 patients were analyzed, including 6 in the
sorafenib group and 15 in the control group. Group
Allelic ratio
ELN stratification Subgroup
Whole cohort
FLT3−ITD AR
high
low
ELN 2017 risk
Favorable
Intermediate
Adverse
Unknown
Mutations
Triple−mutated AML
DNMT3A
IDH1/2
EP300
CD101
NPM1
TET2
TET1
RUNX1
ASXL1
CEBPA
Ontology groups
transcription
activated signaling
DNA methylation
chromatin modifiers
myeloid transcription factors
tumor suppressors
Sorafenib
events(n)/cases(N)
55/275
24/96
22/134
7/77
21/84
22/83
5/31
5/32
10/47
6/31
3/21
3/19
15/91
11/39
3/17
3/15
4/17
6/30
1/19
3/38
18/95
13/54
11/51
8/25
Control
events(n)/cases(N)
124/338
49/118
36/123
22/83
27/75
44/103
31/77
15/34
24/53
13/35
7/13
4/12
35/105
22/44
5/14
8/18
5/16
7/30
5/15
14/45
42/106
22/58
17/56
7/22
Hazard ratio(95%CI)
0.50 (0.37−0.69)
0.55 (0.34−0.90)
0.55 (0.32−0.94)
0.32 (0.14−0.76)
0.67 (0.38−1.20)
0.55 (0.33−0.91)
0.32 (0.12−0.84)
0.32 (0.10−0.99)
0.36 (0.15−0.85)
0.37 (0.12−1.15)
0.37 (0.08−1.78)
0.41 (0.08−2.07)
0.48 (0.26−0.89)
0.52 (0.24−1.11)
0.56 (0.10−3.23)
0.57 (0.14−2.39)
0.60 (0.11−3.35)
1.12 (0.36−3.50)
0.15 (0.01−1.53)
0.20 (0.06−0.73)
0.46 (0.27−0.80)
0.63 (0.31−1.29)
0.72 (0.33−1.56)
1.16 (0.39−3.45)
P value
< 0.001
0.02
0.03
0.01
0.18
0.02
0.02
0.049
0.02
0.09
0.21
0.28
0.02
0.09
0.52
0.44
0.56
0.85
0.11
0.02
0.01
0.20
0.40
0.79
0.05
0.25 0.50 1.00 2.00 4.00
20.00
Fig. 4
Multivariate COX results of sorafenib maintenance post-transplantation effects on the subgroups with different ELN risk groups, FLT3-
TD AR, and genetic patterns Subgroup
Whole cohort
FLT3−ITD AR
high
low
ELN 2017 risk
Favorable
Intermediate
Adverse
Unknown
Mutations
Triple−mutated AML
DNMT3A
IDH1/2
EP300
CD101
NPM1
TET2
TET1
RUNX1
ASXL1
CEBPA
Ontology groups
transcription
activated signaling
DNA methylation
chromatin modifiers
myeloid transcription factors
tumor suppressors
Sorafenib
events(n)/cases(N)
55/275
24/96
22/134
7/77
21/84
22/83
5/31
5/32
10/47
6/31
3/21
3/19
15/91
11/39
3/17
3/15
4/17
6/30
1/19
3/38
18/95
13/54
11/51
8/25
Control
events(n)/cases(N)
124/338
49/118
36/123
22/83
27/75
44/103
31/77
15/34
24/53
13/35
7/13
4/12
35/105
22/44
5/14
8/18
5/16
7/30
5/15
14/45
42/106
22/58
17/56
7/22
Hazard ratio(95%CI)
0.50 (0.37−0.69)
0.55 (0.34−0.90)
0.55 (0.32−0.94)
0.32 (0.14−0.76)
0.67 (0.38−1.20)
0.55 (0.33−0.91)
0.32 (0.12−0.84)
0.32 (0.10−0.99)
0.36 (0.15−0.85)
0.37 (0.12−1.15)
0.37 (0.08−1.78)
0.41 (0.08−2.07)
0.48 (0.26−0.89)
0.52 (0.24−1.11)
0.56 (0.10−3.23)
0.57 (0.14−2.39)
0.60 (0.11−3.35)
1.12 (0.36−3.50)
0.15 (0.01−1.53)
0.20 (0.06−0.73)
0.46 (0.27−0.80)
0.63 (0.31−1.29)
0.72 (0.33−1.56)
1.16 (0.39−3.45)
P value
< 0.001
0.02
0.03
0.01
0.18
0.02
0.02
0.049
0.02
0.09
0.21
0.28
0.02
0.09
0.52
0.44
0.56
0.85
0.11
0.02
0.01
0.20
0.40
0.79
0.05
0.25 0.50 1.00 2.00 4.00
20.00
Fig. Group
Allelic ratio
ELN stratification Eight patients lost
FLT3-ITD at relapse, including 3 in the sorafenib group and 5 in the
control
group. Five
patients
acquired
“activated
signaling”
mutations at relapse (2 acquired NRAS, 2 acquired KRAS, and 1
acquired KIT), among which 4 received sorafenib (3 received pre-
transplantation sorafenib, and 1 received both pre- and post-
transplantation sorafenib) (Supplementary Fig. S12). Of note, 3
patients in the sorafenib and 1 patient in the control group
acquired FLT3 tyrosine kinase domain (TKD) mutation at relapse. However, none of these patients received NGS and were thus not
analyzed. y
As for gene mutations, FLT3-mutated AML patients with NPM1
receiving chemotherapy were reported to benefit from sorafenib,
gilteritinib and midostaurin.18,28,29 Recently, Smith et al. reported
that gilteritinib improved OS in the patients with co-occurring
mutations on NPM1, DNMT3A and triple-mutated, but could not
overcome those with TP53.28 These results came mainly from the
patients undergoing chemotherapy. In this study, we focused on
the effect of sorafenib on the outcomes of FLT3-ITD AML patients
undergoing allo-HSCT. The results of our large-scale cohort
revealed that most concomitant genetic patterns showed a trend
of favoring the sorafenib group. Patients with co-occurring NPM1,
DNMT3A and triple-mutated benefited significantly from sorafenib
maintenance post-transplantation, which were in consistent with
the results reported in the chemotherapy setting.18,28 However,
those with co-occurring CEBPA mutation did not benefit from
sorafenib
maintenance
post-transplantation. One
reasonable
interpretation of this finding was that the beneficial effects of
sorafenib might be overwhelmed by allo-HSCT in patients with Group
Allelic ratio
ELN stratification Univariable and multivariate analyses for overall survival, disease–free survival, and relapse
Overall survivala
Disease–free survivala
Cumulative incidence of relapseb
Univariate
HR (95% CI); p
Multivariate
HR (95% CI); p
Univariate
HR (95% CI); p
Multivariate
HR (95% CI); p
Univariate
HR (95% CI); p
Multivariate
HR (95% CI); p
Sex, male vs female
1.15 (0.86–1.54); 0.35
–
1.10 (0.84–1.43); 0.50
–
1.08 (0.79–1.47); 0.65
–
Age, >36 years vs ≤36 years
1.24 (0.92–1.66); 0.16
–
1.19 (0.91–1.56); 0.19
–
1.11 (0.81–1.52); 0.51
–
WBC, >53 × 109/L vs ≤53 × 109/L
1.09 (0.81–1.46); 0.59
–
1.10 (0.84–1.44); 0.48
–
1.09 (0.80–1.49); 0.60
–
Transplant modality
0.70
–
0.56
–
0.37
–
MSD
1
–
1
–
1
–
MUD
1.34 (0.67–2.67); 0.41
–
1.39 (0.76–2.55); 0.28
–
1.61 (0.83–3.13); 0.16
–
HID
1.09 (0.73–1.62); 0.67
–
1.08 (0.76–1.53); 0.67
–
1.15 (0.77–1.72); 0.51
–
ELN risk stratification
0.0052
0.044
0.00053
0.0073
0.00072
0.0018
Favorable
1
1
1
1
1
1
Intermediate
1.77 (1.12–2.81); 0.015
1.78 (1.11–2.84); 0.016
1.85 (1.21–2.82); 0.0047
1.90 (1.23–2.92); 0.0036
1.96 (1.18–3.27); 0.010
2.04 (1.23–3.41); 0.0061
Adverse
2.20 (1.42–3.41);
0.00040
1.87 (1.16–3.03); 0.011
2.19 (1.46–3.28);
0.00014
2.11 (1.35–3.30); 0.0011
2.38 (1.46–3.86);
0.00048
2.40 (1.47–3.90);0.00043
Unknown
1.89 (1.16–3.09); 0.011
1.26 (0.60–2.66); 0.55
2.34 (1.51–3.63);
0.00015
2.05 (1.00–4.21); 0.052
2.81 (1.68–4.70);
<0.0001
2.56 (1.53–4.29); 0.00037
Allelic ratio, ≥0.5 vs < 0.5
1.66 (1.18–2.34); 0.0040
1.35 (0.91–1.99); 0.13
1.41 (1.30–1.94); 0.032
1.09 (0.76–1.55); 0.64
1.29 (0.89–1.86); 0.18
–
Pre-transplantation sorafenib, used vs not
used
0.74 (0.55–0.99); 0.043
0.73 (0.54–0.99); 0.041
0.70 (0.54–0.92); 0.011
0.71 (0.54–0.94); 0.015
0.68 (0.49–0.93); 0.015
0.69 (0.50–0.94); 0.019
Post-transplantation sorafenib, used vs
not used
0.50 (0.37–0.69);
<0.0001
0.52 (0.38–0.72);
<0.0001
0.48 (0.36–0.64);
<0.0001
0.50 (0.37–0.67);
<0.0001
0.47 (0.33–0.66);
<0.0001
0.50 (0.35–0.70); 0.00062
aResults of COX regression analyses Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Signal Transduction and Targeted Therapy (2023) 8:348 DISCUSSION In this study, we characterized the mutational landscape and its
clinical significance in 613 patients with FLT3-ITD AML evaluating
the effect of sorafenib maintenance post-transplantation, suggest-
ing a broad beneficial effect of sorafenib across various genetic Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Shao et al. 8 CEBPA mutation.34 Although these findings were very interesting
and provided basis for further studies, they had to be interpreted
cautiously due to small numbers. activated signaling genes at relapse, most of whom received
sorafenib,
either
pre-
or
post-transplantation. The
different
mutational evolution patterns might be related to the different
pharmacological characteristics of FLT3 inhibitors. A study by
Alotaibi et al. showed that FLT3-mutated patients might have
different patterns of mutational evolution between those who
received type I and type II FLT3 inhibitors.43 However, considering
the diverse study settings and relatively small sample sizes of
current studies, further studies were warranted to confirm these
findings. cautiously due to small numbers. The effects of FLT3 inhibitors on FLT3-ITD AML patients carrying
abnormalities on different concomitant gene ontology groups
were
rarely
reported. Recently,
Jahn
et
al. reported
that
midostaurin might improve OS and DFS of FLT3-mutated AML
patients with chromatin-spliceosome mutations.29 Smith et al. reported that gilteritinib might improve OS in FLT3-mutated
patients carrying mutated DNA methylation/hydroxymethylation
mutations, while it did not improve the outcome of those with
mutated RTK/Ras signaling genes.28 In this study, we found that
the patients with “activated signaling” and “DNA methylation”
mutations might benefit from sorafenib. Despite the different
population and intervention of both studies, the pharmacological
characteristics between sorafenib and gilteritinib might help
explain this difference.2,30,35 As a first-generation FLT3 inhibitor,
besides directly blocking the activity of FLT3, sorafenib had also
potential inhibition effect on other tyrosine kinase receptors like
PDGFR and KIT, and downstream molecules of FLT3 signaling such
as KRAS and BRAF.2,30 On the other hand, we also found that
patients with “tumor suppressors” and “myeloid transcription
factors” mutations did not response significantly to sorafenib. For
tumor suppressors, wild type p53 protein was reported to inhibit
the phosphorylation of STAT3, and the transcriptional activity of
both STAT3 and STAT5, which could be lost through TP53
mutation.36,37 Similarly, our data showed that TP53 mutation
might increase sorafenib resistance via activating STAT3. DISCUSSION PHF6
mutation might induce sorafenib resistance via upregulating JAK-
STAT signaling and increasing the ubiquitination of the p53
protein.38,39 As for myeloid transcription factors, CEBPA mutations
were also associated with activated JAK-STAT signaling, especially
those with biallelic mutation.40 (Supplementary Fig. S13). Never-
theless, although several different gene mutations were shown to
correlate with upregulated JAK-STAT signaling, the exact role JAK-
STAT pathway played in the disease development and sorafenib
resistance
should
be
discussed
in
a
mutation-by-mutation
manner. Further basic studies are warranted before clinical
attempts of combing sorafenib and other targeted therapies
(STAT inhibitors, etc) in certain genetic subgroups of FLT3-ITD AML
could be made. Our study had a few limitations. Patients included in this study
was a pooled population from four prospective and retrospective
cohort with differences in details such as sorafenib administration. Also, despite the large-scale of this study, the number of patients
in certain genetic pattern subgroups was still too small for a
statistically significant result. In conclusion, our study identifies the response of genetic
patterns to sorafenib, and further confirms the role of sorafenib in
FLT3-ITD AML patients undergoing allo-HSCT. This study provides
new viewpoints for the optimal use of sorafenib in FLT3-ITD AML
patients undergoing allo-HSCT based on genetic patterns. MATERIALS AND METHODS Study design and participants y
g
p
p
In this multicenter, cohort study, the study population came from
our four studies, including a prospective observational study
(NCT03620955), an RCT (NCT02474290),9 and two retrospective
studies.14,44 Patients met the following criteria were enrolled: (a)
aged 18–65 years; (b) diagnosed with FLT3-ITD AML; (c) under-
went first allo-HSCT. Patients were excluded from the study if they
met any of the following criteria: (a) diagnosed with acute
promyelocytic leukemia; (b) received other FLT3 inhibitors pre-
transplantation or as maintenance therapy post-transplantation;
(c) failed to achieve CRc, relapsed or died within 90 days post-
transplantation; (d) initiated sorafenib maintenance after 180 days
post-transplantation; (e) lack of concomitant genomic data. The
diagnosis and risk stratification of AML were according to the
guideline of the National Comprehensive Cancer Network and the
2017 ELN AML recommendation.4 CRc comprised complete CR, CR
with incomplete platelet recovery, and CR with incomplete
hematological recovery.9 CRc and partial remission (PR) were
defined as per the 2017 ELN AML recommendations.4 NR was
defined as achieving the standards of neither CRc nor PR. The
protocol was reviewed and approved by the institutional review
board of each participating center and was conducted in
accordance with the Declaration of Helsinki. Written informed
consent was obtained from the donors and recipients before the
initiation of the study. The role of FLT3 inhibitors in FLT3-ITDhigh AML has been widely
established, while controversial results are reported regarding the
effects of FLT3 inhibitors on FLT3-ITDlow AML patients receiving
chemotherapy.18,41 In our study, sorafenib pre-transplantation
improved OS in FLT3-ITDhigh AML patients, but it did not in FLT3-
ITDlow AML. This concorded with that reported by Abou Dalle et al. in the patients receiving chemotherapy.18 In contrast, we found
that sorafenib maintenance post-transplantation might improve
the survival of both FLT3-ITDhigh and FLT3-ITDlow AML patients,
suggesting that sorafenib maintenance post-transplantation was
required in FLT3-ITDlow AML. Signal Transduction and Targeted Therapy (2023) 8:348 Outcomes Analyses of OS, DFS, relapse and cGVHD were mainly compared
between the sorafenib and control groups. OS and DFS were
compared using the Kaplan-Meier analysis with the log-rank test. Cumulative incidences of relapse and cGVHD were calculated and
compared using the Fine and Gray model.48 Non-relapse mortality
was a competing risk for relapse. Relapse and death without
cGVHD were competing risks for cGHVD. The endpoints in this study were OS, DFS, relapse, and GVHD in
the whole cohort and OS in genetic pattern subgroups. OS was
defined as duration since transplantation till death of any cause. DFS was defined as duration since transplantation till the
occurrence of relapse, or death from any cause. Relapse was
defined as the existence of any of the following: (a) reappearance
of leukemic blasts in the peripheral blood; (b) bone marrow blasts
≥5% as shown by bone marrow aspirate or biopsy specimen
which
could
not
be
explained
by
any
other
reason;
(c)
reappearance or new appearance of extramedullary leukemia. GVHD, including aGVHD and cGVHD, was defined according to
guidelines.45,46 HR and 95% CI were calculated using the COX proportional
hazards models for OS and DFS, and competing risk regression
model for relapse. The following variables were included in the
COX or competing risk regression models for the whole cohort:
(a) sex (male vs female), (b) age (>36 years vs ≤36 years), (c)
white blood cell (WBC) counts at diagnosis (>53 × 109/L vs
≤53 × 109/L), (d) transplant modality (HID, MUD vs MSD), (e) ELN
2017 risk stratification (intermediate, adverse, unknown vs
favorable), (f) FLT3-ITD AR (≥0.50 vs <0.50), (g) sorafenib pre-
transplantation (used vs not used), and (h) sorafenib post-
transplantation (used vs not used). Variables were analyzed
using a univariable model respectively at first, and only the
variables with p < 0.10 were included into the multi-variable
models. Univariable COX regression models were used to
analyze
the
effect
of
sorafenib
usage
before
and
after
transplantation (pre-transplantation only, post-transplantation
only, both pre- and post-transplantation vs non-sorafenib) on
ELN risk groups and FLT3-ITD AR. Bioinformatic analyses y
Patients with bulk RNA-seq data within the BeatAML and TCGA-
LAML datasets was screened for FLT3 mutation status. Counts,
clinical, mutational, and drug sensitivity (for the BeatAML dataset)
data
of
FLT3-ITD
positive
AML
patients
was
downloaded. Procedures Patients who received sorafenib maintenance post-transplantation
for >4 weeks were allocated to the sorafenib group, and those
who did not receive sorafenib maintenance post-transplantation
or received sorafenib maintenance for <4 weeks were allocated to
the control group. Some patients received pre-transplantation
sorafenib as part of the induction therapy combined with
chemotherapy, or post-remission maintenance therapy, or both. Patients who used sorafenib for at least 4 weeks before allo-HSCT
were considered receiving sorafenib pre-transplantation, regard-
less of the context. Those who did not receive sorafenib, or
received for less than 4 weeks pre-transplantation were consid-
ered not receiving sorafenib pre-transplantation. For patients who
received sorafenib, the initial dose was 400 mg twice daily, and
adjusted according to tolerance of patients under the guidance of
physicians or researchers. For patients from the prospective
studies, the methods for dose modification were reported
previously.9 q
There are currently few data on the mutational evolution of
FLT3-ITD AML in the context of FLT3 inhibitors. Smith et al. reported that 9 of 39 FLT3-mutated patients receiving gilteritinib
lost FLT3 mutation at relapse, and 5 patients acquired the FLT3
F691L “gatekeeper” mutattion.28 Schmalbrock et al. reported a
46% rate of losing FLT3 mutation at relapse in patients receiving
midostaurin, compared to 19% in those who did not.42 In our
study, 8 in 21 patients lost FLT3-ITD at relapse. Four additional
patients (3 in the sorafenib and 1 in the control group) acquired
FLT3-TKD. The sorafenib group seemed to have slightly higher rate
of losing FLT3-ITD (3 in 6) compared to the control group (5 in 15). For activated signaling genes, in the study of Smith et al., 16 in 39
patients receiving gilteritinib acquired NRAS, KRAS or PTPN11.28
However, in the study of Schmalbrock et al., only 4 in 54 patients
receiving midostaurin acquired activated signaling genes at
relapse.42 Our data showed that 5 in 21 patients acquired Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 9 continuous variables between groups were conducted using
Mann-Whitney U test, and comparations of categorical variables
between groups were performed using χ2 test or Fisher’s exact
test. The
mutual
exclusivity
and
co-occurrence
of
genetic
abnormalities were tested using the discrete independence
statistic controlling for observations with varying event rates
(DISCOVER) method.47 Cytogenetic analyses were performed with the Giemsa and
reverse banding techniques, and FISH. ACKNOWLEDGEMENTS Cells were transferred into 96-well plates (Corning, New York, USA)
at a density of 5000 cells per well, and exposed to DMSO (YEASEN,
Wuhan, China), 5 μg/ml of sorafenib (MCE, New Jersey, USA), or
5 μg/ml of sorafenib combined with 3 μg/ml of STAT3 inhibitor
(MCE, New Jersey, USA) for 0, 24 and 48 h. Cell viability was
assessed using the CCK-8 solution (FDbio, Hangzhou, China) at
different timepoints and measured using the MB-580 Microplate
Analyzer (HEALES, Shenzhen, China). This work was supported by the National Natural Science Foundation of China
(82170213 to L.X., 81970161 to Q.L.), the National Key Research and Development
Projects of China (2021YFC2500301–4 to Q.L., 2022YFC2502600–5 to L.X.), and Clinical
Research Program of Nanfang Hospital, Southern Medical University (2021CR002 to
L.X.). The authors reported no other grants in support of this work. We thank Dr. Rongtao Xue for her guidance on preliminary experiments. Outcomes Mutations were screened according to the mutation data in the
cBioPortal database for the TCGA-LAML dataset, and the results
from clinical genotyping data or targeted DNA sequencing/whole
exome sequencing for the BeatAML dataset. The DEseq2 method was applied for removing batch effect and
differential analyses. The threshold for significant difference of
gene transcription level between groups was adjusted P-value <
0.05 and log2(fold change) > 1. Differentially expressed genes
were used for enrichment analyses. Raw counts matrices were
used for GSVA analyses. All levels of significance were set at two-sided 5% level. All
statistical analyses were done using SPSS 25.0 IBM (IBM Corp.,
Armonk, NY) and R 4.1.0 (R Project for Statistical Computing,
Vienna, Austria). y
The IC50 of sorafenib was extracted from the drug sensitivity
data in the BeatAML dataset and compared among groups within
cases with available drug sensitivity data. Procedures Gene mutations were
tested using direct sequencing and a 167-gene NGS (Table S4). PCR and direct sequencing, or NGS was used to test FLT3-ITD. FLT3-ITD positive was judged using the threshold of mutant-to-
wild-type AR ≥0.03. Electrotransfection The cells were passaged 24 h before the electrotransfection to
ensure they were in logarithmic growth. Before electrotransfec-
tion, the concentration of cells was adjusted to 107/ml using 1640
medium. The pLenti-CMV-TP53(R248Q)-GFP-Puro, pLenti-CMV-
TP53-GFP-Puro, or pLenti-CMV-GFP-Puro plasmid (PPL, Nanjing,
China) was added to the cell suspension, adjusting the final
concentration of plasmids to 20 μg/ml. Electrotransfection was
performed using ECM830 (BTX, New York, USA), and confirmed by
GFP expression under the IX73 inverted microscope (Olympus,
Tokyo, Japan). DATA AVAILABILITY The RNA-seq, drug sensitivity, and metadata of TCGA-LAML and BeatAML datasets
are available from their original source data. For the prospective cohorts
(NCT03620955
and
NCT02474290),
de-identified
individual
participant
data
underlying the results reported in this paper, and the study protocol will be
made available beginning 9 months after publication of the original paper. For the
retrospective cohorts, de-identified individual participant data underlying the
results reported in this paper will be made available beginning 9 months after
publication of this paper. All requests for data should be made by contacting Prof. Qifa Liu (liuqifa628@163.com), and will be assessed by an independent review
committee on a case-by-case basis. After 36 months of publication of each dataset,
corresponding data will be available on request to Prof. Qifa Liu, as per the access
approach of the data repository unit at Southern Medical University, Guangzhou,
China. Signal Transduction and Targeted Therapy (2023) 8:348 REFERENCES 9, 436–451 (2019). leukemia stem cell activity in T-All. Cancer Discov. 9, 436–451 (201 40. Lavallée, V. P. et al. Chemo-genomic interrogation of CEBPA mutated AML reveals
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after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine
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harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1
mutation: Relevance to post-remission therapy. Blood 121, 2734–2738 (2013). ADDITIONAL INFORMATION 23. Chen, F. et al. Impact of FLT3-ITD allele ratio and ITD length on therapeutic
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insertion site in acute myeloid leukemia: RATIFY study results. Leukemia 36,
90–99 (2022). Statistical analysis L.X., Y.W. and Q.L. designed the study. R.S., Y.Z., F.H. and Z.F. wrote the report,
collected data, and did the statistical analysis. Y.X., N.X., Y.L., L.D., Xi.Z., J.C., M.H., X.Lu.,
S.J.Y. and X.Li., Xi.L, P.S., Z.W., L.J., Xu.Z., R.L., Y.C., S.T. and J.S. performed the study. R.S., J.H. and K.Y. performed bioinformatic analyses and did preliminary experiments. All authors contributed cases and provided clinical data. All authors have read and
approved the article. The statistical analysis for the clinical data was done on September
1, 2022. Continuous variables were presented as mean and
standard deviation for those normally distributed, or median and
IQR for those non-normally distributed. All categorical variables
were presented as frequency and proportion. Comparations of Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. Impact of genetic patterns on sorafenib efficacy in patients with. . . Shao et al. 10 Signal Transduction and Targeted Therapy (2023) 8:348 Impact of genetic patterns on sorafenib efficacy in patients with. . .
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Knowledge and use of biosimilars in oncology: a survey by the European Society for Medical Oncology
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University of Groningen University of Groningen Knowledge and use of biosimilars in oncology DOI:
10.1136/esmoopen-2018-000460 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below. Document Version
Publisher's PDF also known as Version of record Document Version
Publisher's PDF, also known as Version of record Link to publication in University of Groningen/UMCG research database Citation for published version (APA):
Giuliani, R., Tabernero, J., Cardoso, F., McGregor, K. H., Vyas, M., & de Vries, E. G. E. (2019). Knowledge
and use of biosimilars in oncology: a survey by the European Society for Medical Oncology. ESMO Open,
4(2), Article 000460. https://doi.org/10.1136/esmoopen-2018-000460 Citation for published version (APA):
Giuliani, R., Tabernero, J., Cardoso, F., McGregor, K. H., Vyas, M., & de Vries, E. G. E. (2019). Knowledge
and use of biosimilars in oncology: a survey by the European Society for Medical Oncology. ESMO Open,
4(2), Article 000460. https://doi.org/10.1136/esmoopen-2018-000460 Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Citation for published version (APA):
Giuliani, R., Tabernero, J., Cardoso, F., McGregor, K. H., Vyas, M., & de Vries, E. G. E. (2019). Knowledge
and use of biosimilars in oncology: a survey by the European Society for Medical Oncology. ESMO Open,
4(2), Article 000460. https://doi.org/10.1136/esmoopen-2018-000460 Abstract Abstract
Background Biosimilars can potentially improve
the sustainability of cancer care; however, uptake is
sometimes limited by safety concerns and a lack of
understanding of the concept of extrapolation. The
European Society for Medical Oncology (ESMO) conducted
a survey to assess the current level of knowledge,
understanding and comfort of use of biosimilars among
prescribers specialised in oncology. Methods A 19-question survey was developed using
the SurveyMonkey online platform (https://www.
surveymonkey.com/). Data collection occurred between
September and October 2017 and included paper and
online responses. Abstract
Background Biosimilars can potentially improve
the sustainability of cancer care; however, uptake is
sometimes limited by safety concerns and a lack of
understanding of the concept of extrapolation. The
European Society for Medical Oncology (ESMO) conducted
a survey to assess the current level of knowledge,
understanding and comfort of use of biosimilars among
prescribers specialised in oncology. Open access Original research Open access on 2 August 2019 by guest. P
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from What does this study add? ►
►This European Society for Medical Oncology survey
found encouraging levels of prescriber use and gen-
eral knowledge of biosimilars; however, a substan-
tial need for further education remains, especially
for improving prescriber understanding of extrapo-
lation of indications. Results Overall, 393 responses were received from
prescribers. Overall, 49.0% of prescribers use biosimilars
in clinical practice and most (79.2%) rate their general
knowledge of biosimilars as average to very high. Potential
increased risk of immunogenicity remains a significant
concern of switching. Gaps in knowledge identified by the
survey include biosimilar development, clinical trial design
and endpoint selection, and requirements for extrapolation,
which should form the focus of future educational
initiatives. A substantial demand remains for further
educational activities with equal preference for online and
face-to-face initiatives. A higher rate of biosimilar use
(56.3% vs 46.5%), knowledge of biosimilar development
and trial design, and comfort with extrapolation, but
a lower knowledge of European Medicines Agency
definitions, was found among prescribers from Asia-Pacific
versus those from Europe. Received 19 October 2018
Revised 25 January 2019
Accepted 28 January 2019 Received 19 October 2018
Revised 25 January 2019
Accepted 28 January 2019 ►
►Discrepancies in responses were found among Asia-
Pacific and European prescribers. ►
►Asia-Pacific prescribers appear more confident in
their understanding of the biosimilar development
process, the concept of extrapolation of indica-
tions and switching, but less confident on European
Medicines Agency definitions. on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/ g
yi
►
►A worldwide effort should be undertaken to align
definitions and regulatory standards. What is already known about this subject? ►
►Biosimilars may potentially reduce care costs and
improve patient access. To cite: Giuliani R, Tabernero J,
Cardoso F, et al. Knowledge
and use of biosimilars in
oncology: a survey by the
European Society for Medical
Oncology. ESMO Open
2019;4:e000460. doi:10.1136/
esmoopen-2018-000460 ►
►However, uptake of biosimilars in oncology has been
limited by safety concerns. ►
►In particular, surrounding switching from a biosim-
ilar to its reference medicine or vice versa, and a
lack of understanding around the requirements for
development, including extrapolation of indications. Methods A 19-question survey was developed using
the SurveyMonkey online platform (https://www.
surveymonkey.com/). Data collection occurred between
September and October 2017 and included paper and
online responses. How might this impact on clinical practice? ►
►Educational initiatives focused on the knowledge
gaps identified in this survey are essential for suc-
cessful integration and uptake of biosimilars in
oncology, which can potentially improve the sustain-
ability of cancer care by increasing the accessibility
of therapeutic and supportive care and providing
lower-cost alternatives to their reference medicines. ►
►Educational initiatives focused on the knowledge
gaps identified in this survey are essential for suc-
cessful integration and uptake of biosimilars in
oncology, which can potentially improve the sustain-
ability of cancer care by increasing the accessibility
of therapeutic and supportive care and providing
lower-cost alternatives to their reference medicines. Conclusion Encouraging levels of prescriber use and
general knowledge of biosimilars were found, but a
substantial need for further education remains. Efforts
should be made worldwide to align terms, definitions and
guidelines for the development and approval of biosimilars. 1Medical Oncology, San Camillo-
Forlanini Hospital, Rome, Italy
2Vall d’Hebron University
Hospital and Institute of
Oncology (VHIO), Universitat
Autònoma de Barcelona,
Barcelona, Spain
3Breast Unit, Champalimaud
Clinical Center/Champalimaud
Foundation, Lisbon, Portugal
4Chief Executive Officer,
European Society for Medical
Oncology (ESMO), Lugano,
Switzerland
5Head of Public Policy, European
Society for Medical Oncology,
Lugano, Switzerland
6Department of Medical
Oncology, University Medical
Center Groningen, University
of Groningen, Groningen, The
Netherlands
© Author (s) (or their
employer(s)) 2019. Re-use
permitted under CC BY.
Published by BMJ on behalf
of the European Society for
Medical Oncology. ►
►Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
esmoopen-2018-000460). Key questions What is already known about this subject? © Author (s) (or their
employer(s)) 2019. Re-use
permitted under CC BY.
Published by BMJ on behalf
of the European Society for
Medical Oncology. Copyright strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of th
or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-
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and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum. Download date: 24-10-2024 Knowledge and use of biosimilars in
oncology: a survey by the European
Society for Medical Oncology on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/
blished as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Rosa Giuliani,1 Josep Tabernero,2 Fatima Cardoso,3 Keith Hanson McGregor,4
Malvika Vyas,5 Elisabeth G E de Vries6 ►
►Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
esmoopen-2018-000460). Results
D Demographics, basic knowledge and use
Overall, 495 responses were collected. Of the 480
responders who mentioned their country, most were
from Europe (n=321), then Asia (n=84), America (n=55),
Africa (n=13) and Australia (n=7). Despite the potential for reducing care costs and
improving patient access, uptake of biosimilars in oncology
has been limited potentially by a lack of understanding
of their development and of the regulatory assessment,
including requirements for extrapolation of indications.7
Extrapolation is the approval, by a regulatory agency, of
a biosimilar in one or more indications of the reference
biologic without the requirement to carry out clinical
trials of the biosimilar in all those indications.16 17 If simi-
larity between the biosimilar and its reference biologic is
credibly shown through ‘totality of evidence’ in one indi-
cation, extrapolation permits approval of the biosimilar
in all other indications held by the reference biologic.18
Extrapolation has the potential to reduce the costs asso-
ciated with biosimilar development, increasing access to
biologic therapies and reducing cancer care costs.7 These analyses include responses from prescribing physi-
cians only and evaluate responses from all prescribers,
European and Asia-Pacific prescribers. Overall, 80.0%
(393/491, 4 skipped) of responders were prescribing
physicians (Europe: 79.7%, n=255; Asia-Pacific: 87.9%,
n=80), with most being ESMO members (92.0%, n=357)
and specialised in oncology (94.3%, n=367). on 2 August 2019 by guest. Protected by copyright. esmoopen.bmj.com/ When asked to rate their overall knowledge of biosim-
ilars, the most commonly selected option on a scale of 1
(very low) to 5 (very high) was option 3 (45.5%, 177/389,
4 skipped; figure 1A). Options 3, 4 and 5 were selected
by 79.2% (n=308; sum of responses) of prescribers indi-
cating that most consider themselves to have an average
to very high level of knowledge of biosimilars. In total,
74.6% (291/390, 3 skipped) of prescribers were able to
identify the most appropriate definition of ‘biosimilar’
(‘highly similar to an approved biological medicine, with
no clinically meaningful differences in safety and efficacy
profile’). This definition was selected by 77.9% (197/253,
2 skipped) of European and 64.6% (51/79, 1 skipped) of
Asia-Pacific prescribers. Uncertainties exist among HCPs regarding switching,
the decision to administer a biosimilar in a patient previ-
ously treated with the reference biologic or vice versa,
and the potential for reduced efficacy or increased
immunogenicity in both the oncology and non-oncology
settings.3 19–22 by guest. Protected by copyright. Open access can potentially be improved through the use of safe and
effective biosimilars, which expand the treatment options
available to clinicians and patients, increase accessibility
of therapeutic and supportive care, and provide lower-
cost alternatives to their reference medicines.2 5 7 8 Introduction Cancer treatment has been advanced by, but
become reliant on, biologics.1 2 Biologics are
typically large proteins such as monoclonal
antibodies, interferons and recombinant
hormones.3 Processes for biologic production
involve living systems and complex proce-
dures requiring the utmost precision to guar-
antee final product consistency and quality.3 4 y guest. Protected by copyright. in biologics being expensive,2 5 adding to the
already high costs of cancer treatment. Cancer care cost is rapidly becoming a
significant issue driven by rising cancer inci-
dence, ageing populations and the increasing
price of treatments.5 Patent expiration has
occurred or is approaching for many biologics
used in oncology.6 It has been proposed that
the sustainability of cancer care worldwide Correspondence to
Professor Elisabeth G E de Vries;
e.g.e.de.vries@umcg.nl These complex manufacturing processes, as
well as their long development times, result 1 Giuliani R, et al. ESMO Open 2019;4:e000460. doi:10.1136/esmoopen-2018-000460 Methods ESMO developed a 19-question survey using the Survey-
Monkey online platform (https://www.surveymonkey.
com/), which sought information regarding responders’
use and basic knowledge of biosimilars, understanding of
biosimilar development and level of comfort with extrap-
olation, interchangeability and switching (see online
supplementary appendix). A biosimilar is a biologic that matches its reference
medicine in terms of quality, activity, safety and effi-
cacy.9–11 In 2006, a recombinant human growth hormone
(Omnitrope) was the first biosimilar to receive Euro-
pean Medicines Agency (EMA) approval,12 followed by
EMA approval of biosimilars for epoetin alfa in 2007
and recombinant human granulocyte colony-stimulating
factor (rhG-CSF) in 2009.13 14 The biosimilar rhG-CSF
(Zarxio) was the first biosimilar to receive approval from
the US Food and Drug Administration (FDA).15 Data collection occurred between September and
October 2017 and included both paper and online
responses. During the ESMO 2017 Congress, attendees
completed paper copies of the survey; results were then
inputted into the SurveyMonkey platform. Additionally,
a link to the online survey was sent in an email to ESMO
members and their wider professional network. Results
were summarised using descriptive statistics. g
Regulatory requirements for biosimilars are evolving
and becoming more familiar among healthcare profes-
sionals (HCPs). The EMA, FDA and WHO require
substantial evidence demonstrating that a biosimilar
matches its reference medicine.9–11 The objective of a
biosimilar development programme is to demonstrate no
clinically meaningful differences based on the ‘totality of
evidence’ approach, that is, a comprehensive comparison
of the proposed biosimilar and the reference medicine
with respect to structure, function, pharmacokinetics,
pharmacodynamics,
clinical
immunogenicity,
safety
and efficacy.9–11 Unlike the standard requirements for
drug approval, the development process for biosimilars
demands a relatively larger amount of preclinical than
clinical data. The survey contained a mixture of checkbox answers
and questions asking responders to rank their level of
agreement, knowledge, comfort or importance of each
statement from 1 to 5 or 10. For these questions, results
were pooled and a weighted average (WA) score out of
5 or 10 was assigned. An open comments box at the end
of the survey asked responders to provide suggestions for
future educational initiatives. Results
D In order to assess the current knowledge, under-
standing and comfort of use of biosimilars in oncology,
with a particular focus on extrapolation and switching,
the European Society for Medical Oncology (ESMO)
conducted a survey among its members and attendees at
the 2017 ESMO Congress in Madrid, Spain. p
Overall, 49.0% (191/390, 3 skipped) of prescribers use
biosimilars in routine clinical practice (excluding clinical
trials; figure 2). A higher proportion of prescribers from
Asia-Pacific (56.3%, 45/80) use biosimilars versus those
from Europe (46.5%, 118/254, 1 skipped; figure 2). Overall, 49.0% (191/390, 3 skipped) of prescribers use
biosimilars in routine clinical practice (excluding clinical
trials; figure 2). A higher proportion of prescribers from
Asia-Pacific (56.3%, 45/80) use biosimilars versus those
from Europe (46.5%, 118/254, 1 skipped; figure 2). 2 Giuliani R, et al. ESMO Open 2019;4:e000460. doi:10.1136/esmoopen-2018-000460 Open access Open access on 2 August 2019 by guest. Protect
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Open access
Figure 1 Prescribers’ responses rating their level of knowledge/understanding on a scale of 1–5. Prescribers’ responses, by
region, when asked to rate their knowledge/understanding of (A) biosimilars overall; (B) the biosimilar development process
and threshold of clinical evidence required for approval; (C) clinical trial design and endpoint selection for biosimilar studies;
(D) requirements needed to be met for extrapolation of indications to be granted for a biosimilar. on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/
first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Figure 1 Prescribers’ responses rating their level of knowledge/understanding on a scale of 1–5. Prescribers’ responses, by
region, when asked to rate their knowledge/understanding of (A) biosimilars overall; (B) the biosimilar development process
and threshold of clinical evidence required for approval; (C) clinical trial design and endpoint selection for biosimilar studies;
(D) requirements needed to be met for extrapolation of indications to be granted for a biosimilar. Compared with the entire European group, rate of use was
lower among prescribers from the UK (31.3%, 10/32). Biosimilars are not used by 24.1% (94/390, 3 skipped) of
prescribers due to lack of approval or reimbursement in
their country (figure 2). Compared with the entire European group, rate of use was
lower among prescribers from the UK (31.3%, 10/32). Biosimilars are not used by 24.1% (94/390, 3 skipped) of
prescribers due to lack of approval or reimbursement in
their country (figure 2). Results
D a scale of 1 (very low) to 5 (very high; figure 1B). Option
3 was the most frequent choice by Asia-Pacific and Euro-
pean prescribers (43.9% vs 37.0%; figure 1B) with the
second most commonly selected choices being option 4
(24.2%) and option 2 (22.2%), respectively (figure 1B). August 2019 by guest. Protected by copyright. On a scale of 1 (not at all) to 5 (very), prescribers were
asked to rate their comfort with the concept of using an
EMA-approved biosimilar to treat a patient suitable for
the reference biologic. Options 4 and 5 were chosen
by 57.4% (217/378, 15 skipped, sum of responses) of
prescribers (figure 3A). Clinical safety and efficacy data are the best under-
stood data types by all prescribers (WA [out of 5] 3.67),
followed by immunogenicity data (WA 3.10). However,
the two regions differed on the least understood type of
data (Europe: physicochemical, WA 2.64; Asia-Pacific:
in vitro, WA 2.36). In addition, clinical study safety (WA
[out of 10] 8.80) and efficacy (WA 8.65; table 1) data are
considered the most important among prescribers in
determining the suitability of a biosimilar for use. The
type of data considered least important is physicochem-
ical data demonstrating structural similarity (WA 7.23;
table 1). y guest. Protected by copyright. on 2 August 2019 by g
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ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Open access on 2 Au
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ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Open access
Figure 2 Level of routine use of biosimilars by prescribers in clinical practice to treat patients. on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/
first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Figure 2 Level of routine use of biosimilars by prescribers in clinical practice to treat patients. to moderate level of knowledge regarding clinical trial
design and endpoint selection for biosimilar studies, with
59.8% (195/326, 16 skipped, sum of responses) selecting
options 3 and 4 (figure 1C). Nearly half of the prescribers
(49.7%, 161/324, 69 skipped) chose ‘the endpoint consid-
ered most sensitive for detecting differences between the
biosimilar and reference biologic, and least influenced by
patient or disease-related factors’ as the most appropriate
for studies comparing the clinical efficacy of a biosimilar
with its reference medicine. From three options, 45.2% (146/323, 70 skipped)
of prescribers were able to select the most appropriate
definition of ‘sensitive indication’ in terms of biosimilar
development (‘the population that is most representative
of the patients to whom the biologic is most frequently
prescribed’). This definition was selected by 42.1%
(88/209, 46 skipped) of European and 60.0% (39/65, 15
skipped) of Asia-Pacific prescribers. The second preferred
definition (‘a population where product-related differ-
ences in clinical performance can be best detected’) was
chosen by 31.3% (101/323, 70 skipped) of all prescribers
(Europe: 33.5%, 70/209, 46 skipped; Asia-Pacific: 26.2%,
17/65, 15 skipped). Moreover, 33.4% (108/323, 70 skipped) of prescribers
feel that the most appropriate indication for a study
comparing the clinical efficacy and safety of a biosimilar
with a reference biologic is ‘the indication representing
the most sensitive population for detecting any potential pp
On a scale of 1 (very low) to 5 (very high), responses
suggest that most prescribers feel they have an average Figure 3 Prescribers’ responses rating their level of comfort on a scale of 1–5. Prescribers’ responses, by region, when
asked to rate their comfort with (A) the concept of using an EMA-approved biosimilar to treat a patient suitable for the
reference biologic; (B) using an EMA-approved biosimilar in extrapolated indications that the reference biologic is approved
for. EMA, European Medicines Agency. on 2 August 2019 by guest. Protected by copyright. oopen.bmj.com/ Figure 3 Prescribers’ responses rating their level of comfort on a scale of 1–5. Biosimilar development Most prescribers feel they have an average to moderate
level of knowledge of the biosimilar development
process and the threshold of clinical evidence required
for approval of a biosimilar, with 61.1% (204/334, 59
skipped, sum of responses) selecting options 3 and 4 on 3 Giuliani R, et al. ESMO Open 2019;4:e000460. doi:10.1136/esmoopen-2018-000460 on 2 August 2
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Table 1 Prescribers’ responses rating the importance and sensitivity of different data types in determining the suitability of a
biosimilar for use
Type of data (weighted average)
Importance
Sensitivity
All
Europe
Asia-Pacific
All
Europe
Asia-Pacific
Physicochemical data demonstrating
structural similarity
7.23
7.05
7.30
7.24
7.07
7.56
In vitro and in vivo data demonstrating
similarity in biological activity
7.76
7.74
7.66
7.58
7.46
7.82
PK and PD data demonstrating
similarity
7.94
7.85
8.10
7.83
7.75
8.10
Clinical study data demonstrating
similar efficacy
8.65
8.56
8.72
8.61
8.57
8.75
Clinical study data demonstrating
similar safety
8.80
8.78
8.83
8.75
8.72
8.79
Clinical study data demonstrating
similar immunogenicity
8.24
8.24
8.10
8.30
8.23
8.41
Clinical study data demonstrating
the ability to switch from reference
to biosimilar and vice versa without
impairing safety or efficacy
8.07
8.02
8.27
8.11
8.02
8.36
Weighted average of prescribers’ responses, by region, on a scale of 1 (not important/sensitive) to 10 (very important/sensitive). PD, pharmacodynamic; PK, pharmacokinetic. on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/
irst published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Weighted average of prescribers’ responses, by region, on a scale of 1 (not important/sensitive) to 10 (very important/sensitive). PD, pharmacodynamic; PK, pharmacokinetic. Interchangeability and switching difference between the products’. The next most frequent
response, selected by 27.9% (90/323, 70 skipped), was
‘comparative efficacy and safety should be studied in
every indication of the reference biologic’, suggesting
that there is a lack of understanding surrounding the
concept of extrapolation of indications. Respondents were presented with correct EMA defini-
tions of interchangeability and switching, and an incor-
rect definition of substitution. Only 36.3% (110/303, 90
skipped) of prescribers were able to identify the incor-
rect definition and the other two correct definitions were
also widely chosen (interchangeability: 29.7%, 90/303, 90
skipped; switching: 34.0%, 103/303, 90 skipped). Similar
proportions of European (36.0%, 71/197, 58 skipped)
and Asia-Pacific (35.5%, 22/62, 18 skipped) prescribers
were able to successfully identify the incorrect definition
of substitution. However, the same proportion of Asia-Pa-
cific prescribers (35.5%, 22/62, 18 skipped) believed the
definition of switching was incorrect. on 2 August 2019 by g
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Prescribers’ responses, by region, when
asked to rate their comfort with (A) the concept of using an EMA-approved biosimilar to treat a patient suitable for the
reference biologic; (B) using an EMA-approved biosimilar in extrapolated indications that the reference biologic is approved
for. EMA, European Medicines Agency. Giuliani R, et al. ESMO Open 2019;4:e000460. doi:10.1136/esmoopen-2018-000460 4 Open access Open access Discussion This ESMO survey shows that nearly half of prescribers
(49.0%) use biosimilars in their clinical oncology prac-
tice; lack of approval and reimbursement is a barrier to
use. Responses suggest that most prescribers (79.2%) feel
they have an average to very high level of general biosim-
ilar knowledge, with nearly three quarters (74.6%) able
to identify the most appropriate definition of ‘biosimilar’. Overall, 57.4% of prescribers feel comfortable using an
EMA-approved biosimilar. Most prescribers feel they only have an average to
moderate level of knowledge about biosimilar devel-
opment, the level of clinical evidence required for a
biosimilar approval, clinical trial design and selection of
endpoints; these therefore present as topics for future
educational activities. Indeed, less than half (45.2%) of
prescribers were able to identify the most appropriate
definition of ‘sensitive indication’. Uncertainties were
also demonstrated in differentiating ‘interchangeability’,
‘substitution’ and ‘switching’. Despite nearly two-thirds of
prescribers being able to identify the most appropriate
definition of ‘extrapolation of indications’, most rated
their understanding of the requirements for extrapo-
lation of indications as below average. However, most
prescribers feel comfortable using a biosimilar in an
extrapolated indication. Therefore, it seems that many
prescribers trust and accept the scientific principle of
extrapolation though may not fully understand it. were primarily concerned with potential AEs (WA 3.35;
table 2), despite a high level of agreement with not antici-
pating additional AEs on a switch in the previous question. Extrapolation of indications doi:10.1136/esmoopen-2018-000460 Open access
Table 2 Prescribers’ responses rating their concern
of potential consequences when switching a patient’s
treatment from a reference biologic to a biosimilar or vice
versa
Potential
consequence
(weighted average)
All
Europe
Asia-Pacific
Potential loss of
clinical efficacy
3.29
3.23
3.30
Potential for adverse
events
3.35
3.32
3.35
Potential for increased
risk of immune
reactions
3.35
3.39
3.17
Weighted average of prescribers’ responses, by region, on a scale
of 1 (not at all) to 5 (very). Table 2 Prescribers’ responses rating their concern
of potential consequences when switching a patient’s
treatment from a reference biologic to a biosimilar or vice
versa
Potential
consequence
(weighted average)
All
Europe
Asia-Pacific
Potential loss of
clinical efficacy
3.29
3.23
3.30
Potential for adverse
events
3.35
3.32
3.35
Potential for increased
risk of immune
reactions
3.35
3.39
3.17
Weighted average of prescribers’ responses, by region, on a scale
of 1 (not at all) to 5 (very). communicated a higher interest in receiving training on
the efficacy and safety of biosimilars while Asia-Pacific
prescribers were more interested in training tailored for
developing countries. Table 2 Prescribers’ responses rating their concern
of potential consequences when switching a patient’s
treatment from a reference biologic to a biosimilar or vice
versa Extrapolation of indications Most prescribers (61.7%, 192/311, 82 skipped) were able
to identify the most appropriate definition of ‘extrap-
olation of indications’ (‘authorisation of a biosimilar
in indications of the reference biologic in the absence
of specific clinical trial/data for the biosimilar in those
indications’). Fewer Asia-Pacific prescribers selected this
definition versus European prescribers (53.2% vs 65.4%),
although it was the preferred option in both groups. on 2 August 2019 by guest. Protected by copyright. esmoopen.bmj.com/ Regarding switching a patient from a biosimilar to
a reference biologic or vice versa, the statement most
agreed with by prescribers was “I do not anticipate that
switching will have a significant effect on the treatment
benefit the patient receives from the product” (WA
[out of 5] 3.50). This statement was the most commonly
chosen option by both European (WA 3.47) and Asia-Pa-
cific prescribers (WA 3.55). However, among prescribers
from Asia-Pacific, there was a similar level of agreement
(WA 3.54) with the statement “I do not anticipate that
switching will lead to emergence of additional adverse
events”. Despite the high proportion of prescribers being able to
define ‘extrapolation of indications’, most consider their
understanding of extrapolation to be below average, with
62.3% (190/305, 88 skipped, sum of responses) selecting
options 2 and 3 on a scale of 1 (very low) to 5 (very high;
figure 1D). August 2019 by guest. Protected by copyright. Overall, responses indicate that prescribers feel
comfortable using a biosimilar in an extrapolated indi-
cation. On a scale of 1 (not at all) to 5 (very), options
3, 4 and 5 were chosen by 76.7% (237/309, 84 skipped,
sum of responses) of prescribers (figure 3B). These three
options were chosen by 74.3% (150/202, 53 skipped,
sum of responses) of European and 82.8% (53/64, 16
skipped, sum of responses) of Asia-Pacific prescribers
(figure 3B), indicating that Asia-Pacific prescribers may
feel more comfortable with the concept of extrapolation
than those from Europe. Among all prescribers, equal levels of concern were
expressed for the potential for adverse events (AEs)
and increased risk of immune reactions when switching
(WA 3.35; table 2). European prescribers were mainly
concerned with the potential increased risk of immune
reactions (WA 3.39) whereas Asia-Pacific prescribers 5 Giuliani R, et al. ESMO Open 2019;4:e000460. Further education ESMO is undertaking a range of educational initia-
tives including two previous sessions during the ESMO
2017 meeting in Madrid and ESMO Asia 2017, and
another two Colloquia during the 2018 annual meeting
in Munich, Germany, and ESMO Asia 2018, to improve
the understanding of biosimilars within the community. ESMO is also working on developing patient materials to
help their understanding of biosimilars. However, in most questions concerning EMA defi-
nitions, a lower proportion of Asia-Pacific prescribers
answered correctly versus European prescribers. The
only instance where this was not the case was the defi-
nition of ‘sensitive indication’, correctly answered by
60.0% of Asia-Pacific and 42.1% of European prescribers,
indicating that Asia-Pacific prescribers may have a better
understanding of the clinical evidence required for a
biosimilar to gain approval and clinical trial design. Lastly,
responses suggest that prescribers from Asia-Pacific are
more comfortable with the concept of extrapolation than
those from Europe. These differences in responses, particularly regarding
EMA definitions, may be a result of differing guidelines
available on biosimilars in each region. Europe follows
standardised regulations outlined by the EMA for biosim-
ilar approval whereas the regulations in Asia-Pacific coun-
tries differ greatly in the data types required.44 Since
2008, guidance ensuring the quality, safety and efficacy
of biosimilar medicines has been available in the Asia-Pa-
cific region.45 EMA guidance was followed initially in
many countries in the Asia-Pacific region prior to them
implementing their own individual guidelines.45 Coun-
tries including South Korea, Japan and Malaysia estab-
lished their own guidance by taking elements from EMA
and WHO guidelines.45–48 In August 2016, India updated
its initial guidance originally published in 2012 to ensure
a clearer and more thorough regulatory pathway, and to
make parallel with other guidelines available around the
world.49 on 2 August 2019 by guest. Protected by copyright. ttp://esmoopen.bmj.com/ Limitations of the survey include the fact that no
hypothesis was tested and the questionnaire was purely
developed to document the current level of biosim-
ilar knowledge, use and comfort; not all replies were
complete, so data could not be analysed in its entirety; and
responses were limited to ESMO members, their wider
network and participants at the ESMO 2017 Congress, so
may not accurately represent all prescribers worldwide. on 2 August 2019 by guest. Protected by copyright. Further education doi:10.1136/esmoopen-2018-000460 6 Open access Open access data and world-evidence studies that will ultimately help
to guide clinical decision-making. biosimilar development and trial design, as well as under-
standing and comfort of extrapolation of indications,
were similar between prescribers specialised in oncology
and haematology. However, a higher proportion of
haematology versus oncology prescribers feel they have
a high to very high level of comfort using an EMA-ap-
proved biosimilar (72.8% vs 57.4%) and use biosimilars
in routine practice (63.6% vs 49.0%). g
g
Regarding knowledge, use and comfort with biosimi-
lars, some differences in responses were found between
European and Asia-Pacific prescribers. First, a higher rate
of biosimilar use in routine clinical practice was found
among Asia-Pacific (56.3%) versus European prescribers
(46.46%). This may be a result of numerous regulatory
bodies in Asia heavily investing in accelerated development
of biosimilars.44 Furthermore, a lower rate of biosimilar
use was found among prescribers from the UK (31.3%)
compared with the whole group of European prescribers. Responses also suggest that Asia-Pacific prescribers may
be more confident in their understanding of biosimilar
development than European prescribers. on 2 August 2019 by guest. Protected by copyright. http://esmoopen.bmj.com/
lished as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Overall, the level of prescriber knowledge on biosimi-
lars ascertained by this survey is encouraging. However,
a substantial need for continued education emerged
as well. Future efforts should focus in particular on
improving prescriber understanding of extrapolation of
indications as well as physicochemical data, which was
found to be the least understood data type in determining
the suitability of a biosimilar for use when in fact it is
considered by regulatory authorities as the most determi-
nant data type required. This survey found a substantial
demand among prescribers for educational activities and
materials regarding biosimilars, especially in Asia-Pacific. Responses suggest that preference is fairly even between
online (56 responses) and face-to-face (51 responses)
educational activities. The low response to this question
is potentially due to its open comment box design which
is more demanding for respondents and, being the final
question, it is feasible that responders ran out of time. Prescribers from the two different regions had differing
preferences for topics that future training initiatives
should focus on. European prescribers displayed a high
interest in receiving training on the efficacy and safety
of biosimilars, while many from Asia-Pacific conveyed an
interest for more training adapted for developing coun-
tries. Further education com/ Currently, the requirements outlined by regulatory
authorities in different regions regarding biosimilar
approval vary.9 47 A worldwide effort should be under-
taken to align definitions and standards for the develop-
ment and approval of biosimilars. This could potentially
reduce confusion surrounding scientific terms and
concepts, lead to better understanding of the biosimilar
development process and ultimately increase accessibility
and affordability of cancer care.8 guest. Protected by copyright. Further education Overall, 86.7% (195/225, 168 skipped) of prescribers
would like ESMO to provide more educational activities
concerning biosimilars; a much higher proportion of
Asia-Pacific prescribers expressed this (97.9%, 47/48, 32
skipped) versus European prescribers (82.9%, 121/146,
109 skipped). Prescribers suggested numerous topics for future
educational activities, including clinical trial design and
endpoints, bioequivalence criteria and studies, approval
procedures, principles of pricing and reimbursement,
and treatment outcome comparisons between biosimilars
and their reference medicines. Communication chan-
nels suggested included online educational activities and
materials (courses, quizzes, articles, guideline handbooks
and updates on key developments; n=56) and face-to-face
educational activities (congress sessions, preceptorships,
workshops and seminars; n=51). European prescribers on 2 August 2019 by guest. Protected by copyright. ttp://esmoopen.bmj.com/ p
g
y
y
The main concerns oncology prescribers have with
switching are the potential for AEs and increased risk
of immune reactions. Currently, the majority of data
available on switching are from real-world and clinical
studies in immune-mediated inflammatory diseases, such
as rheumatoid arthritis, inflammatory bowel disease and
psoriasis, which have found no clinically meaningful
effects when switching between a biosimilar and its refer-
ence biologic.23–42 Presently, there is one published study
on switching in oncology, which reported no meaningful
differences in efficacy, safety or immunogenicity when
switching biosimilar rhG-CSF with its reference biologic
to prevent severe neutropenia in patients with breast
cancer undergoing myelosuppressive chemotherapy.43 A
recent systematic literature review of 90 switching studies,
treating 14 disease indications and enrolling over 14 000
patients and healthy volunteers, concluded that there is
little risk of increased immunogenicity or treatment-re-
lated AEs, or reduction in efficacy, when switching
between reference medicines and biosimilars.21 An
increase in the confidence of switching biosimilar medi-
cines with their reference biologics among the oncology
community, like in other disease areas, may occur after
increased availability of results from further real-world Table 2 Prescribers’ responses rating their concern
of potential consequences when switching a patient’s
treatment from a reference biologic to a biosimilar or vice
versa
Potential
consequence
(weighted average)
All
Europe
Asia-Pacific
Potential loss of
clinical efficacy
3.29
3.23
3.30
Potential for adverse
events
3.35
3.32
3.35
Potential for increased
risk of immune
reactions
3.35
3.39
3.17
Weighted average of prescribers’ responses, by region, on a scale
of 1 (not at all) to 5 (very). August 2019 by guest. Protected by copyright. y guest. Protected by copyright. Giuliani R, et al. ESMO Open 2019;4:e000460. on 2 August 2019 by
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Lastly, some differences in responses between Euro-
pean and Asia-Pacific prescribers may be attributed to
differences in guidance available in the two regions. Efforts should be made worldwide to align definitions and
regulatory standards for the development and approval
of biosimilars. Continued education will lead to more
informed discussion and decision-making regarding
biosimilars, which will help their successful integration
and uptake in oncology.8 6. Chopra R, Lopes G. Improving access to cancer treatments: the role
of biosimilars. J Glob Oncol 2017;3:596–610. 7. Curigliano G, O'Connor DP, Rosenberg JA, et al. Biosimilars:
Extrapolation for oncology. Crit Rev Oncol Hematol 2016;104:131–7. 8. Rak Tkaczuk KH, Jacobs IA. Biosimilars in oncology: from
development to clinical practice. Seminars in Oncology
2014;41(Suppl 3):S3–S12. 9. European Medicines Agency, 2014. Guideline on similar biological
medicinal products containing biotechnology-derived proteins
as active substance: non-clinical and clinical issues. Available:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/
general/general_content_000886.jsp&mid=WC0b01ac058002956b
[Accessed Sep 2018]. 10. US Food and Drug Administration, 2015. Scientific considerations
in demonstrating biosimilarity to a reference product: guidance
for industry. Available: http://www.fda.gov/downloads/drugs/guid
ancecomplianceregulatoryinformation/guidances/ucm291128.pdf
[Accessed Sep 2018]. Correction notice This article has been corrected since it first published online. The open access licence type has been amended. Acknowledgements Thanks to Monica Gheorghe from ESMO for supporting
the project. Editorial support was provided by Terri Penfold of Spirit Medical
Communications Ltd. Final approval of the manuscript rested solely with the
scientific authors. 11. World Health Organization. Expert Committee on biological
standardization. 2009. Guidelines on evaluation of similar
biotherapeutic products (SBPs). Available: http://www.who.int/
biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_
WEB_22APRIL2010.pdf [Accessed Sep 2018]. Contributors RG was responsible for the study design, the writing, and final
approval of the manuscript. FC was responsible for the study design, the writing,
and final approval of the manuscript. KHM was responsible for the study design,
the writing, and final approval of the manuscript. MV was responsible for the study
design, the writing, and final approval of the manuscript. EGEdV was responsible for
the study design, the writing, and final approval of the manuscript. All authors agree
to be accountable for all aspects of the work. Monica Gheorghe was responsible
for data collection and statistical analysis. Editorial support was provided by Terri
Penfold of Spirit Medical Communications Ltd. 12. European Medicines Agency, 2018. Omnitrope—authorisation
details. Available: http://www.ema.europa.eu/ema/index.jsp?curl=
pages/medicines/human/medicines/000607/human_med_000946.
jsp&mid=WC0b01ac058001d124 [Accessed Sep 2018]. 13. European Medicines Agency, 2018. Epoetin alfa Hexal—
authorisation details. Available: http://www.ema.europa.eu/ema/
index.jsp?curl=pages/medicines/human/medicines/000726/human_
med_000768.jsp&mid=WC0b01ac058001d125 [Accessed Sep
2018]. Conclusion
I
l
i In conclusion, this survey conducted by ESMO found an
encouraging level of prescriber use and general knowl-
edge of biosimilars in oncology; however, need for further
education remains. Future educational initiatives should
focus on improving prescriber understanding of extrapo-
lation of indications as well as physicochemical data. Differences in responses were also noted between
prescribers specialised in oncology and haematology. Of the 393 prescribers who responded, 22 (5.6%) were
specialised in haematology. Overall, knowledge of 7 Giuliani R, et al. ESMO Open 2019;4:e000460. doi:10.1136/esmoopen-2018-000460 Provenance and peer review Not commissioned; externally peer reviewed. Provenance and peer review Not commissioned; externally peer reviewed. 23. Avouac J, Moltó A, Abitbol V, et al. Systematic switch from innovator
infliximab to biosimilar infliximab in inflammatory chronic diseases in
daily clinical practice: the experience of Cochin University Hospital,
Paris, France. Semin Arthritis Rheum 2018;47:741–8. Open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and any changes made are indicated. See: http://creativecommons.org/licenses/
by/4.0/. 24. Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity
and efficacy after switching from reference infliximab to biosimilar
Sb2 compared with continuing reference infliximab and Sb2 in
patients with rheumatoid arthritis: results of a randomised, double-
blind, phase III transition study. Ann Rheum Dis 2018;77:234–40.i 25. Gerdes S, Thaçi D, Griffiths CEM, et al. Multiple switches between
GP2015, an etanercept biosimilar, with originator product do
not impact efficacy, safety and immunogenicity in patients with
chronic plaque-type psoriasis: 30-week results from the phase
3, confirmatory EGALITY study. J Eur Acad Dermatol Venereol
2018;32:420–7. on 2 August 2019 by
http://esmoopen.bmj.com/
ESMO Open: first published as 10.1136/esmoopen-2018-000460 on 6 March 2019. Downloaded from Competing interests JT reports consultancy roles for Array Biopharma,
AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech Inc.,
Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen,
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https://openalex.org/W2977055466
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https://cris.unibo.it/bitstream/11585/722381/1/sensors-19-04206.pdf
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English
| null |
A Dynamic Access Probability Adjustment Strategy
 for Coded Random Access Schemes
|
Sensors
| 2,019
|
cc-by
| 10,722
|
Received: 13 August 2019; Accepted: 25 September 2019; Published: 27 September 2019 Abstract: In this paper, a dynamic access probability adjustment strategy for coded random access
schemes based on successive interference cancellation (SIC) is proposed. The developed protocol
consists of judiciously tuning the access probability, therefore controlling the number of transmitting
users, in order to resolve medium access control (MAC) layer congestion states in high load conditions. Th
t
l i
i
d f t
t
E ti
ti
f th
b
f t
itti
d
i
th Abstract: In this paper, a dynamic access probability adjustment strategy for coded random access
schemes based on successive interference cancellation (SIC) is proposed. The developed protocol
consists of judiciously tuning the access probability, therefore controlling the number of transmitting
users, in order to resolve medium access control (MAC) layer congestion states in high load conditions. The protocol is comprised of two steps: Estimation of the number of transmitting users during the
current MAC frame and adjustment of the access probability to the subsequent MAC frame, based on
the performed estimation. The estimation algorithm exploits a posteriori information, i.e., available
information at the end of the SIC process, in particular it relies on both the frame configuration
(residual number of collision slots) and the recovered users configuration (vector of recovered users)
to effectively reduce mean-square error (MSE). During the access probability adjustment phase,
a target load threshold is employed, tailored to the packet loss rate in the finite frame length case. Simulation results revealed that the developed estimator was able to achieve remarkable performance
owing to the information gathered from the SIC procedure. It also illustrated how the proposed
dynamic access probability strategy can resolve congestion states efficiently. Keywords: congestion; estimation; irregular repetition slotted ALOHA; medium access control;
random access; successive interference cancellation sensors sensors sensors A Dynamic Access Probability Adjustment Strategy
for Coded Random Access Schemes Jingyun Sun 1, Rongke Liu 1,* and Enrico Paolini 2,*
1
School of Electronics and Information Engineering, Beihang University, 37 Xueyuan Road, Haidian Dis
Beijing 100191, China; sunjingyun@buaa.edu.cn
2
Department of Electrical, Electronic, and Information Engineering, University of Bologna,
via Dell’Universitá 50, 47522 Cesena (FC), Italy
*
Correspondence: rongke_liu@buaa.edu.cn (R.L.); e.paolini@unibo.it (E.P.);
Tel.: +86-10-8233-9475 (R.L.); +39-0547-339137 (E.P.) Jingyun Sun 1, Rongke Liu 1,* and Enrico Paolini 2,* Jingyun Sun 1, Rongke Liu 1,* and Enrico Paolini 2,*
1
School of Electronics and Information Engineering, Beihang University, 37 Xueyuan Road, Haid
Beijing 100191, China; sunjingyun@buaa.edu.cn
2
Department of Electrical, Electronic, and Information Engineering, University of Bologna,
via Dell’Universitá 50, 47522 Cesena (FC), Italy
*
Correspondence: rongke_liu@buaa.edu.cn (R.L.); e.paolini@unibo.it (E.P.);
Tel.: +86-10-8233-9475 (R.L.); +39-0547-339137 (E.P.)
1. Introduction Since then,
coded random access emerged as a new paradigm and has been the subject of several investigations
over the past few years (e.g., [6–12] and references therein). As a result, the throughput has substantially
increased which makes it a practical and efficient solution to support uncoordinated access. p
pp
Despite their numerous advantages, coded random access schemes exhibit lower critical points in
traffic load. In other words, the throughput of these schemes is maximized for load values less than
1 and, for larger values of the load, it decreases very rapidly. Congestion occurs when the number
of active users is greater than the receiver processing capacity. Several control methods for random
access schemes have been investigated, which may be classified into two kinds: Dynamic frame
length based methods and dynamic access probability based methods. In dynamic framed slotted
ALOHA (DFSA) systems, the frame size is adjusted dynamically according to the estimated number
of active users in order to maximize the system efficiency [13–17]. In dynamic access probability based
schemes, on the other hand, an access controller is required to adjust the users access probability under
high traffic loads in order to limit the number of transmitting users [18–21]. However, in [18–20],
the estimation process was simply based on the status of frame slots before the application of SIC
and in [21], the estimation is assumed to be ideal at the receiver. Furthermore, the proposed random
access control mechanisms in [18] are based on random access schemes without SIC at the receiver,
which is not applicable for coded random access schemes. In both [19,20], users directly employ the
load threshold from [5], which is obtained via asymptotic analysis (frame length and user population
size tending to infinity, their ratio remaining constant). When applied to the finite frame length case,
asymptotic load thresholds tend to be beyond the actual critical point, which may yield considerable
throughput losses. In this paper, a dynamic access probability based strategy for coded random access schemes
is proposed to resolve congestion. The proposed strategy performs two main tasks: Estimation of
number of transmitting users in the current frame and the adjustment of access probability in the next
frame based on the estimation results. 1. Introduction In machine-type and Internet-of-Things (IoT) communications, users generate a large amount of
bursty traffic to transmit over a shared communication medium. Coordinated multiple access schemes
turn to be impractical and generally inefficient in such scenarios. For this reason, random access
schemes have attracted a renewed interest, as they provide a practical way for uncoordinated users to
contend for channel resource. Pure ALOHA scheme [1] was proposed in 1968 to share a channel among a number of users
sending packets as soon as they have data to transmit. Classical slotted ALOHA [2] is a distributed
random access scheme in which time is divided into slots of equal duration with each transmission
starting only at the beginning of a time slot. In both variants, an absence of coordination among users
may lead to collisions (two or more packets are received in overlapping time windows). All packets
involved in a collision are often reported as useless and are retransmitted after a random delay,
according to some probability distribution, or (in the framed case) in the next frame. As a result,
pure ALOHA and slotted ALOHA suffer from a throughput penalty and an under-utilization of
channel resource. The optimal normalized throughput of pure ALOHA is 0.18 and the throughput of
slotted ALOHA is increased to 0.37. www.mdpi.com/journal/sensors Sensors 2019, 19, 4206; doi:10.3390/s19194206 www.mdpi.com/journal/sensors Sensors 2019, 19, 4206 2 of 18 The expression of “coded random access” refers to a set of random access schemes that combine
the packet repetition of users with successive interference cancellation (SIC) at the receiver. The first
coded random access scheme is collision resolution diversity slotted ALOHA (CRDSA) [3], where each
user sends two packet replicas in two random slots of the frame, and then SIC is applied to recover the
collided packets in an iterative fashion. After CRDSA, CRDSA++ [4] was proposed to further improve
throughput by increasing the number of packet replicas. In [5], where irregular repetition slotted
ALOHA (IRSA) was proposed, the SIC-based random access process is conveniently described by a
bipartite graph, establishing a bridge between the SIC procedure and the iterative erasure decoding
of graph-based codes. In IRSA, the packet repetition rate is irregular from user to user and is chosen
independently by each active user according to a suitably designed probability distribution. 1. Introduction In our previous work [22–24] techniques for a more reliable
estimation of the number of transmitting users in coded random access schemes were developed
and more specially, the number of transmitting users in the current frame was estimated using a
posteriori information gathered throughout the SIC process. A posteriori estimation was considered
for CRDSA in [22], for IRSA in [23] and for CRDSA over a packet and slot erasure channel in [24]. Notably, [22–24] were entirely focused on the estimation process, without any attempt to exploit it
within a dynamic access probability adjustment protocol. The usage of a target load threshold tailored
to the finite frame length case and the introduction of a state judgment to avoid not fully reliable
estimation in high traffic load conditions are other original features of this manuscript. The system model and some preliminary definitions are provided in Section 2. The estimation
algorithm for the number of transmitting users in the current frame is addressed in Section 3.1,
while the access probability adjustment strategy is proposed in Section 3.2. Numerical results are
illustrated in Section 4 and concluding remarks are given in Section 5. 3 of 18 Sensors 2019, 19, 4206 2.1. System Model We consider a scenario where multiple users contend for access to a single central receiver. The medium access control (MAC) layer is organized into frames and the random access scheme is a
slotted one. We denote random variables by capital letters, while their realizations and deterministic
quantities are denoted by lower case letters. The frame length is fixed and divided into m time slots
with equal duration. Active users are the ones who have packets to transmit. Congestion occurs when the number
of active users is too large in comparison to the available resources (a more precise definition of
congestion is given in Section 3.2). We use the subscript (k) to represent the index of the MAC frame. If there is no congestion or the congestion is resolved, the index (k) is re-initialized to (0) in the next
frame, otherwise, it keeps counting. As such, a frame index k ≥1 indicates that we are in the k-th
frame of the current congestion event. User population size is npop. The number of active users is unknown to the receiver and is
modeled by a random variable Na; the number of active users at the beginning of frame k is N(k)
a . No new user activates before the current congestion has been resolved. Denoting by ∆(k), the number
of users that are recovered while processing frame k, for k ≥1 we have: N(k)
a
= N(k−1)
a
−∆(k−1). (1) (1) Transmitting users are the ones who are allowed to transmit their packets in the frame. Let T(k)
a
be the number of transmitting users during frame k. Moreover, denote by p(k)
ac the access probability
of the active users during frame k. At the beginning of the k-th frame, each active user becomes a
transmitting one with probability p(k)
ac , independently of other active users. Hence, the conditional
expected value of T(k)
a
is: E[T(k)
a |n(k)
a ] = n(k)
a p(k)
ac . (2) (2) Each transmitting user is frame- and slot- synchronous and attempts at most one packet transmission
per frame. In every frame corresponding to k = 0, all active users transmit their packets to the receiver, i.e.,
we have p(0)
ac = 1 and t(0)
a
= n(0)
a . 2.1. System Model However, as soon as the contribution of interference, generated by
some transmitting users on the slot, is canceled and only one packet replica is left in it, the slot status
is updated to singleton. Similarly, if all of the packet replicas transmitted in the slot are recovered
by the receiver, the slot status (singleton slot or collision) is updated to empty. Packet replicas from
singleton slots are always correctly received, which means that packet losses may only be generated
by unresolved collisions. After transmissions, the pointers to twin replicas in the header of the packet enable SIC at the
receiver. At first, the receiver stores the content of the frame. Then, the receiver performs iteratively
the following procedure, consisting of two subsequent steps: 1. Pick out the singleton slots in the frame. For each singleton slot, extract the transmitting user
index, the content of the packet replica, and positions of other twin replicas. Identified users in this
step become recovered users; 2. For each user recovered at step 1, remove the user’s contribution of interference in the slots
where the packet replicas have been transmitted. A new singleton slot will appear if, after interference
cancellation, they contain only one replica. 2. For each user recovered at step 1, remove the user’s contribution of interference in the slots
where the packet replicas have been transmitted. A new singleton slot will appear if, after interference
cancellation, they contain only one replica. The iterative SIC procedure terminates when all slots are empty ones, in which case SIC succeeds,
or when no singleton slot can be found but collision slots still exist, in which case it fails. At the end of
the SIC procedure, the residual number of empty slots in the frame is denoted by Me, and the residual
number of collided slots per frame by Mc. Obviously, we have Me + Mc = m. Example 1. With reference to Figure 1, ta = 4 users transmit their packets to a frame with m = 5 slots. User
u1 generates three replicas of his packet, and sends them to s1, s3, and s4, respectively. Each of the other users
generate two replicas of the corresponding packets and transmit them as illustrated in the figure. At the receiver,
slots s1 and s4 are singleton slots and the left s2, s3, and s5 are collison slots. 2.1. System Model The instantaneous channel load over frame k is defined as: G(k) = t(k)
a
m
(3) (3) and represents the average number of packet transmissions per slot. The throughput over frame k is
defined as: and represents the average number of packet transmissions per slot. The throughput over frame k is
defined as: T(k)
h
= t(k)
a
m (1 −PL)
(4) (4) representing the average number of successfully recovered packets per slot by the receiver. The quantity
PL in Equation (4) is the packet loss rate over the frame, which is expressed as: representing the average number of successfully recovered packets per slot by the receiver. The quantity
PL in Equation (4) is the packet loss rate over the frame, which is expressed as: PL = 1 −δ(k)
t(k)
a
. (5) (5) Sensors 2019, 19, 4206 4 of 18 In IRSA, each transmitting user sends L packet replicas to slots picked uniformly at random. The number of replicas, named user degree, is a discrete random variable probability mass function
(p.m.f.) {Λl}, where Λl = P(L = l) is the probability that a user generates l packet replicas. Users
choose their replica factor (i.e., user degree) L independently of each other, with no coordination,
and the values of user degree are according to distribution {Λl}. We also represent {Λl} in polynomial
form, as Λ(x) = ∑dmax
l=1 Λlxl, where dmax is the maximum number of packet replicas per user. Both
information about the transmitting user index (assuming users are indexed from 1 to npop) and pointers
to the slots where the other replicas have been transmitted are included in the header of each packet
replica. CRDSA can be seen as IRSA with Λ(x) = xdmax. In this paper, a classical collision channel model is adopted. After packet replica transmissions,
each slot takes one of the following three states: Empty slot (no packet replica transmitted in that
slot), singleton slot (only one packet replica transmitted in that slot), and collision slot (two or more
than two packet replicas transmitted in that slot). The receiver can always correctly classify the state
of each slot. Collision slots provide no information to the receiver about the number and content of
collided packet replicas directly. 2.1. System Model Figure 2 provides a graphical interpretation (first proposed in [5]) of the iterative SIC procedure performed
on the frame of Figure 1. In the presented graph, “slot nodes" represent slots and “user nodes" represent users. In the first SIC iteration, s1 and s4 are singleton slots and the corresponding packet replicas are correctly received,
making u1 a recovered user. The pointer to slot s3, where the twin of the replica in s1 has been transmitted,
is extracted (step 1). After the interference from recovered user u1 in slot s3 is canceled and only one packet
replica is left in s3, making s3 a new singleton slot (step 2). Then a second iteration is triggered. After three SIC
iterations, users u2 and u3 remain unrecovered, there are no singleton slots in the frame, and SIC terminates
with failure. The feedback frame configuration signal is {0, 1, 0, 0, 1} which indicates that s1, s3 and s4 are empty slots
and that s2 and s5 are unresolved collision slots. Receiving this feedback signal, u2 and u3 become aware that
their packets have not been successfully received. 5 of 18 Sensors 2019, 19, 4206 u4
u3
u2
u1
s1
s2
s3
s4
s5
u4,1
u4,2
u3,1
u3,2
u2,1
u2,2
u1,1
u1,2
u1,3
1
Figure 1. Example of a MAC frame with ta = 4 transmitting users and m = 5 slots. User u1 sends three
packet replicas and the other users each send two packet replicas. Slots s1 and s4 are singleton slots
and the left s2, s3, and s5 are collision slots. 1
Figure 1. Example of a MAC frame with ta = 4 transmitting users and m = 5 slots. User u1 sends three
packet replicas and the other users each send two packet replicas. Slots s1 and s4 are singleton slots
and the left s2, s3, and s5 are collision slots. slot nodes
user nodes
1
Figure 2. Example of successive interferece cancellation (SIC) procedure corresponding to Figure 1. Squares correspond to slots and circles correspond to users. Figure 2. Example of successive interferece cancellation (SIC) procedure corresponding to Figure 1. Squares correspond to slots and circles correspond to users. 2.2. Threshold Definition and Notation Throughout the paper we define a load threshold G◦as the maximum load such that the packet
loss rate falls below a given target value P◦
L. In other words, when the instantaneous load G is below
G◦, we have PL ≤P◦
L, otherwise we have PL > P◦
L. In Table 1, some examples of probability distributions Λ(x) are shown with the corresponding
target load threshold values. The first two rows in the table represent CRDSA schemes, where each
user transmits the same number of replicas. The last two rows represent IRSA schemes, where the
number of replicas per user is irregular. The values of G◦have been obtained via a Monte Carlo
simulation, for MAC frame length m = 200 and target packet loss rate P◦
L = 0.01. ble 1. Load threshold G◦for different probability distributions Λ(x), for MAC frame length m = 200,
d
k
l
P◦
0 01 Table 1. Load threshold G◦for different probability distributions Λ(x), for MAC frame length m = 200,
and packet loss rate target P◦
L = 0.01. Table 1. Load threshold G◦for different probability distributions Λ(x), for MAC frame length m = 200,
and packet loss rate target P◦
L = 0.01. Table 1. Load threshold G◦for different probability distributions Λ(x), for MAC frame length m = 200,
and packet loss rate target P◦
L = 0.01. Distribution, Λ(x)
G◦
Λ1(x) = x2
0.35
Λ2(x) = x4
0.69
Λ3(x) = 0.5x2 + 0.28x3 + 0.22x8
0.705
Λ4(x) = 0.25x2 + 0.6x3 + 0.15x8
0.76 Load threshold G◦for different probability distributions Λ(x), for MAC frame length m = 200,
ket loss rate target P◦
L = 0.01. Sensors 2019, 19, 4206 6 of 18 Figure 3 shows the packet loss rate PL versus instantaneous load G for the distributions in Table 1
and frame length m = 200. As previously remarked, the SIC process in IRSA can be described by a
bipartite graph, where unresolved collisions are associated with graphical structures known, in the
low-density parity-check (LDPC) coding jargon, as stopping sets. It is well known that the impact
of small stopping sets on the finite-length performance is strictly related to the fraction of degree-2
variable nodes in its bipartite graph and a similar role is played by degree-2 users in IRSA. 2.2. Threshold Definition and Notation As observed
in the figure, the limitation of degree-2 repetition has a better error floor performance, but a poorer
waterfall performance. The detailed packet loss rate performance analysis for IRSA schemes have been
addressed in [5]. 0
0.2
0.4
0.6
0.8
1
10−4
10−3
10−2
10−1
100
G
PL
Λ1
Λ2
Λ3
Λ4
Figure 3. Packet loss rate PL versus instantaneous load G for frame length m = 200 and the distributions
in Table 1. Figure 3. Packet loss rate PL versus instantaneous load G for frame length m = 200 and the distributions
in Table 1. 2.3. Combinatorial Parameters We denote by |⃗v| = ∑n
i=1 |vi| the ℓ1 norm of a real-valued vector ⃗v = (v1, . . . , vn). Moreover,
given a second vector ⃗w = (w1, . . . , wn) whose elements are nonnegative integers, we use the compact
notation ⃗v⃗w for vw1
1 · · · vwn
n . Let⃗o = (o1, . . . , odmax) be a vector whose elements are all nonnegative integers. Let M(⃗o, b) be
the set of all |⃗o| × b binary matrices M, with rows and columns indexed from 1 to |⃗o| and from 1 to b,
respectively, that fulfill the following properties: 1. The matrix M has the structure: M = [MT
1 MT
2 · · · MT
dmax]T where Mi has dimension oi × b and all of its rows have Hamming weight i. 2. Every column of M has
Hamming weight at least 2. where Mi has dimension oi × b and all of its rows have Hamming weight i. 2. Every column of M has
Hamming weight at least 2. Example 2. Let⃗o = (o1, o2, o3) = (0, 1, 3) and b = 5. Each matrix in M ∈M(⃗o, b) has dimension 4 × 5. Its row indexes should be thought as partitioned into the two subsets {1} and {2, 3, 4}. The row of index 1
has weight 2, and the rows of indexes 2, 3, and 4 have weight 3. Every column of M has weight of at least 2. An example of matrix M ∈M(⃗o, b) is: 7 of 18 Sensors 2019, 19, 4206 M =
1
0
0
1
0
0
1
0
1
1
1
1
1
0
0
0
0
1
1
1
. M =
1
0
0
1
0
0
1
0
1
1
1
1
1
0
0
0
0
1
1
1
. The following lemma provides a formal expression for the cardinality of the set M(⃗o, b). The following lemma provides a formal expression for the cardinality of the set M(⃗o, b). The following lemma provides a formal expression for the cardinality of the set M(⃗o, b). Lemma 1. For given ⃗o and b, let h(⃗o, b) be the cardinality of the set M(⃗o, b). 3. Dynamic Access Probability Algorithm In this section we introduce the proposed multiple access strategy based on a dynamic adjustment
of the users access probability. Section 3.1 addresses estimation of the number of transmitting users;
Section 3.2 exploits the developed estimator to perform congestion detection and resolution via
dynamic access probability adjustment. 2.3. Combinatorial Parameters Sensors 2019, 19, 4206 8 of 18 In particular, it is obtained by applying Newton’s binomial formula twice and by exploiting the identity
coeff(∑i αiPi(⃗x),⃗x ⃗w) = ∑i αicoeff(Pi(⃗x),⃗x ⃗w). In particular, it is obtained by applying Newton’s binomial formula twice and by exploiting the identity
coeff(∑i αiPi(⃗x),⃗x ⃗w) = ∑i αicoeff(Pi(⃗x),⃗x ⃗w). 2.3. Combinatorial Parameters Moreover, let ⃗x =
(x1, x2, . . . , x|⃗o|) and: Lemma 1. For given ⃗o and b, let h(⃗o, b) be the cardinality of the set M(⃗o, b). Moreover, let ⃗x =
(x1, x2, . . . , x|⃗o|) and: ⃗q = (1, . . . , 1
| {z }
o1
, 2, . . . , 2
| {z }
o2
, . . . , dmax, . . . , dmax
|
{z
}
odmax
). (6) (6) Define the multivariate polynomials A(⃗x) and Bj,l(⃗x) as: Define the multivariate polynomials A(⃗x) and Bj,l(⃗x) as: A(⃗x) =
|⃗o|
∏
i=1
(1 + xi) −
1 +
|⃗o|
∑
i=1
xi
! (7) A(⃗x) =
|⃗o|
∏
i=1
(1 + xi) −
1 +
|⃗o|
∑
i=1
xi
! (7) (7) and: and: Bj,l(⃗x) =
|⃗o|
∑
i=1
xi
!l |⃗o|
∏
i=1
(1 + xi)
!j
. (8) Bj,l(⃗x) =
|⃗o|
∑
i=1
xi
!l |⃗o|
∏
i=1
(1 + xi)
!j
. (8) (8) Then, we have: Then, we have: Then, we have: h(⃗o, b) = coeff((A(⃗x))b,⃗x⃗q)
(9)
=
b
∑
j=0
b−j
∑
l=0
b
j
b −j
l
(−1)b−jcoeff(Bj,l(⃗x),⃗x⃗q)
(10) (9) (10) where coeff(P(⃗x),⃗x⃗r) is the coefficient of ⃗x⃗r in the multivariate polynomial P(⃗x) where coeff(P(⃗x),⃗x⃗r) is the coefficient of ⃗x⃗r in the multivariate polynomial P(⃗x). Proof. Let⃗c T = (c1, . . . , c|⃗o|)T be the generic column and define a multivariate enumerating function
for valid columns (i.e., columns with weight of at least 2): A(⃗x) = ∑
⃗c:|⃗c|≥2
⃗x⃗c. (11) (11) It is easy to recognize that an equivalent expression for A(⃗x) is the one shown in Equation (7). This is because (1 + x1) · · · (1 + x|⃗o|) provides the sum of all monomials in the variables x1, . . . x|⃗o|
with a unitary coefficient, to which we subtract all monomials of degrees 0 and 1 as required by the
condition of validity. Considering now b columns and applying properties of generating functions, coeff((A(⃗x))b,⃗x ⃗w)
is the number of |⃗o| × b binary matrices such that all matrix columns are valid and such that
the weight of row i is wi. This immediately leads to Equation (9). The equivalent expression of
Equation (10) is obtained by simple algebraic manipulation of the multivariate polynomial (A(⃗x))b. 3.1. Number of Transmitting Users Estimation In this subsection, we exploit frame configuration information at the end of SIC to estimate
the number t(k)
a
of transmitting users in the k-th frame, when an SIC failure occurs. For the sake of
notational simplicity, the superscript (k) is temporarily omitted. The total number of transmitting users is denoted by ta. We also denote by ta,l the number
of such users that employ the replica factor l. Clearly, we have ta = ∑dmax
l=1 ta,l. The vector
⃗ta = (ta,1, ta,2, . . . , ta,dmax) is referred to as transmitting users configuration at the beginning of the
frame. The number of transmitted users that are recovered at the end of the SIC process is denoted by
δ ≤ta. Out of these δ recovered users, δl ≤ta,l are the ones using replica factor l, so that δ = ∑dmax
l=1 δl. The vector ⃗δ = (δ1, δ2, . . . , δdmax) is referred to as the recovered users configuration at the end of SIC. max
Hereafter we develop a compact expression for the a posteriori probability distribution of
the configuration⃗ta of transmitting users, given the number mc of residual collision slots and the
configuration⃗δ of recovered users observed at the end of SIC. This probability is denoted by P(⃗ta|mc,⃗δ). Note that, as transmitting users pick their slots uniformly at random, it is sufficient to condition to
the number of collision slots (and not to their positions in the frame). The corresponding probability
distribution of the number ta of transmitting users is given by: P(ta|mc,⃗δ) =
∑
⃗ta:|⃗ta|=ta
P(⃗ta|mc,⃗δ). (12) (12) A maximum a posteriori (MAP) estimator for the number of transmitting users then returns
the value: A maximum a posteriori (MAP) estimator for the number of transmitting users then returns
the value: ˆt
argmax P(t |m ⃗δ)
(13) (13) ˆta = argmax
ta
P(ta|mc,⃗δ). (13) Theorem 1. The a posteriori probability distribution of the configuration⃗ta of the transmitting users fulfills: Theorem 1. The a posteriori probability distribution of the configuration⃗ta of the transmitting users fulfills: P(⃗ta|mc,⃗δ) ∝
⃗ta
⃗δ
h(⃗ta −⃗δ, mc)
∏dmax
l=1 (m
l )ta,l P(⃗ta)
(14) (14) where h(⃗o, b) is given by Lemma 1, (
⃗ta
⃗δ) = ∏l (ta,l
δl ), and P(⃗ta) is the a priori probability that the transmitting
users configuration equals⃗ta. 3.1. Number of Transmitting Users Estimation where h(⃗o, b) is given by Lemma 1, (
⃗ta
⃗δ) = ∏l (ta,l
δl ), and P(⃗ta) is the a priori probability that the transmitting
users configuration equals⃗ta. Proof. From Bayes’ rule we have: From Bayes’ rule we have: Proof. From Bayes’ rule we have: P(⃗ta|mc,⃗δ) = P(mc,⃗δ|⃗ta)P(⃗ta)
P(mc,⃗δ)
∝P(mc,⃗δ|⃗ta)P(⃗ta). (15) (15) 9 of 18 Sensors 2019, 19, 4206 Let T(⃗ta, mc,⃗δ) be the number of ways in which |⃗ta| transmitting users with configuration ⃗ta can
transmit their packet replicas in the frame so that, at the end of SIC, there are mc unresolved collision
slots and a recovered users configuration ⃗δ. Moreover, let T(⃗ta) be the number of ways in which |⃗ta|
transmitting users with configuration⃗ta can place their packet replicas in the frame. The conditional
probability P(mc,⃗δ|⃗ta) can be expressed as: Let T(⃗ta, mc,⃗δ) be the number of ways in which |⃗ta| transmitting users with configuration ⃗ta can
transmit their packet replicas in the frame so that, at the end of SIC, there are mc unresolved collision
slots and a recovered users configuration ⃗δ. Moreover, let T(⃗ta) be the number of ways in which |⃗ta|
transmitting users with configuration⃗ta can place their packet replicas in the frame. The conditional
probability P(mc,⃗δ|⃗ta) can be expressed as: P(mc,⃗δ|⃗ta) = T(⃗ta, mc,⃗δ)
T(⃗ta)
. (16) (16) The quantity T(⃗ta) is readility shown to be given by: The quantity T(⃗ta) is readility shown to be given by: T(⃗ta) =
dmax
∏
l=1
m
l
ta,l
. (17) (17) To develop an expression for T(⃗ta, mc,⃗δ), we proceed as follows. At the end of SIC, |⃗ta −⃗δ| transmitting
users with configuration ⃗ta −⃗δ remain unrecovered. The number of ways in which these users transmit
their packet replicas to mc slots, forming mc collisions (at least two replicas per slot) is h(⃗ta −⃗δ, mc). If we let g(⃗δ, mc) be the number of ways in which |⃗δ| transmitting users with configuration ⃗δ can place
their packet replicas in a frame with m −mc free slots and mc unresolvable collision slots, so that
SIC can recover all of them, we can write (no formal expression for g(⃗δ, mc) is provided because this
parameter, not depending on⃗ta does not play any role in the estimation process of Equation(13)): T(⃗ta, mc,⃗δ) =
⃗ta
⃗δ
m
mc
h(⃗ta −⃗δ, mc)g(⃗δ, mc). 3.1. Number of Transmitting Users Estimation (18) (18) Incorporating Equation (17) and Equation (18) into Equation (16) and then Equation (16) into
Equation (15), and omitting all terms not depending on ⃗ta, we obtain Equation (14). Incorporating Equation (17) and Equation (18) into Equation (16) and then Equation (16) into
Equation (15), and omitting all terms not depending on ⃗ta, we obtain Equation (14). Although Equations (13) and (14) define an exact MAP estimator, computing h(⃗ta −⃗δ, mc) turns
out to be a complex task, becoming already intractable for frame sizes in the order of a few tens. For this reason we employ an approximated MAP estimator. In the approximation, all packet replicas,
even from the same user, are regarded as distinguishable packets. Equivalently, each user chooses l
slots with replacement. In this approximate setting, we have P(⃗ta|mc,⃗δ) ∝
⃗ta
⃗δ
h((∑dmax
l=1 (tl −δl)l), mc)
m∑dmax
l=1
tll
P(⃗ta)
(19) (19) where (∑dmax
l=1 (tl −δl)l) represents a vector with only one element, corresponding to⃗o = (o1) in h(⃗o, b). The value of h((∑dmax
l=1 (tl −δl)l), mc) is the number of ways in which ∑dmax
l=1 (tl −δl)l packet replicas are
sent to mc slots, such that each slot receives not less than 2 packet replicas [25]; m∑dmax
l=1
tll is the total
number of ways in which ∑dmax
l=1 tll packet replicas can be accommodated into the m slots. As an estimator performance measure we consider the MSE, defined as: Mϵ = E[ϵ2]
(20) (20) Mϵ = E[ϵ2] where ϵ = ˆt(k)
a
−t(k)
a
is the estimation error. 10 of 18 Sensors 2019, 19, 4206 3.2. Access Probability Adjustment Strategy 3.2. Access Probability Adjustment Strategy We say that we have a congestion on frame k whenever We say that we have a congestion on frame k whenever n(k)
a
> G◦m,
(21) (21) where we recall that n(k)
a
is the number users that are active on frame k. Our purpose is to exploit the
developed estimator to detect congestion states and dynamically adjust the users access probability to
improve overall efficiency. Congestion states are resolved by tuning the access probability to control
the number of transmitting users in the next frame. where we recall that n(k)
a
is the number users that are active on frame k. Our purpose is to exploit the
developed estimator to detect congestion states and dynamically adjust the users access probability to
improve overall efficiency. Congestion states are resolved by tuning the access probability to control
the number of transmitting users in the next frame. The proposed scheme is based on the definition of three possible states for a frame, name •
Not fully reliable estimate. In high load conditions, SIC typically stops prematurely with a
relatively small number of recovered users. We say that the estimate ˆt(k)
a
is not fully reliable when
the number of users recovered by processing the frame is smaller than the number of users that
could not be recovered: •
Not fully reliable estimate. In high load conditions, SIC typically stops prematurely with a
relatively small number of recovered users. We say that the estimate ˆt(k)
a
is not fully reliable when
the number of users recovered by processing the frame is smaller than the number of users that
could not be recovered: δ(k) < t(k)
a
−δ(k)
(22) δ(k) < t(k)
a
−δ(k)
(22)
δ(k) < t(k)
a /2. (23) (22) or, equivalently, δ(k) < t(k)
a /2. (23) (23) •
Congestion with reliable estimate. The number of active users is above threshold G◦m, but the
number of users recovered by processing the frame is not less than the number of users that could
not be recovered: •
Congestion with reliable estimate. The number of active users is above threshold G◦m, but the
number of users recovered by processing the frame is not less than the number of users that could
not be recovered: n(k)
a
> G◦m
and
δ(k) ≥t(k)
a
−δ(k). (24) (24) •
No congestion. The number of active users is below threshold G◦m: •
No congestion. 3.2. Access Probability Adjustment Strategy 11 of 18 Sensors 2019, 19, 4206 Algorithm 1: Receiver procedure Algorithm 1: Receiver procedure Algorithm 1: Receiver procedure
1 if m(k)
c
> 0 && P(t(k)
a >2δ(k)|m(k)
c ,⃗δ (k))
P(t(k)
a ≤2δ(k)|m(k)
c ,⃗δ (k)) > 1 then
2
p(k+1)
ac
←
Gom
npop−∑k
i=0 δ(i) ;
3
k ←k + 1;
4 else
5
if m(k)
c
== 0 then
6
ˆt(k)
a
= δ(k);
7
else
8
calculate ˆt(k)
a
according to Equation (19)
9
end
10
ˆn(k)
a
= ˆt (k)
a
/p(k)
ac ;
11
if ˆn(k)
a
> G◦m then
12
p(k+1)
ac
←
Gom
ˆn(k)
a −δ(k) ;
13
k ←k + 1;
14
else
15
p(1)
ac ←1;
16
k ←0;
17
end
18 end
19 broadcast k, p(k)
ac , and C(k) to the users; Algorithm 1: Receiver procedure
1 if m(k)
c
> 0 && P(t(k)
a >2δ(k)|m(k)
c ,⃗δ (k))
P(t(k)
a ≤2δ(k)|m(k)
c ,⃗δ (k)) > 1 then
2
p(k+1)
ac
←
Gom
npop−∑k
i=0 δ(i) ;
3
k ←k + 1;
4 else
5
if m(k)
c
== 0 then
6
ˆt(k)
a
= δ(k);
7
else
8
calculate ˆt(k)
a
according to Equation (19
9
end
10
ˆn(k)
a
= ˆt (k)
a
/p(k)
ac ;
11
if ˆn(k)
a
> G◦m then
12
p(k+1)
ac
←
Gom
ˆn(k)
a −δ(k) ;
13
k ←k + 1;
14
else
15
p(1)
ac ←1;
16
k ←0;
17
end
18 end
19 broadcast k, p(k)
ac , and C(k) to the users; 19 broadcast k, p(k)
ac , and C(k) to the users; The first step (line 1) consists of detecting whether Equation (23) is fulfilled or not. When SIC
succeeds (m(k)
c
= 0), the estimation is perfect. The algorithm jumps to line 6 and simply sets ˆt (k)
a
= δ(k). In case of an SIC failure (m(k)
c
> 0), the algorithm applies a two-hypotheses MAP detector, whose
development is presented in Appendix A, to decide whether Equation (23) holds (in which case
estimation is considered unreliable) or not. Concretely, if P(t(k)
a
> 2δ(k)|m(k)
c ,⃗δ (k))
P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ (k))
> 1,
(26) (26) then Equation (23) is assumed to hold and the estimation Equation (19) is regarded as not reliable
enough. Otherwise, the estimate ˆt(k)
a
is employed to design the access probability in the next frame. 3.2. Access Probability Adjustment Strategy The number of active users is below threshold G◦m: n(k)
a
≤G◦m. (25) (25) In the first case, a large number of transmitting users is unrecovered, and the packet loss rate is
larger than 0.5. As illustrated in the numerical results section, the estimation MSE increases with the
number of transmitting users and the estimate is therefore regarded as not suitable to design the access
probability pac in the subsequent frame. In contrast, in the last two cases the access probability in the
next frame is calculated directly by employing the estimate of the number of transmitting users. In the generic frame k, after all transmitting users have performed the transmission of their
packet replicas, the receiver performs the SIC procedure. At the end of SIC, the receiver executes the
procedure described in Algorithm 1. This procedure is executed regardless of the SIC termination
status (success or failure). An explanation of Algorithm 1 is provided in the following. 3.2. Access Probability Adjustment Strategy When Equation (26) is satisfied, a ’not fully reliable estimate’ state is detected and the number
of transmitting users is detected to be large enough to create a congestion but the relatively large
estimation MSE prevents from relying on ˆt (k)
a
to reliably adjust the access probability in the next frame. At the end of frame k a number ∑k
i=0 δ(i) of active users have been recovered since the beginning of
congestion. Therefore, at the beginning of the subsequent frame, the number of unresolved active
users fulfills n(k+1)
a
≤npop −∑k
i=0 δ(i). To make the expected number of transmitting users in the
subsequent frame below the target number G◦m, we set the access probability according to (line 2) p(k+1)
ac
=
G◦m
npop −∑k
i=0 δ(i) . (27) (27) This way, the conditional expected number of transmitting users in the next frame is This way, the conditional expected number of transmitting users in the next frame is 12 of 18 Sensors 2019, 19, 4206 E[T(k+1)
a
|n(k+1)
a
] = n(k+1)
a
p(k+1)
ac
= n(0)
a
−∑k
i=0 δ(i)
npop −∑k
i=0 δ(i) G◦m,
(28) (28) where n(0)
a
−∑k
i=1 δ(i) represents the actual number of unrecovered active users at the beginning of
frame k + 1. When the estimation result is detected to be reliable, an acceptable estimation MSE is assumed
by the receiver, which exploits ˆt(k)
a
(equal to δ(k) in case of a SIC success or by Equation (19) in case
of a failure) to obtain an estimate of the number of active users on frame k. Specifically, the receiver
performs (line 10): ˆn(k)
a
= ˆt(k)
a /p(k)
ac . (29) (29) The estimate ˆn(k)
a
is compared with the threshold G◦m (line 11). If ˆn(k)
a
> G◦m the receiver
declares a congestion with a reliable estimate state. The system is suffering from congestion, but most
of (or all of) transmitting users have been recovered by SIC. The relatively low estimation MSE allows
confidently using ˆn(k)
a
to set the access probability for the next frame. If the access probability is kept
unchanged in the subsequent frames, the number of transmitting users will deviate progressively from
the target G◦m, leading to a low throughput. 3.2. Access Probability Adjustment Strategy To make efficient use of channel resources, we increase
the access probability in such a way as to maintain the number of transmitting users close to the
target G◦m in the next frame. From Equation (1), the estimated number of unrecovered active users
at the beginning of the frame k + 1 is ˆn(k+1)
a
= ˆn(k)
a
−δ(k). The target conditional expected number of
transmitting users in frame k + 1 is E[T(k+1)
a
|n(k+1)
a
] = G◦m. (30) (30) Thus, the access probability over frame k + 1 is set to (line 12): Thus, the access probability over frame k + 1 is set to (line 12): Thus, the access probability over frame k + 1 is set to (line 12): p(k+1)
ac
=
G◦m
ˆn(k)
a
−δ(k) . (31) (31) If ˆn (k)
a
< G◦m, a no congestion state is detected. The frame index k is re-initialized to 0 and the
users access probability is set to be 1 (lines 15 and 16). As a last step (line 19), the receiver broadcasts to the users the index of the next frame (index of
the current frame increased by 1 if a congestion is detected and 0 otherwise), the access probability to
be employed by active users in the next frame, and the list of indexes of collision slots at the end of
SIC in the current frame. Upon receiving feedback from the receiver, users behave as follows: •
If k > 0 (congestion), in the next frame each backlogged user attempts access to the frame with
probability equal to the new access probability. Each non-backlogged user is prevented from
transmitting new packets; •
If k > 0 (congestion), in the next frame each backlogged user attempts access to the frame with
probability equal to the new access probability. Each non-backlogged user is prevented from
transmitting new packets; •
If k = 0 (no congestion), users that are in a backlog state retransmit their packet. Users that are
not backlogged take their normal access activity. Users are updated by the receiver about congestion or no congestion simply through the index k. Moreover, each of them knows whether or not it is in a backlog state simply by looking at the list of
collision slot indexes C(k). 3.2. Access Probability Adjustment Strategy Note that, if k = 0 (no congestion) is broadcasted by the receiver, this does
not necessarily mean that SIC has succeeded as there may be a small number of users unrecovered 13 of 18 Sensors 2019, 19, 4206 even though the system is not suffering from congestion. In this case, we simply let backlogged users
retransmit packet replicas with probability 1 in the subsequent frame, together with possible fresh
replicas from newly activated users. even though the system is not suffering from congestion. In this case, we simply let backlogged users
retransmit packet replicas with probability 1 in the subsequent frame, together with possible fresh
replicas from newly activated users. 4. Numerical Results This section is organized into two subsections. In Section 4.1 we show results on the estimation of
the number of transmitting users, while in Section 4.2 we address the performance achieved by the
proposed scheme. 4.1. Estimation of Transmitting Users It is also worth
noting that the performance of the proposed estimator relies on the SIC performance. In low load
conditions, the SIC procedure stops with a large number of users recovered, so in this region the
proposed estimation algorithm is more effective. In contrast, in high load conditions SIC almost always
stops prematurely, recovering a small number of users, leading the proposed estimation algorithm to
be less effectively. 0
0.2
0.4
0.6
0.8
1
10−2
10−1
100
101
102
G
Mε
Before SIC
After SIC
1
Figure 5. Mean squared error (MSE) versus G for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. 2. Dynamic Access Probability Simulation Results 1
Figure 5. Mean squared error (MSE) versus G for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. D
i A
P
b bili
Si
l i
R
l 1
Figure 5. Mean squared error (MSE) versus G for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. 1
Figure 5. Mean squared error (MSE) versus G for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. 4.2. Dynamic Access Probability Simulation Results In this subsection, we present the simulation results for dynamic access probability based coded
random access schemes using the mentioned estimation methods. The frame length is m = 200
and the user population size is npop = 2000. Moreover, the considered IRSA distribution is
Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. Each non-backlogged user activates, independently of the other
users, with probability π = 0.8 at the beginning of every frame with k = 0. At the first frame, there are
no backlogged users. The target traffic threshold G◦is set to 0.65, 0.705, 0.80, and 0.938 respectively,
of which G◦= 0.708 is associated with P◦
L = 0.01 and G◦= 0.938 is the asymptotic threshold of the
considered IRSA distribution [5]. The initial access probability is p(0)
ac = 1. We analyzed the system
performance, during congestion resolution periods, through numerical simulations. Every simulation
consisted of a sufficiently large number of runs and, in each run, the simulation was stopped when the
congestion was resolved. As a benchmark, consider transmission without any dynamic access probability adjustment
process. The expected number of active users (transmitting users) in the initial frame is 1600. The average repetition rate is 3.6, corresponding to an expected number of 6480 packet replicas
transmitted over the 200 slots. 4.1. Estimation of Transmitting Users In this section, we present Monte Carlo simulation results using the approximated estimator
discussed at the end of Section 3.1. Let the frame length be m = 200 and the user population size be
npop = 400. Users are assumed to activate independently of each other at the beginning of every new
frame. In each run, after users transmissions, SIC is applied at the receiver and then the developed
approximated estimator is applied. Figure 4 shows the average throughput and throughput standard deviation versus the
instantaneous load G for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8 [5]. The maximum average
throughput is achieved at a value of G that is approximately equal to 0.8. However, the realizations
of the per-frame throughput fluctuate around its statistical mean, the throughput standard deviation
representing a reliable measure of the bobbing range (i.e., dispersion). A large standard deviation
makes the average throughput a not fully meaningful parameter since, due to the per-frame throughput
fluctuations, we have a higher probability that the system falls into a not fully reliable estimate state. In this respect, the peak average throughput is not necessarily a good working point, as the statistical
mean alone is not able to capture the probability of falling into such an “outage” state. 0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
G
0
0.2
0.4
0.6
0.8
1
Average Throughput
0
0.2
0.4
Throughput Standard Deviation
Figure 4. Average throughout and throughput standard deviation versus the instantaneous load G for
IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. Figure 4. Average throughout and throughput standard deviation versus the instantaneous load G for
IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. Figure 5 shows the estimation performance after SIC iterations, letting the SIC-based receiver run
until no active user is recovered. As a comparison, we also consider the estimation performance using
the frame configuration before SIC iterations, which is reviewed in Appendix B. In the figure, the solid
line is relevant to the proposed estimation making use of the frame configuration and recovered users
configuration after SIC iterations. Moreover, a dashed line corresponds to the estimation based on
the initially received frame, before SIC is applied. As observed in the figure, the proposed estimation 14 of 18 Sensors 2019, 19, 4206 algorithm is able to reduce the MSE effectively over the whole range of G values. 4.1. Estimation of Transmitting Users At the receiver, we have a vanishing probability to find singleton slots
capable of triggering the SIC process. Without dynamic access probability adjustment, the packet loss
rate becomes very close to 1 and the throughput very close to 0, meaning that almost no users are
recovered in the subsequent frames, making system congestion unresolvable. Figures 6–8 show that the proposed access probability algorithm works well to resolve congestion. The users access probability is adjusted dynamically to track the number of active users. At frame
1, the access probability is decreased quickly to avoid working in the high load region. In this way,
the estimator can provide a reliable estimate at the end of the frame and the receiver is able to perform
an accurate access probability design for the users in the next frame. Then the access probability is
adjusted dynamically to make the number of transmitting users around the target G◦m. It is increased 15 of 18 Sensors 2019, 19, 4206 slowly as some users are recovered by the receiver in each transmission. Each curve is plotted up to
the maximum value of k for which congestions remain unresolved, which is different for the different
choices of the target load threshold. 0
5
10
15
20
25
30
k
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
pac
Go=0.65
Go=0.705
Go=0.80
Go=0.938
Figure 6. Access probability pac versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. Figure 6. Access probability pac versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. 0
5
10
15
20
25
30
k
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Th
Go=0.65
Go=0.705
Go=0.80
Go=0.938
Figure 7. Throughput performance Th versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3
+ 0.22x8. Figure 7. Throughput performance Th versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3
+ 0.22x8. 0
5
10
15
20
25
k
10-4
10-3
10-2
10-1
100
PL
Go=0.65
Go=0.705
Go=0.80
Go=0.938
Figure 8. Packet loss rate PL versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. Back to Figure 3, we have seen that the IRSA scheme tends to show a packet loss rate floor Figure 8. Packet loss rate PL versus frame index k for IRSA with Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. 4.1. Estimation of Transmitting Users Back to Figure 3, we have seen that the IRSA scheme tends to show a packet loss rate floor at
low offered traffic regimes, the floor appearing around PL = 10−2 (corresponding to G = 0.705) for Back to Figure 3, we have seen that the IRSA scheme tends to show a packet loss rate floor at
low offered traffic regimes, the floor appearing around PL = 10−2 (corresponding to G = 0.705) for Sensors 2019, 19, 4206 16 of 18 16 of 18 Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. For larger values of G (corresponding to the waterfall packet loss rate
region), the packet loss rate increases rapidly: A PL ≃0.08 is achieved at G = 0.80 and a PL ≃0.5
is achieved at G = 0.938. Consequently, in Figure 8, systems with target G◦= 0.65 and G◦= 0.705
have a similar packet loss rate performance, and they perform better than those with target G◦= 0.80
and G◦= 0.938. Furthermore, due to estimation errors and to fluctuations of the actual number of
transmitting users, we observe a minor packet loss rate deviation between Figure 8 and Figure 3. For example, in Figure 8, the packet loss rate with target G◦= 0.80 is around 0.2, while in Figure 3,
the packet loss rate at G◦= 0.80 is approximately equal to 0.008. Λ(x) = 0.5x2 + 0.28x3 + 0.22x8. For larger values of G (corresponding to the waterfall packet loss rate
region), the packet loss rate increases rapidly: A PL ≃0.08 is achieved at G = 0.80 and a PL ≃0.5
is achieved at G = 0.938. Consequently, in Figure 8, systems with target G◦= 0.65 and G◦= 0.705
have a similar packet loss rate performance, and they perform better than those with target G◦= 0.80
and G◦= 0.938. Furthermore, due to estimation errors and to fluctuations of the actual number of
transmitting users, we observe a minor packet loss rate deviation between Figure 8 and Figure 3. For example, in Figure 8, the packet loss rate with target G◦= 0.80 is around 0.2, while in Figure 3,
the packet loss rate at G◦= 0.80 is approximately equal to 0.008. As a final remark, recall that the throughput is defined as G(1 −PL). The influence of PL at
G ≤0.705 is small, so that the per-frame throughput T(k)
h
is approximately equal to the instantaneous
load G. 5. Conclusion In this paper, we proposed a technique to estimate the number of transmitting users in each
frame of an IRSA-based coded random access system. The estimated number of transmitting users
in the current frame was exploited to adjust the users access probability in the next frame. Frame
configuration information as well as recovered users configuration information at the end of the
SIC procedure were employed to make the estimation more accurate. Numerical results revealed
how the derived dynamic access probability strategy could resolve congestion efficiently, with a
stable throughput and a target packet loss rate performance for a proper choice of the parameter
G◦. Interesting directions of investigation include the exact efficient evaluation of the h(⃗o, b) function
(addressed in Lemma 1), to make the optimum estimator applicable to large communication networks. Adjusting the frame length dynamically in situations of slowly varying traffic load over a large scale
is another direction of investigation that, to the best of the authors’ knowledge, has not been so far
addressed in the coded random access context. Author Contributions: All the authors contributed extensively to the work presented in this paper and to writing
the paper itself. J.S. and E.P. conceived the idea and developed the proposed approaches. E.P. gave advice
on the research and helped in editing the paper. E.P. and R.L. improved the quality of the manuscript and
completed revision. Funding: This research was funded by the China Scholarship Council (grant No. 201706020024). Conflicts of Interest: The authors declare no conflict of interest. 4.1. Estimation of Transmitting Users That is why in Figure 7, the throughput performance with target G◦= 0.705 is better than that
with target G◦= 0.65. However, for the cases G◦= 0.8 and G◦= 0.938, the influence of PL can not be
ignored any more. The system performance is worse even though the load target G◦is higher, since
the packet loss rate is now considerably higher. Appendix B. Estimation Using Collision Slots before SIC The user’s repetition rate is Λ(x). Define Λ′(1) as the average user repetition rate given by
Λ′(1) = ∑l lΛl. It is easy to verify that the probability that a generic user sends a packet replica within
a given slot is Λ′(1)/m. As the users send packet replicas randomly, the slot degree distribution is
binomially distributed. The probability that a slot has l collided users is given by: Ψl =
ta
l
Λ′(1)
m
l
1 −Λ′(1)
m
ta−l
. (A3) (A3) Before SIC iterations, the probability pe that a given slot is empty, the probability ps that a
given slot is singleton and the probability pc that a given slot is a collision one can be expressed
respectively as: Before SIC iterations, the probability pe that a given slot is empty, the probability ps that a
given slot is singleton and the probability pc that a given slot is a collision one can be expressed
respectively as: pe =
1 −Λ′(1)
m
ta
,
(A4)
ps = ta
Λ′(1)
m
1 −Λ′(1)
m
ta−1
(A5) (A4) (A5) and: and: and: pc = 1 −pe −ps. (A6) pc = 1 −pe −ps. (A6) An estimation for Ta using frame configuration before SIC performs: ˆta = argmax
ta
P(ta|wc),
(A7) ˆta = argmax
ta
P(ta|wc),
(A7) (A7) where wc is the number of collision slots before SIC iterations. Following Bayes’ rule, P(ta|wc) may be
developed as: P(ta|wc) ∝P(wc|ta)P(ta)
∝pcwc(1 −pc)m−wc. (A8) (A8) Appendix A. Justification and Implementation of Equation (26) This appendix justifies and addresses the implementation of the two-hypotheses MAP detection
rule Equation (26). Let the two hypotheses be H0 and H1. Moreover, let r represent the observation. The optimum detection rule consists of making the decision ˆH0 when P(H0|r) > P(H1|r) and of
making the decision ˆH1 otherwise. In our case, H0 corresponds to a ’not fully reliable estimate’ state (satisfied Equation (23)); H1
corresponds to a ’reliable estimate’ state (Equation (23) not holding). The observation is (m(k)
c ,⃗δ (k)). Hence, we have: P(t(k)
a
> 2δ(k)|m(k)
c ,⃗δ (k))
P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ (k))
ˆH0
≷
ˆH1
1,
(A1) (A1) 17 of 18 17 of 18 Sensors 2019, 19, 4206 where P(t(k)
a
> 2δ(k)|m(k)
c ,⃗δ (k)) = ∑t (k)
a
: t (k)
a
>2δ(k) P(t(k)
a |m(k)
c ,⃗δ (k)) and P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ (k)) =
∑t(k)
a : t(k)
a ≤2δ(k) P(t(k)
a |m(k)
c ,⃗δ (k)). The probability P(t(k)
a |m(k)
c ,⃗δ (k)) can be expressed as: P(t(k)
a
> 2δ(k)|m(k)
c ,⃗δ (k)) = ∑t (k)
a
: t (k)
a
>2δ(k) P(t(k)
a |m(k)
c ,⃗δ (k)) and P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ (k)) =
(k)
(k) ⃗(k)
(k)
(k) ⃗(k) where P(t(k)
a
> 2δ(k)|m(k)
c ,⃗δ (k)) = ∑t (k)
a
: t (k)
a
>2δ(k) P(t(k)
a |m(k)
c ,⃗δ (k)) and P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ
∑(k)
(k)
(k) P(t(k)
a |m(k)
c ,⃗δ (k)). The probability P(t(k)
a |m(k)
c ,⃗δ (k)) can be expressed as: k)|m(k)
c ,⃗δ (k)) and P(t(k)
a
≤2δ(k)|m(k)
c ,⃗δ (k)) = P(t(k)
a |m(k)
c ,⃗δ (k)) =
∑
⃗ta:|⃗t (k)
a
|=t(k)
a
P(⃗t (k)
a
|mc,⃗δ (k)),
(A2) (A2) where P(⃗t (k)
a
|mc,⃗δ (k)) comes from the estimator Equation (14). where P(⃗t (k)
a
|mc,⃗δ (k)) comes from the estimator Equation (14). where P(⃗t (k)
a
|mc,⃗δ (k)) comes from the estimator Equation (14). where P(⃗t (k)
a
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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English
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Public preferences for vaccination and antiviral medicines under different pandemic flu outbreak scenarios
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BMC public health
| 2,015
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cc-by
| 11,631
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RESEARCH ARTICLE Open Access * Correspondence: s.michie@ucl.ac.uk
1Health Psychology Research Group, University College London, London
WC1E 7HB, UK
Full list of author information is available at the end of the article Rubinstein et al. BMC Public Health (2015) 15:190
DOI 10.1186/s12889-015-1541-8 Helena Rubinstein1, Afrodita Marcu2, Lucy Yardley2 and Susan Michie1* Helena Rubinstein1, Afrodita Marcu2, Lucy Yardley2 and Susan Michie1* © 2015 Rubinstein et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated. Background This body of research suggests that, in a future pan-
demic, the public would benefit from more knowledge
about the health threat and about who will be at-risk
from infection, how the infection spreads, how to
self-diagnose, short and long term consequences of the
illness if precautionary measures are not taken, and the
potential side effects of vaccination and antiviral drug
treatments [30-32,34,35], including safety and efficacy
tests for a new vaccine that would be rapidly deployed
[30]. In some instances, trust was found to be an
important component in acceptance and compliance
with recommended behaviours; however, trust in public
officials has been found to be weak compared with trust
in medical professionals [31,34,36-38]. Although the
research described above has identified a range of factors
promoting pandemic vaccination, there is less about those
factors influencing uptake of antiviral medicines. Evidence shows that the factors that have been found to
promote uptake of vaccination included being vaccinated
for seasonal flu [8-10], perceiving that the outbreak was se-
vere and resulting in high morbidity and mortality [11,12],
high levels of worry and anxiety [13], being in a priority
group [14] and believing that the vaccine was effective and
safe [14,15]. In addition, social influences were important;
for example knowing someone who had the disease and
knowing that others had a favourable view of the vaccine
[11] as well as trust in the source of information
[11,15-17]. Factors that have been found to act as barriers
to uptake of pandemic influenza vaccination were: believ-
ing that the outbreak was not serious [16,17], and not iden-
tifying oneself as being at-risk [17]. Fears about the safety
and side effects of the vaccine were also a barrier to H1N1
vaccine uptake [8,14,18-20]. It appeared that the public
preferred to take the risk of harm posed by the disease over
any harm that might be caused by being vaccinated
[21,22]. The scant research in the UK and elsewhere about
the public’s response to antiviral medicines in the last pan-
demic suggests that the public knew relatively little about
antiviral medicines and had limited experience of their use
[23]. Frequent travellers had more positive perceptions of
antiviral medication as a result of prior usage [24,25] and
research with pregnant women found a tension between
women’s desire to protect the foetus from harm and worry
about the safety of taking medicines when pregnant [26]. Background Research conducted with the public in advance of an
outbreak can inform the type of messages that are likely
to be effective in promoting acceptance of these recom-
mended behaviours [27,28]. Such past research has
investigated hypothetical scenarios of varying degrees of
severity and advice on a variety of precautionary behav-
iours including hand-washing, covering the mouth, vac-
cination and seeking medical attention [29-32]. Results
showed that the public was largely unfamiliar with the
term ‘pandemic’ and tended to believe that pandemic
influenza was similar to seasonal influenza [29,31]. Most people do not know whether the symptoms of
pandemic flu are different from pandemic influenza and
are unsure how to recognise the signs [29,32,33]. g
The 2009 A/(H1N1) influenza pandemic was less mark-
edly severe than previous strains such as the H3N2 virus
in 1968 [1]. The groups that were most at-risk from
infection were those aged below 19 years [2], pregnant
women and individuals with underlying illnesses such
as diabetes, asthma, respiratory diseases, immune sup-
pression and renal disease [3]. One dose of pandemic
vaccine conferred good protection against the infection
in approximately 70% of cases [4]. However, despite the
effectiveness of the vaccine, the public demand for vac-
cination was low and many people were not vaccinated. For example, in the UK uptake of vaccination among
clinically at-risk groups was 37.6% [5]. For those who
contracted pandemic influenza, antiviral medicines were
recommended as a treatment, and the provision of anti-
viral medicines (also as a preventive measure) was a major
component of emergency plans in many countries [6]. Data from the UK National Pandemic Flu Service (NPFS)
indicated that of the 1.8 m courses of antiviral medicines
that were authorised, only 1.16 million were collected and
many patients failed to complete a full course [7]. This
suggests that there is a need to develop effective commu-
nications to improve uptake and to consider how best to
advise the public on the nature of the disease, why they
should seek prevention (vaccination) or treatment (antiviral
medication), who should seek it and when. Abstract Background: During the 2009-2010 A(H1N1) pandemic, many people did not seek care quickly enough, failed to
take a full course of antivirals despite being authorised to receive them, and were not vaccinated. Understanding
facilitators and barriers to the uptake of vaccination and antiviral medicines will help inform campaigns in future
pandemic influenza outbreaks. Increasing uptake of vaccines and antiviral medicines may need to address a range
of drivers of behaviour. The aim was to identify facilitators of and barriers to being vaccinated and taking antiviral
medicines in uncertain and severe pandemic influenza scenarios using a theoretical model of behaviour change,
COM-B. Methods: Focus groups and interviews with 71 members of the public in England who varied in their at-risk status. Participants responded to uncertain and severe scenarios, and to messages giving advice on vaccination and antiviral
medicines. Data were thematically analysed using the theoretical framework provided by the COM-B model. Results: Influences on uptake of vaccines and antiviral medicines - capabilities, motivations and opportunities - are
part of an inter-related behavioural system and different components influenced each other. An identity of being
healthy and immune from infection was invoked to explain feelings of invulnerability and hence a reduced need
to be vaccinated, especially during an uncertain scenario. The identity of being a ‘healthy person’ also included
beliefs about avoiding medicine and allowing the body to fight disease ‘naturally’. This was given as a reason for
using alternative precautionary behaviours to vaccination. This identity could be held by those not at-risk and by
those who were clinically at-risk. Conclusions: Promoters and barriers to being vaccinated and taking antiviral medicines are multi-dimensional
and communications to promote uptake are likely to be most effective if they address several components of
behaviour. The benefit of using the COM-B model is that it is at the core of an approach that can identify effective
strategies for behaviour change and communications for the future. Identity beliefs were salient for decisions about
vaccination. Communications should confront identity beliefs about being a ‘healthy person’ who is immune from
infection by addressing how vaccination can boost wellbeing and immunity. Keywords: Pandemic influenza, Vaccination, Antiviral medicines, Behaviour Rubinstein et al. BMC Public Health (2015) 15:190 Page 2 of 13 Background While research has often focused on the public’s
response to advice during severe or moderate pandemic
outbreaks little is known about how the public would
respond to advice in an explicitly uncertain situation
where the risk is less clear cut. For example, Teasdale &
Yardley [32] studied the public’s response to advice in
scenarios where the consequences were described as
moderate or severe; Elledge and collegues [31] investi-
gated mild and severe scenarios for avian flu and
McGlone et al studied [39] responses to a severe sce-
nario. Understanding how the public responds when the
progress and impact of a pandemic is uncertain will be
important because it is during the emergent, uncertain
stages of a pandemic that the public will be asked to
consider the potential risk of contracting pandemic
influenza and to take precautionary measures to reduce
the likelihood of personal infection and spread. The majority of studies that have investigated how the
public respond to precautionary advice has rarely been
informed by a theoretical understanding of behaviour
change. Using a theoretical framework helps to integrate
empirical findings and elucidate processes of change and
mechanisms of action of effective communication and Page 3 of 13 Rubinstein et al. BMC Public Health (2015) 15:190 other intervention strategies. A useful framework for this
purpose is the COM-B model summarising factors
necessary for behaviour to change across behavioural
domains [40] (Figure 1). The initials stand for ‘capabil-
ity’, ‘opportunity’, ‘motivation’ and ‘behaviour’, and the
model recognises that behaviour is part of an interacting
system involving all these components. Changing behav-
iour will involve changing one or more of them in such
a way as to put the behavioural system into a new con-
figuration and minimise the risk of it reverting. Because
of the interacting nature of these components, one may
increase, for example, motivation by increasing capability
(e.g. knowledge and skills) and opportunity (e.g. access to
resources and social influence). reflects the brain processes that direct behaviour which
may be reflective (evaluations and plans) or automatic
(emotions and impulses arising from associated learning). COM-B has been elaborated into 14 theoretical domains,
the Theoretical Domains Framework (TDF) [41]. The study aimed to systematically identify facilitators
of and barriers to being vaccinated and taking antiviral
medicines in uncertain and severe pandemic influenza
scenarios using the COM-B framework. Method
Design and recruitment
S
d f By specifying the factors that need to change for a
behaviour to occur, the model can identify the kinds of
interventions that are likely to be effective. The model
postulates that for any behaviour to occur a person must
have the psychological and physical capability to perform
the behaviour; the physical and social opportunity to
engage in it, and must be motivated to do so at the
relevant moment compared with some other behaviour. Psychological and physical capability refers to the range
of capacities such as knowledge, physical and mental
skills and facilities such as strength and stamina. Oppor-
tunity can be physical and social and refers to environ-
mental factors that permit the behaviour including access,
availability, time and financial resources and social factors
such as the cultural milieu we operate in. Motivation Background An uncertain
scenario was used in addition to a severe scenario
because in the early stages of a pandemic there is often
uncertainty about how the situation will unfold, how
rapidly the infection will spread, or what impact this
could have on the population. Hence it is important to
understand how people respond to precautionary advice
in these conditions of uncertainty, how they make sense
of the risk, and what types of precautionary measures
they express preference for. We adopted the COM-B model in our approach to the
uptake of pandemic flu vaccination and antiviral medi-
cines because changing the incidence of any behaviour
in a group or population is likely to involve changing
more than one driver of behaviour. Sample Sampling was purposeful and individuals who varied in
their risk status were recruited. Of the 71 participants,
23 were men and 48 were women; Details of the demo-
graphic profile are shown in Table 1. Thirty-five were
from designated at-risk groups of whom 10 had an
underlying condition, and six were pregnant. Of the 36
participants not designated as being at-risk, nine were
specifically recruited because they were mothers with
young children. Thirty-eight of the participants were
vaccinated for seasonal influenza regularly (of whom 20
were from clinical at-risk groups) and two had been
vaccinated for seasonal influenza for the first time this
year. Eighteen people who did not consider themselves
to be at risk had been vaccinated at least once before for
seasonal influenza. Reasons for being vaccinated among
those who were designated as not being at high risk
included recommendation by a GP, and being offered Materials Two scenarios were developed: an uncertain and a severe
scenario. The severe scenario was based on that used by
Teasdale and Yardley (2011) which described a severe level
of risk, severe health consequences and the national im-
pact of the pandemic. The uncertain scenario was devel-
oped to reflect the early conditions that occurred during
the 2009/10 pandemic. This described an uncertain situ-
ation, uncertain health consequences and uncertain public
impact of the pandemic (see Table 2). Short messages promoting the uptake of vaccinations
and antiviral medicines for pandemic influenza were
developed to reflect evidence from prior research that
identified barriers to uptake but also to reflect the key
drivers of behaviour as defined in the COM-B frame-
work. These were presented as advice from official
sources (see Table 3). Table 1 Profile characteristics of participants
Gender
Type of group
Male
23
Mothers/young children
9
Female
48
Elderly - aged 65 years and over
19
Underlying illness*
10
Pregnant
6
General public
27
Location
Been vaccinated for seasonal flu
London
47
Yes
40
Southampton
24
No
31
Age
Perceived risk of catching influenza
16-35 years
21
Not at risk
35
36-64 years
20
At risk
17
65 years and over
30
Not stated
19
Ethnicity
H1N1 vaccine
White/White British
42
Yes
12
Black/Black African
22
No
56
Other
7
NA
3
Education
Antiviral for H1N1
Secondary school
7
Yes
3
College
7
No
65
University educated
36
NA
3
Not stated
21
*i.e., diabetic, asthma, COPD. Table 1 Profile characteristics of participants Design and recruitment Semi-structured focus groups and interviews were con-
ducted with a diverse sample of the general public. To
ensure that participants were from a range of social and
ethnic backgrounds we recruited from a variety of orga-
nizations in London and Southampton including chil-
dren’s centres, AgeUK lunch clubs, community centres,
students from a university, voluntary organisations and
support groups for those with underlying conditions
such as diabetes, COPD (Chronic Obstructive Pulmon-
ary Disease) and PSC (Primary Sclerosing Cholingitis). Advertisements were placed in these centres explaining
the purpose of the study, who was eligible, how to par-
ticipate and offering a small monetary compensation for Figure 1 Schematic of the components and relationships in the COM-B model. Figure 1 Schematic of the components and relationships in the COM-B model. Rubinstein et al. BMC Public Health (2015) 15:190 Page 4 of 13 participation. The managers of the centres where inter-
views were held advertised the study and made rooms
available for the focus groups to take place. the vaccine at work. 12 participants had received mono-
valent H1N1 vaccine and three had antiviral medicines
during the 2009-2010 pandemic. Ethical approval for the study was granted by University
College London (Reference: 5081/001) and the University
of Southampton (Reference: 7387) ethics committees. It should be noted that groups were not always mutu-
ally exclusive. For example, some individuals who had
been recruited as ‘elderly’ (over 65 years of age) also
reported that they had other underlying conditions that
would put them in another at-risk category. *i.e., diabetic, asthma, COPD. Data analysis Audio recordings were transcribed verbatim and NVivo
10 was used to code and to maintain a trail of memo
and theme development. Analysis was iterative and each
transcript was read and re-read numerous times by the
first two authors independently. Transcripts were coded
line by line and analysed comparatively to identify simi-
larities and differences [42]. A data audit was conducted
by the first two authors to clarify meanings, remove
duplicated codes and identify data that did not match
the coding scheme [43]. Results Responses to the uncertain and severe scenarios differed:
in the uncertain scenario participants were hesitant and
ambivalent about following advice because the risk was
unclear whereas in the severe scenario the need to act
seemed more obvious and almost all claimed they would
comply with the official advice. The focus of this paper is on facilitators and barriers
to uptake of pandemic influenza vaccination, because
participants knew relatively little about antiviral medi-
cines and were less able to discuss them. Responses to
advice about antiviral medicine were more limited, as
the participants were largely unfamiliar with these medi-
cines, but were broadly similar to responses to advice
about being vaccinated; any differences are highlighted
after the responses in common are presented. Inductive analysis was used to identify responses to
the uncertain and severe scenarios. Deductive analysis
was used to identify facilitators and barriers to following
recommended advice to be vaccinated and take antiviral
medicines. In addition, code names were assigned to the
six COM-B components: physical and psychological
capabilities; automatic and reflective motivations, and
social and physical opportunities (see Additional files 1
and 2 – code frames). For the purposes of analysis, the
Theoretical Domains Framework [41] was used. This is
a variant of the COM-B which subdivides the themes
into 14 detailed components that map directly onto
COM-B. These are: ‘knowledge’; ‘skills’; ‘memory, atten-
tion and decision processes’; ‘behavioural regulation’;
‘social/professional role and identity’; ‘beliefs about cap-
abilities’; ‘optimism’; ‘beliefs about consequences’; ‘inten-
tions’; ‘goals’; ‘reinforcement ‘emotion’; ‘environmental
context and resources’; and ‘social influences’a. Most people who catch flu feel very ill for around a week. Almost 1
in every 10 people who catch flu need hospital care, and 1 in every 50
healthy people who catch flu die. Most people who catch flu feel very ill for around a week. Almost 1
in every 10 people who catch flu need hospital care, and 1 in every 50
healthy people who catch flu die. When the virus reaches the UK, we don’t know whether life will carry
on much as usual or whether there will be serious problems with services
such as the NHS, schools or vital supplies. Life cannot continue as usual. Most schools close, there is very high
sickness absence at work and so there are problems with essential supplies,
and health care services are not coping and have to be prioritised for the
most seriously ill. being in a priority group (36 people – men and women
under 65 years, mothers with young children). being in a priority group (36 people – men and women
under 65 years, mothers with young children). Table 2 Uncertain and Severe Scenarios of Pandemic Influenza used in the research
Uncertain Scenario
Severe scenario Table 2 Uncertain and Severe Scenarios of Pandemic Influenza used in the research Table 2 Uncertain and Severe Scenarios of Pandemic Influenza used in the research
Uncertain Scenario
Severe scenario Flu virus has spread to where you live, 1 in 2 of those coming into
close contact with an infected person catch flu. Scientists do no yet know how badly the flu virus will affect people in
the UK - doctors are trying to learn about the virus as fast as they
can, but do not know if it will be mild or serious. Procedure
D
ll Data collection took place in London and Southampton
from November 2013 to March 2014. Nine focus groups,
three paired interviews and six individual interviews
were conducted by the first two authors at the centres
from which participants were recruited. Written in-
formed consent was obtained from all participants who
received a small monetary compensation for their in-
volvement. Interviews lasted between 20 and 65 minutes
and were audio recorded with the participants’ consent. An interview schedule structured into two sections
was used to guide the discussion. The first section was
to establish what participants knew about pandemic
influenza, vaccinations, and antiviral medicines for pan-
demic influenza, and personal experiences of pandemic
influenza. The second section focused on responses to
two scenarios and advice concerning vaccinations and
antiviral medicines. Participants were asked to imagine
that they were in a given situation and to consider what
they would think, feel and do if this were to occur. The
Uncertain scenario (Table 2) was always shown first,
followed by the advice about antiviral medicines (Table 3). The Severe scenario (Table 2) was shown second followed
by the advice on vaccinations (Table 3), and then antiviral
medicines. All participants were debriefed in full at the
end of the interview and reassured that these were
fictional scenarios. Page 5 of 13 Rubinstein et al. BMC Public Health (2015) 15:190 Severe scenario The [pandemic] flu virus has not yet reached the area where you live but
it is now spreading to the UK. In other countries hundreds of people are
infected - some people do not have any symptoms but 15 have died. Flu virus has spread to where you live, 1 in 2 of those coming into
close contact with an infected person catch flu. Capability
Knowledge The majority of participants knew little about pandemic
influenza and many were unsure of the meaning of the
word ‘pandemic’. Overall, few people linked ‘pandemic
influenza’ to the A/H1N1 pandemic influenza outbreak
of 2009-2010. They tried to make sense of it by likening
it to other more familiar phrases such as ‘epidemic’,
inferring that it was probably a more widespread and
more serious form of influenza: You’d step up your vitamin C etc. and your cod liver
oil. (Male, over 65 years) I would be watching more people touching- for me per-
sonally, washing my hands er you know being aware if
someone sneezes I’d probably ask them to cover their
face. (Mother with young children) I just thought pandemic flu was all kinds of flu, I
didn’t…oh well I actually thought maybe pandemic
sounds like a flu that is outbreaking and very
dangerous and they want to keep it under control. (Pregnant woman) I just thought pandemic flu was all kinds of flu, I
didn’t…oh well I actually thought maybe pandemic
sounds like a flu that is outbreaking and very
dangerous and they want to keep it under control. (Pregnant woman) In this situation, it was thought to be important to
‘keep an eye on the media’ to find out what general
advice was being given. In contrast, the most common response to the severe
scenario was to take action. 32 million people in the UK with flu, yeah. Okay. I’m
off to the doctor. (Male, not at-risk) Only two people in the study spontaneously referred
to the fact that pandemic influenza is a novel strain of
virus. When this information was presented, people
found the notion of it being a novel strain helpful in
explaining the threat it posed beyond seasonal influenza: You’d probably be ringing up your GP and going ‘I need
to look after my daughter - I don’t want to get it. Can
you put me in a priority group? (Female, not at-risk) You’d probably be ringing up your GP and going ‘I need
to look after my daughter - I don’t want to get it. Can
you put me in a priority group? Barriers and facilitators to vaccination uptake
Five of the six components in the COM-B model
accounted for participants’ responses (Table 4). some evidence to suggest that the uncertainty was experi-
enced as disconcerting, the majority did not see the need
for vaccination or antiviral medicines. Rather, participants
suggested that they would do more of the behaviours they
already practiced such as following good hand and respira-
tory hygiene and taking more Vitamin C: Capability
Knowledge (Female, not at-risk) It’s just the word they use when it is worldwide and it
is spreading from chickens in China or something, but
other than that I didn’t know what it meant, that it
was new, why don’t they just say new? I mean they want
new, it’s the new one for which there isn’t any vaccine
yet; that should be said. (Female, over 65 years) The ‘call to action’ occurred because this situation was
thought to be serious. ‘Serious’ was often interpreted in
terms of the disease being emotionally and physically
close rather than in terms of the absolute number of
people who were ill, hospitalised or had died. If it is your neighbour - it is really – being really ill
with flu, if they got it and their baby got it it’s near to
you and you know people and I would feel influenced I
think. Well I’ve got a baby at home and my elderly
mum lives next door I should get it because I don’t
want to put them at-risk by me getting or vice versa
but if it is on the news and they are telling you in
China – you know whatever I am thinking ‘whatever,
am I at-risk? Is my family at-risk? It’s on the TV. I don’t
know –am I going to get this? (Female, not at-risk) In the absence of this new information, some thought
that pandemic influenza could be like seasonal influenza. What are the symptoms? Are there different symptoms
from swine flu and ordinary flu? What would you look
out for? How would you know you had one from the
other? They could be the same. (Male, not at-risk) Responses to the scenarios: procrastination vs. call to
action The most common response to the uncertain scenario
was to ‘wait and see’ or ‘do nothing yet’. There were two
reasons given for this: the situation was likened to the
swine flu outbreak, which was not considered to be ser-
ious, and it was thought to be distant - both emotionally
and physically - and hence, less worrying: It hasn’t got into the country at the moment, so um
I’m not sure if there are people that have the
pandemic flu. (Pregnant womanb) The facilitators and barriers to being vaccinated and take
antiviral medicines were reviewed separately. Responses to
accepting advice were also investigated according to two
broad categories – those designated as being in a priority
group (35 people – men and women over 65 years, preg-
nant, underlying illnesses) and those not designated as Personal risk was perceived to be low, even amongst
those in a designated priority group. Although there was Table 3 Advice to take antiviral medicines and to be vaccinated used in the research
Antiviral medicines
Vaccinations
PEOPLE WITH PANDEMIC FLU are advised to take antiviral medicines to
reduce their symptoms, and the length of time they are ill. You are advised by your GP to get vaccinated at once to protect you
and your family from getting pandemic flu. PEOPLE IN A PRIORITY GROUP will be provided with antiviral medicines
to prevent them from catching flu. Vaccines for pandemic flu have been through the same careful tests
as vaccines for seasonal flu and are safe to use Table 3 Advice to take antiviral medicines and to be vaccinated used in the research PEOPLE WITH PANDEMIC FLU are advised to take antiviral medicines to
reduce their symptoms, and the length of time they are ill. Rubinstein et al. BMC Public Health (2015) 15:190 Page 6 of 13 Barriers and facilitators to vaccination uptake
Five of the six components in the COM-B model
accounted for participants’ responses (Table 4). Automatic motivations In the uncertain scenario, the participants expressed lit-
tle concern about the pandemic outbreak. Most partici-
pants were not worried and so many could not see a
need to be vaccinated or take antiviral medicine: Memory (Pregnant female) …it’s a good first step, I guess, you know, to try and get
the word out there that this could potentially be a
problem, but this wouldn’t be the deciding factor [to
be vaccinated]. (Pregnant female) able to avoid catching it or something, and then like…
but then, the next day, it will be like, oh, actually,
there’s only one person in Yorkshire that’s got it…
(Female, not at-risk) able to avoid catching it or something, and then like…
but then, the next day, it will be like, oh, actually,
there’s only one person in Yorkshire that’s got it…
(Female not at risk) (Female, not at-risk) Having been offered the seasonal influenza vaccine
previously was put forward as a reason for considering
pandemic influenza vaccination – ‘it would never stop
me because I have been having them [seasonal flu jab]
for years and years’ (Female, underlying illness). …there’s nothing to do yet. I feel like this is worrying
about nothing (Male, not at-risk) Memory Some participants spontaneously linked the word ‘pan-
demic’ to bird flu or swine flu but many did not. Recall
of the swine flu pandemic was low, partly because only
four participants in our sample had contracted it, and
partly because few knew anyone who had. A prevalent
comment was that media had exaggerated the risk of
swine flu: In severe scenarios, there was a high level of anxiety and
an awareness of personal susceptibility. As one woman
with young children commented ‘this is normal people
and they are dying’. The need to take novel precautionary
measures, of any kind, was less likely to be disputed: It’s almost like you get kind of a mixed picture of what
it actually is, and then, it will be reported in a way
that people will think it’s…that they’re not going to be I think people follow any advice [in this scenario] that
is given from an authority figure anyway, even if it
was poison…(Female, not at–risk) I think people follow any advice [in this scenario] that
is given from an authority figure anyway, even if it
was poison…(Female, not at–risk) Page 7 of 13 Rubinstein et al. Memory BMC Public Health (2015) 15:190 able to avoid catching it or something, and then like…
but then, the next day, it will be like, oh, actually,
…it’s a good first step, I guess, you know, to try and get
the word out there that this could potentially be a
Table 4 Factors that can influence uptake of vaccine for pandemic influenza identified in the study using COM-B
CAPABILITY
MOTIVATION
OPPORTUNITY
The capacity to engage in the behaviour
Brain processes that energise and direct
behaviour
Factors lying outside the individual that
act as barriers or promoters of behaviour
Psychological
Automatic
Physical
Capacity to engage in necessary thought
processes
Emotions and impulses
Physical opportunity in the environment
Knowledge of the disease
Emotion: Fear
Access
• Pandemic influenza is a novel strain
• Expressed not just numerically but in terms
of physical and emotional proximity
• to treatments
• Awareness of morbidity, mortality and
transmission rates
• to professional advice
Memory
Habitual behaviour
Able to book to see GP
• Media exaggeration of last pandemic
• Being vaccinated for seasonal influenza and
taking medicines in general
Avoiding ‘hubs of infection’
Physical
Reflective
Social
Capacity to engage in necessary
physical processes
Evaluation and plans
Cultural milieu that affects what we think about
things
• Not salient/not mentioned
Beliefs about consequences
Social influences
• Pandemic influenza is not more serious than
seasonal influenza
• Respected others are being vaccinated
• The vaccine has not been adequately tested
and may be unsafe or ineffective
• Believing that it is unacceptable to put others
at risk
Omission bias
Trust
• Believing that the risks of being vaccinated outweigh
the risk of being ill with pandemic influenza
• Recommendation from trusted health
professional
• Respected others recommend
Identity (health)
Group identity
• Believing that a healthy lifestyle confers immunity
• Being part of an at-risk support group
Optimistic bias
• Tending to the view that they will not be infected or
will make an easy recovery from pandemic influenza
Social role
• Responsibility for other family members, including
unborn
Anticipated regret
• Concern that the outbreak could be more serious
than expected and have not been vaccinated • Responsibility for other family members, including
unborn Anticipated regret • Concern that the outbreak could be more serious
than expected and have not been vaccinated …it’s a good first step, I guess, you know, to try and get
the word out there that this could potentially be a
problem, but this wouldn’t be the deciding factor [to
be vaccinated]. able to avoid catching it or something, and then like…
but then, the next day, it will be like, oh, actually,
there’s only one person in Yorkshire that’s got it…
(F
l
t t i k) Social identity
Th
h Participants tended to believe that pandemic influenza
was similar to seasonal influenza, which was not consid-
ered to be a serious illness. If participants thought that
the consequences of being ill with pandemic influenza
were minimal there was little incentive to take precau-
tionary measures. Those who were accepting of vaccination and antiviral
medicines tended to view themselves as less healthy and
acknowledged that they could be at risk of infection
from pandemic influenza. They were frequently in con-
tact with medical professionals and followed their advice
and routinely took medication and the seasonal influ-
enza vaccination. Many were from a seasonal influenza
priority group and regarded the decision to get vacci-
nated or take medicines as ‘normal’: A week being ill [with flu] isn’t the end of the world. I
think if I thought it was going to be much worse than
that, you know, I would be more concerned and more
likely to have the vaccine. (Female, underlying illness) I think if you are already in a group such as us, who
are already taking loads of medications, constant
checks and tests, you tend to be a bit more accepting. Whereas if you don’t take medications, you’re
normally quite healthy and you are suddenly being
told ‘we want you to have this, we recommend you
take it’. (Female, underlying illness) There was a view that the consequences of being vac-
cinated were potentially worse than becoming ill from
influenza. In many cases this was related to concerns
about side effects or a belief that it was possible to con-
tract influenza from the vaccine itself. These views were
not shaped by personal experience. What I feel about vaccines is that you actually get a
virus or not – what you get is a small amount so you
are not supposed to get an illness. I am not sure that
is true. I have heard that many people do get ill after
having the vaccine… (Mother with young children) Pregnant women considered themselves to be tempor-
arily in the at-risk category, although most commented
that they would prefer not to take medicines in case of
harm to the foetus but would do so if a medical profes-
sional recommended it. By comparison, those participants who were less accept-
ing of vaccination advice tended to perceive themselves as
‘fit and healthy’ and have had less frequent contact with
medical professionals. Reflective motivations …there’s nothing to do yet. I feel like this is worrying
about nothing (Male, not at-risk) In the uncertain scenario, participants tended to make a
‘risk assessment’ (e.g. male, not at-risk) and ‘weigh up the Rubinstein et al. BMC Public Health (2015) 15:190 Rubinstein et al. BMC Public Health (2015) 15:190 Rubinstein et al. BMC Public Health (2015) 15:190 Page 8 of 13 risk in my mind, the side effects of the vaccine versus am
I going to lose my life or be significantly impacted by it’
(e.g. female, underlying condition). Participants delib-
erated about the consequences of being ill with influ-
enza as opposed to the consequences of being ill with
side-effects from the vaccine. In doing so, they drew
on their current status as a healthy person who would
not need to be vaccinated; on their role in society as
a responsible person who should be vaccinated to
prevent family members (especially children) from
becoming ill; and on feelings of anticipated regret if
the virus became worse and they had failed to be
vaccinated. By contrast, a facilitator of vaccine uptake was the
belief that a vaccine would be protective. This was of
particular relevance to those who were aware that they
could have complications as a result of becoming ill, for
example, pregnant women who were concerned to pro-
tect their babies: ‘It’s only because I’m pregnant that I’m
more worried, because otherwise I wouldn’t [be]’. A further facilitator of vaccine uptake was anticipated
regret: a tendency to consider that the situation could
become worse and that there could be negative conse-
quences from not being vaccinated early enough. As this
young man who was not at-risk said: ‘It would be a
brave man to say no, I’m not taking anything at all when
everyone around you is dropping’. Social opportunities Social influences included recommendations from trusted
sources, especially health professionals, taking account of
the behaviour of respected others, and the influence of the
media. pp
Physical opportunities The main physical opportunity that appeared to promote
uptake of vaccination was access to advice and treat-
ment. Participants anticipated that vaccination would be
readily available at GP surgeries or at pharmacies. How-
ever, surgeries were considered to be a ‘hub for infection’
which should be avoided: I would be very happy for my own body to make an
attempt to try and fight it because what I know about
vaccines is that they break the immune system. (Female, mother with young children) I’m not a great fan of taking medicine for medicines
sake really. I think that’s probably the criteria that I
applied and I’m just reluctant I think to take
something which at the end of the day um I don’t
really see the benefit of really. (Male, not at-risk) You are going into an environment where you are prone
to get flu because there is different people, so I’d be
scared. I think I’d be like can’t you just post it through
the door, like send it, I don’t know, I wouldn’t go to the
centre. Would you? (Mother with young children) Beliefs about being fit and healthy and being able to
naturally fight disease contributed to a sense of optimism:
the belief that that they were less vulnerable than others
to being infected with pandemic influenza: The anxiety about attending a surgery prompted one
participant to suggest that mobile dispensaries should
come to local neighbourhoods ‘to bring the medication
to you’ (Male, not at-risk). In addition, there was concern
about the difficulty of booking an appointment in a timely
fashion because of pressures on the health service. …touch wood, I feel I’m quite healthy anyway…I seem
to be alright. (Pregnant woman) …touch wood, I feel I’m quite healthy anyway…I seem
to be alright. (Pregnant woman) I’m alright, I’ll do the best I can, I’ll do my exercise
which is my overall shield, my barrier against all
diseases… (Male, underlying illness) Social identity
Th
h Notions of being ‘fit and healthy’,
rarely becoming ill and having a strong immune system
were invoked to deny the need for vaccination because
they were unlikely to be at–risk. A range of behaviours
such as, eating healthily and exercising were believed to
confer this immunity. Only a minority of participants were openly critical of
vaccine safety or efficacy but where such concerns were
expressed they were given as reasons not to be vacci-
nated. In expressing scepticism about the safety of a
newly developed vaccine the participants drew on beliefs
or representations of how drugs are developed and made
available to the public, and argued that a pandemic flu
vaccine cannot meet the standard safety criteria due to
its ‘sudden’ production: …look after yourself, eat healthier and do a bit of
exercise and try and keep away from people with
viruses and that sort of thing and um I do that
without sort of getting neurotic about it. (Male,
underlying illness) Every other drug has been tested for years and years
before it can go on the shelf. How can they suddenly
produce something in six months and put it on the
shelf? I’d be very suspicious of that. (male, not at-risk) Page 9 of 13 Rubinstein et al. BMC Public Health (2015) 15:190 their social role as a protector of their family or as a role
model to family members would influence them in the
direction of being vaccinated: Three types of behaviours were commonly cited as a
way to stave off infection: social distancing, lifestyle re-
lated activities, and improving basic hygiene. More than
half of participants spontaneously mentioned distancing
behaviours as a means to reduce the risk of being in-
fected, e.g. avoiding crowds, not travelling on public
transport, and staying at home: If you are a family person and you have got children
that are under sixteen, for example, it’s up to you to
decide whether they would have this vaccination, and
if you say no, I’m not going to let them have it and they
die, that’s a big responsibility on you. (Male, not at-risk) I think people will stay indoors, and people will not
congregate - meetings or anything like that, supermarkets,
trains… (Male, not at risk) …this is a collective thing (Female, not at-risk) …it’s not just about you is it, it’s about everyone else
(Pregnant woman) …it’s not just about you is it, it’s about everyone else
(Pregnant woman) …it’s not just about you is it, it’s about everyone else
(Pregnant woman) About one third cited lifestyle behaviours as a means
of staving off infection such as eating properly, drinking
more water, exercising and supplementing their diet with
vitamin C, cod liver oil or orange juice. Finally, improved
hygiene behaviour was often mentioned such as using
hand gels, washing hands more frequently, cleaning sur-
faces and covering one’s face when sneezing or coughing. However, only a minority of participants believed that
they had a social responsibility to be vaccinated in order to
prevent the circulation of the virus within the wider society. Virtually no participant referred to the notion of herd im-
munity and to the duty of every citizen to vaccinate to
reduce others’ risk of infection. Thus, it could be argued
that the risk of pandemic influenza was primarily under-
stood as a personal rather social issue, with little attention
being paid to the social aspects of a pandemic outbreak. Using alternative behaviours to vaccination related to
the view that medicine should be avoided where possible
and that it was better to allow the body to fight off dis-
eases ‘naturally’. Arguably, some people preferred these
precautionary behaviours to vaccination because they
seemed without side-effects and also more within their
direct control. People who held these views could be
from either an at-risk or not-at-risk group: Discussion and conclusions The aim of this study was to systematically identify
facilitators of and barriers to being vaccinated and take
antiviral medicines in uncertain and severe pandemic
influenza scenarios using the COM-B framework. The
influences on vaccination and antiviral uptake were
wide-ranging, including various aspects of capability,
motivation and social opportunity, with some evidence
that addressing one aspect could impact on others in
the system. For example, social opportunity in the
form
of
recommendations
from
respected
others
influenced
reflective
motivations
in
the
form
of
beliefs about vaccine efficacy. This suggests that the
influences on vaccine and antiviral uptake are multi-
dimensional and that communications to promote
uptake are likely to be most effective if they address
several components. Additional factors that may influence uptake of antiviral
medicines Beliefs about antiviral medicines tended to be ill-informed,
for example, considering that they were antibiotics and
that they would be delivered in injection form. If it is very, very strongly recommended [in uncertain
scenario], well then I would go and beat the surgery
door down and get a vaccine, but um if the advice
isn’t that strong well then I’d leave it for a bit and see
how I get on. (Male, underlying illness) Many were unsure whether they would recognise the
signs of pandemic influenza, for example, ‘What are
the symptoms? Are there different symptoms from
swine flu and ordinary flu? What would you look out
for? How would you know you had one from the
other?’ (Male, not at-risk) Participants were also likely to respond to sources of
informal advice, for example close friends and family, an
authority in the workplace or a local community leader. This was particularly evident among a group of elderly
Somali women and a group of men in a close-knit area
of Central London who said that they would actively
seek the advice of community leaders. Most of the participants commented that the advice to
take antiviral medicines seemed ‘sensible’ and compared
with vaccination fewer concerns were raised. Overall
there was less resistance to uptake because ‘if you were
feeling ill and feeling like death, you would take anything’
(Male, not at risk). Participants acknowledged that the media will play a
role during a pandemic outbreak and they expected that
they would get information ‘from reliable newspapers
not the Sun or Metro’ (Pregnant woman). A common ex-
pectation was that the media would exaggerate the situ-
ation because ‘you hear it on the news and you obviously
have to take it with a pinch of salt because the news
media are always out for a story’ (Male, not at-risk). Social role Participants believed that they would actively seek
advice from their GP in a pandemic situation and would Pregnant women were aware of their social role to pro-
tect their unborn child but others also commented that Page 10 of 13 Rubinstein et al. BMC Public Health (2015) 15:190 and it’s a different age demographic to me, I probably
think actually I am not going to take that risk [of
being vaccinated]….. (Female, underlying illness) put faith in the recommendations made by them because
‘I am not a medic and therefore I follow his advice’
(Male, not at-risk). However, in an uncertain scenario
some participants commented that they would seek
additional supporting evidence on the internet. Never-
theless, if a GP made a strong recommendation to
be vaccinated, most participants would follow their
advice: put faith in the recommendations made by them because
‘I am not a medic and therefore I follow his advice’
(Male, not at-risk). However, in an uncertain scenario
some participants commented that they would seek
additional supporting evidence on the internet. Never-
theless, if a GP made a strong recommendation to
be vaccinated, most participants would follow their
advice: Group identity It is beyond the scope of this paper to
enumerate the range of potential interventions but a
few examples are described below: The study indicated that identity as a ‘healthy person’
was a barrier to being vaccinated. Messages that
address these beliefs – for example, explaining how
no-one is immune to a new strain of flu and that being
vaccinated can enhance health by boosting immunity Beliefs about being able to boost one’s natural immun-
ity were held by those who were clinically at-risk, as
well as by those who were not at-risk. This study
suggests that many people in priority groups do not
self-identify as being vulnerable and may, therefore, not
make the connection with messages aimed at them. Such a disconnection could explain why only 37.65% of
those in priority groups in the UK were vaccinated dur-
ing the last pandemic [5]. More may need to be done to
ensure that those in a priority group are able to identify
themselves as being more susceptible to the effects of
pandemic influenza than others. – may be effective in increasing uptake. A further barrier to uptake was a belief that lifestyle
behaviours such as eating healthily and exercising
could confer immunity and make people less
vulnerable to contracting pandemic influenza. Communications that address these beliefs might
include information about why people are
vulnerable to a new strain of influenza and about
the effectiveness of vaccines in reducing the risk of
infection or in boosting immunity. Promoters of and barriers to uptake cannot be consid-
ered separately from the context of the scenario: in a
high risk scenario intentions to follow advice to be vacci-
nated or to take antiviral medicines were high whereas
in the uncertain scenario there was hesitancy and am-
bivalence and it was in this situation that the full range
of doubts, concerns and misperceptions emerged. Although the participants were purposively sampled to
represent a range of risk profiles, a limitation of this
research was that the sample may not reflect the views
of the wider population because it was not represen-
tative and focus groups may attract people who are
particularly interested in the topic area. Furthermore, it
is not clear whether being in the habit of being vacci-
nated or not being vaccinated conditioned responses to
different scenarios. This could be explored in future
research. Group identity Identifying as being part of a group was a factor in
decision-making about vaccination. This was because
several people with underlying conditions belonged to
support groups either in person or on-line. These groups
would sometimes discuss the need for vaccination …the people in the online forum talk about flu
vaccination…. I know from reading online that it
covers people like me (Female, underlying illness) Identity as a healthy or at-risk individual influenced
whether or not people thought they were vulnerable to
contracting pandemic influenza and whether they be-
lieved that practicing alternative protective behaviours
could be as effective as vaccination. Feelings of vulner-
ability were engendered by being labelled as being in a
clinically at-risk group (having an underlying illness,
being older or pregnant), and by the severity of the
scenario because if it was perceived to be very severe all
people will be susceptible to pandemic influenza. However, despite being aware that one was part of an
at-risk group, some people who were in the at-risk
groups distanced themselves emotionally from the need
to be vaccinated. One female participant who had Pri-
mary Sclerosing Cholangitisc argued that she would only
think of herself as being vulnerable if the people who
were infected were from the same country and demo-
graphic as herself: I think does the risk of getting the vaccine outweigh the
risk of the impact on my life. I guess when it is a
million miles away and very few people are getting it In contrast, those who felt invulnerable to pandemic
influenza cited the rarity of being ill with flu and be-
lieved that they were, young, healthy or fit and hence Rubinstein et al. BMC Public Health (2015) 15:190 Page 11 of 13 Page 11 of 13 had a strong immune system. Those who had con-
structed an identity as ‘a healthy person’ were less will-
ing to follow advice to be vaccinated and did not view
using biomedicine as ‘normalised’. The use of alternative
behaviours, especially eating well, exercising and using
vitamin supplements was thought to boost immunity
and hence, reduce the risk of being infected and the
need for vaccination. behaviour. It is at the centre of the Behaviour Change
Wheel [40] - a tool to guide intervention design by
identifying which intervention functions are likely to be
most effective. Endnotes aThe original TDF was developed by an international
panel of 32 experts in behaviour change who identified
128 constructs from 33 behaviour change theories and
simplified them into domains. Usability was developed
with an international team of implementation scientists. The TDF has been validated and refined by an inter-
national panel of 36 experts in behaviour change. 5. Sethi M, Pebody R. Pandemic H1N1 (Swine) Influenza Vaccine Uptake
amongst Patient Groups in Primary Care in England 2009/10. UK:
Department of Health; 2010. 6. Berera D, Zambon M. Antivirals in the 2009 pandemic - Lessons and
implications for future strategies. Influenza Other Respir Viruses. 2013;7:72–9 6. Berera D, Zambon M. Antivirals in the 2009 pandemic - Lessons and
implications for future strategies. Influenza Other Respir Viruses. 2013;7:72–9. 7. Pandemic Influenza Preparedness Team. National Pandemic Flu Service: An
Evaluation. 2011. 7. Pandemic Influenza Preparedness Team. National Pandemic Flu Service: An
Evaluation. 2011. 8. Li M, Chapman GB, Ibuka Y, Meyers LA, Galvani A. Who got vaccinated
against H1N1 pandemic influenza? – A longitudinal study in four US cities. Psychol Health. 2012;27:101–15. 8. Li M, Chapman GB, Ibuka Y, Meyers LA, Galvani A. Who got vaccinated
against H1N1 pandemic influenza? – A longitudinal study in four US cities. Psychol Health. 2012;27:101–15. bParticipants are referred to by gender and whether
they are in an at-risk group (over 65 years, pregnant,
underlying illness) or not in an at-risk group (included
mothers with young children). 9. Bíró A. Determinants of H1N1 vaccination uptake in England. Prev Med. 2013;57:140–2. 9. Bíró A. Determinants of H1N1 vaccination uptake in England. Prev Med. 2013;57:140–2. 10. Frew PM, Painter JE, Hixson B, Kulb C, Moore K, del Rio C, et al. Factors
mediating seasonal and influenza A (H1N1) vaccine acceptance among
ethnically diverse populations in the urban south. Vaccine. 2012;30:4200–8 10. Frew PM, Painter JE, Hixson B, Kulb C, Moore K, del Rio C, et al. Factors
mediating seasonal and influenza A (H1N1) vaccine acceptance among
ethnically diverse populations in the urban south. Vaccine. 2012;30:4200–8. cPSC is a disease of the liver and people with this con-
dition are recommended to have the influenza vaccine
because they have lowered immunity as a result of the
treatments they receive. 11. Bish A, Yardley L, Nicoll A, Michie S. Factors associated with uptake of
vaccination against pandemic influenza: a systematic review. Vaccine. 2011;29:6472–84. 11. Bish A, Yardley L, Nicoll A, Michie S. Endnotes Factors associated with uptake of
vaccination against pandemic influenza: a systematic review. Vaccine. 2011;29:6472–84. 12. Kok G, Jonkers R, Gelissen R, Meertens R, Schaalma H, de Zwart O. Behavioural intentions in response to an influenza pandemic. BMC Public
Health. 2010;10:174. 12. Kok G, Jonkers R, Gelissen R, Meertens R, Schaalma H, de Zwart O. Behavioural intentions in response to an influenza pandemic. BMC Public
Health. 2010;10:174. Group identity Van-Tam J, Sellwood C. Pandemic Influenza. 2nd ed. Oxford: CABI; 2013. 4. Valenciano M, Kissling E, Cohen J-M, Oroszi B, Barret A-S, Rizzo C, et al. Estimates of pandemic influenza vaccine effectiveness in Europe, 2009–2010:
results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE)
multicentre case-control study. PLoS Med. 2011;8:e1000388. Competing interests The authors declare that they have no competing interests. 16. D’ Alessandro E, Hubert D, Launay O, Bassinet L, Lortholary O, Jaffre Y, et al. Determinants of refusal of A/H1N1 pandemic vaccination in a high risk
population: a qualitative approach. PLoS One. 2012;7:e34054. Additional file 1: Coding frame: responses to uncertain and severe
scenario. Additional file 1: Coding frame: responses to uncertain and severe
scenario. 14. Brien S, Kwong JC, Buckeridge DL. The determinants of 2009 pandemic A/H1N1
influenza vaccination: a systematic review. Vaccine. 2012;30:1255–64. 14. Brien S, Kwong JC, Buckeridge DL. The determinants of 2009 pandemic A/H1N1
influenza vaccination: a systematic review. Vaccine. 2012;30:1255–64. Authors’ contributions All authors (HR, AM, SM, LY) contributed to the design of this study. HR and
AM recruited and interviewed participants. HR led the analysis of the data
and writing of the article. All authors (HR, AM, SM, LY) read and approved
the manuscript. 17. Blank PR, Bonnelye G, Ducastel A, Szucs TD. Attitudes of the general public
and general practitioners in five countries towards pandemic and seasonal
influenza vaccines during season 2009/2010. PLoS One. 2012;7:e45450. and writing of the article. All authors (HR, AM, SM, LY) read and approved
the manuscript. 18. Ashbaugh A, Herbert C, Saimon E, Azoulay N, Olivera- Figueroa L, Brunet A. The decision to vaccinate or not during the H1N1 pandemic: selecting the
lesser of two evils? PLoS One. 2013;8:e588852. Author details
1
l h
h l 1Health Psychology Research Group, University College London, London
WC1E 7HB, UK. 2School of Psychology, University of Southampton,
Southampton SO17 1BJ, UK. 1Health Psychology Research Group, University College London, London
WC1E 7HB, UK. 2School of Psychology, University of Southampton, 22. Ritov I, Baron J. Reluctance to vaccinate: omission bias and ambiguity. J Behav Decis Mak. 1990;4:263–77. Southampton SO17 1BJ, UK. 23. McNulty C, Joshi P, Butler CC, Atkinson L, Nichols T, Hogan A, et al. Have
the public’s expectations for antibiotics for acute uncomplicated respiratory
tract infections changed since the H1N1 influenza pandemic? A qualitative
interview and quantitative questionnaire study. BMJ Open. 2012;2:e000674. Received: 29 August 2014 Accepted: 16 February 2015 Received: 29 August 2014 Accepted: 16 February 2015 24. Masuet-Aumatell C, Toovey S, Zuckerman JN. Prevention of influenza
among travellers attending at a UK travel clinic: beliefs and perceptions. A
cross-sectional study. Influenza Other Respir Viruses. 2013;7:574–83. Acknowledgments The manuscript has been read and approved for publication by the
Department of Health. 19. Böhmer MM, Walter D, Falkenhorst G, Müters S, Krause G, Wichmann O. Barriers to pandemic influenza vaccination and uptake of seasonal influenza
vaccine in the post-pandemic season in Germany. BMC Public Health. 2012;12:938. Funding This research was conducted as part of the project Improving Communication
With the Public About Antivirals and Vaccination During the Next Pandemic,
funded by the Department of Health through the Policy Research Programme
funding stream (grant code: 019/0060). The views expressed in this publication
are those of the authors and not necessarily those of the Department of Health. 20. Lau JTF, Yeung NCY, Choi KC, Cheng MYM, Tsui HY, Griffiths S. Factors in
association with acceptability of A/H1N1 vaccination during the influenza
A/H1N1 pandemic phase in the Hong Kong general population. Vaccine. 2010;28:4632–7. 21. Brown KF, Kroll JS, Hudson MJ, Ramsay M, Green J, Vincent CA, et al. Omission
bias and vaccine rejection by parents of healthy children: Implications for the
influenza A/H1N1 vaccination programme. Vaccine. 2010;28:4181–5. Additional file 2: Code frame: barriers and promoters of uptake. Additional file 2: Code frame: barriers and promoters of uptake. 15. Gilles I, Bangerter A, Clémence A, Green EGT, Krings F, Staerklé C, et al. Trust
in medical organizations predicts pandemic (H1N1) 2009 vaccination
behavior and perceived efficacy of protection measures in the Swiss public. Eur J Epidemiol. 2011;26:203–10. Group identity COM-B as a framework for analysis was a useful
starting point for identifying the range of factors
associated with uptake of vaccination and antiviral
medicines. The barriers and facilitators of uptake could
be classified within the framework which allowed an
explanation of behaviour across several components. Many of the factors discussed have been identified in
previous studies; for example this study supports previ-
ous research that one of the most consistent predictors
of vaccine uptake is the habit of being vaccinated for
seasonal influenza [8-10,14,19], that the role of emo-
tion (automatic motivations) is highly relevant [11] and
that a barrier to vaccine uptake is negative beliefs about
the vaccine such that the consequences of being vacci-
nated are perceived to be as or more problematic than
the consequences of becoming ill with pandemic influ-
enza [18,19,21,33,44,45]. Future research needs to take account of the extent to
which messages about vaccination can be transparent in
addressing concerns about the vaccine; for example
being more open about how the vaccine is developed. In
addition, we should investigate whether messages that
address identity are effective in promoting uptake of
vaccination. In particular, to examine whether positively
framed health messages that focus on wellbeing are
more effective than messages about risk reduction for
individuals who do not self-identify as being vulnerable
to infection. The promoters and barriers to being vaccinated and
taking antiviral medicines are multi-dimensional, and
communications to promote uptake are likely to be
most effective if they address several components of be-
haviour. The benefit of using the COM-B model is that
it is at the core of an approach that can identify effective
strategies for behaviour change or communications for
the future. People from at-risk groups do not always
perceive themselves to be at-risk because they have
constructed an identity as a healthy person who is However, comparison between studies is made difficult
because different researchers select a small sub-set of
predictor variables to examine; only a minority make use
of a model of behaviour to explain why these variables
were selected (exceptions are Teasdale & Yardley 2011 [27],
Myers & Goodwin 2012 [46], and Kok et al 2010 [12])
or accommodate different levels of severity. COM-B is a theoretical starting point for understand-
ing behaviour within specific contexts and to make a
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Eur Commun Dis Bull. 2013;18:pii=20623. Submit your next manuscript to BioMed Central
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intention to vaccinate against pandemic swine flu in priority groups in the
UK. Public Health. 2012;126:S53–6. • Convenient online submission
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MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence
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MASK 2017: ARIA digitally‑enabled,
integrated, person‑centred care for rhinitis
and asthma multimorbidity using
real‑world‑evidence J. Bousquet1,2,3*, S. Arnavielhe4, A. Bedbrook1, M. Bewick5, D. Laune4, E. Mathieu‑Dupas4, R. Murray6,
G. L. Onorato1, J. L. Pépin7,8, R. Picard9, F. Portejoie1, E. Costa10, J. Fonseca11,12, O. Lourenço13,
M. Morais‑Almeida14, A. Todo‑Bom15, A. A. Cruz16,17, J. da Silva18, F. S. Serpa19, M. Illario20, E. Menditto21,
L. Cecchi22, R. Monti23, L. Napoli24, M. T. Ventura25, G. De Feo26, D. Larenas‑Linnemann27, M. Fuentes Perez28,
Y. R. Huerta Villabolos28, D. Rivero‑Yeverino29, E. Rodriguez‑Zagal30, F. Amat31,32, I. Annesi‑Maesano33,
I. Bosse34, P. Demoly35, P. Devillier36, J. F. Fontaine37, J. Just31,32, T. P. Kuna38, B. Samolinski39, A. Valiulis40,41,
R. Emuzyte42, V. Kvedariene43, D. Ryan44,45, A. Sheikh46, P. Schmidt‑Grendelmeier47, L. Klimek48,49, O. Pfaar48,49,
K. C. Bergmann50,51, R. Mösges52,53, T. Zuberbier50,51, R. E. Roller‑Wirnsberger54, P. Tomazic55, W. J. Fokkens56,
N. H. Chavannes57, S. Reitsma56, J. M. Anto58,59,60,61, V. Cardona62, T. Dedeu63,64, J. Mullol65,66, T. Haahtela67,
J. Salimäki68, S. Toppila‑Salmi67, E. Valovirta69,70, B. Gemicioğlu71, A. Yorgancioglu72,73, N. Papadopoulos74,75,
E. P. Prokopakis76, S. Bosnic‑Anticevich77, R. O’Hehir78,79, J. C. Ivancevich80, H. Neffen81, E. Zernotti82, I. Kull83,
E. Melen84,85, M. Wickman86, C. Bachert87, P. Hellings3,88,89, S. Palkonen90, C. Bindslev‑Jensen91, E. Eller91,
S. Waserman92, M. Sova93, G. De Vries94, M. van Eerd94, I. Agache95, T. Casale96, M. Dykewickz97, R. N. Naclerio98,
Y. Okamoto99, D. V. Wallace100 and MASK study group Bousquet et al. Clin Transl Allergy (2018) 8:45
https://doi.org/10.1186/s13601-018-0227-6 Bousquet et al. Clin Transl Allergy (2018) 8:45
https://doi.org/10.1186/s13601-018-0227-6 Clinical and
Translational Allergy Open Access Background evidence based approach [1, 23–25] to care pathways
using mobile technology in AR and asthma multimorbid-
ity [26]. ARIA appears to be close to the patient’s needs
but real-life data suggest that few patients follow guide-
line recommendations and that they often self-medicate. Moreover, patients frequently using OTC medications
dispensed in pharmacies [27]. Shared decision making
(SDM) centered around the patient for self-management
should be used more often. g
Allergic rhinitis (AR) is the most common chronic
disease worldwide. Evidence-based guidelines have
improved knowledge on rhinitis and made a significant
impact on AR management. However, many patients
remain inadequately controlled and the costs for society
are enormous, in particular due to the major impact of
AR on school and work productivity [1, 2]. Unmet needs
have identified clearly many gaps. These include (1) sub-
optimal rhinitis and asthma control due to medical, cul-
tural and social barriers [3, 4], (2) poor understanding
of endotypes [5], better characterization of phenotypes
and multimorbidities [6], better understanding of gen-
der differences [7], (3) assessment of sentinel networks
in care pathways for allergen and pollutants exposures,
using symptom variation [8], (4) lack of stratification of
patients for optimized care pathways [9] and (5) lack of
multidisciplinary teams within integrated care pathways,
endorsing innovation in real life clinical trials [8] and
encouraging patient empowerment [10, 11]. Mobile Airways Sentinel networK (MASK), the Phase
3 ARIA initiative, has been initiated to reduce the global
burden of rhinitis and asthma multimorbidity, giving the
patient and the health care professional simple tools to
better prevent and manage respiratory allergic diseases. More specifically, MASK is focusing on (1) understand-
ing the disease mechanisms and the effects of air pollu-
tion in allergic diseases and asthma, (2) better appraising
the burden incurred by medical needs and indirect costs,
(3) the implementation of multi-sectoral care pathways
integrating self-care, air pollution and patient’s literacy,
using emerging technologies with real world data using
the AIRWAYS ICPs algorithm [28], (4) proposing indi-
vidualized and predictive medicine in rhinitis and asthma
multimorbidity, (5) proposing the basis for a sentinel
network at the global level for pollution and allergy and
(6) assessing the societal implications of exposure to air
pollution and allergens and its consequences on health
inequalities globally. g
g p
p
Mobile health (mHealth) is the use of information and
communication technology (ICT) for health services and
information transfer [12]. Background mHealth, including apps run-
ning on consumer smart devices (i.e., smartphones and
tablets), is becoming increasingly popular and has the
potential to profoundly impact on healthcare [13]. Novel
app-based collaborative systems can have an important
role in gathering information quickly and improving
coverage and accessibility of prevention and treatment
[14]. Implementing mHealth innovations may also have
disruptive consequences [15], so it is important to test
applicability in each individual situation [16]. A rapid
growth of the health apps market has been seen with an
estimated 325,000 health apps available in 2017 for most
fields of medicine [17]. Benefits and drawbacks have been
estimated for a number of disease [18]. The application
of mHealth solutions can support the provision of high
quality care to patients with AR or asthma, to the satisfac-
tion of both patients and health care professionals, with a
reduction in both health care utilization and costs [19]. Appropriately identifying and representing stakeholders’
interests and viewpoints in evaluations of mHealth is a
critical part of ensuring continued progress and innova-
tion [20]. Patient, caregiver and clinician evaluations and
recommendations play an important role in the develop-
ment of asthma mHealth tools to support the provision
of asthma management [21]. Smart devices and inter-
net-based applications are already used in rhinitis and
asthma and may help to address some unmet needs [22]. However, these new tools need to be tested and evaluated
for acceptability, usability and cost-effectiveness. The freely available MASK app (the Allergy Diary,
Android and iOS) [26] is combined with an inter-oper-
able tablet for physicians and other health care profes-
sionals (HCPs [29]), using the same extremely simple
colloquial language to manage AR (Visual Analogue
Scale: VAS) [30, 31]. It is being combined with data on
allergen and pollution exposure (POLLAR). MASK will be scaled up using the EU EIP on AHA
strategy [32]. Phase 4 is starting in 2018 and will focus
on “change management”. MASK is supported by several
EU grants and is a WHO GARD (Global Alliance against
Chronic Respiratory Diseases) research demonstration
project (Table 1). Abstract mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential
to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not
always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the
best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and
asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision
making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel
networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and
iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an over‑
view of the methods used in MASK and the key results obtained to date. These include a novel phenotypic charac‑
terization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns
in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the
Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored
by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary. Keywords: App, ARIA, Asthma, Care pathways, MASK, mHealth, Rhinitis *Correspondence: jean.bousquet@orange.fr
1 MACVIA‑France, Fondation Partenariale FMC VIA-LR, CHRU Arnaud de
Villeneuve, 371 Avenue du Doyen Gaston Giraud, Montpellier, France
Full list of author information is available at the end of the article *Correspondence: jean.bousquet@orange.fr
1 MACVIA‑France, Fondation Partenariale FMC VIA-LR, CHRU Arnaud de
Villeneuve, 371 Avenue du Doyen Gaston Giraud, Montpellier, France
Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 2 of 21 Methods
Usersh The Allergy Diary is used by people who searched the
internet, Apple App store, Google Play or in any other
way. The pages of the App are on the Euforea-ARIA web-
site (www.euforea.eu/about-us/aria.html). A few users
were clinic patients to whom the app was recommended
by their physicians. Users were not requested to com-
plete the diary for a minimum number of days. However,
due to anonymization of data, no specific information on
the route of access to the app could be gathered [33, 34]. f
Allergic Rhinitis and its Impact on Asthma (ARIA) has
evolved from an evidence-based guideline using the best Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 3 of 21 Bousquet et al. Clin Transl Allergy Table 1 European Union and World Health Organization links of ARIA and MASK
Date
WHO
EU
ARIA
1999
Workshop
WHO HQ
2003–2013
CC rhinitis and asthma
Montpellier
2012–
GARD demonstration project
WHO HQ
2004–2010
GA2LEN
FP6
2011–2015
MeDALL
FP7
MASK
2014–
MACVIA-LR
DG Santé-CNECT
2014–
GARD demonstration project
WHO HQ
2014–
EIP on AHA B3
DG Santé-CNECT
2015–2016
SPAL
Structural and develop‑
ment funds
2015–2017
Sunfrail
2017–
Twinning
DG Santé-CNECT
2018–
POLLAR
EIT Health Table 1 European Union and World Health Organization links of ARIA and MASK The first question of the App is “I have allergic rhini-
tis”: Yes/No. We tested the sensitivity and specificity of
this question [33]. 93.4% users with a positive answer had
nasal symptoms versus 12.1% of users with a negative
answer. In the first two versions of the App, allergy was
not considered in the user’s questionnaire and AR cannot
be differentiated from chronic rhinosinusitis. It is now
included in the third version of the App (June 2018) and
we will be able to answer more appropriately to this ques-
tion in the next study. The results of the pilot study were
confirmed in over 9000 users. data but also to be considered as an identifier itself [38,
39]. Processing personal data by means of an app, like e.g. App Diary, besides Directive 95/46/EC [37] also Directive
2002/58/EC [40] as amended by Directive 2009/136/EC
[41] applies. Geolocation was studied for all people who used the
Allergy Diary App from December 2015 to November
2017 and who reported medical outcomes. Privacy assessment impact MASK is available in 23 countries and 16 languages. To
date (01-09-2018) the app has been used by over 24,000
people. Privacy impact assessments (PIAs), also known as data
protection impact assessments (DPIAs) in EU law, is
required by GDPR (Article 35 Working Party (WP35). PIA is a systematic process to assess privacy risks to
individuals in the collection, use, and disclosure of their
personal data. The GDPR introduced PIAs to identify
high risks to the privacy rights of individuals when pro-
cessing their personal data. The assessment shall con-
tain at least: Ethics and privacy of datah The Allergy Diary is CE1 registered. The terms of use
were translated into all languages and customized by law-
yers according to the legislation of each country, allow-
ing the use of the results for research and commercial
purposes. The example of the UK terms of use have been
provided in a previous paper [33]. 1. a systematic description of the envisaged process-
ing operations and the purposes of the processing,
including, where applicable, the legitimate interest
pursued by the controller; Methods
Usersh In contradis-
tinction to noise addition (randomization), k-anonymity
[42, 43] is an acceptable method for the anonymization of
MASK data (generalization) [44] and results can be used
for other databases. Geolocation EU data protection rules have changed since the imple-
mentation of the General Data Protection Regulation
(Art. 4 para. 1 no. 1 GDPR) [35]. Data anonymization is
a method of sanitization for privacy. Anonymization ren-
ders personal data “in such a manner that the data sub-
ject is not or no longer identifiable” [36]. The European
Commission’s Article 29 Working Party (WP29) stated
already in 2014 with regards to the Directive 95/46/EC
[37] that geolocation information is not only personal 2. an assessment of the necessity and proportionality of
the processing operations in relation to the purposes; 3. an assessment of the risks to the rights and freedoms
of data subjects and 4. the measures envisaged to address the risks, includ-
ing safeguards, security measures and mechanisms to
ensure the protection of personal data and to dem- Page 4 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy Table 2 Questions on symptoms and impact of symptoms
(from Bousquet et al. [33]) Table 2 Questions on symptoms and impact of symptoms
(from Bousquet et al. [33]) onstrate compliance with this Regulation taking into
account the rights and legitimate interests of data
subjects and other persons concerned. When these risks are identified, the GDPR expects that
an organization formulates measures to address these
risks. Those measures may take the form of technical
controls such as encryption or anonymization of data.h The PIA analysis is a self-declarative analysis. In France,
the local GDPR representative (Commission Informa-
tique et Liberté, CNIL) has provided a software to guide
the reflexion around security of personal data and the
exposure risks in case of security fails. This software has
been used to assess all the risks to be considered through
the app uses. The conclusion was that is “negligeable”.hi Transfer of personal data from the App to a print
Patients cannot give access to their electronic data to a
HCP due to privacy policies. However, they can eas-
ily print the daily control of their disease and the medi-
cations that they filled in the Allergy Diary as follows
(Fig. 3). h
The field is moving very fast. In France, June, 10 2018,
the modified law “LIL” (Loi Informatique et Liberté,
2018-493,
https://www.cnil.fr/fr/loi-78-17-du-6-janvi
er-1978-modifiee) was enacted with a special focus on
health-related personal data. Allergy Diaryh The app collects information on AR and asthma symp-
toms experienced (nasal and ocular) and on disease type
(intermittent/persistent) [33] (Table 3). Anonymized and
geolocalized users assess daily how symptoms impact
their control and AR treatment using the touchscreen
functionality on their smart phone to click on five con-
secutive VAS (i.e. general, nasal and ocular symptoms,
asthma and work) (Table 2; Fig. 1). Users input their daily
medications using a scroll list that contains all coun-
try-specific OTC and prescribed medications available
(Fig. 2). The list populated using IMS data and revised
by country experts is continuously revised by country
experts. Additional questionnaires MASK also includes EQ-5D (EuroQuol) [46–48], Work
Productivity and Activity Impairment Allergic Specific
(WPAI-AS) [49] and Control of AR and Asthma Test
(CARAT) [50–53]. The Epworth Sleepiness Question-
naire [54, 55] is included (June 2018). Adherence to treatment Globally, non-adherence to medications is a major
obstacle to the effective delivery of health care. Many
mobile phone apps are available to support people
to take their medications and to improve medication
adherence [57, 58]. However, a recent meta-analysis
found that the majority did not have many of the desir-
able features and were of low quality [57]. However,
it is unknown how people use apps, what is consid-
ered adherent or non-adherent in terms of app usage,
or whether adherence with an app in anyway reflects
adherence with medication or control. There is a high degree of correlation between these
VAS measurements. The example of VAS global meas-
ured and VAS nose is presented in Fig. 2. Medications A scroll list is available for all OTC and prescribed
medications of the 23 countries. The International Non-
proprietary Names classification was used for drug
nomenclature [56]. 85 INNs and 505 medications were
identified (Fig. 1). Geolocation Even if the articulation of
GDPR and LIL is still unclear, we can anticipate that the
app use will remain risk free. Outcomes Five VAS measurements [VAS-global measured, VAS-
nose, VAS-eye, VAS-asthma and VAS-work (Table 4)]
and a calculated VAS-global score (VAS-nasal + VAS-
ocular divided by 2) were assessed [34]. VAS levels range
from zero (not at all bothersome) to 100 (very bother-
some). Independency of VAS questions was previously
confirmed using the Bland and Altman regression analy-
sis [34, 45]. In MASK, we did not use adherence questionnaires
but first attempted to assess short-term adherence and
then to address the long-term issues. [59]. Digitalized ARIA symptom‑medication score Symptom-medication scores are needed to assess the
control of allergic diseases. They are currently being Page 5 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy developed for MASK and are being compared with
existing ones [60]. MASK algorithm and clinical decision support system
best evidence and algorithms to aid patients and health
care professionals to jointly determine the treatment
and its step-up or step-down strategy for an optimal
disease control. Fig. 1 Allergy Diary screens relating to Visual Analogue Scale and medications (from Bousquet et al. [26]) Fig. 1 Allergy Diary screens relating to Visual Analogue Scale and medications (from Bousquet et al. [26]) Fig. 1 Allergy Diary screens relating to Visual Analogue Scale and medications (from Bousquet et al. [26]) Fig. 1 Allergy Diary screens relating to Visual Analogue Scale and medications (from Bousquet et al. [26]) developed for MASK and are being compared with
existing ones [60]. best evidence and algorithms to aid patients and health
care professionals to jointly determine the treatment
and its step-up or step-down strategy for an optimal
disease control. MASK algorithm and clinical decision support system The selection of pharmacotherapy for AR patients
depends on several factors, including age, prominent
symptoms, symptom severity, AR control, patient
preferences and cost. Allergen exposure, pollution
and resulting symptoms vary, needing treatment Clinical decision support systems (CDSS) are software
algorithms that advise health care providers on the
diagnosis and management of patients based on the
interaction of patient data and medical information,
such as prescribed drugs. CDSS should be based on the Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 6 of 21 Fig. 2 Correlation between Visual Analog Scale (VAS) global measured and nasal symptoms (VAS nose) (unpublished) Fig. 2 Correlation between Visual Analog Scale (VAS) global measured and nasal symptoms (VAS nose) (unpublished) • Equity. • Practice. • Ethical considerations. • Evaluation. • Empowerment and participation. • Target population. • Sustainability. • Governance. • Scalability adjustment. In AR, The MASK CDSS is incorporated
into an interoperable tablet [29] for HCPs (ARIA
Allergy Diary Companion) [10, 26]. This is based on an
algorithm to aid clinicians to select pharmacotherapy
for AR patients and to stratify their disease severity [26]
(Fig. 4). It uses a simple step-up/step-down individual-
ized approach to AR pharmacotherapy and may hold
the potential for optimal control of symptoms, while
minimizing side-effects and costs. However, its use var-
ies depending on the availability of medications in the
different countries and on resources. The algorithm is
now digitalized and available in English (Fig. 5). • Empowerment and participation. • Target population. • Sustainability. • Governance. • Scalability As part of SUNFRAIL, MASK tested the 27 item cri-
teria of CHRODIS and was found to be an example of
Good Practice [62]. As part of SUNFRAIL, MASK tested the 27 item cri-
teria of CHRODIS and was found to be an example of
Good Practice [62]. MASK follows the CHRODIS criteria of “Good
Practice” The European Commission is co-funding a large col-
laborative project named JA-CHRODIS in the context
of the 2nd EU Health Programme 2008–2013 [61]. JA-
CHRODIS has developed a check-list of 27 items for the
evaluation of Good Practices (GP) (http://chrodis.eu/
our-work/04-knowledge-platform/). According to the
JA-CHRODIS, a Good Practice has been proven to work
well and produce good results, and is therefore recom-
mended as a model to be scaled up. The JA-CHRODIS
criteria are grouped into nine categories: Validation of the MASK Visual Analogue Scale
on cell phones VAS included in the Allergy Diary was found to be a vali-
dated tool to assess control in AR patients following COS-
MIN guidelines [63] in 1225 users and 14,612 days: internal
consistency (Cronbach’s α-coefficient > 0.84 and test–
retest > 0.7), reliability (intra-class correlation coefficients),
sensitivity and acceptability [64]. In addition, e-VAS had
a good reproducibility when users (n = 521) answered the
e-VAS twice in less than 3 h. Pilot study of mobile phone technology in AR y
p
gy
A pilot study in 3260 users found that Allergy Diary users
were able to properly provide baseline simple phenotypic
characteristics. Troublesome symptoms were found mainly
in the users with the largest number of symptoms. Around
50% of users with troublesome rhinitis and/or ocular
symptoms suffered work impairment. Sleep was impaired
by troublesome symptoms and nasal obstruction (Fig. 6). results suggest novel concepts and research questions in
AR that may not be identified using classical methods [33]. Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 7 of 21 Fig. 3 Transfer of patient information on a computer and printed information (from Bousquet et al. [46] Fig. 3 Transfer of patient information on a computer and printed information (from Bousquet et al. [46] mHealth tools (i.e. the Allergy Diary and CARAT)
in 23 Reference Sites or regions across Europe and
Argentina, Australia, Brazil and Mexico [46]. This will
improve understanding, assessment of burden, diagno-
sis and management of rhinitis in the elderly by com-
parison with an adult population. The pilot study has
been completed in Germany and the project is fully
operative using two protocols (Table 3). Transfer of innovation of AR and asthma
multimorbidity in the elderly: Reference Site
Twinning (EIP on AHA) AR impairs social life, work and school productivity. Indirect costs associated with lost work productivity
are the principal contributor to the total AR costs and
result mainly from impaired work performance by pres-
enteeism [2]. The severity of AR symptoms was the most
consistent disease-related factor associated with impact
of AR on work productivity, although ocular symptoms
and sleep disturbances may independently affect work The EIP on AHA includes 74 Reference Sites. The aim
of this TWINNING was to transfer innovation from
the MASK App to other reference sites. The phenotypic
characteristics of rhinitis and asthma multimorbidity
in adults and the elderly are compared using validated Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy Page 8 of 21 productivity. Overall, the pharmacologic treatment of AR
showed a beneficial effect on work productivity. A
cross-sectional
study
using
Allergy
diary
in
productivity of uncontrolled AR assessed by VAS [34]. In users with uncontrolled rhinitis (VAS global meas-
ured≥50) approximately 90% had some work impair-
Fig. 4 Clinical decision support systems consensus for allergic rhinitis (from Bousquet et al. [28])
Fig. 5 CDSS digitalization (submitted) Fig. 4 Clinical decision support systems consensus for allergic rhinitis (from Bousquet et al. [28]) Fig. 4 Clinical decision support systems consensus for allergic rhinitis (from Bousquet et al. [28]) Fig. 4 Clinical decision support systems consensus for allergic rhinitis (from Bousquet et al. [28]) productivity. Overall, the pharmacologic treatment of AR
showed a beneficial effect on work productivity. A cross-sectional study using Allergy diary in
1136 users (5659 days) assessed the impact on work
productivity of uncontrolled AR assessed by VAS [34]. In users with uncontrolled rhinitis (VAS global meas-
ured ≥ 50), approximately 90% had some work impair-
ment and over 50% had severe work impairment
Fig. 5 CDSS digitalization (submitted) productivity. Overall, the pharmacologic treatment of AR
showed a beneficial effect on work productivity. A cross-sectional study using Allergy diary in
1136 users (5659 days) assessed the impact on work
productivity of uncontrolled AR assessed by VAS [34]. In users with uncontrolled rhinitis (VAS global meas-
ured ≥ 50), approximately 90% had some work impair-
ment and over 50% had severe work impairment
Fig. 5 CDSS digitalization (submitted) productivity. Overall, the pharmacologic treatment of AR
showed a beneficial effect on work productivity. productivity. Overall, the pharmacologic treatment of AR
showed a beneficial effect on work productivity. Transfer of innovation of AR and asthma
multimorbidity in the elderly: Reference Site
Twinning (EIP on AHA) A cross-sectional study using Allergy diary in
1136 users (5659 days) assessed the impact on work productivity of uncontrolled AR assessed by VAS [34]. In users with uncontrolled rhinitis (VAS global meas-
ured ≥ 50), approximately 90% had some work impair-
ment and over 50% had severe work impairment if
A cross-sectional study using Allergy diary in
1136 users (5659 days) assessed the impact on work Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 9 of 21 Bousquet et al. Clin Transl Allergy Fig. 6 Impact of allergic rhinitis depending on the number of
symptoms (from Bousquet et al. [33]) Novel phenotypes of allergic diseases Novel phenotypes of allergic diseases Multimorbidity in allergic airway diseases is well known
[6], but no data exist regarding the daily dynamics of
symptoms. The Allergy Diary assessed the presence
and control of daily allergic multimorbidity (asthma,
conjunctivitis, rhinitis) and its impact on work produc-
tivity in 4025 users and 32,585 days monitored in 19
countries from May 25, 2015 to May 26, 2016. VAS lev-
els < 20/100 were categorized as “Low” burden and VAS
levels ≥ 50/100 as “High” burden. VAS global measured
levels assessing the global control of the allergic disease
were significantly associated with daily allergic multi-
morbidity. Eight hypothesis-driven patterns were defined
based on “Low” and “High” VAS levels. There were < 0.2%
days of Rhinitis Low and Asthma High or Conjunctivi-
tis High patterns. There were 5.9% days with a Rhinitis
High—Asthma Low pattern. There were 1.7% days with
a Rhinitis High—Asthma High—Conjunctivitis Low pat-
tern. A novel Rhinitis High—Asthma High—Conjunc-
tivitis High pattern was identified in 2.9% days and had
the greatest impact on uncontrolled VAS global meas-
ured and impaired work productivity (Fig. 9). The mobile
technology enabled investigation in a novel approach of
the intra-individual variability of allergic multimorbidity
using days. It identified an unrecognized extreme pattern
of uncontrolled multimorbidity [59]. Fig. 6 Impact of allergic rhinitis depending on the number of
symptoms (from Bousquet et al. [33]) (VAS-work ≥ 50). There was a significant correla-
tion between VAS-global calculated and VAS-work
(Rho = 0.83, p < 0.00001, Spearman rank test). The study
has been extended to almost 17,000 days and similar
results were observed (Fig. 7).h The baseline study found that bothersome symptoms,
nasal obstruction and ocular symptoms were involved in
work productivity impact [33] (Fig. 8). Treatment of allergic rhinitis using mobile technology
with real world data The Allergy Diary includes the WPAI:AS in six EU
countries. All consecutive users who completed the
VAS-work from June 1 to July 31, 2016 were included
in the study [66]. A highly significant correlation was
found between Questions 4 (impairment of work) and 9
(impairment of activities) in 698 users (Rho = 0.85). Large observational implementation studies are needed
to triangulate the findings from randomized control tri-
als (RCTs) as they reflect “real world” everyday practice. We attempted to provide additional and complemen-
tary insights into the real-life AR treatment using mobile
technology. The Allergy Diary was filled in by 2871 users All these studies combine to confirm the impact of
uncontrolled AR on work productivity. Table 3 Twinning protocols (from Bousquet et al., [65])
Protocol 1
Protocol 2
Short version
Long version
Allergy Diary
+
+
Equation 5D
Optional
+
Physician’s questionnaire
+
Ethics committee
Not needed
Needed (obtained in some Reference Sites)
Inform consent
Terms of Reference on App
From with patient’s signature
Recruitment
Any user
Persons attending clinic visits can be included
Persons attending clinic visits included with a physician’s
diagnosis of allergic disease and allergen sensitization (IgE
and/or skin tests)
Physician’s questionnaire
+ Table 3 Twinning protocols (from Bousquet et al., [65])
Protocol 1
Protocol 2
Short version
Long version
Allergy Diary
+
+
Equation 5D
Optional
+
Physician’s questionnaire
+
Ethics committee
Not needed
Needed (obtained in some Reference Sites)
Inform consent
Terms of Reference on App
From with patient’s signature
Recruitment
Any user
Persons attending clinic visits can be included
Persons attending clinic visits included with a physician’s
diagnosis of allergic disease and allergen sensitization (IgE
and/or skin tests)
Physician’s questionnaire
+ Table 3 Twinning protocols (from Bousquet et al., [65]) Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 10 of 21 Fig. 7 Correlation between VAS work and VAS global measured, nose, eye and asthma (Bousquet unpublished) Fig. 7 Correlation between VAS work and VAS global measured, nose, eye and asthma (Bousquet unpublished) Fig. 7 Correlation between VAS work and VAS global measured, nose, eye and asthma (Bousquet unpublished) Fig. 8 Impact of symptoms on work, school and daily activities (from Bousquet et al. [33]) Fig. 8 Impact of symptoms on work, school and daily activities (from Bousquet et al. [33]) Fig. 8 Impact of symptoms on work, school and daily activities (from Bousquet et al. [33]) Bousquet et al. Treatment of allergic rhinitis using mobile technology
with real world data Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy Page 11 of 21 who reported 17,091 days of VAS in 2015 and 2016. between classes (intranasal corticosteroid use containing
Fig. 9 VAS levels in severe rhinitis depending on multimorbidity (from Bousquet et al. [60])
Fig. 10 Treatments received in MAS (from Bousquet et al. [59]) Fig. 9 VAS levels in severe rhinitis depending on multimorbidity (from Bousquet et al. [60]) Fig. 9 VAS levels in severe rhinitis depending on multimorbidity (from Bousquet et al. [60]) Fig. 9 VAS levels in severe rhinitis depending on multimorbidity (from Bousquet et al. [60]) Fig. 10 Treatments received in MAS (from Bousquet et al. [59]) between classes (intranasal corticosteroid use containing
medications and oral H1-antihistamines). The control of
days differed between no (best control), single or multi-
ple treatments (worst control) (Fig. 10). The study con-
firms the usefulness of the Allergy Diary in accessing and
assessing everyday use and practice in AR [59]. who reported 17,091 days of VAS in 2015 and 2016. Medications were reported for 9634 days. The assess-
ment of days appeared to be more informative than the
course of the treatment as, in real life, patients rarely use
treatment on a daily basis; rather, they appear to increase
treatment use with the loss of symptom control and
to stop it when symptoms disappear. The Allergy Diary
allowed the differentiation between treatments within or Adherence to medications was studied in almost 7000
users reporting medications. 1770 users reported over Bousquet et al. Clin Transl Allergy (2018) 8:45 Page 12 of 21 pollution and allergy and (6) assess the societal implica-
tions of the interaction. 7 days of VAS between January 1, 2016 and August
31, 2016 and a major lack of adherence to treatment
was observed for all medications (Menditto et al., in
preparation). POLLAR will use the freely existing application for AR
monitoring (Allergy Diary, 14,000 users, TLR8) com-
bined with a new tool allowing queries on allergen and
pollen (TLR2) and existing pollution data. Machine
learning will be used to assess the relationship between
air pollution and AR comparing polluted and non-pol-
luted areas in 6 EU countries. Data generated in 2018
will be confirmed in 2019 and extended by the individ-
ual assessment of pollution (Canarin®, portable sensor,
TLR6) in AR and sleep apnea patients used as a control
group having impaired sleep. Global applicability of MASK and POLLAR,
and their benefits Although MASK has been devised to optimize care path-
ways in rhinitis and asthma multimorbidity, its applica-
bility is far more extensive (Table 4). MASK in the pharmacy Multidisciplinary integrated care is necessary to reduce
the burden of chronic diseases. A significant proportion
of patients with AR self-manage their condition and often
the pharmacist is the first HCP that a person with nasal
symptoms contacts [66, 67]. Pharmacists are trusted in
the community and are easily accessible. As such, phar-
macists are an important part of the multidisciplinary
healthcare team, acting at different steps of rhinitis care
pathways. y
Google Trends (GT) searches trends of specific que-
ries in Google and reflects the real-life epidemiology of
AR. We compared GT terms related to allergy and rhi-
nitis in all European Union countries, Norway and Swit-
zerland from January 1, 2011 to December, 20 2016. An
annual and clear seasonality of queries was found in most
countries but the terms ‘hay fever’, ‘allergy’ and ‘pollen’—
show cultural differences [70]. Using longitudinal data in
different countries and multiple terms, we identified an
awareness-related spike of searches (December 2016)
[70]. In asthma, GTs can identify spikes of mortality as
was found in Australia and Kuwait in 2016. However, the
usual peaks of asthma during allergen exposure or virus
infections cannot be easily monitored [71]. Pharmacists are important in many areas of interven-
tion in AR: • Recognizing (identification).i i
• Risk assessment/stratification. • OTC treatment.i • Manage refils. i
• Patient education. • Referral to a physician. • Administration of topical treatment technique and
adherence to treatment. • Administration of topical treatment technique and
adherence to treatment. • Administration of topical treatment technique and
adherence to treatment. Simple algorithms and tools are essential in the routine
implementation of these steps. A first approach was
made by ARIA in the pharmacy [68] and is currently
being updated using MASK. POLLAR (Impact of air POLLution on Asthma
and Rhinitis) AR and asthma are impacted by allergens and air pollu-
tion. However, interactions between air pollution, sleep
[55, 69] and allergic diseases are insufficiently under-
stood. POLLAR aims at combining emerging technolo-
gies [search engine TLR2 (technology readiness level);
pollution sampler TLR6, App TLR9] with machine learn-
ing to (1) understand effects of air pollution in AR and
its impact on sleep, work, asthma, (2) propose novel care
pathways integrating pollution and patient’s literacy,
(3) study sleep, (4) improve work productivity, (5) pro-
pose the basis for a sentinel network at the EU level for For MASK, several steps have been achieved. Treatment of allergic rhinitis using mobile technology
with real world data The geographic information
system GIS will map the results.i of Allergy and Airways Diseases Patients’ Associations; EIP on AHA: European
Innovation Partnership on AHA; EIP: European Innovation Partnership; EQ-5D:
Euroquol; GARD: WHO Global Alliance against Chronic Respiratory Diseases;
GDPR: General Data Protection Regulation; GIS: geographic information sys‑
tem; GP: Good Practice; GT: Google Trends; HCP: health care professional; ICP:
integrated care pathway; IMS: Institute of Medical Science; JA-CHRODIS: Joint
Action on Chronic Diseases and Promoting Healthy Ageing across the Life
Cycle; MACVIA-LR: contre les MAladies Chroniques pour un VIeillissement Actif MASK The Allergy Diary has
the potential to improve the control of allergic diseases and to significantly improve work productiv‑
ity at the EU level For public health purposes, a perfect patient characterization in real life is needed to identify the
prevalence, burden and costs incurred by patients in order to improve quality of care and optimize
health care planning and policies For public health purposes, a perfect patient characterization in real life is needed to identify the
prevalence, burden and costs incurred by patients in order to improve quality of care and optimize
health care planning and policies Inequities still exist in the EU for allergic diseases prevalence and burden (not only sex/gender inequi‑
ties). POLLAR will attempt to understand them and to propose policies and health promotion
strategies Inequities still exist in the EU for allergic diseases prevalence and burden (not only sex/gender inequi‑
ties). POLLAR will attempt to understand them and to propose policies and health promotion
strategies Conclusion MASK is a novel approach to obtain real-life data con-
cerning rhinitis and asthma multimorbidity and to help
patients and physicians for a better SDM. It can be used
for multiple purposes in a friendly manner in order to
improve the control of allergic diseases in a cost-effective
approach. Page 13 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy Abbreviations
AHA: active and healthy ageing; AIRWAYS ICPs: integrated care pathways for
airway diseases; AR: allergic rhinitis; ARIA: Allergic Rhinitis and Its Impact on
Asthma; CARAT: Control of Allergic Rhinitis and Asthma Test; CDSS: clinical
decision support system; CNIL: Commission Informatique et Liberté; CRD:
Chronic Respiratory Disease; DG CONNECT: Directorate General for Com‑
of Allergy and Airways Diseases Patients’ Associations; EIP on AHA: European
Innovation Partnership on AHA; EIP: European Innovation Partnership; EQ-5D:
Euroquol; GARD: WHO Global Alliance against Chronic Respiratory Diseases;
GDPR: General Data Protection Regulation; GIS: geographic information sys‑
tem; GP: Good Practice; GT: Google Trends; HCP: health care professional; ICP:
integrated care pathway; IMS: Institute of Medical Science; JA-CHRODIS: Joint
Table 4 Global applicability of MASK
Applicability
MASK
Clinical practice
Physicians will be able to read the files of the patients in order to
Optimize treatment for the patient and, in particular, the current or the next pollen season
Assess and increase the adherence to treatment
Help for shared decision making
Prescribe allergen immunotherapy (AIT) more rapidly when the patient is not controlled despite
optimal pharmacologic treatment
Determine the efficacy of AIT in patients
The Allergy Diary is an essential tool to provide personalized medicine in AR and asthma
Change management
The first results of MASK indicate that many patients are uncontrolled and non-adherent to treatment
Moreover, they appear to use their medications as needed and not as a regular basis as prescribed
Change management is needed
Patient empowerment
Better understanding of the symptoms
Sentinel network linking aerobiology data and control
Improved adherence
Self-management
Patient empowerment
Messages sent by the App
Clinical trials
For RCTs, it is essential to have clarity on definitions, and relevant tools. MASK Observational studies are of key importance to confirm RCTs and bring new hypotheses for the treat‑
ment of AR and asthma Observational studies are of key importance to confirm RCTs and bring new hypotheses for the treat‑
ment of AR and asthma Controlled trials designed with a uniform approach will be more easily evaluated by the Health
Technology Assessment agencies (such as NICE) for reimbursement. The Allergy Diary uses EQ-5D, a
validated measure of utility Controlled trials designed with a uniform approach will be more easily evaluated by the Health
Technology Assessment agencies (such as NICE) for reimbursement. The Allergy Diary uses EQ-5D, a
validated measure of utility Better understanding of direct and indirect costs Controlled trials designed with a uniform approach will help to synchronize data from real-life world
regarding clinical effects and safety/tolerability of new drugs (post-marketing pharmacovigilance A uniform definition and a collaborative approach to epidemiological, genetic and mechanistic
research are important and will be enhanced by the stratification of patients using the Allergy Diary Different levels of phenotype characterization (granularity) can be applied to assess phenotypic char‑
acterization in old age subjects In epidemiologic population studies, standardized definitions and tools are fundamental. The Allergy
Diary allows novel approaches combining classical cross-sectional and longitudinal studies with real
life studies in large populations In epidemiologic population studies, standardized definitions and tools are fundamental. The Allergy
Diary allows novel approaches combining classical cross-sectional and longitudinal studies with real
life studies in large populations AR and asthma represent a major burden for the employers, and the estimated annual costs in the EU
range from 30 to 60 B€. Better control of the disease was shown to reduce costs. The Allergy Diary has
the potential to improve the control of allergic diseases and to significantly improve work productiv‑
ity at the EU level AR and asthma represent a major burden for the employers, and the estimated annual costs in the EU
range from 30 to 60 B€. Better control of the disease was shown to reduce costs. Conclusion The Allergy Diary allows
To better stratify the patients needing AIT
To assess the efficacy of AIT during the trial
To assess the efficacy when AIT is stopped
Observational studies are of key importance to confirm RCTs and bring new hypotheses for the treat‑
ment of AR and asthma
Registration and reimbursement of medicines
Controlled trials designed with a uniform approach will be more easily evaluated by the Health
Technology Assessment agencies (such as NICE) for reimbursement. The Allergy Diary uses EQ-5D, a
validated measure of utility
Better understanding of direct and indirect costs
Controlled trials designed with a uniform approach will help to synchronize data from real-life world
regarding clinical effects and safety/tolerability of new drugs (post-marketing pharmacovigilance
Research on mechanisms and genetics
A uniform definition and a collaborative approach to epidemiological, genetic and mechanistic
research are important and will be enhanced by the stratification of patients using the Allergy Diary
Different levels of phenotype characterization (granularity) can be applied to assess phenotypic char‑
acterization in old age subjects
Epidemiology
In epidemiologic population studies, standardized definitions and tools are fundamental. The Allergy
Diary allows novel approaches combining classical cross-sectional and longitudinal studies with real
life studies in large populations
Employers
AR and asthma represent a major burden for the employers, and the estimated annual costs in the EU
range from 30 to 60 B€. Better control of the disease was shown to reduce costs. The Allergy Diary has
the potential to improve the control of allergic diseases and to significantly improve work productiv‑
ity at the EU level
Public health planning
For public health purposes, a perfect patient characterization in real life is needed to identify the
prevalence, burden and costs incurred by patients in order to improve quality of care and optimize
health care planning and policies
Reduction of inequities
Inequities still exist in the EU for allergic diseases prevalence and burden (not only sex/gender inequi‑
ties). POLLAR will attempt to understand them and to propose policies and health promotion
strategies Table 4 Global applicability of MASK Table 4 Global applicability of MASK Author details
1 1 MACVIA‑France, Fondation Partenariale FMC VIA-LR, CHRU Arnaud de
Villeneuve, 371 Avenue du Doyen Gaston Giraud, Montpellier, France. 2 INSERM U 1168, VIMA: Ageing and Chronic Diseases Epidemiological
and Public Health Approaches, Villejuif, Université Versailles St-Quentin-en-
Yvelines, UMR-S 1168, Montigny le Bretonneux, France. 3 Euforea, Brussels,
Belgium. 4 KYomed-INNOV, Montpellier, France. 5 iQ4U Consultants Ltd,
London, UK. 6 MedScript Ltd, Dundalk, Co Louth, Ireland. 7 Laboratoire HP2,
Grenoble, INSERM, U1042, Université Grenoble Alpes, Grenoble, France. 8 CHU
de Grenoble, Grenoble, France. 9 Conseil Général de l’Economie Ministère de
l’Economie, de l’Industrie et du Numérique, Paris, France. 10 UCIBIO, REQUINTE,
Faculty of Pharmacy and Competence Center on Active and Healthy Ageing,
University of Porto (Porto4Ageing), Porto, Portugal. 11 Center for Health
Technology and Services Research‑ CINTESIS, Faculdade de Medicina,
Universidade do Porto, Porto, Portugal. 12 Medida, Lda, Porto, Portugal. 13 Faculty of Health Sciences and CICS – UBI, Health Sciences Research Centre,
University of Beira Interior, Covilhã, Portugal. 14 Allergy Center, CUF Descober‑
tas Hospital, Lisbon, Portugal. 15 Imunoalergologia, Centro Hospitalar
Universitário de Coimbra and Faculty of Medicine, University of Coimbra,
Coimbra, Portugal. 16 ProAR – Nucleo de Excelencia em Asma, Federal
University of Bahia, Vitória da Conquista, Brazil. 17 WHO GARD Planning Group,
Salvador, Brazil. 18 Allergy Service, University Hospital of Federal University
of Santa Catarina (HU-UFSC), Florianópolis, Brazil. 19 Asthma Reference Center,
Escola Superior de Ciencias da Santa Casa de Misericordia de Vitoria, Vitória,
Esperito Santo, Brazil. 20 Division for Health Innovation, Campania Region
and Federico II University Hospital Naples (R&D and DISMET), Naples, Italy. 21 CIRFF, Federico II University, Naples, Italy. 22 SOS Allergology and Clinical
Immunology, USL Toscana Centro, Prato, Italy. 23 Department of Medical
Sciences, Allergy and Clinical Immunology Unit, University of Torino &
Mauriziano Hospital, Torino, Italy. 24 Consortium of Pharmacies and Services
COSAFER, Salerno, Italy. 25 Unit of Geriatric Immunoallergology, University
of Bari Medical School, Bari, Italy. 26 Department of Medicine, Surgery
and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy. 27 Center of Excellence in Asthma and Allergy, Hospital Médica Sur, México
City, Mexico. 28 Mexico City, Mexico. 29 Puebla, Puebla, Mexico. 30 Ciutad
Mexico, Mexico. 31 Allergology Department, Centre de l’Asthme et des
Allergies Hôpital d’Enfants Armand-Trousseau (APHP), Paris, France. 32 UPMC
Univ Paris 06, UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de Santé
Publique, Sorbonne Universités, Equipe EPAR, 75013 Paris, France. Authors’ contributions All authors are MAKS members and have contributed to the design of the pro‑
ject. Many authors also included users and disseminated the project in their
own country. All authors read and approved the final manuscript. Abbreviations 98 Johns Hopkins School of Medicine, Baltimore, MD, USA. 99 Department of Otorhinolaryngology, Chiba University Hospital, Chiba,
Japan. 100 Nova Southeastern University, Fort Lauderdale, Florida, USA. A k
l d
t (Fighting chronic diseases for AHA); MASK: Mobile Airways Sentinel networK;
MeDALL: Mechanisms of the Development of ALLergy (FP7); mHealth: mobile
health; NCD: non-communicable disease; OTC: over the counter; PIA: privacy
Impact Assessment; POLLAR: Impact of air POLLution on Asthma and Rhinitis;
QOL: quality of life; SCUAD: severe chronic upper airway disease; TRL: technol‑
ogy readiness level; TWINNING: transfer of innovation of mobile technology;
VAS: Visual Analogue Scale; WHO: World Health Organization; WPAI-AS: Work
Productivity and Activity Questionnaire. Abbreviations of Allergy and Airways Diseases Patients’ Associations; EIP on AHA: European
Innovation Partnership on AHA; EIP: European Innovation Partnership; EQ-5D:
Euroquol; GARD: WHO Global Alliance against Chronic Respiratory Diseases;
GDPR: General Data Protection Regulation; GIS: geographic information sys‑
tem; GP: Good Practice; GT: Google Trends; HCP: health care professional; ICP:
integrated care pathway; IMS: Institute of Medical Science; JA-CHRODIS: Joint
Action on Chronic Diseases and Promoting Healthy Ageing across the Life
Cycle; MACVIA-LR: contre les MAladies Chroniques pour un VIeillissement Actif AHA: active and healthy ageing; AIRWAYS ICPs: integrated care pathways for
airway diseases; AR: allergic rhinitis; ARIA: Allergic Rhinitis and Its Impact on
Asthma; CARAT: Control of Allergic Rhinitis and Asthma Test; CDSS: clinical
decision support system; CNIL: Commission Informatique et Liberté; CRD:
Chronic Respiratory Disease; DG CONNECT: Directorate General for Com‑
munications Networks, Content & Technology; DG Santé: Directorate General
for Health and Food Safety; DG: Directorate General; EFA: European Federation Page 14 of 21 Page 14 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 University of Edinburgh, Medical School, Edinburgh, UK. 46 Centre of Medical
Informatics, Usher Institute of Population Health Sciences and Informatics, The
University of Edinburgh, Edinburgh, UK. 47 Allergy Unit, Department
of Dermatology, University Hospital of Zurich, Zürich, Switzerland. 48 Center
for Rhinology and Allergology, Wiesbaden, Germany. 49 Department
of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin
Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany. 50 Comprehensive Allergy‑Centre‑Charité, Department of Dermatol‑
ogy and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. 51 Global
Allergy and Asthma European Network (GA2LEN), Berlin, Germany. 52 Institute
of Medical Statistics, and Computational Biology, Medical Faculty, University
of Cologne, Cologne, Germany. 53 CRI-Clinical Research International-Ltd,
Hamburg, Germany. 54 Department of Internal Medicine, Medical University
of Graz, Graz, Austria. 55 Department of ENT, Medical University of Graz, Graz,
Austria. 56 Department of Otorhinolaryngology, Academic Medical Centre,
Amsterdam, The Netherlands. 57 Department of Public Health and Primary
Care, Leiden University Medical Center, Leiden, The Netherlands. 58 ISGlobAL,
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. 59 IMIM (Hospital del Mar Research Institute), Barcelona, Spain. 60 CIBER
Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. 61 Universitat
Pompeu Fabra (UPF), Barcelona, Spain. 62 Allergy Section, Department
of Internal Medicine, Hospital Vall ‘dHebron & ARADyAL Research Network,
Barcelona, Spain. 63 AQuAS, Barcelona, Spain. 64 EUREGHA, European Regional
and Local Health Association, Brussels, Belgium. Abbreviations 65 Rhinology Unit and Smell
Clinic, ENT Department, Hospital Clínic, University of Barcelona, Barcelona,
Spain. 66 Clinical and Experimental Respiratory Immunoallergy, IDIBAPS,
CIBERES, University of Barcelona, Barcelona, Spain. 67 Skin and Allergy Hospital,
Helsinki University Hospital, Helsinki, Finland. 68 Association of Finnish
Pharmacists, Helsinki, Finland. 69 Department of Lung Diseases and Clinical
Immunology, University of Turku, Turku, Finland. 70 Terveystalo Allergy Clinic,
Turku, Finland. 71 Department of Pulmonary Diseases, Cerrahpasa Faculty
of Medicine, Istanbul University, Istanbul, Turkey. 72 Department of Pulmonary
Diseases, Faculty of Medicine, Celal Bayar University, Manisa, Turkey. 73 GARD
Executive Committee, Manisa, Turkey. 74 Center for Pediatrics and Child Health,
Institute of Human Development, Royal Manchester Children’s Hospital,
University of Manchester, Manchester, UK. 75 Allergy Department, 2nd
Pediatric Clinic, Athens General Children’s Hospital “P&A Kyriakou”, University
of Athens, 11527 Athens, Greece. 76 Department of Otorhinolaryngology,
University of Crete School of Medicine, Heraklion, Greece. 77 Woolcock
Institute of Medical Research, University of Sydney and Sydney Local Health
District, Glebe, NSW, Australia. 78 Department of Allergy, Immunology
and Respiratory Medicine, Alfred Hospital and Central Clinical School, Monash
University, Melbourne, VIC, Australia. 79 Department of Immunology, Monash
University, Melbourne, VIC, Australia. 80 Servicio de Alergia e Immunologia,
Clinica Santa Isabel, Buenos Aires, Argentina. 81 Director of Center of Allergy,
Immunology and Respiratory Diseases, Santa Fe, Argentina Center for Allergy
and Immunology, Santa Fe, Argentina. 82 Universidad Católica de Córdoba,
Córdoba, Argentina. 83 Department of Clinical Science and Education,
Karolinska Institutet, Södersjukhuset, Stockholm, Sweden. 84 Sachs’ Children
and Youth Hospital, Södersjukhuset, Stockholm, Sweden. 85 Institute
of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 86 Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna,
Sweden. 87 Upper Airways Research Laboratory, ENT Department, Ghent
University Hospital, Ghent, Belgium. 88 Department of Otorhinolaryngology,
Univ Hospitals Leuven, Louvain, Belgium. 89 Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands. 90 EFA European
Federation of Allergy and Airways Diseases Patients’ Associations, Brussels,
Belgium. 91 Department of Dermatology and Allergy Centre, Odense
University Hospital, Odense Research Center for Anaphylaxis (ORCA), Odense,
Denmark. 92 Department of Medicine, Clinical Immunology and Allergy,
McMaster University, Hamilton, ON, Canada. 93 University Hospital Olomouc,
Olomouc, Czech Republic. 94 Peercode BV, Geldermalsen, The Netherlands. 95 Faculty of Medicine, Transylvania University, Brasov, Romania. 96 Division
of Allergy/Immunology, University of South Florida, Tampa, USA. 97 Section
of Allergy and Immunology, Saint Louis University School of Medicine, Saint
Louis, MO, USA. Mask Study Group
1 3 FER Simons325, V Siroux326, JC Sisul327, I Skrindo378, D Solé328, D Somekh329, M
Sondermann330, T Sooronbaev331, M Sova332, M Sorensen333, M Sorlini334, O
Spranger139, C Stellato118, R Stelmach335, R Stukas336, J Sunyer14–17, J Strozek193,
A Szylling193, JN Tebyriçá337, M Thibaudon338, T To339, A Todo-Bom340, PV
Tomazic341, S Toppila-Salmi163, U Trama342, M Triggiani118, C Suppli Ulrik343, M
Urrutia-Pereira344, R Valenta345, A Valero346, A Valiulis347, E Valovirta348, M van
Eerd119, E van Ganse349, M van Hague350, O Vandenplas351, MT Ventura352, G
Vezzani353, T Vasankari354, A Vatrella118, MT Verissimo211, F Viart78, G Viegi355,
D Vicheva356, T Vontetsianos357, M Wagenmann358, S Walker359, D Wallace360,
DY Wang361, S Waserman362, T Werfel363, M Westman364, M Wickman191,
DM Williams365, S Williams366, N Wilson, J Wright367, P Wroczynski40, P
Yakovliev368, BP Yawn369, PK Yiallouros370, A Yorgancioglu371, OM Yusuf372, HJ
Zar373, L Zhang374, N Zhong200, ME Zernotti375, M Zidarn376, T Zuberbier35, C
Zubrinich259, A Zurkuhlen377 Mask Study Group
J Bousquet1–3, PW Hellings4, W Aberer5, I Agache6, CA Akdis7, M Akdis7, MR
Alberti8, R Almeida9, F Amat10, R Angles11, I Annesi-Maesano12, IJ Ansotegui13,
JM Anto14–17, S Arnavielle18, E Asayag19, A Asarnoj20, H Arshad21, F Avolio22,
E Bacci23, C Bachert24, I Baiardini25, C Barbara26, M Barbagallo27, I Baroni28, BA
Barreto29, X Basagana14, ED Bateman30, M Bedolla-Barajas31, A Bedbrook2, M
Bewick32, B Beghé33, EH Bel34, KC Bergmann35, KS Bennoor36, M Benson37, L
Bertorello23, AZ Białoszewski38, T Bieber39, S Bialek40, C Bindslev-Jensen41, L
Bjermer42, H Blain43,44, F Blasi45, A Blua46, M Bochenska Marciniak47, I Bogus-
Buczynska47, AL Boner48, M Bonini49, S Bonini50, CS Bosnic-Anticevich51, I
Bosse52, J Bouchard53, LP Boulet54, R Bourret55, PJ Bousquet12, F Braido25,
V Briedis56, CE Brightling57, J Brozek58, C Bucca59, R Buhl60, R Buonaiuto61,
C Panaitescu62, MT Burguete Cabañas63, E Burte3, A Bush64, F Caballero-
Fonseca65, D Caillot67, D Caimmi68, MA Calderon69, PAM Camargos70, T
Camuzat71, G Canfora72, GW Canonica25, V Cardona73, KH Carlsen74, P Carreiro-
Martins75, AM Carriazo76, W Carr77, C Cartier78, T Casale79, G Castellano80, L
Cecchi81, AM Cepeda82, NH Chavannes83, Y Chen84, R Chiron68, T Chivato85, E
Chkhartishvili86, AG Chuchalin87, KF Chung88, MM Ciaravolo89, A Ciceran90, C
Cingi91, G Ciprandi92, AC Carvalho Coehlo93, L Colas94, E Colgan95, J Coll96, D
Conforti97, J Correia de Sousa98, RM Cortés-Grimaldo99, F Corti100, E Costa101,
MC Costa-Dominguez102, AL Courbis103, L Cox104, M Crescenzo105, AA
Cruz106, A Custovic107, W Czarlewski108, SE Dahlen109, C Dario110, J da Silva111,
Y Dauvilliers112, U Darsow113, F De Blay114, G De Carlo115, T Dedeu116, M de
Fátima Emerson117, G De Feo118, G De Vries119, B De Martino120, N de Paula
Motta Rubini121, D Deleanu122, P Demoly12,68, JA Denburg123, P Devillier124, S Di
Capua Ercolano125, N Di Carluccio66, A Didier126, D Dokic127, MG Dominguez-
Silva128, H Douagui129, G Dray103, R Dubakiene130, SR Durham131, G Du Toit132,
MS Dykewicz133, Y El-Gamal134, P Eklund135, E Eller41, R Emuzyte136, J Farrell95,
A Farsi81, J Ferreira de Mello Jr137, J Ferrero138, A Fink-Wagner139, A Fiocchi140,
WJ Fokkens141, JA Fonseca142, JF Fontaine143, S Forti97, JM Fuentes-Perez144,
JL Gálvez-Romero145, A Gamkrelidze146, J Garcia-Aymerich14, CY García-
Cobas147, MH Garcia-Cruz148, B Gemicioğlu149, S Genova150, C George151, JE
Gereda152, R Gerth van Wijk153, RM Gomez154, J Gómez-Vera155, S González
Diaz156, M Gotua157, I Grisle158, M Guidacci159, NA Guldemond160, Z Gutter161,
MA Guzmán162, T Haahtela163, J Hajjam164, L Hernández165, JO’B Hourihane166,
YR Huerta-Villalobos167, M Humbert168, G Iaccarino169, M Illario170, JC
Ivancevich171, EJ Jares172, E Jassem173, SL Johnston174, G Joos175, KS Jung176,
M Jutel177, I Kaidashev178, O Kalayci179, AF Kalyoncu180, J Karjalainen181, P
Kardas182, T Keil183, PK Keith184, M Khaitov185, N Khaltaev186, J Kleine-Tebbe187,
L Klimek188, ML Kowalski189, M Kuitunen190, I Kull191, P Kuna47, M Kupczyk47,
V Kvedariene192, E Krzych-Fałta193, P Lacwik47, D Larenas-Linnemann194, D
Laune18, D Lauri195, J Lavrut196, LTT Le197, M Lessa198, G Levato199, J Li200, P
Lieberman201, A Lipiec193, B Lipworth202, KC Lodrup Carlsen203, R Louis204,
O Lourenço205, JA Luna-Pech206, K Maciej47, A Magnan94, B Mahboub207, D
Maier208, A Mair209, I Majer210, J Malva211, E Mandajieva212, P Manning213, E De
Manuel Keenoy214, GD Marshall215, MR Masjedi216, JF Maspero217, E Mathieu-
Dupas18, JJ Matta Campos218, AL Matos219, M Maurer220, S Mavale-Manuel221, O
Mayora97, MA Medina-Avalos222, E Melén223, E Melo-Gomes26, EO Meltzer224,
E Menditto225, J Mercier226, N Miculinic227, F Mihaltan228, B Milenkovic229,
G Moda230, MD Mogica-Martinez231, Y Mohammad232, I Momas233,234, S
Montefort235, R Monti236, D Mora Bogado237, M Morais-Almeida238, FF
Morato-Castro239, R Mösges240, A Mota-Pinto241, P Moura Santo242, J Mullol243,
L Münter244, A Muraro245, R Murray246, R Naclerio247, R Nadif3, M Nalin28, L
Napoli248, L Namazova-Baranova249, H Neffen250, V Niedeberger251, K Nekam252,
A Neou253, A Nieto254, L Nogueira-Silva255, M Nogues2,256, E Novellino257,
TD Nyembue258, RE O’Hehir259, C Odzhakova260, K Ohta261, Y Okamoto262, K
Okubo263, GL Onorato2, M Ortega Cisneros264, S Ouedraogo265, I Pali-Schöll266,
S Palkonen115, P Panzner267, NG Papadopoulos268, HS Park269, A Papi270, G
Passalacqua271, E Paulino272, R Pawankar273, S Pedersen274, JL Pépin275, AM
Pereira276, M Persico277, O Pfaar278,279, J Phillips280, R Picard281, B Pigearias282, I
Pin283, C Pitsios284, D Plavec285, W Pohl286, TA Popov287, F Portejoie2, P Potter288,
AC Pozzi289, D Price290, EP Prokopakis291, R Puy259, B Pugin292, RE Pulido
Ross293, M Przemecka47, KF Rabe294, F Raciborski193, R Rajabian-Soderlund295,
S Reitsma141, I Ribeirinho296, J Rimmer297, D Rivero-Yeverino298, JA Rizzo299,
MC Rizzo300, C Robalo-Cordeiro301, F Rodenas302, X Rodo14, M Rodriguez
Gonzalez303, L Rodriguez-Mañas304, C Rolland305, S Rodrigues Valle306, M
Roman Rodriguez307, A Romano308, E Rodriguez-Zagal309, G Rolla310, RE Roller-
Wirnsberger311, M Romano28, J Rosado-Pinto312, N Rosario313, M Rottem314,
D Ryan315, H Sagara316, J Salimäki317, B Samolinski193, M Sanchez-Borges318,
J Sastre-Dominguez319, GK Scadding320, HJ Schunemann58, N Scichilone321,
P Schmid-Grendelmeier322, FS Serpa323, S Shamai240, A Sheikh324, M Sierra96, 1University Hospital, Montpellier, France. Mask Study Group
1 3 2MACVIA-France, Fondation
partenariale FMC VIA-LR, Montpellier, France. 3VIMA. INSERM U 1168, VIMA :
Ageing and chronic diseases Epidemiological and public health approaches,
Villejuif, Université Versailles St-Quentin-en-Yvelines, UMR-S 1168, Montigny le
Bretonneux, France and Euforea, Brussels, Belgium. 4Laboratory of Clinical
Immunology, Department of Microbiology and Immunology, KU Leuven,
Leuven, Belgium. 5Department of Dermatology, Medical University of Graz,
Graz, Austria. 6Transylvania University Brasov, Brasov, Romania. 7Swiss Institute
of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzer‑
land. 8Project Manager, Chairman of the Council of Municipality of Salerno,
Italy. 9Center for Health Technology and Services Research- CINTESIS,
Faculdade de Medicina, Universidade do Porto; and Medida, Lda Porto,
Portugal. 10Allergology department, Centre de l’Asthme et des Allergies
Hôpital d’Enfants Armand-Trousseau (APHP); Sorbonne Université, UPMC Univ
Paris 06, UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de Santé
Publique, Equipe EPAR, Paris, France. 11Innovación y nuevas tecnologías, Salud
Sector sanitario de Barbastro, Barbastro, Spain. 12Epidemiology of Allergic and
Respiratory Diseases, Department Institute Pierre Louis of Epidemiology and
Public Health, INSERM and Sorbonne Université, Medical School Saint Antoine,
Paris, France 13Department of Allergy and Immunology, Hospital Quirón
Bizkaia, Erandio, Spain. 14ICREA and Climate and Health (CLIMA) Program,
ISGlobal, Barcelona, Spain. 15IMIM (Hospital del Mar Research Institute),
Barcelona, Spain. 16CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona,
Spain. 17Universitat Pompeu Fabra (UPF),Barcelona, Spain. 18KYomed INNOV,
Montpellier, France. 19Argentine Society of Allergy and Immunopathology,
Buenos Aires, Argentina. 20Clinical Immunology and Allergy Unit, Department
of Medicine Solna, Karolinska Institutet, Stockholm, and Astrid Lindgren
Children’s Hospital, Department of Pediatric Pulmonology and Allergy,
Karolinska University Hospital, Stockholm, Sweden. 21David Hide Asthma and
Allergy Research Centre, Isle of Wight, United Kingdom. 22Regionie Puglia, Bari,
Italy. 23Regione Liguria, Genoa, Italy. 24Upper Airways Research Laboratory, ENT
Dept, Ghent University Hospital, Ghent, Belgium. 25Allergy and Respiratory
Diseases, Ospedale Policlinico San Martino, University of Genoa, Italy. 26PNDR,
Portuguese National Programme for Respiratory Diseases, Faculdade de
Medicina de Lisboa, Lisbon, Portugal. 27Director of the Geriatric Unit,
Department of Internal Medicine (DIBIMIS), University of Palermo, Italy. 28Telbios SRL, Milan, Italy. 29Universidade do Estado do Pará, Belem, Brazil. 30Department of Medicine, University of Cape Town, Cape Town, South Africa. 31Hospital Civil de Guadalajara Dr Juan I Menchaca, Guadalarara, Mexico. 32iQ4U Consultants Ltd, London, UK. 33Section of Respiratory Disease,
Department of Oncology, Haematology and Respiratory Diseases, University
of Modena and Reggio Emilia, Modena, Italy. 34Department of Respiratory
Medicine, Academic Medical Center (AMC), University of Amsterdam, The
Netherlands. Author details
1 33 Epidemi‑
ology of Allergic and Respiratory Diseases, Department Institute Pierre Louis
of Epidemiology and Public Health, INSERM, UPMC Sorbonne Université,
Medical School Saint Antoine, Paris, France. 34 La Rochelle, France. 35 Depart‑
ment of Respiratory Diseases, Montpellier University Hospital, Montpellier,
France. 36 UPRES EA220, Pôle des Maladies des Voies Respiratoires, Hôpital
Foch, Université Paris-Saclay, Suresnes, France. 37 Reims, France. 38 Division
of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical
University of Lodz, Lodz, Poland. 39 Department of Prevention of Environmen‑
tal Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland. 40 Clinic of Children’s Diseases, and Institute of Health Sciences Department
of Public Health, Vilnius University Institute of Clinical Medicine, Vilnius,
Lithuania. 41 European Academy of Paediatrics (EAP/UEMS-SP), Brussels,
Belgium. 42 Clinic of Children’s Diseases, Faculty of Medicine, Vilnius University,
Vilnius, Lithuania. 43 Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 44 Woodbrook Medical Centre, Loughborough, UK. 45 Allergy and Respiratory
Research Group, Usher Institute of Population Health Sciences and Informatics, Acknowledgements
None. Acknowledgements
None. Page 15 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy Mask Study Group
1 3 156Head and Professor, Centro Regional de
Excelencia CONACYT y WAO en Alergia, Asma e Inmunologia, Hospital
U i
it i
U i
id d A tó
d N
L ó
M
t
NL M
i 43Department of Geriatrics, Montpellier University Hospital, Montpellier,
France. 44EA 2991, Euromov, University Montpellier, France. 45Department of
Pathophysiology and Transplantation, University of Milan, IRCCS Fondazione
Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy. 46Argentine Association
of Respiratory Medicine, Buenos Aires, Argentina. 47Division of Internal
Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University
of Lodz, Poland. 48Pediatric Department, University of Verona Hospital, Verona,
Italy. 49Department of Public Health and Infectious Diseases, Sapienza
University of Rome, Italy. 50Second University of Naples and Institute of
Translational Medicine, Italian National Research Council. 51Woolcock Institute
of Medical Research, University of Sydney and Woolcock Emphysema Centre
and and Sydney Local Health District, Glebe, NSW, Australia. 52Allergist, La
Rochelle, France. 53Associate professor of clinical medecine, Laval’s University,
Quebec city, Head of medecine department, Hôpital de la Malbaie, Quebec,
Canada. 54Quebec Heart and Lung Institute, Laval University, Québec City,
Quebec, Canada. 55Centre Hospitalier Valenciennes, France. 56Head of
Department of Clinical Pharmacy of Lithuanian University of Health Sciences,
Kaunas, Lithuania. 57Institute of Lung Health, Respiratory Biomedical Unit,
University Hospitals of Leicester NHS Trust, Leicestershire, UK; Department of
Infection, Immunity and Inflammation, University of Leicester, Leicester, UK. 58Department of Health Research Methods, Evidence and Impact, Division of
Immunology and Allergy, Department of Medicine, McMaster University,
Hamilton, ON, Canada. 59Chief of the University Pneumology Unit- AOU
Molinette, Hospital City of Health and Science of Torino, Italy. 60Universitäts‑
medizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany. 61Pharmacist, Municipality Pharmacy, Sarno, Italy. 62University of Medicine and
Pharmacy Victor Babes, Timisoara, Romania. 63Instituto de Pediatria, Hospital
Zambrano Hellion Tec de Monterrey, Monterrey, Mexico. 64Imperial College
and Royal Brompton Hospital, London, UK. 65Centro Medico Docente La
Trinidad, CaRacas, Venezuela. 66Regional Director Assofarm Campania and Vice
President of the Board of Directors of Cofaser, Salerno, Italy 67Service de
pneumologie, CHU et université d’Auvergne, Clermont-Ferrand, France. 68Department of Respiratory Diseases, Montpellier University Hospital, France. 69Imperial College London - National Heart and Lung Institute, Royal
Brompton Hospital NHS, London, UK. 70Federal University of Minas Gerais,
Medical School, Department of Pediatrics, Belo Horizonte, Brazil 71Assitant
Director General, Montpellier, Région Occitanie, France. 72Mayor of Sarno and
President of Salerno Province, Director, Anesthesiology Service, Sarno “Martiri
del Villa Malta” Hospital, Italy. Mask Study Group
1 3 35Comprehensive Allergy Center Charité, Department of
Dermatology and Allergy, Charité - Universitätsmedizin Berlin; Global Allergy
and Asthma European Network (GA2LEN), Berlin, Germany. 36Deptt of
Respiratory Medicine, National Institute of Diseases of the Chest and Hospital,
Dhaka, Bangladesh. 37Centre for Individualized Medicine, Department of
Pediatrics, Faculty of Medicine, Linköping, Sweden. 38Department of
Prevention of Environmental Hazards and Allergology, Medical University of
Warsaw, Poland. 39BIEBER. Department of Dermatology and Allergy, Rheinische
Friedrich-Wilhelms-University Bonn, Bonn, Germany 40Dept of Biochemistry
and Clinical Chemistry, Faculty of Pharmacy with the Division of Laboratory
Medicine, Warsaw Medical University, Warsaw, Poland. 41Department of
Dermatology and Allergy Centre, Odense University Hospital, Odense
Research Center for Anaphylaxis (ORCA), Odense, Denmark. 42Department of
Respiratory Medicine and Allergology, University Hospital, Lund, Sweden. Page 16 of 21 Page 16 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 Generale), Milan, Italy. 101UCIBIO, REQUINTE, Faculty of Pharmacy and
Competence Center on Active and Healthy Ageing of University of
Porto(Porto4Ageing), Porto, Portugal. 102Mexico City, Mexico. 103IMT Mines
Alès, Unversité Montpellier, Alès, France. 104Department of Medicine, Nova
Southeastern University, Davie, University of Miami Dept of Medicine, Miami,
Florida, USA. 105Regional Director Assofarm Campania and Vice President of
the Board of Directors of Cofaser, Salerno, Italy. 106ProAR – Nucleo de
Excelencia em Asma, Federal University of Bahia, Brasil and WHO GARD
Planning Group, Brazil. 107Centre for Respiratory Medicine and Allergy, Institute
of Inflammation and Repair, University of Manchester and University Hospital
of South Manchester, Manchester, UK. 108Medical Consulting Czarlewski,
Levallois, France. 109The Centre for Allergy Research, The Institute of
Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 110Azienda
Provinciale per i Servizi Sanitari di Trento (APSS-Trento), Italy. 111Department of
Internal Medicine, Federal University of Santa Catarina, Trindade, Florianópolis,
Santa Catarina, Brazil. 112Sleep Unit, Department of Neurology, Hôpital
Gui-de-Chauliac Montpellier, Inserm U1061, France. 113Department of
Dermatology and Allergy, Technische Universität München, Munich, Germany;
ZAUM-Center for Allergy and Environment, Helmholtz Center Munich,
Technische Universität München, Munich, Germany. 114Allergy Division, Chest
Disease Department, University Hospital of Strasbourg, Strasbourg, France. 115EFA European Federation of Allergy and Airways Diseases Patients’
Associations, Brussels, Belgium 116AQuAS, Barcelna, Spain & EUREGHA,
European Regional and Local Health Association, Brussels, Belgium
117Policlínica Geral do Rio de Janeiro, Rio de Janeiro – Brasil 118Department of
Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of
Salerno, Salerno, Italy. 119Peercode BV, Geldermalsen,The Netherlands. Mask Study Group
1 3 120Social
workers oordinator, Sorrento, Italy. 121Federal University of the State of Rio de
Janeiro, School of Medicine and Surgery, Rio de Janeiro, Brazil 122Allergology
and Immunology Discipline, “Iuliu Hatieganu” University of Medicine and
Pharmacy, Cluj-Napoca, Romania. 123Department of Medicine, Division of
Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario,
Canada. 124Laboratoire de Pharmacologie Respiratoire UPRES EA220, Hôpital
Foch, Suresnes, Université Versailles Saint-Quentin, Université Paris Saclay,
France. 125Farmacie Dei Golfi Group, Massa Lubrense, Italy. 126Rangueil-Larrey
Hospital, Respiratory Diseases Department, Toulouse, France. 127University
Clinic of Pulmology and Allergy, Medical Faculty Skopje, R Macedonia. 128Mexico City, Mexico. 129Service de Pneumo-Allergologie, Centre Hospitalo-
Universitaire de Béni-Messous, Algiers, Algeria. 130Clinic of infectious, chest
diseases, dermatology and allergology, Vilnius University, Vilnius, Lithuania. 131Allergy and Clinical Immunology National Heart and Lung Institute, Imperial
College London, UK. 132Guy’s and st Thomas’ NHS Trust, Kings College London,
UK. 133Section of Allergy and Immunology, Saint Louis University School of
Medicine, Saint Louis, Missouri, USA. 134Pediatric Allergy and Immunology Unit,
Children’s Hospital, Ain Shams University, Cairo, Egypt. 135Department of
Computing Science, Umeå University, Sweden and Four Computing Oy,
Finland. 136Clinic of Children’s Diseases, Faculty of Medicine, Vilnius University,
Vilnius, Lithuania. 137University of São Paulo Medical School, Sao Paulo, Brazil
138Andalusian Agency for Healthcare Quality, Seville, Spain. 139Global Allergy
and Asthma Platform GAAPP, Vienna, Austria. 140Division of Allergy, Depart‑
ment of Pediatric Medicine - The Bambino Gesù Children’s Research Hospital
Holy see, Rome, Italy. 141Department of Otorhinolaryngology, Amsterdam,
University Medical Centres, AMC, Amsterdam the Netherlands. 142CINTESIS,
Center for Research in Health Technologies and Information Systems,
Faculdade de Medicina da Universidade do Porto, Porto, Portugal and
MEDIDA, Lda, Porto, Portugal 143Allergist, Reims, France. 144Hospital general
regional 1 “Dr Carlos Mc Gregor Sanchez Navarro” IMSS, Mexico City, Mexico. 145Regional hospital of ISSSTE, Puebla, Mexico. 146National Center for Disease
Control and Public Health of Georgia, Tbilisi, Georgia. 147Guadalarara, Mexico. 148Allergy Clinic, National Institute of Respiratory Diseases, Mexico City, Mexico. 149Department of Pulmonary Diseases, Istanbul University-Cerrahpasa,
Cerrahpasa Faculty of Medicine, Istambul,Turkey. 150Allergology unit, UHATEM
“NIPirogov”, Sofia, Bulgaria. 151Medical University, Faculty of Public Health,
Sofia. 152Allergy and Immunology Division, Clinica Ricardo Palma, Lima, Peru. 153Department of Internal Medicine, section of Allergology, Erasmus MC,
Rotterdam, The Netherlands. 154Allergy & Asthma Unit, Hospital San Bernardo
Salta, Argentina. 155Allergy Clinic, Hospital Regional del ISSSTE ‘Lic. López
Mateos’, Mexico City, Mexico. Mask Study Group
1 3 73Allergy Section, Department of Internal
Medicine, Hospital Vall d’Hebron & ARADyAL Spanish Research Network,
Barcelona, Spain. 74Department of Paediatrics, Oslo University Hospital and
University of Oslo, Oslo, Norway. 75CEDOC, Integrated Pathophysiological
Mechanisms Research Group, Nova Medical School, Campo dos Martires da
Patria, Lisbon, and Serviço de Imunoalergologia, Centro Hospitalar de Lisboa
Central, EPE, Lisbon, Portugal. 76Regional Ministry of Health of Andalusia,
Seville, Spain. 77Allergy and Asthma Associates of Southern California, Mission
Viejo, CA, USA. 78ASA - Advanced Solutions Accelerator, Clapiers, France. 79Division of Allergy/Immunology, University of South Florida, Tampa, Fla, USA. 80Celentano pharmacy, Massa Lubrense, Italy. 81SOS Allergology and Clinical
Immunology, USL Toscana Centro, Prato, Italy. 82Allergy and Immunology
Laboratory, Metropolitan University Hospital, Branquilla, Columbia. 83Depart‑
ment of Public Health and Primary Care, Leiden University Medical Center,
Leiden, The Netherlands 84Capital Institute of Pediatrics, Chaoyang district,
Beijing, China. 85School of Medicine, University CEU San Pablo, Madrid, Spain. 86David Tvildiani Medical University - AIETI Highest Medical School, David
Tatishvili Medical Center Tbilisi, Georgia. 87Pulmonolory Research Institute
FMBA, Moscow, Russia and GARD Executive Committee, Moscow, Russia. 88National Heart & Lung Institute, Imperial College, London, UK. 89Specialist
social worker, Sorrento, Italy. 90Argentine Federation of Otorhinolaryngology
Societies, Buenos Aires, Argentina. 91Eskisehir Osmangazi University, Medical
Faculty, ENT Department, Eskisehir,Turkey. 92Medicine Department,
IRCCS-Azienda Ospedaliera Universitaria San Martino, Genoa, Italy. 93Universi‑
dade Federal da Bahia, Escola de Enfermagem, Brazil. 94Plateforme Transversale
d’Allergologie, Institut du Thorax, CHU de Nantes, Nantes, France. 95LANUA
International Healthcare Consultancy, Northern Ireland, UK. 96Innovación y
nuevas tecnologías, Salud Sector sanitario de Barbastro, Barbastro, Spain. 97Innovation and Research Office, Department of Health and Social Solidarity,
Autonomous Province of Trento, Italy. 98Life and Health Sciences Research
Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal;
ICVS/3B’s PT Government Associate Laboratory Braga/Guimarães Portugal Page 17 of 21 Page 17 of 21 Page 17 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 Portugal; Ageing@Coimbra EIP-AHA Reference Site, Coimbra, Portugal. 212Medical center Iskar Ltd Sofia, Bulgaria. 213Department of Medicine (RCSI),
Bon Secours Hospital, Glasnevin, Dublin, Ireland. 214Kronikgune, International
Centre of Excellence in Chronicity Research Barakaldo, Bizkaia, Spain
215Division of Clinical Immunology and Allergy, Laboratory of Behavioral
Immunology Research, The University of Mississippi Medical Center, Jackson,
Mississippi, USA. 216Tobacco Control Research Centre;Iranian Anti Tobacco
Association, Tehran, Iran. 217Argentine Association of Allergy and Clinical
Immunology, Buenos Aires, Argentina. 218Mexico City, Mexico. 219University of
Southeast Bahia, Brazil. Mask Study Group
1 3 220Allergie-Centrum-Charité at the Department of
Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Germany
221Maputo Central Hospital--Department of Paediatrics, Mozambique. 222Veracruz, Mexico. 223Sachs’ Children and Youth Hospital, Södersjukhuset,
Stockholm and Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden. 224Allergy and Asthma Medical Group and Research
Center, San Diego, California, USA. 225CIRFF, Federico II University, Naples, Italy. 226Department of Physiology, CHRU, University Montpellier, Vice President for
Research, PhyMedExp, INSERM U1046, CNRS UMR 9214, France. 227Croatian
Pulmonary Society. 228National Institute of Pneumology M Nasta, Bucharest,
Romania. 229Clinic for Pulmonary Diseases, Clinical Center of Serbia, Faculty of
Medicine, University of Belgrade, Serbian Association for Asthma and COPD,
Belgrade, Serbia. 230Regione Piemonte, Torino, Italy. 231Col Jardines de Sta
Monica, Tlalnepantla, Mexico. 232National Center for Research in Chronic
Respiratory Diseases, Tishreen University School of Medicine, Latakia, Syria. 233Department of Public health and health products, Paris Descartes
University-Sorbonne Paris Cité, EA 4064 and Paris Municipal Department of
social action, childhood, and health, Paris, France. 234Paris municipal
Department of social action, childhood, and health, Paris, France. 235Lead
Respiratory Physician Mater Dei Hospital Malta, Academic Head of Dept and
Professor of Medicine University of Malta, Deputy Dean Faculty of Medicine
and Surgery University of Medicine, La Valette, Malta. 236Department of
Medical Sciences, Allergy and Clinical Immunology Unit, University of Torino &
Mauriziano Hospital, Torino, Italy. 237Instituto de Prevision Social IPS HC, Socia
de la SPAAI, Tesorera de la SLAAI, Asuncion, Paraguay. 238Allergy Center, CUF
Descobertas Hospital, Lisbon, Portugal. 239Universidade de São Paulo, São
Paulo, Brazil. 240Institute of Medical Statistics, and Computational Biology,
Medical Faculty, University of Cologne, Germany and CRI-Clinical Research
International-Ltd, Hamburg, Germany. 241General Pathology Institute, Faculty
of Medicine, University of Coimbra, Portugal; Ageing@Coimbra EIP-AHA
Reference Site, Coimbra, Portugal. 242Federal University of Bahia, Brazil. 243Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic; Clinical &
Experimental Respiratory Immunoallergy, IDIBAPS, CIBERES, University of
Barcelona, Spain. 244Danish Commitee for Health Education, Copenhagen East,
Denmark. 245Food Allergy Referral Centre Veneto Region, Department of
Women and Child Health, Padua General University Hospital, Padua, Italy. 246Director, Medical Communications Consultant, MedScript Ltd, Dundalk, Co
Louth, Ireland and Honorary Research Fellow, OPC, Cambridge, UK Ireland. 247Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 248General
Manager of COFASER - Pharmacy Services Consortium, Salerno, Italy. 249Scientific Centre of Children’s Health under the MoH, Moscow, Russian
National Research Medical University named Pirogov, Moscow, Russia. Mask Study Group
1 3 250Director of Center of Allergy, Immunology and Respiratory Diseases, Santa
Fe, Argentina Center for Allergy and Immunology, Santa Fe, Argentina. 251Dept
of Otorhinolaryngology, Medical University of Vienna, AKH, Vienna, Austria. 252Hospital of the Hospitaller Brothers in Buda, Budapest, Hungary. 253Die
Hautambulanz and Rothhaar study center, Berlin, Germany. 254Neumología y
Alergología Infantil, Hospital La Fe, Valencia, Spain. 255Center for Health
Technology and Services Research - CINTESIS and Department of Internal
Medicine, Centro Hospitalar Sao Joao, Porto, Portugal. 256Caisse d’assurance
retraite et de la santé au travail du Languedoc-Roussillon (CARSAT-LR),
Montpellier, France. 257Director of Department of Pharmacy of University of
Naples Federico II, Naples, Italy. 258ENT Department, University Hospital of
Kinshasa, Kinshasa, Congo. 259Department of Allergy, Immunology and
Respiratory Medicine, Alfred Hospital and Central Clinical School, Monash
University, Melbourne, Victoria, Australia; Department of Immunology, Monash
University, Melbourne, Victoria, Australia. 260Medical center “Research expert”, and Clinical Immunology, Tbilisi, Georgia. 158Latvian Association of Allergists,
Center of Tuberculosis and Lung Diseases, Riga, Latvia. 159Federal District Base
Hospital Institute, Brasília, Brazil. 160Institute of Health Policy and Management
iBMG, Erasmus University, Rotterdam, The Netherlands 161University Hospital
Olomouc – National eHealth Centre, Czech Republic. 162Immunology and
Allergy Division, Clinical Hospital, University of Chile, Santiago, Chile. 163Skin
and Allergy Hospital, Helsinki University Hospital, University of Helsinki,
Helsinki, Finland. 164Centich : centre d’expertise national des technologies de
l’information et de la communication pour l’autonomie, Gérontopôle
autonomie longévité des Pays de la Loire, Conseil régional des Pays de la Loire,
Centre d’expertise Partenariat Européen d’Innovation pour un vieillissement
actif et en bonne santé, Nantes, France. 165Autonomous University of Baja
California, Ensenada, Baja California, Mexico. 166Department of Paediatrics and
Child Health, University College Cork, Cork, Ireland. 167Hospital General
Regional 1 “Dr. Carlos MacGregor Sánchez Navarro” IMSS, Mexico City, Mexico. 168Université Paris-Sud; Service de Pneumologie, Hôpital Bicêtre; Inserm
UMR_S999, Le Kremlin Bicêtre, France. 169Dipartimento di medicina, chirurgia e
odontoiatria, università di Salerno, Italy. 170Division for Health Innovation,
Campania Region and Federico II University Hospital Naples (R&D and
DISMET) Naples, Italy. 171Servicio de Alergia e Immunologia, Clinica Santa
Isabel, Buenos Aires, Argentina. 172President, Libra Foundation, Buenos Aires,
Argentina. 173Medical University of Gdańsk, Department of Allergology,
Gdansk, Poland. 174Airway Disease Infection Section, National Heart and Lung
Institute, Imperial College; MRC & Asthma UK Centre in Allergic Mechanisms of
Asthma, London, UK. 175Dept of Respiratory Medicine, Ghent University
Hospital, Ghent, Belgium. 176Hallym University College of Medicine, Hallym
University Sacred Heart Hospital, Gyeonggi-do, South Korea. Mask Study Group
1 3 351Department of Chest Medicine, Centre Hospitalier Universitaire UCL Namur,
Université Catholique de Louvain, Yvoir, Belgium. 352University of Bari Medical
School, Unit of Geriatric Immunoallergology, Bari, Italy. 353Pulmonary Unit,
Department of Medical Specialties, Arcispedale SMaria Nuova/IRCCS, AUSL di
Reggio Emilia, Italy. 354FILHA, Finnish Lung Association, Helsinki, Finland. 355Pulmonary Environmental Epidemiology Unit, CNR Institute of Clinical
Physiology, Pisa, Italy ; and CNR Institute of Biomedicine and Molecular
Immunology “A Monroy”, Palermo, Italy. 356Medical University, Plovdiv, Bulgaria,
Department of Otorhinolaryngology, Plovdiv, Bulgaria. 357Sotiria Hospital,
Athens, Greece. 358Dept of Otorhinolaryngology, Universitätsklinikum
Düsseldorf, Germany. 359Asthma UK, Mansell street, London, UK. 360Nova
Southeastern University, Fort Lauderdale, Florida, USA. 361Department of
Otolaryngology, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore, Singapore. 362Department of Medicine, Clinical
Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada. 363Division of Immunodermatology and Allergy Research, Department of
Dermatology and Allergy, Hannover Medical School, Hannover, Germany. 364Department of Medicine Solna, Immunology and Allergy Unit, Karolinska
Institutet and Department of ENT diseases, Karolinska University Hospital,
Stockholm, Sweden. 365Eshelman School of Pharmacy, University of North
Carolina, Chapel Hill, NC, USA. 366International Primary Care Respiratory Group
IPCRG, Aberdeen, Scotland. 367Bradford Institute for Health Research, Bradford
Royal Infirmary, Bradford, UK. 368Allergologyst - Medical College of Medical
Faculty, Thracian University, Stara Zagora, Bulgaria. 369Department of Research,
Olmsted Medical Center, Rochester, Minnesota, USA. 370Cyprus International
Institute for Environmental & Public Health in Association with Harvard School
of Public Health, Cyprus University of Technology, Limassol, Cyprus;
Department of Pediatrics, Hospital “Archbishop Makarios III”, Nicosia, Cyprus. 371C l l B
U
D
f P l
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M
T k
372Th Medicine; Messerli Research Institute of the University of Veterinary Medicine
and Medical University, Vienna, Austria.267Department of Immunology and
Allergology, Faculty of Medicine and Faculty Hospital in Pilsen, Charles
University in Prague, Pilsen, Czech Republic. 268Division of Infection, Immunity
& Respiratory Medicine, Royal Manchester Children’s Hospital, University of
Manchester, Manchester, UK, and Allergy Department, 2nd Pediatric Clinic,
Athens General Children’s Hospital “P&A Kyriakou,” University of Athens, Athens,
Greece. 269Department of Allergy and Clinical Immunology, Ajou University
School of Medicine, Suwon, South Korea. 270Respiratory Medicine, Department
of Medical Sciences, University of Ferrara, Ferrara, Italy. 271Allergy and
Respiratory Diseases, Ospedale Policlino San Martino -University of Genoa,
Italy. 272Farmacias Holon, Lisbon, Portugal. 273Department of Pediatrics,
Nippon Medical School, Tokyo, Japan. 274University of Southern Denmark,
Kolding, Denmark. 275Université Grenoble Alpes, Laboratoire HP2, Grenoble,
INSERM, U1042 and CHU de Grenoble, France. Mask Study Group
1 3 276Allergy Unit, CUF-Porto
Hospital and Institute; Center for Research in Health Technologies and
information systems CINTESIS, Universidade do Porto, Portugal. 277Sociologist,
municipality area n33, Sorrento, Italy. 278Center for Rhinology and Allergology,
Wiesbaden, Germany. 279Department of Otorhinolaryngology, Head and Neck
Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim,
Heidelberg University, Mannheim, Germany. 280Centre for empowering people
and communites, Dublin, UK. 281Conseil Général de l’Economie Ministère de
l’Economie, de l’Industrie et du Numérique, Paris, France. 282Société de
Pneumologie de Langue Française, Espace francophone de Pneumologie,
Paris, France. 283Département de pédiatrie, CHU de Grenoble, Grenoble France. 284Medical School, University of Cyprus, Nicosia, Cyprus. 285Children’s Hospital
Srebrnjak, Zagreb, School of Medicine, University J.J. Strossmayer, Osijek,
Croatia. 286Karl Landsteiner Institute for Clinical and Experimental Pneumology,
Hietzing Hospital, Vienna, Austria. 287University Hospital ‘Sv. Ivan Rilski’”, Sofia,
Bulgaria. 288Allergy Diagnostic and Clinical Research Unit, University of Cape
Town Lung Institute, Cape Town, South Africa. 289Vice-Presidente of IML,
Milano, Italy. 290Centre of Academic Primary Care, Division of Applied Health
Sciences, University of Aberdeen, Aberdeen, United Kingdom ; Observational
and Pragmatic Research Institute, Singapore, Singapore. 291Department of
Otorhinolaryngology University of Crete School of Medicine, Heraklion,
Greece. 292European Forum for Research and Education in Allergy and Airway
Diseases (EUFOREA), Brussels, Belgium. 293Cancun, Quintana Roo, Mexico. 294LungenClinic Grosshansdorf, Airway Research Center North, Member of the
German Center for Lung Research (DZL), Grosshansdorf, Germany Department
of Medicine, Christian Albrechts University, Airway Research Center North,
Member of the German Center for Lung Research (DZL), Kiel, Germany. 295Department of Nephrology and Endocrinology, Karolinska University
Hospital, Stockholm, Sweden. 296Farmácia São Paio, Vila Nova de Gaia, Porto,
Portugal. 297St Vincent’s Hospital and University of Sydney, Sydney, New South
Wales, Australia. 298Puebla, Mexico. 299Serviço de Pneumologia-Hosp das
Clinicas UFPE-EBSERH, Recife, Brazil. 300Universidade Federal de São Paulo, São
Paulo, Brazil. 301Centre of Pneumology, Coimbra University Hospital, Portugal. 302Polibienestar Research Institute, University of Valencia, Valencia, Spain. 303Pediatric Allergy and Clinical Immunology, Hospital Angeles Pedregal,
Mexico City, Mexico. 304Getafe University Hospital Department of Geriatrics,
Madrid, Spain. 305Association Asthme et Allergie, Paris, France. 306Universidade
Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 307Primary Care Respiratory
Research Unit Institutode Investigación Sanitaria de Palma IdisPa, Palma de
Mallorca, Spain. 308Allergy Unit, Presidio Columbus, Rome, Catholic University
of Sacred Heart, Rome and IRCCS Oasi Maria SS, Troina, Italy. 309Mexico City,
Mexico. 310Regione Piemonte, Torino, Italy. 311Medical University of Graz,
Department of Internal Medicine, Graz, Austria. 312Serviço de Imunoalergolo‑
gia Hospital da Luz Lisboa Portugal. Mask Study Group
1 3 211Coimbra Institute for Clinical and Page 18 of 21 Page 18 of 21 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 Bousquet et al. Clin Transl Allergy (2018) 8:45 Department of Immunology, Faculty of Medicine, University of Manitoba,
Winnipeg, Manitoba, Canada. 326INSERM, Université Grenoble Alpes, IAB, U
1209, Team of Environmental Epidemiology applied to Reproduction and
Respiratory Health, Université Joseph Fourier, Grenoble, France. 327Sociedad
Paraguaya de Alergia Asma e Inmunologı´a, Paraguay. 328Division of Allergy,
Clinical Immunology and Rheumatology, Department of Pediatrics, Federal
University of São Paulo, São Paulo, Brazil. 329European Health Futures Forum
(EHFF), Dromahair, Ireland. 330ENT, Aachen, Germany. 331Kyrgyzstan National
Centre of Cardiology and Internal medicine, Euro-Asian respiratory Society,
Bishkek, Kyrgyzstan. 332University Hospital Olomouc, Czech Republic. 333Department of Paediatric and Adolescent medicine, University Hospital of
North Norway, Tromsø, Paediatric Research Group, Deptarment of Clinical
Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,
Tromsø, Norway. 334Presidente, IML (Lombardy Medical Initiative), Bergamo,
Italy. 335Pulmonary Division, Heart Institute (InCor), Hospital da Clinicas da
Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. 336Public Health Institute of Vilnius University, Vilnius, Lithuania. 337Universi‑
dade Federal do Estado do Rio de Janeiro, Rio de Janeiro - Brazil 338RNSA
(Réseau National de Surveillance Aérobiologique), Brussieu, France. 339The
Hospital for Sick Children, Dalla Lana School of Public Health, University of
Toronto, Canada. 340Imunoalergologia, Centro Hospitalar Universitário de
Coimbra and Faculty of Medicine, University of Coimbra, Portugal. 341Depart‑
ment of ENT, Medical University of Graz, Austria. 342Campania Region, Division
on Pharmacy and devices policy, Naples, Italy. 343Department of Respiratory
Medicine, Hvidovre Hospital & University of Copenhagen, Denmark. 344Universidade Federal dos Pampas, Uruguaiana, Brazil. 345Division of
Immunopathology, Department of Pathophysiology and Allergy Research,
Center for Pathophysiology, Infectiology and Immunology, Medical University
of Vienna, Vienna, Austria. 346Pneumology and Allergy Department CIBERES
and Clinical & Experimental Respiratory Immunoallergy, IDIBAPS, University of
Barcelona, Spain. 347Vilnius University Institute of Clinical Medicine, Clinic of
Children’s Diseases, and Institute of Health Sciences, Department of Public
Health, Vilnius, Lithuania; European Academy of Paediatrics (EAP/UEMS-SP),
Brussels, Belgium. 348Department of Lung Diseases and Clinical Immunology
Allergology, University of Turku and Terveystalo allergy clinic, Turku, Finland. 349PELyon; HESPER 7425, Health Services and Performance Resarch - Université
Claude Bernard Lyon, France.350Immunology and Allergy Unit, Department of
Medicine Solna, Karolinska Institutet and University Hospital, Stockholm. Mask Study Group
1 3 177Department of
Clinical Immunology, Wrocław Medical University, Poland. 178Ukrainina Medical
Stomatological Academy, Poltava, Ukraine. 179Pediatric Allergy and Asthma
Unit, Hacettepe University School of Medicine, Ankara, Turkey. 180Hacettepe
University, School of Medicine, Department of Chest Diseases, Immunology
and Allergy Division, Ankara, Turkey. 181Allergy Centre, Tampere University
Hospital, Tampere, Finland. 182First Department of Family Medicine, Medical
University of Lodz, Poland. 183Institute of Social Medicine, Epidemiology and
Health Economics, Charité - Universitätsmedizin Berlin, Berlin, and Institute for
Clinical Epidemiology and Biometry, University of Wuerzburg, Germany. 184Department of Medicine, McMaster University, HealthSciences Centre 3V47,
West, Hamilton, Ontario, Canada. 185National Research Center, Institute of
Immunology, Federal Medicobiological Agency, Laboratory of Molecular
immunology, Moscow, Russian Federation. 186GARD Chairman, Geneva,
Switzerland. 187Allergy & Asthma Center Westend, Berlin, Germany. 188Center
for Rhinology and Allergology, Wiesbaden, Germany. 189Department of
Immunology and Allergy, Healthy Ageing Research Center, Medical University
of Lodz, Lodz, Poland. 190Children’s Hospital and University of Helsinki, Finland. 191Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna,
Sweden. 192Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 193Department of Prevention of Envinronmental Hazards and Allergology,
Medical University of Warsaw, Poland. 194Center of Excellence in Asthma and
Allergy, Médica Sur Clinical Foundation and Hospital, México City,, Mexico. 195Presidente CMMC, Milano, Italy. 196Head of the Allergy Department of Pedro
de Elizalde Children’s Hospital, Buenos Aires, Argentina. 197University of
Medicine and Pharmacy, Hochiminh City, Vietnam. 198Federal University of
Bahia, Brazil. 199Sifmed, Milano, Italy. 200State Key Laboratory of Respiratory
Diseases, Guangzhou Institute of Respiratory Disease, the First Affiliated
Hospital of Guangzhou Medical University, Guangzhou, China. 201Departments
of Internal Medicine and Pediatrics (Divisions of Allergy and Immunology),
University of Tennessee College of Medicine, Germantown, TN, USA. 202Scottish Centre for Respiratory Research, Cardiovascular & Diabetes
Medicine, Medical Research Institute, Ninewells Hospital, University of Dundee,
UK. 203Oslo University Hospital, Department of Paediatrics, Oslo, and University
of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo, Norway. 204Department of Pulmonary Medicine, CHU Sart-Tilman, and GIGA I3 research
group, Liege, Belgium. 205Faculty of Health Sciences and CICS – UBI, Health
Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. 206Department of Philosophical, Methodological and Instrumental Disciplines,
CUCS, University of Guadalajara, Guadalajara, Mexico. 207Department of
Pulmonary Medicine, Rashid Hospital, Dubai, UAE. 208Biomax Informatics AG,
Munich, Germany. 209Director Gerneral for Health and Social Care, Scottish
Government, Edinburgh, UK. 210Department of Respiratory Medicine,
University of Bratislava, Bratislava, Slovakia. Competing interests OP reports
grants and personal fees from ALK-Abelló, Allergopharma, Stallergenes Greer,
HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy
Therapeutics, Lofarma, Biotech Tools S.A., Laboratorios LETI/LETI Pharma,
Anergis S.A., grants from Biomay, Nuvo, Circassia, Glaxo Smith Kline, personal
fees from Novartis Pharma, MEDA Pharma, Mobile Chamber Experts (a
GA2LEN Partner), Pohl-Boskamp, Indoor Biotechnologies, grants from, outside
the submitted work. AMTB reports grants and personal fees from Novartis,
Boehringer Ingelheim, Mundipharma, GSK (GlaxoSmithKline), personal fees
from Teva Pharma, AstraZeneca, grants from Leti, outside the submitted work. SW reports personnal fees from Merck, GSK, Novartis, Behring, Shire, Sanofi,
Barid Aralez, Mylan Meda, Pediapharm outside the submitted work. 3. Bousquet J, Bachert C, Canonica GW, Casale TB, Cruz AA, Lockey RJ, et al. Unmet needs in severe chronic upper airway disease (SCUAD). J Allergy
Clin Immunol. 2009;124(3):428–33. 4. Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani
CE, Bleecker ER, et al. Uniform definition of asthma severity, con‑
trol, and exacerbations: document presented for the World Health
Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926–38. 5. De Greve G, Hellings PW, Fokkens WJ, Pugin B, Steelant B, Seys SF. Endotype-driven treatment in chronic upper airway diseases. Clin Transl
Allergy. 2017;7:22. 6. Cingi C, Gevaert P, Mosges R, Rondon C, Hox V, Rudenko M, et al. Multi-
morbidities of allergic rhinitis in adults: European Academy of Allergy and
Clinical Immunology task force report. Clin Transl Allergy. 2017;7:17. 7. Frohlich M, Pinart M, Keller T, Reich A, Cabieses B, Hohmann C, et al. Is
there a sex-shift in prevalence of allergic rhinitis and comorbid asthma
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grated care pathways for airway diseases (AIRWAYS-ICPs). Eur Respir J. 2014;44(2):304–23. 9. Hellings PW, Fokkens WJ, Bachert C, Akdis CA, Bieber T, Agache I, et al. Positioning the principles of precision medicine in care pathways for
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AIRWAYS ICP statement. Allergy. 2017;72(9):1297–305. 10. Bousquet J, Schunemann HJ, Fonseca J, Samolinski B, Bachert C,
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2015;70(11):1372–92. 11. Hellings PW, Fokkens WJ, Akdis C, Bachert C, Cingi C, Dietz de Loos D,
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we stand today? Allergy. 2013;68(1):1–7. 12. mHealth. Competing interests SBA reports personal fees from Boehringer Ingelheim, GSK, AstraZeneca, TEVA,
grants from TEVA, MEDA outside the submitted work. JB reports personal
fees and other from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan,
Novartis, Sanofi-Aventis, Takeda, Teva, Uriach, other from Kyomed, outside the
submitted work. AAC reports grants and personal fees from GlaxoSmithKline,
personal fees from Boehrinher Ingelheim, personal fees from AstraZeneca,
personal fees from Novartis, personal fees from Merk, Sharp & Dohma,
personal fees from MEDA Pharma, personal fees from EUROFARMA, personal
fees from Sanofi Aventis, outside the submitted work. MD reports other
from Allergan, outside the submitted work. WF reports grants from Meda,
outside the submitted work. TH reports personal fees from Mundipharma,
Novartis, and Orion Pharma, outside the submitted work. JJ reports grants and
personal fees from novartis, ALK abello, personal fees from thermofischer, astra
zeneca outside the submitted work. PK reports personal fees from Adamed,
Boehringer Ingelheim, AstraZeneca, Chiesi, FAES, Berlin Chemie, Novartis, Polp‑
harma, Allergopharma, outside the submitted work. VK has received payment
for consultancy from GSK and for lectures from Stallergens, Berlin-CHemie
outside the submitted work. DLL reports personal fees from GSK, Astrazeneca,
MEDA, Boehringer Ingelheim, Novartis, Grunenthal, UCB, Amstrong, Siegfried,
DBV Technologies, MSD, Pfizer, grants from Sanofi, Astrazeneca, Novartis,
UCB, GSK, TEVA, Chiesi, Boehringer Ingelheim, outside the submitted work. RM reports personal fees from ALK, grants from ASIT biotech, Leti, BitopAG,
Hulka, Ursapharm, Optima; personal fees from allergopharma, Nuvo, Meda,
Friulchem, Hexal, Servier, Bayer, Johnson&Johnson, Klosterfrau, GSK, MSD,
FAES, Stada, UCB, Allergy Therapeutics; grants and personal fees from Bencard,
Stallergenes; grants, personal fees and non-financial support from Lofarma;
non-financial support from Roxall, Atmos, Bionorica, Otonomy, Ferrero; per‑
sonal fees and non-financial support from Novartis. NP reports personal fees
from Novartis, Faes Farma, BIOMAY, HAL, Nutricia Research, Menarini, Novartis,
MEDA, Abbvie, MSD, Omega Pharma, Danone, grants from Menarini, outside
the submitted work. JLP reports grants from Air Liquide Foundation, AGIR à
dom, Astrazeneca, Fisher & Paykel, Mutualia, Philips, Resmed, Vitalaire, other
from AGIR à dom, Astrazeneca, Boehringer Ingelheim, Jazz Pharmaceutical,
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Ovarian cryopreservation after laparoscopic ovariectomy using the Endo-GIA stapling device and LAPRO-clip absorbable ligating clip in a woman: a case report
|
Journal of medical case reports
| 2,011
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cc-by
| 1,240
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Roux et al. Journal of Medical Case Reports 2011, 5:48
http://www.jmedicalcasereports.com/content/5/1/48
JOURNAL OF MEDICAL
CASE REPORTS
CASE REPORT
Open Access
Ovarian cryopreservation after laparoscopic
ovariectomy using the Endo-GIA stapling device
and LAPRO-clip absorbable ligating clip in a
woman: a case report
Isabelle Roux1, Michaël Grynberg1,2, Jenna Linehan1, Alexandra Messner3, Xavier Deffieux1,2,4*
Abstract
Introduction: Several options are available for preserving fertility before cytotoxic treatment, including ovarian
tissue cryopreservation. Most reported surgical techniques include electrocoagulation. Our hypothesis is that
avoidance of electrocoagulation may decrease ovarian cortex injury during cryopreservation procedures.
Case presentation: We report a laparoscopic technique of whole-ovary removal without coagulation using
Endo-GIA forceps and clips. Laparoscopic ovariectomy was performed for cryopreservation in a 37-year-old
Caucasian woman with breast cancer and for whom chemotherapy was planned. The procedure was completed
quickly and without complication. This Endo-GIA procedure was of short duration with a short period of ischemia
before freezing.
Conclusion: Laparoscopic ovariectomy using the Endo-GIA stapling device procedure without coagulation may
diminish ovary injury before ovarian cryopreservation.
Introduction
Several options are available for preserving fertility
before cytotoxic treatment, namely embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. Embryo cryopreservation results in good
pregnancy rates, but the patient needs to be of pubertal
or postpubertal age, have a partner and be able to
undergo a cycle of ovarian stimulation [1]. Ovarian stimulation is not possible when chemotherapy cannot be
delayed or when stimulation is contraindicated. Ovarian
tissue transplantation after cryopreservation is an option
despite being an experimental technique with few live
births reported [2]. Either a part of cortical tissue [3] or
whole ovary can be removed.
Case presentation
We report a laparoscopic ovariectomy technique performed for cryopreservation in a 37 year-old Caucasian
* Correspondence: xavier.deffieux@abc.aphp.fr
1
AP-HP, Service de Gynécologie-Obstétrique et Médecine de la
Reproduction, Hôpital Antoine Béclère, Clamart, F-92141, France
Full list of author information is available at the end of the article
woman with breast cancer and for whom chemotherapy
was planned. Despite being informed of the poor outcome
in women of her age, this woman elected to undergo combined techniques for fertility preservation. As an adjuvant
to the tissue preservation, immature oocyte retrieval was
performed one day before the surgery. During laparoscopy,
the ureter and the iliac vessels were identified. Through
the medial 12-mm trocar, the Endo-GIA Roticulator
(Tyco Healthcare, Covidien, Elancourt, France) was used
to cut the infundibulopelvic ligament and mesovarium
(Figures 1 and 2). The utero-ovarian ligament was then
clamped with two vascular absorbable clips (Figure 3).
The removed ovary was immediately handed over to a
biologist team that was present in the operating room. No
complications were reported from this procedure. Pathology revealed “normal” ovarian tissue. Our hypothesis is
that avoidance of electrocoagulation may decrease ovarian
cortex injury during cryopreservation procedure. There
are no precise data demonstrating that electrocoagulation
causes damage to the ovarian tissue in the course of ovarian tissue harvesting and cryopreservation. However, many
experimental studies have shown that electrocoagulation
© 2011 Roux et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Roux et al. Journal of Medical Case Reports 2011, 5:48
http://www.jmedicalcasereports.com/content/5/1/48
Figure 1 The Endo-GIA Roticulator is used to cut the
infundibulopelvic ligament and mesovarium.
(monopolar and bipolar energies) may be associated with
damage to ovarian tissue. For example, ovarian drilling,
especially bipolar electrocoagulation, causes extensive
destruction of the ovary [4]. Furthermore, some data suggest that bipolar electrocoagulation of the ovarian parenchyma during laparoscopic ovarian cystectomy
adversely affects ovarian function [5,6]. These data show
possible impact of electrocoagulatory ovarian tissue
damage on the outcome of ovarian tissue harvesting and
reimplantation. Further studies should assess ovarian tissue damage and the results of ovarian cryopreservation
according to the ovarian removal procedure (Endo-GIA
vs. electrocoagulatory).
This Endo-GIA procedure was of short duration with
a short period of ischemia before freezing. Furthermore,
it is known that the Endo-GIA stapling device requires
significantly less time than electrocoagulation [7]. However, some centers do not remove a whole ovary for
ovarian tissue cryopreservation; instead, they remove
only half to two-thirds of one macroscopically normal
Page 2 of 3
Figure 3 Clamping the utero-ovarian ligament using vascular
absorbable clips.
ovary’s cortex. The Endo-GIA removal procedure cannot be used in these cases.
Conclusion
Laparoscopic ovariectomy using the Endo-GIA stapling
device procedure without coagulation is an optional
ovariectomy technique that should diminish ovary injury
before ovarian cryopreservation.
Consent
Written informed consent was obtained from the patient
for publication of this case report and accompanying
images. A copy of the written consent is available for
review from the Editor-in-Chief of this journal.
Author details
1
AP-HP, Service de Gynécologie-Obstétrique et Médecine de la
Reproduction, Hôpital Antoine Béclère, Clamart, F-92141, France. 2Univ ParisSud, Faculté de Médecine Paris Sud, Le Kremlin Bicêtre, F-94275, France. 3APHP, Department of Reproductive Biology, Antoine Béclère Hospital, Clamart,
F-92141, France. 4ER6, UPMC, Paris, F-75013, France.
Authors’ contributions
Each author participated sufficiently in the work. IR, XD and MG performed
surgical procedure and analyzed and interpreted the patient data regarding
the surgical management. JL and AM performed the ovarian
cryopreservation and were major contributors in writing the manuscript. All
authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 22 April 2010 Accepted: 3 February 2011
Published: 3 February 2011
Figure 2 Cutting the mesovarium using the Endo-GIA stapling
device.
References
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the American Society for Reproductive Medicine and the Practice
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doi:10.1186/1752-1947-5-48
Cite this article as: Roux et al.: Ovarian cryopreservation after
laparoscopic ovariectomy using the Endo-GIA stapling device and
LAPRO-clip absorbable ligating clip in a woman: a case report. Journal
of Medical Case Reports 2011 5:48.
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Indonesian
| null |
Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir Kritis dan Hasil Belajar Siswa di Indonesia: Sebuah Meta-Analisis
|
Jurnal Sustainable
| 2,023
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cc-by
| 6,919
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Abstrak Penelitian ini bertujuan untuk mengetahui pengaruh flipchart terintegrasi STEM terhadap kemampuan berpikir dan hasil
belajar siswa di Indonesia. Jenis penelitian ini adalah meta-analisis. Sumber data dalam penelitian ini berasal dari 11 jurnal
nasional dan internasional. Proses penulusuran sumber data dari google scholar, Emerald, ScienceDirect, Eric, Taylor of
Francis dan ProQuest. Teknik pengumpulan data melalui observasi langsung melalui database online. Kriteria sumber
data harus memenuhi kriteria inklusi. Kriteria inklusi yang dijadikan data meta-analisis yaitu jurnal terindeks SINTA, DOAJ,
Scopus dan WOS, Jurnal harus berbahasa Inggris dan Indonesia serta jurnal yang terbit dari tahun 2015-2023. Hasil meta-
analisis menunjukan bahwa nilai Effect Size (ES = 0.902) dengan kriteria sedang. Temuan ini menunjukan pembelajaran
flipchart terintegrasi STEM memberikan pengaruh positif terhadap kemampuan berpikir kritis dan hasil belajar siswa di
Indonesia. Penerapan pembelajaran flipchar terintegrasi STEM membantu guru dan siswa dalam menigkatkan proses
pembelajaran di sekolah. Kata kunci: Flipchart, STEM, Berpikir Kritis, Hasil belajar, Meta-analisis History:
Received : 29 Mei 2023
Revised : 06 Juni 2023
Accepted : 09 Juni 2023
Published : 30 Juni 2023
1Universitas Sebelas Maret
2Universitas Islam 45 Bekasi
3Universitas Negeri Padang
4Universitas Bina Sarana Informatika
568Akademi Teknik Adikarya Kerinci
7IAIN Kerinci
*Author Correspondent: ilwandri001@gmail.com
Publishers: LPM IAIN Shaykh Abdurrahman Siddik Bangka
Belitung, Indonesia
Licensed: This work is licensed under
aCreative Commons Attribution 4.0 International License. History:
Received : 29 Mei 2023
Revised : 06 Juni 2023
Accepted : 09 Juni 2023
Published : 30 Juni 2023
1Universitas Sebelas Maret
2Universitas Islam 45 Bekasi
3Universitas Negeri Padang
4Universitas Bina Sarana Informatika
568Akademi Teknik Adikarya Kerinci
7IAIN Kerinci
*
h
d
l
d
@ Publishers: LPM IAIN Shaykh Abdurrahman Siddik Bangka
Belitung, Indonesia Licensed: This work is licensed under
aCreative Commons Attribution 4.0 International License. *Author Correspondent: ilwandri001@gmail.com Volume 6 Number 1 2023, 95-107
E-ISSN: 2655-0695
DOI:https://doi.org/ 10.32923/kjmp.v6i1.3391 Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir Kritis
dan Hasil Belajar Siswa di Indonesia: Sebuah Meta-Analisis
Abdul Rahman1*, Yayat Suharyat2, Zulyusri Zulyusri3, Upris Yastati4, Tomi Apra Santosa5,
Revi Gina Gunwan6, Suhaimi7, Ilwandri8 Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir Kritis
dan Hasil Belajar Siswa di Indonesia: Sebuah Meta-Analisis
Abdul Rahman1*, Yayat Suharyat2, Zulyusri Zulyusri3, Upris Yastati4, Tomi Apra Santosa5,
Revi Gina Gunwan6, Suhaimi7, Ilwandri8 Pendahuluan Kemampuan berpikir merupakan suatu kemampuan harus dimiliki siswa dalam menghadapi
pembelajaran abad-21 (Kurniawan et al., 2021; Zulkifli et al., 2022; Temel, 2022). Kemampuan ber-
pikir kritis ini membantu siswa lebih mudah dalam mengidentifikasi dan menyelesaikan masalah
(Fakhriyah, 2014). Siswa yang mempunyai kemampuan berpikir kritis akan lebih mudah dalam
menerima dan memahami materi pelajaran (Elfira et al., 2023; Rahman et al., 2023; Sofianora et al.,
2023; Fikriyatii et al., 2022). Selain itu, kemampuan berpikir kritis sangat penting bagi siswa untuk
menyelesaikan masalah dalam kegiatan belajar mengajar (Arisoy & Aybek, 2021; Palavan, 2020). Siswa mempunyai kemampuan berpikir kritis lebih mudah untuk meningkatkan hasilnya belajarnya
(Ferry et al., 2019; Ramdani, 2016). Hasil belajar dan kemampuan berpikir kritis menjadi tujuan utama dalam proses pembelaja-
ran (Yusuf et al., 2020(Gültepe & Kılıç, 2021) ; Supriyadi et al., 2023; Suharyat et al., 2022); (Santosa,
2021). Sudjana dalam Lestari (2015) menyatakan hasil belajar merupakan suatu ketrampilan yang
dimiliki siswa ketika telah selesai melaksanakan kegiatan belajar. Siswa harus mampu mencapai
hasil belajar yang lebih baik dalam kegiatan pembelajaran (Mursid et al., 2022). Hasil belajar menen-
tukan tingkat keberhasilan siswa dalam memahami materi yang telah dipelajari (Zulyusri et al.,
2022; Sanjaya et al., 2022; Wuryandani & Herwin, 2021;Oktarina et al., 2021; Litualy et al., 2022). Se-
lanjutnya, hasil belajar siswa menjadi kriteria dalam meningkatkan kualitas pembelajaran di 95 Hadi WiyonoAbdul Rahman et al sekolah (Lena et al., 2022; Yusuf et al., 2022). Sjukur (2013) menyatakan hasil belajar mendukung
siswa untuk membentuk karakter berpikirnya dalam pembelajaran. Kuliatas pembelajaran siswa di Indonesia masih dalam ketegori rendah (Fradila et al., 2021). Tingkat kemampuan berpikir kritis dan hasil belajar siswa Indonesia masih tergolong rendah
dibandingkan dengan negara lainnya (Ndiung et al., 2021; Rahman et al., 2023; Aliman et al., 2019). Hasil survei Program for International Student Assesment (PISA) tahun 2015 menunjukan bahwa
tingkat literasi berpikir siswa Indonesia memperoleh skor 403 menduduki peringkat 62 dari 72
negara anggota (Alatas & Fauziah, 2020). PISA Tahun 2018 tingkat literasi sains siswa menduduki
peringkat 72 dari 78 memperoleh skor 396 (Suharyat et al., 2023; Razak et al.., 2021;Santosa et al.,
2021); . Hasil penelitian PISA dalam Adiwiguna et al.,( 2019) menyatakan kualitas literasi sains si-
sawa dalam memahami pelajaran masih rendah hanya 29 % konten pelajaran, 30 % untuk proses
pembelajaran serta 32 % siswa memahami konteks pelajaran. Rendahhnya kualitas belajar siswa disebabkan oleh proses pembelajaran terlalu terpusat
pada guru (Anggreni et al., 2020). Pendahuluan Proses belajar mengajar siswa belum mengarah kepada ket-
rampilan berpikir kritis (Suharyat et al., 2022; Santosa et al., 2021; Surur et al., 2022). Aiman et al.,
(2019) menyatakan rendahhnya kemampuan berpikir kritis siswa dipengaruhi model dan metode
pembelajaran yang digunakan guru. Pemelihan model pembelajaran yang tepat membantu siswa
lebih termotivasi untuk belajar (Goodnough & Nolan, 2008; Bannon et al., 2017; Shi et al., 2020). Selain itu, model pembelajaran yang digunakan belum mendorong kemampuan berpikir kritis dan
hasil belajar siswa (Supiandi & Julung, 2016). Hal ini menunjukan perlu adanya sebuah pembelaja-
ran yang dapat menumbuhkan kemampuan berpikir siswa. g
Selanjutnya salah satu pembelajaran yang mampu mendorong kemampuan berpikir kritis
dan hasil belajar siswa adalah flipchart (Pramita et al., 2019; Talakua et al., 2021). Flipchart merupa-
kan sebuah lembaran kertas yang disusun secara sistematis yang dimanfaatkan sebagai media
pemebelajaran (Dryburgh & Jackson, 2016). Romaliyana & Putra (2019) menyatakan pembelajaran
dengan flipchart dapat meningkatkan kompetensi pengetahuan siswa dalam belajar. Pembelajaran
flipchart membantu proses belajar mengajar siswa lebih menarik. Media flipchart dapat menyajikan
pembelajaran dengan ringkas dan praktis (Andri, 2015; Andhini et al., 2020). Pembelajaran flipchart
integrasi STEM mendorong siswa dalam meningkatkan ketrampilan berpikir kritis dan hasil belajar. STEM merupakan pendekatan pembelajaran yang mengkombinasikan sains teknologi teknik dan
matematika dalam proses pembelajaran (Kulakoglu, 2023; Waters & Orange, 2022; Wilson et al.,
2022). Pembelajaran flipchart integrasi STEM membantu siswa dalam memahami teknologi yang
mendukung kemampuan berpikir kritisnya. Hasil penelitian Dewi et al., (2022) menyatakan pembelajaran dengan flipchart dapat mening-
katkan pengetahuan siswa dalam belajar, sehingga memebuat siswa lebih aktif. Hasil penelitian
Sastri et al.,( 2021) menyatakan pembelajaran flipchart mendorong siswa dalam penguatan literasi
sainsnya. Eluri et al., (2022) pembelajaran dengan flipchart dapat meningkatkan pengetahuan dan
proses berpikir siswa dalam kegiatan belajar mengajar sehingga membuat pembelajaran lebih
menarik. Pembelajaran flipchart ini efektif diterapkan untuk mengembangkan pengetahuan dan
kemampuan berpikir siswa (Izhar, 2022). Penelitian sebelumnya oleh Arundhati et al.,( 2019) menyatakan penerapan Flipchart dalam
kegiatan pembelajaran mendorong kemandirian dan hasil beajar siswa. Penelitian sebelum oleh
Indahyani & Rianto (2014) penggunaan media flipchart dalam pembelajaran akan mampu mening-
katkan kemampuan komunikasi siswa. Selanjutnya penelitian oleh Sitanaya (2019) menyetakan
pembelajaran melalui flipchart efektif menrangsang pengetahuan siswa dalam belajar. Namun ken-
yataan, belum banyak penelitian yang menggambarkan seberapa besar dampak Flipchart dalam
meningkatkan kemampuan berpikir kritis dan hasil belajar siswa secara keseluruhan. Oleh karena
itu, perlu untuk menganalisis hal tersebut agar bisa menjadi bahan evaluasi guru. Pendahuluan Beradasarkan hal
di atas tujuan penelitian ini untuk pengaruh flipchart terintegrasi STEM terhadap kemampuan ber-
pikir dan hasil belajar siswa di Indonesia. 96 Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir kritis dan Hasil Belajar Siswa di Indonesia : Sebuah Meta-Analisis Metode Penelitian ini adalah jenis penelitian meta-analisis. Meta-analisis adalah penelitian yang
menganalisis studi-studi yang terkait dengan masalah penelitian yang dapat dianalisis secara statis-
tik (Funa, 2021; Suharyat et al., 2022; Ridwan et al., 2021).Sumber data dalam penelitian ini berasal
dari 11 jurnal nasional dan internasional. Penelusuran sumber data dalam penelitian melalui google
scholar, Wiley, Eric, Proquest dan ScienceDirect. Proses penyeleksian sumber data menggunakan
metode PRISMA dapat dilihat (Gambar.1). Teknik pengumpulan data adalah observasi secara lang-
sung melalui database online. Tahapan-tahapan dalam meta-analisis yaitu 1) proses penelusuran
literatur; 2) mengumpulkan masing-masing temuan; 3) melakukan evaluasi terhadap kualitas studi;
4) melakukan analisis hasil studi serta 5) menginterpretasikan hasil studi (Alshammari, 2022;
Sternberg et al., 2021; Kaçar et al., 2021). Meta-analisis dalam penelitian berkaitan dengan pengaruh
flipchart terintegrasi STEM terhadap kemampuan berpikir kritis dan hasil belajar siswa. Kriteria inklusi penelitian meta-analisis ini yakni 1) Jurnal nasional yang terbit dari tahun 2015-
2023; 2) jurnal harus berbahasa Indonesia dan Inggri; 3) masing-masing studi terdapat kelas eksper-
imen dan kelas kontrol; 4) Studi harus terindeks SINTA, DOAJ, Scopus dan WOS. 5) Studi harus
berupa jurnal atau prosiding conference; 5) Masing-masing studi harus berkaitan dengan Flipchart,
STEM, Ketrampilan berpikir kritia dan hasil belajar. Analisis data dalam penelitian ini dengan Com-
prehensive meta-anayisis (CMA) versi 3.0 yang berfungsi untuk menghitung nilai effect size, stand-
ard deviasi masing-masing studi. Adapun kriteria nilai Effect Size dapat dilihat pada Tabel 2. Tabel 2. Kriteria nilai Effect Size
Effect Size
Kriteria
0.00 ≤ ES < 0.20
0.20 ≤ ES ≤ 0.50
0.50 ≤ ES ≤ 0.80
0.80 ≤ ES ≤ 1.30
1.30 ≤ ES
Diabaikan
Kecil
Sedang
Besar
Sangat besar
Sumber: (Suparman et al. , 2020; Santosa et al., 2021; Putra et al., 2023) g
Sumber: (Suparman et al. , 2020; Santosa et al., 2021; Putra et al., 2023) 97 97 Hadi WiyonoAbdul Rahman et al Gambar 1. PRISMA Proses Penyeleksian Studi Meta-analisis Gambar 1. PRISMA Proses Penyeleksian Studi Meta-analisis Hasil dan Diskusi Dari analisis 497 jurnal nasional dan internasional tentang pengaruh flipchart terintegrasi
STEM hanya 11 studi yang telah memenuhi kriteria inklusi. Studi yang telah menenuhi kriteria
inklusi tesebut diambil untuk sumber data meta-analisis yang dapat dilihat (Tabel 2.). Sumber data
masing-masing Studi tersebut dihitung berdasarkan nilai Effect Size, Standart Deviasi (SD), ting-
katan pendidikan, Ukuran sampel dan tahun publikasi. Tabel 2. Hasil Meta-analisis Sumber Data Berdasarkan Kriteria Inklusi
No
Penulis
Ta-
hun
Tingkatan
Pendidi-
kan
Ukuran
Sampel
Effect
Size (ES)
SD
Kriteria
1
Pramita et al.,
2019
SD
143
1.20
2.35
Besar
2
Novika et al.,
2019
SD
41
0.91
4.10
Besar
3
Arisetya
2019
SMP
40
0.87
3.11
Besar
4
Yulianto et al.,
2022
SD
18
0.66
2.10
Sedang
5
Ayu & Amran
2021
SD
20
0.43
1.02
Kecil
6
Nofita
2022
SD
42
0.87
5.23
Besar
7
Muchtar et al.,
2018
SMP
40
0.67
1.56
Sedang
8
Izhar
2022
PT
60
1.40
4.20
Sangat
besar
9
Sastri, et al.,
2021
SMP
20
0.77
2.13
Sedang 98 Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir kritis dan Hasil Belajar Siswa di Indonesia : Sebuah Meta-Analisis 10
Haryani et al.,
2022
SD
80
2.30
5.51
Sangat
besar
11
Aziz et al.,
2020
SD
20
0.72
3.05
Sedang
Nilai rata-rata effect size
0.902
Sedang
Gambar 1. Jumlah Tingkatan Pendidikan Yang Menerapkan Pembelajaran Flipchart
0
1
2
3
4
5
6
7
SD
SMP
SMA
PT Gambar 1. Jumlah Tingkatan Pendidikan Yang Menerapkan Pembelajaran Flipchart Berdasarkan Tabel 2. Menunjukan nilai rata-rata effect size ( ES = 0.902) dengan kriteria sedang. Hasil ini menjelaskan bahwa pembelajaran flipchart terintegrasi STEM memberikan pengaruh sig-
nifikan terhadap ketrampilan berpikir kritis dan hasil belajar siswa. Pembelajaran dengan flipchart
dapat meningkatkan pengetahuan berpikir dan hasil belajar siswa (Susanti et al., 2020). Caagbay
et al., (2020) pembelajaran flipchart membantu siswa lebih kreatif dan aktif dalam kegiatan belajar. Selanjutnya, pembelajaran flipchart terintegrasi STEM siswa lebih mudah memahami materi dan
konten pelajaran yang dipelajari ( Jannah et al., 2022; Yuniana & Purwanti, 2022). Proses pembela-
jaran yang terintegrasi STEM membuat siswa dapat mengembangkan ide-ide kreatifnya dalam
belajar (Nurtanto et al., 2020; Wahyuni, 2021); , sehingga siswa lebih aktif dalam belajar. Astuti et
al.,( 2021) menyatakan pembelajaran yang diintergrasi STEM membantu siswa dalam mengusai
teknologi pembelajara yang dapat merangsang kemampuan berpikir kritis dan hasil belajarnya. Berdasarkan Tabel 2. Menunjukan nilai rata-rata effect size ( ES = 0.902) dengan kriteria sedang. Hasil dan Diskusi Hasil ini menjelaskan bahwa pembelajaran flipchart terintegrasi STEM memberikan pengaruh sig-
nifikan terhadap ketrampilan berpikir kritis dan hasil belajar siswa. Pembelajaran dengan flipchart
dapat meningkatkan pengetahuan berpikir dan hasil belajar siswa (Susanti et al., 2020). Caagbay
et al., (2020) pembelajaran flipchart membantu siswa lebih kreatif dan aktif dalam kegiatan belajar. Selanjutnya, pembelajaran flipchart terintegrasi STEM siswa lebih mudah memahami materi dan
konten pelajaran yang dipelajari ( Jannah et al., 2022; Yuniana & Purwanti, 2022). Proses pembela-
jaran yang terintegrasi STEM membuat siswa dapat mengembangkan ide-ide kreatifnya dalam
belajar (Nurtanto et al., 2020; Wahyuni, 2021); , sehingga siswa lebih aktif dalam belajar. Astuti et
al.,( 2021) menyatakan pembelajaran yang diintergrasi STEM membantu siswa dalam mengusai
teknologi pembelajara yang dapat merangsang kemampuan berpikir kritis dan hasil belajarnya. Gambar 1. Menunjukan bahwa penerapan pembelajaran Flipchart berintegrasi STEM banyak dit-
erapkan pada sekolah dasar ( n= 7), Sekolah Menengah Pertama ( n= 3), dan PT ( n= 1). Penerapan
pembelajaran flipchart pada Sekolah Dasar lebih banyak karena siswa menyukai media pembelaja-
ran yang lebih menarik (Sitanaya, 2019; Ichsan et al., 2022; Santosa & Sepriyani, et al., 2021). Pramita
et al., (2019) flipchart membantu siswa lebih kreatif dalam menuangkan ide-ide melalui tulisannya. Selanjutnya, pembelajaran flipchart terintegrasi STEM mendorong siswa belajar lebih efektif dan
praktis dalam memahami materi pelajaran (Ziliwu, 2019). Tahapan selanjutnya, menentukan
menentukan model Effect size maka dilakukan uji heterogenitas. Hasil uji heterogenitas dapat
dilihat pada Tabel 3. g
g
g
g
Gambar 1. Menunjukan bahwa penerapan pembelajaran Flipchart berintegrasi STEM banyak dit-
erapkan pada sekolah dasar ( n= 7), Sekolah Menengah Pertama ( n= 3), dan PT ( n= 1). Penerapan
pembelajaran flipchart pada Sekolah Dasar lebih banyak karena siswa menyukai media pembelaja-
ran yang lebih menarik (Sitanaya, 2019; Ichsan et al., 2022; Santosa & Sepriyani, et al., 2021). Pramita
et al., (2019) flipchart membantu siswa lebih kreatif dalam menuangkan ide-ide melalui tulisannya. Selanjutnya, pembelajaran flipchart terintegrasi STEM mendorong siswa belajar lebih efektif dan
praktis dalam memahami materi pelajaran (Ziliwu, 2019). Tahapan selanjutnya, menentukan
menentukan model Effect size maka dilakukan uji heterogenitas. Hasil uji heterogenitas dapat
dilih t
d T bel 3 Tabel 3. Hasil dan Diskusi Hasil Uji Heterogenitas Berdasakan Model Effect
Model
Number
Studies
Hedge’s
95 % CL
Null Hypothesis
Test (2-Tail)
Heterogenity
Z-value
P-value
Q- Value
df(Q)
p-
valu
e 99 Hadi WiyonoAbdul Rahman et al Fixed
11
0.310
[0.281; 0.312]
12.510
0.000
140.19
10
0.000
Random
11
0.480
[0.293; 0.491]
7.810
0.000 Berdasarkan Tabel. 3 menjelaskan effect size dari keseluruhan studi mempunyai perbedaan
yang signifikan. Nilai p-value < 0.05 ( 0.00 < 0.05), maka meta-analisis ini menggunakan random
effect model yang lebih daripada menggunakan fixed effect model (Tamur & Wijaya, 2021). Hasil ini
menunjukan random effect model sebagai model untuk melalukan analisis. Hasil hipotesis pada
(Tabel.3) menunjukan penerapan model pembelajaran flipchart terintegrasi STEM memberikan
pengaruh yang signifikan terhadap ketrampilan berpikir kritis dan hasil belajar siswa dibandingkan
dengan model pembelajaran konvensional. Pembelajaran flipchart memberikan pengaruh yang
singifikan terhadap pengetahuan, motivasi dan hasil belajar siswa (Rukmana, 2022). Model flip-
chart terintegrasi STEM merangsang kemampuan pengetahuan dan motivasi dalam belajar se-
hingga materi pelaran yang diberikan oleh guru mudah dipahami (Young, 2019; Rahman et al. 2023;
Santosa, 2021). Selain itu, pembelajaran dengan flipchart informasi yang diberikan oleh guru lebih
mudah dipahami oleh siswa . Rizqi, (2021) menyatakan pembelajaran flipchart membantu kemam-
puan berbicara siswa di dalam kelas sehingga suasana belajarnya lebih menarik. p
gg
Selanjutnya dari hasil heterogenitas karakteristik sampel dan publikasi salah satu penyebab
variasi effect size dalam penerapam pembelajaran flipchart terintegrasi STEM pada siswa. Jadi, un-
tuk penting untuk dianalisis faktor-faktor menyebabkan effect size tersebut. Hasil analisis karak-
teristik dari sampel dan publikasi dapat dlihat pada Tabel 4. Tabel 4. Hasi analisis Karakteristik sampel dan publikasi
Karakteris-
tik Studi
Kelompok
Nomor
Studi
Hedge’s
g
Null Hypotesis -
Test
Heterogenity
Sampel
Z-value
p-value
Qb
df
p-value
Ukuran sam-
pel
≤ 20 pe-
serta
12
0.412
5.014
0.000
1.041
1
0.240
>20 pe-
serta
5
0.481
2.780
0.000
5.190
3
0.118
Tingkat pen-
didikan
SD
2
0.317
SMP
7
0.267
2.054
0.000
PT
4
0.610
4.110
0.000
Publikasi
Tahun pub-
likasi
2015-2023
1
0.781
3.590
0.000
2.170
1
0.341
Tipe Pub-
likasi
Jurnal
20
1.040
4.171
0.000
3.720
1
0.230
Prosiding
4
1.610
3.230
0.000
Berdasarkan Tabel 4. Menunjukan bahwa tingkat pendidikan memberikan pengaruh yang
sangat signifikan memepengaruhi heterogenitas pengaruh pembelajaran flipchart terintegrasi
STEM pada siswa. Tingkatan pendidikan mempengaruhi kemampuan berpikir siswa dalam belajar
(Sachdeva, 2021). Hasil dan Diskusi Siswa yang memiliki tingkatan pendidikan yang lebih tinggi akan lebih mudah
dalam merangsang kemampuan berpikir kritis dan hasil belajarnya (Kizilhan, 2022; Santosa et al.,
2021; Maison et al. , 2022). Pembelajaran melalui Flipchart terintegrasi STEM siswa akan lebih mu-
dah memahami materi sehingga mendorong kemampuan berpikir kritisnya. Demir( 2022) menya-
takan penerapan model pembelajaran yang siswa akan lebih mudah untuk berpikir kritis serta me-
meperoleh hasil belajar yang lebih baik. Tabel 4. Hasi analisis Karakteristik sampel dan publikasi
Karakteris-
tik Studi
Kelompok
Nomor
Studi
Hedge’s
g
Null Hypotesis -
Test
Heterogenity
Sampel
Z-value
p-value
Qb
df
p-value
Ukuran sam-
pel
≤ 20 pe-
serta
12
0.412
5.014
0.000
1.041
1
0.240
>20 pe-
serta
5
0.481
2.780
0.000
5.190
3
0.118
Tingkat pen-
didikan
SD
2
0.317
SMP
7
0.267
2.054
0.000
PT
4
0.610
4.110
0.000
Publikasi
Tahun pub-
likasi
2015-2023
1
0.781
3.590
0.000
2.170
1
0.341
Tipe Pub-
likasi
Jurnal
20
1.040
4.171
0.000
3.720
1
0.230
Prosiding
4
1.610
3.230
0.000 Tabel 4. Hasi analisis Karakteristik sampel dan publikasi Tabel 4. Hasi analisis Karakteristik sampel dan publikasi Berdasarkan Tabel 4. Menunjukan bahwa tingkat pendidikan memberikan pengaruh yang
sangat signifikan memepengaruhi heterogenitas pengaruh pembelajaran flipchart terintegrasi
STEM pada siswa. Tingkatan pendidikan mempengaruhi kemampuan berpikir siswa dalam belajar
(Sachdeva, 2021). Siswa yang memiliki tingkatan pendidikan yang lebih tinggi akan lebih mudah
dalam merangsang kemampuan berpikir kritis dan hasil belajarnya (Kizilhan, 2022; Santosa et al.,
2021; Maison et al. , 2022). Pembelajaran melalui Flipchart terintegrasi STEM siswa akan lebih mu-
dah memahami materi sehingga mendorong kemampuan berpikir kritisnya. Demir( 2022) menya-
takan penerapan model pembelajaran yang siswa akan lebih mudah untuk berpikir kritis serta me-
meperoleh hasil belajar yang lebih baik. 100 Pengaruh Flipchart Terintegrasi STEM Terhadap Kemampuan Berpikir kritis dan Hasil Belajar Siswa di Indonesia : Sebuah Meta-Analisis Pembelajaran Flipchart ini sangat efektif untuk diterapkan pada proses pembelajaran di
sekolah. Pembelajaran flipchart terintegrasi STEM membantu meningkatkan literasi sains yang
dapat mendukung kemampuan berpikir kritisnya (Alharbi, 2022; Elmedina et al. 2022; Daga et al.,
2022). Kemampuan berpikri kritis sangat diperlu siswa untuk menyelesaikan berbagai fenomena
yang terjadi dalam kehidupan. Kaya (2022) siswa yang memiliki kemampuan berpikir kritis mampu
mengaplikasikan materi pelajaran dengan lingkunagan belajar. Oleh karena itu, melalui pembelaja-
ran flipchart yang terintegrasi STEM memberikan dampak positif untuk siswa dalam merangsang
kemampuan berpikir kritis dan hasil belajar. Hasil dan Diskusi Siswa yang mempunyai hasil belajar yang baik menjadi
sebuah keberhasil dalam melaksanakan pembelajaran (Öztürk, 2022). Selanjutnya, Pembelajaran
ini membantu siswa untuk memahami teknologi dalam melaksanakan proses belajar mengajar
dalam kelas (Isroani, 202; Yusuf et al., 2020). Kesimpulan Berdasarkan hasil penelitian ini dapat disimpulkan bahwaa. Temuan ini menunjukan nilai
effect size (ES = 0.902) artinya pembelajaran flipchart terintegrasi STEM memberikan pengaruh
positif terhadap kemampuan berpikir kritis dan hasil belajar siswa di Indonesia. Penerapan
pembelajaran flipchart terintegrasi STEM membantu guru dan siswa dalam menigkatkan proses
pembelajaran di sekolah. Pembelajaran melalui flipchart terintegrasi STEM menciptakan suasana
belajar yang menyenangkan bagi siswa. Pembelajaran flipchart siswa lebih mudah untuk
menyapaikan ide-ide yang dimilikinya Arisetya, D. (2019). PENGARUH PEMANFAATAN MEDIA PEMBELAJARAN FLIP CHART TERHADAP
HASIL BELAJAR BIOLOGI SISWA SMP KELAS VIII PADA MATERI SISTEM RANGKA MANUSIA.
Jurnal Pengembangan Ilmu Komunikasi Dan Sosial, 1(1), 12–21. Arisetya, D. (2019). PENGARUH PEMANFAATAN MEDIA PEMBELAJARAN FLIP CHART TERHADAP
HASIL BELAJAR BIOLOGI SISWA SMP KELAS VIII PADA MATERI SISTEM RANGKA MANUSIA. Jurnal Pengembangan Ilmu Komunikasi Dan Sosial, 1(1), 12–21. Arisoy, B., & Aybek, B. (2021). The effects of subject-based critical thinking education in
mathematics on students’ critical thinking skills and virtues*. Eurasian Journal of Educational
Research, 2021(92), 99–120. https://doi.org/10.14689/ejer.2021.92.6 Arisoy, B., & Aybek, B. (2021). The effects of subject-based critical thinking education in
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Negeri 24 Maluku Tengah ). BIODIK: Jurnal Ilmiah Pendidikan Biologi, 7, 95–101. Tamur, M., & Wijaya, T. T. (2021). Using Problem-Based Learning to Enhance Mathematical Abilities
of Primary School Students : A Systematic Review and Meta-Analysis. JTAM (Jurnal Teori Dan
Aplikasi Matematika), 5(1), 144–161. TEMEL, H. (2022). The Effect of Critical Thinking Course Carry Out with Distance Education on
Critical Thinking Skills and Dispositions. Arisetya, D. (2019). PENGARUH PEMANFAATAN MEDIA PEMBELAJARAN FLIP CHART TERHADAP
HASIL BELAJAR BIOLOGI SISWA SMP KELAS VIII PADA MATERI SISTEM RANGKA MANUSIA.
Jurnal Pengembangan Ilmu Komunikasi Dan Sosial, 1(1), 12–21. International Journal of Psychology and Educational
Studies, 9(3), 792–808. https://doi.org/10.52380/ijpes.2022.9.3.894 Tomi Apra Santosa*, Abdul Razak, Azwir Anhar, R. S. (2021). Efektivitas Model Blended Learning
Terhadap Hasil Belajar Mahasiswa Pada Mata Kuliah Zoologi di Era Covid-19. BIODIK: Jurnal
Ilmiah Pendidikan Biologi, 7(1), 77–83. Wahyuni, D. (2021). Developing creativity through STEM education. Journal of Physics: Conference
Series PAPER, 1806, 1–6. https://doi.org/10.1088/1742-6596/1806/1/012211 Waters, C. C., & Orange, A. (2022). STEM-driven school culture : Pillars of a transformative STEM
approach. Journal of Pedagogical Research, 6(2), 72–90. Wilson, C., Campbell-gulley, B., Anthony, H. G., Pérez, M., England, M. P., Wilson, C., Campbell-
gulley, B., Anthony, H. G., Pérez, M., & Meghan, P. (2022). Integrated STEM Education : A
Content Analysis of Three STEM Education Research Journals To cite this article : Integrated
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The World Before Her: A Review
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Feminist dissent
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I’d like to begin at the end. As Nisha Pahuja’s engaging documentary, The World Before Her, winds
down, the protagonists are seen leaving the two spaces that were the
focus of the film. Ruhi Singh, the aspiring Miss India, departs from the
beauty pageant boot camp and competition and flies to her hometown of
Jaipur. Heart broken and sullen after her loss, she walks out of the airport
clouded in loneliness and is met by her father. A few hundred kilometres
away, in another part of the state of Maharashtra, the Hindu nationalist
camp organised for young girls and women by Durga Vahini (The Army of
Durga) also concludes. The young leader of the camp, Prachi Trivedi, slows
down, her resolute and aggressive persona giving way to quiet
contemplation. As she ponders over her future in the Hindutva movement,
the young girls leave the camp amidst loud and prolonged goodbyes. Numbers are exchanged, promises to meet are made, hugs are traded, and
the girls enthusiastically wave to one another as cars take them away from
the camp to their homes. How did a camp organised by an exclusionary nationalist right-wing
movement that was teaching young girls to perpetuate communal
violence and imbibing them with hatred become a space for friendship and
intimacy to flourish? How do we reconcile the politics of those loving long
goodbyes with the politics of violence that the documentary showcased a
mere few frames ago? On the other end, how does a competition that
reduces a group of young women to an indistinguishable collective of
bodies in identical clothing and make-up (so much so that in one scene the
protagonist Ruhi Singh’s parents are unable to locate her in a group photo
of all the Miss India contestants) allow for the emergence of individual
subjectivities and a multiplicity of stories, narratives, and emotions? It is
these kinds of questions, contradictions, and tensions that contain the
brilliance of The World Before Her. Nisha Pahuja’s film not only compels
the viewer to register the details of these two ‘worlds’ available to Indian
women but also allows her to leave the screening with new questions and
unseen answers. Mehta. Feminist Dissent 2016 (1), pp. 139-143 Mehta. Feminist Dissent 2016 (1), pp. 139-143 © Copyright: The
Authors. This article is
issued under the terms of
the Creative Commons
Attribution Non-
Commercial Share Alike
License, which permits
use and redistribution of
the work provided that
the original author and
source are credited, the
work is not used for
commercial purposes and
that any derivative works
are made available under
the same license terms. The film opens with a snapshot of the life of Miss India contestants moving
headlong into preparation for the big competition. Ruhi Singh, a nineteen
year old contestant from Jaipur, appears confident and determined, telling
the camera that she wanted to win the competition to make her parents
proud. Wanting to live a life where she was ‘free’ and able to make her 139 Mehta. Feminist Dissent 2016 (1), pp. 139-143 own choices, she had left her small town in search of opportunities in the
fashion and beauty industry. In particularly poignant scenes we meet her
parents who are fully supportive of her choices, looking out for her
newspaper appearances (and later on, watching the competition on
television) with excitement. At the beauty pageant boot camp, young
women from all over the country are thrown into the world of fitness
training, gym workouts, beauty, hair, and make-up consultants, diction
experts, ramp-walk trainers, fashion designers, and cosmetic surgeons. With an attitude that can be best summarised by the dialogue – “It hurts? It looks fab!”- they are painfully sculpted into identical bodies that must
give perfunctory answers with the perfect intonation. But as the film draws
deeper into life at the boot-camp, the viewer gets glimpses into the
multiple stories – full of vulnerability, insecurities, and strength – behind
their flawless exteriors. Ruhi, plagued by anxiety about the competition,
sits on the balcony crying and calling her parents for reassurance. Ankita,
hesitant to wear a bikini in public, wonders how far she is willing to go to
get the crown. Pooja, the former Miss India, narrates the heart-breaking
story of her father and his family rejecting her at birth because of her sex. Another contestant speaks of how her father sent her to live in a Buddhist
monastery when she was very young. Although her story drew astonished
laughs from the audience, it connects to the rest in similar ways. These
young women were in search of forms of independence, freedom, choice,
and equality in a country that they often saw as suffocating and limiting. As they navigated the beauty industry in carefully crafted and instrumental
ways, they were also simultaneously reduced to subjects of patriarchy and
neoliberalism that capitalised on their bodies and dehumanised them
regularly. In what seems like a world away, we meet Prachi Trivedi, a young member
and teacher of the Hindu nationalist women’s organisation Durga Vahini
(The Army of Durga). Established in the early 1990s the organisation
adheres to the larger right-wing Hindu nationalist ideology, embracing the
idea of a Bharat (India) where Hindus are given an elevated status and
minority groups such as Muslims and Christians are excluded and
suppressed. Key to organising and running a residential training camp for
young girls held at a local school, Prachi tells the viewer of her long
involvement in the movement, voicing her hatred for ”weak figures like
Gandhi” and her espousal of violence for the benefit of the nation. The
camp, a part of a carefully crafted system of similar gatherings at various
levels (national, regional, district, and local), aims to impart intellectual,
spiritual, and physical education to girls (between the ages of 18 and 35)
to transform them into strong and moral members of the Hindutva
movement. Through Pahuja’s coverage of the camp we see the nuances
and aesthetics of the daily rituals and everyday politics of this gendered
Hindu nationalist space. The trainees are made to wake up early and
partake in rigorous exercises and prayers in the school ground as the
saffron nationalist flag sways with the wind and a photograph of Bharat
Mata (the Mother Goddess represented cartographically on a map of the 140 Mehta. Feminist Dissent 2016 (1), pp. 139-143 subcontinent) glistens in front of them. They then take lessons on various
topics – from their spiritual duties as daughters and wives-to-be to
morality and mythology to holding guns and learning martial arts. Scholars
such as Yuval-Davis (1997) have elaborated in depth on the intersections
of gender and nationalism. Women are not only the reproducers and
symbolic markers of nations and nationalisms but are also the imparters
of moral and family values these movements espouse. As the
documentary unfolds its scenes of pedagogical practices and strategies of
this Hindu nationalist women’s organisation, the aforementioned
arguments of feminist scholars come alive. However, looking at the
strategic and laborious formulation of the training programmes (as well as
the inclusion of physical training, warrior goddesses, ‘feminised’ histories
and aesthetics, and even career counselling for the girls), the film also
compels the viewer to ask – are the teachers in the camp merely holding
on to their ‘natural’ roles of mothers/educators or are they challenging
these assigned roles and male-dominated discourses and reshaping
Hindutva? Is there space for gendered (or even feminist) dissent within the
Hindu nationalist project? Although we hear from some of the members of this camp (including a
young girl who takes great pride in not having any Muslim friends) and
witness their blossoming friendships, Prachi shines as the protagonist tying
the scenes from the Hindu nationalist camp together. Strong and
confident, at a point in the film she looks into the camera and utters that
she would kill for Hindutva and harm anyone that goes against her nation. But alongside her tough exterior that screams at and terrifies the girls in
the camp and learns to fight with aggression, the film portrays the
contradictions and gendered conundrums that occupy her mind. Prachi’s
father, a staunch and easily dislikeable patriarch who takes great pride at
telling the viewers that he has used physical punishments to discipline his
precious daughter, wants her to get married and have a family. Prachi,
wanting to devote her life to Hindutva and the Hindu nation, longs for
freedom and wants to achieve it by fighting for a belief system and
ideology that is entrenched in patriarchy. Prachi goes through the film
jokingly shutting down her father’s aspirations for her while being visibly
anxious and teary about these expectations. Perplexed by gendered
norms, in a delightfully queer moment in the film, she laments that she is
neither a girl nor a boy and she simply does not know how to be either. Her personal tensions and contradictions pointing to political ones for the
movement itself. While these ‘two worlds’ seem disconnected at first, the documentary’s
juxtaposition of them draws unnerving and interesting parallels. On an
interview in a green rural Maharashtra, Prachi Trivedi tells the viewers that
she is alright with her father hitting her as “he let her live” in spite of her
being a girl child. A few scenes apart, the mother of former Miss India
Pooja Sharma, tearfully speaks of giving birth to Pooja, a girl, and being
asked to kill the baby by her husband and in-laws. Refusing to commit 141 Mehta. Feminist Dissent 2016 (1), pp. 139-143 infanticide, she leaves her husband, raising her daughter alone. The
undertone of patriarchal control (in personal, public, and political spheres)
connect the two stories in concrete ways forcing the viewer to ask – how
different are these worlds really? The embodied nature of this control in
the two spaces further solidifies this connection. As women in the Hindu
nationalist camp train their bodies in preparation for self-defence,
reducing themselves to exercise counts and objects of martial arts
manoeuvres, in a particularly dehumanising scene, women in the Miss
India boot-camp walk down a beach, their faces and bodies covered with
white cloths, only their legs visible as objects of the shoot. Women’s
bodies in both these worlds are rendered sites of control and
objectification but as these bodies train for larger goals (Hindutva or Miss
India), do they also become sites of subversion, agency, and bargains? Alongside patriarchy, the film also (mildly) engages with neoliberalism as
a force that is re-shaping the lives of Indian women. The Hindutva
movement embraces neoliberalism in the name of ‘development’ and the
movement’s women are now being trained to build respectable careers
alongside becoming wives and mothers. Their aspirations (voiced by Prachi
in particular) resonating sometimes with the latte-sipping Miss India
contestants that embrace globalisation and cosmopolitanism with ease. Finally, in both these spaces, the viewer can locate the numerous everyday
bargains and negotiations with patriarchy that these women undertake to
find their space in an India that has room for many worlds. (Kandiyoti,
1988) Bargains that allow them agency and even partial empowerment in
systems that were built on patriarchy. But how far will these negotiations
and bargains take them in their quest for freedom? What shape does this
freedom take? As Miss India contestants glide on stage with their sashes, dresses, and
high-heels, exhibiting the results of their beauty and fitness regimes and
answering mundane (and often ridiculous) questions with poise; Pahuja
takes us back to the Hindu Nationalist camp. The young girls get dressed
in white outfits with saffron sashes, ready to participate in a public parade
of their training. They joke that the sashes make them feel like beauty
pageant contestants. They walk through the city’s streets, holding
banners, beating drums, showing off their swords and guns, singing and
shouting slogans, and marking their gendered nationalist space in the
public domain. Both these parades while focusing on the women of the
film, show the viewer glimpses of the audiences. And it is in these glimpses
of those excluded from a film about Indian women that one can ask the
final questions – What other worlds exist for Indian women? How do they
overlap and how do we represent them in their entire complexity and
depth? References 142 Dissent 2016 (1), pp. 139-143
Kandiyoti, D. (1988) Bargaining with Patriarchy. Gender and Society, Vol.2
(3): 274-290. Yuval-Davis, N. (1997) Gender and Nation. London: Sage. To cite this article:
Mehta, Akanksha. (2016). The World Before Her: A Review. Feminist Dissent,
(1), 139-143. Retrieved from:
http://journals.warwick.ac.uk/index.php/feministdissent/article/view/16 Mehta. Feminist Dissent 2016 (1), pp. 139-143 Dissent 2016 (1), pp. 139 143
Kandiyoti, D. (1988) Bargaining with Patriarchy. Gender and Society, Vol.2
(3): 274-290. Yuval-Davis, N. (1997) Gender and Nation. London: Sage. To cite this article:
Mehta Akanksha (2016) The World Before Her: A Review Feminist Dissent Kandiyoti, D. (1988) Bargaining with Patriarchy. Gender and Society, Vol.2
(3): 274-290. Yuval-Davis, N. (1997) Gender and Nation. London: Sage. To cite this article: Mehta, Akanksha. (2016). The World Before Her: A Review. Feminist Dissent,
(1), 139-143. Retrieved from:
http://journals.warwick.ac.uk/index.php/feministdissent/article/view/16 143
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Predictors of temporary epicardial pacing wires use after valve surgery
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Journal of cardiothoracic surgery
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cc-by
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© 2014 AlWaqfi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated. RESEARCH ARTICLE Open Access AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 Abstract Background: Although temporary cardiac pacing is infrequently needed, temporary epicardial pacing wires are
routinely inserted after valve surgery. As they are associated with infrequent, but life threatening complications, and
the decreased need for postoperative pacing in a group of low risk patients; this study aims to identify the
predictors of temporary cardiac pacing after valve surgery. Methods: A retrospective analysis of data collected prospectively on 400 consecutive valve surgery patients
between May 2002 and December 2012 was performed. Patients were grouped according to avoidance or insertion
of temporary pacing wires, and were further subdivided according to temporary cardiac pacing need. Multiple
logistic regression was used to determine the predictors of temporary cardiac pacing. Results: 170 (42.5%) patients did not have insertion of temporary pacing wires and none of them needed
temporary pacing. 230 (57.5%) patients had insertion of temporary pacing wires and among these, only 55 (23.9%)
required temporary pacing who were compared with the remaining 175 (76.1%) patients in the main analysis. The
determinants of temporary cardiac pacing (adjusted odds ratios; 95% confidence interval) were as follows: increased
age (1.1; 1.1, 1.3, p = 0.002), New York Heart Association class III- IV (5.6; 1.6, 20.2, p = 0.008) , pulmonary artery
pressure ≥50 mmHg (22.0; 3.4, 142.7, p = 0.01), digoxin use (8.0; 1.3, 48.8, p = 0.024), multiple valve surgery (13.5;
1.5, 124.0, p = 0.021), aorta cross clamp time ≥60 minutes (7.8; 1.6, 37.2, p = 0.010), and valve annulus calcification
(7.9; 2.0, 31.7, p = 0.003). Conclusion: Although limited by sample size, the present results suggest that routine use of temporary epicardial
pacing wires after valve surgery is only necessary for high risk patients. Preoperative identification and aggressive
management of predictors of temporary cardiac pacing and the possible modulation of intraoperative techniques
can decrease the need of temporary cardiac pacing. Prospective randomized controlled studies on a larger number
of patients are necessary to draw solid conclusions regarding the selective use of temporary epicardial pacing wires
in valve surgery. Keywords: Pacing heart, Temporary pacing, Heart valves [4]. The use of PWs is associated with increased re-
source utilization and infrequent, but life threatening
complications including hemorrhage, cardiac tamponade,
serious arrhythmias, and death. Also the retention of PWs
after cardiac surgery is not necessarily safe and may cause
serious complications [5-11]. Predictors of temporary epicardial pacing wires
use after valve surgery Nizar R AlWaqfi1*, Khaled S Ibrahim1, Yousef S Khader2 and Ahmad Abu Baker3 * Correspondence: nizarwaqfi@hotmail.com
1Department of General Surgery, Jordan University of Science and
Technology and King Abdullah University Hospital, Princess Muna Heart
Center, Floor 8 C, Po Box 630001, Irbid 22110, Jordan
Full list of author information is available at the end of the article Methods
Patients This study is a retrospective review of the clinical, opera-
tive, and outcome data that is part of the prospectively
recorded cardiac intensive care unit (CICU) database. We
excluded patients who underwent redo valve surgery due
to their small number and patients with preoperative
high degree atrioventricular block (AVB). A total of
400 patients, 18 years or older underwent valve surgery at
King Abdullah University Hospital (KAUH), Jordan be-
tween May, 2002 and December, 2012, was included in
the analysis. Background Starting 1960s, temporary epicardial pacing wires (PWs)
were routinely placed in all cardiac operations for thera-
peutic as well as diagnostic purposes [1,2]. They remain
in place anywhere from 24 hours to several days postop-
eratively and are used to maintain heart rate and rhythm
which are necessary to optimize haemodynamics [3] and
to suppress both atrial and ventricular tachyarrhythmias The available data supports the use of PWs for selec-
ted cases after coronary artery bypass grafting (CABG)
surgery [5,6]. However, PWs are routinely inserted after
valve and congenital heart surgeries promoted by histo-
rical evidence of increased need for temporary cardiac
pacing (TCP) in such surgeries [12-14]. Recent limited * Correspondence: nizarwaqfi@hotmail.com
1Department of General Surgery, Jordan University of Science and
Technology and King Abdullah University Hospital, Princess Muna Heart
Center, Floor 8 C, Po Box 630001, Irbid 22110, Jordan
Full list of author information is available at the end of the article AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 Page 2 of 7 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 by hypokalemic cold crystalloid antegrade cardioplegia
(10-12 ml/kg) at a rate of 200 – 250 ml/min, in addition
to 300 ml repeated every 10 to 15 minutes. In aortic valve
surgery an extra half dose of cardioplegia was given dir-
ectly into the coronary ostia. Patients were cooled down
to 28-32°C. Cold saline was used to cool surface of the
heart. Valve annulus debridement of calcium was done
usually in a blunt fashion. Patients were evaluated on an
individual basis to determine if TCP is required. Patients
who received PWs had ventricular wires on the anterior
surface of the right ventricle. Atrial wires were additionally
placed when AVB occurred after separation from CPB. After surgery all patients were transferred to CICU on
mechanical ventilation. Continuous ECG monitoring was
used in all patients. 12-lead ECG was performed for all pa-
tients upon CICU admission and daily till discharge from
hospital. publications suggest a trend towards selective use [15,16]. Ferrari et al. [15] reported TCP in 17% of their valve sur-
gery cases and Gupta et al. [16] in 30% of their congenital
heart surgery cases. The aim of this study was to determine the predictors
of TCP in valve surgery with the potential to regulate
PWs insertion at our center. Statistical analysis Statistical analysis was carried out using Statistical Pack-
age for Social Sciences (SPSS, version 15). Descriptive sta-
tistics were obtained, such as mean values for continuous
variables and proportions for categorical variables. The re-
lationships between pacing and possible predictors were
analyzed using Chi square test. Multiple logistic regres-
sion was used to determine the predictors of pacing in
the multivariate analysis. Only factors that were shown
to be significant predictors remained in the final regres-
sion model. A P-value ≤0.05 was considered statistically
significant. Lately, it is our clinical practice, and upon surgeon’s
discretion based on patient’s individual characteristics to
selectively insert PWs in valve surgery patients. According to insertion or avoidance of PWs, two groups
of patients were identified: group 1; did not have PWs
inserted and never needed to be paced and group 2; had
PWs inserted. Group 2 was subdivided into patients who
needed TCP and those who did not need TCP. This study
was approved by the ethical committee at KAUH. Results The need for postoperative TCP (if patients were paced
at the time of chest closure or at any time before hos-
pital discharge) was the outcome variable of interest. We
identified the demographic, clinical, preoperative (inclu-
ding drugs directly affecting the conduction system), and
intraoperative variables (including type of valve surgery)
as potential predictors of TCP (Table 1). Preoperative ar-
rhythmias were defined as atrial fibrillation (AF), low
grade AVB, or a bundle branch block diagnosed by elec-
trocardiogram (ECG). Type of valve surgery was sub-
divided into; mitral valve, aortic valve, multiple valve
(double or triple), and valve with CABG surgeries. There
were no cases of only-tricuspid valve surgery, but part of
a combined procedure. A total of 400 consecutive patients underwent valve sur-
gery with ages ranging from 18 to 80 years with mean
age (standard deviation- SD) of 51.81 (13.71) years. Group 1 consisted of 170 (42.5%) patients with mean
age (SD) of 44.25 (12.85) years. No patient in group1 re-
quired pacing by any means nor suffered any complica-
tion attributed to avoidance of PWs. Group 2 consisted
of 230 (57.5%) patients with mean age (SD) of 57.39
(11.49) years. Table 1 shows the characteristics of both
groups with p-values. Among patients in group 2, only
55 (23.9%) needed TCP (mean age (SD) = 62.27 (10.87)
years) and were compared with the remaining 175 (76.1%)
patients (mean age (SD) = 55.86 (11.27) years) who did
not need TCP. 12-lead ECG was used to diagnose conduc-
tion disturbances. The primary reasons for pacing in-
cluded AVB of any degree in 25 (45.5%) patients, nodal or
junctional rhythms in 8 (14.6%) patients, low cardiac out-
put in 13 (23.6%) patients, sinus bradycardia in 5 (9.1%)
patients, and asystole in 4 (7.2%) patients. In no case were
PWs used for diagnostic purposes, rapid atrial pacing, or
left ventricular pacing. PWs were left in place for a mini-
mum of 3 days. The mean (SD) duration of pacing was Operative technique All patients had median sternotomy. In mitral valve
surgery, cardiopulmonary bypass (CPB) was established
between the ascending aorta and bicaval venous cannula-
tion. Mitral valve was approached through a conventional
left lateral atriotomy. Perfusion was maintained at 2.0 to
2.4 L/min/m2, and systemic perfusion pressure was kept
at 60 - 80 mmHg. Myocardial protection was achieved AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 AlWaqfi et al. Operative technique Table 1 Characteristics of total patients and by group
according to demographic, preoperative, and
intraoperative dataa (Continued) 53.12 (31.81) hours; the median was 12.5 hours. Only 5
(9.1%) of the 55 patients who needed TCP, had implant-
ation of permanent pacemaker, accounting for 1.25% of
the cohort analyzed. The average time from surgery to im-
plantation of permanent pacemaker was 65.33 hours. Table 2 shows the univariate analysis of demographic,
clinical, and preoperative characteristics of patients in
group 2, in relation to TCP. The use of TCP differed sig-
nificantly according to patients’ age, diabetes mellitus,
left ventricular ejection fraction (EF), New York Heart
Association (NYHA) status, pulmonary artery pressure
(PAP), and being on amiodarone. Patients on beta bloc-
kers were significantly less likely to need TCP. Table 3 shows the univariate analysis of intraoperative
variables in relation to TCP. When analyzed by type of
surgery; 10% of patients who underwent mitral valve,
13.9% who underwent aortic valve, 34.8% who under-
went valve with CABG, and 44.2% who underwent mul-
tiple valve surgeries needed TCP. Table 4 shows the predictors of TCP in the multivari-
ate analysis. Increased age by 1 year was associated with
increased odds of TCP by 10%. Those who underwent
multiple valve surgery were significantly more likely to
need TCP compared to patients who underwent single
valve surgery. Operative technique Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 Page 3 of 7 Table 1 Characteristics of total patients and by group
according to demographic, preoperative, and
intraoperative dataa
Variable
Total
Group 1
Group 2
p-value
(n = 400)
(n = 170)
(n = 230)
Age (year)
< 0.005
< 40
78 (19.5)
62 (79.5)
16 (20.5)
40 – 59
187 (46.8)
88 (47.1)
99 (52.9)
≥60
135 (33.7)
20 (14.8)
115 (85.2)
Sex
0.141
Female
177 (44.3)
68 (38.4)
109 (61.6)
Male
223 (55.7)
102 (45.7)
121 (54.3)
Renal failure
(Creatinine ≥1.5 mg/dl)
29 (7.3)
8 (27.6)
21 (72.4)
0.092
Diabetes mellitus
80 (20)
19 (23.7)
61 (76.3)
< 0.005
COPD
49 (12.3)
29 (59.2)
20 (40.8)
0.012
History of arrhythmia
43 (10.8)
3 (7)
40 (93)
< 0.005
NYHA Class
0.027
I – II
280 (70)
129 (46.1)
151 (53.9)
III – IV
120 (30)
41 (34.2)
79 (65.8)
Left ventricle ejection
fraction (%)
0.006
> 35
259 (64.5)
123 (47.5)
136 (52.5)
≤35
141 (35.5)
47 (33.3)
94 (66.7)
PAP (mmHg)
0.043
< 50
360 (90)
159 (44.2)
201 (55.8)
≥50
40 (10)
11 (27.5)
29 (72.5)
Preoperative medications
< 0.005
Beta blockers
107 (26.8)
45 (42.1)
62 (57.9)
Digoxin
42 (10.5)
19 (55.2)
23 (54.8)
Amiodarone
18 (4.5)
2 (11.1)
16 (88.9)
Left atrium diameter (mm)
0.876
< 5.2
347 (86.7)
148 (42.7)
199 (57.3)
≥5.2
53 (13.3)
22 (41.5)
31 (58.5)
Type of surgery
< 0.005
Mitral valve
140 (35)
80 (57.1)
60 (42.9)
Aortic valve
129(32.3)
57 (44.2)
72 (55.8)
Multiple valve
73 (18.2)
21 (28.8)
52 (71.2)
Valve with coronary
artery bypass
58 (14.5)
12 (20.7)
46 (79.3)
Valve annulus calcification
70 (17.5)
17 (24.3)
53 (75.7)
< 0.005
Cardiopulmonary bypass
time (minute)
< 0.005
< 100
317 (79.3)
157 (49.5)
160 (50.5)
≥100
83 (20.7)
13 (15.7)
70 (84.3) Table 1 Characteristics of total patients and by group
according to demographic, preoperative, and
intraoperative dataa Table 1 Characteristics of total patients and by group
according to demographic, preoperative, and
intraoperative dataa (Continued)
Aorta cross clamp time
(minute)
< 0.005
< 60
318 (79.5)
160 (50.3)
158 (49.7)
≥60
82 (20.5)
10 (12.2)
72 (87.8)
Intraoperative bradycardia
101 (25.3)
46 (45.5)
55 (54.5)
0.474
a Data are given as no. (%). COPD = chronic obstructive pulmonary disease; NYHA = New York Heart
Association; PAP = pulmonary artery pressure; PW = temporary epicardial
pacing wires. Discussion Historically, PWs have been routinely used after cardiac
operations to optimize cardiac function and to suppress
both atrial and ventricular tachyarrhythmias [4]. How-
ever, their use is not innocuous and associated with in-
frequent but lethal complications. Insertion can prolong
the operative time and increase the risk of bleeding. Their extended use can result in failure of sensing or
capturing [17]. During removal, patients are at risk of
ventricular arrhythmias [18] and to a lesser extent bleed-
ing due to injury of nearby structures [19-21]. Also re-
tention of PWs may be complicated by deep seated
infections or migration to different structures in the
chest [7-9,22,23]. Page 4 of 7 Page 4 of 7 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 During the last decade, routine insertion of PWs in
CABG surgery, being on-pump or a beating heart, has
been well studied and many centers turned to limit their
use [5,6,24]. We already comply with these policies. In
valvular and pediatric surgeries there is a historical evi-
dence of routine use of PWs due to the increased risk of
Table 2 Univariate analysis (group 2) for use of
temporary pacing according to demographic, and
preoperative variablesa
Variable
Temporary
cardiac pacing
No
Yes
p-value
Age (year)
0.013
< 40
13 (81.3)
3 (18.8)
40–59
84 (84.8)
15 (15.20)
≥60
78 (67.8)
37 (32.2)
Sex
Female
79 (72.5)
30 (27.5)
0.223
Male
96 (79.3)
25 (20.7)
Renal failure (creatinine > 1.5 mg/dl)
0.991
No
159 (76.1)
50 (23.9)
Yes
16 (76.2)
5 (23.8)
Diabetes mellitus
0.001
No
119 (70.4)
50 (29.6)
Yes
56 (91.8)
5 (8.2)
COPD
0.504
No
161 (76.7)
49 (23.3)
Yes
14 (70.0)
6 (30.0)
History of arrhythmia
0.818
No
144 (75.8)
46 (24.2)
Yes
31 (77.5)
9 (22.5)
NYHA class
0.000
I-II
136 (90.1)
15 (9.9)
III-IV
39 (49.4)
40 (50.6)
Left Ventricle ejection fraction (%)
0.001
> 35
114 (83.8)
22 (16.2)
≤35
61 (64.9)
33 (35.1)
PAP (mmHg)
0.000
< 50
171 (85.1)
30 (14.9)
≥50
4 (13.8)
25 (86.2)
Left atrium diameter (mm)
0.104
< 5.2
155 (77.9)
44 (22.1)
≥5.2
20 (64.5)
11 (35.5)
Beta blockers
0.002
No
119 (70.8)
49 (29.2)
Yes
56 (90.3)
6 (9.70)
Digoxin
0.440
No
159 (76.8)
48 (23.2)
Yes
16 (69.6)
7 (30.4)
Amiodarone
0.011
No
167 (78.0)
47 (22.0)
Yes
8 (50.0)
8 (50.0)
aData are given as no. (%). Discussion D
CA
be
us
va
de
Table 2 Univariate analysis (group 2) for use of
temporary pacing according to demographic, and
preoperative variablesa
Variable
Temporary
cardiac pacing
No
Yes
p-value
Age (year)
0.013
< 40
13 (81.3)
3 (18.8)
40–59
84 (84.8)
15 (15.20)
≥60
78 (67.8)
37 (32.2)
Sex
Female
79 (72.5)
30 (27.5)
0.223
Male
96 (79.3)
25 (20.7)
Renal failure (creatinine > 1.5 mg/dl)
0.991
No
159 (76.1)
50 (23.9)
Yes
16 (76.2)
5 (23.8)
Diabetes mellitus
0.001
No
119 (70.4)
50 (29.6)
Yes
56 (91.8)
5 (8.2)
COPD
0.504
No
161 (76.7)
49 (23.3)
Yes
14 (70.0)
6 (30.0)
History of arrhythmia
0.818
No
144 (75.8)
46 (24.2)
Yes
31 (77.5)
9 (22.5)
NYHA class
0.000
I-II
136 (90.1)
15 (9.9)
III-IV
39 (49.4)
40 (50.6)
Left Ventricle ejection fraction (%)
0.001
> 35
114 (83.8)
22 (16.2)
≤35
61 (64.9)
33 (35.1)
PAP (mmHg)
0.000
< 50
171 (85.1)
30 (14.9)
≥50
4 (13.8)
25 (86.2)
Left atrium diameter (mm)
0.104
< 5.2
155 (77.9)
44 (22.1)
≥5.2
20 (64.5)
11 (35.5)
Beta blockers
0.002
No
119 (70.8)
49 (29.2)
Yes
56 (90.3)
6 (9.70)
Digoxin
0.440
No
159 (76.8)
48 (23.2)
Yes
16 (69.6)
7 (30.4)
Amiodarone
0.011
No
167 (78.0)
47 (22.0)
Yes
8 (50.0)
8 (50.0)
aData are given as no. (%). COPD = chronic obstructive pulmonary disease; NYHA = New York Heart
Association; PAP =pulmonary artery pressure. Ta
tem
int
Va
Typ
An
Car
Ao
Bra
aDa
Ta
tem
Va
Ag
NY
PA
Pre
Typ
Ao
60
Val
NY Table 2 Univariate analysis (group 2) for use of
temporary pacing according to demographic, and
preoperative variablesa During the last decade, routine insertion of PWs in
CABG surgery, being on-pump or a beating heart, has
been well studied and many centers turned to limit their
use [5,6,24]. We already comply with these policies. Discussion COPD = chronic obstructive pulmonary disease; NYHA = New York Heart
Association; PAP =pulmonary artery pressure. Table 3 Univariate analysis (group 2) for use of
temporary pacing according to procedure and
intraoperative variablesa
Variable
Temporary
cardiac pacing
No
Yes
p-value
Type of surgery
0.000
Mitral valve
54 (90.0)
6 (10.0)
Aortic valve
62 (86.1)
10 (13.9)
Multiple valve
29 (55.8)
23 (44.2)
Valve with coronary artery bypass
30 (65.2)
16 (34.8)
Annulus Calcification
0.000
No
154 (87.0)
23 (13.0)
Yes
21 (39.6)
32 (60.4)
Cardiopulmonary bypass time (minute)
0.000
< 100
140 (87.5)
20 (12.5)
≥100
35 (50.0)
35 (50.0)
Aorta cross clamp time (minute)
0.000
< 60
143 (90.5)
15 (9.5)
≥60
32 (44.4)
40 (55.6)
Bradycardia
0.003
No
125 (71.4)
50 (28.6)
Yes
50 (90.9)
5 (9.1)
aData are given as no. (%). Table 4 Multivariate analysis of factors associated with
temporary cardiac pacing
Variable
Odds
ratio (OR)
95% confidence
interval (CI)
P-value
Age
1.1
(1.1, 1.3)
0.002
NYHA class (III- IV)
5.6
(1.6, 20.2)
0.008
PAP ≥50 mmHg
22.0
(3.4, 142.7)
0.001
Preoperative digoxin use
8.0
(1.3, 48.8)
0.024
Type of surgery
Mitral valve
1.0
Aortic valve
2.2
(0.3, 14.7)
0.431
Multiple valve
13.5
(1.5, 124.0)
0.021
Valve with coronary artery
bypass
3.6
(0.4, 30.7)
0.242
Aorta cross clamp time ≥
60 min
7.8
(1.6, 37.2)
0.010
Valve annulus calcification
7.9
(2.0, 31.7)
0.003
NYHA = New York Heart Association; PAP = pulmonary artery pressure. Discussion In
valvular and pediatric surgeries there is a historical evi-
dence of routine use of PWs due to the increased risk of Table 4 Multivariate analysis of factors associated with
temporary cardiac pacing
Variable
Odds
ratio (OR)
95% confidence
interval (CI)
P-value
Age
1.1
(1.1, 1.3)
0.002
NYHA class (III- IV)
5.6
(1.6, 20.2)
0.008
PAP ≥50 mmHg
22.0
(3.4, 142.7)
0.001
Preoperative digoxin use
8.0
(1.3, 48.8)
0.024
Type of surgery
Mitral valve
1.0
Aortic valve
2.2
(0.3, 14.7)
0.431
Multiple valve
13.5
(1.5, 124.0)
0.021
Valve with coronary artery
bypass
3.6
(0.4, 30.7)
0.242
Aorta cross clamp time ≥
60 min
7.8
(1.6, 37.2)
0.010
Valve annulus calcification
7.9
(2.0, 31.7)
0.003
NYHA = New York Heart Association; PAP = pulmonary artery pressure. Table 4 Multivariate analysis of factors associated with
temporary cardiac pacing AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 Page 5 of 7 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 Page 5 of 7 AVB [12]. However, these recommendations are decades
old and may not reflect modern surgical techniques and
practice. Recent few reports studied the rate and the
predictors of TCP after valvular and pediatric cardiac
surgeries [15,16,25]. At our center, to avoid the above
mentioned complications and in accordance with the
published literature, and it is upon surgeon’s discretion
to safely select patients, we limited the insertion of PWs
in valve surgery (usually based on; young age with min-
imal comorbidities, uncomplicated single valve surgery,
not involving extensive decalcification, and after separ-
ation from CPB in sinus rhythm, and hemodynamically
stable on minimal support, including recently, patients
in sinus bradycardia who responds to minimal doses of
beta-adrenergic drugs) (Table 1). it acts on the right ventricular dimensions and shape,
and interventricular septal thickness imposing progres-
sive mechanical stretch that could affect the conduction
system by altering the electrophysiological properties of
its fibers. Preoperative use of digoxin and beta-blockers are pos-
tulated as predictors of postoperative conduction dis-
turbance [14,31], especially of those with the block nature. In a recent study on patients after mitral valve surgery by
Berdjas et al. [14], both digoxin and beta blockers, were
found to significantly lower the risk of conduction distur-
bances. In our study, only digoxin was a predictor of TCP. Discussion Digoxin’s primary mechanism of action is to increase the
force of myocardial contractility in failing hearts by in-
creasing the intracellular calcium concentration. However,
its vagomimetic effect decreases sinoatrial and atrioven-
tricular conduction and prolongs atrioventricular node re-
fractory period, thus increasing the need for TCP [32]. Also digoxin has, even at therapeutic levels, an arrhyth-
mogenic effect on ischemic hearts [33], which may include
periods of prolonged crossclamping time. The need for TCP was mainly based on the presence
of a mechanical injury to the conduction system caused
by operative procedures in close physical proximity to
the atrioventricular node or the His bundle, or an is-
chemic injury to the conduction system resulting during
cardioplegic arrest, especially if associated with extensive
coronary artery disease. Both mechanisms may evoke
preexisting conduction defects or generate new ones. Type of surgical procedure was a determinant of TCP. Patients who had multiple valve surgery and/or debride-
ment of heavy annular calcification at the atrioventricu-
lar sinus area (the posterior commissure of the anterior
mitral leaflet, the commissure between right- and non-
coronary cusps of the aortic valve, and the septal leaflet
of the tricuspid valve) were at an increased risk of phys-
ical injury to the atrioventricular node and conduction
system and were significantly more likely to need TCP
after separation from CPB. Although the need for pacing
in combined valve and CABG surgery was more than in
isolated single valve surgery, this difference did not reach
statistical significance. This might be due to small sample
size of this subgroup. In such patients it may be difficult
to assure adequate and uniform delivery of the cardio-
plegic solution to protect the myocardium leading to new
or further exacerbating existing conduction disturbances. These results coincide with other peer reviews [29,34]. In our study, only 23.9% of valve surgery patients with
PWs insertion needed TCP which led us to reevaluate
the use of PWs and to attempt to identify a subpopula-
tion of valve patients for whom PWs are appropriate. In the current series, patients who had PWs inserted
were almost 10 years older than those who did not, and
those more than 60 years old were, by both univariate
and multivariate analysis, more likely to be paced. Gender was not a predictor of TCP. This is consistent
with other peer reviews [15,26]. Discussion Data in the literature regarding the significance of chro-
nic comorbidities such as chronic renal failure, chronic
obstructive pulmonary disease, diabetes mellitus and pre-
operative arrhythmias as predictors of postoperative pa-
cing are conflicting [14,15,27]. In our study none of the
above mentioned comorbidities were significantly associ-
ated with the need for TCP in the multivariate analysis. Aortic crossclamp time more than 60 minutes, by both
univariate and multivariate analysis, was a predictor of
TCP. This is consistent with other peer reviews [35]. The
occurrence of ischemic injury to the conduction system
and the development of myocardial edema following pro-
longed periods of crossclamping might explain these
findings. Advanced NYHA class was a predictor of TCP in both
univariate and multivariate analysis. Pacing was used in
patients with advanced NYHA class to improve cardiac
output after separation from CPB to achieve hemody-
namic stability. Also, most of them had severe left ven-
tricular dysfunction with increased risk of developing
various conduction disturbances [28]. This finding was
supported by Gordon et al. [29]. On the contrary, ad-
vanced NYHA status was not a predictor of TCP by
Ferrari et al. [15]. In the interpretation of the study findings, we need to
consider that this study is a retrospective analysis with a
relatively limited number of patients done over a long
time; however patients were followed prospectively du-
ring their hospitalization. Although a team of different
surgeons performed the operations with different thre-
shold for postoperative PWs insertion and pacing, all
the patients were treated at a single center, and the Increased PAP was an independent predictor of TCP
by both univariate and multivariate analysis. Limongelli,
et al. [30] reported pulmonary hypertension a risk factor
for postoperative AVB following aortic valve surgery, as Page 6 of 7 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 AlWaqfi et al. Journal of Cardiothoracic Surgery 2014, 9:33
http://www.cardiothoracicsurgery.org/content/9/1/33 operative methods remained substantially unchanged dur-
ing the study. 2. Mills NL, Ochsner JL: Experience with atrial pacemaker wires implanted
during cardiac surgery. J Thorac Cardiovasc Surg 1973, 66:878–886. 3. Hartzler GO, Maloney JD, Curtis JJ, Barnhorst DA: Hemodynamic benefits of
atrioventricular sequential pacing after cardiac surgery. Am J Cardiol
1977, 40:232–236. Competing interests The authors declare that they have neither financial nor non-financial
competing interests. The authors declare that they have neither financial nor non-financial
competing interests. 14. Berdajs D, Schurr UP, Wagner A, Seifert B, Turina MI, Genoni M: Incidence
and pathophysiology of atrioventricular block following mitral valve
replacement and ring annuloplasty. Eur J Cardiothorac Surg 2008, 34:55–61. Authors’ contribution 15. Ferrari AD, Süssenbach CP, Guaragna JC, Piccoli Jda C, Gazzoni GF,
Ferreira DK, Albuquerque LC, Goldani MA: Atrioventricular block in the
postoperative period of heart valve surgery: incidence, risk factors and
hospital evolution. Rev Bras Cir Cardiovasc 2011, 26:364–372. NA participated in clinical practice, contributed to conception, design,
acquisition of data, drafting the manuscript, and revising it critically for
important intellectual content. KI participated in clinical practice, contributed
to design, helped in drafting the manuscript, and revising it critically for
important intellectual content. YK contributed to design, analysis and
interpretation of data, and helped in drafting the manuscript. AA
participated in clinical practice, helped in drafting the manuscript, and
revising it critically for important intellectual content. All authors read and
approved the final manuscript. 16. Gupta P, Jines P, Gossett JM, Maurille M, Hanley FL, Reddy VM, Miyake CY,
Roth SJ: Predictors for use of temporary epicardial pacing wires after
pediatric cardiac surgery. J Thorac Cardiovasc Surg 2012, 144:557–562. 17. Elmi F, Tullo NG, Khalighi K: Natural history and predictors of temporary
epicardial pacemaker wire function in patients after open heart surgery. Cardiology 2002, 98:175–180. 18. Carroll KC, Reeves LM, Andersen G, Ray FM, Clopton PL, Shively M, Tarazi RY:
Risks associated with removal of ventricular epicardial pacing wires after
cardiac surgery. Am J Crit Care 1998, 7:444–449. Author details
1 g
y
g
20. Price C, Keenan DJ: Injury to a saphenous vein graft during removal of a
temporary epicardial pacing wire electrode. Br Heart J 1989, 61:546–547. 1Department of General Surgery, Jordan University of Science and
Technology and King Abdullah University Hospital, Princess Muna Heart
Center, Floor 8 C, Po Box 630001, Irbid 22110, Jordan. 2Department of Public
Health, Community Medicine, and Family Medicine, Jordan University of
Science and Technology and King Abdullah University Hospital, Po Box
630001, Irbid 22110, Jordan. 3Princess Muna Heart Center, Department of
Anesthesia, Jordan University of Science and Technology and King Abdullah
University Hospital, Po Box 630001, Irbid 22110, Jordan. 21. Matsushita T, Fuse H, Takeuchi K, Masuda S, Inoue T: Aortic bleeding One
week after removal of an intraoperative epicardial temporary pacing
wire. Ann Thorac Cardiovasc Surg 2013, 19:231–233. 22. Benson CC, Valentine AM, Economy KE, Hoffman-Sage Y, Bevilacqua LM,
Podovei M, Opotowsky AR: Discovery and management of diaphragmatic
hernia related to abandoned epicardial pacemaker wires in a pregnant
women with S, L, L transposition of the great arteries. Congenit Heart Dis
2012, 7:183–188. Received: 19 September 2013 Accepted: 5 February 2014
Published: 12 February 2014 23. Cohen SB, Bartz PJ, Earing MG, Sheil A, Nicolosi A, Woods RK: Myocardial
infarction due to a retained epicardial pacing wire. Ann Thorac Surg 2012,
94:1724–1726. Acknowledgments
W
ld lik t
th We would like to thank Dr. Motasem Abuelreish for his help in revising and
editing the manuscript. We would like to thank Dr. Motasem Abuelreish for his help in revising and
editing the manuscript. 19. Del Nido P, Goldman BS: Temporary epicardial pacing after open heart
surgery: complications and prevention. J Card Surg 1989, 4:99–103. 19. Del Nido P, Goldman BS: Temporary epicardial pacing after open heart
surgery: complications and prevention. J Card Surg 1989, 4:99–103. 20. Price C, Keenan DJ: Injury to a saphenous vein graft during removal of a
temporary epicardial pacing wire electrode. Br Heart J 1989, 61:546–547. Abbreviations
PW
T PWs: Temporary epicardial pacing wires; CABG: Coronary artery bypass
grafting; TCP: Temporary cardiac pacing; CICU: Cardiac intensive care unit;
KAUH: King Abdullah University Hospital; AVB: Atrioventricular block;
AF: Atrial fibrillation; ECG: Electrocardiogram; CPB: Cardiopulmonary bypass;
SD: Standard deviation; EF: Left ventricular ejection fraction; NYHA: New York
Heart Association; PAP: Pulmonary artery pressure. 12. Waldo AL, MacLean WA, Cooper TB, Kouchoukos NT, Karp RB: Use of
temporarily placed epicardial atrial wire electrodes for the diagnosis and
treatment of cardiac arrhythmias following open-heart surgery. J Thorac
Cardiovasc Surg 1978, 76:500–505. 13. Ceresnak SR, Pass RH, Starc TJ, Hordof AJ, Bonney WJ, Mosca RS,
Liberman L: Predictors for hemodynamic improvement with temporary
pacing after pediatric cardiac surgery. J Thorac Cardiovasc Surg 2011,
141:183–187. Conclusion 4. Archbold RA, Schilling RJ: Atrial pacing for the prevention of atrial
fibrillation after coronary artery bypass graft surgery: a review of the
literature. Heart 2004, 90:129–133. Although limited by sample size, the present results sug-
gest that routine use of PWs after valve surgery is neces-
sary for high risk patients. Predictive factors of TCP after
valve surgery were increased age, NYHA class (III-IV),
PAP ≥50 mmHg, digoxin use, complex surgical proce-
dures (i.e. multiple valve surgery), heavy annular calcifi-
cation, and crossclamp time ≥60 min. Better patients
selection, in addition to optimizing the medical condi-
tion through aggressive treatment of heart failure and
pulmonary hypertension, shortening the cross clamping
and CPB times, and careful debridement of calcified valve
annulus, may lower the need for postoperative pacing in
our practice. Prospective randomized well controlled stud-
ies on a larger number of patients, including quantitative
assessment of valve annular calcium load and distribution,
are necessary to draw solid conclusions on safely selected
patients who do not require postoperative PWs insertion. 5. Puskas JD, Sharoni E, Williams WH, Petersen R, Duke P, Guyton RA: Is
routine use of temporary epicardial pacing wires necessary after either
OPCAB or conventional CABG/CPB? Heart Surg Forum 2003, 6:E103–106. 6. Imren Y, Benson AA, Oktar GL, Chema FH, Comas G, Naseem T: Is use of
temporary pacing wire following coronary artery bypass surgery really
necessary? J Cardiovasc Surg (Torino) 2008, 49:261–7. 7. Kapoor A, Syal S, Gupta N, Gupta A: Right paracardiac mass due to
organized pericardial hematoma around retained epicardial pacing wires
following aortic valve replacement. Interact CardioVasc Thorac Surg 2011,
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After CABG: Complication of retained epicardial pacing wires. Ann Thorac
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unusual complication of a retained epicardial pacing wire. Interact
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Cite this article as: AlWaqfi et al.: Predictors of temporary epicardial
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Evidence of Rapid Modulation by Social Information of Subjective, Physiological, and Neural Responses to Emotional Expressions
|
Frontiers in behavioral neuroscience
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ORIGINAL RESEARCH
published: 09 January 2018
doi: 10.3389/fnbeh.2017.00231 Evidence of Rapid Modulation by
Social Information of Subjective,
Physiological, and Neural Responses
to Emotional Expressions Martial Mermillod 1, 2*, Delphine Grynberg 3, 4, Léo Pio-Lopez 5, Magdalena Rychlowska 5, 6,
Brice Beffara 1, Sylvain Harquel 1, Nicolas Vermeulen 7, 8, Paula M. Niedenthal 9,
Frédéric Dutheil 10, 11 and Sylvie Droit-Volet 5 1 Univ. Grenoble Alpes, CNRS, LPNC, Grenoble, France, 2 Institut Universitaire de France, Paris, France, 3 Univ. Lille, CNRS,
CHU Lille, UMR 9193 - SCALab - Sciences Cognitives et Sciences Affectives, Lille, France, 4 Univ. Lille, Villeneuve d’Ascq,
France, 5 Université Clermont Auvergne, CNRS, LaPSCo, Clermont-Ferrand, France, 6 Queen’s University Belfast, Belfast,
United Kingdom, 7 IPSY, Université Catholique de Louvain, Louvain-la-Neuve, Belgium, 8 Fund for Scientific
Research (FRS-FNRS), Brussels, Belgium, 9 Department of Psychology, University of Wisconsin-Madison, Madison, WI,
United States, 10 Université Clermont Auvergne, Centre National de la Recherche Scientifique, LaPSCo, Stress Physiologique
et Psychosocial, CHU Clermont-Ferrand, Santé Travail Environnement, WittyFit, Clermont-Ferrand, France, 11 Faculty of
Health, School of Exercise Science, Australian Catholic University, Melbourne, VIC, Australia Recent research suggests that conceptual or emotional factors could influence the
perceptual processing of stimuli. In this article, we aimed to evaluate the effect of social
information (positive, negative, or no information related to the character of the target) on
subjective (perceived and felt valence and arousal), physiological (facial mimicry) as well
as on neural (P100 and N170) responses to dynamic emotional facial expressions (EFE)
that varied from neutral to one of the six basic emotions. Across three studies, the results
showed reduced ratings of valence and arousal of EFE associated with incongruent social
information (Study 1), increased electromyographical responses (Study 2), and significant
modulation of P100 and N170 components (Study 3) when EFE were associated with
social (positive and negative) information (vs. no information). These studies revealed that
positive or negative social information reduces subjective responses to incongruent EFE
and produces a similar neural and physiological boost of the early perceptual processing
of EFE irrespective of their congruency. In conclusion, the article suggests that the
presence of positive or negative social context modulates early physiological and neural
activity preceding subsequent behavior. Citation: Mermillod M, Grynberg D,
Pio-Lopez L, Rychlowska M,
Beffara B, Harquel S, Vermeulen N,
Niedenthal PM, Dutheil F and
Droit-Volet S (2018) Evidence of Rapid
Modulation by Social Information of
Subjective, Physiological, and Neural
Responses to Emotional Expressions. Front. Behav. Neurosci. 11:231. doi: 10.3389/fnbeh.2017.00231 Edited by:
Bahar Güntekin,
School of International Medicine,
Istanbul Medipol University, Turkey Reviewed by:
Julieta Ramos-Loyo,
University of Guadalajara, Mexico
Andrea Hildebrandt,
University of Greifswald, Germany Reviewed by:
Julieta Ramos-Loyo,
University of Guadalajara, Mexico
Andrea Hildebrandt,
University of Greifswald, Germany *Correspondence:
Martial Mermillod
martial.mermillod@
univ-grenoble-alpes.fr *Correspondence:
Martial Mermillod
martial.mermillod@
univ-grenoble-alpes.fr *Correspondence:
Martial Mermillod
martial.mermillod@
univ-grenoble-alpes.fr Received: 10 May 2017
Accepted: 07 November 2017
Published: 09 January 2018 Keywords:
emotion,
social
cognition,
electromyography,
electroencephalography,
top-down
processes,
embodiment theory Keywords:
emotion,
social
cognition,
electromyography,
electroencephalography,
top-down
processes,
embodiment theory Mermillod M, Grynberg D,
Pio-Lopez L, Rychlowska M,
Beffara B, Harquel S, Vermeulen N,
Niedenthal PM, Dutheil F and
Droit-Volet S (2018) Evidence of Rapid
Modulation by Social Information of
Subjective, Physiological, and Neural
Responses to Emotional Expressions.
Front. Behav. Neurosci. 11:231.
doi: 10.3389/fnbeh.2017.00231 INTRODUCTION Extant behavioral research suggests the relevance of top-down processes in the use of concepts
(Schyns et al., 1998; Vermeulen et al., 2009), percepts (Bar, 2004; Quétard et al., 2015, 2016), and
affects (Scherer, 1997; Hess et al., 2007; Rudrauf et al., 2008; Niedenthal et al., 2009). For instance,
participants’ personality (e.g., Campanella et al., 2012) or facial expressions (Niedenthal et al., 2009)
modulate the detection or recognition of emotional facial expressions (EFE). In addition, research
has pointed to a modulation of EFE processing by social factors, such as the degree of friendship Extant behavioral research suggests the relevance of top-down processes in the use of concepts
(Schyns et al., 1998; Vermeulen et al., 2009), percepts (Bar, 2004; Quétard et al., 2015, 2016), and
affects (Scherer, 1997; Hess et al., 2007; Rudrauf et al., 2008; Niedenthal et al., 2009). For instance,
participants’ personality (e.g., Campanella et al., 2012) or facial expressions (Niedenthal et al., 2009)
modulate the detection or recognition of emotional facial expressions (EFE). In addition, research
has pointed to a modulation of EFE processing by social factors, such as the degree of friendship January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org Rapid Social Modulation Mermillod et al. between the participant and the target (Hess et al., 1995) or the
social norms of the participants (Scherer, 1997). (Dimberg, 1990; Hess et al., 1995; Barsalou, 1999; Niedenthal,
2007),
which
assumes
that
the
processing
of
emotional
information is grounded in the brain’s perceptual, affective,
and sensory-motor systems. Several studies have shown that
the processing of emotional concepts (e.g., emotional words or
EFE) leads individuals to simulate this concept and re-create
the corresponding bodily experience (Niedenthal et al., 2009). Recent research also suggests that imitation of perceived and
simulated emotions plays a causal role in the recognition of
facial expressions (Künecke et al., 2014). Indeed, preventing
participants from simulating emotional concepts (i.e., blocking
participants’ facial expressions) during EFE recognition task
reduced recognition accuracy (Havas et al., 2010). Finally, it
has been shown that the recognition of EFE is influenced by
the activation (or inhibition) of facial muscles used to express
the perceived emotion (Niedenthal, 2007). Similar findings were
reported with direct Transcranial Magnetic Stimulation (TMS)
modulation of the sensorimotor cortex (Pitcher et al., 2008). Together, these studies support that EFE are bodily grounded
and that their processing is modulated through the embodied
simulation. INTRODUCTION To our knowledge,
only one study investigated whether positive, negative or neutral
characteristics of the target modulated facial mimicry of EFE
(Likowski et al., 2008). This article revealed that positive traits
(e.g., kind) enhanced Zygomatic activity for happy expressions
and Corrugator activity for sad expressions. Moreover, negative
(e.g., malicious) and neutral traits had no influence on Zygomatic
but reduced Corrugator activity for sad expressions. Although
this study highlights the influence of positive or negative traits
on EMG responses to EFE (i.e., enhanced mimicry for positive
targets), each avatar had their specific traits thus preventing the
control for the perceptual stability of facial expressions. g
y
p
g
However, a recurrent methodological limitation of articles
related to top-down processes was that the stimuli differ in
terms of emotion but also in terms of perceptual properties. For instance, it is difficult to determine to what extent the EEG
activity observed by Achaibou et al. (2008) at the level of the P100
and N170 components for, as an example, happy expression, is
due to the feeling of happiness or, alternatively, to the big white
area (related to the teeth) inherent to happy facial expressions. In
other words, the limitations of this paper relate to the fact that
the stimuli differed not only in terms of emotions but also in
terms of perceptual properties that could have induced the EEG
difference reported. Therefore, we have decided to address this
methodological concern while extending their princeps results to
more general social information. In a new set of experiments,
we used the same dynamic videos of facial expressions as used
in Achaibou et al. (2008). However, before each stimulus, we
provided participants with a social information (either positively-
or negatively-valenced, compared to a control situation without
social information) about the actor displaying the emotional
expression. We then recorded participants behavioral, EEG, and
EMG responses to these stimuli. Therefore, the aim of the present article was to examine
whether high-level social information about the same perceptual
target influence subjective responses to EFE but also impact
automatic facial mimicry and neural processes involved in
EFE categorization. The investigation of such influence is
highly relevant as recent models propose that the psychological
and neural underpinnings of the perception of EFE depend
on the understanding of social context (Niedenthal et al.,
2010). INTRODUCTION Moreover, negative
(e.g., malicious) and neutral traits had no influence on Zygomatic
but reduced Corrugator activity for sad expressions. Although
this study highlights the influence of positive or negative traits
on EMG responses to EFE (i.e., enhanced mimicry for positive
targets), each avatar had their specific traits thus preventing the
control for the perceptual stability of facial expressions. Therefore, the aim of the present article was to examine
whether high-level social information about the same perceptual
target influence subjective responses to EFE but also impact
automatic facial mimicry and neural processes involved in In a social neuroscience perspective, recent studies show that
the physiological (i.e., facial mimicry) and neural underpinnings
of the perception of EFE may also depend upon high-level
social factors associated with the targets or with the participants. For instance, facial emotions expressed by cultural in-group
(compared to out-group) targets modulate facial mimicry
of participants (Mondillon et al., 2007) and event-related
potentials in response to these EFE (Kubota and Ito, 2007). In
another study, happy expressions of targets presented as future
interaction partners (socially relevant) lead to enhanced late
positive potentials (LPP) amplitudes relative to non socially-
relevant targets (Bublatzky et al., 2014). Because LPP amplitudes
are larger for high arousing (vs. low arousing) stimuli (Schupp
et al., 2006), these results suggest that social relevance may
function as top-down factor on positive EFE, leading observers to
perceive happy faces as more relevant (i.e., larger LPP amplitude). Together, these studies suggest that social factors associated
with the participant, the target or with the social interaction
between them may influence the processing of EFE at subjective
(recognition accuracy), physiological (facial mimicry), and
neural (event-related potentials) levels. However, most of these
studies have either focused on the participants’ characteristics
(e.g., Likowski et al., 2008) or manipulated the social appraisal
of the targets by varying either the perceptual features (e.g.,
ethnicity) of the face itself (e.g., Kubota and Ito, 2007) or the
nature of the interaction between the participant and the target
(e.g., Bublatzky et al., 2014). There is so far little evidence that
rapid physiological and neural responses to EFE are influenced
by higher-order social information about the expresser. This
theoretical question is even more acute if this expresser is strictly
identical at a perceptual level (i.e., the same actor presented
with a positive social valence for half of the participants and a
negative social valence for the other half). Frontiers in Behavioral Neuroscience | www.frontiersin.org INTRODUCTION With respect to the moderating role of social
information on the effect of EFE on subjective, physiological, and
neural responses, we postulate that through their influence on
embodied simulation of EFE, social factors associated with the
target may influence their processing. social norms of the participants (Scherer, 1997). In a social neuroscience perspective, recent studies show that
the physiological (i.e., facial mimicry) and neural underpinnings
of the perception of EFE may also depend upon high-level
social factors associated with the targets or with the participants. For instance, facial emotions expressed by cultural in-group
(compared to out-group) targets modulate facial mimicry
of participants (Mondillon et al., 2007) and event-related
potentials in response to these EFE (Kubota and Ito, 2007). In
another study, happy expressions of targets presented as future
interaction partners (socially relevant) lead to enhanced late
positive potentials (LPP) amplitudes relative to non socially-
relevant targets (Bublatzky et al., 2014). Because LPP amplitudes
are larger for high arousing (vs. low arousing) stimuli (Schupp
et al., 2006), these results suggest that social relevance may
function as top-down factor on positive EFE, leading observers to
perceive happy faces as more relevant (i.e., larger LPP amplitude). Together, these studies suggest that social factors associated
with the participant, the target or with the social interaction
between them may influence the processing of EFE at subjective
(recognition accuracy), physiological (facial mimicry), and
neural (event-related potentials) levels. However, most of these
studies have either focused on the participants’ characteristics
(e.g., Likowski et al., 2008) or manipulated the social appraisal
of the targets by varying either the perceptual features (e.g.,
ethnicity) of the face itself (e.g., Kubota and Ito, 2007) or the
nature of the interaction between the participant and the target
(e.g., Bublatzky et al., 2014). There is so far little evidence that
rapid physiological and neural responses to EFE are influenced
by higher-order social information about the expresser. This
theoretical question is even more acute if this expresser is strictly
identical at a perceptual level (i.e., the same actor presented
with a positive social valence for half of the participants and a
negative social valence for the other half). To our knowledge,
only one study investigated whether positive, negative or neutral
characteristics of the target modulated facial mimicry of EFE
(Likowski et al., 2008). This article revealed that positive traits
(e.g., kind) enhanced Zygomatic activity for happy expressions
and Corrugator activity for sad expressions. January 2018 | Volume 11 | Article 231 INTRODUCTION Furthermore, we postulate that the effect of social
information on EFE processing could be interpreted within
the theoretical framework of emotional embodied simulation Therefore, the present article aimed to investigate and
extend the top-down influence of social information during
perception of EFE on their subjective, physiological, and neural
responses. This is based on previous findings showing that
mimicry, assessed by electromyography (EMG) activity, but also
P100 and N170 event-related potentials (ERP), were modulated
during a EFE recognition task of dynamic stimuli (Achaibou
et al., 2008). In other words, the aim of the present research
was to examine whether the valence of social information
(either positive or negative compared to an absence of social
information) modulates early neural components associated with January 2018 | Volume 11 | Article 231 2 Rapid Social Modulation Mermillod et al. to the emotion displayed by the stimulus compared to no
social label. For example, we expected that congruency trials
(i.e., happy facial expression with a positive label) should elicit
higher EMG activity in muscles involved with producing facial
expressions of joy (zygomaticus major and orbicularis oculi)
compared to the same EFE presented without social information. This hypothesis is based on previous research showing that social
factors may increase facial mimicry of likable targets or in-
group members (Mondillon et al., 2007; Likowski et al., 2008). Conversely, incongruent trials (e.g., happy facial expression with
a negative label) should produce lower EMG activity of the
corresponding facial muscles (zygomaticus major and orbicularis
oculi) compared to the same EFE without social information. visual processing and linked with activity of visual and face areas
(P100 and N170, respectively). Given that the impact of social
information on later components such as LPP was already and
extensively shown elsewhere (Schupp et al., 2006; Bublatzky et al.,
2014), we focused our analysis on the early ERP components
in order to provide evidence that social information modulates
not only high-level cognitive functions such as attention and
executive functions, but also perception and categorization of
emotional stimuli. The P100 component, occurring ∼120 ms after the stimulus
onset, is associated with the processing of exogenous visual
stimulation in extrastriate cortical areas (Clark and Hillyard,
1996), suggesting that the P100 is modulated by the physical
properties of the stimulus. Participants Twenty-four undergraduate students (19 females) (Mage = 20.50,
SDage = 2.54) at the University Clermont Auvergne, Clermont-
Ferrand (France) with corrected-to-normal vision, participated
in exchange for course credits. All participants gave written
informed consent and had normal or corrected vision and no
psychiatric or neurological disorders. STUDY 1 The influence of social context on the processing of emotional
faces was first investigated at the subjective level. The goal was to
examine the effects of social context on the ratings of valence and
intensity of the EFE as well as the emotions felt in response to
these EFE. INTRODUCTION With regards to EFE processing, the
exogenous nature of the P100 component has been supported
by previous studies showing that fearful emotions generated
larger amplitudes as compared to neutral emotions (Pourtois
et al., 2004, 2005). However, the emotional stimuli used in these
studies were different at the emotional (endogenous) and at
the perceptual (exogenous) level. For instance, angry vs. happy
faces differ at the emotional level, but they are also considerably
different at a purely perceptual level, even after a careful control
of luminance or contrast information. Therefore, the modulation
of the P100, as well as the modulation of N170 component
(related to facial processing) by endogenous variables, (e.g., social
information) remains a matter of debate. Thus, in addition, the
current study also aimed to determine whether the P100 and
N170 components could be modulated by endogenous social
factors applied on strictly identical EFE at a perceptual level. Furthermore, at a physiological level, we aimed to evaluate
whether mimicry processes, assessed by EMG responses to EFE,
are modulated by social information. Study 3 examined the potential effects of social information
on two early visual ERP components, namely the P100 and
N170. Based on the findings of Achaibou et al. (2008), showing
early effects of dynamic emotional expressions on mimicry
and neural activity assessed by P100 and N170 components,
we expected higher amplitudes of the P100 and N170 when
the EFE is congruent with the preceding social information
compared to the control situation in which no social information
is provided. Our hypothesis is based on a similar assumption
of top-down higher-level processes influencing early neural and
facial responses. However, the current study manipulates social
information rather than emotional expressions, thus ensuring
that bottom-up perceptual factors are strictly identical. Method Study 1 examined the effect of a positive, negative, or no social
information on participants’ ratings of the valence and intensity
of EFE. We expected significantly higher ratings of valence and
intensity when the valence of the EFE was congruent with the
valence of the social label (e.g., joy expressed by nice nurse)
compared to the control situation without social information. Conversely, we expected lower ratings of valence and intensity
for a given EFE when the valence of the EFE and the social label
(i.e., joy expressed by a serial rapist) was incongruent compared
to the control situation without social label. We also examined
how the emotion felt by the participants was modulated by
social information. Indeed, it has been shown that the social
information (i.e., ethnicity) about the target depicted in the EFE
modulates empathic emotional responses (Drwecki et al., 2011). Frontiers in Behavioral Neuroscience | www.frontiersin.org Perceived Valence At the level of valence, we observed a significant two-way
interaction, F(10, 230) = 5.38, p < 0.001, between social label
and EFE (Table 1). Given the number of potential combinations
of pairwise comparisons, we did not conduct post-hoc analyses. However, descriptive statistics provided in Table 1 illustrate this
interaction by showing that positive emotions were perceived
as less positive after exposure to negative compared to the
situation without social label. Conversely, negative emotions
were perceived as less negative for actors presented with a positive
compared to an absence of social information. Statistical Analyses y
All the statistical analyses were performed using the STATISTICA
7 software. We conducted an analysis of variance (ANOVA)
on valence and intensity of the emotion perceived (Phase 1
and 2) and valence and intensity of the emotion felt by the
participant (for Phase 2 only) as the dependent variables, and
EFE (Anger; Disgust; Fear; Happiness; Sad; Surprise or Neutral)
and social label (Phase 1—no social label; Phase 2—negative
social label; Phase 2—positive social label) as within-subjects
independent variables. Concerning the emotional intensity of
EFE, for simplicity and clarity reasons, we only kept the
intensity level related to each emotion (e.g., anger responses after
presentation of an angry faces) and not the entire confusion
matrices. Procedure Participants were seated in front of a computer screen on which
the dynamic EFE was displayed in central vision. EFE pictures
were presented using the E-Prime software (Psychology Software
Tools, http://www.pstnet.com) creating the compelling illusion
of a short movie clip displaying a dynamic facial expression from
neutral to emotional expressions. The experiment was divided
into two phases. In the first experimental phase, participants were
exposed to a central fixation cross for a duration varying from 500
to 1,000 ms, followed by a video presenting one EFE (2,680 ms). After each of the 70 videos, participants were instructed to rate
the EFE in terms of valence on a continuous pixel scale ranging
from 0 (positive) to 100 (negative). Next, participants rated the
intensity of the EFE on each of the six basic emotions (anger,
disgust, fear, happiness, sad, or surprise) on an identical pixel
scale (ranging from 0: not at all, to 100: totally).The second phase
was similar to the first phase, except that each of the 70 videos
was preceded by a positive or negative label. A specific identity
from the database (for every EFE expressed by this individual)
was associated with a positive label (e.g., nice nurse) for half of
the participants, and a negative label for the other half (e.g., serial
rapist). The social valence of each identity was counterbalanced
across participants. After seeing the label displayed on the screen Dynamic EFE
Th
d
i The dynamic faces expressed a neutral emotion and then
either gradually changed to express the full intensity of six
basic emotions (anger, disgust, fearful, happiness, sadness, and
surprise; Ekman and Friesen, 1976) or remained neutral (no
emotion). For each emotional category, there were 10 different
face identities (4 females and 6 males). We aimed to balance
as much as possible the gender of the stimuli (given the
database available) since the gender of the emotional expression,
irrespective of the gender of the participant, might interact
with the expressed emotions: notably, female faces tend to be
perceived as happier and male faces as angrier (Villepoux et al.,
2015). This made a total of 70 different movie clips (10 identities x
7 EFE). For a reliable control of the onset, duration, and intensity
of emotional expressions, we used dynamic expressions from a set
of morphed pictures from a neutral to an emotional expression
of the same face identity on the basis of Benson and Perrett’s
morphing technique (Benson and Perrett, 1993). Thus, we used
18 frames per face with increasing emotional intensity for each
emotion. Each of the first 17 frames was exposed for 40 ms and
the 18th frame lasted for 2,000 ms (Figure 1). Perceived Emotional Intensity Analyses of the intensity of the perceived emotional expressions
revealed a significant two-way interaction, F(10, 230) = 2.01,
p < 0.05, between social label and EFE (Table 2) on the intensity
of the corresponding emotion. Again, pairwise comparisons were
not significant after post-hoc corrections but Table 2 illustrates
this interaction and reveals that positive emotions were perceived
as less intense when accompanied by negative compared to the
situation without social label. Conversely, negative emotions
were perceived as less intense for actors presented with a positive
compared to an absence of social information. Material and Procedure
Social information The social context of EFE was operationalized with verbal labels
referring to positive and negative categories. Each label was
composed of two words (noun and adjective; e.g., loving mother). Thirty-two labels were initially created: 16 positive and 16
negative adjectives referring to either male or female nouns (see
Appendix). A pilot study was carried out with 24 undergraduate
psychology students (20 females; Mage 20.70; SDage = 2.54) to test
the pleasantness and unpleasantness of all labels. For each label,
participants rated the extent to which the person described by the
label was pleasant or unpleasant with two 7-point Likert scales for
pleasantness and unpleasantness (ranging from 0 to 6; not at all to Study 2 investigated the impact of social information on
EMG activity. We recorded EMG over six facial muscles
involved in specific expressions, such as the contraction of
the zygomaticus major (i.e., in response to happiness) and the
corrugator supercilii (i.e., in response to anger). We expected
increased EMG activity of the corresponding muscle when the
facial expression was preceded by social information congruent January 2018 | Volume 11 | Article 231 3 Rapid Social Modulation Mermillod et al. totally). The six labels rated as most pleasant (i.e., loving mother,
passionate teacher, humanitarian doctor, nice nurse, cheerful
sportsman, caring father; pleasant scale: M = 5.76, SD = 0.29;
unpleasant scale: M = 2.06, SD = 0.37) and six rated as most
unpleasant (i.e., dangerous schizophrenic, sadistic killer, serial
rapist, asocial necrophiliac, brutal coach, pedophile therapist;
pleasant scale: M = 1.63, SD = 0.49; unpleasant scale: M = 6.30,
SD = 0.58) were retained for the experiments. Subsequent
analysis showed that positive labels significantly differed from
negative labels in terms of pleasantness [t(10) = 17.69, p < 0.001]
and unpleasantness [t(10) = −15.12, p < 0.001]. for 2,000 ms, participants were exposed to a fixation cross (from
500 to 1,000 ms) before each video depicting a specific EFE of a
specific person (for 2,680 ms). Similarly to phase 1, participants
had to assess the valence and the intensity of the perceived
EFE. Moreover, participants were also instructed to evaluate the
emotion they felt after exposure to each video on the same
continuous scales as Phase 1 (i.e., valence and intensity). The
presentation order of movie clips was randomized for each phase. Frontiers in Behavioral Neuroscience | www.frontiersin.org Felt Valence Displayed EFE
Social label
No social
label
Negative social
label
Positive social
label
Anger
69.43 (3.7)
70.00 (3.37)
63.59 (3.88)
Disgust
57.27 (3.4)
45.22 (5.5)
43.09 (4.07)
Fear
59.10 (3.68)
54.70 (4.08)
50.29 (4.97)
Happy
87.22 (1.69)
81.47 (3.39)
86.40 (2.51)
Sad
60.25 (4.05)
59.35 (4.71)
56.85 (4.87)
Surprise
83.40 (2.88)
76.24 (3.95)
77.59 (3.97)
Standard errors are indicated into brackets. Displayed EFE
Social label
No social
valence
Negative social
valence
Positive social
valence
Anger
9.19 (1.87)
10.96 (2.18)
16.77 (2.42)
Disgust
11.08 (2.08)
12.15 (2.05)
20.05 (2.34)
Fear
12.26 (2.07)
14.90 (2.53)
18.55 (2.93)
Happy
92.46 (1.22)
81.40 (3.92)
90.24 (1.99)
Sad
11.92 (1.71)
17.80 (2.46)
18.26 (2.37)
Surprise
43.16 (2.71)
40.63 (2.97)
45.59 (2.66)
Standard errors are indicated into brackets. Standard errors are indicated into brackets. Felt Emotional Intensity We also found a significant interaction between social label and
EFE [F(5, 115) = 17.80, p < 0.001] regarding the intensity of
corresponding emotion felt by the participants. For instance,
participants perceived negative emotions as more intense after
negative than after positive labels. Conversely, participants
reported a higher level of positive emotions after positive labels
than after negative labels (Table 4). Displayed EFE
Social label
Negative social label
Positive social label
Anger
18.38 (3.14)
32.49 (3.31)
Disgust
17.82 (2.34)
35.48 (3.28)
Fear
28.07 (3.71)
33.87 (2.49)
Happy
44.75 (4.48)
81.04 (3.09)
Sad
29.54 (3.26)
34.50 (2.81)
Surprise
37.68 (2.95)
50.55 (3.02)
Standard errors are indicated into brackets. Felt Valence We observed that the social valence of the stimulus affected the
participants’ responses concerning felt valence. More precisely,
results point to a significant interaction between the social
information and EFE [F(5, 115) = 20.6, p < 0.001]. As for
perceived valence, negative labels were associated with more
negative feelings than were positive labels for negative emotions. Conversely, positive labels were associated with more positive
feelings than were negative labels for positive emotions (Table 3). January 2018 | Volume 11 | Article 231 4 Mermillod et al. Rapid Social Modulation FIGURE 1 | Example of dynamic facial expressions. Copyright available in Ekman and Friesen (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists
Press. TABLE 2 | Average ratings of intensity of perceived emotional expression, from 0
(not expressed) to 100 (fully expressed), as a function of the valence of labels
(negative, positive, or no labels). Displayed EFE
Social label
No social
label
Negative social
label
Positive social
label
Anger
69.43 (3.7)
70.00 (3.37)
63.59 (3.88)
Disgust
57.27 (3.4)
45.22 (5.5)
43.09 (4.07)
Fear
59.10 (3.68)
54.70 (4.08)
50.29 (4.97)
Happy
87.22 (1.69)
81.47 (3.39)
86.40 (2.51)
Sad
60.25 (4.05)
59.35 (4.71)
56.85 (4.87)
Surprise
83.40 (2.88)
76.24 (3.95)
77.59 (3.97)
Standard errors are indicated into brackets. TABLE 3 | Average rated level of felt valence, from 0 (negative) to 100 (positive), of
each emotional expression depending on the valence of the label (negative vs. positive). Displayed EFE
Social label
Negative social label
Positive social label
Anger
18.38 (3.14)
32.49 (3.31)
Disgust
17.82 (2.34)
35.48 (3.28)
Fear
28.07 (3.71)
33.87 (2.49)
Happy
44.75 (4.48)
81.04 (3.09)
Sad
29.54 (3.26)
34.50 (2.81)
Surprise
37.68 (2.95)
50.55 (3.02)
Standard errors are indicated into brackets. TABLE 1 | Average rated level of perceived valence, from 0 (negative) to 100
(positive), of each emotional expression depending on the valence of the label
(negative, positive, or no label). TABLE 2 | Average ratings of intensity of perceived emotional expression, from 0
(not expressed) to 100 (fully expressed), as a function of the valence of labels
(negative, positive, or no labels). (not expressed) to 100 (fully expressed), as a function of the valence of labels
(negative, positive, or no labels). Material and Procedure The experimental design of Study 2 is similar to Study 1,
except that we recorded participants’ EMG activity during the
experimental task. Electrodes were fixed on the participant’s face
in order to record facial muscle electrical activity (EMG). Before
attaching the electrodes, the skin was cleaned with alcohol in
order remove sebum. Six pairs of electrodes were placed on the
following muscle regions (see Fridlund and Cacioppo, 1986 for
details): frontalis pars medialis (mainly related to surprise and
fear), corrugator supercilii (mainly related to anger), orbicularis
occuli pars orbitalis (mainly related to happiness), levator labii
superioris (mainly related to disgust), zygomaticus major (mainly
related to smile), and orbicularis oris inferior (mainly related
to sadness). The reference electrode was clipped on the ear
lobe. Because of the large electrode size, both sides of the face
were required. Half of the electrodes (corrugator, levator, and
orbicularis oris) were placed on the right side of the face while the
other three electrodes (frontalis, orbicularis occuli, zygomaticus
major) were placed on the left side. The placement of the
electrodes was identical for all participants. Locations for each
specific muscle were chosen to allow the setting of the six pairs
of electrodes while (i) allowing the minimum of overlap between
close muscles (e.g., corrugator and levator) and (ii) use the most
responsive right side of the face (Fridlund and Cacioppo, 1986)
for the weakest muscles (corrugator, levator, and orbicularis oris). After checking the position of each pair, study instructions were
given to the participants and the experiment began. terms reduce the evaluation of valence and intensity of the
EFE and congruent trials led to higher intensity of felt
emotions. Moreover, incongruent trials led to a lower valence
of felt emotions compared to a control situation of perceiving
emotional expressions without social information. We thus
extend upon previous findings suggesting that top down social
factors influence EFE processing (e.g., Kubota and Ito, 2007;
Likowski et al., 2008; Bublatzky et al., 2014). In terms of affective
responses to EFE, we support Drwecki et al.’s (2011) findings that
emotional responses are influenced by social information (i.e.,
ethnicity) about the target depicted in the EFE. More globally, this study is in line with previous articles
showing the influence of participants’ appraisal of the target on
the emotional evaluation and responses to EFE. For instance,
Lamm et al. STUDY 2 In this experiment, we investigated the impact of social
information on mimicry within the theoretical framework of the
embodiment theory. More specifically, we expected increased
EMG activity in the corresponding muscles when EFE was
preceded by a congruent social label compared to an EFE without
social label. Conversely, incongruent trials should produce lower Data Acquisition Study 2 and 3 aim to determine the neural and physiological
processes underpinning the modulation of social information
of EFE on behavioral responses. According to the embodiment
theory, we assume that the embodied processing of EFE might
be modulated by social information, such that participants
might have simulated to a lesser extent the EFE associated with
incongruent social information. Each EMG signal was acquired by bipolar electrodes used for
electrophysiological acquisition and amplified by Multi-Channel
Bio Amps GT201 band pass filtered from 10 to 1,000 Hz
(ADInstruments equipment, ML880 Powerlab 16/30). We used
the absolute value of the EMG signal. The EMG data were
averaged during the 5,000 ms after stimulus onset. The dependent
variable of interest was measured as the difference between the
mean activity 5,000 ms after the stimulus and the baseline activity
recorded during the 500 ms before the stimulus onset, when a
fixation cross was displayed on the screen. Participants Twenty healthy subjects (19 females) (Mage = 20.80 years,
SDage = 2.26) at the University Clermont Auvergne, Clermont-
Ferrand (France), with corrected-to-normal vision, participated
in exchange for course credits. All participants gave written
informed consent and had no psychiatric or neurological
disorders. Material and Procedure (2007) assessed how reappraisal might influence
participants’ evaluation of the pain expressed by faces of patients
undergoing painful treatment. When participants were told that
the treatment was effective (vs. non-effective), they judged the
experience of the person as being less painful. Results also showed
that participants from the “non-effective” group reported higher
distress than those from “effective” group. Therefore, in line
with Lamm et al.’s (2007) results, the present findings showed
for the first time that appraising EFE as socially congruent or
incongruent with the expression modulates their evaluation as
well as their emotional effects. Discussion With regards to perceived valence of facial expressions, this study
showed that expressions of negative emotions were perceived
as less negative when preceded by a positive label compared
to a neutral situation whereas positive emotions were rated as
less positive when preceded by a negative label compared to an
absence of social information. We observed a similar interaction
effect modulating the ratings of the intensity perceived of the
emotional expressions, negative emotions were perceived as less
intense when preceded by positive social labels, and conversely
for a negative social information. Moreover, we observed the same interaction effect for the valence of the emotion felt but also
in the ratings of the felt emotional intensity. same interaction effect for the valence of the emotion felt but also
in the ratings of the felt emotional intensity. This study thus supports hypothesis 1 according to which
target-related social information influences the ratings of valence
and intensity of the EFE as well as the emotions felt in
response to these EFE. More precisely, incongruent social January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org 5 Rapid Social Modulation Mermillod et al. EMG activity of the corresponding facial muscles compared to
the same EFE with no social label. TABLE 4 | Average ratings of intensity of felt emotion, from 0 (not expressed) to
100 (fully expressed), as a function of the valence of labels (negative vs. positive
labels). TABLE 4 | Average ratings of intensity of felt emotion, from 0 (not expressed) to
100 (fully expressed), as a function of the valence of labels (negative vs. positive
labels). labels). Displayed EFE
Social label
Negative social label
Positive social label
Anger
22.77 (5.44)
11.95 (4.74)
Disgust
31.74 (5.72)
17.17 (4.81)
Fear
20.38 (5.32)
20.01 (5.88)
Happy
20.09 (5.82)
53.73 (6.31)
Sad
19.10 (4.90)
31.72 (4.79)
Surprise
18.83 (5.37)
21.42 (5.80)
Standard errors are indicated into brackets. Frontiers in Behavioral Neuroscience | www.frontiersin.org Participants Fifteen healthy subjects (10 females) (Mage = 21.67; SDage = 6.64)
from
University
Clermont
Auvergne
participated in
this
experiment in exchange for course credits. All participants gave
written informed consent and had normal or corrected vision and
no psychiatric or neurological disorders. Results We observed a significant interaction between emotion and
muscle, F(5.54, 105.22) = 2.37, p < 0.05, confirming that each
emotion was related to a specific set of muscles (e.g., zygomaticus
major with joy, corrugator supercilii with anger). Therefore, we
focused the analyses on the muscles specific to each emotion
(Figure 2). Statistical analyses revealed a significant main effect
of social label, F(1.36, 25.36) = 8.32, p < 0.01. As shown on
Figure 2, labels of positive and negative social valence produced
a significant increase (relative to baseline) in EMG activity in
response to EFE compared to the EMG activity elicited by EFE
displayed to the control situation without social information. Negative [t(19) = 3.34, p < 0.01, two-tailed t-test] and positive
[t(19) = 2.83, p < 0.05, two-tailed t-test] social labels produced
a significant increase in EMG activity compared to control
situation without social labels, while the effect of positive and
negative social labels on EMG activity did not differ [t(19) = 0.80,
p = 0.93, two-tailed t-test]. No main effect was observed for either
emotion or muscle, and interaction effects (emotion x social
label; muscle x social label; muscle x emotion x social label) were
not significant. Therefore specific pairwise comparisons were not
analyzed. Statistical Analyses All analyses were performed using PASW Statistics 18 (SPSS Inc.,
Chicago, IL). We conducted an analysis of variance (ANOVA)
with EMG activity (6 levels: frontalis pars medialis, corrugator
supercilii, orbicularis occuli pars orbitalis, levator labii superioris, Frontiers in Behavioral Neuroscience | www.frontiersin.org January 2018 | Volume 11 | Article 231 6 Rapid Social Modulation Mermillod et al. the modulatory impact of (in)congruency. Several reasons might
explain the absence of interaction between (in)congruency
condition and EFE. First, while some studies found an association
between subjective and expressive responses to emotional stimuli
(Schwartz et al., 1980) others failed to find such effect (e.g., Sloan
et al., 1997; Calder et al., 2000; Rottenberg et al., 2002). For
instance, although spontaneous mimicry leads to greater affective
empathy while watching people expressing facial emotions (Stel
and Vonk, 2010), Calder et al. (2000) showed that, despite their
facial paralysis, patients with a Möbius syndrome accurately
recognize facial expressions. Therefore, EMG activity induced
by social labels may not be the main determinant of subjective
response found in Study 1. Second, the present findings may
suggest that significant increase in EMG activity constitutes a
physiological mechanism that allows an enhanced processing
of the relevant social information, beyond the object of this
information. In other words, the social relevance of individuals
may be processed prior to their emotional state. This may elicit
bodily reactions to social context, no matter the emotional state
of the targets. zygomaticus major, and orbicularis oris inferior) as dependent
variables and EFE displayed on screen (Anger; Disgust; Fear;
Happiness; Sad; Surprise or Neutral) and social label (no social
label; negative social label; positive social label) as within-subjects
independent variables. Corrections of Greenhouse-Geisser were
also applied for variance analysis when violations of sphericity
occurred. STUDY 3 Social information modulated the subjective (Study 1) and
physiological responses (Study 2) to emotional expressions in
a different manner (irrespective of congruency in Study 2). Study 3 aimed to examine whether early neural responses to
EFE (i.e., P100 and N170 components) are modulated by social
context. We hypothesized that the subjective and physiological
modulations observed in Studies 1 and 2, respectively, could
be related to a modulation of rapid neural components related
to visual perception. More precisely, we expected that social
information might modulate P100 and N170 components in
response to EFE in a way congruent with the social information
provided to the participant. Our hypothesis also extends the
results reported by Achaibou et al. (2008) indicating that facial
mimicry (assessed by EMG activity) is related to P100 and N170
EEG components. Precisely, we expected higher amplitudes of
the P100 and N170 in response to congruent trials (e.g., happy
face following positive social information) compared to the
control trials (no social label). Conversely, we expected lower
amplitudes of the P100 and N170 in response to incongruent
trials (e.g., happy face following negative social information)
compared to the control trials (no social label). Social information modulated the subjective (Study 1) and
physiological responses (Study 2) to emotional expressions in
a different manner (irrespective of congruency in Study 2). Study 3 aimed to examine whether early neural responses to
EFE (i.e., P100 and N170 components) are modulated by social
context. We hypothesized that the subjective and physiological
modulations observed in Studies 1 and 2, respectively, could
be related to a modulation of rapid neural components related
to visual perception. More precisely, we expected that social
information might modulate P100 and N170 components in
response to EFE in a way congruent with the social information
provided to the participant. Our hypothesis also extends the
results reported by Achaibou et al. (2008) indicating that facial
mimicry (assessed by EMG activity) is related to P100 and N170
EEG components. Precisely, we expected higher amplitudes of
the P100 and N170 in response to congruent trials (e.g., happy
face following positive social information) compared to the
control trials (no social label). Conversely, we expected lower
amplitudes of the P100 and N170 in response to incongruent
trials (e.g., happy face following negative social information)
compared to the control trials (no social label). Frontiers in Behavioral Neuroscience | www.frontiersin.org Discussion Whereas we hypothesized that social information will modulate
facial mimicry in response to congruent EFE, we found a
significant increase of EMG activity when EFE were preceded
by
both
positive
and
negative
social
label
compared
to
the control situation without social information. Contrary
to the behavioral response reported in Experiment 1, the
influence of social information on EMG responses was thus
independent of congruency between the social label and the
EFE. Therefore, these findings suggest that the mimicry process
is significantly enhanced by the mere presence of social
information, independently of its valence. In respect to the main effect of social information, we
supported the hypothesis that social information constitutes a
top-down factor that can modulate physiological responses to
emotional expressions. This study is thus in line with previous
findings that mimicry of smiles is enhanced in the presence of
friends but not in the presence of strangers (Hess et al., 1995)
and in the presence of in-group members (Mondillon et al.,
2007; Niedenthal et al., 2010; Wang and Hamilton, 2012). In
this study, we showed for the first time that social information
about the expresser of a given EFE also modulates their
processing. Stimuli and Procedure However, we did not show an interaction between social
information and EMG responses to EFE, thus failing to extend
the behavioral findings of Study 1 to EMG activity and to support The stimuli were identical to those used in Study 1 and 2. The
procedure was also similar except (a) that EEG were recorded
during the experiment, (b) that the number of presented blocks January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org 7 Rapid Social Modulation Mermillod et al. FIGURE 2 | Mean change in EMG activity (compared to neutral situation without social information) as a function of emotional expression on the facial muscle related
to this emotional expression for each social valence of the stimulus. FIGURE 2 | Mean change in EMG activity (compared to neutral situation without social information) as a function of emotional expression on the facial muscle related
to this emotional expression for each social valence of the stimulus. artifacts for every subject and then automatically generalizes
this removal of artifacts for the entire recording. Trials were
epoched from −200 to +1,000 ms with respect to the stimulus
onset. After averaging, we obtained the peaks of the components
using BESA. ERPs were averaged for every subject and every
condition, and corrected using a baseline of 200 ms prior to the
stimulus onset. Finally, grand averages were computed across
subjects for all the conditions. The P100 and N170 components
were studied on the cluster of electrodes where their amplitudes
were the highest: O1, O2, PO7, PO8, P7, P8, P9, P10. Mean
amplitudes of P100 (time window: 100–140 ms) and N170 (time
window: 150–190 ms) were analyzed for each condition. Peak
latency extracted with BESA was at the mean latency of 121.90 ms
for the P100 component and the mean latency of 167 ms for the
N170 component. The topographic map of each component was
provided on Figure 3. was increased, and (c) that emotional intensity and valence of the
EFE were only rated after the first block for phase 1 (composed of
3 blocks in total) and after the first block for phase 2 (composed of
4 blocks in total). The subsequent blocks for each phase required
only passive observation of the EFE (i.e., without subjective
responses). Data Acquisition q
Scalp EEG was amplified using the BIOSEMI Active-Two
amplifier and was recorded from 64 electrodes distributed on an
elastic cap. The distribution of electrodes was made according
to the EEG 10–20 system: the electrodes included Fp1, AF3,
AF7, F1, F3, F5, F7, FC1, FC3, FC5, FT7, C1, C3, C5, T7, CP1,
CP3, CP5, TP7, P1, P3, P5, P7, P9, PO3, PO7, O1 for the left
hemisphere; the equivalent electrodes for the right hemisphere;
and FPz, AFz, Fz, FCz, Cz, CPz, Pz, POz, Oz, Iz for the electrodes
of the conventional midline sites. Two other electrodes, CMS
(Common Mode Sense) and DRL (Driven Right Leg) were
respectively used as electrodes of reference and mass. CMS was
the active electrode while DRL was the passive electrode. Data
were filtered with a low-pass filter of 200 Hz and digitized with a
sampling rate of 512 Hz. Stimuli and Procedure Thus, seven blocks were presented to the subjects,
including 3 blocks for phase 1 with EFE without social labels
(control situations) and 4 blocks for phase 2 with EFE preceded
by a social label (either positive or negative). The participants
were placed in front of the same screen (CRT 17") as in Study 1,
but were fitted with the EEG electrodes. EEG recordings were
performed during the five blocks of passive exposure to EFE
stimuli. Frontiers in Behavioral Neuroscience | www.frontiersin.org Statistical Analyses All the statistical analyses were performed using the STATISTICA
7 software. Mean amplitudes of P100 were analyzed using
repeated-measures
ANOVA. Mean
amplitudes
of
both
components were analyzed as a function of displayed Emotion
(7 levels: neutral, anger, sadness, enjoyment, disgust, surprise,
and fear), Social Label (3 levels: no social label, positive social
label, negative social label) and Hemisphere (2 levels: right,
left). Greenhouse-Geisser corrections were applied for variance
analysis when violations of sphericity occurred (ε referred to
as Greenhouse-Geisser estimate epsilon). The condition of
sphericity was verified by a test of Mauchley. EEG signal processing was performed with the software BESA
(http://www.besa.de/). The data were all re-referenced to the
average reference then filtered with a 1–40 Hz pass-band filter. For every recording of each subject, a correction of artifacts (such
as eye blinks) was applied. BESA allows to manually identify GENERAL DISCUSSION Influence of Social Context on Subjective,
Physiological, and Neural Activities P100 Component Analyses revealed a main effect of social label, F(1.43, 20.02) = 5.76,
p < 0.02, ε = 0.71, indicating that the mean amplitudes of the January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org 8 Rapid Social Modulation Mermillod et al. FIGURE 3 | (A,B) EEG activity for the P100 and N170 components. (C) Topography map of P100 (121.90 ms, 0.5 µV by color gradients) and N170 component
(167 ms, 0.31 µV by color gradients). FIGURE 3 | (A,B) EEG activity for the P100 and N170 components. (C) Topography map of P100 (121.90 ms, 0.5 µV by color gradients) and N170 component
(167 ms, 0.31 µV by color gradients). with any of the EFE. This effect was observed for the N170,
and largely associated with cognitive processes involved in
recognition of categorization of human faces (Bentin et al.,
1996). Even more surprising, we observed a modulation of
the P100 component which is associated with basic visual
perceptual processing (Allison et al., 1999) confirming that this
basic perceptual component could be modulated by endogenous
variables (Pourtois et al., 2005). In other words, we confirm and
extend previous findings that point to a modulation of rapid
neural components to higher-level (but perceptually identical)
endogenous variables related to social information. P100 component differ as a function of the associated social label
(Figure 3). EFE preceded by social label, regardless of its valence,
elicited larger amplitudes of the P100 compared to EFE presented
without social label (but did not differ between positive and
negative label). Neither the hemisphere, nor emotion effects were
significant. However, the interaction Hemisphere x Emotion was
significant, F(6, 84) = 2.49, p < 0.03, indicating higher amplitudes
of P100 on the right hemisphere for specific emotions (but post-
hoc corrected pairwise comparisons were not significant). No
other interaction was significant. N170 Component Moreover, this modulation quantitatively increased the neural
processes associated with perceptual processing of EFE of the
specific individuals but did not qualitatively modulate these
processes in regards to the congruency between the social valence
and the emotion displayed by the face. Thus, this study is
in accordance with the findings of Study 2, which showed a
significant increase of EMG activity when EFE were preceded
by both positive and negative social label, irrespective of the
congruency between the social label and the EFE. Similarly to the P100 component, analyses of the N170
component
revealed
a
main
effect
for
social
label,
F(1.29, 18.13) = 5.47, p < 0.03, ε = 0.64. The amplitude was
significantly higher for EFE when preceded by positive and
negative social label than for EFE without social label (Figure 3)
but there was no significant differences between positive and
negative social labels. We also observed a main effect for
emotion, F(6, 84) = 4.15, p < 0.002, indicating that the N170
amplitudes differed significantly as a function of displayed facial
expression (Figure 4). Analyses showed neither a main effect of
the hemisphere, nor any other interaction effect. Frontiers in Behavioral Neuroscience | www.frontiersin.org Discussion However, no study up to date had
investigated the effect of higher-level social information about
the target on EFE processing by maintaining strictly identical the
perceptual features. p
p
f
In Study 1, we supported our hypothesis that social
information modulates EFE processing at a subjective level. Indeed, we showed that incongruent valence between social
information and EFE reduces the valence and intensity of
perceived and felt emotions. Specifically, we showed that negative
expressions were perceived as less negative and less intense when
preceded by a positive label compared to no label. Conversely,
a positive facial expression was rated as less positive and less
intense when preceded by a negative label compared to no
label. Our results thus extend previous findings on modulation
of EFE recognition by social factors (e.g., Kubota and Ito,
2007; Mondillon et al., 2007). We show that higher-level social
information may impact EFE processing. This finding supports
the influence of top-down information (extended to higher-order
social information and crucially, strictly identical perceptually)
on emotional processing of EFE. In Study 3, our goal was to determine whether this non-
specific boost observed at a psychophysiological level could
be related to a modulation, at a neural level, of low level
perceptual processes. Our results indicate a main effect of social
information as positive and negative social information produced
higher amplitudes of P100 and N170 components compared to
situations without social information. Therefore, Study 3 extends
previous results reported by Achaibou et al. (2008) pointing
to a modulation of the P100 and N170 by EFE in relation
to EMG activity and demonstrates their relevance to higher-
level social information. Our results are also in line with other
findings showing that top-down factors related to the target may
modulate neural responses to EFE (Kubota and Ito, 2007; Tortosa
et al., 2013). Finally, they also support fMRI studies that have
shown that social information modulates the neural correlates of
facial expression (e.g., Winston et al., 2002; Singer et al., 2004;
Vrtiˇcka et al., 2009; Cloutier et al., 2012). However, similarly
to Study 2 and contrary to our initial hypotheses, this effect
was independent on the congruency between social information
and EFE. Discussion Our results indicate a modulation of the N170 component
depending on emotion. More importantly, we observed higher
amplitudes of the P100 and N170 in response to trials associated
with a social information compared to control trials (without
social label). However, contrary to our initial hypothesis, there
was no significant interaction between social label and emotional
expressions. Rather, electrophysiological data indicate a main
effect of social label on both P100 and N170 components
compared to the control situation and irrespective to the
valence (and therefore, congruency) of the social label associated The aim of this article was to investigate whether social
information about the target expressing a facial emotion could
modulate the processing of EFE at subjective, physiological, and
neural levels. Specifically, we aimed to evaluate the effect of
valence congruency between social information about targets and
their EFE on the processing of these EFE. The study was based on
previous findings showing that perceptual-social characteristics
of the expresser (e.g., ethnicity) influence the processing of black
vs. white emotional expressions for N100 to P300 components January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org 9 Rapid Social Modulation Mermillod et al. FIGURE 4 | (A,B) N170 component for each emotional expression irrespective to social valence. (C) Topography map of N170 component (167 ms, 0.31 µV by color
gradients). FIGURE 4 | (A,B) N170 component for each emotional expression irrespective to social valence. (C) Topography map of N170 component (167 ms, 0.31 µV by color
gradients). ent for each emotional expression irrespective to social valence. (C) Topography map of N170 component (167 ms, 0.31 µV by col any social label (control condition). However, contrary to our
hypotheses, we found a significant increase of EMG activity when
expressions were preceded by both positive and negative social
label, irrespective of the congruency between the social label
and the EFE. This suggests that embodiment circuitries may
act as a boost for subsequent cognitive or emotional processes
when the situation is socially relevant for the individual, but
irrespective of its specific content (either negative or positive
social situations). This supports and extends previous articles
suggesting a predominant role of arousal (compared to valence)
during embodiment of emotional cues (Beffara et al., 2012, 2016;
Kever et al., 2015). (e.g., Kubota and Ito, 2007). Frontiers in Behavioral Neuroscience | www.frontiersin.org LIMITATIONS AND PERSPECTIVES respectively). Despite the consistency of our results across the
three studies and even if these sample sizes are consistent
with other studies in the field (Achaibou et al., 2008), further
experiments should replicate and extend the current findings
with larger numbers of participants since the power of behavioral,
physiological or neurological effect could be unstable with lower
sample sizes (e.g., Simmons et al., 2011; Schönbrodt and Perugini,
2013). Our findings extend the current state-of-the-art by revealing
that the observed top-down influences cannot be explained by
bottom-up perceptual factors (e.g., the perceptual difference
between happy and angry faces) since our stimuli were
strictly identical at a perceptual level (e.g., an identical smile
expressed by a negative vs. positive individual). Moreover, our
findings revealed that social information can influence low
level perceptual processes of EFE. Therefore, these findings
demonstrate that social context has an influence, as early as
120 or 170 ms after onset, on low-level perceptual and cognitive
processing of emotional expressions. Finally, further studies will have to examine whether this
modulation of early neural activity could be mediated by a
differential allocation of attentional resources to perceptual
processes (simple quantitative changes in neural processes) or
whether the top-down modulation is able to qualitatively modify
directly the perception of emotions. More precisely, our current
data does not allow to determine whether the top-down effects
reported here qualitatively modify the perceptual processes
occurring at the level of the extrastriate cortex or whether it only
constitutes a quantitative boost under the influence of attentional
processes. Another important question for further research is to
determine the extent to which a non-specific boost observed at
the quantitative level of neural and physiological processes (i.e.,
independently to the congruency between social information and
the EFE) is related to further qualitative evaluation observed
at a subjective level (and related the congruency between the
social valence and the emotion expressed by the target). In other
words, it remains to be explained how the interaction between
social valence and emotional expressions observed at a subjective
level is related to the mere allocation of neural and physiological
resources (i.e., irrespective to the social valence of the stimuli) at
the early stages of the processing of emotions. Discussion As concerns the results of Study 2 examining EMG responses
to facial expressions, our results build on and extend recent
models of embodied cognition assuming that circuits of mimicry
are preferentially activated when the observed emotion is
socially relevant (Niedenthal et al., 2010; Wang and Hamilton,
2012). More specifically, previous data pointed to a significant
modulation of embodiment circuitry by social information such
as the presence of friends, but not strangers (Hess et al., 1995)
or in the presence of in-group compared to out-group members
(Mondillon et al., 2007). In the present study, we found weak
general EMG activity (including the muscle associated with each
specific EFE) when facial expressions were presented without January 2018 | Volume 11 | Article 231 10 Rapid Social Modulation Mermillod et al. LIMITATIONS AND PERSPECTIVES However, although Study 2 and 3 support a top-down
influence during visual perception of emotional stimuli, it
remains to be tested whether increased physiological and neural
reactions after social information priming are specific to social
information or could be accounted for by either conceptual or
other social factors. Future studies should thus include other
control situations in order to understand whether the effects
reported in the current study are specific to social information
contrasted in valence. We can imagine that other types of
social (e.g., group membership, discriminated individuals) but
also more general conceptual information could produce similar
patterns of rapid physiological and neural modulation. Finally,
one could argue that EMG activity also results from higher
relevance for the self (i.e., involving the observer) during social
vs. no social priming (Grèzes et al., 2013). Moreover, although we did not examine the neural activity
with a high spatial resolution, we hypothesize that the processing
of EFE could be influenced by high-level cortical areas
(i.e. orbitofrontal and somatosensory cortices) or subcortical
structures through a rapid activation of the amygdala (Mermillod
et al., 2009, 2010; McFadyen et al., 2017) which would go
on to modify perceptual processing of the expression. Among
neural models that support the influence of top-down factors
on perceptual processing (Niedenthal et al., 2010), most of
them suggest that perceptual recognition in temporal cortical
areas could be influenced by top-down information generated
in the orbitofrontal cortex during the recognition of emotions
(Kveraga et al., 2007; Barrett and Bar, 2009). In those models,
early neural activity provided by frontal areas would allow
a prediction that guides further bottom-up visual processes. Neuroimaging studies with high spatial resolution will have
to determine the possible involvement of frontal cortical areas
as the origin of the top-down effects reported in the current
article. CONCLUSION To conclude, our data provide evidence that top-down social
information about a target expressing an emotion modifies the
perception of this emotion at subjective, physiological, and neural
levels. In addition, our results suggest that the effect of social
label on early neural activity does not systematically vary as
a function of its valence (either positive or negative) and the
EFE, but, alternatively, produces a global increase of early neural
(EEG) and later peripheral (EMG) activity compared to the
perception of emotional expressions presented without social
context. These findings support and extend recent models of
embodied condition, suggesting that the neural and physiological
processing of emotional expressions could be modulated by the
social context since its very first perceptual stages (Niedenthal
et al., 2010; Wang and Hamilton, 2012). However, further studies
should determine whether the effect we obtained with a social
label is specific to social information or if other types of relevant
and semantic information, emotional or non-emotional, could
produce similar top-down influences. Another potential limitation of the current research lies in
the sample size and participants’ characteristics. This population
was composed of Bachelor degree students similar in age,
cultural environment, gender, and level of education. This
could constitute a methodological limitation and future studies
investigating this research question could investigate top-
down processes during recognition of emotional expressions
using more diverse populations. We also acknowledge that
the size of our different samples was relatively low (24; 20
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study
was
carried
out
in
accordance
with
the
recommendations of the “Comité de Protection des Personnes January 2018 | Volume 11 | Article 231 11 Mermillod et al. Rapid Social Modulation (CPP) Sud-Est 1” with written informed consent from all
subjects. All
subjects
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written
informed
consent
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accordance with the Declaration of Helsinki. The protocol
was approved by the “Comité de Protection des Personnes (CPP)
Sud-Est 1, n◦2009-014056-30. experiment and analyzed the data. All authors participated to
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Vermeulen, Niedenthal, Dutheil and Droit-Volet. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the
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Positive social label
Negative social label
Male characters
Cheerful sportsman
Pedophile therapist
Caring father
Sadistic killer
Nice nurse
Serial rapist
Female characters
Loving mother
Asocial necrophilia
Humanitarian doctor
Brutal coach
Passionate teacher
Dangerous schizophrenic APPENDIX
Positive social label
Negative social label
Male characters
Cheerful sportsman
Pedophile therapist
Caring father
Sadistic killer
Nice nurse
Serial rapist
Female characters
Loving mother
Asocial necrophilia
Humanitarian doctor
Brutal coach
Passionate teacher
Dangerous schizophrenic Frontiers in Behavioral Neuroscience | www.frontiersin.org January 2018 | Volume 11 | Article 231 APPENDIX January 2018 | Volume 11 | Article 231 Frontiers in Behavioral Neuroscience | www.frontiersin.org 14
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Application of a distributed verification in Islamic microfinance institutions: a sustainable model
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creativecommons.org/licenses/by/4.0/. Application of a distributed verification
in Islamic microfinance institutions:
a sustainable model Peter Wanke1, M. Kabir Hassan2* , Md. Abul Kalam Azad3, Md. Azizur Rahman4 and Naznin Akther3 Peter Wanke1, M. Kabir Hassan2* , Md. Abul Kalam Azad3, Md. Azizur Rahman4 and Naz JEL Classification: E49, G30, Q01 JEL Classification: E49, G30, Q01 Wanke et al. Financial Innovation (2022) 8:80
https://doi.org/10.1186/s40854-022-00384-z Wanke et al. Financial Innovation (2022) 8:80
https://doi.org/10.1186/s40854-022-00384-z Financial Innovation Open Access 3 Department of Business
and Technology Management,
Islamic University of Technology,
Gazipur 1704, Bangladesh
4 Department of Business
Administration, Faculty
of Business & Entrepreneurship,
Daffodil International University,
Dhaka, Bangladesh Abstract The literature gap in microfinance paradox of double bottom line (financial per-
formance vs. outreach) has always been an interesting area of research. This paper
proposes a theoretical model most suitable for Islamic Microfinance Institutions (MFIs)
which enables Islamic MFIs’ to operate together with the existing financial models
compliant with Islamic Shariah Law. This model is based on a distributed verification/
decision-making process that might be realized (but not necessary) through block-
chain. Among the available distributed verification techniques, blockchain technology
is an attractive emerging computing paradigm due to its decentralized, immutable,
shared, and secure data structure characteristics. This model proposes three significant
propositions. First, sharing information through blockchain will allow a transparent
network in MFI operations, which will raise confidence for donors resulting in a causal
effect of a relatively lower profit rate to be charged by the MFIs. Second, the consensus
mechanism will enable risk-sharing, a character of Islamic finance; thus, the MFIs will
operate without any collateral for low-risk firms. Third, the double bottom line of MFIs’
long-lasting paradox would be solved. As for practical implication of this proposed
model, the causal impact of lower cost investment by the lenders would increase
social welfare because of no collateral and no initial wealth requirement. The proposed
model proposes a credit rationing approach where profit can be negative. No collateral
will be used when calculating the creditworthiness of a borrower. 1 COPPEAD Graduate Business
School, Federal University of Rio
de Janeiro, Rua Paschoal Lemme,
355, Rio de Janeiro 21949‑900,
Brazil 2 Department of Economics
and Finance, University of New
Orleans, New Orleans, LA 70148,
USA 3 Department of Business
and Technology Management,
Islamic University of Technology,
Gazipur 1704, Bangladesh
4 Department of Business
Administration, Faculty
of Business & Entrepreneurship,
Daffodil International University,
Dhaka, Bangladesh Keywords: Blockchain, Islamic microfinance, Double bottom line, Distributed
verification JEL Classification: E49, G30, Q01 *Correspondence:
mhassan@uno.edu
1 COPPEAD Graduate Business
School, Federal University of Rio
de Janeiro, Rua Paschoal Lemme,
355, Rio de Janeiro 21949‑900,
Brazil
2 Department of Economics
and Finance, University of New
Orleans, New Orleans, LA 70148,
USA
3 Department of Business
and Technology Management,
Islamic University of Technology,
Gazipur 1704, Bangladesh
4 Department of Business
Administration, Faculty
of Business & Entrepreneurship,
Daffodil International University,
Dhaka, Bangladesh Introductionhi The global financial crisis in 2008 instigated developing a stable, transparent, independ-
ent, and sustainable financial system worldwide (Kayed and Hassan 2011; Petrick 2009). These financial anomalies have strained regulators consistently restrict managerial activ-
ities with rigid rules. However, facts have shown otherwise. Strict regulation in finan-
cial sectors probes a lack of investor confidence, which is against the logic of sustainable
development (Nguyen 2016). Besides the regular performance agenda among the finan-
cial institutions, transparency in corporate data have been critical factors of investor Wanke et al. Financial Innovation (2022) 8:80 Page 2 of 12 confidence (Berger et al. 2011; Hoff and Stiglitz 1990; Nguyen 2016). Recent financial
scandals and the adverse impact of the financial crisis on the performance of microfi-
nance institutions (MFIs) urges for a sustainable financial model. i
The precondition of a sustainable model is that an institution must have been operat-
ing without any significant influence from any internal and external institutions, which
may include intermediaries, government, and relevant regulators (Adegbite et al. 2013). In practice, the traditional MFIs operation permits external institutions to privatize
profits and socialize the potential losses (Adegbite et al. 2013; McGuire and Conroy
2000). However, the two are not necessarily in tension. Literature indicates that recent
digital innovations, such as blockchain, have great potential to change today’s business
mechanism and an entire economy (Nguyen 2016). As a way out, tech-savvy enthusiasts
use the internet and innovate blockchain embedded cryptocurrency. Sulkowski (2018)
examined entrepreneurs’ opinions who actively bring blockchain-embedded technolo-
gies into the potential market. The results reveal that blockchain-enabled technologies
improve transparency and reliability which will only be realized when there is a support-
ive law framework. Besides the ’tamper-proof’ technology of blockchain from alteration of data, some
high-profile hacks treat blockchain as un-hackable as the Titanic was unsinkable1! Even
if the technology works flawlessly, the underlying human fascination for corruption
while creating the underlying records cannot be tackled using blockchain technology.2
Blockchain is just a technology. It could be an immutable database system with excellent
tracing records capabilities promoting transparency. Yet, it is just a system in which the
accuracy of its output depends on the accuracy of the input. Besides a flawless block-
chain-enabled technology for MFIs operation, a supportive legal framework and govern-
ment policy are prerequisites before offering a sustainable model. 1 Swati Khandelwal, Hackers Stole $32 Million in Ethereum; 3rd Heist in 20 Days, THE HACKER NEWS (July 19,
2017), https://thehackernews.com/2017/07/ethereum-cryptocurrency-hacking.html (accessed August/24/2020).
2 See The great chain of being sure about things, THE ECONOMIST (Oct. 31, 2015), (accessed August/24/2020)
https://www.economist.com/briefing/2015/10/31/the-great-chain-of-being-sure-about-things.
3 See
https://www.securingindustry.com/food-and-beverage/ey-partners-with-ezlab-on-blockchain-wine-security-
project/s104/a4014/#.X0SyZ8gzbIV (accessed August/24/2020).
4 Data from https://coinmarketcap.com (accessed August/23/2020). Tokens are digital assets such as vouchers, debt
instruments (IOUs), or real-world objects. They are mostly based on the Ethereum blockchain. Introductionhi f
The application of blockchain-enabled technologies in recent times reportedly func-
tions well in diverse areas: inventory authentication (Düdder and Ross 2017); proof-of-
provinces (Verberne 2018); good labor environment and practice3 along with finance
sectors (Chen and Bellavitis 2020; Treleaven et al. 2017; Xu et al. 2019). The first cryp-
tocurrency was launched in 2009 with the name bitcoin that works as both a payment
system and a fully digital currency (García-Corral et al. 2022). Today there are more
than 6,537 cryptocurrencies on the market and 200 tokens.4 Recently the term block-
chain has shifted slightly to mean distributed ledger technology, which sheds light on
a worldview that blockchain technology has potential application possibilities in many
sectors beyond today’s imagination (Dujak and Sajter 2019; Iansiti and Lakhani 2017;
Wang et al. 2018; Fang, F., Ventre, C., Basios, M. et al.,2021). This paper proposes a
blockchain-embedded model for its sustainable development and operations for micro-
finance institutions. Wanke et al. Financial Innovation (2022) 8:80 Wanke et al. Financial Innovation (2022) 8:80 Page 3 of 12 The ability to access credit in MFIs have restricted the potential growth and develop-
ment of MFIs in many countries (Azad et al. 2016). Having considered the principles
of blockchain technology, this paper proposes a theoretical model that will make MFIs
operations sustainable. This proposed model is named a sustainable model considering
its capacity to reduce profit rate for credit distribution (Hassan 2014; Chong 2021) and
reduce information asymmetry due to theoretically meager chances to manipulate infor-
mation (Hoff and Stiglitz 1990). Islamic MFIs, like other MFIs, aim to provide financial
services on a micro-scale to assist poor people who are forsaken by commercial banks
(Handayani et al. 2018). Islamic MFIs can only offer contracts to their clients based on
pre-agreed profit- and loss-sharing partnerships. Thus, a blockchain embedded interest
free model is most suitable for Islamic MFIs by ensuring their stability. The contributions of this proposed model are threefold. First, by challenging the con-
ventional credit system, our proposed blockchain-embedded model solves some criti-
cal issues in Islamic MFIs, such as information asymmetry and credit rationing, which
ensures the financial sustainability of MFIs and enhances social outreach. A lower profit
rate will be charged by the MFIs because the information in blockchain consensus can-
not be altered or amended. Thus, the consensus mechanism will enable the risk-sharing
character of Islamic MFIs (Mohamed and Ali 2018). Introductionhi Second, we remove the traditional
non-negativity restriction in the credit rationing approach, which allows profits to be
negative, and developed a model theory that does not need collateral during the loan/
credit evaluation process. Third, our proposed model helps ensure sustainable social
wealth by enhancing social welfare and provides a reliable and transparent credit system
compared to conventional credit systems. Additionally, reliability and transparency will
improve quality disclosure to lenders and borrowers and regulatory agencies and gov-
ernments by facilitating the standardized monitoring of MFIs. In recent literature, moni-
toring has been identified to reduce loan repayment problems (Berns et al. 2021) and
corrupt behavior (Azim et al. 2017). At this point, the decentralized sharing of informa-
tion through our proposed model will solve the current monitoring challenges of MFIs,
helping to build reputation and image by reducing the possibility of corruption scandals.hh This paper has six sections. The second section reviews the literature on Islamic MFIs. "Blockchain technology: scope and areas of application in Islamic MFIs" section explains
the scope and principles of blockchain technology for sustainable operations of Islamic
MFIs. The proposed model for sustainable MFI operations is given in "Proposed model
for MFIs" section, followed by propositions in "Propositions" section. Finally, "Conclu-
sion" section is the conclusion. Literature review The target borrowers of MFIs are not financially eligible to access bank services due to
financial status. Examining present conditions of more than two billion people among
the developing economies with limited to no access to banking resources, Larios-
Hernández (2017) studied five characteristics for the demographic: cash preference,
accustomed lending practices, traditional money transfer system and remittance receipt
preference, identification of personnel, and availability of infrastructure. While the sce-
nario of financial inclusion varies across developed, developing, and underdeveloped
economics, access to financial services remains a challenge in rich countries (including Wanke et al. Financial Innovation (2022) 8:80 Page 4 of 12 the UK) (Datta 2018). Relating to microfinance operations, Mader and Morvant-Roux
(2019) discussed different financial inclusion approaches. Moreover, Muslims who are
religious, believe in interest-free investments also possess extra sensitivity to accessing
financial services from traditional MFIs since their operations are interest-rate-based. i
Islamic microfinance is a special type of microfinance consistent with the principles of
Islamic laws (Shariah). It is a practical application through the development of Islamic eco-
nomics (Haque and Yamao 2011). Shariah prohibits the payment of fees for the loaning of
money for specific terms, which is commonly known as interest (in Islamic terminology,
’riba’). All Muslim scholars are adamant that this prohibition extends to all forms of riba and
that there is no difference between interest-bearing funds for consumption or investment
purposes (El-Zoghbi and Tarazi 2013). Instead, money can be exchanged for any product or
service in the form of collateral (Ahmad and Rafique Ahmad 2009). In the same logic, Sha-
riah prohibits interest in personal investments. Hassan (2014) found that collective actions
through Islamic microfinance groups help increase environmental awareness, economic bet-
terment of the members, and fruitful management of the liquidity coverage ratio. Abubakar
et al. (2019) examine various aspects of cryptocurrency and its Shariah compliance.h The main distinction between conventional institutions and MFIs is that the former
is interest-based. At the same time, the latter is interest-free since the sharia prohibits
the receiving and giving of any fixed, predetermined rate of return on financial transac-
tions, or in other words, interest (El-Zoghbi and Tarazi 2013; Ghouse et al. 2021; Mirzaei
et al. 2022). Literature review All the monotheistic religions prohibit interest due to its exploitative nature
that creates inequality within society as it allows the lender to extract more wealth from
vulnerable borrowers who may need to borrow money to meet their basic consump-
tion requirements (El-Zoghbi and Tarazi 2013). It is also unfair because such a prac-
tice makes the lender richer and the borrower poorer, and the latter also must bear all
the risks in the financial transaction (Austin 2004). Moreover, interest is also deemed an
inequitable form of the transaction as it charges interest on loans for a productive pur-
pose. At the same time, the moral economy of Islam encourages profit and loss sharing
that reflects the level of participation between both parties. l
Despite the rapid growth of MFIs in terms of their financial performances, their social out-
reach remains very poor compared to the total number of poor people worldwide (Church-
ill 2020; González Vega 1998; Meyer 2019; Sakti 2021). González Vega (1998) categorized
microfinance outreach in six groups: (i) Quality- each client’s value of any MFIs; (ii) Cost-
both interest/profit cost and transactions cost; (iii) Depth- social value to extend the services
of MFIs to any client groups; (iv) Breadth- total number of clients; (v) Length- the number
credits have been offered to a client; and (v) Variety- types of financial services offered to the
clients. Theoretically as well as empirically, if a microfinance institute is somehow becoming
profitable, there is a high probability that it did not outreach successfully (Churchill 2020;
McGuire and Conroy 2000; Meyer 2019). Thus, the objective of achieving the double bottom
line (financial performance and outreach) of MFIs has been continuing to be a paradox. Blockchain technology: scope and areas of application in Islamic MFIs The first proposal of the blockchain concept was proposed by Nakamoto (2008). In
plain words, blockchain is a type of digital record-keeping (Iansiti and Lakhani 2017). The technical elements required to enable and store are blocks, chain structure, hash Wanke et al. Financial Innovation (2022) 8:80 Page 5 of 12 algorithm, timestamp, and Merkle tree (Cong and He 2018; Iansiti and Lakhani 2017;
Wang et al. 2018). Besides explaining the technical terminologies, the basic operations of
a blockchain platform can be summarized to include a ’chain’ of ’blocks’; a block stands
for the digital data of any kind, and chain stands for the decentralized public database in
which anyone of the chain owns the data without any intermediation and central control
of the distribution of data. Furthermore, the timestamp, hash algorithm, and Merkle tree
are technical applications to keep the record completely traceable and un-interrupt (Ian-
siti and Lakhani 2017; Wang et al. 2018). The underlying technology of blockchain can be summarized in five principles (Iansiti
and Lakhani 2017). First, with a distributed database, no one has control over the data-
base. Each party within a network has equal access to the database to verify any transac-
tion without an intermediary. Second, with the peer-to-peer transmission, no member/
node works as a central node for sharing information, but rather, each node transmits
and records information of a single transaction to all other nodes. Third, transparency
means anyone in the system can see the information and amount of each transaction. Fourth, irreversibility of records indicates the record cannot be altered because data are
linked to every node of the system. And fifth is computational logic. Using the compu-
tational logic or programmed rules, blockchain technology can automate a trigger for
completing a transaction between nodes. The digital nature of a blockchain transaction allows computer programmers to set up
algorithms that automatically complete a transaction between two nodes (García-Cor-
ral et al. 2022). Therefore, the blockchain technology in the financial system will ena-
ble users to have a semi-formal since blockchain system offers a distributed ledger and
privacy embedded with utmost security platform to access fund and completely ignore
the need to use an interest-based financial system for operation. Thus, the adoption of
blockchain technology in Islamic microfinance operations would offer a sustainable
solution to poor communities and resolve the moral issue of riba among poor Muslim
communities globally. Blockchain technology: scope and areas of application in Islamic MFIs Several successful applications of blockchain-enabled technologies in Islamic finan-
cial institutions can be traced, aiming to strengthen Shariah-compliant business models
(Abubakar et al. 2019; Alam et al. 2019; Kabra et al. 2020; Mohamed and Ali 2018; Fang
et al. 2021; García-Corral et al. 2022). For example, Emirates NBR can be tracked as the
first Islamic bank to integrate blockchain technology initially for cheque-based payment
(Kabra et al. 2020). Similarly, Al Hilal bank was followed for the first successful applica-
tion of blockchain technology for Sukuk (an income-bearing Islamic Shariah contract
similar to conventional bond) transactions (Alam et al. 2019). Blossom’s SmartSukuk is
another successful blockchain-enables Sukuk initiative by Indonesia. In addition, South
Africa-based POCertify applied blockchain for halal certifications. Finally, global Sad-
aqah is a Malaysian-based blockchain initiative of a charity organization. Traditional credit model The traditional MFI credit model is described in Fig. 1. MFIs receive funds from either
or all available sources: private equity, financial institutions, and personal donors
(Ledgerwood 1998). According to their policy, organizational structure, and partner Page 6 of 12 Wanke et al. Financial Innovation (2022) 8:80 Wanke et al. Financial Innovation Fig. 1 Traditional credit model in MFIs Fig. 1 Traditional credit model in MFIs organizations, the MFIs then distribute and channelize the fund to the poor people
(Ledgerwood 1998). Based on the character of institutional structure (i.e., formal,
semi-formal, and informal), MFIs’ objectives and operations may differ (Ledgerwood
1998; McGuire and Conroy 2000). Recently, MFIs have been cooperating with other
development agencies (i.e., government, NGOs, donors) to enhance operating effi-
ciency (Adegbite et al. 2013; Austin 2004; McGuire and Conroy 2000). Thus, the part-
ner organizations’ characteristics may also impact MFIs’ objectives and operations. g
y
p
j
p
Among others, the traditional credit model was described by Stiglitz and Weiss
(1981), Bester (1985), and Wang et al. (2018). Based on the theory of collateral and
limited liability along with the presence of information asymmetry, Stiglitz and Weiss
(1981) examined why banks cannot increase the collateral requirement (or decrease
borrowers’ debt-to-equity ratio) besides knowing that there is a relatively higher
demand of loans out in the market? Here, as per the credit channel theory, asymmet-
ric information in the credit market propagates the effect of the interest rate channel. Their findings revealed that the observationally identical borrowers may or may not
receive loans from a bank. Even if the rejected borrowers are willing to pay a higher
interest rate for their loans or increase their collaterals, this would only upsurge the
riskiness of a bank’s portfolio by either encouraging them to invest in risky projects or
discouraging safe investors. Details of the model are given below. Following the models of Adegbite et al. (2013), Austin (2004), Ledgerwood
(1998), McGuire and Conroy (2000), Stiglitz and Weiss (1981), and Wang et al. (2018), this section will describe the traditional credit model of MFIs. Assume
that a hypothetical credit market has asymmetric information. Let us consider
that loan takers classify under either i =: 1 : lowrisk, 2 : highrisk . The total credit
amount is presented as M. Traditional credit model After adjusting the assumptions of Islamic MFIs into the traditional credit
market model, the modified equations would be as follows: (3)
πi(r) = Pi(Xi −MR)
(4)
ρi(r) = PiMR −M(1 + s) πi(r) = Pi(Xi −MR) (3) (4)
ρi(r) = PiMR −M(1 + s) (4)
ρi(r) = PiMR −M(1 + s) ρi(r) = PiMR −M(1 + s) (4) The modifications are based on the following assumptions: The modifications are based on the following assumptions: The modifications are based on the following assumptions: The modifications are based on the following assumptions: a) Initial wealth W is 0 a) Initial wealth W is 0 b) Collateral C is 0 c) If a project fails, the return is negative but not more than the loan amount M. Thus, the estimated loss is ≤ M. Here, Eqs. 3 and 4 completely ignores the probabil-
ity of failure of any project based on the assumptions of W = 0 and C = 0. Theoretically,
with higher collateral, the rate of interest/profit (R) is supposed to get lower (Berger
et al. 2011). In the case of Islamic MFIs, this paper proposes a new scheme based on
blockchain to indicate the rate of R. 5 In probability and statistics, a mean-preserving spread (MPS) is a change from one probability distribution A to
another probability distribution B, where B is formed by spreading out one or more portions of A’s probability density
function or probability mass function while leaving the mean (the expected value) unchanged. See https://www.scien
cedirect.com/science/article/abs/pii/0022053170900384?via%3Dihub. Traditional credit model The expected return, probability of success of an invest-
ment/project, and probability of failure of an investment/project shall be given as
πi(r) for loan taker and pi(r) for MFIs, Pi and 1 −Pi respectively. Wanke et al. Financial Innovation (2022) 8:80 Page 7 of 12 According to Stiglitz and Weiss (1981), P1X1 = P2X2 because of mean preserving
spread of returns5 (Xi) . The MR indicates total profit/interest earned, where R indicates
gross profit rate (we are calling this profit rate since Islamic MFIs cannot charge interest)
asked by MFIs. Primarily, R is determined by the market by analyzing opportunity costs. Finally, we assume that a credit institution depositor a deposit rate as denoted with (s) . Based on the above assumptions, the basic models of expected returns in a traditional
financing system can be expressed in Eq. 1 and 2. They explain the expected return
expected of a loan taker and an MFIs, respectively. (1)
The expected return of loan taker πi(r) = Pi(Xi + W −MRi)+(1 −Pi)(W −C)−W (1)
The expected return of loan taker πi(r) = Pi(Xi + W −MRi)+(1 −Pi)(W −C)−W (1)
The expected return of loan taker πi(r) = Pi(Xi + W −MRi)+(1 −Pi)(W −C)−W
(2)
The expected return of MFI ρi(r) = PiMRi + (1 −Pi)C −M(1 + s) (2)
The expected return of MFI ρi(r) = PiMRi + (1 −Pi)C −M(1 + s) (2) We now assume that initial investment (W) is 0, collateral ( C ) is 0, and probability of
success of a high-risk project (P2) is higher than a low-risk project ( P1) : P2 > P1 . This
is to be mentioned here that, unlike the traditional MFIs operation, this model contrib-
utes theoretically by proposing that a loan taker can receive MFIs loan even without any
collateral and initial investment. Theoretically, this assumption may increase the default
risk of that loan taker, yet our model illustrates a better probability of success for a high-
risk project. Blockchain embedded model The underlying condition for getting approval of credit from a blockchain-embedded sys-
tem requires receiving a decentralized consensus by providing a minimum degree of infor-
mation for verification approval of credit (Cong and He 2018). Therefore, a modified model
for a blockchain embedded credit system is provided in this subsection. For illustration, Wanke et al. Financial Innovation (2022) 8:80 Page 8 of 12 Page 8 of 12 a low-risk investment from MFIs will be examined using a blockchain-embedded model,
and a high-risk investment is presented with a traditional model. Finally, Eq. 5 describes the
expected return of a low-risk loan taker through a blockchain model. a low-risk investment from MFIs will be examined using a blockchain-embedded model,
and a high-risk investment is presented with a traditional model. Finally, Eq. 5 describes the
expected return of a low-risk loan taker through a blockchain model. (5)
π1(r) = P1(X1 + W −MR1) + (1 −P1)(W −D) −W −f
= P1X1 −P1MR1 −(1 −P1)D −f (5) Here, f is the usage fee of blockchain technology for the loan taker, and D is the default
loss of a loan receiver. As shown in Eq. 5, M is the compensation the lender would make in a
traditional model. However, in the case of Islamic MFIs, W is 0; hence, the modified model
would be: (6)
π1(r) = P1(X1 −MR1) + (1 −P1)(D) −f
= P1X1 −(1 −P1)D −P1MR1 −f
= P1X1 −(1 −P1)D −(1 −P1)(1 −a)M −M(1 + s) −f (6) Here, the equation introduces a category in a total investment of credit by all MFIs with
( a) and (1 −a) is the portion of MFIs credit distributed by the government as we assumed
that in any country, collaborative work between MFIs and the government could only work
appropriately (Sulkowski 2018; Treleaven et al. 2017). Furthermore, without involving gov-
ernment in the blockchain embedded MFIs operation, the legal framework would not work
prospectively. Thus, the expected return of MFIs from investments into a low-risk invest-
ment would be: (7)
ρ1(r) = P1MR + (1 −P1)aM −M(1 + s) −g (7) Here, g is the cost involved by MFIs for using blockchain technology (Janssen et al. 2020). Figure 2 depicts a blockchain-embedded credit system for Islamic MFIs. Blockchain embedded model Figure 2 presents
that during a transactions in the blockchain-embedded credit system, all the stakehold-
ers: donors; financial institutions; Islamic MFIs; credit receiver and private equity provid-
ers, will be notified and through distributive ledger system of blockchain, the Islamic MFIs
require no additional document to be produced and submitted to the creditors, loan receiv-
ers, government agencies and whatsoever. Nevertheless, distributive ledger automatically
updates all stakeholders on the updates of any loan repayments and failures. For the blockchain service provider, the return can be calculated using δi(r): (8)
δi(r) = f + g −(1 −Pi)M δi(r) = f + g −(1 −Pi)M (8) Now, if the expected return from a high-risk firm is intended with a low-risk firm (assum-
ing that R1 will equal here), its expected return would be: (9)
π2(r) = X0 −(1 −P2)D −P2MR1 −f
= P1X1 −(1 −P2)D −P2
P1
M(1 + s) −(1 −P1)(1 −a)M −f
−f (9) Propositions The first proposition for using blockchain-embedded technology by Islamic MFIs is
reducing information asymmetry among MFIs, donors, government, loan receivers,
and all other parties. The information will be decentralized, and under consensus, the
lending and borrowing function in Islamic MFIs would be more seamless and effec-
tive (González Vega 1998; Iansiti and Lakhani 2017; Treleaven et al. 2017). Secondly,
the causal effect of such symmetric information with all the Islamic MFI stakeholders
would ignore collateral requirements (Stiglitz and Weiss 1981). Thus, the traditional
credit market could easily fit into the modified model, as shown in Eq. 6. ii
The third and most important opportunity of using a blockchain-embedded model in
Islamic MFIs would be a low-profit rate R since creditor information is available, thus
lowering the probability of manipulation; this formulates a self-sufficient system to track
risky investors. In addition, the tamper-proof and algorithmic execution characteristics
of blockchain technology may also enhance the reliability of the conventional credit sys-
tem. It is also easy to ensure proper monitoring by the regulators or doners. Finally, the
overall social wealth will increase for applying blockchain technology among the MFIs. Blockchain in Islamic MFI financing—does the adoption improve social welfare? Subject to the ability of this blockchain-embedded model to distinguish between a low-
risk firm and a high-risk firm, the return from a low-risk firm would be positive (Eq. 10). Page 9 of 12 Wanke et al. Financial Innovation (2022) 8:80 Wanke et al. Financial Innovation Fig. 2 Proposed blockchain embedded credit system for MFIs Fig. 2 Proposed blockchain embedded credit system for MFIs However, if a high-risk firm that takes a loan from the traditional system can be intended
with its counterpart (low-risk firm R1 ), the return of a high-risk firm would be lower
than the benefit derived from the traditional manner (Eq. 11). (10)
P1X1 −(1 −P1)D −(1 −P1)(1 −a −b)M −M(1 + s) > 0 (10) (11)
P1X1 −(1 −P2)D −P2
P1
M(1 + s) −(1 −P1)(1 −a −b)M −f
−f < P1X1 −M (11) Now, subject to the satisfaction parameter of default loss D: Now, subject to the satisfaction parameter of default loss D: (12)
(P2(1 −P1)(1 −a −b) + P1 −P2)M + (P2 −P1)f −P2s
P1(1 −P1)
< D < P1X1 −(1 −P1)(1 −a −b)M −M(1 + s)
(1 −P1) (12) Thus, the expected outcome of this proposed blockchain embedded Islamic MFI
model would explain a reasonable default cost, D, within which all low-risk firms would
prefer to switch their business to a blockchain-embedded credit market. In contrast,
high-risk firms will continue in the traditional market. Thus, the credit rationing prob-
lem (high-risk vs. low-risk firms) in any credit market (Bester 1985) has been mitigated
through a blockchain model.i Finally, since the high-risk firms will continue borrowing from the local market, the
total social wealth will maximize with an assumption that low-risk firms will adopt
blockchain technology: (13)
W = P1X1 −(1 −P1)D −M(1 + s) W = P1X1 −(1 −P1)D −M(1 + s) (13) (14)
D < P1X1 −M(1 + s)
(1 −P1)
(when W > 0) (14) Page 10 of 12 Wanke et al. Financial Innovation (2022) 8:80 Wanke et al. Financial Innovation Conclusion New developments in the era of technological innovation and adoption include the
acceptance and advancement of next-generation information technologies (i.e., cloud
computing, data mining, artificial intelligence, and mobile internet). Blockchain, one
of the most attractive technologies in recent years, has seen extensive growth and
great potential for applications in financial sectors (Conoscenti et al. 2016; Iansiti
and Lakhani 2017; Larios-Hernández 2017; Nguyen 2016; Wang et al. 2018). How-
ever, blockchain is just a technology. It could be an immutable database system with
excellent tracing records capabilities promoting transparency. Yet. It is just a system
in which the accuracy of its output depends on the accuracy of the input. The gov-
ernance issues of blockchain technology can be a challenge to the proposed model. Last but not least, high operating costs and computer able experts can be considered
as detrimental factors for implementation of blockchain embedded MFIs. Borrow-
ers’ or loan takers’ computer literacy is also a concern. MFIs are mostly targeting on
‘Ultra poor’- who might not have smart phone or even internet access, then how the
proposed model to solve this issue? Yes, some countries like Bangladesh initiates the
Union digitalization Programs- every Union Offices should have internet access. fi
The proposed theoretical model has the following implications: First, this paper
addresses the unsolved issue of information asymmetry and credit rationing in the tradi-
tional credit system of MFIs, specifically in Islamic MFIs. The nature of an Islamic MFI
business model kept the MFIs from reaching the double bottom-line (financial sustain-
ability and social outreach). Second, this paper develops a model theory to show that
social wealth will grow sustainably if low-risk firms receive loans from Islamic MFIs
through our blockchain embedded model. Finally, one of the primary upgrades on this
proposed model is that a credit rationing approach is introduced where profit can be
negative. No collateral will be used when calculating the creditworthiness of a borrower. Wanke et al. Financial Innovation (2022) 8:80 Page 11 of 12 Wanke et al. Financial Innovation (2022) 8:80 To the best of our knowledge, this is one of the first papers that examines the appli-
cation possibility of using blockchain technology in MFIs, especially in Islamic MFIs. Despite the earlier relevant model provided by Wang et al. (2018), the major contribu-
tion of this model that it mainly suitable for Islamic MFIs instead of traditional MFIs. Competing interests
The authors declare that they have no competing interests. Competing interests
The authors declare that they have no competing interests. Received: 9 April 2020 Accepted: 18 August 2022 Received: 9 April 2020 Accepted: 18 August 2022 Conclusion This model may however, also application to general MFIs. Since Islamic Law strictly
prohibits fixed income generated money transaction agreement, only transparent and
accountable model like this is most application. Overall, with the assumption of zero
initial wealth and zero collateral of this model perfectly fits this model for the actual
group of needy people in the society. Finally, the proposed model also justifies that
overall social welfare may be achieved. Therefore, this paper provides a lot of scope
for future research. A few key areas would be including smart contracts in analyzing
and distributing information asymmetry and credit rationing for the MFI financing
issue and examining financial inclusion for socio-economic development. ut o co t but o s
PW participated in concept development and editing. MH has developed the idea further and editing. AKA participated
in concept development and has written the first draft. AR has revised the first draft. NA has contributed to model devel-
opment. All authors read and approved the final manuscript. Funding
None. Availability of data and materials
None. Availability of data and materials
None. Author contributions PW participated in concept development and editing. MH has developed the idea further and editing. AKA participated
in concept development and has written the first draft. AR has revised the first draft. NA has contributed to model devel-
opment. All authors read and approved the final manuscript. References Palgrave Macmillan, Cham, pp 349–378 Verberne J (2018) How can blockchain serve society? Paper presented at the World Economic Forum. Greece References Harv Bus Rev 95(1):118–127
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finance and sustainable development. Publisher’s Note Publisher s Note
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Fog Computing Enabling Industrial Internet of Things: State-of-the-Art and Research Challenges
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Received: 14 August 2019; Accepted: 23 October 2019; Published: 5 November 2019 Abstract:
Industry is going through a transformation phase, enabling automation and data
exchange in manufacturing technologies and processes, and this transformation is called Industry
4.0. Industrial Internet-of-Things (IIoT) applications require real-time processing, near-by storage,
ultra-low latency, reliability and high data rate, all of which can be satisfied by fog computing
architecture. With smart devices expected to grow exponentially, the need for an optimized fog
computing architecture and protocols is crucial. Therein, efficient, intelligent and decentralized
solutions are required to ensure real-time connectivity, reliability and green communication. In this
paper, we provide a comprehensive review of methods and techniques in fog computing. Our focus
is on fog infrastructure and protocols in the context of IIoT applications. This article has two main
research areas: In the first half, we discuss the history of industrial revolution, application areas of
IIoT followed by key enabling technologies that act as building blocks for industrial transformation. In the second half, we focus on fog computing, providing solutions to critical challenges and as an
enabler for IIoT application domains. Finally, open research challenges are discussed to enlighten fog
computing aspects in different fields and technologies. Keywords:
Industry 4.0; Internet of Things; Industrial Internet of Things; Cyber Physical
System; cloud computing; fog computing; edge computing; smart devices; smart factory;
industrial automation Rabeea Basir 1, Saad Qaisar 1, Mudassar Ali 1,2,* , Monther Aldwairi 3,
Muhammad Ikram Ashraf 4, Aamir Mahmood 5 and Mikael Gidlund 5 Rabeea Basir 1, Saad Qaisar 1, Mudassar Ali 1,2,* , Monther Aldwairi 3,
Muhammad Ikram Ashraf 4 Aamir Mahmood 5 and Mikael Gidlund 5 Rabeea Basir 1, Saad Qaisar 1, Mudassar Ali 1,2,* , Monther Aldwairi 3,
4
5
5 Rabeea Basir 1, Saad Qaisar 1, Mudassar Ali 1,2,* , Monther Aldwairi 3,
Muhammad Ikram Ashraf 4, Aamir Mahmood 5 and Mikael Gidlund 5 1
School of Electrical Engineering and Computer Science, National University of Science and Technology,
Islamabad 44000, Pakistan; rbasir.dphd17@seecs.edu.pk or rabeeabasir@gmail.com (R.B.);
saad.qaisar@seecs.edu.pk (S.Q.) 1
School of Electrical Engineering and Computer Science, National University of Science and Technology,
Islamabad 44000, Pakistan; rbasir.dphd17@seecs.edu.pk or rabeeabasir@gmail.com (R.B.);
saad.qaisar@seecs.edu.pk (S.Q.) q
p
2
Department of Telecommunication Engineering, University of Engineering and Technology,
Taxila 47050, Pakistan 2
Department of Telecommunication Engineering, University of Engineering and Technology,
Taxila 47050, Pakistan
3 3
College of Technological Innovation, Zayed University, Abu Dhabi 144534, UAE; monther.aldwairi@zu.ac.ae
4 3
College of Technological Innovation, Zayed University, Abu Dhabi 144534, UAE; monther.aldwairi@zu.ac.ae
4
Centre for Wireless Communication, University of Oulu, 90014 Oulu, Finland; ikram.ashraf@oulu.fior
ik
h
f@
il 3
College of Technological Innovation, Zayed University, Abu Dhabi 144534, UAE; monther.aldwairi@zu.ac.ae
4
Centre for Wireless Communication, University of Oulu, 90014 Oulu, Finland; ikram.ashraf@oulu.fior
ikramashraf@gmail.com
5 College of Technological Innovation, Zayed University, Abu Dhabi 144534, UAE; monther.aldwairi@zu.ac.ae
4
Centre for Wireless Communication, University of Oulu, 90014 Oulu, Finland; ikram.ashraf@oulu.fior
ikramashraf@gmail.com 5
Department of Information Systems and Technology, Mid Sweden University, 85170 Sundsvall, Swede
aamir.mahmood@miun.se (A.M.); mikael.gidlund@miun.se (M.G.) *
Correspondence: mudassar.ali@hotmail.com or mudassar.ali@seecs.edu.pk Received: 14 August 2019; Accepted: 23 October 2019; Published: 5 November 2019 sensors sensors sensors www.mdpi.com/journal/sensors 1. Introduction Revolution in any realm is required with the passage of time. Every field changes to go forward
with better solutions dealing with the challenges of the era. Industrial Internet of Things (IIoT) is
revolutionizing the classical communication methodologies. With the emergence of smart devices
(mobile, machines, sensors) coupled with a diverse range of applications requirements, IIoT is the
way forward. It is expected that 26 billion IoT devices of heterogeneous capabilities will be installed
to perform functions with different Quality-of-Service (QoS) requirements by 2020 [1]. IIoT gives
rise to 4th industrial revolution based on Cyber-Physical Systems (CPS) with the need arising back
in 2015 originated basically in Germany [2]. Industry 4.0 defines diverse use cases ranging from Sensors 2019, 19, 4807; doi:10.3390/s19214807 www.mdpi.com/journal/sensors www.mdpi.com/journal/sensors 2 of 38 Sensors 2019, 19, 4807 interconnected digital technologies, CPS, Mobile Cloud Computing (MCC) and Internet of Things (IoT)
for promoting the whole industry in terms of efficiency, effectiveness, supporting heterogeneous data,
higher production, automation, and integrating knowledge [3]. These key enabling technologies have
been deployed to some extent in industrial domains such as healthcare, transportation, smart cities,
micro-grids, and smart factory. This trend gives rise to intelligent, distributed and self-organizing
solutions to support these application domains. Deploying industry 4.0 involves three-layer implementation; physical layer, network layer, and
intelligent-application layer [4]. The physical layer comprises identification and location awareness
entities i.e. actuators, sensors, and terminal devices; the network layer comprises of the development
of a network that can support industrial automation, network can be cellular, indoor, cloud or
private. Factory automation and coordination are processed on the application layer. Infrared (IR),
Radio-Frequency Identification (RFID), Bluetooth, 6LoWPAN, IEEE 802.11 af, IEEE 802.11 a/b/n/ac
for short range connectivity; Ultra-Wideband (UWB), cellular (2G, 3G, 4G, LTE-MTC, 5G), Sigfox, Long
range (LoRa) for long range connectivity, are a few of the majorly used communication standards for
IIoT [5,6]. The future of automation is based on decentralized intelligence in which all machines
can communicate with one another to arrive at independent or consensus inference, called
Machine-to-Machine (M2M) communication. These decentralized intelligent solutions play a vital
role in industry 4.0 digital transformation. The decentralized solutions provide flexibility and quick
decision assistance over centralized solutions. For M2M communication, 802.11ah technology has
evolved in the recent past. Exchanging machine data demands real-time communication ensuring
latency, security, reliability, bandwidth and privacy measures in all IIoT domains. 1. Introduction To satisfy these
critical requirements, there is a need to explore new enabling solutions that support these applications. In the future, 5G cellular technology will support such heterogeneous networks with massive number
of IIoT devices. It is anticipated that future 5G networks not only provide flexibility but can optimize
the usage of available resources of bandwidth, power, energy, connectivity to different applications at
the same time [7]. In the last decade, computation and processing requirements of end users have increased
exponentially. It has become increasingly challenging for designers to scale the processing and
data storage capabilities for users within the given device size and battery constraints. To meet these
growing requirements, researchers have come up with the solution to offload services to a centralized
location known as the cloud. Cloud computing is an alternative for data computation, storage
and management. It supports intensive computation and manages heterogeneous devices of next
generation networks [8–10]. Additionally, cloud computing architecture involves the direct connection
between devices and the cloud server. Practically, we are beginning to understand the connection
between and the enormous number of IIoT devices and a single cloud server. However, cloud-based
systems are unable to meet the requirement such as heavy data computation, real-time device
control, security and management results in insufficient support of IIoT application requirements [11]. Considering a wide variety of IoT scenarios, some of the challenges [10–16] in cloud computing are
listed below: Large distance between the cloud and edge devices causes propagation and transmission delays •
Large computational load on a single cloud server causes processing and queuing delays
•
Increased number of smart devices has hindered meeting the bandwidth requirements. g
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creased number of smart devices has hindered meeting the bandwidth requirements. •
Enormous number of smart devices will bring scalability, speed, and computational issues. Enormous number of smart devices will bring scalability, speed, and computational issues. Wireless medium between cloud and smart devices brings resource management issues. •
Heterogeneity property of smart devices in terms of accessing technology will bring difficulty in
handling at the cloud. •
Heterogeneity property of smart devices in terms of accessing technology will bring difficulty in
handling at the cloud. •
Mobility of IoT devices bring service availability issues, cloud server may not be able to provide
services due to network congestion and failure. 1. Introduction g
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In fog computing, data processing in single server (fog cloud) helps in achieving real-time and
reliable communication. It puts the safety and security of personal data back into our premises. Furthermore, a cost effective approach can be used in fog computing such that data transmission
and storage fees can be reduced based on service premises. Therefore, fog computing has the
potential to provide affordable solutions for large IIoT projects. Instead of being restricted to only
one expensive cloud connection, fog computing gives the freedom to choose any hardware from
Information Technology (IT) solutions. It supports all existing legacy devices and non-IIoT devices that
never intended to be the part of IIoT application. This is not only economical but also more flexible. When it comes to speed, fog computing allows real-time processing and supports to process data
as fast as our local system. Fog can be managed securely from remote places. It can be scaled and
updated dynamically. It gives more security, better performance, and lower costs. Fog incorporates
positive attributes of cloud and provides benefits that may support future IIoT applications [18–23]. Fog computing and edge computing being extended form of cloud computing gives solutions to
the challenges faced by cloud computing that is attractive for IIoT real-time applications. The terms
fog computing and edge computing are often used by industry interchangeably. Both these computing
technologies bring computing and processing capabilities near the vicinity where data originates. Edge computing complements fog computing by bringing computation to one of the devices of a
network. This device is named as E-node and is close to the data. E-node has more power, computation
capabilities and intelligent controllers, such as programmable automation controllers (PAC). Presence
of E-node in edge computing improves latency, reliability, security and privacy issues [24,25]. E-node
acts as an interface/bridge between the data sources and the cloud. The basic architecture for fog
network is given in Figure 1 depicting fog cloud serving as a middle layer between the cloud server and
smart end-devices. Figure 1 demonstrates a basic idea of cloud, fog and edge computing promoting
different IIoT application domains. Fog is a relatively new paradigm that brings new challenges in terms of efficient and scalable
network architecture. It is expected that it will gradually develop over the next few years for realizing
the Industry 4.0. 1. Introduction •
Mobility of IoT devices bring service availability issues, cloud server may not be able to provide
services due to network congestion and failure. Sensors 2019, 19, 4807 3 of 38 •
Security is a very critical thread, as the cloud is exposed to the whole world over the public internet. •
Security is a very critical thread, as the cloud is exposed to the whole world over the public internet. •
Security is a very critical thread, as the cloud is exposed to the whole world over the public internet. •
Computing offloading every-time at cloud causes a loss in energy and battery lifetime •
Computing offloading every-time at cloud causes a loss in energy and battery lifetime Computing offloading every-time at cloud causes a loss in energy and battery lifetime. •
Although data storage at cloud brings benefits to application developers, they should be careful
of integrity and authentication demands of IIoT applications. •
Although data storage at cloud brings benefits to application developers, they should be careful
of integrity and authentication demands of IIoT applications. •
Cloud computing is a centralized and complex architecture for real-time applications of IIoT. •
Cloud computing is a centralized and complex architecture for real-time applications of IIoT. All these limitations require a change, how and where we process data. These challenges motivate
us to explore new decentralized approaches/solutions in IIoT domains. A new concept of fog
computing is introduced by Bonomi et al. [15] for handling data locally at the network edge in
order to overcome the limitations of cloud architecture. Fog computing complements existing cloud
architecture and has addressed the issue of latency and bandwidth efficiency [17]. Because of its
distributed architecture, it calls for a strong check on QoS requirements to make it useful. Fog is
mainly based on distributed networking with ubiquitous pervasive computing. It comprises small
scale data centers or a group of computers known as cloudlets (fog clouds) that provide services to
devices located in close proximity [17,18]. The initial installation cost, latency, and energy consumption
is far less as compared to that of the cloud, but the operational cost varies. Fog architecture can
leverage computations either from dedicated edge servers or adhoc infrastructure. For promoting IIoT
architecture with fog computing as a key enabler technology, a group of fog clouds can also be used. 1. Introduction Challenges, such as energy conservation, real-time communication, efficient spectrum
use, cache memory on edge devices and optimized allocation of resources are open issues that need
to be addressed for future automation. Without such considerations, guaranteed QoS requirements
of IoT devices may not be fulfilled. In the future, solutions to these challenges must be provided by
researchers for the development of the industrial revolution. This paper is written with an aim to
give a summarized version of existing solutions using fog computing acting as an enabler for IIoT
applications. 4 of 38 Sensors 2019, 19, 4807 Figure 1. Generalized view: IIoT application domains with cloud, fog and edge computing. Figure 1. Generalized view: IIoT application domains with cloud, fog and edge computing. The paper is organized as follows; Section 2 briefly introduces IIoT. Benefits of IIoT applications
in daily life and their critical requirements are briefly explained in Section 3. Section 4 presents
protocol/solution proposed by various researchers promoting fog computing as an enabling technology
for IIoT development. Section 5 describes challenges and solutions in communication and networking
proposed in the literature to use fog computing in IIoT. Section 6 lists down several open research
issues in fog computing. Finally, the paper is concluded in Section 7. The flow of this survey paper is
shown in Figure 2. Figure 2. Flow of the paper. Figure 2. Flow of the paper. Sensors 2019, 19, 4807 5 of 38 2. Evolution and Enablers of Industrial Internet of Things As discussed earlier, IIoT or Industry 4.0 is a new emerging term for future industry, which
involves many key enabling technologies and applications of IoT. In this section, Industry 4.0
evolutional phases, IoT connectivity technologies, benefits from IIoT and key enabling technologies
that endorse industrial revolution are briefly explained. 2.1. Industry 4.0-Evolution The industrial revolution with the passage of time has many phases according to the requirement
and challenges of the respective era. Figure 3 gives an idea about evolution towards Industry 4.0 with
its elements. The industrial revolution with the passage of time has many phases according to the requirement
and challenges of the respective era. Figure 3 gives an idea about evolution towards Industry 4.0 with
its elements. Figure 3. Evolution towards Industry 4.0/IIoT. Figure 3. Evolution towards Industry 4.0/IIoT. Industry 1.0: At the end of the 18th century, the 1st industrial revolution started with the help
of water and steam power, which systematizes the factory floor. First, the mechanical weaving loom
was established in 1784, and the first mechanical system was built thorough mechanical production
facilities. Industry 2.0: In the beginning of the 20th century, the 2nd industrial revolution started
using electrical energy. The first assembly line using electrical energy was established in 1870. The introduction of mass production in industry 2.0 enhanced the industry. Industry 3.0: Beginning of the 1970s i.e., in 1969, the first control system using programming
language was established. Industry was slowly shifted to automation using information technology
and micro-electronics’s applications. This is the 3rd industrial revolution [26]. Industry 3.0: Beginning of the 1970s i.e., in 1969, the first control system using programming
language was established. Industry was slowly shifted to automation using information technology
and micro-electronics’s applications. This is the 3rd industrial revolution [26]. Industry 4.0: This previous industrial revolutions give rise to the development of industry
4.0. Industry 4.0 contributes a revolution to all domains comprising economic, academic, research,
industrial and manufacturing sectors. There is a huge impact of the industrial revolution on
the manufacturing processes of many fields. Implementing industry 4.0 demands change in
many technologies namely automation, identification, computer, network communication, digital
manufacturing, production process, production control management, decision making, judgment,
sensing and analysis [27]. In the future, the manufacturing industry is expected to change on a large
scale because of all new generation networks and interfaces offered by the environment of industry
4.0. This transformation is already in process in many industrial sectors. Up till now, for the fourth
industrial revolution, exponentially growing technologies are sensor technology, artificial intelligence, Sensors 2019, 19, 4807 6 of 38 machine learning, robotics, nanotechnology, and 3D printing [28]. 2.2. Industry 4.0-Concept Increasing progress is witnessed in automation of industry using advancement in digitization,
networking and new communication technologies, satisfying the market and consumer requirements [29]. Lenze SE, Corporate Communications Public Relations use idea of machine modularization. According to
the demand of market/consumers, different modules are added or removed during the manufacturing
process; machines are retooled smartly using smart communication technologies A cloud solution was
given by Lenze, which is secure as no customer wants to share their demands and production details. Details about the customer’s machine are saved in a cloud and he can investigate all the system details
especially faults. This cloud solution is vulnerable to hackers, Lenze, along with another company, have
provided a secure solution that is acceptable for today’s industry [30]. Charlotta Johnsson explained the idea of industry 4.0 using four terms, these are smart devices
and smart production processes with horizontally and vertically integrated manufacturing systems. Smart devices result in the production of intelligent products, these products do self-monitoring,
self-controlling and self-manufacturing, have a uniquely identifiable ID, know how to solve and achieve
goals [31]. The intelligent production process comprises smart starting and ending of manufacturing
processes. Vertical and horizontal integration means all the steps during the smart/intelligent
production process are integrated throughout the life cycle i.e., from starting phase to ending phase [30]. Industry 4.0 results in a faster manufacturing process, product development and improves
the handling of complex environments inside an industry. The term first originated in Germany
named as Industrie 4.0; in United States term used for this fourth generation is Smart Manufacturing,
Chinese researchers have used term China 2020. Industrial Digitisation is the term used in Sweden
for transformation of industry to automation [32]. It is believed that this industrial revolution will
increase global competitiveness, preserve the domestic manufacturing industry and will have a huge
impact on the business market as well. Now many countries around the globe have taken initiatives
for automation in industries. 2.1. Industry 4.0-Evolution These technologies were invented
decades ago, but their minimum cost and exponential growth will shape industry 4.0. To change the
industrial process, researchers are focusing on providing the evolved form of these technologies in
terms of flexibility and fast computational process. All this automation in industry is very important
for the economic growth of a country. 2.3. Industry 4.0-Merging CPS and IoT The Industry 4.0 environment is comprised of the Internet of data, Internet of things, Internet
of people and Internet of services. Interface of Industry 4.0 with existing smart infrastructure such
as smart buildings, smart homes, smart grids, smart logistics, social web, and business web build a
CPS system. This revolution will merge the real and virtual world on the basis of CPS. A CPS system
has a computer-based algorithm that integrates the Internet and its users. It is simply digitization,
in which these systems make connection of information technology with electronic/mechanical device
components that exchange information among each other using a network. Using computer-based
algorithms, CPS brings software and hardware components working in an automated and controlled
manner to perform a certain task without human’s assistance. The basic visualization of a CPS
is given in Figure 4. After collection and analysis of big data, CPS can increase performance in
terms of high-quality, low-cost goods production. With the advancement in sensors and computing
technologies, various CPSs are emerging. CPS has evolved to Cyber Physical Production Systems
(CPPS) to encourage the development and production process of Industry 4.0 [33]. CPPS combines
physical smart IoT devices, networking technologies to compute in the production process. Robotics,
remote machinery control and diagnosis, smart devices, heavy industry, transportation, health and
condition monitoring, energy production, smart cities, and food manufacturing are IIoT services enable
by CPS/CPPS architecture. Figure 5 represents the comparative analysis between CPS and IoT in 7 of 38 Sensors 2019, 19, 4807 7 of 38 the form of a Venn diagram. The similarities between the two give support for the development of
Industry 4.0/IIoT. y
/
Figure 4. A cyber physical system architecture. Figure 5. Comparison of CPS and IoT; supporting Industry 4.0 development. Figure 4. A cyber physical system architecture. Figure 4. A cyber physical system architecture. Figure 5. Comparison of CPS and IoT; supporting Industry 4.0 development. Figure 5. Comparison of CPS and IoT; supporting Industry 4.0 development. Sensors 2019, 19, 4807 8 of 38 The layered architecture of Industry 4.0 is given in Figure 3, which involves the common attributes
of CPS and IoT. The physical or sensing layer should be designed to the extent that IIoT applications
can sense/control information from physical environment and integrates with hardware sensors and
actuators accordingly. 2.3. Industry 4.0-Merging CPS and IoT The second layer should be optimized to provide a reliable connection to
support data transfer over a communication medium (wired/wireless). So far, IIoT applications used
wired medium to provide solutions. In the near future, the wireless medium is required because of
shifting from centralized to decentralized solutions. Connectivity technologies, such as NB-IoT/5G
and beyond 5G over different architecture such as SDN, NFV, cloud computing or fog computing will
give solution to different applications. The intelligent-application layer, providing services to users
has to be optimized in terms of service production, satisfaction, interaction, and management. 2.4. Industry 4.0-Key Enabling Technologies With the use of advance technologies of wireless communication, diverse new emerging protocols
and architectures are supporting automated industry 4.0 development. Resources can be efficiently
used after integration of communication technology and big data processing in real time, this will
result in better performance. Industry 4.0 development involves many communication technologies;
however, big data, IoT, 5G, mobile computing and cloud/fog/edge computing are the key enabling
technologies [2,34,35]. An extensive range of IIoT projects have been deployed in domains of building
automation, manufacturing systems, health care systems, transportation systems, processing food and
agricultural systems in the past few years. Reaching a common task in an IIoT application; sensing,
integration, and communication are main steps. RFID tags are used for sensing, network topologies
and protocols are used for communication. All these smart devices are associated with each other
using internet. Many connectivity technologies are available for supporting IIoT applications. Critical
requirements of IIoT applications have many open challenges in all domains (smart grid, smart cities,
smart devices, D2D, healthcare) such as capacity, real-time connectivity, remote maintenance and
topology of communication networks. Figure 6 gives a general overview of technologies to connect
things to the Internet, representing short-range and long-range wireless technologies. All technologies
work differently with aim of low-latency, low-power consumption, low-bandwidth requirement,
and reliable communication. Figure 6. Different connectivity technologies in IIoT. Figure 6. Different connectivity technologies in IIoT. Sensors 2019, 19, 4807 9 of 38 For connecting IIoT devices, all technologies have to work with the objective of maximum
throughput, minimum power consumption, minimum transmission delay, and maximum transmission
distance range. 2G, 3G, 4G, LTE are cellular technologies that were used for long range connectivity
in wireless wide area networks (WWAN). IIoT application’s critical requirements and the increasing
number of smart devices need additional resources for connectivity. Increase in smart devices results
in more data processing for which connectivity technology is moving towards 5G. The 3rd Generation
Partnership Project (3GPP) proposed Extended Coverage-Global System for Mobile Communications
for the Internet of Things (EC-GSM-IoT) and Narrowband-Internet of Things (NB-IoT) for supporting
M2M, enhanced MTC (eMTC), massive MTC (mMTC) and critical MTC (cMTC) communication
networks for IIoT applications [5]. 5G cellular technology gives super low latency, ultra-reliable and
high availability to cMTC applications (industrial application and control, remote surgery, remote
training, remote manufacturing, and traffic safety and control). 2.5. Industry 4.0-Building Blocks Fourth manufacturing revolution, i.e., digital industrial technology provides services in industries
that involves data exchange among machines making more efficient and fast processes. In words,
the IIoT can be defined as: Devices with centralized controllers, sensors, battery and memory attributes will
interact with each other using Artificial Intelligence (AI) and Machine Learning (ML) algorithms. Real time
connection is possible using decentralized analytics and decision making of these devices. This section
will give building blocks that are used in transforming industry 4.0 development. 2.4. Industry 4.0-Key Enabling Technologies Low cost, low energy, and the massive
number of intelligent devices in smart agriculture, smart meter, tracking, fleet management, and
logistics domain are supported by 5G as well. 5G is beneficial for IIoT applications comprising from
mMTC, cMTC to enhanced mobile broadband. The distributed model of IIoT applications require a
massive amount of data rate with minimum latency, 5G technology gives 10 Gbps with 1 ms latency. 5G is use case driven communication technology for upcoming IIoT applications. For distributed ultra-low-latency and reliable connectivity in IIoT applications, 5G-IoT is an
emerging solution. 5G-IoT scenario extends capabilities of IoT smart devices used in all domains. Recent research is focusing on low-latency, end-to-end reliability, and low energy consumption for
both uplink and downlink communication. There is a lot of potential in research on IIoT with
5G communication technologies, to overcome challenges. This research will help in the industrial
revolution. With the evolution of Industry 4.0, 5G is rapidly evolving in order to meet the requirement
of IIoT applications mainly real time functioning, energy efficiency, less power consumption, shared
spectrum regulation, reliable communication, and handing massive amount of data. Almost 90% of
needs met using fixed line 3G and 4G cellular technologies, but need for deployment of industrial
revolution can be fulfilled using 5G. 5G as an enabler of industry 4.0 gives multi-channel, capability,
multi-network management, operating both local and global networks, supporting heterogeneous
networks [27]. Mobile computing and cloud computing brings accurate data for IIoT application and
provide efficiency to industry 4.0 infrastructure. Details of cloud computing in comparison with fog
and edge computing is explained in the next section. 2.5.6. Cloud Computing Cloud computing is centralized and complex technology that supports high speed, high
performance, flexible resource use and dynamic allocation in a network. As IIoT application
requirements are low latency, high speed and reliable communication, privacy and security, efficient
allocation of resources and energy-efficient communication technology. Some limitations regarding
use of cloud computing for IIoT applications are: •
Confidential data and personal information of an industry should not be shared with outsid •
Confidential data and personal information of an industry should not be shared with out •
Security and privacy are in high demand by an industry from the cloud service provider. •
Data location on the basis of geographic follows rules and regulations. It also helps in securing the
information. •
High load demands high-speed internet connectivity. This processing causes delays in communication. •
Memory and storage capacity may get exhausted because of many applications simultaneously
accessing a single cloud server. •
Context awareness is required for speedy processes. •
Different standards cause problems in exchanging data, information, services, and applications
among different clouds at different locations. •
Recovery and back-up update are required for industrial processing and decision making, cloud
computing will cause delay. 2.5.5. Cyber-security Exponential increase in connections among devices in industry 4.0 will increase threats to systems,
networks, and processes. Cyber-security is a process that prevents unwanted intruders from accessing,
destroying, interrupting or changing sensitive information about company/organization as well as
business market networks; gives them secure and reliable communication systems. 2.5.4. Augmented Reality The idea of taking decisions remotely in real-time results in improving work procedures and will
be implemented in the future as Augmented Reality (AR). In this augmented reality-based systems
send repairing requirements or selection of new components. 2.5.3. Additive Manufacturing Additive manufacturing is the process in which a 3D model is manufactured by joining the raw
materials, usually layer by layer. It is the opposite of subtractive manufacturing in which raw material
is carved to create a 3D model. 2.5.1. Simulation, Autonomous Robots A virtual model of a physical world which comprises machines, humans, and products can be
interpreted in real time technology named as simulation. Every new product or updating process in available
products for any machine can be verified, tested and optimized via simulation-based applications. It will
result in increasing the quality of machinery and save the resources in the physical world. An autonomous
robot collects information from its environment and learns from it and does work in the future without the
involvement of humans using its self-learning algorithms (machine learning). These robots will transform
the industries into automated industry. This technology will have a large impact on the industrial revolution. These robots are cheap and more capable of doing tasks efficiently. Sensors 2019, 19, 4807 10 of 38 10 of 38 2.5.2. Big Data and Analytics, Horizontal and Vertical System Integration Different systems, ranging from customer to enterprise-level systems, have to collect, manage
and evaluate the big amount of data. Three main goals of big data analytics result in the reduction
of cost, efficient decision making and emerging new services and products. Industry 4.0 involves
digital transformation in vertical and horizontal value chain networks. These networks result in
the integration of customer and enterprise systems of companies, departments and business market-
exchanging data. These value chain processes should be transparent and flexible with real-time
functioning constraint. 2.5.7. Fog Computing Fog computing or “fogging” is an extended form of cloud computing, in respect of industrial
revolution giving applications and services (low latency and high processing) to autonomous
heterogeneous devices inside an industry [36]. The idea is to bring processing, storage, maintenance Sensors 2019, 19, 4807 11 of 38 Sensors 2019, 19, 4807 and intelligence control to the proximity of data devices. Inside industry 4.0, there is critical
requirement of real-time services with high data processing, maximum capacity and scalability. Fog
computing gives the best solutions for such an environment because of its significant benefits over
cloud computing. Extension of cloud computing, aims to minimize the burden on the cloud by
introducing network edge computing concept. For industrial automation, real-time services and decision making processes require low latency
and enhanced cache memory. Required performance parameters are mobility, real time applications,
low-latency, location-awareness, number of nodes and cache-enabled edge devices on this basis of
geographical distribution. Virtualized nodes frequently known as cloudlets or fog nodes are placed
between clouds of internet and end user devices. Fog computing provides services and applications as
a cloud does with better QoS parameters performance covering critical requirements of IIoT. Important
advantages of fog computing that influence its use for IIoT are: •
Data storage on network edge nodes eliminates the transmission delay by removing the need for
accessing data from far-away clouds. •
Data storage on network edge nodes eliminates the transmission delay by removing the need for
accessing data from far-away clouds. •
Fog computing supports to process and analyze the data on faster speed for IIoT application •
Data storage on edge nodes will reduce the processing and computing delay. •
Cache enabled nodes will prevent transmission of irrelevant information over the network. •
Can give support to all IoT applications e.g., smart grids, smart cities, D2D, Vehicular Ad-hoc
networks (VANETS) using edge networking concept. Provides filtered and required interaction between end devices and cloud service providers. •
Provides filtered and required interaction between end devices and cloud service provide Fog computing is the building stone to provide solutions for more efficient, effective and
manageable communication way for the massive number of smart IoT devices in the near future. Fog
computing with extra features as compared to cloud computing in terms of latency, security, location
awareness, location, and number of server nodes, real-time connectivity and mobility is a promising
enabler for industrial automation. 3.1.1. Smart City Applications About 6 billion people are expected to be part of cities of the earth in 2050 [38]. With the advent
of technology infrastructure, this increase in population will result in more data origination and
demand for services. This big data origination is called Big Data. To develop future smart city,
there are many domains that need to be intelligent, such as the smart home, smart office, smart
institution, smart health-care centers, smart agriculture, and smart transportation. All these domains
have different IIoT applications with different requirements. The development policy of a smart city
has six factors namely, smart economy, smart mobility, smart environment, smart people, smart living,
and smart governance [2]. Numerous research has been carried out in the domain of smart cities. For
instance, [39] presents a framework with which, smart cities can overcome current limitations. This
smart city transformation will take time. 2.5.8. Edge Computing Introduction of enormous smart devices making an industrial revolution in all domains, causes
extensive data processing, computation and burden of traffic on a single server either a cloud server
or cloudlet. This motivates researchers to develop a new computing technology named as edge
computing. The idea is to develop embedded automation controllers on devices named as edge-node
(e-node) in the literature. This device is intelligent, with low processing power, better hardware
security. Edge computing is an extending form of previous fog and cloud computing technologies. It comprises peer-to-peer networking, self-organizing network, and remotely manageable server. It gives following advantages: •
Encourages real-time connectivity. •
Overall network traffic reduces, as some computation is done on the edge of the network •
Enhances security by encryption of data near to the network core. •
Optimize the resource usage. IIoT applications have critical communication requirements. Cloud computing, fog computing,
and edge computing platforms need to be optimized for better, efficient results. Cloud computing can
be used where there is no high requirement of real-time connections, privacy, and security. On a local
area network, fog computing uses a centralized system which interacts between the network and
cloud server, whereas edge computing does computation on embedded systems of the network. Edge computing has direct interaction with sensors and actuators. The need for cloud, fog and edge
computing architectures is increased with the growth of the IIoT application. To increase the use of
IIoT smart devices, researchers are focusing on fog or edge computing paradigms which results in
industrial development. Sensors 2019, 19, 4807 12 of 38 12 of 38 3.1. IIoT-Applications From the identification of faults to solutions via communication and networking technologies,
every step needs to be optimized and has research potential. Possessing attributes of intelligence,
reliability, safety, sustainability, privacy, and efficiency; these applications are called smart in the
literature. This revolution results in the development of new infrastructure. According to [37], smart
city, smart factory and smart product are the main applications of industry 4.0. 3.1.2. Smart Factory Applications Smart industry comprises distributed automated systems and robotics. This future smart factory floor
is possible using ML algorithms and AI technology. These automated devices are integrated with sensors,
actuators, microchips, autonomous systems, and controllers. Relying upon CPS and IoT technologies
for evolution industrial processes required ultra-reliable and low-latency communication (URLLC). For monitoring, managing and controlling such environment, IoT nodes can handle bounded latency of
millisecond scale. These applications are characterized using latency, jitter, energy consumption, workload
parameters. M2M and D2D are emerging supporting technologies for smart factory development. In the
smart factory manufacturing process, machines will have high-level of automation and self-optimization
attributes. These attributes will fulfill complex requirements of products. This has open issues regarding
network communication technologies, number of devices, security, and cost. 3.1.3. Smart Product Applications IoT, cloud computing, big data, cloud computing and production time are drivers of industry 4.0
development. The products in industry 4.0 are smart because they are integrated with sensors and
microchips. Existing production systems need to be integrated with industry 4.0 architecture (IoT+CPS+WSN). This integration will allow communication interaction between human beings and products [40]. 3. Industrial Internet of Things Applications and Requirements Information about the occurrence of faults, components, inventory, different demands and
different orders continuously needs to be shared among smart devices/processes resulting in improved
efficiency, tracking, capacity use, quality of production and development in industries. From IIoT
perspective; smart cities, smart factories, and smart products are important IIoT beneficial examples. The basic three-layer architecture of IoT as discussed in Section 2.3, need to be evolved according to
the requirements of specific IIoT applications. 3.2. IIoT Application Design Parameters To the increasing demand of customers and market requirements, the manufacturing industry
is now facing problems in achieving desired goals. Industry 4.0 came up with an innovative idea of
automation inside in the industry increasing the production process flexibly. Industry 4.0 key point is 13 of 38 Sensors 2019, 19, 4807 M2M communication, in which machines communicate with each other over the Internet. Developing
and manufacturing industry, communication of intelligent machines with each other using different
technologies depending on the coverage area, give rise to high production and self-regulation of the
manufacturing process in an industry. These are the goals of industry 4.0; all this is assured by IT
systems as they provide enabling smart technologies. The integration of these heterogeneous devices
in a network with other devices and existing communication technologies is also the main requirement
for designers. Every IIoT application has critical design goal requirements to improve QoS in providing
solutions. These design parameters are: •
Energy & Long Battery Life: Overall network energy should be preserved for better and efficient
outcomes. Smart devices should have enough battery storage so that they can use for long time. •
Energy & Long Battery Life: Overall network energy should be preserved for better and efficient
outcomes. Smart devices should have enough battery storage so that they can use for long time. •
Latency: Some IIoT applications are time-sensitive, a bound should be there to limit all types of
delays including processing, propagation, transmission, and computation. •
Throughput: Amount of data for processing is different for different applications. It should
satisfy the application requirement. •
Network Topology: How the number of servers (cloud, fog, e-node) and smart devices are placed
in a network for better QoS requirements. •
Reliability: Solutions by IIoT applications demand reliable real-time connectivity. •
Security, Safety & Privacy: These are very demanding and major requirements for all IIoT
applications. For example, inside a smart factory there should be privacy and security such that no
one can access the private information. For healthcare applications, patient’s information should
be safe and not easily accessible and changeable. 3A’s; Authentication, Access, and Authorization
are steps involved in the strictly secure system. The demand of end to end communication in IIoT
applications requires privacy of data as well. Sensors and actuators should be safe from intruders
as well as environmental hazards. 3.3. IIoT Applications in Relation to Cloud, Fog and Edge Computing All IIoT applications require critical QoS parameters in order to produce benefits in every field. Fog term used in computer science is an extension of cloud architecture which offers services of
cloud to edge devices. It is seen as a new cloud or it will replace the cloud in future but it is just an
architecture that complements cloud architecture in order to provide solutions for critical applications. Entry points in any network are called edge devices. Entry points are part of second and third layer,
it has hardware devices named as switches, routers and WAN devices. Cloud is a centralized solution
and fog brings solutions at a distributed level by bringing data storage and its computation near the
edge of a network. It allows getting services in the proximity of IoT devices. Fog combines services
provided by cloud and IIoT applications; or it enables IIoT applications. Cloud architecture is efficient, beneficial and provides solutions. It offers services after storing
data in remote centers from the Internet. These remote data centers face less delay and computation
as compared to internet. It saves the cost of physical resources, makes connections more reliable
and results in an increase in efficiency and performance. It is a flexible, innovative framework in the
networking field. It helps in accessing resources anywhere anytime. Question is why fog architecture
is needed when cloud is already the best solution to many issues? There are certain issues and
requirements of IoT applications and fog can provide solutions. First and foremost, the low-latency
requirement of IIoT applications in every field can be attained effectively. It stores data in the proximity
of users. Propagation delay between cloud and users will be reduced; computation delay due to huge
data traffic at cloud can be reduced. It supports time-sensitive tasks effectively. Second IoT challenge
was using network bandwidth in an optimized manner, fog being in the center of cloud servers and
end devices. It helps in less usage of bandwidth; data doesn′t have to travel fog-to-cloud distance. Popular content is available at the network edge. This will also result in minimizing cost, lifespan of
devices, energy consumption and complexity during every demand which goes on the users-to-cloud
path. Security issues can be seen on the fog server; it can act as a proxy-server controller. Privacy and
safety of data is another important IIoT devices requirement. Fog helps in monitoring such tasks. 3.2. IIoT Application Design Parameters •
Performance: There is always a performance trade-off among these QoS requirements. There
should be an optimized, supportive, and efficient trade-off among the factors affecting
performance. Performance maintenance solutions are required for future automation. 3.2. IIoT Application Design Parameters •
Low Cost: Smart devices used for IIoT applications should be low cost so that doesn′t affect the
CAPEX/OPEX. Deployment involved in industry 4.0 should not be so much that will cause loss
in marketplace. •
Long Coverage: A device should be capable enough to cover the desired range. •
Standardization: So far, there is no such network standardization and is an open challenge
for researchers. •
Integration: IIoT applications are composed of heterogeneous devices and hybrid networks, there
are a lot of issues in integration. •
Communication/Enabling Technology:
Communication technology for supporting IIoT
application should provide assured performance services. •
Device Maintenance: Heterogeneous device in an industry 4.0 environment, require constant
device management as devices are connected with each other and the Internet. Software Defined
Networking (SDN) is used for such failure and changing maintenance issues of devices. •
Monitoring Network: Wireless, environmental and mobility nature may cause a change in
network topology which requires the system to be monitored and managed frequently. •
Configuration & Management of System:
Self-configurable, self-control, reconfiguration
functionality in addition of new devices in network. •
Traffic congestion & Overload: Smart devices will be increased with time in any IIoT application. System should be able to adjust according to the traffic burden and data requirement. •
Mobility: IIoT applications, such as transportation, inside industry and healthcare devices, have
the property of mobility from one place to another. •
Scalability: Scalability brings many issues, some are: How many numbers of smart devices are
enough to support an industrial application environment? or how many devices are served by a
server easily? how to optimally design a system under energy/spectrum issues? •
Scalability: Scalability brings many issues, some are: How many numbers of smart devices are
enough to support an industrial application environment? or how many devices are served by a
server easily? how to optimally design a system under energy/spectrum issues? Sensors 2019, 19, 4807 14 of 38 •
Heterogeneity & Interoperability: Heterogeneous smart IIoT devices have to communicate and
collect information among themselves and the Internet. This integration is an issue to solve. Standardization is required for interoperability of IIoT devices. •
Performance: There is always a performance trade-off among these QoS requirements. There
should be an optimized, supportive, and efficient trade-off among the factors affecting
performance. Performance maintenance solutions are required for future automation. 3.3. IIoT Applications in Relation to Cloud, Fog and Edge Computing Exponential increase in IIoT applications in every field making world a cutting edge technology
paradigm. Figure 7 shows both these architectures; cloud computing in which IoT devices are directly
connected to data centers and cloud server and fog computing in which fog server is in the middle of
cloud and IoT devices. Fog works on network edge which improves speed, computing capabilities and
provides distributed and better solutions. Fog has complemented the cloud architecture in many ways. Cloud is a centralized solution while fog can work in both a centralized and decentralized manner. Over large geographical area a group of fog nodes can be monitored and managed in a centralized way. Cloud size is large as compared to fog, as it has massive storage of data from the Internet. Fog size is a
flexible parameter that can be altered according to the demand of users. For example, for a vehicle tiny
sized fog would be enough while for an institution many small fogs can work in a form of network or
may be a large-sized fog would be sufficient. Fog has fewer deployment complexities as compared to
the cloud. Similarly, cloud management is tricky and more time taking as compared to a fog because
of its flexibility. This flexibility will support mobility in networks. 15 of 38 Sensors 2019, 19, 4807 Figure 7. Industry 4.0, IIoT applications versus cloud and fog computing. Figure 7. Industry 4.0, IIoT applications versus cloud and fog computing. Sensors 2019, 19, 4807 16 of 38 16 of 38 Because of architecture complexity, the cloud can only be operated by technical experts while
fog can be managed and operated by little human effort. Large companies control cloud networks,
while fog can be controlled by small as well as large companies. Low-latency critical IIoT applications
will be handled by fog, while applications that can tolerate large delays leverage the cloud services. Internet connection between user IoT devices and a cloud server should be reliable for the entire time
of connection, while in fog architecture connection with cloud is not necessarily required for the whole
time. Bandwidth requirement increases for both frameworks as the number of IoT devices is increasing
exponentially. It provides awareness property, which means it knows about the requirements of
customers and will provide solutions accordingly. It can be placed anywhere between the cloud and
user nodes according to the demands. 3.3. IIoT Applications in Relation to Cloud, Fog and Edge Computing Performance and efficiency parameters of IIoT application
services can be enhanced using fog framework. In addition, the scalability issue can be handled
using it. Data storage at network edge will result in minimization of service delays and supports
real-time processing. The big amount of data produced from heterogeneous smart devices requires
huge data storage and computation at the cloud server. IIoT applications requires data storage at
their backbone. This big data is giving rise to edge computing for future. Edge computing is also
called Mobile Edge Computing (MEC). This technology supports IIoT applications by building better
operational connectivity. It brings cloud computing capabilities at the devices that are present on the
edge of a network, these devices named as edge servers or edge devices. The edge devices are part of
the Internet and participate in processing and computation near the data location. This technology is
an industrial initiative by the European Telecommunication Standards Institute (ETSI) [41]. 4. Protocols/Algorithms Protocol is a basic set of rules that defines how communication happen between different devices
in a network. Protocols have to be devised intelligently in order to achieve the defined goals. As the future is industrial automation in industry 4.0 revolutionized era, there is an exponential
increase in smart, intelligent devices in IIoT applications. A major requirement is that the emerging
network protocols must meet required goals in performance affecting parameters, such as energy
efficiency, latency minimization, spectrum efficiency, cache memory maximization, and bandwidth
use requirements. A summarized discussion on pre-existing protocols in the context of fog computing
proposed by researchers is given below in following subsections. 4.1. Routing Dong et al. [42] have introduced redundant fog loops for WSNs. The proposed fog loop-based
scheme has two main steps. Creation of fogs using loop paths is the first step, while the second
mechanism creates fog nodes in the source node areas along with many other interfering fogs within
the network. This proposed scheme has helped in finding the exact location of the source node
in terms of energy efficiency and privacy. Results were compared to the efficiency offered by the
Phantom Routing Scheme (PRS). The proposed scheme gives improved efficiency by 4 folds and can
also improve the privacy and security up to 8 folds. Since fog computing lowers latency and offers energy saving, they are tailor-made for dealing
with WSNs [43]. Sensors in WSNs are resource-constrained, therefore energy efficiency is an important
issue. It needs to be addressed for the network to increase network life-time of operation and working
efficiently for a prolonged period of time. Sensors in a form of clusters collected data and send to the
base station using energy-efficient routing protocols. In this approach, using multi-hop communication,
data is transferred to the sink/destination node. The nodes acting as a cluster head are used for
multi-hop communications. For networking, apart from the routing problem, another issue that
needs to be catered is increasing network lifetime. Network lifetime can be effectively increased by
optimizing energy and power consumption at nodes. Some examples of these routing protocols are
Low-Energy-Adaptive-Clustering-Hierarchy (LEACH) and Stable-Election-Protocol (SEP). LEACH
protocol involves Deterministic Cluster Selection Head and abbreviated as LEACH-DCHS [44]. 17 of 38 Sensors 2019, 19, 4807 Handy et al. [45] have proposed LEACH in which rotation of the cluster heads in a randomized
manner is used for energy distribution to the nodes evenly. These algorithms haven′t been used for
fog computing yet, but can be used in future incorporating fog computing. SEP was proposed by
Smaragdakis et al. [46], prolongs the period of stability of wireless sensor networks. A modified
version of SEP (M-SEP) proposed by Singh et al. [47] is suitable for heterogeneous WSNs. Some of
the nodes in this approach might have a greater chance of getting selected as a cluster head and have
more energy. Moreover, in large WSNs, the data to be processed from heterogeneous devices is in
large volumes. Processing time is significantly large, so an alternate approach is to use fog computing. 4.1. Routing The time required to process large amount of data gets considerably reduced using fog as the sensors in
the network get interconnected with the Internet in order to make smart by making them autonomous
in making decisions. Another routing protocol that is energy-efficient named as new-SEP is proposed by
Naranjo et al. [48], prolongs the stability of sensor networks supported by fog more than SEP. Optimal clustering nodes are elected by considering various sensor node features such as the ratio
of heterogeneity in the network, residual energy, distance between cluster heads. Results were
compared with baseline schemes of LEACH and SEP, the proposed scheme performs better in terms
of energy-preservation and network lifetime. Considering increasing the network’s stability periods,
N-SEP performs better than LEACH (50 percent) and SEP (25 percent). An efficient route optimization
algorithm was presented in [49] to address the mobility control issue in fog-based SDN networks. The proposed SDN-enabled fog computing architecture had three-layered structure namely, fog layer,
network layer and application layer. Results showed that there is a great improvement in network
performance. A three-layered plane architecture was proposed to generate efficient routing paths
by the authors in [50] for data-center-based heterogeneous networks, using tensor decomposition
methods. These three planes do three different tasks, edge plane considers the traffic, bandwidth and
delay requirements; fog planes computes and controls the available paths and finally cloud plane do
the routing. 4.3. Load Balancing When one edge device has to do a lot of work e.g., computing tasks all by itself, it consumes
resources. However, this can be reduced with the help of distributed architecture in which load is
evenly distributed among the edge devices present in the network. This distribution of load is called
load balancing. Load Balancing in combination with fog computing makes a formidable combination. A fog network can provide a platform for cooperation and coordination between edge devices in a
load-balanced network. Authors have proposed a load balancing offloading algorithm for latency
minimization in Vehicular fog computing (VFC). VFC is an integration of vehicular networks and fog
computing technology, which is an efficient field to achieve real-time and location-aware for vehicles
in a smart city. Zhaolong et al. in [59] has formulated a response time minimization problem using a
three-layered decentralized network system model to balance the traffic among vehicles. These three
layers are cloud layer with a high computing cloud data center, cloudlet layer processed the received
data from vehicles before sending to the cloud center. Lower layer has vehicle clusters, clusters are
made for traffic balancing. The fog-vehicle interface manages and alleviates the traffic load. Traffic overhead results in inefficient resource management, which is also a challenge to be
solved for healthcare applications. WSNs based health monitoring systems have become a convenient
choice as elderly people can frequently require health services. The basic requirements for healthcare
applications are energy efficiency, high-response time, low-latency and real-time connection. Fog
computing can be considered to be an important enabling technology for such time-sensitive
applications. Authors in [60] provide a very significant critical review of existing solutions provided by
researchers in the healthcare domain using fog computing. The authors in [61] proposed a fog-cloud
hybrid solution to load-balancing problem. If a client’s requirement is more critical, it will be handled
by cloud otherwise servicing is done by foglets. Results shows that network utility can be enhanced
in terms of latency and load balancing. They used iFogSim tool for experiments. Forough et al. [62]
proposed an Energy Balancing Algorithm (EBA) for Fog-IoT networks to reduce delay and energy
consumption. The authors have proposed two optimization problems, first one is to find an optimal
transmission rate and power for terminal nodes (TNs) and the second one is to find an efficient
topology between TNs and fog nodes (FNs). 4.2. Resource Allocation One way to meet the growing IIoT application requirements is to use fog computing. Interactions
in real time takes place in fog application rather than batch processing. Services supported by fog
include mobility, heterogeneity, working with cloud to extend cloud services, user optimization,
etc. Resource allocation or resource management in any network is one of the biggest challenges. This defines new protocols for networking and communication. Many researchers have done
work in this context and already proposed some protocols. Resource allocation was done with
a specific defined objective, it can be maximizing energy efficiency or throughput; minimizing
latency or power consumption or network cost. A joint min-max optimization problem of resource
allocation and offloading decision making was proposed by the authors in [51]. They have proposed
Computation-Offloading-Decision-Making and Resource-Allocation Algorithm (CORA) to minimize
the maximal network cost (delay & energy consumption). Results were explained using fractional
programming theory and lagrangian dual decomposition. Fog Radio Access Networks (F-RAN),
an extension of the Services provided by Cloud Radio Access Network (C-RAN), has gathered attention
globally and several advantages can be taken by providing functions of baseband signal processing
near the edge or making the edge devices cache-enabled. F-RAN is the best example in which we are
using edge devices as well as network devices (access points) as fog nodes to achieve the best results. Moreover, due to the cooperative communication, benefits of C-RAN such as enhanced spectral and
energy efficiency are also conserved in F-RAN. Resource allocation is a challenge for the upcoming
F-RAN. Authors in [52] have proposed a Stackelberg equilibrium (SE) for a hierarchical problem
of network slicing customization between global radio resource manager (GRRM) and local radio
resource managers (LRRMs). A game is formulated to alleviate the burdens in GRRM and LRRM;
GRRM assigned resources to each slice and then LRRM in every slice provides resources to UEs. UEs Sensors 2019, 19, 4807 18 of 38 could be divided into clusters on basis of respective objective functions and accordingly get resources. Authors have provide two algorithms for LRRM 1 slice and LRRM 2 slice with an objective function of
maximizing high data rate and minimizing latency, respectively. To meet low latency, high throughput and connectivity requirements in future RANs,
non-orthogonal multiple access (NOMA) is a promising technique. Zhang et al. 4.2. Resource Allocation in [53] have formulated
a problem for maximizing the net utility under interference constraint for resource allocation problem
for NOMA-based FRAN system model. Results were compared with the conventional orthogonal
frequency division modulation (OFDM) technique. Madsen and Albeanu [54] discuss platforms
involving fog computing in which there is communication going on between the smart devices,
fog, and cloud. A model for internet applications in future is presented by Hong et al. [55] in
which applications are delay-sensitive and distributed geographically. For improving the rendering
performance of a webpage, Zu et al. [56] exploit information available only at the network’s edge. Companies that want to deliver content such as Netflix uses fog computing to reach their geographically
distributed customers. As indicated by [57], ensuring significantly large streamed data to be delivered
in the proximity of the end-user (customer), is done using fog computing. Minimizing the energy consumed in geographically distributed applications and resource
allocation using fog computing is discussed in [58] for video services. Size of fog nodes deployment
shows the application demand in that region. To maximize social welfare, some of the user data needs
to be controlled. Optimization on large scale is also possible using proximal and distributed algorithms. The algorithm proposed gives a near-optimal solution. 4.3. Load Balancing The system model was designed under the constraint of
channel conditions between TN and corresponding FN. A major challenge in edge computing is the Sensors 2019, 19, 4807 19 of 38 19 of 38 inefficient deployment of resources as it reduces the overall efficiency of the network. This results in
definite increase in power consumption. A low service block is preferred for maintaining lower latency,
which will otherwise be detrimental to the high-performance requirements of edge computing. Unlike
cloud computing, fog computing has a limitation of resources, which can be overcome if we allow
cooperation between various data centers. A cooperative scheme by Beraldi et al. [63] is proposed in
which data centers near the edge exchange processing requests and shares the load of highly loaded
data centers. The request arriving at a busy data center is forwarded to any other data center having
the request buffer partially filled. The proposed scheme maintains a threshold of requests with the
help of Markov Chains to make sure that load is equally distributed among all the data centers. This
leads to much-improved performance as lightly loaded data centers can absorb the burden of heavily
loaded ones during peak hours. g p
Full use of edge resources cannot be done by cloud computing polymerization calculation [64]. The edge devices are not part of the cloud computing, which is undesirable for delay-sensitive
requirements. Ningning et al. [65] have explored how fog computing can turn the nodes or edges
into virtual machines using Cloud Atomization Technology to improve on this problem. The authors
use graph partitioning for developing an efficient load balancing algorithm. Consequently, a flexible
network can be built by making fog networking possible after atomizing the cloud and eventually
reduce the cost of the system that were high before implementing the load balancing algorithm. Deng et al. [66] investigate power consumption and transmission delay trade-off. Problem of workload
allocation is formulated to obtain the minimal power consumption subject to the constraint of service
delay. Three sub-problems result after the decomposition of the primal problem. Based on the
obtained results, it is shown that cloud performance is enhanced by using fog computing. Moreover,
latency is reduced and bandwidth can be saved by sacrificing some of the computational resources. Computational clusters are formed on the basis of cooperation behavior between the Small Cells
(SC) to share computational resources. 4.3. Load Balancing However, the cooperation is dependent upon many factors
such as resource availability, resource allocation, delay constraints of the application, distribution of
computational load and size of the cluster. The joint distribution of resources for the mobile end-users
and the cloud is the main objective problem of this framework. All the data that is being frequently accessed by the edge devices is stored at the Radio Units (RU),
which considerably decreases the overall delay in the network of Fog-Radio Access Networks (F-RAN). However, in such systems, the energy efficiency aspect has always been a matter of serious concern
due to the addition of extra smart components in the system. In [67], the authors have proposed a
novel scheme by designing a green network in which an efficient algorithm is incorporated to optimize
the selection of RU. Furthermore, the algorithm also jointly optimizes the formation of clustering
and beamforming while maintaining the QoS and balancing the load of each of active backhaul as a
measure of its capacity. While copying data from the database, edge devices may interfere with each
other. To avoid this mishap, data replication techniques are used for copying data electronically from
the main database where the data of all the users is hosted. Uniform distribution of data and processing
is crucial over the network which in turn helps in managing the large amount of data and workload
with efficiency. Fog computing not only helps in achieving higher efficiency, it also helps in balancing
load across distributed platforms and achieving higher energy efficiency due to fewer performance
bottlenecks. Verma et al. [68] have focused on making a network that is less dependent on cloud
computing and bringing the storage and processing capabilities near the edge devices. The results are
simulated with the help of CloudSim by testing different geographically separated servers and their
configurations and then make comparisons between cloud and fog computing for various attributes. 5. Challenges with Solutions In general, there are many challenges towards industry 4.0 digital transformation. For M2M
communication, reliable and stable connectivity with bounded delays is a mandatory requirement. Real-time communication is on the higher priority for this fourth revolution, which brings many Sensors 2019, 19, 4807 20 of 38 20 of 38 technical challenges for future network development. A well-designed network architecture can
increase the sustainability and performance of the entire system. The journey towards industry 4.0
is on its way and until now there are no such standards, regulations, and certification to follow
them.Although fog becoming a developing key enabling technology for IoT architecture, it still faces
some issues while integrating into the current architecture. Complex software applications and
solutions are needed to achieve an efficient fog network. Fog network will be analyzed in terms
of key performance measurements, which are bandwidth use, energy consumption, low latency,
maximum throughput, and resource management. In this section, critical technical communication
and networking challenges in the context of fog computing for IIoT applications are listed. All of them
have potential for future work. •
Power Consumption/Energy Efficiency: Several smart devices supporting an IIoT application
will consume a massive amount of energy on a different scale according to their requirements. Ensuring network QoS with minimum energy consumption of smart IoT devices, fog nodes and
cloud in an optimized way is an open challenge for every upcoming future IIoT application. •
Throughput/Rate/Capacity: Throughput or network bandwidth, data rate and storage capacity
depends on how much data is used and where data is stored in a fog network. This data placement
on fog nodes or edge devices or cloud server has effects on cost, delays, bandwidth, and network
coverage. The optimal placement of data on cloud server or fog cloudlet is one of the critical
technical challenges for fog-IoT architecture. •
Spectrum Use/Resource Allocation: Geographically separated fog, cloud nodes and their
interconnection makes the backbone of any network that relies on offloading services. Most
of the cloud computing interconnection mechanisms are not enough for fog networking due to
their limitations including relying on a centralized cloud which cannot fulfill the latency and
location awareness requirements of distributed devices, etc. Fog computing must encompass
features, such as multi-tenancy, scalability, heterogeneity and quick resource provisioning. An architecture including fog and cloud computing must meet all these requirements for which
resource allocation/use is the most critical challenge for better network performance. 5. Challenges with Solutions It has effects
on all other QoS parameters. •
Latency:
IIoT applications requirement is real-time connectivity. All applications are
time-sensitive and require real-time streaming rather than batch processing. Fog computing gives
a better result for such decentralized solutions. It gives low latency with reliable connectivity
and mobility. Optimized placement of data centers, resource allocation, network architecture,
energy consumption of nodes, and storage capacity of nodes have impact on latency. Latency for
a network is the sum of transmission, processing, propagation and queuing delays. To achieve
the low-latency requirement, there is need mitigate all types of delays. •
Cache Enabled Edge Devices: Caching content locally, reduces the access delay time and
increases the energy and spectral usage efficiency. Since the Internet has multiple bottlenecks
while accessing data from across continents and oceans, caching does not have to be dependent on
any of these bottlenecks and instead makes the same data available locally. Furthermore, caching
incredibly reduces the load on backhaul links since they do not have to be used anymore for
accessing data. Since all the users have to access the data from the same centralized location
(internet/cloud server), a certain degree of fairness is needed to avoid inefficiency in accessing
data. Since all the backhauls have certain capacity constraints, there is a need for an efficient load
balancing mechanism to overcome this issue. Further, we discuss existing solutions to these mentioned challenges. Further, we discuss existing solutions to these mentioned challenges 5.1. Power Consumption/Energy Efficiency Objects are extensively being connected together using the IoT technologies. Heterogeneous smart
objects, in the context of hardware and software, can perform efficiently in the availability of memory Sensors 2019, 19, 4807 21 of 38 and high computational power. Network’s complexity increases day by day, because of scalability
issues of smart objects supporting IIoT applications. Virtualization has played a very crucial role in improving the overall efficiency of the data centers
and now research has also been done on how virtualization can help in fog networks. Virtualization
makes it easiest to deploy fog functionalities on an existing node (by isolating and securing fog services
in a virtual machine or container). It also helps in conserving energy by efficiently consolidating
the tasks on a single fog node. A comparison in terms of power consumption was studied in [69]
between C-RAN and F-RAN using network function virtualization (NFV) technology. The authors
have formulated a mixed integer linear programming (MILP) problem, results for F-RAN are 30%
more improved in terms of power-saving as compared to C-RAN. Roca et al. [70] have developed a platform using Fog-Function Virtualization, which works
and builds on the concept of Network Function Virtualization (NFV) for multiple IoT applications. This, further with the help of node constellation creation, helps in easy deployment and reduces
the cost considerably as less energy is required for running the system due to efficiently performing
virtualization. Task scheduling is necessary as it helps with the load balancing aspect of networking
and can provide services to multiple users. Cooperative games between the containers and brokers are
studied for energy-efficient task selection algorithm. Kaur et al. [71] have achieved efficiency with
the help of container-as-a-service (CaaS). Lightweight containers have been used which considerably
reduce the energy consumption by a container migration techniques. This kind of virtualization is
more cost-efficient for distributed architecture, where a large number of devices with different running
applications/processes can be allocated to resources efficiently. Results achieved by the authors prove
that the system is more energy-efficient. Graph-Based Heuristic algorithms were proposed by the authors in [72]. Type of problem is the
integer linear programming (ILP) problem, the objective is to increase the energy efficiency under
association and capacity threshold constraints for hybrid cloud-fog RAN (CF-RAN) architecture. Minimization of latency and power consumption is also addressed in the proposed system model. 5.1. Power Consumption/Energy Efficiency Fog computing along with NFV gives excellent outcomes in terms of reducing latency and power
consumption. Energy can be saved by incorporating techniques, such as Message Queue Telemetry
Transport (MQTT) in a fog-based environment [22]. In this scheme, the number of transmissions is
reduced to save energy of the end devices. Using energy-efficient routing protocols is imperative
to achieve energy efficiency. MQTT supports sensor data in real time due to its many-to-many
communication nature. The concept of MQTT focuses on introducing another layer between the fog
and cloud with lower complexity. MQTT broker place is at the fog layer. The intermediate layer is
responsible for predicting the future measurements, and acts as a gateway for the upper layer. It helps
to offload the computationally expensive tasks from the cloud to save in the storage memory of the
fog server. This results in a reduced number of transmissions as the update only occurs in case of a
mismatch. 5.2. Throughput/Rate/Capacity For network designing, a new paradigm known as Socially-Aware-Networking (SAN) has been of
major interest [73]. To achieve efficient performance, SAN brings the human behavior and CPS
together via intelligently designing of a network. This design should be adaptable as well for
all environments. The resources available to mobile devices differ depending on the models and
specifications. This resource availability results in a group of mobile devices that might be sufficient
in terms of processing and storage parameters. Group of some might not be self-sufficient. The best
solution to this problem is given by SAN and Fog-Radio Access Networking (F-RAN). D2D communication comprises the direct sharing of contents among mobile devices. Direct
sharing is a key feature supporting D2D communication. For achieving efficient performance results,
an imperative design of network embedded with all technologies is required. Research has shown that
the system performance in terms of utility, throughput and energy efficiency is maximized using the 22 of 38 Sensors 2019, 19, 4807 download mode with the help of branch and bound algorithm [74]. Klas et al. [75] and Cau et al. [76]
worked on improving network efficiency Mobile Edge Computing (MEC). MEC is a domain under
fog and focuses on providing cloud computing capabilities near the edge of network. Efforts and
improvements have been made in MEC in order for it to support 5G communications. Another target
of MEC is to achieve access to information provided by the radio network for application development
and distribution of the content. It is predicted that data traffic over mobile devices will increase
manifold in the next few years. Such increasing needs must be satisfied using efficient mechanisms. y
g
g
A reliable service with an extremely low latency (URLLC) and high capacity is the foremost
requirement of IIoT networks. Throughput maximization of the F-RAN system is compared with three
different back-haul strategies for Small Cell Networks (SCN) in [77]. All these strategies namely, decode
and forward, direct transmission and C-RAN were studied under delay threshold, rate constraint, and
backhaul and fronthaul links. The authors proposed iterative algorithms for all strategies. For F-RAN,
Pontois et al. in [78] formulated a non-convex optimization problem under fronthaul constraints. A
hybrid semi-distributed resource allocation algorithm was proposed by the authors for the proposed
weighted sum-rate maximization problem. Results show that there is a trade-off between maximum
throughput and system latency. 5.2. Throughput/Rate/Capacity A multi-objective optimization problem was proposed by the authors
in [79]. They have proposed three parallel algorithms to improve latency, throughput and resource
management. A queuing model was studied under task buffering, offloading and resource allocation
algorithms. Lyapunov drift was used by the authors to design the resource allocation policy. In
results for better system performance, trade-off between latency and throughput is observed. [80]
end-to-end performance is guaranteed after composition of problem as Multi-Constrained Optimal
Path (MCOP). The authors propose a solution from the network architecture’s perspective and cloud
service relation. The proposed algorithm provides better results in terms of efficiency and effectiveness. QoS parameters (capacity, delay and cost) gets improved by the proposed network-cloud service
provisioning system model. 5.3. Spectrum Use/Resource Allocation Fog networking can provide a solution for resource management issue in future 5G networks. With a growing number of smart devices, the major issue is of spectrum use and resource allocation. Spectrum pricing and allocation scheme (SPAS) was proposed in [81] for F-RAN framework. Three
areas were defined for the whole network, and double game theory was applied to give the solution
for efficient spectrum use. Proposed two algorithms are named as game-model (GM-SPAS) and
multiple-spectrum-reuse-technologies (MSRT-SPAS). Their presented results are effective in terms
of revenue and efficiency. The problem of resource allocation with utility maximization objective
under QoS constraints was formulated in [82]. Analytic Hierarchy Process (AHP) was proposed by the
authors for finding the QoS requirements of IoT devices. Afterward, the matching theory was applied
for user association. In [83], the authors have used the calculus of variation to find out the optimal spatial density of
nodes such that the distribution of nodes can support the whole network. A Parallel Imperialistic
Competitive Algorithm (PICA) is used to determine the initial positions of the access points. WSNs with
immense scalability, immobility factor and low-deployment cost properties have limited processing
and are resource-constrained. Smart Mobile Access Point (SMAP), which has been proposed by
Majd et al. [84] aims at achieving higher resource use and energy efficiency with the adoption of
hierarchical placement of SMAP in WSNs using fog computing. Moreno-Vozmediano et al. [85] have
presented a framework for interconnection of fog and cloud computing, Hybrid Fog and Cloud (HFC),
that provides effective, simple and productive resource provisioning. It also automates the process
of configuring various virtual networks that are part of the network for interconnecting important
components. The proposed architecture covers the salient features, such as security and scalability
along with fog to fog, and fog to cloud communication mechanism. Sensors 2019, 19, 4807 Sensors 2019, 19, 4807 23 of 38 23 of 38 Shojafar et al. [86] propose a resource scheduler for Networked Fog Centers (NetFCs) that
not only provides services to the vehicular client but is also energy efficient. NetFCs operate from
vehicular network’s edge via Infrastructure to Vehicle (I2V) mobile links to the vehicular clients that
are being served. Not only does the overall computation and communication energy efficiency get
maximized but also the network performs better in terms of QoS requirements. 5.4. Latency Fog networking is a key paradigm to provide solutions to latency-sensitive future IIoT applications. Many researchers have contributed to cater latency minimization problem. Online Fog Network
Formation Algorithm was proposed by Gilsoo et al. in [87] for minimizing the overall maximum
latency (communication and processing) of a fog network. The objective problem constitutes of the
sum of two types of delays i.e., fog network formation and task distribution. A joint energy and
latency optimization (JELO) scheme for F-RAN was proposed in [88]. The joint optimization of
energy consumption and latency was formulated as an integer-programming (IP) problem subject to
user association, capacity and latency threshold. The proposed complex problem was divided into
two sub-problems of knapsack and semi-assignment problem. The proposed algorithm gives better
results as compared to the existing techniques in the literature. A latency minimization problem was
formulated for IoT-fog network under user association, workload and latency threshold constraints. The authors have proposed a matching-game theory for the proposed resource management problem
for network latency minimization [89]. Over the last few years, the Internet of Vehicles (IoV) has been a matter of growing interest. Cloud computing provides high performing IoT services to IoV, still, there are many shortcomings
when it comes to mobility support, latency and location awareness. Xiuli Hi et al. [90] have
integrated fog computing into SDN. While fog Computing helps with the latency of the network, SDN
provides flexibility in the centralized control and providing the complete global knowledge of the
network. Vehicle to Vehicle (V2V), Vehicle to Infrastructure (V2I) and Vehicle to Base station (V2B)
communication can be supported by a weighted undirected graph having Road Side Units (RSUs). The simulation results given by the aforementioned authors decrease the latency and achieve a higher
QoS. The scheme proposed by Skarlat et al. [91] tackles an optimization problem, providing a solution
that there is no trade-off between communication and using resources and energy for computation. The applied system model demonstrates that in optimization scenarios, reduced average round-trip
time (RTT) and delays up to 39 percent can be achieved using fog. The scheme also considers an
independent cooperative number of working nodes. For the smart city, Fairness Cooperation Algorithm (FCA) was proposed by Dong et al. [92], for the
joint optimization problem. 5.4. Latency The authors have formulated a convex-non-linear programming problem
of minimizing the total system cost (delay and energy consumption), subject to power, workload and
computation capacity threshold constraints. QoE and fairness of users under FCA was compared with
baseline algorithm (BA) and distributed optimization algorithm (DOA). 5.3. Spectrum Use/Resource Allocation Moreover, hard
QoS requirements induced by the application are met, such as reducing transmission rates, delay,
and jitter. Resource scheduler is responsible for admission control, dispatching the allowed traffic
using minimum energy and adaptively controlling the traffic that is being injected into the mobile
connections. Few of the important characteristics of the scheduler include providing QoS guarantees
induced by the application, implantation of the scheduler is both scalable and distributive. 5.5. Cache Enabled Edge Devices Fog networking is a vast field, which uses both smart objects and the already deployed network
infrastructure. System can ensure QoS either by using already deployed network devices or by
optimally dividing the tasks among edge devices or using both at the same time. Cache placement
in edge devices/fog nodes in a network improves the efficiency of a system in terms of low power
consumption, low-latency, high throughput, and efficient spectrum use. To deal with the congestion 24 of 38 Sensors 2019, 19, 4807 problem at the backhaul link of F-RAN, authors have proposed a projection gradient method in [93]. To increase the throughput, they have used stochastic geometry to derive a close-form of successful
transmission probability (STP). Afterward, the optimal placement of cache over the network was
done. To fulfill the delay requirements, authors in [94] have proposed a decentralized asynchronous
coding caching scheme. The result shows that the proposed algorithm is more efficient than existing
algorithms present in the literature. A convex optimization problem of minimizing the worst-case
fronthaul delay was formulated by the authors. Depending on application delay requirements, the
proposed coded scheme gives synchronous and asynchronous transmission methods. The problem
of user association with a fog node on the basis of lower latency is formulated in [95]. The authors
have formulated the problem using game theory, for which they have used a proactive caching scheme
and Boltzmann-Gibbs learning algorithm for solution. Latency of proposed fog network is the sum of
computing and queuing delays. Different researchers have worked on the F-RAN design considering various aspects. For a green
system, as discussed by Chen et al. [67,96], minimization of energy consumption is done by considering
an F-RAN that is cache-enabled for the selection of Remote Radio Head (RRHs). For balancing
front-haul traffic, Park et al. [97] have discussed a scheme to deliver data from Base Band Unit (BBU)
and RRHs. Content placement problem involving caching has been discussed in X Peng et al. [98] and
Dai et al. [99]. F-RANs accommodate caching in the road-side units. Di Chen et al. [100] have worked
on maximizing the Signal to Interference Noise Ratio (SINR) to ensure fairness while jointly optimizing
cluster formation and multicast beamforming. The objective function in this work has non-convex
constraints and is collectively an NP-hard problem. Sensor-cloud system gives solutions to many
applications in a smart city. 5.5. Cache Enabled Edge Devices The system was developed by the integration of CPS and cloud computing. Besides many benefits, a major problem is coupling resource management, which was discussed
in [101]. They have introduced a fog layer between sensor and cloud layer, which emphasizes the
services. Firstly, authors have proposed an algorithm for caching at fog layer, afterwards, Hungarian
algorithm was extended to deal with the optimal use of resources on basis of maximum matching. The proposed algorithms result in the minimization of latency for sustainable services. 6. Open Research IIoT Application Domains, Fog Computing as an Enabler 6. Open Research IIoT Application Domains, Fog Computing as an Enabler In Industry 4.0, the digital transformation of the industry requires research development in all
fields (smart city, D2D communication, transportation, healthcare, etc.). These all IIoT domains have
same critical issues in communication and networking. Even though, fog computing has umpteenth
applications in multiple research areas, few notable applications in respective of IIoT domain have
been listed in Table 1 to gain an idea about the diverse use of fog computing. The main objective is
achieving maximum benefits/solutions using fog computing for this industrial revolution at efficient
optimized QoS measurements. Many authors have proposed solutions in past years to networking
and communication challenges in order to leverage benefits using fog computing in all domains of
IIoT. Some has started to provide prototypes for supporting their research, Table 2 has listed some
case studies for various areas of open research. In this section, some of the past research works
are summarized for readers to get an idea about the integration of fog computing with different
pre-existing network architectures. This integration brings solutions to support IIoT applications, yet
there are many open research areas in all fields that need to be solved in the coming future towards the
industrial development. 25 of 38 Sensors 2019, 19, 4807 Table 1. Literature Review: R.A=Resource Allocation, L=Latency, E=Energy, T/R/C=Throughput/Rate/Capacity, Cc=Cache, P=Power, H=Handover, B=Bandwidth,
S=Security, T.L=Transmission Link. ew: R.A=Resource Allocation, L=Latency, E=Energy, T/R/C=Throughput/Rate/Capacity, Cc=Cache, P=Power, H=Handover, B=Bandwidth, Ref. 6. Open Research IIoT Application Domains, Fog Computing as an Enabler Table 2. Case studies, Fog Computing as an enabler. Ref. No
IIoT Application
Domain
Case Study: Key Focus
[122]
smart city
Smart city solutions have been deployed in cities, such as Barcelona and Venice,
to make further advancements in e-governance
[123]
smart traffic
control and health
monitoring
To increase flexibility in a fog computing in the context of Complex event
processing (CEP), a case study is presented. The methodology, called
“mechanism transitions”, is used to study how and where a query should be
processed and how this decision affects the performance. [124]
smart city
Fog Computing Architecture Network (FOCAN) is presented to give low-latency
and energy-efficient solution for smart city applications. It manages different
application’s requirements by categorizing the traffic type and its flow. [125]
city, factory,
building, home
Using an open-source platform Distributed Node-RED (DNR), authors have
presented how applications can be decomposed and deployed. They build
prototype for scalability and dynamic nature solutions using the network
simulator Omnet++. [126]
smart pipeline
monitoring
A sequential machine learning algorithm on every layer of fog-cloud architecture,
sensors and Markov model are used to monitor, control and detection of
hazardous events of a pipeline system. A working prototype was constructed
to observe 12 distinct events. This prototype could be used for future city-wide
pipeline safety measurements
[127]
smart
transportation
The extended policy management to support secure travel to user’s is presented
by the authors. Four different route guiding scenarios are explained; namely
depending on traffic condition, emergency connected vehicles (ECV), connected
vehicle (CV) and probable collision detection. [128]
smart
transportation
Smart transportation framework is proposed for Vehicle to Vehicle (V2V)
communication by the authors, on basis of the current traffic situation (road and
vehicle’s condition, capacity). [129]
big data
Case study named as “Streamcloud” is presented to provide real-time
energy-efficient solution. [130]
healthcare
Personalized missing data resilient decision-making approach is validated on a
real human subject trial on maternity health. Data missing in critical applications
is a very crucial challenge, that needs to be solved. [131]
healthcare
Table 2 in the mentioned paper gives some projects for healthcare monitoring
supported by fog computing, cloud computing, and IoT. [132]
healthcare
A demo test-bed is developed on edge-IoT architecture for e-healthcare
applications. Proposed EH-IoT gives better results towards bandwidth and
latency requirements. The article also presents the benefits leveraging from IoT
and edge computing from an industrial perspective. 6. Open Research IIoT Application Domains, Fog Computing as an Enabler [133]
cardiac diseases
A case study using Electrocardiogram (ECG) feature is discussed in the article to
monitor health in real time. 6. Open Research IIoT Application Domains, Fog Computing as an Enabler No
IIoT Application Domain
R.A
L
E
T/R/C
Cc
P
H
B
S
T.L
Architecture
[49]
Mobility
Routing
SDN
[50]
Big Data Analytics
Routing
HetNets
[51]
Smart IoT devices
Downlink
Cloud Computing
[52]
Smart IoT devices
Downlink
RANs
[53]
Big Data Analytics
Downlink
NOMA+RANs
[59]
VANETS
Downlink
Cloud Computing
[61]
Healthcare
Downlink+Uplink
Cloud Computing
[62]
Smart IoT devices
Downlink
Fog-IoT
[69]
5G network
Downlink
NFV+RANs
[72]
Virtualized Passive Optical Networks (VPON)/5G
Downlink+Uplink
RANs + Cloud Computing
[77]
Small Cell Networks (SCNs)/5G
Uplink
RANs
[78]
5G network
Downlink
RANs
[79]
Downlink
Cloud Computing
[81]
5G network
Downlink
RANs
[82]
Heterogeneous IoT applications
Downlink
HetNets
[102]
VANETs
VFC
[84]
Smart monitoring systems
Downlink
WSN+CPS
[85]
Security
Routing
VN+Cloud Computing
[87]
Heterogeneous IoT applications
Downlink
Cloud Computing
[88]
Time-sensitive IoT applications
Uplink
RANs
[89]
Heterogeneous IoT applications
Downlink
Cloud Computing
[93]
Wireless network
RANs
[94]
Downlink
RANs
[95]
5G network
Downlink
Fog-IoT
[103]
Microgrid
Downlink
VM+Cloud Computing
[104]
Security+Microgrids
Downlink
Cloud Computing
[105]
Microgrid
Downlink
Cloud Computing
[101]
Smart city
Routing
CPS+Cloud Computing
[92]
Smart city
Downlink
Fog-IoT
[106]
Multimedia
Downlink
Cloud Computing
[107]
Secure and time saving multimedia
Routing
ICN
[108]
Secure IoT applications
Downlink
D2D
[109]
Downlink
D2D+RANs
[110]
5G mobile network+V2G services
Routing
V2G
[111]
VANETs
IoT+ITS Sensors 2019, 19, 4807 26 of 38 Table 1. Cont. Ref. No
IIoT Application Domain
R.A
L
E
T/R/C
Cc
P
H
B
S
T.L
Architecture
[112]
Mobility+VANETs
Downlink
Cloud Computing
[113]
Mobility+VANETs
Downlink
Fog-Ues
[114]
Mobility+Smart city
RANs+Cloud Comptinig
[115]
VANETs
Routing
SDN
[116]
Heterogeneous IoT applications
Routing
SDN+Blockchain
[117]
e-Healthcare
Downlink
Blockchain
[118]
Cooperative+secure healthcare
Routing
Fog+IoT
[119]
Big-Data Analytics+ security
Cloud Computing
[120]
Smart home
a case study
Cloud Computing
[121]
Smart city video applications
Routing
Cloud Computing Table 1. Cont. 27 of 38 Sensors 2019, 19, 4807 Table 2. Case studies, Fog Computing as an enabler. 6.2. Smart-Grids (SGs) Due to an increase in the number of devices required by a user at home, residential usage of
electricity has been increasing with time. The proposed modern solutions, such as SGs, greatly
improve the reliability, efficiency, and sustainability of the system in an automated way. Using
communication technologies, SGs works on gathered information about consumer’s and supplier’s
behavior. As SGs are distributed systems implemented on a very large scale, fog computing is ideal to
deal with such a scenario. For this purpose, Foteini Beligianni et al. [135] have discussed how IoTs
and fog computing can be integrated into the power systems without compromising user privacy. The proposed architecture works on demand-response service to ensure privacy by using standard
protocols and open-source resources. For devising a power plan for all the devices, a load scheduler is
placed in the system while data management performs all the necessary actions that are required to
process the data. The software architecture of the proposed solution is based on Lambda architecture
which embodies edge computing. To meet the demands of real time processing, collecting information,
computing and storing the data generated by multiple smart meters, the aforementioned researchers
have proposed a fog-based solution. Fog networking acts as a bridge between the cloud and the SG. With fog networking, geographically distributed smart meters can be employed. Latency is reduced
while improving location awareness and privacy for SG. Furthermore, Rao et al. [136] have worked
on how to maintain the QoS by minimizing the expense of electricity using coordination between
data centers. 6.1. Micro-Grids (MGs) Multiple loads and distributed renewable energy resources combine to form an electrical system
named as MG. This energy is stored in the storage devices, though, it can have significant power
losses when power is exchanged between different MGs. It increases reliability and efficiency of the
system. In [104] authors implemented their proposed framework on a test MG system. Performance
was observed for the proposed three-layer fog computing system. A convex linear programming
problem was formulated with an objective of minimizing the total cost in terms of power consumption. The constraints are total load threshold which was calculated using the power balance equation. The equation has three types of powers with threshold range namely, dispatchable, non-dispatchable
and grid power. Graph theory was applied to the proposed system and a fast consensus-based
algorithm by taking advantage of fog computing was proposed. An optimization problem of power
demand problem was discussed in [105] for hybrid fog-cloud system. The high volume of data by the 28 of 38 Sensors 2019, 19, 4807 28 of 38 number of smart devices results computation delays at cloud also it involves more power consumption. This power consumption can be optimized after load balancing among fog nodes and cloud server. Jalali et al. [134] have discussed various ways for the deployment of IoT nodes in an energy-efficient
way. The authors have used MGs and fog computing as an enabler with an aim to reduce the energy
consumption by the IoT specific applications. Energy consumption of various types has been discussed
i.e., energy consumed during computation and balancing traffic on fog as well as the cloud. Renewable
energy is stored in MGs, which can be used for further processing. Dynamic decisions such as weather
forecasting or renewable energy availability causes dependent energy-saving processes. 6.3. Multimedia Multimedia communication involves a large amount of audio and video data, being produced
by smart IIoT devices. This ever-increasing amount of multimedia content brings new challenges. Low-latency and energy-efficient solutions are required to provide services. A direct consequence of
increasing multimedia traffic is overburdening of the already strained mobile access network channels. The essential components of a multimedia communication system can be visualized with the help of
Figure 1. The authors in [106], have formulated a cost minimization optimization problem, this cost
depends on scheduler decisions. Scheduler takes decisions regarding distribution and states (open or
close) of fog nodes. This cost minimization problem alternatively converted into multimedia user’s
(MMU) response time minimization problem under capacity, coverage zone area and association
constraints. The authors have introduced a fog node to resolve the resource management and latency
issues between cloud and MMUs. Using Stackelberg game, an online resource allocation scheme was
proposed. The enormous amount of data production for smart applications, need security and privacy
as well. The authors have proposed a chaotic cryptographic method to ensure security along with
low-latency requirements for Information-Centric Multimedia Network (ICMN) [107]. The speed of
encryption and decryption of multimedia streams in the cryptographic method, was enhanced using
fog computing. 6.4. Device to Device (D2D) Communication 6.4. Device to Device (D2D) Communication Researchers have to find a new way in which devices can independently work without using the
existing cellular infrastructure. The demand for new infrastructure development is due to the increase 29 of 38 Sensors 2019, 19, 4807 in the number of smart devices that causes scarcity in spectrum and resources. This idea gives rise to
D2D communication technology in which devices are part of the Internet and can communicate with
each other without the involvement of internet infrastructure. This direct communication will result in
less usage of the wireless spectrum. A device is itself constrained-bounded in terms of parameters, such
as energy or resources, hence cloud and fog computing technologies support them. These emerging
technologies enhance processing capabilities and result in efficient system formation. Cloud services
for D2D communications have performance bottleneck as devices use direct communication, hence
an alternative fog service is required. Fog with the same set of services, provide better performance. Fog networking act as an alternative of cloud, as it provides desired requirements in the vicinity of
edge devices. Researchers have proposed D2D fogging to address energy-efficient task offloading in
D2D communication [137]. The proposed method includes a framework for task offloading and uses
assistance from the network for D2D. Mobile users use the communication and computation resources
of each other dynamically. After discussing several security issues in fog computing, authors have
proposed three lightweight anonymous authentication protocols (LAAPs) [108]. The proposed scheme with the aid of D2D communication, is feasible for IoT devices which
are resource-limited. Li et al. [109] proposed a F-community architecture for F-RAN followed by a
data caching scheme. The caching scheme for UEs in D2D aided F-RAN helps in reduction of delays. Nodes in the system with higher chances of being selected as the central nodes store the most popular
content in their cache. For access to any data, a user receives data from the cache stored previously. Kaur et al. [138] have proposed cachinMobile, which, compared to the cloud, can meet the low latency
and energy efficiency requirements by using the elastic services provided by the nodes at the edge. Energy efficiency and low latency requirements is a major issue in this technique as the resources at
the edge and the devices that are mobile. 6.4. Device to Device (D2D) Communication This approach has proposed to use D2D communication
to carry out communication at a short distance and save network resources. CachinMobile not only
improves energy efficiency but also maintains QoS. 6.6. Big-Data Analytics As the next revolutionized era comprises enormous smart devices that supports IIoT applications,
this causes the generation of a significant amount of data. Due to the widespread acceptance of fog
computing, significant research has been carried out in the domain of big-data analytics. Recent
advancements show an indication that fog networking has the potential to provide solutions in this
field. Fog computing, as an extension of cloud computing, gives solutions to problems such as
location-awareness, mobility, big-data analytics, and cyber threats. Author in [119] have designed a
three-layer architecture of IoT-Fog-Cloud that supports big-data analytics and security applications. Author summarized cyber attack types and compared the existing security solutions. The authors
in [140] provide a review article on fog computing challenges in the context of big IoT analytics. 6.5. Vehicular Ad-hoc Networks (VANETs) When renewable energy is available it is used to charge plug-in electric vehicles. Otherwise, these
electric vehicles are used as the source of energy. The use of alternative energy source will reduce
the power burden on the grid during peak hours. Owners of these plug-in electric vehicles got paid
by electric companies using metering systems. It provides some relief to electric companies in terms
of payment, traffic load, and energy consumption during peak hours. In smart grids, a distributed
architecture with storage and processing capabilities is need to be deployed, as there is a high factor of
mobility in V2G. To implement the V2G services in the 5G network, a hybrid fog and cloud architecture
was proposed by researchers in [110]. Open issues, such as energy efficiency, resource management,
security, and privacy are needed to be addressed in the future to improve system efficiency. Security
is a big challenge in VANETS, fog computing integration is smart transportation brings solution to
this challenge. Ma et al. [111] have designed a new authenticated key agreement (AKA) protocol for
fog-based VANETs. The authors in [112] compared fog and cloud computing performance in a real VANET
environment. Results shows that fog computing gives better services for real-time scenario applications,
namely traffic detection and time estimation. Fog computing performs well because it supports
the main attributes of VANETs that are location-awareness, mobility and real-time communication. Integration of the Internet of Things with VANETs gives rise to Internet of Vehicles (IoV) is a matter of
growing interest over the last few years [139]. 6.5. Vehicular Ad-hoc Networks (VANETs) This area is named as Intelligent Transportation System (ITS), which is an emerging area with
many open issues that need to be solved. A transportation service and automobile service management
involves the controlling and monitoring of the transportation network. ITS is designed in such a
way that this system can satisfy the required QoS parameters of the transportation network. These
QoS requirements involve reliable connection, efficient performance, safety, and privacy requirement,
mobility and scalability requirement. A transportation network system aided with ITS technology
has components that can be optimized. These are Global Positing System (GPS), RFID sensor tags
and readers, road-side equipment for example traffic lights, signals, road bank cameras, cars. These
ITS subsystems integrated with IoT technology elements will help in monitoring and managing of
transportation environment; distribution of vehicles according to the scenario; manufacturing of ITS;
shipping, tracking and monitoring of physical objects. Enormous number of such physical objects embedded with data processing capabilities, integrated
with RFID sensors along with networking technologies will promote IIoT applications. These IIoT
applications will help in monitoring the exact original location as well as destination location of
vehicle or aero-plane or ships along with the followed path traffic condition or environment effects
or any emergency road situation. Many authors have done research in designing ITS supportive
transportation networks optimizing wireless communication technologies, RFID tags or antennas. The use of IoT technology in the transportation industry and systems results in new research domains
such as vehicular ad-hoc networks (VANETs), internet of vehicles (IoV) and vehicle to grid (V2G). These domains are very promising areas of research. In recent times the integration of VANETs
with fog computing results in better efficient system designing. Services of automotive connectivity
architecture can be improved using fog computing as an enabler for smart transportation (ITS), such
as the one shown in Figure 1 (Transportation). Efficiency is improved in terms of minimizing the 30 of 38 30 of 38 Sensors 2019, 19, 4807 latency for time-sensitive applications using fog computing. Being an integral part of the ITS, VANETs
have many applications. Computation and communication demands are hard to meet in the cloud
architecture. Incorporating fog networking not only fulfills the demands but also improves latency,
location awareness and energy efficiency. For power management, there is a need for new technologies. For this problem Vehicle to Grid (V2G) is a recent concept with open issues, that uses renewable energy. 6.7. Software Defined Networking (SDN) SDN is an evolving concept to remotely control the entire network from a centralized location. Distributed networks can be integrated with SDN architecture for more granularity of control in
the network. Since edge computing is done near the edge devices, there is a high probability that
the edge devices are mobile due to the exponential evolution of smartphones and other handheld
devices. Similarly, the ever-changing requirements of resources for each user brings a certain degree
of dynamism in the network which needs to be catered to ensure efficient operation. Since fog is a
new concept and it cannot completely replace the existing cloud architecture, both fog and cloud work
hand in hand for smooth operation of the network. The interplay between fog networking and cloud
computing is always there when both work in an integrated fashion. The four-layer architecture was
studied for end-to-end delay, energy consumption and packet loss ratio in [115]. The authors formulate
mixed integer programming (MIP) problem of minimizing the energy consumption under data rate,
bandwidth and delay threshold constraints. A new routing protocol was proposed for VANET
applications using SDN and fog computing, named as Energy Efficient Multicast routing protocol
(EEMSFV). SDN controller, OpenFlow switches and fog computing works under two algorithms, Sensors 2019, 19, 4807 31 of 38 priority based scheduling algorithm for classifying the traffic message type (emergency or safety
applications) and a classification algorithm to schedule the requests. priority based scheduling algorithm for classifying the traffic message type (emergency or safety
applications) and a classification algorithm to schedule the requests. 7. Conclusions Acknowledgments: This work was supported by Zayed University Research Office, Research Cluster Award
# R17079. Acknowledgments: This work was supported by Zayed University Research Office, Research Cluster Award
# R17079. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. 7. Conclusions Industry 4.0, a revolutionized era which will have a massive number of smart devices that will
support IIoT applications in every field. This deployment of smart devices will change all domains of
human life’s perspective. IIoT applications will provide solutions to all fields, such as transportation,
healthcare, food supply chain, education, and industry. These IIoT applications will provide efficient,
effective solutions for future networks. There are challenges in communication and networking in
terms of latency, bandwidth, resource allocation, and storage. All these advanced IIoT applications will create a huge amount of data, causing a burden on the
cloud. Even though cloud computing provides services to the edge devices, it incurs huge latency,
resource allocation challenges, caching placement problems, energy consumption. These issues are
detrimental to the QoS aspect of a network. Fog as an extension of cloud provides a platform to
compute, control, store and manage these IIoT devices. In the future, it will reshape all sectors
involving IIoT applications, with the integration of important existing communication technologies
namely, CPS, SDN, NFV, 5G, D2D. This brings computation, resource management, and storage
challenges. In this paper, first, we gave an overview of IIoT applications and its enabling technologies
used for new revolutionized era. The pre existing protocols and solutions to challenges related to fog
computing are summarized. In the end, we have mentioned open research IIoT domains, in which fog
computing can act as an enabler. We have previewed the work carried out by numerous researchers
incorporating fog computing to provide services to IIoT edge devices leveraging towards Industry 4.0
way. Critical review of some existing work is summarized in the table, which can be used to find open
research challenges. Towards the development of this industrial transformative epoch, most of the
research work is still uncertain and waiting. This is an interesting era to discover what fog computing
may contribute to the world of automation in the coming future. Author Contributions:
R.B. is the main author for this survey article, who wrote the original draft. M.A. (Mudassar Ali), S.Q., M.A. (Monther Aldwairi), M.I.A., and A.M. contributed in terms of conceptualization,
organization and validation of the article. A.M., M.G. and M.A. (Monther Aldwairi) also contributed to
acquire funds. ding: This work was supported by the Swedish Knowledge Foundation under Grant 20180178. Funding: This work was supported by the Swedish Knowledge Foundation under Grant 20180178. References 1. Rivera, J.; Goasduff, L. Gartner says a thirty-fold increase in internet-connected physical devices
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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English
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Best approximation and variational inequality problems involving a simulation function
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Fixed point theory and applications
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© 2016 Tchier et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, pro-
vided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made. R ES EA RCH Open Access 1 Introduction Let A and B be two nonempty subsets of a metric space (X,d) and T : A →B be a non-self-
mapping. The equation Tx = x is known as a general fixed point equation and its solution
is related to the solution of many practical situations arising in pure and applied sciences. For instance, it is well known that many problems involving differential equations may
be solved by searching for the existence of a fixed point of an integral operator. But for
the existence of a fixed point of T, we need that T(A) ∩A ̸= ∅, otherwise d(x,Tx) > for
all x ∈A. In such a situation, it is natural to search a point x ∈A such that x is closest
to Tx in some sense. To clarify and support this assertion, we recall the following best
approximation theorem due to Ky Fan [], in a metric version. Fairouz Tchier1, Calogero Vetro2* and Francesca Vetro3 *Correspondence:
calogero.vetro@unipa.it
2Department of Mathematics and
Computer Sciences, University of
Palermo, Via Archirafi34, Palermo,
90123, Italy
Full list of author information is Abstract We prove the existence of a g-best proximity point for a pair of mappings, by using
suitable hypotheses on a metric space. Moreover, we establish some convergence
results for a variational inequality problem, by using the variational characterization of
metric projections in a real Hilbert space. Our results are applicable to classical
problems of optimization theory. Full list of author information is
available at the end of the article Full list of author information is
available at the end of the article MSC: 41A65; 47J20 Keywords: best proximity point; metric projection; proximal Z-contraction;
variational inequality Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26
DOI 10.1186/s13663-016-0512-9 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26
DOI 10.1186/s13663-016-0512-9 Best approximation and variational
inequality problems involving a simulation
function Fairouz Tchier1, Calogero Vetro2* and Francesca Vetro3 Fairouz Tchier1, Calogero Vetro2* and Francesca Vetro3 *Correspondence:
calogero.vetro@unipa.it
2Department of Mathematics and
Computer Sciences, University of
Palermo, Via Archirafi34, Palermo,
90123, Italy
Full list of author information is
available at the end of the article Theorem .([]) Let A be a nonempty compact convex subset of a normed linear space
X and T : A →X be a continuous mapping. Then there exists x ∈A such that ∥x – Tx∥=
d(Tx,A). This result is related to the existence of an approximate solution to the equation Tx = x. Theoretical and practical aspects of this theorem have been discussed by various mathe-
maticians; we refer the reader to [–]. On the other hand, very recently Khojasteh et al. [] introduced the concept of
Z-contraction, by using a notion of simulation function. Consequently, fixed point re-
sults involving a Z-contraction are established in []. This approach has been of great
importance to discuss various fixed point problems from an unifying point of view; see Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 2 of 15 Page 2 of 15 for instance [–] and the references therein. For more contributions on the develop-
ment of fixed point theorems see [–]. We generalize and extend many results in the existing literature, by establishing some
best proximity point theorems involving Z-proximal contractions; see [, ]. In partic-
ular, we prove the existence of a unique g-best proximity point, which is a point x ∈A
such that d(gx,Tx) = d(A,B), where g : A →A is a self-mapping. As an application, we give
sufficient conditions to ensure the existence of a unique solution for a variational inequal-
ity problem and propose a convergent iterative algorithm to approximate this solution, by
using metric projections. Our results are applicable to some classical problems of opti-
mization theory. for all x,y ∈X, where k ∈[,[. for all x,y ∈X, where k ∈[,[. Definition .Let A and B be two nonempty subsets of a metric space (X,d). A non-self-
mapping T : A →B is said to be a proximal contraction of the first kind if d(u,Tx) = d(A,B),
d(v,Ty) = d(A,B)
⇒
d(u,v) ≤kd(x,y), for all u,v,x,y ∈A, where k ∈[,[. for all u,v,x,y ∈A, where k ∈[,[. 2 Preliminaries Let R, N, and Q denote the sets of all real numbers, positive integers and rational numbers,
respectively. Let A and B be two nonempty subsets of a metric space (X,d). By using the
usual notation in nonlinear analysis, we recall the following notions: A=
x ∈A : d(x,y) = d(A,B),for some y ∈B
,
B=
y ∈B : d(x,y) = d(A,B),for some x ∈A
. A=
x ∈A : d(x,y) = d(A,B),for some y ∈B
,
B=
y ∈B : d(x,y) = d(A,B),for some x ∈A
. Kirk et al. gave sufficient conditions to ensure that Aand Bare nonempty sets; see
[]. On the other hand, Sadiq Basha and Veeramani proved that Ais contained in the
boundary of A; see []. In the sequel, we are interested in establishing results involving new types of proximal
contraction and hence we recall the fundamental definitions in this direction; see [, ]. Definition .Let A and B be two nonempty subsets of a metric space (X,d). A non-self-
mapping T : A →B is said to be a contraction if d(Tx,Ty) ≤kd(x,y), Finally, Khojasteh et al. in [] defined a simulation function as follows. Definition .A simulation function is a mapping ζ : [,+∞[×[,+∞[→R satisfying
the following conditions: Definition .A simulation function is a mapping ζ : [,+∞[×[,+∞[→R satisfying
the following conditions: for all u,v,x,y ∈A, where k ∈[,[. for all u,v,x,y ∈A, where k ∈[,[. Definition .Let A and B be two nonempty subsets of a metric space (X,d). A non-self-
mapping T : A →B is said to be a proximal contraction of the second kind if d(u,Tx) = d(A,B),
d(v,Ty) = d(A,B)
⇒
d(Tu,Tv) ≤kd(Tx,Ty), for all u,v,x,y ∈A, where k ∈[,[. for all u,v,x,y ∈A, where k ∈[,[. Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 3 of 15 Many authors generalized these concepts and proved their best approximation theo-
rems; see for instance [–]. In , Sankar Raj [] introduced the notion of P-property as follows. Definition .([], Definition ) Let A and B be two nonempty subsets of a metric space
(X,d) with A̸= ∅. Then the pair (A,B) is said to have the P-property if and only if d(x,y) =
d(A,B) = d(x,y) implies d(x,x) = d(y,y) where x,x∈Aand y,y∈B. By using Definition ., Sankar Raj in [] gave an extended version of the contraction
mapping principle in []. Of course, for every nonempty subset A of X, the pair (A,A) has
the P-property. We shall consider this property in a remark of the next section. Definition .Let A and B be two nonempty subsets of a metric space (X,d). Let g : A →
A be a self-mapping and T : A →B a non-self-mapping. Then
(i) g ∈GA if g is continuous and d(x,y) ≤d(gx,gy) for all x,y ∈A;
(ii) T ∈Tg if d(Tx,Ty) ≤d(Tgx,Tgy) for all x,y ∈A. Definition .Let A and B be two nonempty subsets of a metric space (X,d). Let g : A →
A be a self-mapping and T : A →B a non-self-mapping. Then
(i) g ∈GA if g is continuous and d(x,y) ≤d(gx,gy) for all x,y ∈A;
(ii) T ∈Tg if d(Tx,Ty) ≤d(Tgx,Tgy) for all x,y ∈A. Finally, Khojasteh et al. in [] defined a simulation function as follows. In order to avoid confusion, we refer to the following definition. In order to avoid confusion, we refer to the following definition. Definition .A simulation function is a mapping ζ : [,+∞[×[,+∞[→R satisfying
the conditions (ζ) and (ζ). Definition .A simulation function is a mapping ζ : [,+∞[×[,+∞[→R satisfying
the conditions (ζ) and (ζ). 3 Best proximity point theorems In view of Definition ., we consider the following notions of proximal contractions. In view of Definition ., we consider the following notions of proximal contractions. In view of Definition ., we consider the following notions of proximal contractions. Definition .Let A and B be two nonempty subsets of a metric space (X,d). A non-self-
mapping T : A →B is said to be a Z-proximal contraction of the first kind if there exists
a simulation function ζ : [,+∞[×[,+∞[→R such that d(u,Tx) = d(A,B),
d(v,Ty) = d(A,B)
⇒
ζ
d(u,v),d(x,y)
≥, d(u,Tx) = d(A,B),
d(v,Ty) = d(A,B)
⇒
ζ
d(u,v),d(x,y)
≥, for all u,v,x,y ∈A. for all u,v,x,y ∈A. Remark .If T : A →B is a Z-proximal contraction of the first kind and (A,B) has the
P-property, then T is a Z-contraction. Example .Let X = R be endowed with the usual metric d(x,y) = |x – y| for all x,y ∈X. Consider A = [,
] and B = [,] so that d(A,B) = . Define a mapping T : A →B by Tx =
x
+ x,
for all x ∈A, Tx =
x
+ x,
for all x ∈A, and the simulation function ζ : [,+∞[×[,+∞[→R by ζ(t,s) =
s –
t
–t
if t ∈[,
],
s – t
otherwise. ζ(t,s) =
s –
t
–t
if t ∈[,
],
s – t
otherwise. It is easy to show that T is a Z-proximal contraction of the first kind, but not a proximal
contraction of the first kind. Indeed, from d(u,Tx) = d(v,Ty) = = d(A,B), we get (x,y) = ( u
–u,
v
–v), with u,v ∈[,
],
d h It is easy to show that T is a Z-proximal contraction of the first kind, but not a proximal
contraction of the first kind. It is easy to show that T is a Z-proximal contraction of the first kind, but not a proximal
contraction of the first kind. Definition .A simulation function is a mapping ζ : [,+∞[×[,+∞[→R satisfying
the following conditions: (ζ) ζ(,) = ; (ζ) ζ(,) = ; (ζ) ζ(t,s) < s – t, for all t,s > ; (ζ) if {tn}, {sn} are sequences in ],+∞[ such that limn→∞tn = limn→+∞sn = ℓ∈],+∞[,
then limsupn→+∞ζ(tn,sn) < . Consequently, they established the existence and uniqueness of fixed point for a self-
mapping defined in a complete metric space. Theorem .([]) Let (X,d) be a complete metric space and f : X →X be a Z-
contraction with respect to a certain simulation function ζ, that is, () ζ
d(fx,fy),d(x,y)
≥,
for all x,y ∈X. () Then f has a unique fixed point. Moreover, for every x∈X, the Picard sequence {f nx}
converges to this fixed point. Successively, Argoubi et al. [] point out the fact that condition (ζ) is not mentioned
in the proof of Theorem .. Moreover, by putting x = y in (), it follows that ζ(,) ≥
and hence, if ζ(,) < , the set of mappings f : X →X satisfying condition () is an empty
set. Consequently, Argoubi et al. proposed a slight modification of Definition ., by remov-
ing the condition (ζ) and retaining the rest. Remark .Every simulation function of Khojasteh et al. is also a simulation function of
Argoubi et al. However, the converse is not true. Remark .Every simulation function of Khojasteh et al. is also a simulation function of
Argoubi et al. However, the converse is not true. Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 4 of 15 Example .([], Example .) Let ζλ : [,+∞[×[,+∞[→R be the function defined
by by ζλ(t,s) =
if (s,t) = (,),
λs – t
otherwise, ζλ(t,s) =
if (s,t) = (,),
λs – t
otherwise, where λ ∈],[. Then ζλ satisfies (ζ) and (ζ) with ζλ(,) > . where λ ∈],[. Then ζλ satisfies (ζ) and (ζ) with ζλ(,) > . where λ ∈],[. Then ζλ satisfies (ζ) and (ζ) with ζλ(,) > . 3 Best proximity point theorems Indeed, from d(u,Tx) = d(v,Ty) = = d(A,B), we get (x,y) = ( u
–u,
v
–v), with u,v ∈[,
],
and hence ζ
d(u,v),d(x,y)
= ζ
d(u,v),d
u
– u,
v
– v
=
u
– u –
v
– v
–
|u – v|
– |u – v| ≥, since u + v ≥|u – v| + uv. Thus, T is a Z-proximal contraction of the first kind. since u + v ≥|u – v| + uv. Thus, T is a Z-proximal contraction of the first kind. Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 5 of 15 On the other hand, there does not exist k ∈[,[ such that d(u,v) = |u – v| ≰k
|u – v|
– u – v + uv = kd
u
– u,
v
– v
= kd(x,y), for all u,v ∈[,
], and hence T is not a proximal contraction of the first kind. for all u,v ∈[,
], and hence T is not a proximal contraction of the first kin Definition .Let A and B be two nonempty subsets of a metric space (X,d). A non-
self-mapping T : A →B is said to be a Z-proximal contraction of the second kind if there
exists a simulation function ζ : [,+∞[×[,+∞[→R such that d(u,Tx) = d(A,B),
d(v,Ty) = d(A,B)
⇒
ζ
d(Tu,Tv),d(Tx,Ty)
≥, for all u,v,x,y ∈A. Example .Let X = R be endowed with the usual metric d(x,y) = |x – y| for all x,y ∈X,
and A = B = [,]. Define a mapping T : [,] →[,] by Example .Let X = R be endowed with the usual metric d(x,y) = |x – y| for all x,y ∈X,
and A = B = [,]. Define a mapping T : [,] →[,] by Tx =
if x ∈Q ∩[,],
otherwise. Tx =
if x ∈Q ∩[,], Now, consider the function ζλ : [,+∞[×[,+∞[→R given in Example .. It is easy
to show that T is a Z-proximal contraction of the second kind, but not a Z-proximal
contraction of the first kind. The following lemma is useful to show that a given sequence is Cauchy; see Lemma .. in []; see also Lemma .. in []. Lemma .Let (X,d) be a metric space and {xn} a given sequence in X. Suppose that lim
n→+∞d(xn,xn+) = . lim
n→+∞d(xn,xn+) = . If {xn} is not a Cauchy sequence, then there exists an ε > for which we can find subse-
quences {xnk} and {xmk} of {xn} such that If {xn} is not a Cauchy sequence, then there exists an ε > for which we can find subse-
quences {xnk} and {xmk} of {xn} such that quences {xnk} and {xmk} of {xn} such that (i) nk > mk ≥k, k ∈N; (i) nk > mk ≥k, k ∈N; (ii) d(xnk,xmk) ≥ε, d(xnk–,xmk) < ε, k ∈N; (ii) d(xnk,xmk) ≥ε, d(xnk–,xmk) < ε, k ∈N; (iii) limk→+∞d(xnk,xmk) = ε = limk→+∞d(xnk+,xmk+). (iii) limk→+∞d(xnk,xmk) = ε = limk→+∞d(xnk+,xmk+). On this basis, we construct our results. Precisely, we establish some theorems of g-best
proximity point for Z-proximal contractions and deduce some corollaries. Theorem .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that Ais nonempty and closed. for all u,v ∈[,
], and hence T is not a proximal contraction of the first kind. Assume also that the mappings T : A →B and
g : A →A satisfy the following conditions: Theorem .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that Ais nonempty and closed. Assume also that the mappings T : A →B and
g : A →A satisfy the following conditions: g : A →A satisfy the following conditions: (a) T is a Z-proximal contraction of the first kind; (b) g ∈GA; (c) T(A) ⊆B; Page 6 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Then there exists a unique point x ∈A such that d(gx,Tx) = d(A,B). Moreover, for every x∈
Athere exists a sequence {xn} ⊆A such that d(gxn+,Txn) = d(A,B) for every n ∈N ∪{}
and xn →x. Proof Let x∈A. Since T(A) ⊆Band A⊆g(A), there exists x∈Asuch that Proof Let x∈A. Since T(A) ⊆Band A⊆g(A), there exists x∈Asuch that d(gx,Tx) = d(A,B). d(gx,Tx) = d(A,B). Clearly, for x∈A, there exists x∈Asuch that d(gx,Tx) = d(A,B). By repeating this process, for xn ∈A, we can find xn+∈Asuch that By repeating this process, for xn ∈A, we can find xn+∈Asuch that d(gxn+,Txn) = d(A,B),
for all n ∈N. In the constructive process of {xn}, if for some m > n, we have Txm = Txn, then we choose
xm+= xn+. Also, if there exists m ∈N such that d(gxm+,gxm) = , then xm+= xm, and
hence Txm+= Txm and xm+= xm+. It follows that xn = xm for all n ∈N with n ≥m and so
the sequence {xn} converges to xm ∈A. We also have d(gxm,Txm) = d(A,B). Then we suppose that < d(xn+,xn) ≤d(gxn+,gxn) ̸= for all n ∈N. Since T is a
Z-proximal contraction of the first kind and g ∈GA, we write ≤ζ
d(gxn+,gxn),d(xn,xn–)
< d(xn,xn–) – d(gxn+,gxn)
≤d(xn,xn–) – d(xn+,xn),
() ≤ζ
d(gxn+,gxn),d(xn,xn–)
< d(xn,xn–) – d(gxn+,gxn)
≤d(xn,xn–) – d(xn+,xn), () for every n ∈N. This implies that the sequence {d(xn,xn–)} is decreasing and hence there
exists r ≥such that d(xn,xn–) →r. Suppose r > . From (), we deduce also that for every n ∈N. This implies that the sequence {d(xn,xn–)} is decreasing and hence there
exists r ≥such that d(xn,xn–) →r. Suppose r > . From (), we deduce also that d(gxn+,gxn) ≤d(xn,xn–),
for all n ∈N. d(gxn+,gxn) ≤d(xn,xn–),
for all n ∈N. for all u,v ∈[,
], and hence T is not a proximal contraction of the first kind. d(gxn+,gxn) ≤d(xn,xn–),
for all n ∈N. On the other hand g ∈GA and hence On the other hand g ∈GA and hence d(xn+,xn) ≤d(gxn+,gxn) ≤d(xn,xn–),
for all n ∈N. Consequently, Consequently, lim
n→+∞d(gxn+,gxn) = r. Now, using the property (ζ) of a simulation function, we write Now, using the property (ζ) of a simulation function, we write ≤limsup
n→+∞
ζ
d(gxn+,gxn),d(xn,xn–)
< , which is a contradiction and hence r = . which is a contradiction and hence r = . Page 7 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 7 of 15 The next step is to show that the sequence {xn} is Cauchy. By contradiction, assume
that {xn} is not a Cauchy sequence. Then, by Lemma ., there exist an ε > and two
subsequences {xnk} and {xmk} of {xn} such that nk > mk ≥k and d(xnk,xmk) ≥ε for all
k ∈N and lim
k→+∞d(xnk,xmk) = ε = lim
k→+∞d(xnk+,xmk+). lim
k→+∞d(xnk,xmk) = ε = lim
k→+∞d(xnk+,xmk+). Then we can assume that d(xnk+,xmk+) > for all k ∈N. Since T is a Z-proximal con-
traction of the first kind and d(gxnk+,Txnk) = d(A,B) = d(gxmk+,Txmk), we obtain Then we can assume that d(xnk+,xmk+) > for all k ∈N. Since T is a Z-proximal con-
traction of the first kind and d(gxnk+,Txnk) = d(A,B) = d(gxmk+,Txmk), we obtain ≤ζ
d(gxnk+,gxmk+),d(xnk,xmk)
< d(xnk,xmk) – d(gxnk+,gxmk+), for all k ∈N. Thus, the previous inequality and g ∈GA ensure that lim
k→+∞d(gxnk+,gxmk+) = ε. By using the property (ζ) of a simulation function, with tk = d(gxnk+,gxmk+) and sk =
d(xnk,xmk), we obtain By using the property (ζ) of a simulation function, with tk = d(gxnk+,gxmk+) and sk =
d(xnk,xmk), we obtain ≤limsup
k→+∞
ζ
d(gxnk+,gxmk+),d(xnk,xmk)
< , which is a contradiction. We conclude that the sequence {xn} is Cauchy. Since (X,d) is
complete and Ais closed, then Ais complete and hence there exists x ∈Asuch that
xn →x. Moreover, by the continuity of g, we have gxn →gx and thus gx ∈A, since gxn ∈
Afor all n ∈N and Ais closed. On the other hand, since x ∈Aand T(A) ⊆B, there
exists z ∈Asuch that d(z,Tx) = d(A,B). Now, if z = gxn for infinite n ∈N, then z = gx. Hence we assume that z ̸= gxn for all n ∈N. Also there exists a subsequence {xnk} of {xn} such that xnk ̸= x for all k ∈N. which leads to x = x∗, a contradiction. □ which leads to x = x∗, a contradiction. □ We get the following corollary, by setting g as the identity mapping on A in Theorem .. Corollary .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that Ais nonempty and closed. Assume also that the mapping T : A →B satisfies
the following conditions: (a) T is a Z-proximal contraction of the first kind;
(b)
(A ) (a) T is a Z-proximal contraction of the first kind; (b) T(A) ⊆B. Then there exists a unique point x ∈A such that d(x,Tx) = d(A,B). Moreover, for every
x∈Athere exists a sequence {xn} ⊆A such that d(xn+,Txn) = d(A,B) for every n ∈N∪{}
and xn →x. Then there exists a unique point x ∈A such that d(x,Tx) = d(A,B). Moreover, for every
x∈Athere exists a sequence {xn} ⊆A such that d(xn+,Txn) = d(A,B) for every n ∈N∪{}
and xn →x. Example .Let X, A, B, d, T, and ζ be as in Example .. Notice that A= A = Bis
closed and T(A) ⊆B. Thus, by an application of Corollary ., the mapping T : A →B
has a unique point x ∈A such that d(x,Tx) = = d(A,B); here x = . From Theorem ., we obtain the following corollary which is a generalization of The-
orem .of []. Corollary .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that Ais nonempty and closed. Assume also that the mappings T : A →B and
g : A →A satisfy the following conditions: (a) T is a proximal contraction of the first kind; (a) T is a proximal contraction of the first kind; (b) g ∈GA; (b) g ∈GA; (c) T(A) ⊆B; (c) T(A) ⊆B; Then there exists a unique point x ∈A such that d(gx,Tx) = d(A,B). Moreover, for every x∈
Athere exists a sequence {xn} ⊆A such that d(gxn+,Txn) = d(A,B) for every n ∈N ∪{}
and xn →x. Proof Note that a proximal contraction of the first kind is a Z-proximal contraction of
the first kind with respect to the simulation function ζ : [,+∞[×[,+∞[→R defined by
ζ(t,s) = ks – t for all t,s ∈[,+∞[, where k ∈[,). □ The following theorem establishes a result of existence of a g-best proximity point for a
Z-proximal contraction of the second kind. Consequently, Again, since T
is a Z-proximal contraction of the first kind, we get ζ
d(z,gxnk+),d(x,xnk)
< d(x,xnk) – d(z,gxnk+), and hence and hence d(z,gxnk+) < d(x,xnk),
for all k ∈N. Letting k →+∞, we obtain d(z,gxnk+) →and then z = gx. This implies that Letting k →+∞, we obtain d(z,gxnk+) →and then z = gx. This implies that
d(gx,Tx) = d(A,B). Letting k →+∞, we obtain d(z,gxnk+) →and then z = gx. This implies that d(gx,Tx) = d(A,B). To prove the uniqueness, let x∗̸= x be another point in Asuch that d
gx∗,Tx∗
= d(A,B). d
gx∗,Tx∗
= d(A,B). Page 8 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 8 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Since g ∈GA and T is a Z-proximal contraction of the first kind, we write ≤ζ
d
gx,gx∗
,d
x,x∗
< d
x,x∗
– d
gx,gx∗
≤d
x,x∗
– d
x,x∗
= , which leads to x = x∗, a contradiction. which leads to x = x∗, a contradiction. On the other hand T ∈Tg and hence On the other hand T ∈Tg and hence d(Txn+,Txn) ≤d(Tgxn+,Tgxn) < d(Txn,Txn–),
for all n ∈N. which leads to x = x∗, a contradiction. Theorem .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that T(A) is nonempty and closed. Assume also that the mappings T : A →B
and g : A →A satisfy the following conditions: Page 9 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 9 of 15 (a) T is a Z-proximal contraction of the second kind;
(b) T is injective on A;
(c) T ∈Tg;
(d) T(A) ⊆B;
(e) A⊆g(A). (a) T is a Z-proximal contraction of the second kind; (b) T is injective on A; (b) T is injective on A; Then there exists a unique point x ∈A such that d(gx,Tx) = d(A,B). Moreover, for every x∈
Athere exists a sequence {xn} ⊆A such that d(gxn+,Txn) = d(A,B) for every n ∈N ∪{}
and xn →x. Proof By following a similar reasoning to that in the proof of Theorem ., one can con-
struct a sequence {xn} ⊆Asuch that d(gxn+,Txn) = d(A,B) for all n ∈N. Moreover, in
the constructive process of {xn} if Txm = Txn for some m > n, then we choose xm+= xn+. This condition ensures that if, for some m ∈N, we have xm = xm+, then xn = xm for all
n ≥m. So the sequence {xn} converges to xm and also d(gxm,Txm) = d(A,B). Thus, we can
suppose that d(xn+,xn) ̸= for all n ∈N ∪{}. Since T is a Z-proximal contraction of the
second kind, we have ζ
d(Tgxn+,Tgxn),d(Txn,Txn–)
≥,
for all n ∈N. ζ
d(Tgxn+,Tgxn),d(Txn,Txn–)
≥,
for all n ∈N. From T ∈Tg and T being injective on A, we deduce that d(Tgxn+,Tgxn) > and
d(Txn,Txn–) > for all n ∈N. By using the property (ζ) of a simulation function, we
get ≤ζ
d(Tgxn+,Tgxn),d(Txn,Txn–)
< d(Txn,Txn–) – d(Tgxn+,Tgxn)
≤d(Txn,Txn–) – d(Txn+,Txn),
() () for every n ∈N. This implies that the sequence {d(Txn,Txn–)} is decreasing and hence
there exists r ≥such that d(Txn,Txn–) →r. Suppose r > . From () we deduce also that for every n ∈N. This implies that the sequence {d(Txn,Txn–)} is decreasing and hence
there exists r ≥such that d(Txn,Txn–) →r. Suppose r > . From () we deduce also that d(Tgxn+,Tgxn) < d(Txn,Txn–),
for all n ∈N. d(Tgxn+,Tgxn) < d(Txn,Txn–),
for all n ∈N. which leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. ch leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. □ which leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. which leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. □ We get the following corollary, by setting g as the identity mapping on A in Theorem .. Corollary .Let A and B be two nonempty subsets of a complete metric space (X,d). Suppose that T(A) is nonempty and closed. Assume also that the mapping T : A →B
satisfies the following conditions: (a) T is a Z-proximal contraction of the second kind; (b) T is injective on A; (b) T is injective on A; (c) T(A) ⊆B. Then there exists a unique point x ∈A such that d(x,Tx) = d(A,B). Moreover, for every
x∈Athere exists a sequence {xn} ⊆A such that d(xn+,Txn) = d(A,B) for every n ∈N∪{}
and xn →x. Then there exists a unique point x ∈A such that d(x,Tx) = d(A,B). Moreover, for every
x∈Athere exists a sequence {xn} ⊆A such that d(xn+,Txn) = d(A,B) for every n ∈N∪{}
and xn →x. Example .Let X = R be endowed with the usual metric d(x,y) = |x – y| for all x,y ∈X. Consider A = [–,–], B = [,] so that d(A,B) = and define T : A →B by Example .Let X = R be endowed with the usual metric d(x,y) = |x – y| for all x,y ∈X. Consider A = [–,–], B = [,] so that d(A,B) = and define T : A →B by Tx =
+ x
if x ∈[–,–],
–– x
if x ∈]–,–]. We have We have A=
x ∈A : d(x,y) = d(A,B) = ,for some y ∈B
= {–},
B=
y ∈B : d(x,y) = d(A,B) = ,for some x ∈A
= {}, and hence T(A) = {} = B. and hence T(A) = {} = B. and hence T(A) = {} = B. and hence T(A) = {} = B. It is easy to show that T is a Z-proximal contraction of the second kind, where the
function ζλ : [,+∞[×[,+∞[→R is given in Example .. Consequently, lim
n→+∞d(Tgxn+,Tgxn) = r. Now, using the property (ζ) of a simulation function, we write Now, using the property (ζ) of a simulation function, we write ≤limsup
n→+∞
ζ
d(Tgxn+,Tgxn),d(Txn,Txn–)
< , which is a contradiction and hence r = . Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 10 of 15 Next step is to show that the sequence {Txn} is Cauchy. By contradiction, assume that
{Txn} is not a Cauchy sequence. Then, by Lemma ., there exist an ε > and two sub-
sequences {Txnk} and {Txmk} of {Txn} such that nk > mk ≥k and d(Txnk,Txmk) ≥ε for all
k ∈N and lim
k→+∞d(Txnk,Txmk) = ε = lim
k→+∞d(Txnk+,Txmk+). Then we can assume that d(Txnk+,Txmk+) > for all k ∈N. Since T is a Z-proximal con-
traction of the second kind and d(gxnk+,Txnk) = d(A,B) = d(gxmk+,Txmk), we obtain ≤ζ
d(Tgxnk+,Tgxmk+),d(Txnk,Txmk)
< d(Txnk,Txmk) – d(Tgxnk+,Tgxmk+), < d(Txnk,Txmk) – d(Tgxnk+,Tgxmk+), for all k ∈N. Thus the previous inequality and T ∈Tg ensure that for all k ∈N. Thus the previous inequality and T ∈Tg ensure that lim
k→+∞d(Tgxnk+,Tgxmk+) = ε. By using the property (ζ) of a simulation function, with tk = d(Tgxnk+,Tgxmk+) and sk =
d(Txnk,Txmk), we obtain By using the property (ζ) of a simulation function, with tk = d(Tgxnk+,Tgxmk+) and sk =
d(Txnk,Txmk), we obtain ≤limsup
k→+∞
ζ
d(Tgxnk+,Tgxmk+),d(Txnk,Txmk)
< , which is a contradiction. We conclude that the sequence {Txn} is Cauchy. which is a contradiction. We conclude that the sequence {Txn} is Cauchy. By the completeness of (X,d) and since T(A) is closed, we have Txn →Tu ∈B. More-
over, there exists z ∈Asuch that d(z,Tu) = d(A,B). Since A⊆g(A), we obtain z = gx for some x ∈A, and hence d(gx,Tu) = d(A,B). Clearly, if x = xn for infinite n ∈N, then Tx = Tu. Therefore, we assume that x ̸= xn for
all n ∈N. Also there exists a subsequence {xnk} of {xn} such that Txnk ̸= Tu for all k ∈N. Again, since T is a Z-proximal contraction of the second kind, we get ≤ζ
d(Tgx,Tgxnk+),d(Tu,Txnk)
< d(Tu,Txnk) – d(Tgx,Tgxnk+) and hence and hence d(Tx,Txnk+) ≤d(Tgx,Tgxnk+) < d(Tu,Txnk), for all k ∈N, since T ∈Tg. Letting k →+∞, we obtain d(Tx,Txnk+) →and hence Tx =
Tu. This implies that d(gx,Tx) = d(A,B). Consequently, Page 11 of 15 Page 11 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 To prove the uniqueness, let x∗̸= x be another point in Asuch that d
gx∗,Tx∗
= d(A,B). d
gx∗,Tx∗
= d(A,B). Since T ∈Tg is injective on Aand T is a Z-proximal contraction of the second kind, we
write ≤ζ
d
Tgx,Tgx∗
,d
Tx,Tx∗
< d
Tx,Tx∗
– d
Tgx,Tgx∗
≤d
Tx,Tx∗
– d
Tx,Tx∗
= , ≤ζ
d
Tgx,Tgx∗
,d
Tx,Tx∗
< d
Tx,Tx∗
– d
Tgx,Tgx∗
≤d
Tx,Tx∗
– d
Tx,Tx∗
= , which leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. which leads to contradiction; we conclude that Tx = Tx∗and hence x = x∗. Indeed, from d(u,Tx) = d(v,Ty) = = d(A,B), we get (u,v) = (–,–) for x,y ∈{–,–}
and hence Indeed, from d(u,Tx) = d(v,Ty) = = d(A,B), we get (u,v) = (–,–) for x,y ∈{–,–}
and hence ζ
d(Tu,Tv),d(Tx,Ty)
= ζ
d(,),d(,)
= ζ(,) = . Therefore all the conditions of Corollary .hold true and x = –is the unique point such
that d(–,T(–)) = = d(A,B). Page 12 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Lemma .Let z ∈H. Then u ∈K satisfies the inequality ⟨u – z,y – u⟩≥, for all y ∈K if
and only if u = PKz. Lemma .Let S : H →H be monotone. Then u ∈K is a solution of ⟨Su,v – u⟩≥, for all
v ∈K, if and only if u = PK(u – λSu), with λ > . On this basis, we give some general convergence results on the solution of Problem .. Theorem .Let K be a nonempty, closed, and convex subset of a real Hilbert space H and
IK be the identity operator on K. Assume that the monotone operator S : H →H satisfies
the following condition: (a) PK(IK – λS) : K →K is a Z-contraction, with λ > . (a) PK(IK – λS) : K →K is a Z-contraction, with λ > . Then there exists a unique point u ∈K such that ⟨Su,v – u⟩≥for all v ∈K. Moreover,
for every u∈K, there exists a sequence {un} ⊆K such that un+= PK(un – λSun) for every
n ∈N ∪{} and un →u. Then there exists a unique point u ∈K such that ⟨Su,v – u⟩≥for all v ∈K. Moreover,
for every u∈K, there exists a sequence {un} ⊆K such that un+= PK(un – λSun) for every
n ∈N ∪{} and un →u. Proof Define T : K →K by Tx = PK(x–λSx) for all x ∈K so that, by Lemma ., u ∈K is a
solution of ⟨Su,v–u⟩≥for all v ∈K if and only if u = Tu. Clearly, the operator T satisfies
all the hypotheses of Theorem .by setting A = B = K. We deduce that the conclusions
of Theorem .hold true as an immediate consequence of Theorem .. □ Inspired by Theorem ., one can consider the following algorithm to solve Problem .. 4 Variational inequality problems Let H be a real Hilbert space, with inner product ⟨·,·⟩and induced norm ∥· ∥. Let K be a
nonempty, closed, and convex subset of H. We consider a monotone variational inequality
problem as follows; see [, ]. Problem .Find u ∈K such that ⟨Su,v – u⟩≥for all v ∈K, where S : H →H is a
monotone operator (i.e., ⟨Su – Sv,v – u⟩≥for all u,v ∈K). Problem .Find u ∈K such that ⟨Su,v – u⟩≥for all v ∈K, where S : H →H is a
monotone operator (i.e., ⟨Su – Sv,v – u⟩≥for all u,v ∈K). The interest for variational inequalities theory is due to the fact that a wide class of
equilibrium problems, arising in pure and applied sciences, can be treated in an unified
framework []. Now, we recall the metric projection, say PK : H →K, which is a powerful
tool for solving a variational inequality problem. Referring to classical books on approxi-
mation theory in inner product spaces, see [], we recall that for each u ∈H, there exists
a unique nearest point PKu ∈K such that ∥u – PKu∥≤∥u – v∥,
for all v ∈K. The theoretical background of projection and related approximation methods can be
found in [], too. Here, we need the following crucial lemmas, relating the existence of a
solution for a variational inequality problem and the existence of a fixed point of a certain
mapping. Lemma .Let z ∈H. Then u ∈K satisfies the inequality ⟨u – z,y – u⟩≥, for all y ∈K if
and only if u = PKz. Variational inequality problem solving algorithm Step (Initialization): Select an arbitrary starting point u∈K. Step (Initialization): Select an arbitrary starting point u∈K. Page 13 of 15 Page 13 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Step (Iteration): Given the current approximation point un ∈K, n ∈N ∪{}, compute un+= PK(un – λSun), satisfying Theorem .(a). satisfying Theorem .(a). In view of the proof of Theorem .(and hence Theorem .), this algorithm generates
sequences converging to a unique solution of Problem .. From Corollary ., we obtain the following result for the solution of a variational in-
equality problem. Theorem .Let K be a nonempty, closed, and convex subset of a real Hilbert space H and
IK be the identity operator on K. Assume that the monotone operator S : H →H satisfies
the following conditions: Theorem .Let K be a nonempty, closed, and convex subset of a real Hilbert space H and
IK be the identity operator on K. Assume that the monotone operator S : H →H satisfies
the following conditions: f
g
(a) PK(IK – λS) : K →K is a Z-proximal contraction of the second kind, with λ > ; (b) PK(IK – λS) is injective on K; (b) PK(IK – λS) is injective on K; (c) PK(IK – λS)(K) is closed. Then there exists a unique point u ∈K such that ⟨Su,v – u⟩≥for all v ∈K. Moreover,
for every u∈K, there exists a sequence {un} ⊆K such that un+= PK(un – λSun) for every
n ∈N ∪{} and un →u. Inspired by Theorem ., one can consider the following algorithm to solve Problem .. Variational inequality problem solving algorithm Step (Initialization): Select an arbitrary starting point u∈K. Step (Initialization): Select an arbitrary starting point u∈K. Step (Iteration): Given the current approximation point un ∈K, n ∈N ∪{}, compute un+= PK(un – λSun), Author details
1 1Mathematics Department, College of Science (Malaz), King Saud University, P.O. Box 22452, Riyadh, Kingdom of Saudi
Arabia. 2Department of Mathematics and Computer Sciences, University of Palermo, Via Archirafi34, Palermo, 90123,
Italy. 3Department of Energy, Information Engineering and Mathematical Models (DEIM), University of Palermo, Viale
delle Scienze, Palermo, 90128, Italy. Competing interests
h
h
d
l
h Competing interests
The authors declare that they have no competing interests. p
g
The authors declare that they have no competing interests. satisfying Theorem .(a)-(c). Our results apply to some fundamental problems of optimization theory. In fact, as a
special case of Problem ., we retrieve the following constrained minimization problem. Problem .Find u ∈K such that ⟨∇fu,v–u⟩≥for all v ∈K, where f : H →R is a con-
tinuously differentiable function which is convex on K with ∇f denoting the gradient of f . A second special case of Problem ., is the following hierarchical variational inequality
problem. Problem .Let Fix(g) := {x ∈K : x = gx}, where g : K →K is such that ∥gx–gy∥≤∥x–y∥
(i.e., g is nonexpansive). Find u ∈Fix(g) such that ⟨Su,v – u⟩≥for all v ∈Fix(g), where
S : K →K is a monotone continuous operator. Finally, by using the Gâteaux directional derivative of a metric projection, we denote K
x,–S(x)
:= lim
t→+
PK(x – tS(x)) – x
t
, K
x,–S(x)
:= lim
t→+
PK(x – tS(x)) – x
t
, where S : K →H is continuous. where S : K →H is continuous. where S : K →H is continuous. Theory and Applications ( 2016) 2016:26
Page 14 of 15 Tchier et al. Fixed Point Theory and Applications ( 2016) 2016:26 Page 14 of 15 Now, consider the initial value problem: Now, consider the initial value problem: Now, consider the initial value problem: dx(t)
dt
= K
x(t),–S
x(t)
,
x() = x∈K,
t ∈[,+∞[, dx(t)
dt
= K
x(t),–S
x(t)
,
x() = x∈K,
t ∈[,+∞[,
() () whose critical points satisfy dx(t)
dt = . In [], the authors proved that the set of critical points of () coincides with the set of
solutions of a monotone variational inequality problem involving the operator S. Thus, our
theory is applicable to the study of (), which is associated to various economic problems;
see again []. Authors’ contributions
All
th
t ib t d Authors’ contributions
All authors contributed equally and significantly in writing this article. All authors read and approved the final manuscript. Authors contributions
All authors contributed equally and significantly in writing this article. All authors read and approved the final manuscript 5 Conclusions Best approximation and fixed point theories are continuously expanding topics due to
their applications in many fields of pure and applied mathematics. Thus, we gave new
theorems of g-best proximity point by using a notion of simulation function. This ap-
proach is useful to cover existing results in the literature from an unifying point of view. A discussion of the solvability of monotone variational inequality problems and related
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English
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Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA
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International journal of molecular sciences
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Ilka Kristiansen 1, Carsten Stephan 2, Klaus Jung 3, Manfred Dietel 4, Anja Rieger 4,
Yuri Tolkach 1,† and Glen Kristiansen 1,*,† Ilka Kristiansen 1, Carsten Stephan 2, Klaus Jung 3, Manfred Dietel 4, Anja Rieger 4,
Yuri Tolkach 1,† and Glen Kristiansen 1,*,† 1
Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany; ilka.kristiansen@gmx.de (I.K.);
Yuri.tolkach@ukbonn.de (Y.T.) 1
Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany; ilka.kristiansen@gmx.de (I.K.);
Yuri.tolkach@ukbonn.de (Y.T.) (
)
2
Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; carsten.stephan@charite.de
3
Berlin Institute of Urologic Research, 10117 Berlin, Germany; klaus.jung@charite.de
4
Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
Manfred.dietel@charite.de (M.D.); Anja.rieger@charite.de (A.R.)
*
Correspondence: glen.kristiansen@ukbonn.de; Tel.: +49-228-287-15375, Fax: +49-228-287-15030
†
These authors contributed equally to this work. A
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Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
Manfred.dietel@charite.de (M.D.); Anja.rieger@charite.de (A.R.) †
These authors contributed equally to this work. Academic Editor: William Chi-shing Cho Academic Editor: William Chi-shing Cho d: 16 April 2017; Accepted: 24 May 2017; Published: 2 Received: 16 April 2017; Accepted: 24 May 2017; Published: 29 May 2017 Abstract: Aims: Determining the origin of metastases is an important task of pathologists to allow for
the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been
suggested as a new marker for the detection of prostatic origin. The aim of this study was to evaluate
the diagnostic sensitivity of HOXB13 in comparison to commonly used immunohistochemical
markers for prostate cancer. Materials and methods: Histologically confirmed prostate cancer lymph
node metastases from 64 cases were used to test the diagnostic value of immunohistochemical
markers: prostate specific antigen (PSA), Prostatic acid phosphatase (PSAP), prostate specific
membrane antigen (PSMA), homeobox gene NKX3.1, prostein, androgen receptor (AR), HOXB13,
and ETS-related gene (ERG). All markers were evaluated semi-quantitatively using Remmele’s
immune reactive score. Results: The detection rate of prostate origin of metastasis for single markers
was 100% for NKX3.1, 98.1% for AR, 84.3% for PSMA, 80.8% for PSA, 66% for PSAP, 60.4% for
HOXB13, 59.6% for prostein, and 50.0% for ERG. Conclusions: Our data suggest that HOXB13 on its
own lacks sensitivity for the detection of prostatic origin. Therefore, this marker should be only used
in conjunction with other markers, preferably the highly specific PSA. The combination of PSA with
NKX3.1 shows a higher sensitivity and thus appears preferable in this setting. Keywords: prostate cancer; metastasis; immunohistochemistry; detection; PSA; PSAP; PSMA;
NKX3.1; prostein; HOXB13; ERG; AR International Journal of
Molecular Sciences Keywords: prostate cancer; metastasis; immunohistochemistry; detection; PSA; PSAP; PSMA;
NKX3.1; prostein; HOXB13; ERG; AR www.mdpi.com/journal/ijms Sensitivity of HOXB13 as a Diagnostic
Immunohistochemical Marker of Prostatic Origin
in Prostate Cancer Metastases: Comparison to PSA,
Prostein, Androgen Receptor, ERG, NKX3.1, PSAP,
and PSMA Ilka Kristiansen 1, Carsten Stephan 2, Klaus Jung 3, Manfred Dietel 4, Anja Rieger 4,
Yuri Tolkach 1,† and Glen Kristiansen 1,*,† 1. Introduction Determining the origin of the primary tumor in metastases is an important task of pathologists to
allow for the initiation of a tumor-specific therapy. Since its description in the 1970s, prostate specific
antigen (PSA) has in due course become the dominant prostate marker in serum [1,2]. PSA could be
detected by immunohistochemistry in tissue and was quickly adopted by pathologists as a diagnostic
marker [3,4]. PSA is still regarded as a highly specific marker of prostatic origin, but due to its
decreased or even lost expression in higher grade or metastatic tumors, which was already noted in Int. J. Mol. Sci. 2017, 18, 1151; doi:10.3390/ijms18061151 www.mdpi.com/journal/ijms 2 of 9 Int. J. Mol. Sci. 2017, 18, 1151 initial studies, its sensitivity is clearly limited, which necessitates the use of additional markers in PSA
negative cases [5]. Prostein, coded by the SLC45A3 gene and identified by transcript profiling studies
of prostate cancer, was found to be highly specific for prostatic origin and displays a characteristic
Golgi-type cytoplasmic staining pattern [6,7]. As seen with PSA, prostein expression also shows a
slightly diminished expression with tumor progression, but in combination with PSA it proved to be
a valuable tool to identify prostatic origin [8,9]. An alternative marker for prostatic origin was the
protein coded by the homeobox gene NKX3.1, which shows nuclear staining on immunohistochemistry
and which was also found to be highly though not exclusively specific for prostate tissues [10,11]. At the 2014 consensus conference of the International Society of Urological Pathology (ISUP), it was
recommended to use immunohistochemistry for PSA, NKX3.1 and prostein to ascertain a prostatic
origin in doubtful cases [5]. Another diagnostic candidate marker that was not considered at that conference was
homeobox protein Hox-B13 (HOXB13), which was characterized as a marker for prostate cancer
by Edwards et al. [12]. HOXB13 also has a nuclear staining pattern and has been recommended by
several studies as a prostate specific marker [13–16]. To date, the diagnostic value and especially the
performance of HOXB13 immunohistochemistry as a marker of prostatic origin in direct comparison
to the commonly used prostate markers (PSA, prostein, ERG, the androgen receptor (AR), NKX3.1,
Prostatic acid phosphatase (PSAP) and prostate specific membrane antigen (PSMA)) in metastases has
not been evaluated, which was therefore the aim of this study. 2.1. Immunohistochemical Staining Patterns (F) ERG is also located in the nucleus and has a
higher degree of heterogeneity, as seen here. (G) Homeobox gene NKX3.1 commonly displays strong
nuclear staining. (H) Homeobox protein HOXB3 is also seen in nuclei, however, the staining intensity
is weaker. All images are taken in 400×. Figure 1. Immunohistochemistry of candidate diagnostic prostate markers. (A) Prostate specific
antigen (PSA) shows diffuse cytoplasmic staining with a higher degree of heterogeneity in this
case. (B) Prostein immunoreactivity is restricted to the Golgi apparatus area. (C) Prostate specific
alkaline phosphatase (PSAP) also displays a diffuse cytoplasmic staining pattern. (D) Prostate specific
membrane antigen (PSMA) has characteristic cytoplasmic but also membranous staining. (E) Androgen
receptor shows epithelial nuclear staining. (F) ERG is also located in the nucleus and has a higher
degree of heterogeneity, as seen here. (G) Homeobox gene NKX3.1 commonly displays strong nuclear
staining. (H) Homeobox protein HOXB3 is also seen in nuclei, however, the staining intensity is weaker. All images are taken in 400×. 2.1. Immunohistochemical Staining Patterns All markers showed the expected patterns of immunoreactivity in metastatic prostate cancer. Prostate specific antigen (PSA) and prostatic phosphatase (PSAP) displayed diffuse cytoplasmic
staining (Figure 1A,C), where prostein showed the characteristic Golgi-type staining (Figure 1B). Prostate specific membrane antigen (PSMA, Figure 1D) showed a predominantly membranous but
also cytoplasmic immunoreactivity. Nuclear staining was seen for the androgen receptor (AR), ERG,
NKX3.1, and HOXB13 (Figure 1E–H). Int. J. Mol. Sci. 2017, 18, x FOR PEER REVIEW
3 of 9 Figure 1. Cont. Figure 1. Cont. 3 of 9 Int. J. Mol. Sci. 2017, 18, 1151 Figure 1. Immunohistochemistry of candidate diagnostic prostate markers. (A) Prostate specific
antigen (PSA) shows diffuse cytoplasmic staining with a higher degree of heterogeneity in this case. (B) Prostein immunoreactivity is restricted to the Golgi apparatus area. (C) Prostate specific alkaline
phosphatase (PSAP) also displays a diffuse cytoplasmic staining pattern. (D) Prostate specific
membrane antigen (PSMA) has characteristic cytoplasmic but also membranous staining. (E)
Androgen receptor shows epithelial nuclear staining. (F) ERG is also located in the nucleus and has a
higher degree of heterogeneity, as seen here. (G) Homeobox gene NKX3.1 commonly displays strong
nuclear staining. (H) Homeobox protein HOXB3 is also seen in nuclei, however, the staining intensity
is weaker. All images are taken in 400×. Figure 1. Immunohistochemistry of candidate diagnostic prostate markers. (A) Prostate specific
antigen (PSA) shows diffuse cytoplasmic staining with a higher degree of heterogeneity in this
case. (B) Prostein immunoreactivity is restricted to the Golgi apparatus area. (C) Prostate specific
alkaline phosphatase (PSAP) also displays a diffuse cytoplasmic staining pattern. (D) Prostate specific
membrane antigen (PSMA) has characteristic cytoplasmic but also membranous staining. (E) Androgen
receptor shows epithelial nuclear staining. (F) ERG is also located in the nucleus and has a higher
degree of heterogeneity, as seen here. (G) Homeobox gene NKX3.1 commonly displays strong nuclear
staining. (H) Homeobox protein HOXB3 is also seen in nuclei, however, the staining intensity is weaker. All images are taken in 400×. Figure 1. Immunohistochemistry of candidate diagnostic prostate markers. (A) Prostate specific
antigen (PSA) shows diffuse cytoplasmic staining with a higher degree of heterogeneity in this case. (B) Prostein immunoreactivity is restricted to the Golgi apparatus area. (C) Prostate specific alkaline
phosphatase (PSAP) also displays a diffuse cytoplasmic staining pattern. (D) Prostate specific
membrane antigen (PSMA) has characteristic cytoplasmic but also membranous staining. (E)
Androgen receptor shows epithelial nuclear staining. 2.2. Statistical Evaluation of Prostate Markers
2.2. Statistical Evaluation of Prostate Markers The highest detection rate was seen with NKX3.1 followed by the androgen receptor and PSMA. PSA, as the most commonly used antibody to specifically recognize prostate cancer, correctly
detected nearly 81% of cases. ERG labeled, as expected, only 50% of prostate cancer metastases. The highest detection rate was seen with NKX3.1 followed by the androgen receptor and PSMA. PSA, as the most commonly used antibody to specifically recognize prostate cancer, correctly detected
nearly 81% of cases. ERG labeled, as expected, only 50% of prostate cancer metastases. Prostein, PSAP,
and HOXB13 were only slightly superior, detecting approximately two thirds of cases (Table 1). Table 1. Detection rates of prostate markers in prostate cancer metastases. Table 1. Detection rates of prostate markers in prostate cancer metastases. Marker
Detection Rate (%)
Mean IRS
Number of Cases
PSA
80.8
6.3
52
PSAP
66.0
3.5
53
PSMA
84.3
6.0
51
Prostein
59.6
4.2
52
Androgen receptor (AR)
98.1
6.7
53
ERG
50.0
2.6
52
NKX3.1
100.0
8.0
50
HOXB13
60.4
4.7
53
Abbreviations: IRS = immunoreactive Score according to Remmele. A Spearman rank correlation analysis of IRS values of these markers revealed the following
significant associations: AR and HOXB13 (correlation coefficient (CC) = 0.358, p = 0.009), AR and
NKX3.1 (CC = 0.505, p = 0.001), AR and PSAP (CC = −0.277, p = 0.047), ERG and HOXB13 (CC = 0.283,
p = 0.044), PSA and Prostein (CC = 0.367, p = 0.008), PSA and PSAP (CC = 0.623, p = 0.001), PSA and
PSMA (CC = 0.350, p = 0.012), prostein and PSAP (CC = 0.277, p = 0.049), and prostein and HOXB13
(CC = −0.296, p = 0.035). Int. J. Mol. Sci. 2017, 18, 1151 4 of 9 We then investigated which combination of prostate markers would achieve the highest
detection rate by combining the most commonly used marker PSA with the other markers in cross
tables. PSAP recognized 10% of PSA negative cases, which did not add significant information. PSMA performed slightly better, labelling 50% of PSA negative cases. HOXB13 correctly recognized
70%, and finally NKX3.1 correctly detected all PSA negative cases, leading to a detection rate (of the
combination of PSA and NKX3.1) of 100% in this dataset. Prostein and PSA correctly detected 82% of
cases, HOXB13 and PSA labeled 94.2% of cases correctly, AR and PSA detected 100% of cases, and ERG
and PSA recognized 88% of prostate cancer metastases. 2.2. Statistical Evaluation of Prostate Markers
2.2. Statistical Evaluation of Prostate Markers In a direct analysis of HOXB13 and NKX3.1 expression, both markers together recognized 100%,
as NKX3.1 labeled 100% of HOXB13 negative cases. NKX3.1 combined with AR also achieved a
detection rate of 100%. 3.1. Case Selection and Construction of Tissue Microarray First, prostate cancer patients who underwent radical prostatectomy (RP) and lymphadenectomy
and who were diagnosed at the Institute of Pathology, Charité–Universitätsmedizin Berlin between
1998 and 2005 were identified. Histologically confirmed metastases from 64 cases were used for tissue
microarray construction with one spot per case and a punch size of 1 mm. The tissue microarray
comprised of two blocks. The metastases consisted of 57 local lymph node metastases and seven
systemic metastases (4× bone, 1× penis, 1× oral mucosa, 1× cervical lymph node). Lymph nodes
were submitted to frozen section analysis prior to RP, which was usually not performed in case of a
positive node. Only 13 RPs were performed. Therefore, histopathological RP data on the primary
tumor was not available for the majority of cases. For the thirteen RP cases that were completed,
the Gleason scores (GS) were: GS7-2, GS8-4, GS9-4, GS10-3. The pT categories (according to Union for
International Cancer Control (UICC) TNM classification of malignant tumors, 8th edition) were: pT2-2,
pT3a-1, pT3b-10. Positive margins were seen in 11 cases. The bilateral lymphonodectomy specimens
(n = 57) contained a median of 12 lymph nodes (range 1 to 23). Twenty-nine cases had a single positive
lymph node, 15 cases had two metastases, seven cases had three metastases and six cases had four or
more positive nodes (maximum 11). The use of this tissue was approved by the Charité University
Ethics Committee (EA1/06/2004). No animals were involved in this study. 4. Discussion This study evaluates the sensitivity of prostate markers to detect lymph node and distant
metastases of prostate cancer. It confirms that PSA, as the most commonly used antibody for routine
purposes, has a relatively high detection rate of nearly 81%. The value of PSA is its high specificity,
as apart from prostate cancer only breast cancer may be PSA positive, but this is usually not in the closer
differential diagnosis [18]. The loss of PSA expression with tumor dedifferentiation and progression is
long known and constitutes the necessity to use other markers in a combination. As prostate cancer is an androgen-driven disease, the high rates of androgen receptor expression
found in primary and metastatic prostate tumors are not surprising, and again this study confirms
that metastases retain their AR expression well. The disadvantage of AR is the relative lack of
specificity, as other neoplasms including urothelial carcinoma or salivary gland tumors may also be
AR positive [19,20]. The overexpression of ERG, often resulting from the Transmembrane protease, serine
2-erythroblast transformation-specific-related gene TMPRSS2-ERG translocation which is found in
nearly half of primary prostate cancer cases, is therefore typical of prostate cancer, but with a detection
rate of 50% it clearly lacks sensitivity [21]. It is less well known that even though the genomic
translocation is highly specific for prostate cancer, ERG protein expression is seen in a variety of other
tumors, too. This includes, apart from vascular tumors, round cell sarcomas and leukemias, the more
common differential diagnosis of urothelial carcinoma and, according to the human protein atlas
(hppt://www.proteinatlas.org), also melanoma, testicular, and gastrointestinal tumors [22–24]. pp
p
g
g
Prostein was described and characterized by Xu et al. as a prostate specific protein, which was
quickly used by surgical pathologists for the differential diagnosis of prostate cancer, especially to rule
out urothelial carcinoma, which is almost consistently prostein-negative [6,7,9,25,26]. Prostein also has
the advantage of a distinctive Golgi-type staining pattern, which can be reassuring in cases with only
weak positivity. In primary prostate cancer, prostein expression is inversely correlated with Gleason
scores and is a prognostic marker of disease progression [27]. As our study confirms, the sensitivity of
prostein in metastases is fairly limited with a detection rate of 59%, and even in conjunction with PSA
only 82% of cases can be confirmed as prostatic in origin, which equals the detection rate of PSA alone
in our cohort. 3.2. Immunohistochemistry Immunohistochemistry was conducted using semi-automated platforms (Benchmark Ultra,
Roche, and Autostainer, Medac) with protocols that are in routine use at the Institute of Pathology,
University of Bonn (Table 2). Table 2. Antibodies used for immunohistochemistry in this study. Antigen
Clone
Provider
Dilution
Platform
Protocol
PSA
Polyclonal, rabbit
DAKO
1:20,000
Autostainer
No pretreatment
PSAP
PASE/4LJ
Cell Marque
1:6000
Autostainer
HIER (pH 6, 20 s 98 °C)
PSMA
3E6
DAKO
1:500
Benchmark
CC1 (pH 8), ultraview
Prostein
10E3
DAKO
1:100
Benchmark
CC1 (pH 8), ultraview
Androgen
Receptor (AR)
AR441
DAKO
1:400
Autostainer
HIER (pH 6, 20 s 98 °C)
ERG
EPR3864
Biologo
1:100
Autostainer
HIER (pH 6, 20 s 98 °C)
NKX3.1
EP356
Cell Marque
1:200
Benchmark
CC1 (pH 8), ultraview
HOXB13
F-9
Santa Cruz
1:50
Benchmark
CC1 (pH 8), optiview
Abbreviations: HIER-Heat Induced Epitope Retrieval. Table 2. Antibodies used for immunohistochemistry in this study. Abbreviations: HIER-Heat Induced Epitope Retrieval. Int. J. Mol. Sci. 2017, 18, 1151 5 of 9 3.4. Statistics All data were processed using SPSS (IBM SPSS Statistics for Macintosh, Version 22.0, IBM Corp.,
Armonk, NY, USA). Spearman Rank correlations were used to analyze the associations among markers. 3.3. Evaluation of Immunohistochemistry All markers were evaluated semi-quantitatively using the immune reactive score (IRS), which
gives the product of categorized percentage of stained cells (0: negative, 1: 1–10%, 2: 11–50%, 3:
51–80%, and 4: >80%) and staining intensity (ranging from negative (0) to strong (3)), and hence has a
range from 0 to 12. For statistical evaluation, an IRS below 3 was considered a negative test and higher
values were considered as positive, as suggested by Remmele and Stegner in their original proposal
of the IRS scoring system [17]. The evaluation was carried out under the immediate supervision of a
Genito–Urinary pathologist with broad expertise in immunohistochemistry (Glen Kristiansen). 4. Discussion As we found that both markers correlated, this redundancy of diagnostic information
is not surprising. The same holds true for PSAP, which we found strongly and highly positively
correlated to PSA, and this did not add significant information as only 10% of PSA negative cases were
picked up by PSAP. A larger cohort may be necessary to demonstrate the additional diagnostic value
of prostein or PSAP to PSA. Prostate specific membrane antigen (PSMA) is overexpressed during tumor progression,
and Bostwick et al. found 82% positivity rates in primary prostate cancer [28]. However, despite its Int. J. Mol. Sci. 2017, 18, 1151 6 of 9 name it is not prostate specific at all, but is also seen in a wide variety of tumors including colon,
bladder, and renal cancer, so its use as a marker for prostatic differentiation is now discouraged [29]. NKX3.1 is a homeobox gene that shows a prostate and testis specific expression pattern, but may
also be found in breast cancer. Its crisp nuclear staining pattern and its high rate of positivity in
metastases (98.6%, Gurel et al. [30]), which this study confirms, have made it a popular diagnostic
marker that is already endorsed by ISUP in their recommendations on diagnostic markers for
genito–urinary pathology [11,30–33]. In particular, its combination with PSA is promising, as the high
detection rate of 100% found in this study witnesses. y
HOXB13 is another, so far less acknowledged diagnostic marker candidate, which has been
recommended lately as a prostate specific marker [12,13,15,16]. Barresi et al. analyzed 15 prostate
cancer metastases and found all of them strongly positive (in >75% of tumor cells) which equates a
sensitivity of 100% [15]. Minimally lower rates were reported by Varinot et al., who analyzed 74 cases
of lymph node metastases and 15 additional bone metastases. They found HOXB13 positivity in 33%
of bone metastases and 93% of lymph node metastases. Interestingly, the expression of HOXB13 was
also found as an independent prognostic marker in primary prostate cancer and to correlate with AR
expression [14]. While our study confirms the significant association with AR, the diagnostic value of
HOBX13 appears less convincing, as only 60.4% of prostate cancer metastases were positively stained. Of course, besides aspects of cohort composition that may influence the tumor biology, technical
issues of the immunohistochemistry protocol or the tissue micro array construction may also explain
this rather significant discrepancy. 4. Discussion This detection rate increased markedly to 94.2% if combined with
PSA, but it remains inferior to the combination of PSA with NKX3.1. HOXB13 is also expressed in
other carcinomas including endometrial cancer, which in itself does not limit its diagnostic value,
but also in pancreatic cancer and hepatocellular carcinoma [34–36]. In light of these data, we do not
recommend HOXB13 as a sole marker to detect a prostatic origin in a metastasis, but rather prefer
PSA in conjunction with NKX3.1. However, prostein or HOXB13 may well be considered as third line
markers in doubtful cases, and here combinations are advisable and often necessary [5,37]. This study has several weaknesses. The number of cases is relatively small, which precludes a
more detailed analysis of combinational subgroups. Still, the cohort size is large enough to confirm
the known expression rates of the markers under question and it is the first study to critically analyze
HOXB13 in direct comparison to these other markers in prostate cancer metastases. This study is
restricted to the correct detection of prostate markers in known prostate metastases and hence only
evaluates the sensitivity of these markers. Also, this study lacks data on the Gleason scores of biopsies
of primary tumors, which precludes further correlation analyses of biomarker expression. Finally,
we did not aim to verify the specificity of our candidate biomarkers, which would have necessitated
an additional large analysis of non-prostatic neoplasms [38]. In summary, our data suggest that the novel marker candidate HOXB13 alone is not a good
diagnostic marker for the detection of prostatic origin. Only in combination with PSA does it achieve
satisfactory detection rates. Alternatively, the combination of PSA with the already well-established
marker NKX3.1 shows an even higher sensitivity and is therefore recommended in this setting. Acknowledgments: We are greatly indebted to the Sonnenfeldstiftung, Berlin, who funded the tissue microarrayer. We thank Britta Beyer for excellent technical support and Alfred E. Neumann for his enduring sense of humour
and constructive discussions. Conflicts of Interest: The authors declare no conflict of interest. [CrossRef] [PubMed] 7. Xu, J.; Kalos, M.; Stolk, J.A.; Zasloff, E.J.; Zhang, X.; Houghton, R.L.; Filho, A.M.; Nolasco, M.; Badaro, R.;
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Ilka Kristiansen collected data, prepared the statistics and wrote the paper;
Carsten Stephan and Klaus Jung provided clinical information, supervised the statistics and revised the paper;
Manfred Dietel and Anja Rieger provided tissues and clinico-pathological data, constructed the tissue micro array
(TMA) and revised the paper; Yuri Tolkach and Glen Kristiansen conceived the study, conducted the central
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Correlation of Significantly Decreased Serum Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Level With an Increased Risk of Future Cardiovascular Disease in Adult Patients With Growth Hormone Deficiency
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Frontiers in endocrinology
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ORIGINAL RESEARCH
published: 16 June 2021
doi: 10.3389/fendo.2021.671126 Edited by:
Ilonka Kreitschmann-Andermahr,
University of Duisburg-Essen,
Germany Edited by:
Ilonka Kreitschmann-Andermahr,
University of Duisburg-Essen,
Germany Edited by:
Ilonka Kreitschmann-Andermahr,
University of Duisburg-Essen,
Germany Reviewed by:
Luiz Augusto Casulari,
University of Brasilia, Brazil
Krystallenia I. Alexandraki,
National and Kapodistrian University of
Athens, Greece Ziyu Ren 1†, Yunting Wang 2†, Qing Chen 1, Jiangchuan Long 1, Rui Zhang 1, Xun Wu 2,
Wenjie Qian 2, Yue Chen 3, Dongfang Liu 1* and Wei Ren 2* 1 Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University,
Chongqing, China, 2 Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical
University, Chongqing, China, 3 General Practice, The 958 Hospital of the People’s Liberation Army, Chongqing, China *Correspondence:
Dongfang Liu
300306@hospital.cqum.edu.cn;
ldf023023@qq.com
Wei Ren
renwei67@sina.com
†These authors have contributed
equally to this work Objective: Adult growth hormone deficiency (AGHD) is a rare chronic inflammatory
disease caused by damage to the pituitary gland and is accompanied by disorders of
multiple metabolic pathways. By examining the correlation between the serum
mesencephalic astrocyte-derived neurotrophic factor (MANF) levels of AGHD patients
and those of normal controls, we hope to elucidate the close relationship among MANF,
lipid metabolism and insulin resistance in AGHD and discuss the potential therapeutic
value of MANF. Specialty section:
This article was submitted to
Pituitary Endocrinology,
a section of the journal
Frontiers in Endocrinology
Received: 23 February 2021
Accepted: 01 June 2021
Published: 16 June 2021 Specialty section:
This article was submitted to
Pituitary Endocrinology,
a section of the journal
Frontiers in Endocrinology Methods: This study included 101 AGHD patients and 100 healthy subjects matched for
sex, age, height, and weight. Anthropometric parameters and biochemical indicators such
as body mass index, waist circumference, hip circumference, serum MANF level, blood
lipids and insulin level were measured. The above patients were also divided into several
subgroups for correlation analysis based on indicators such as insulin resistance and BMI. Received: 23 February 2021
Accepted: 01 June 2021
Published: 16 June 2021 INTRODUCTION protein to ER stress and participate in the unfolded protein
response (9). It is well known that to balance the harmful effects
of ERs, the body initiates the unfolded protein response (UPR),
which stimulates the secretion of MANF to reduce the
accumulation of misfolded proteins and restore the normal
function of the endoplasmic reticulum (10). Growth hormone is a polypeptide secreted by somatotroph cells
of the anterior pituitary gland that is released in pulses mainly at
night, and it can participate in anabolism and promote the
growth and development of the body (1, 2). Acquired adult
growth hormone deficiency (AGHD) is a special endocrine
condition in which the growth hormone secretion ability of
somatotroph cells is inhibited due to structural damage to the
pituitary gland in adults, ultimately resulting in lower than
normal absolute levels of growth hormone. Due to the
presence and widespread expression of growth hormone
receptors in various tissues and organs of the body, AGHD is
characterized by abnormal body composition, imbalanced
energy metabolism, decreased exercise capacity, impaired heart
and kidney function, and even impaired psychological health (3). It has been shown that AGHD, similar to metabolic syndrome, is
strongly associated with a chronic inflammatory state and that
serum levels of lipocalin-2 (LCN2) are significantly elevated in
patients with AGHD compared to the healthy population (4). Numerous studies suggest that disruption of the balance of the
growth hormone/insulin-like growth factor 1 axis can induce the
development of various heart diseases. Patients with AGHD have
elevated levels of circulating inflammatory factors, accompanied
by increased levels of oxidative stress and endothelial
dysfunction (5). A body of evidence suggests that patients with
AGHD have a higher risk of developing cardiovascular disease. Pituitary cells are more susceptible to endoplasmic reticulum
stress due to their high secretion of growth hormone and various
prohormones (11). Increasing evidence also suggests a strong
link between MANF and pituitary cells. The MANF-/- mouse
model exhibited severe growth defects compared to normal
controls. The size of the pituitary gland was significantly
smaller, and ER stress and apoptosis were significantly
increased in the pituitary gland (8). MANF has been shown to
play an important therapeutic role in a variety of endoplasmic
reticulum stress-related diseases. MANF has shown promising
protective effects in neurodegenerative diseases, diabetes, and
ischemic diseases of the heart and brain, and it can even
modulate inflammatory factor expression to suppress chronic
inflammatory diseases (12). Citation: Ren Z, Wang Y, Chen Q, Long J,
Zhang R, Wu X, Qian W, Chen Y, Liu D
and Ren W (2021) Correlation of
Significantly Decreased Serum
Circulating Mesencephalic
Astrocyte-Derived Neurotrophic
Factor Level With an Increased Risk
of Future Cardiovascular Disease
in Adult Patients With Growth
Hormone Deficiency. Front. Endocrinol. 12:671126. doi: 10.3389/fendo.2021.671126 Results: The serum circulating MANF content of AGHD patients was significantly lower
than that of the normal control group (5.235 (0.507-17.62) ng/ml (n=101) vs. 10.30 (1.84-
16.65) ng/ml (n=100); p<0.0001), and circulating MANF levels were linearly correlated with
HOMA-IR in the AGHD population (R=0.481, P=0.0041). When MANF was at pathological
concentrations (lower than the mean circulating MANF of normal controls), the lowest
concentration tertile (OR=21.429 p<0.0001) had a significantly higher disease odds ratio,
Framingham risk score and 10-year risk of atherosclerotic cardiovascular disease than the
highest concentration tertile. June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org Ren et al. Cardiometabolic Risk Markers in AGHD Conclusions: MANF has a significant correlation with insulin resistance in the AGHD
state. There is a strong correlation with abnormal glucose and lipid metabolism in the
obese AGHD population. MANF is also a good assessment factor for the risk of
cardiovascular disease in AGHD patients and has excellent therapeutic potential. Conclusions: MANF has a significant correlation with insulin resistance in the AGHD
state. There is a strong correlation with abnormal glucose and lipid metabolism in the
obese AGHD population. MANF is also a good assessment factor for the risk of
cardiovascular disease in AGHD patients and has excellent therapeutic potential. Keywords: adult growth hormone deficiency, mesencephalic astrocyte-derived neurotrophic factor, insulin
resistance, lipid metabolism, cardiovascular risk Keywords: adult growth hormone deficiency, mesencephalic astrocyte-derived neurotrophic factor, insulin
resistance, lipid metabolism, cardiovascular risk INTRODUCTION A growing body of evidence suggests that MANF appears to
have highly valuable therapeutic potential for AGHD, a specific
chronic metabolic endoplasmic reticulum stress-related disorder. Whether MANF can be a novel therapeutic target for AGHD
needs to be supported by various lines of evidence. The purpose
of this research was to investigate whether circulating MANF is
associated with newly diagnosed AGHD and to clarify the
association from a clinical point of view. No relevant research
about serum MANF levels in healthy subjects and patients with
AGHD has been reported thus far. Mesencephalic astrocyte-derived neurotrophic factor
(MANF) was first discovered by Canadian scientists in 2003 as
a secreted protein with selective protective effects on dopamine
neurons (6). However, in recent years, researchers have
increasingly turned their attention to the association of MANF
with metabolic diseases. In addition to neuronal tissues, MANF
protein and mRNA are also widely expressed in metabolically
active nonneuronal tissues and organs such as the testis, thyroid,
and adrenal gland (7). It is also significant for neuroendocrine
organs such as the thalamus and pituitary gland. MANF-
deficient mice have a smaller anterior pituitary gland size than
wild-type mice, thus reducing the number of cells producing
growth hormone and prolactin due to the reduced pituitary
gland size. This eventually leads to dysregulation of pituitary
hormone expression and increased endoplasmic reticulum (ER)
stress and apoptosis (8). Although MANF does not share any
protein sequence homology with typical neurotrophic factors,
MANF can exert the same extracellular effects as typical
neurotrophic factors in regulating the cellular cascade. Interestingly, MANF can also act intracellularly as a reactive Frontiers in Endocrinology | www.frontiersin.org Subjects j
We recruited 101 patients (68 females, 33 males; mean age of
45.87 ± 14.45 years; range 20-76) with newly diagnosed AGHD
from January 2017 to October 2020 in the Department of
Endocrinology of our hospital. AGHD was diagnosed
according to the insulin tolerance test (ITT), which is
recommended by The American Endocrine Society as the gold
standard, with a growth hormone (GH) peak <5.0 mg/L. None of
the patients had been treated with GH prior to diagnosis, and all
the patients were evaluated for thyroid, gonadal, and adrenal
function and received stable hormone replacement therapy for
more than 6 months according to the function of their respective
endocrine glands to ensure the stability of these glands and June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 2 Cardiometabolic Risk Markers in AGHD Ren et al. Experimental Group Design y
The formulas involved in this research were as follows: this assay
adopts the homeostatic model to assess the insulin resistance index
using the following formula: HOMA-IR = fasting insulin (mU/L) ×
[fasting plasma glucose (mmol/L)/22.5]. b cell function was
calculated as follows: HOMA-b = [20 × fasting insulin (mU/L)]/
[fasting plasma glucose (mmol/L)-3.5]. The lipid accumulation
product, LAP, was calculated as follows: LAP (male) =[waist
circumference, WC (cm) -65]×triglycerides, TG (mmol/L); LAP
(female) =[WC (cm) -58]×TG (mmol/L). The visceral adiposity
index was calculated as follows, VAI: VAI (Male) = WC (cm)/
(39.68+1.88×BMI)×TG (mmol/L)/1.03×1.31/HDL (mmol/L);
VAI (Female) = WC (cm)/(39.68+1.89×BMI)×TG (mmol/L)/
0.81×1.52/HDL (mmol/L). The quantitative insulin sensitivity index
was calculated as follows: QUICKI =1/[log(fasting insulin) + log
(fasting glucose)]. In this study, 101 patients with AGHD were divided into the
following three subgroups according to different BMIs, pathogenic
factors and degrees of insulin resistance to investigate the possible
correlation between MANF and different factors. We first divided
the 101 patients with AGHD into an overweight group (BMI>25.0
(n=34)) and a nonobese group (BMI<25.0 (n=67)) based on the
World Health Organization (WHO) proposed criteria that a body
mass index (BMI) over 25 is considered overweight (13). The above
patients were then regrouped according to the most common cause
of AGHD into a postoperative pituitary tumor group
(craniopharyngioma×3; Rathke cleft cyst×2; nonfunctional
pituitary adenoma ×22, n=27), an idiopathic AGHD group
(menstrual disorders of unknown origin×6; primary
amenorrhea×2; insidious onset×52, n=60) and a Sheehan’s
syndrome group (adrenocorticotropic hormone combined with
thyroid hormone deficiency×10; sex hormone combined with
adrenocorticotropic hormone deficiency×4, n=14) (14). However,
since all the patients with Sheehan’s syndrome were female, which
may lead to gender bias in the statistical results, this study excluded
all male patients in the etiological classification for subsequent
comparison (postoperative pituitary tumors group (nonfunctional
pituitary adenoma×19), n=19; idiopathic AGHD group (menstrual
disorders of unknown origin×6; primary amenorrhea×2; insidious
onset×27), n=35; Sheehan’s syndrome group (adrenocorticotropic
hormone combined with thyroid hormone deficiency×10; sex
hormone combined with adrenocorticotropic hormone
deficiency×4), n=14). Finally, 91 patients with AGHD (10 of
whom did not undergo fasting insulin testing) were divided into
an insulin-resistant group (HOMA-IR > 2.71, n=34) and a
noninsulin-resistant group (HOMA-IR < 2.71, n=57) according
to the homeostasis model assessment proposed by the University of
Oxford (15). The possible differences and associations of MANF in
the above subgroups were explored separately. Anthropometric Parameters and
Biochemical Indexes related hormone levels. A total of 100 healthy subjects (66
females, 34 males; mean age of 44.71 ± 10.47 years; range 26-
77) were recruited as controls for our study. The
abovementioned healthy volunteers were roughly matched with
AGHD patients in terms of age, sex, height, and weight. All
subjects participating in this study were informed of the
experimental method and purpose and provided informed
consent signed by themselves. All experimental protocols
conformed to the Declaration of Helsinki and were approved
by the Ethics Committee of our hospital. All the participants completed a comprehensive clinical
questionnaire detailing their physical measurements, including
basic information on physical examination, type of nongrowth
hormone replacement medication, and medication dosage. After
12 hours of fasting, all the participants had elbow venous blood
collected for the evaluation of relevant biochemical parameters. Fresh serum was selected for analysis of the fasting glucose, fasting
insulin (Fins), glycated hemoglobin (HbA1c), insulin-like factor-1
(IGF-1), insulin-like factor binding protein-3 (IGFBP3),
circulating lipids, transaminases, and high-sensitivity C-reactive
protein (hsCRP) levels. The remaining serum was promptly frozen
at -80°C for the later measurement of circulating MANF levels. Plasma glucose was measured using the glucose oxidase method. Lipid metabolic spectra were measured by a biochemical
autoanalyzer (CX-7 Biochemical Autoanalyzer; Beckman, Brea,
CA, USA). The serum insulin, GH, and IGF1 levels were detected
by chemiluminescence immunoassay (Immulite1000). Inclusion Criteria The inclusion criteria were as follows: 1. the subjects in the
experimental group met the diagnostic requirements of ITT
(GH peak value < 5.0 mg/L); 2. the subjects did not have
diabetes or chronic diabetic complications; 3. the subjects were
not treated with drug regimens to interfere with glucose lipid
metabolism; 4. the subjects did not have hypertension or
cardiovascular disease; 5. the subjects did not have a mental
illness or malignant tumors; 6. the subjects did not have severe or
chronic kidney or liver disease; and 7. the subjects did not have
acute symptoms of infection. Ten-year risk scores for atherosclerotic cardiovascular disease
(ASCVD) and Framingham risk scores were determined for all
the participants to assess the risk level for developing
cardiovascular disease over the next ten years (16, 17). Experimental Group Design Measurements of Serum MANF
Serum circulating MANF levels were determined by human
MANF ELISA kits (ab215417, Abcam, USA). The ELISA kit
has an optimal measurement range of 0.25 ng/ml - 16 ng/ml and
a sensitivity of 30 pg/ml. This study used the same batch of kits to
avoid differences between batches that could affect the accuracy
of the experiment. Frontiers in Endocrinology | www.frontiersin.org Statistical Analysis All analyses in this study were performed with the Statistical
Package for Social Sciences version 26 (SPSS Inc., Chicago, IL,
USA). In this experiment, we performed Kolmogorov–Smirnov
tests on all test data from participants to determine their normal
distribution. Continuous variables are expressed as the mean ±
standard deviation (SD), and skewed distribution data are expressed
as medians with interquartile ranges. Demographic and laboratory
characteristics were compared between the AGHD population and June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 3 Cardiometabolic Risk Markers in AGHD Ren et al. the normal control group. The Wilcoxon rank-sum test was used
for comparison of skewed distribution data, and the independent
samples t-test was used for normal variables. Among the subgroups
divided by BMI and homeostatic model, we used Spearman’s
correlation analysis to test the correlation between the MANF
level and other demographic and laboratory characteristics. In
multiple linear regression, we tested multicollinearity for all
independent variables, and if the VIF value exceeded 5, the
variables were considered to be multicollinear. After dividing all
subjects by MANF concentration tertile, we used the Kruskal-
Wallis H test to examine differences in Framingham risk scores
and 10-year risk scores for ASCVD between groups. Binary logistic
regression analysis was used to calculate the odds ratio of AGHD at
different serum MANF concentrations. All reported confidence
interval (CI) values were calculated at the 95% level. Categorical
variables are expressed as absolute and relative (%) values or
proportions. In all analyses, a P value <0.05 was considered
statistically significant. AGHD group, the waist circumference and the levels of TC,
TG, HDL, LDL, hsCRP, LAP, VAI, ALT and AST were
significantly different from those in the control group. In the
AGHD population, the circulating lipid levels were significantly
increased, whereas the HDL level was significantly lower than
that in the control group. The VAI, LAP, and other lipid
metabolism parameters were significantly higher than those in
the control participants. RESULTS p
Since AGHD is closely related to lipid metabolism, 101 patients
with AGHD were grouped according to the WHO definition of
BMI=25.0 as the limit of overweight, were divided into two
subgroups with BMI>25.0 (n=34) and BMI<25.0 (n=67) and
were subjected to comparative statistical analysis. As shown in
Figure 2, serum circulating MANF levels in AGHD patients with
BMI <25.0 were significantly lower than those in subjects with
BMI >25 (4.67 (0.51-17.61) ng/ml vs. 6.92 (0.55-17.62) ng/ml; Circulating MANF Levels in Overweight
AGHD Patients Were Significantly Higher
Than Those in the Nonobese Group Circulating MANF Levels in Overweight
AGHD Patients Were Significantly Higher
Than Those in the Nonobese Group Serum MANF Levels in AGHD Were
Significantly Lower Than Those in the
Control Population Circulating serum MANF levels were significantly lower in the
AGHD subjects than in the healthy controls (5.235 (0.507-17.62)
ng/ml (n=101) vs. 10.30 (1.84-16.65) ng/ml (n=100); p<0.0001),
as shown in Figure 1. SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, Triglycerides; HDL, high-density lipoprotein cholesterol; LDL, low-
density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LAP, lipid accumulation product; VAI, visceral adiposity index; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; Cr, creatinine; UA, uric acid.
The data are presented as the mean±standard deviation or medians with interquartile ranges. *The p values for the comparisons between the two groups were two-tailed and considered
significant at p < 0.05. Correlation of Circulating MANF Level and
Metabolism in AGHD Patients Under
Different Pathogenic Factors FIGURE 1 | Serum circulating MANF levels in AGHD patients and
control populations. FIGURE 1 | Serum circulating MANF levels in AGHD patients and
control populations. g
Due to the diverse etiologies of AGHD, this study aimed to further
investigate the association between serum circulating MANF
factors and the metabolic axis in AGHD patients with different
etiological factors. We categorized 101 patients with AGHD into
the following three groups according to different etiologic factors:
the postoperative group, idiopathic AGHD group, and Sheehan’s
syndrome group, The results of the Kruskal-Wallis H test
suggested that there were differences in the TC, TG, LDL, VAI,
GH, and AST levels among the three groups of subjects, and thus,
further comparisons were made between groups. Significant
differences were found in the TC (p<0.001) and LDL (p<0.001)
levels between the postoperative and idiopathic groups after
Bonferroni correction (significantly higher in the postoperative
group than in the remaining two groups). For comparison of the
anthropometric indexes, we adjusted the sex of the patients in the
postoperative and idiopathic groups and finally selected all female
subjects in both groups for subsequent comparisons (group 1
n=19; group 2 n=35; group 3 n=14). In terms of height
(although not reaching statistical significance, a trend can be
seen, p=0.052), weight, BMI, and IGF1 level, the subjects in
Sheehan’s group exhibited significantly lower values than those
in the other two groups. The postoperative group exhibited
significantly higher values than the other two groups in terms of
the TC and LDL levels, the two lipid metabolism indexes (Table 2). The analysis revealed that the level of MANF was correlated with
different parameters in the three subgroups. In the idiopathic
AGHD group, Spearman’s correlation analysis showed that the
level of MANF was positively correlated with Fins, HbA1C, VAI,
QUICK, weight, BMI, waist circumference, LAP, and ALB. In the
postoperative group, the level of MANF was positively correlated
with DBP and UA. In conclusion, however, the level of MANF was
more closely associated with lipid metabolism in AGHD. FIGURE 1 | Serum circulating MANF levels in AGHD patients and
control populations. FIGURE 2 | Serum circulating MANF levels in two AGHD subgroups of
patients according to BMI=25. Clinical Characteristics of the
Study Subjects All the AGHD and control subjects were matched for height,
weight, age, and sex (P>0.05). Table 1 details the comparison and
differences in demographic data and laboratory parameters
between the AGHD patients and healthy controls. In the TABLE 1 | Main clinical characteristics in AGHD and controls. Variables
Control (n=100)
AGHD (n=101)
P value
Age (y)
45.5(35-52)
46.00(35-56)
0.703
Height (cm)
161.14±7.19
160.09±8.43
0.329
Weight (kg)
58.621±9.84
61.59±13.52
0.411
BMI
23.71±4.01
23.03±3.46
0.501
Gender (M/F)
34/66
34/67
0.842
Waist circumference (cm)
78.08±9.11
85.48±10.94
<0.0001*
SBP (mmHg)
116.91±14.97
119.76±16.99
0.485
DBP (mmHg)
74.00(66.25-80.00)
75.00(66.25-83.00)
0.366
FPG (mmol/L)
5.1(4.90-5.40)
5.2(4.75-5.60)
0.945
TC (mmol/L)
4.44(3.87-4.75)
4.81(4.15-5.85)
<0.0001*
TG (mmol/L)
1.337±0.67
2.187±1.53
<0.0001*
HDL (mmol/L)
1.395(1.19-1.60)
1.18(0.93-1.66)
0.013*
LDL (mmol/L)
2.70(2.19-3.09)
3.09(2.30-3.60)
0.004*
hsCRP (mg/L)
0.51(0.15-0.91)
1.68(0.66-3.76)
<0.0001*
LAP
22.00(8.82-35.04)
47.12(26.79-79.66)
<0.0001*
VAI
1.525(0.91-2.47)
2.65(1.51-4.16)
<0.0001*
AST (u/L)
17.00(14.50-21.00)
22.00(18.00-30.25)
0.004*
ALT (u/L)
15.00(11.50-21.50)
21.00(14.00-30.00)
<0.0001*
ALB (g/L)
45.371±2.31
44.157±4.43
0.102
Cr (mmoI/L)
65.50(57.00-77.00)
72.00(52.25-83.75)
0.059
UA (mmol/L)
297.50(259.00-375.50)
295.00(235.00-370.00)
0.524
HOMA-IR
2.11(1.22-3.57)
1.53(0.75-2.03)
<0.0001*
HOMA-b
110.40(65.56-177.78)
58.43(38.42-107.53)
<0.0001*
SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, Triglycerides; HDL, high-density lipoprotein cholesterol; LDL, low-
density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LAP, lipid accumulation product; VAI, visceral adiposity index; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; Cr, creatinine; UA, uric acid. The data are presented as the mean±standard deviation or medians with interquartile ranges. *The p values for the comparisons between the two groups were two-tailed and considered
significant at p < 0.05. TABLE 1 | Main clinical characteristics in AGHD and controls. June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org Ren et al. Cardiometabolic Risk Markers in AGHD Circulating MANF Levels in AGHD
Subjects in the Insulin-Resistant and
Noninsulin-Resistant Groups To investigate the relationship between circulating MANF levels
and insulin resistance in the AGHD population, the circulating
serum MANF levels in both groups of subjects are shown in
Figure 4. In the insulin-resistant group, circulating MANF levels
were significantly higher than those in the noninsulin-resistant
group (3.86 (0.236-12.64) ng/ml (n=56) vs. 6.94 (0.604-17.62)
ng/ml (n=34); p=0.0006). Spearman correlation analysis showed
that there was a significant positive correlation between the level
of MANF and Fins (r=0.306** p=0.005), HOMA-IR (r=0.288**
p=0.009), HOMA-b (r=0.324** p=0.003), HbA1c (r=0.31*
p=0.032), and waist circumference (r=0.331** p=0.002) in 91
subjects. To verify the existence of an independent linear
correlation between MANF and insulin resistance, multiple
linear regression was performed. In this experiment, MANF
level was found to have an independent influence on HOMA-IR
after consecutively adding the remaining influencing factors, as
shown in Figure 5. FIGURE 2 | Serum circulating MANF levels in two AGHD subgroups of
patients according to BMI=25. p=0.019). The Mann-Whitney U test suggested significant
differences between the two subgroups of subjects in the
Framingham risk scores, 10-year risk scores for ASCVD, Fins,
HOMA-IR, and QUICK (p<0.05). All of the above data in the
obese group were higher than those in the nonobese group. Next,
we examined the relationship between serum MANF levels and
other various parameters in patients in the BMI>25.0 group using
Pearson’s correlation analysis. The results showed that serum
MANF was positively correlated with the levels of TC
(r=0.477** p=0.004), TG (r=0.415* p=0.015), LDL (r=0.391*
p=0.022), and LAP (r=0.434* p=0.01). Multiple linear regression
revealed an independent correlation between the TC and LDL levels
and the level of serum circulating MANF (Figure 3). June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 5 Cardiometabolic Risk Markers in AGHD Ren et al. A
B
FIGURE 3 | Associations between lipid metabolism indexes and circulating MANF in overweight AGHD patients. Scatter plots and correlation coefficients. Scatter
plot and correlation coefficient (R) between LDL (A) and TC (B) and cycle MANF. P values were considered significant at p < 0.05. A B B FIGURE 3 | Associations between lipid metabolism indexes and circulating MANF in overweight AGHD patients. Scatter plots and correlation coefficients. Scatter
plot and correlation coefficient (R) between LDL (A) and TC (B) and cycle MANF. P values were considered significant at p < 0.05. Circulating MANF Levels in AGHD
Subjects in the Insulin-Resistant and
Noninsulin-Resistant Groups TABLE 2 | Comparison of selected parameters between the three groups of subjects after gender correction. Pathogenic
Height,cm
Weight,kg
BMI
IGF1
TC,mmol/L
LDL,mmol/L
G1 (Postoperative, n=19)
160.28±6.31
58.72±8.51
22.31±3.36
78.85(34.40-124.75)
5.75(4.61-6.22)
3.56(2.89-3.73)
G2 (idiopathic AGHD, n=35)
156.68±6.94
57.5±11.18
23.98±4.24
121.5(83.60-221.75)
4.47(3.96-4,84)
2.42(2.02-3.14)
G3 (Sheehan's syndrome, n=14)
155.00±6.47
51.55±6.94
21.48±2.30
48.25(28.63-129.25)
4.74(4.00-5.22)
2.95(2.13-3.56)
Overall Comparison
Intergroup comparison
0.052
0.030*
0.047*
0.002*
0.001*
0.012*
G1 VS G3
P value
0.073
0.798
1.000
0.067
0.077
G2 VS G3
0.038*
0.047*
0.025*
1.000
1.000
G1 VS G2
1.000
0.537
0.092
0.001*
0.001*
G1 means the postoperative group; G2 means the idiopathic AGHD group; G3 means the Sheehan's syndrome group. The data are presented as the mean±standard deviation or
medians with interquartile ranges *The p values for the comparisons between the two groups were two-tailed and considered significant at p < 0.05. TABLE 2 | Comparison of selected parameters between the three groups of subjects after gender correction. G1 means the postoperative group; G2 means the idiopathic AGHD group; G3 means the Sheehan's syndrome group. The data are presented as the mean±standard deviation or
medians with interquartile ranges *The p values for the comparisons between the two groups were two-tailed and considered significant at p < 0.05. FIGURE 4 | Serum circulating MANF levels in two AGHD subgroups of
patients according to homeostasis model assessment. FIGURE 5 | Scatter plot and correlation coefficient (R) between HOMA-IR
and circulating MANF levels in the AGHD population. P values were
considered significant at p < 0.05. FIGURE 4 | Serum circulating MANF levels in two AGHD subgroups of
patients according to homeostasis model assessment. FIGURE 5 | Scatter plot and correlation coefficient (R) between HOMA-IR
and circulating MANF levels in the AGHD population. P values were
considered significant at p < 0.05. FIGURE 5 | Scatter plot and correlation coefficient (R) between HOMA-IR
and circulating MANF levels in the AGHD population. P values were
considered significant at p < 0.05. FIGURE 4 | S
i
l ti
MANF l
l i
t
AGHD
b
f FIGURE 5 | Scatter plot and correlation coefficient (R) between HOMA-IR
and circulating MANF levels in the AGHD population. P values were
considered significant at p < 0.05. FIGURE 5 | Scatter plot and correlation coefficient (R) between HOMA-IR
and circulating MANF levels in the AGHD population. P values were
considered significant at p < 0.05. DISCUSSION Growth hormone is involved in many metabolic pathways such
as sugar, lipid, and protein pathways, but its main metabolic
function is to promote lipolysis (18). Adult growth hormone
deficiency is caused by structural injury to the pituitary gland or
tumors in the pituitary region that leads to a sharp decrease in
the amount of growth hormone in the body, which triggers
structural damage to the heart, skeleton and other organs and is
accompanied by endocrine metabolic disorders. An imbalance in
the GH/IGF1 axis leads to an excessive accumulation of lipids,
which increases the risk of cardiovascular disease. High levels of
LDL as well as low levels of HDL are known to be high-risk
factors for the development of cardiovascular disease (19). In this
study, we found that patients with AGHD have significantly
higher blood lipid levels than normal controls, which
corroborates previous studies stating that AGHD patients are
at a higher risk of developing cardiovascular disease (20). Interestingly, circulating serum levels of a class of endoplasmic
reticulum stress-associated secreted proteins, such as MANF,
were also significantly reduced in the AGHD population. To the
best of our knowledge, this study is the first to link the level of
MANF with AGHD. It also investigates the correlation of MANF
levels with lipids, glucose metabolism and potential therapeutic
value in the AGHD population. Adipose tissue is an important target for growth hormone
action due to the presence of GH receptors, which are extremely
sensitive to the stimulatory feedback of growth hormone (26). Obesity and overnutrition induce chronic ER stress in the liver
and some other tissues (27). In the present study, significant
differences in MANF levels were observed in the nonobese group
and in overweight patients with AGHD. Using the WHO
recommended BMI=25, serum levels were significantly higher
in the obese group of AGHD patients (n=34) than in the
nonobese group (n=67). Circulating MANF levels in the obese
group were positively correlated with the body weight, TC, Tg,
LAP, VAI, and other parameters. The levels of TC and LDL were
independently linearly correlated with the level of MANF. This
result reflects the close relationship between MANF and lipid
metabolism. Several epidemiological trials have validated the
LAP and VAI as reliable markers for predicting cardiovascular
disease risk in the general population (28–30). Different Circulating MANF Concentrations
and Cardiovascular Risk Assessments Different Circulating MANF Concentrations
and Cardiovascular Risk Assessments PCOS-related study, it was noted that the circulating serum
MANF level of the PCOS population was significantly lower
than that of the control group (23). In our study, a trend toward
significantly lower circulating MANF levels was found in the
AGHD population. We divided all the subjects into three subgroups based on the
tertile of the circulating MANF concentration (group 1: <4.17
ng/ml; group 2: 4.17-10.36 ng/ml; group 3: >10.36 ng/ml). The
high MANF concentration group showed lower Framingham
risk scores than group 1 (p<0.0001). In terms of circulating lipid
levels, group 3 also exhibited lower TC, TG, and LDL levels and
higher HDL levels than group 1 and group 2 (however, due to
sample size limitations, statistical significance was not reached). Binary logistic regression showed that the odds ratio for AGHD
in group 1 was 20.429 times higher (OR=20.429 p<0.0001) than
the ratio in group 3. The odds ratio for AGHD in group 2 was
2.869 times (OR=2.869 P=0.012) higher than in group 3. The
model was adjusted for potential confounders such as height,
age, sex and weight. In response to endoplasmic reticulum stress, cells initiate the
unfolded protein response (UPR) to balance the endoplasmic
reticulum. The UPR has been confirmed to form the basis of
chronic metabolic diseases together with inflammation, lipid
metabolism and energy control pathways (24). MANF is a
class of endoplasmic reticulum stress-activated protective
protein factors that stimulate MANF secretion to maintain
endoplasmic reticulum homeostasis in response to cellular
activation of the UPR (25). According to the literature, AGHD
is a special endocrine condition closely related to lipid and
glucose metabolism, and its circulating MANF concentration
seems to be secreted due to the activation of the UPR to play the
role of endoplasmic reticulum balance. However, interestingly,
our study found the opposite, a decreasing trend in MANF levels. We speculate that AGHD patients may be in a decompensated
state of MANF secretion due to prolonged low levels of growth
hormone stimulation, resulting in lower overall circulating levels. Frontiers in Endocrinology | www.frontiersin.org Circulating MANF Levels in AGHD
Subjects in the Insulin-Resistant and
Noninsulin-Resistant Groups June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 6 Cardiometabolic Risk Markers in AGHD Ren et al. DISCUSSION Dysregulation of sympathetic nervous and renin-angiotensin
systems resulting in enhanced stimulation of both adrenergic
and angiotensin II receptors is a typical feature of heart failure
and hypertension and is involved in the pathogenesis of insulin
resistance. Angiotensin II acts through the angiotensin receptor
to inhibit the actions of insulin in vascular tissue, in part, by
interfering with insulin signaling through phosphatidylinositol
3-kinase and downstream protein kinase B signaling pathways
via generation of reactive oxygen species by nicotinamide
adenine dinucleotide phosphate oxidase (33). Evidence
suggests that AGHD patients with insulin resistance may have
a higher risk of cardiovascular morbidity and that MANF may be
a good predictor for cardiovascular risk assessment in
AGHD patients. transmembrane receptors to regulate the intracellular
signaling cascade (38). Two different modes of action also
lead to the possibility that MANF may have different biological
efficacies. In the present study, lower tertile MANF
concentrations had the highest odds ratio for disease,
whereas in the AGHD population, higher MANF was
positively associated with insulin resistance and lipid
deposition. We speculate that the level of MANF content is a
relative concept and that under pathological concentration
conditions, relatively high MANF levels instead show
negative physiological effects. It has been shown that MANF
interacts with PIP4k2b and triggers insulin resistance via an
unknown pathway other than the inflammatory activation
state (39). However, the background of this experiment is
that MANF transgenic mice overexpress MANF factor in the
hypothalamus and exhibit insulin resistance. However, no
further studies have been conducted on a pathological state
model with a low dose of MANF. This is the next step in our
team’s research. We observed that at physiological
concentrations, MANF did not differ significantly based on
insulin resistance or obesity status. The different causative factors of AGHD also provided some
interesting results. The height, weight, and BMI of the patients in
Sheehan’s group were significantly lower than those of the
AGHD patients with the remaining causative factors. Patients
with AGHD due to surgical damage to the pituitary gland had
significantly higher levels of TC, LDL, and other parameters than
idiopathic patients. However, the exact cause could not be
explained yet. This may be due to the limitation of the
specimen size in a rare metabolic disease such as AGHD, and
we also need to expand the sample size in the future to advance
subsequent studies. DISCUSSION Due to the
limitation of the sample size, the linear correlation between
MANF and LAP, VAI, etc., was not observed in the present
study, which needs to be investigated by subsequent case
expansion. However, this does not preclude the use of MANF
as an independent diagnostic factor in the AGHD population
and as an indicator for assessing the risk of cardiovascular
morbidity in obese patients with AGHD. In recent years, increasing evidence has shown that MANF
has unique advantages in relation to endocrine metabolic
pathways and stress protection in the endoplasmic reticulum
(21). In animal models, MANF-/- mice show abnormal pituitary
hormone secretion accompanied by a state of insulin resistance
and growth hormone deficiency, while the mice exhibit severe
growth retardation and endocrine gland atrophy. The
endocrine organs of MANF+/+ mice are more active and
express greater levels of hormone secretion (8). However, the
expression of MANF is inconsistent in human disease, and
studies have shown that circulating serum MANF levels are
significantly elevated in patients with primary diabetes and
early diabetes with abnormal glucose tolerance (22). In another It has previously been shown that MANF triggers insulin
resistance by enhancing the activity of phosphatidylinositol 5-
phosphate 4-kinase type-2 beta (PIP4k2b, a kinase known to
regulate insulin signaling) localized to the endoplasmic reticulum
(31). Patients with AGHD usually show varying degrees of
insulin resistance. Thus, we divided 101 patients into insulin-
resistant and noninsulin-resistant groups according to the
HOMA model. Likewise, there was a surprisingly significant
difference in MANF levels between the two groups. MANF was
significantly higher in the 34 patients with HOMA-IR>2.71 than June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 7 Cardiometabolic Risk Markers in AGHD Ren et al. in the noninsulin-resistant group, and the TG, waist
circumference, hip circumference, waist-to-hip ratio, LAP, and
VAI values were also higher in that group than in the noninsulin-
resistant group. The most significant positive correlation was
between the level of MANF and insulin resistance. Both visceral
obesity and insulin resistance increase cardiometabolic disease
risk. A 2017 study of a large sample of European populations
indicated that the VAI was independently associated with an
increased 10-year risk of cardiovascular disease (32). CONCLUSION MANF, an endoplasmic reticulum stress-secreting protein, is
strongly associated with insulin resistance and abnormal lipid
metabolism under AGHD conditions. This factor may be critical
in the early diagnosis of AGHD and is involved in the occurrence
and development of AGHD. It may have good therapeutic
potential for later cardiovascular disease. MANF, an endoplasmic reticulum stress-secreting protein, is
strongly associated with insulin resistance and abnormal lipid
metabolism under AGHD conditions. This factor may be critical
in the early diagnosis of AGHD and is involved in the occurrence
and development of AGHD. It may have good therapeutic
potential for later cardiovascular disease. These results leave much space for investigation. The
circulating MANF concentrations in the normal population
were significantly higher than those in the AGHD population,
which seems to suggest that MANF at physiological
concentrations is a protective factor for the body and has a
balancing effect on normal lipid and glucose metabolic
pathways. However, as a secreted protein, MANF exerts not
only an extracellular effect on the circulating paracrine
pathway but also intracellular effects of binding to DISCUSSION The main manifestation of AGHD is a decrease in GH
secretion, which is accompanied by a decrease in IGF1 and
IGFBP3. Regrettably, we have not yet detected the correlation
between MANF and IGF1 and IGFBP3. This may be because in
the AGHD population, IGF1 levels do not absolutely correspond
to the disease condition, and many patients may have a normal
level of IGF1. It has also been shown that GH can function
independently of IGF1 (34). There are many reasons why there
may not be a linear relationship between MANF and IGF1. However, it is still necessary to expand the sample size to confirm
this speculation in the future. Overall, this study leaves us with much uncertainty and many
potential research directions. However, it is undeniable that
serum circulating MANF levels may be an excellent target for
predicting the onset of AGHD and serve as an excellent potential
therapeutic factor for cardiovascular disease in AGHD patients. MANF also needs to receive more extensive attention
and research. MANF has also shown good cardioprotective effects in several
studies. In infarction and localized ischemic disease, MANF is
secreted in large quantities after sarcoplasmic reticulum/
endoplasmic reticulum calcium homeostasis is disrupted to
prevent ischemic myocardial injury and has an
antihypertrophic effect (35). Other types of secreted proteins
do not exhibit such secretory characteristics and efficacy (36). Due to varying degrees of insulin resistance status, abnormal
lipid metabolism and visceral adipose deposition lead to vascular
endothelial damage, and patients with AGHD have a higher risk
of cardiovascular disease (37). MANF exhibits excellent
therapeutic potential due to its unique endoplasmic reticulum
balancing function. Frontiers in Endocrinology | www.frontiersin.org REFERENCES Biology, and Therapeutic Roles. Transl Res (2017) 188:1–9. doi: 10.1016/
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Selectivity for Dopaminergic Neurons. J Mol Neurosci (2003) 20(2):173–88. doi: 10.1385/jmn:20:2:173 18. Møller N, Jørgensen JO. FUNDING This research was supported by the Project of the Science and
Technology Committee in Chongqing 2016 (Number:
cstc2016jcyjA0025) and the National Natural Science
Foundation of China (Grant No. 81370467 to DL). This research was supported by the Project of the Science and
Technology Committee in Chongqing 2016 (Number:
cstc2016jcyjA0025) and the National Natural Science
Foundation of China (Grant No. 81370467 to DL). DATA AVAILABILITY STATEMENT The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation. June 2021 | Volume 12 | Article 671126 Cardiometabolic Risk Markers in AGHD Ren et al. ACKNOWLEDGMENTS ZR, DL, and WR jointly conceived and designed this research. ZR and YW performed the data analysis and wrote the
manuscript. QC and JL collected the medical records
and biochemical data for each subject. RZ, XW, WQ, and
YC conducted telephone follow-up interviews of patients
and collected relevant physical information and data. DL
and WR reviewed the full text and guided revisions. We thank the staff of the Department of Endocrinology, First
Affiliated Hospital of Chongqing Medical University, for
the excellent technical service they provided. We are grateful for
the support from The Second Affiliated Hospital of Chongqing
Medical University, where our work was conducted. ETHICS STATEMENT All authors contributed to the article and approved the
submitted version. The studies involving human participants were reviewed and
approved by the Ethics Committee of the First affiliated hospital
of Chongqing medical university. The patients/participants
provided their written informed consent to participate in
this study. Biology, and Therapeutic Roles. Transl Res (2017) 188:1–9. doi: 10.1016/
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Visceral Adiposity Index (VAI) Identifying a Visceral Adipose Dysfunction
Associated With Cardiometabolic Risk in a Caucasian Sicilian Population. Lipids Health Dis (2011) 10:183. doi: 10.1186/1476-511X-10-183 39. Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, et al. The Phosphatidylinositol (PI)-5-phosphate 4-Kinase Type II Enzyme
Controls Insulin Signaling by Regulating PI-3,4,5-trisphosphate
Degradation. Proc Natl Acad Sci U S A (2003) 100(17):9867–72. REFERENCES Effects of Growth Hormone on Glucose, Lipid, and
Protein Metabolism in Human Subjects. Endocr Rev (2009) 30(2):152–77. doi: 10.1210/er.2008-0027 19. Helkin A, Stein JJ, Lin S, Siddiqui S, Maier KG, Gahtan V. Dyslipidemia Part
1–Review of Lipid Metabolism and Vascular Cell Physiology. Vasc Endovasc
Surg (2016) 50(2):107–18. doi: 10.1177/1538574416628654 7. Lindholm P, Voutilainen MH, Laurén J, Peränen J, Leppänen VM, Andressoo
JO, et al. Novel Neurotrophic Factor CDNF Protects and Rescues Midbrain
Dopamine Neurons In Vivo. Nature (2007) 448(7149):73–7. doi: 10.1038/
nature05957 20. Wang Y, Zheng X, Xie X, Qian W, Zhang L, Ren W. Correlation of Increased
Serum Adipsin With Increased Cardiovascular Risks in Adult Patients With
Growth Hormone Deficiency. Endocr Pract (2019) 25(5):446–53. doi: 10.4158/EP-2018-0541 8. Danilova T, Galli E, Pakarinen E, Palm E, Lindholm P, Saarma M, et al. Mesencephalic Astrocyte-Derived Neurotrophic Factor (Manf) Is Highly
Expressed in Mouse Tissues With Metabolic Function. Front Endocrinol
(Lausanne) (2019) 10:765. doi: 10.3389/fendo.2019.00765 21. Lindahl M, Danilova T, Palm E, Lindholm P, Võikar V, Hakonen E, et al. MANF Is Indispensable for the Proliferation and Survival of Pancreatic b
Cells. Cell Rep (2014) 7(2):366–75. doi: 10.1016/j.celrep.2014.03.023 9. Yang S, Li S, Li XJ. Manf: A New Player in the Control of Energy Homeostasis,
and Beyond. Front Physiol (2018) 9:1725. doi: 10.3389/fphys.2018.01725 10. Schröder M, Kaufman RJ. ER Stress and the Unfolded Protein Response. Mutat Res (2005) 569(1-2):29–63. doi: 10.1016/j.mrfmmm.2004.06.056 22. Wu T, Zhang F, Yang Q, Zhang Y, Liu Q, Jiang W, et al. Circulating
Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Increased in
Newly Diagnosed Prediabetic and Diabetic Patients, and Is Associated
With Insulin Resistance. Endocr J (2017) 64(4):403–10. doi: 10.1507/
endocrj.EJ16-0472 11. Sadighi Akha AA, Harper JM, Salmon AB, Schroeder BA, Tyra HM,
Rutkowski DT, et al. Heightened Induction of Proapoptotic Signals in
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Factor (MANF), a New Player in Endoplasmic Reticulum Diseases: Structure, June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 9 Cardiometabolic Risk Markers in AGHD Ren et al. 24. Frontiers in Endocrinology | www.frontiersin.org June 2021 | Volume 12 | Article 671126 REFERENCES doi: 10.1073/pnas.1734038100 30. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index: A Reliable Indicator of Visceral Fat Function
Associated With Cardiometabolic Risk. Diabetes Care (2010) 33(4):920–2. doi: 10.2337/dc09-1825 Conflict of Interest: The authors declare that the research was conducted in the
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(10):881–9. doi: 10.1016/j.numecd.2017.06.015 Copyright © 2021 Ren, Wang, Chen, Long, Zhang, Wu, Qian, Chen, Liu and Ren. This is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction in other forums is
permitted, provided the original author(s) and the copyright owner(s) are credited and
that the original publication in this journal is cited, in accordance with accepted
academic practice. No use, distribution or reproduction is permitted which does not
comply with these terms. 33. Morisco C, Lembo G, Trimarco B. Insulin Resistance and Cardiovascular Risk:
New Insights From Molecular and Cellular Biology. Trends Cardiovasc Med
(2006) 16(6):183–8. doi: 10.1016/j.tcm.2006.03.008 June 2021 | Volume 12 | Article 671126 Frontiers in Endocrinology | www.frontiersin.org 10
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English
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V.—The Fossils of the East Anglian Sub-Crag Boxstones
|
Geological magazine
| 1,917
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public-domain
| 10,016
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1 " The Age of the Chief Intrusions of the Lake District" : Proe. Geol.
Assoc., xxviii, pp. 17-25, 1917.
2 Ibid., plate ii.
3 An interesting and important paper dealing with the petrologv of the
Suffolk " Boxstones " (Crag), by Dr. P. G. H. Boswell, D.I.C., F.G.S. (now
Professor of Geology in the University of Liverpool), appeared in the
GEOLOGICAL MAGAZINE for June, 1915 (pp. 250-9, Plate X, and Figs. 1-3)
and may be consulted with advantage by readers of the present paper. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 407 407 Alfred Bell—Fossils of East Anglian Boxstones. after treatment with a bar-magnet, a grain or two of brown
tourmaline was also found. The specific gravity of both specimens
is 2'63, the same figure as that for the granophyre. ,
g
g
p y
Mr. Hemingway states that the rock is very similar to the white
felsite interbeddecl in the Drygill shales to the north of Brandy Gill. GEOLOGICAL AGE. It may be of interest to draw attention here to the recent work of
Mr. J. F. N. Green on the age of the Carrock Fell complex.1 It is
well known that the complex is of later date than the Borrowdale
volcanic series. An upper limit is fixed by Mr. Green's discovery of
granophyre fragments in the Watch Hill Beds. These consist of
shales and polygenetic grits which form a series of patches lying at'
various horizons on the Skiddaw Slates between Cockermouth
(Watch Hill) and Great Sea Fell.2 Only one pebble of granophyre
was found at Watch Hill, but in the eastern exposures (i.e. in those
near to Carrock Fell) the rock was found to be invariably present in
the coarser bands of the series. Mr. Green shows that the Watch
Hill Beds are younger than the Borrowdale Series and older than the
Devonian earth-movements, and for these and other reasons he
correlates them with the Coniston Limestone Series. Consequently
he considers the igneous rocks of Carrock Fell to be pre-Bala. Mr. Green concludes: "The Borrowdale Series is ascribed to the
Middle Llanvirn . . . The Eskdale granite, Buttermere granophyre,
St. John's granite-porphyry, and Cai'rick Fell complex all belong to
the suite, being intruded before the solfataric stage, but at a late
period of the episode." p
3 An interesting and important paper dealing with the petrologv of the
Suffolk " Boxstones " (Crag), by Dr. P. G. H. Boswell, D.I.C., F.G.S. (now
Professor of Geology in the University of Liverpool), appeared in the
GEOLOGICAL MAGAZINE for June, 1915 (pp. 250-9, Plate X, and Figs. 1-3)
and may be consulted with advantage by readers of the present paper. 1 " The Age of the Chief Intrusions of the Lake District" : Proe. Geol.
Assoc., xxviii, pp. 17-25, 1917.
2 Ibid., plate ii.
3 ,
, pp
2 Ibid., plate ii.
3 A i t
ti By ALFRED BELL. I
!f the opening article of the GEOLOGICAL MAGAZINE (Vol. I, p. 5,
1864) Mr, J. W. Salter remarks: " An obscure but novel group
of organic remains comes to light in some well-worked district for
which we have as yet no fixed geological place," and this description
may well apply to the fauna dealt with in the following pages. I
f Usually considered by geological writers as being derived from
sources outside the East Anglian area, very little attention has been
paid to it, its environment, or to its Continental affinities. The
fossils hereafter referred to occur in a sandstone matrix3 more or
less consolidated, the relics of a former stratum afterwards broken
up, and now found distributed in places beneath the overlying
Pliocene deposits, between Walton-on-the-Naze and Hollesley on the
coast and inland to about Ipswich. 408 Alfred Bell—Fossils of East Anglian Boxstones. Within these boundaries the bed-rock is a floor of London Clay,
formerly covered by a higher zone of the same material, replete with
a fauna of similar type to that found at Sheppey, including fishes and
Crustaceans in fine preservation, the broken-up clay and the fossils
being deeply phosphatized. Upon this, again, there seems to have
been deposited a bed of sand of which the actual presence can only be
inferred, since it has not been found in situ as a separate strati-
giaphical unit or stratum ; but the suggestion is warranted by the
mass of debris yielding a particular group of fossils found in the
irregular blocks of indurated sandstone or loosely distributed in
the adjacent Crag sands, and in the tabular pieces present at
Trimley,- Bucklesham, and other places, of which Dr. J. E. Taylor
writes in White's History of Suffolk, 1874, "that it is not uncommon
to find slabs of the same kind of sandstone which appear to have
undergone little abrasion and to be in nearly the same condition they
were in when the formation to which they originally belonged was
broken up."
Similar pieces of sandstone with sharply defined
impressions of the fossils and shells, more or less unworn, may be
obtained occasionally during low tides at Bawdsey, where a bed of
the nodules may be seen at times near the Haven. The petrology of the "boxstones" has been fully described by
Dr. 1 "Petrology of the Suffolk Boxstones": op. cit.
2 "Sub-Crag Detritus": Proc. Prehistoric Soc. East Anslia, 1915,
vol. xi, pp. 139-48.
3 Quart. Journ. Geol. Soc., vol. xxvi, pp. 493-513, 1870.
4 Quart. Journ. Geol. Soc, vol. viii, p. 282, 1852.
6 Mem. Acad. R. Sci. Bruxelles. vol. xi, 1837.
6 Bull. Soc. Beige Geol., vol. vii, p. 299, 1893.
7 Ann. Nat. Hist. (2), vol. viii, pp. 206-11, 1851. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 1 "Petrology of the Suffolk Boxstones": op. cit.
2 "Sub-Crag Detritus": Proc. Prehistoric Soc. East Anslia, 1915,
vol. xi, pp. 139-48.
3 1 "Petrology of the Suffolk Boxstones": op. cit.
2 gy
p
2 "Sub-Crag Detritus": Proc. Prehistoric Soc. East Anslia, 1915,
vol. xi, pp. 139-48.
3 Q
,
, p
,
6 Mem. Acad. R. Sci. Bruxelles. vol. xi, 1837.
6 g
,
, p
,
7 Ann. Nat. Hist. (2), vol. viii, pp. 206-11, 1851. 6 Bull. Soc. Beige Geol., vol. vii, p. 299, 1893.
7 Alfred Bell—Fossils of East Anglian Boxstones. Alfred Bell—Fossils of East Anglian Boxstones. Clarke, of Ipswich, on the nodule "bed" and its contents, figuring
amongst other items a ziphioid rostrum. This was apparently repro-
duced with other species in an early paper on Red Crag Mammals,1
by Professor Owen. Clarke, of Ipswich, on the nodule "bed" and its contents, figuring
amongst other items a ziphioid rostrum. This was apparently repro-
duced with other species in an early paper on Red Crag Mammals,1
by Professor Owen. y
Mr. S. V. Wood was the first to recognize the shells in the
boxstones,2 specifying several of these by name, but nothing further
was done till Professor Sir Ray Lankester, in 1865, briefly noticed
the deposit and, in 1868,3 discussed at some length its possible origin
and that of its contents. Unfortunately for science, the closing of the "Coprolite" industry
or phosphate diggings, and the little interest taken in the stones
when they were obtainable, limits the scope of our inquiry, and all
that can be done is to utilize the material at hand. This is chiefly
conserved in the Museums of Practical Geology, London, Ipswich,
^Norwich, and York, and in one or two private collections, all of
which, by the courtesy of those in charge of them, it has been my
privilege critically to examine. I have also to thank the Trustees
of the Percy Sladen Memorial Fund for assistance in collecting
information. The specimens upon which the following lists are founded
commonly occur as moulds of the exterior of the shells, showing the
sculpture, or as casts of the interior ; the shelly matter being rarely
preserved. From these it has been possible by the use of wax or
gutta-percha to reproduce the general details of the organism, which
has been done by permission, from a number of the rarer and more
perfect examples, especially those in the York and Norwich Museums. These will be ultimately added to those specimens already preserved
in the Museum of Practical Geology, London. The fossils are so scattered that it may be useful to students to
know the Museums where they can be seen, and to have a reference
to some good figure of the shell referred to in the text. 2 Crag Moll., pt. ii, 1851. 1 Quart. Journ. Geol. Soc, vol. xii, 1856.
2 https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Crag Moll., pt. ii, 1851.
3
- -
— -
—
GEOL. MAG., Vol. II, pp. 103-49, 1865 ; Vol. V, p. 254, 1868 Boxstone Mollusca.
Cylichna sp. Cylichna cylindracea, Ravn, K. Danske Vid. Selsk. Skrift. (7), vol. iii,
p. 367, pi. viii, fig. 15, 1907. Mus. Pract. Geol. London, York. Ringiculci auriculata, Menard. Ringiculci auriculata, Menard. Singicula aurictdata. Beyrich, Zeitsch. deutsch. Geol. Ges., vol. v, p. 330,
pi. v, fig. 13, 1853. Mus. Pract. Geol. London. Alfred Bell—Fossils of East Anglian Boxstones. As a rule
the organisms have suffered little attrition, the sculptural details are
well preserved, and most of the bivalves are found closed, as if
embedded alive before the muscles had become relaxed. By ALFRED BELL. Boswell, F.G.S.,1 and the general features of the detritus by
myself.2 y
In the discussion following the reading of Professor Lankester's
paper3 "On the Newer Tertiaries of Suffolk and their Fauna",
Sir C. Lyell pronounced the boxstones then produced as being similar
to those he had seen at Berchern, near Antwerp, in 1851,4 in a deposit
of Rupelien age, the shells corresponding to those figured by
de Koninck in his well-known memoir5 on the fossil shells of Basele,
Boom, etc. This particular horizon has been referred by M. van den Broeck 8
to the uppermost stage of the Middle Oligocene; a system largely
developecf, according to von Koenen, Eavn, and other writers, in
Denmark, Belgium, and North-West German}-; with a few exceptions
the boxstone species agree with those found in one or other of these
localities. The English literature bearing upon the deposit and the faunas
associated with it before 1865 is very scanty. Charlesworth, in
1837, figured a tooth of Carcharias megalodon, with sundry rvotes on
the phosphatic nodules; and the so-called "Coprolites" and mammalia
recorded between then and 1851 are mentioned in the bibliography
appended to C. Eeid's Pliocene Deposits of Great Britain
(1890). The earliest descriptive account7 is that given by the Rev. W. B. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 409 Voluta (Pyrgomitra) fusus (Philippi). Voluta (Pyrgomitra) fusus (Philippi). Fasciolaria fusus, Philippi, Beit. N.W. deutsch. tert., p. 25, pi. iv,
fig. 14, 1843. l
i h
i
h d
h
l
l
5
i
iii g
,
Voluta parca, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. v, p. 357, pi. viii,
fig. 1, 1853. Mus. York, Ipswich. g
p
[These figures represent the younger and older states of the shell. It has
a longer and narrower canal than the typical V. Lamberti of the Anglo-
Belgian Crag basin. Dr. Morch, in the Journ. de Conch., vol. xvii,
p. 428, 1869, assigns this group to the sub-genus Pyrgomitra.'] Conus cf. ventricosus, Bronn. Conus ventricosus, Homes, Foss. Moll. Tert. Wien, vol. i, p. 32, pi. iii,
figs. 5-6, 1856. g
,
,,
,,
Fontannes, Moll, plioc. Vail, du Rhone, vol. i, p. 144,
pi. viii, fig. 11, 1887. M
I
i h Mus. Ipswich. Cancellaria (Ventrilia) aperia (Beyrich). Cancellaria (Ventrilia) aperia (Beyrich). Cancellaria aperta, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. viii, p. 586
pi. xix, fig. 5, 1856. Mus. York. Ancilla Nysti, F. W. Harmer. Ancilla Nysti, F. W. Harmer, Plioc. Moll. Gt. Brit., pt. i, p. 52, pi. xii,
figs. 32-3, 1913. Harmer Coll. Pleurotoma Steinvorthi, Semper. Pleurotoma Steinvorthi, Semper. Pleurotoma Steinvorthi, von Koenen, Mioc. nord-Deutschl., p. 94, pi. ii,
fig. 10, 1872. fig. 10, 1872. ,,
,,
Norregaard, Dansk. Geol. Foren., vol. v, p. 133,
pi. iii, fig. 10, 1916. ,, Pseudotoma Morreni, de Koninck. Pleurotoma Morreni (de Koninck), Coq. foss. Basele, 1837, p. 21, pi. i,
fig. 3. Mus. Ipswich. fig. 3. Mus. Ipswich. [Mr. F. W. Harmer (Plioc. Moll. Gt. Brit., pt. ii, p. 212, regards this shell
as a variety of PI. intorta, Brocchi, with which it has many points of
resemblance. ] Conus antediluvianus, var. B, Grateloup. Conus antediluvianus, var. B, Grateloup, Atlas Conch, foss. de l'Adour,
No. 44, fig. 6, 1840. Mus. Ipswich, York. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Cancellaria (Trigonostoma) cf. ampullacea (Brocchi). Cancellaria (Trigonostoma) cf. ampullacea (Brocchi). Voluta ampullacea, Brocchi, Conch, foss. Sub-ap., vol. ii, p. 313, pi. iii, fig. 9
T i
ll
S
M ll T
Pi
i
9
i i Voluta ampullacea, Brocchi, Conch, foss. Sub-ap., vol. ii, p. 313, pi. iii, fig. 9
Trigonostoma ampullacea, Sacco, Moll. Tert. terz. Piem., pt. xvi, p. 9, pi. i
figs. 16-20. g
[Some imperfect forms at Ipswich may belong to C. umbilicaris, Brocchi
but as the aperture is not seen in either species, both ascriptions may need
revision.] Ringieula ttriata, Philippi. Ringicula striata, Philippi, Beit. tert. N.W. Deutschl., p. 28, pi. iv, fig. 23,
1843. R
K D
k Vid S l k Sk if
(7)
l iii
365 ,,
Ravn, K. Danske Vid. Selsk. Skrift. (7), vol. iii, p. 365,
pi. viii, fig. 11, 1907. M
P
G
l L
d Mus. Pract. Geol. London. 1 Quart. Journ. Geol. Soc, vol. xii, 1856. 2 1 Quart. Journ. Geol. Soc, vol. xii, 1856. 2 C ag
o ., pt. , 85 . 3
- -
— -
—
GEOL. MAG., Vol. II, pp. 103-49, 1865 ; Vol. V, p. 254, 1868. 410 Alfred Bell—Fossils of East Anglian Boxstones. Conus Dujardini,
Deshayes. Conus Dujardini, Homes, Foss. Moll. Tert. Wien, vol. i, p. 40, pi. v,
figs. 3-8, 1856. g
„
,,
Lankester, Quart. Journ. Geol. Soc, vol. xxvi, p. 502,
pi. xxxiv, fig. 5, 1870. M
I
i h N
i h Conus antediluvianus, var. B, Grateloup. Alfred Bell—Fossils of East Anglian Boxstones. Conus Dujardini,
Deshayes. Mitra cf. futifvrmis, Brocchi. Mitra fusiformis, Cerulli-Irelli, Pal. ital., vol. xvii, p. 235, pi. xxi, fig. 19,
1911. Mus. Pract. Geol., London. 9
. us. act. Geo .,
o do . [The reference is founded on the cast of a long body and next whorl,
60 mm. long, 25 mm. broad, with a nearly straight
figure. Mitra
Venayesina, Fontannes, Moll. Plioc. Vail, du Rhone, vol. i, p. 79, pi. vi,
fig. 1, is closely allied to it.] Sipho gregarius (Philippi), pars. Fusus gregarius, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. viii, p. 59,
pi. v, figs. 7-8, 1856. Mus. Norwich, Ipswich. Sipho multnulcatus (Nyst). Sipho multnulcatus (Nyst). Fusua multisulcatus, Nyst, Coq. foss. Beige, p. 494, pi. xl, fig. 1, 1843. Mus. Pract. Geol. London. [Nyst altered de Koninck's specific name lineatus to multisulcatus, but his
figure is not the same as de Koninck's, which shows a shell having a longer
spire and canal, and narrower in proportion. They may be varieties of
a polymorphous form, but as both varieties occur in the boxstones they
are given accordingly for what they are worth.] [Nyst altered de Koninck's specific name lineatus to multisulcatus, but his
figure is not the same as de Koninck's, which shows a shell having a longer
spire and canal, and narrower in proportion. They may be varieties of
a polymorphous form, but as both varieties occur in the boxstones they
are given accordingly for what they are worth.] Liomesus nudum (S. V. Wood). Liomesus nudum (S. V. Wood). Buccinum nudum, S. V. Wood, Mon. Crag Moll., Suppl. 2, p. 1, pi. i, fig. 1,
1879. Mus. Ipswich. Mus. Ipswich. [This is a large shell, the three lower whorls measuring 80 mm. in length
with a breadth of 35 mm. This and the next species may perhaps represent
a new group, intermediate between Sipho and Fasciolaria, as the moulds of
the upper whorls show traces of costal ornament. Of this group Fusus
(aff.) Konincki, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, pi. v, fig. 10,
might be taken as the type.] Alfred Bell—Fossils of East Anglian
Boxstones.
4 Alfred Bell—Fossils of East Anglian
Boxstones. 411 Voluta (Pyrgomitra) sp. Voluta cf. tarbelliana, var. ventricosa, Grateloup, Atlas Conch, foss. l'Adour
pi. xxxix, fig. 2, 1840. p
g
Voluta auris-leporis, Lankester, Quart. Journ. Geol. Soc, vol. xxvi, p. 502
pi. xxxiv, fig. 6, 1870. M
I
i h Mus. Ipswich. Sipho Ravni, sp. nov. Fusus erraticus, var., Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii,
p. 333, pi. vi, fig. 13, 1907. Mus. Pract. Geol. London, Norwich. Fasciolaria (Surculofusus) erraticus (de Koninck). i
d K
i
k C
f
B
l
19
i ii fi
5 Fusus erraticus, de Koninck, Coq. foss. Basele, p. 19, pi. ii, fig. 5, 1837. f
i
6
i
l fi Fusus erraticus, de Koninck, Coq. foss. Basele, p. 19, pi. ii, fig. 5, 1837. „
,,
Nyst, Coq. foss. Beige, p. 496, pi. xl, fig. 2, 1843. Fusus erraticus, de Koninck, Coq. foss. Basele, p. 19, pi. ii, fig. 5,
„
,,
Nyst, Coq. foss. Beige, p. 496, pi. xl, fig. 2, 1843. „
,,
y , C q
g , p
96, p
,
g
, 8 3
Mus. Pract. Geol. London, Ipswich. Sipho lineatus (de Koninck). Fusus lineatus, de Koninck, Coq. foss. Basele, p. 18, pi. iii, figs. 1, 2, 1837. Mus. Pract. Geol. London, Ipswich, York. Liomesus ventrosus (Beyrich). Fusus ventrosus, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. viii, p. 35,
pi. ii, figs. 3-5, 1856. p
,
g
,
Bucci/wpsis Dalei, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 313,
pi. v, fig. 1, 1907. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Sipho major, A. Bell. Sipho major, A. Bell, .Tourn. Ipswich Field Club, vol. iii, p. 9, 1911. Fusils erraticus, var., Harder, Danm. Geol. Underseg., vol. ii, p. 83, pi. vi,
fig. 31, 1913. M
I
i h Semicassis saburon (Bruguiere). Cassis saburon, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. vi, p. 480, pi. xii
fig. 5, 1854. 5 Cassis saburon, Beyrich, Zeitsch. deutsch. Geol. Ges., vol. vi, p. 480, pi. xi
fig. 5, 1854. Cassidaria sp
Lankester
Quart
Journ
Geol Soc
vol xxvi p 502 g
,
Cassidaria sp., Lankester, Quart. Journ. Geol. Soc, vol. xxvi, p. 502,
pi. xxxiv, fig. 8, 1870. I
t
ll
ti https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Cominella conica, sp. nov. A smooth elongate bucciniform shell, channelled at the upper part of the
volutions. Whorls 5-6, rounded and sub-carinated. Apex blunt. Aperture
semilunate. Outer lip thickened, base but slightly prolonged. Umbilicus
exposed by the loss of shelly matter. Height 35 mm., breadth 20 mm. Mus. Ipswich, Cambridge. Desmoulea conglobata (Brocchi). Echinophoria Rondeleti (Basterot). Cassis Rondeleti, Basterot, Mem. Geol. sur les Env. de Bordeaux, p. 51,
pi. iii, fig. 22 ; pi. iv, fig. 13, 1825. C
i R
dd i R
K D
k Vid S l k Sk if (7)
l iii
307 p
g
p
g
Cassis Ronddeti, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 307,
pi. iv, fig. 9, 1907. M
I
i h us. psw c . [The late Mr. C Reid includes Cassidaria bicatenata in his list of
Mollusea from the Suffolk boxstones. Plioc. Dep. of Britain, p. 13. It is
probably a clerical error.] Ficula acclinis (S. V. Wood). Pyrula acclinis, S. V. Wood, Mon. Crag Moll., pt. ii, p. 311, pi. xxxi, fig. 6,
1850. In most collections. Pyrula acclinis, S. V. Wood, Mon. Crag Moll., pt. ii, p. 311, pi. xxxi, fig. 6,
1850. In most collections. [The most characteristic feature of this- species is the great breadth of
the upper part of the whorls. Pyrula condita in Homes' great work, vol. i,
pi. xxviii, fig. 4, seems to agree with Wood's shell.] [The most characteristic feature of this- species is the great breadth of
the upper part of the whorls. Pyrula condita in Homes' great work, vol. i,
pi. xxviii, fig. 4, seems to agree with Wood's shell.] In most collections. Echinophoria sulcosa (Lamarck). Echinophoria sulcosa (Lamarck). Cassis sulcosa, Homes, Foss. Moll. Tert. Wien, vol. i, p. 179, pi. xv, fig. 8
1856. Cassidaria sp., Lankester, Quart. Journ. Geol. Soc, vol. xxvi, p. 502,
pi. xxxiv, fig. 9, 1870. Mus Pract Geol London Ipswich Mus. Pract. Geol. London, Ipswich. Ficula cingulata (Bronn). Pyrula cingulata, Homes, Foss. Moll. Tert. Wien, vol. i, p. 676, pi. xxviii,
fig. 1, 1856 (figured as P. reticulata). Mus. Pract. Geol. London, York,
Ipswich. Desmoulea conglobata (Brocchi). Buccinum conglobatum, Brocchi, Conch, foss. Subap., vol. i, p. 334, pi. iv
fig. 15, 1814. g
,
Nassa conglobata, S. V. Wood, Mon. Crag Moll., pt. i, p. 32, pi. iii, fig. 9
1848. Mus. Pract. Geol. London, York, Ipswich. Liomems cf. danicus (von Koenen). Buccinopsis danicus, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii,
p. 313, pi. iv, figs. 10-11, 1886. Mus. Pracfc. Geol., London. [The shells figured by Ravn are both imperfect, and the London specimen
is referred to it with some doubt as only the dorsal aspect is exposed. It
is a rare shell on the Continent, as it is only recorded from the Danish
Oligocenes.] Moore and Stanley Coll. y
[Many of the shells found in the Scaldisien beds in Belgium figured as
B. Dalei, Sow., are much nearer to this species than to those in the English
Crag. Fig. 4 in Beyrich's plate is an almost exact delineation of some of
the Belgian forms.] [Many of the shells found in the Scaldisien beds in Belgium figured as
B. Dalei, Sow., are much nearer to this species than to those in the English
Crag. Fig. 4 in Beyrich's plate is an almost exact delineation of some of
the Belgian forms.] https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 412 Liomems cf. danicus (von Koenen). Liomems cf. danicus (von Koenen). Alfred Bell—Fossils of East Anglian Boxstones. Alfred Bell—Fossils of East Anglian Boxstones. Aporrhais ipeciosus (Schlotheim). Aporrhais ipeciosus (Schlotheim). Aporrhais speciosus, Be3'rich, Zeitsch. deutsch. geol. Ges., vol. vi, p. 492
pi. xiv, figs. 1-3, 1854. p
,
g
,
Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii,
p. 302, pi. iii, fig. 24, 1907. Mus. Ipswich. Jiostellaria dentata, Grateloup. Rostellaria denlala, Grateloup, Atlas Conch, foss. de l'Adour, No. 32, fig. 4. 1840. ,,
,,
Cossmann, Ess. Paleoconeh. compar., vol. vi, p. 19. pi. ii, fig. 12, 13, 1904. Mus. Ipswich. Hippochrenes ampin liuioti,
var. nov. Rimella gracilenta (S. V. Wood). Rimella gracilenta (S. V. Wood). g
(
)
Rostellaria (?) gracilenta, S. V. Wood, Mon. Crag Moll., Suppl. 3, p. 1,
pi. i, fig. 1, 1882. Mus. Ipswich. Rostellaria (?) gracilenta, S. V. Wood, Mon. Crag Moll., Suppl. 3, p. pi. i, fig. 1, 1882. Mus. Ipswich. Rimella luoida{?), (S. V. Wood), J. Sowerby. pi. i, fig. 1, 1882. Mus. Ipswich. Rimella luoida{?), (S. V. Wood), J. Sowerby. Rimella luoida{?), (S. V. Wood), J. Sowerby. Hostel/aria lucida (?), S. V. Wood, Mon. Crag Moll., Suppl. 1, pt. i, p. 5,
pi. ii, fig. 14, 1872. Mus. Ipswich. g
Pseudoeassis splmrica (Philippi). Cyprcea spherica, Bevrieh, Zeitsch. deutsch. geol. Ges., vol. v, p. 319
pi. iv, fig. 9, 1853. Mus. York. p
,
g
,
[Mr. F. W. Harmer has in his collection a cast of a shell belonging to
this group, having the inner whorls coiled on a flat plane round the apex
as in some of the Conidae, height 30 mm., breadth 20 mm., found at
Waldringfield. For the genus see Fischer, Manuel de Conchyliologie,
p. 668.]
& l
(
k) https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Trivia pi&olina (Lamarck). p
Cyprma puolina, Lamarck (Deshayes), Anim. sans Vertebr., 2nd ed.,
vol. vii, p. 408, 1822. vol. vii, p. 408, 1822. Trivia piaolina, F. W. Harmer, Plioc. Moll. Gt. Brit., pt. i, p. 50, pi. ii,
fig. 17, 1913. Moore Coll. Hippochrenes ampin liuioti,
var. nov. Rostellaria ampla, Rutot, Ann. Soc. malac. Beige, vol. xi, p. 33, pis. i, ii,
1874. Mus. Norwich (spire), Ipswich (bod}7). Pyrula reticulata, S. V. Wood, Mon. Crag Moll., pt. i, p. 42, pi. ii, fig. 12,
1848 1848. Mus. Pract. Geol. London, York, Ipswich. Ficula cf. geometra (Borson). Ficula cf. geometra (Borson). Pyrula geometra, Homes, Foss. Moll. Tert. Wien, vol. i, p. 271, pi. xxviii
fig. 7, 8, 1856. Mus. Pract. Geol. London. g
, ,
[A graceful cast in this museum may be assigned to this species with
some uncertainty. In form and outline, however, it corresponds to
Homes' and Sacco's figures of the shell.] g
Pseudoeassis splmrica (Philippi). Ficula condita (Brongniart). Pyrula condita, Brongniart, Mem. sur les Terr, du Vicentin, p. 75, pi. vi,
fig. 4, 1823. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Alfred Bell—Fossils of East Anglian Boxstones. 413 Alfred Bell—Fossils of East Anglian Boxstones. Turritella Geinitzi, Speyer. Turritella Geinitzi, Spever, Palseontographica, vol. xvi, p. 22, pi. ii, fig. 2,
1866. ,,
,,
Norregaard, Danske Geol. Forening, vol. v, p. 122,
pi. iii, fig. 7, 1916. M
I
i h Natica achatensis (Recluz MS.), de Koninck. Natica achatensis (Recluz MS.), de Koninck. d
i
k
f
l Natica achatensis, de Koninck, Coq. foss. Basele, p. 9, 1837. Natica glaucinoides, Nyst, Coq. foss. Beige, p. 442, pi. xxxvii, fig. 32, 1843
Mus. Pract. Geol. London, York, Ipswich. Natica achatensis, de Koninck, Coq. foss. Basele, p. 9, 1837
N i
l
i
id
N
t C
f
B i
442
i Natica glaucinoides, Nyst, Coq. foss. Beige, p. 442, pi. xxxvii, fig. 32, 184
Mus. Pract. Geol. London, York, Ipswich. Cerithiwn acuticosta angulatior, Sacco. Ctrithium aaiticosta, var. angulatior, Sacco, Moll. Terr. terz. Piemonte,
pt. xvii, p. 4, pi. i, fig. 6, 1895. Mus. Norwich. Vermetus (Burtinella) Bognoriensii, Mantell. Vermetus Bognoriensis (?), S. V. Wood, Mon. Crag Moll., pt. i, p. 114,
pi. xii, fig. 9, 1848. Mus. Ipswich. p
,
g
,
p
[This shell (or annelid) is commonly diffused in the loose sands of the
older Red Crags, as well as in the hardened original matrix. S. V. Wood,
Suppl. 3, p. 1.] https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 414 Alfred Bell—Fossils of East Anglian
Boxstones. Vermilia flagelliformis (Morris). Serpula flagelliformis, J. Sowerby, Min. Conch., vol. vii, p. 50, pi. Dcxxxiv,
figs. 2, 3, 1844. Attached to shell of Pectuncidus. Mus. York. Mus. Pract. Geol. London. Xenophora scrutaria (Philippi). Natica tlonqata, Michelotti. Natica tlonqata, Michelotti. Natica elongata, Michelotti, Et. Mioc. Inf. d'ltalie, p. 88, pi. x, fig. 34, 1861
Euspirocrommium elongatum, Sacco, Moll. Terr. terz. Piemonte, pt. ix,
p. 10, pi. i, fig. 11, 1891. St
l
C ll Natica elongata, Michelotti, Et. Mioc. Inf. d'ltalie, p. 88, pi. x, fig. 34, 1861
Euspirocrommium elongatum, Sacco, Moll. Terr. terz. Piemonte, pt. ix,
p. 10, pi. i, fig. 11, 1891. S
l
C ll Stanley Coll. Mus. Pract. Geol. London. Mus. Pract. Geol. London. https://doi.org/10.1017/S0016756800198899
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Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Natica, Nysti, ei. D'Orbigny. Natica Nysti, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 293, pi. iii,
fig. 10, 1907. In most collections. Xenophora scrutaria (Philippi). Trochus scrutaria, Philippi, Beit. Tert. N.W. Deutschlands, p. 22, pi. iii,
fig. 37, 1843. X
h
i
i
S
P l
hi
l
i
328
i
i g
Xcnophoria scrutaria, Speyer, Palueontographiea, vol. xvi, p. 328, pi. xxxiv,
fig. 8, 1866. M
P
G
l L
d Xenophora Deshayest (Michelotti). Xenophora Deshayest (Michelotti). Xenophora Deshayesi, Homes, Foss. Moll. Tert. Wien, vol. i, p. 442,
pi. xliv, fig. 12, 1856. S
M ll T
Pi
i ii p
y
p
pi. xliv, fig. 12, 1856. ,,
.,
Sacco, Moll. Terr. terz. Piemonte, pt. xx, pi. ii,
fig. 20, 1896. Mus Pract Geol London p
g
,,
.,
Sacco, Moll. Terr. terz. Piemonte, pt. xx, pi. ii,
fig. 20, 1896. Natica cf. hantoniensis, Pilkington. Natica cf. hantoniensis, Pilkington Natica hantoniensis, von Koenen, Palseontographiea, vol. xvi, p. 148, pi. xii,
fig. 9, 1867. g
,
,,
,,
Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii,
p. 290, pi. iii, fig. 6, 1907. M
Y
k Mus. York. [This fine cast, height 33 mm., breadth 25 mm., is clean from any
adventitious matter. Its globose form and straightness of columella
indicate its connection with the above species. Unfortunately the outer
mould was not preserved.] Natica (Crommium) ferruginea italica (Sacco). Natica (Crommium) ferruginea italica (Sacco). Crominium ferrugineum italica, Sacco, Moll. Terr. terz. Piemonte, pt. ix,
p. 8, pi. i, fig. 8, 1891. Mus. Pract. Geol. London, Ipswich. Natica (Crommium) ferruginea italica (Sacco). Crominium ferrugineum italica, Sacco, Moll. Terr. terz. Piemonte, pt. ix,
p. 8, pi. i, fig. 8, 1891. Mus. Pract. Geol. London, Ipswich. Calliostoma Xavieri (Costa MS. Calliostoma Xavieri (Costa MS.) Calliostoma Xavieri (Costa MS.). i
i D llf
C tt
& G
M ll t
t d
P
t Trochus Xavieri, Dollfus, Cotter, & Gomes, Moll. tert. du Portugal, p. 6,
pi. xxxi, fig. 4, 1903. p
,
g
,
Zizyphinus opislhosthenus, cf. Fontannes, Moll. Plioc. de la Vail, du Rhone,
vol. i, p. 218, p. xi, fig. 22, 1897. M
I
i h Mus. Ipswich. Niso sp. [The cast referred to this genus exhibits the perforated axis very clearly, -
and is probably that of one of the many forms of Niso (Bondlia) terebellata
Grateloup, figured by Sacco, Moll. Terr. terz. Piemonte, pt. xi, pi. i,
figs. 39-52. Harmer Coll.] [The cast referred to this genus exhibits the perforated axis very clearly, -
and is probably that of one of the many forms of Niso (Bondlia) terebellata
Grateloup, figured by Sacco, Moll. Terr. terz. Piemonte, pt. xi, pi. i,
figs. 39-52. Harmer Coll.] https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 415 Alfred Bell—Fossils of East Anglian Boxstones. Alfred Bell—Fossils of East Anglian Boxstones. Bolma granosa mioeenica, Sacco. Bolma granosa mioeenica, Sacco. g
Bolma graiiosa mioeenica, Sacco, Moll. Terr. terz. Piemonte, pt. xxi, p. 1
pi. i, fig. 28, 1896. Mus. Pract. Geol. London. Dentalium sp. (?) Dentalium fossile, Homes, Foss. Moll. Tert. Wien, vol. i, p. 657, pi. i,
fig. 36, 1856. Stanley Coll. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms.
Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Phoreus striatus, Risso. Phorcus striatus, Risso, Hist. Nat. Eur. merid., vol. iv, p. 134, 1826. [Risso's diagnosis of this species, which he only knew as fossil, equally
describes the boxstone shell, so as to render them practically identical. Mus. Ipswich.] Spondylus sp Spondylus sp. [The genus is represented by a perfect upper valve with the inner side
exposed showing the characteristic dentition. It is recorded from the
Belgian Oligocenes. See Vincent, Ann. Soc. malac. de Beige, vol. xxiii,
1888
Mus York ] Spondylus sp. [The genus is represented by a perfect upper valve with the inner side
exposed showing the characteristic dentition. It is recorded from the
Belgian Oligocenes. See Vincent, Ann. Soc. malac. de Beige, vol. xxiii,
1888
Mus York ] 1888. Mus. York.]
Pecten (Chlamys) Malvincs, Dubois de Montperoux. l
b i d
f
lh Pecten (Chlamys) Malvincs, Dubois de Montperoux. Pecten Malvince, Dubois de Montperoux, Coq. foss. Wolhyma, p. 71, pi. viii
figs. 2-3, 1831. Pecten Malvince, Dubois de Montperoux, Coq. foss. Wolhyma, p. 71, pi. vii
figs. 2-3, 1831. g
,
,,
„
Homes, Foss. Moll. Tert. Wien, vol. ii, p. 414, pi. Ixiv,
fig. 5, 1870. l
ll Stanley Coll. Pecten {Chlamys) Sollingensis, von Koenen. Pecten {Chlamys) Sollingensis, von Koenen. Pecten Sollingensis, von Koenen, Palseontographiea, vol. xvi, p. 228, pi. xrvi
figs. 7, 8, 1867. Pecten Sollingensis, von Koenen, Palseontographiea, vol. xvi, p. 228, pi. xrvi
figs. 7, 8, 1867. g
, ,
,,
„
Eavn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 251,
pi. i, fig. 1, 1907. Mus. Pract. Geol. London. Dentalium Kickxii, Nyst.
f
i Dentalium Kickxii, Nyst. f
i Dentalium Kickxii, Nyst, Coq. foss. Beige, p. 342, pi. xxxvi, fig. 1, 1843. R
K D
k Vid S l k Sk if (7)
l iii
286 ,,
„
Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 286,
pi. iii, fig. 4, 1907. Mus Pract Geol London Pecten (Chlamys) Hoeninghausii, Defrance.
P
H
i
h
ii N
C
f
B i
286
i
ii fi Pecten (Chlamys) Hoeninghausii, Defrance. h
f
i
6
i
ii fi Pecten Hoeninghausii, Nyst, Coq. foss. Beige, p. 286, pi. xxii, fig. 2, 1843. P
di
S V W
d M
C
M ll S
l 3
12
i i fi Pecten Hoeninghausii, Nyst, Coq. foss. Beige, p. 286, pi. xxii, fig. 2, 1843. Pecten disparatus, S. V. Wood, Mon. Crag Moll., Suppl. 3, p. 12, pi. i, fig. 17
1882. St
l
C ll B it M
(N t Hi t ) L
d Pecten Hoeninghausii, Nyst, Coq. foss. Beige, p. 286, pi. xxii, fig. 2, 1843. Pecten disparatus, S. V. Wood, Mon. Crag Moll., Suppl. 3, p. 12, pi. i, fig. 17,
1882. Stanley Coll., Brit. Mus. (Nat. Hist.) London. p
Calliostoma millegranus prcecedens (von Koenen). p
Calliostoma millegranus prcecedens (von Koenen). Trochus labarum (?), Basterot, Mem. Geol. de l'Env. de Bordeaux, 1825,
p. 33, pi. i, fig. 23. p
, p
, g
Trochus miliaris, Homes, Foss. Moll. Tert. Wiefi, vol. i, p. 454, pi. xlv,
fig. 9, 1856. g
,
Trochus millegranus prccedens, von Koenen, Mioc. N. Deutschlands
(Marburg), p. 308, 1872. Mus. Pract. Geol. London. Stanley Coll., Brit. Mus. (Nat. Hist.) London. Pecten (Chlamys) substriatus, D'Orbigny. y
g y
Pecten substriatus, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 408, pi. Ixiv,
fig., 1870. Harmer Coll. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 416 Alfred Bell—Fossils of East Anglian
Boxstones. Pectunculus Bormidianus,
Mayer. Pectunculus Bormidianus,
Mayer, Foss. Mus. Zurich, pt. iii, p. 49, 1868. Axinea Bormidiana,
Sacco, Moll. Terr. terz. Piemonte, pt. xxvi, p. 37,
pi. ix, figs. 11-15, 1898. Mus Norwich etc Mus. Norwich, etc. Pecten (Chlamys) cf. Erslevi, Harder. Pecten (Chlamys) cf. Erslevi, Harder. Pecten Erslevi, Harder, Danm. geol. Undersag., vol. ii, p. 44, pi. iii, figs. 3, 4,
1913. Mus. Pract. Geol. London. [A fragment in the M.P.G. seems to agree with Harder's figure.] Pecten (Chlamys) excisus, Bronn. Chlamys excisus, Dollfus & Cotter, Moll. Tert. du Portugal, 1909, p. 77,
pi. viii, figs. 5-9. [I found a characteristic fragment of this species in Newbourne Crag pit.] pi. viii, figs. 5 9. [I found a characteristic fragment of this species in Newbourne Crag pit.] Mytilus corruffatus, Brongniart. Mytilus corrugatus, Brongniart, Mem. sur les tert. du Vicentin, p. 78, pi. v,
fig. 6, 1823. Stanley Coll. Mus. York, Stanley Coll. Mytilus corruffatus, Brongniart. p
Pectunculus Philippi, Deshayes. Pectunculus Philippi, Deshayes. Pectunculus pulvinatus, var., Philippi, Beit. N.W. deutsch. tert., p. 13, pi. ii,
fig. 13, 1843. pp
y
Pectunculus pulvinatus, var., Philippi, Beit. N.W. deutsch. tert., p. 13, pi. ii,
fig. 13, 1843. g
,
Pectunculus Philippi, Eavn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 262,
pi. i, fig. 17, 1907. Mus Ipswich Pinna pectinata Brocchi (D'Orbigny). Pinna
Brocchi, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 372, pi. i,
figs. 1, 2, 1870. g
Pinna pectinata Brocchi, Sacco, Moll. Terr. terz. Piemonte, pt. xxv, p. 29,
pi. viii, fig. 1, 1898. Mus. York, Stanley Coll. Peeten (Chlamys) rupeliensis (von Koenen). Pecten rupeliensis, von Koenen, Palseontographica, vol. xvi, p. 232, pi. xxvi,
fig. 12, 1867. Mus. Pract. Geol. London, Stanley Coll. Jlinnites crispus (Broechi). Hinnites crispus, Sacco, Moll. Terr. terz. Piemonte, pt. xxix, p. 10, pi. ii,
fig. 1, 1897. Stanley Coll. Pinna pectinata Brocchi (D'Orbigny). Pecten (Peplum) sp. Pecten verrucopsis, de Gregorio, Ann. de Geol., pt. xiii, p. 26, pi. iv, figs. 89,
90, 1894. ,
Pecten clavatus, Ravn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 252, pi. i,
fig. 2, 1907. M
P
G
l L
d g
,
Mus. Pract. Geol. London. [Of the two figures cited above, Gregorio's comes nearest to the M.P.G. fragment.] Pecten (Chlamys) excisus, Bronn. Arcoperna sericea (Bronn). Modiola sericea, Philippi, En. Moll. Sic, vol. i, p. 71, pi. v, fig. 14, 1836. S. V. Wood, Mon. Crag Moll., pt. ii, p. 61, pi. viii, fig. 3,
1850. M
I
i h https://doi.org/10.1017/S0016756800198899
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Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Venericardia antiquata rhomhoidea (Brocchi). Venericardia antiquata rhomhoidea (Brocchi). Chama rhomboidea, Brocchi, Conch, foss. Subap., p. 523, pl. xii, fig. 16, 1814. Cardita (Olans) rhomboidea, Cerulli-Irelli, Pal. ital., vol. xiii, p. 135, pl. xii,
fig. 28, 1907. Mus. York. Aetarte cf. solidula, Deshayes. Astarte solidula tauroscalarata, Sacco, Moll. Terr. terz. Piemonte, pt. xxvii,
p. 25, pl. vi, fig. 29, 1899. Mus. Pract. Geol. London. [Length 18 mm., breadth 22 mm.; sculpture, 6 or 7 thick concentric ribs. The number of these vary according to Saceo's figures of A. solidula.] Astarte Jlenclceliusiana, Nyst. Astarte Henckeliusiana,
Nyst, Coq. foss. Beige, p. 154, pl. ix, fig. 4, 1843. ,,
,,
von Koenen, PaliEontographica, vol. xvi, p. 250
pl. xxix, fig. 7, 1867. Mus. Pract. Geol. London. Nucula donaciformis, Harder. Nucula donaciformis, Harder, Danm. geol. Unders0g., vol. ii, p. 49, pl. iii,
fig. 10, 1913. Stanley Coll. Nucula placentina, Lamarck. Niccula placentina, Philippi, En. Moll. Sic, vol. i, p. 65, pl. v, fig. 7, 1836. ,,
,,
Sacco, Moll. Terr. terz. Piemonte, pt. xxvi, p. 46, pl. x,
figs. 35-40, 1898. i h Mus. Ipswich. Nucula Ilaesendonckii, ]S"yst & Westendorp. Nucula Ilaesendonckii, ]S"yst & Westendorp. Nucula Ilaesendonckii, Nyst, Coq. foss. Beige, 1843, p. 236, pl. xviii, fig. 5. [Sir E. Ray Lankester informs me that he had identified this very distinct
species in the collection of the late Dr. Taylor in Ipswich. Unfortunately the
specimen has been lost sight of.] Nucula Ilaesendonckii, Nyst, Coq. foss. Beige, 1843, p. 236, pl. xviii, fig. 5. [Sir E. Ray Lankester informs me that he had identified this very distinct
species in the collection of the late Dr Taylor in Ipswich
Unfortunately the Nucula turgens, S. V. Wood. Nucula turgens, S. V. Wood, Mon. Crag Moll., Suppl. 2, p. 44, pl. v, fig. 6,
1879. Mus. Brit. Nat. Hist., Wood Coll. Leda Deshayesiana
(Du Chastel Coll.). Antarte Kichxii, Nyst. Astarte Kickxii, Nyst, Coq. foss. Beige, p. 157, pl. x, fig. 3, 1843. k
k
id S l k Sk if
( )
l iii Astarte Kickxii, Nyst, Coq. foss. Beige, p. 157, pl. x, fig. 3, 1843. Astarte Kicksii, Eavn, K. Danske Vid. Selsk. Skrift (7), vol. iii. p. 268, pl. i,
fig. 21, 1907. M
P
t G
l L
d
St
l
C ll y
q
g
p
p
g
Astarte Kicksii, Eavn, K. Danske Vid. Selsk. Skrift (7), vol. iii. p. 268, pl. i,
fig. 21, 1907. M
P
G
l L
d
S
l
C ll https://doi.org/10.1017/S0016756800198899
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Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Pectunculus inflatm (Brocchi). Area inflata, Brocchi, Conch, foss. Subap., p. 494, pi. xi, fig. 7, 1814. Axinea inflata, Sacco, Moll. Terr. terz. Piemonte, pt. xxvi, p. 32, pi. viii,
figs. 1-6, 1898. In most collections. In most collections. In most collections. https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 417 Alfred Bell—Fossils of East Anglian Boxstones. [Pectunculus pilosus and P . glycimeris are amongst the commonest forms
in the boxstones, and probably other members of this variable group are
present.] Nucula donaciformis, Harder. Leda Deshayesiana
(Du Chastel Coll.). Nucula Deshayesiana, Nyst, Coq. foss. Beige, p. 221, pi. xv, fig. 8, 1843. Leda Deshayesiana, H&vn, K. Danske Vid. Selsk. Skrift (7), vol. iii, p. 258,
pl. i, figs. 7, 8, 1907. Stanley Coll Cyprina islandicoides, Lamarck. Venus islandicoides. Homes, Foss. Moll. Tert. Wien, vol. ii, p. 121, pi. xiii,
fig. 2, 1870. g
Amiantis islandicoides, Sacco, Moll. Tert. terz. Piemonte, pt. xxviii, p. 21,
pi. v, figs. 1-4, 1900. Cyprina scutellaria (Lamarck). Cyprina scutellaria (Lamarck). Cyprina scutellaria, Nyst, Coq. foss. Beige, p. 145, pi. vii, fig. 5 ; pi. viii,
fig. 1, 1843. In most collections. Cyprina islandica aqualis (J. Sowerby). Cyprina csqualis, Goldfuss, Petr. Germ., p. 236, pi. cxlviii, fig. 5, 1838. C
i
i l
di
S
V
W
d
M
C
M ll
t
ii
196
i Cyprina islandica,
S. V. Wood, Mon. Crag Moll., pt. ii, p. 196, pi. xviii,
figs, la, o, 1850. Isocardia lunulata, Nyst. y
Isocardia lunulata, Nyst, Coq. foss. Beige, p. 198, pi. xv, fig. 2, 1843. „
,,
Lankester, Quart. Journ. Geol. Soc, vol. xxvi, p. 502,
pi. xxxiv, fig. 10, 1870. In all collections. Isocardia cor (Linne). Isocardia cor, S. V. Wood, Mon. Crag Moll., pt. ii, p. 193, pi. xv, fig. 9, 1850. ,,
,, Forbes & Hanley, Brit. Moll., vol. i, p. 472, vol. iv, pi. xxxiv,
fig. 2, 1853. Mus. York, Ipswich. Cardium subdecorticatum, A. Bell. Cardium subdecorticatum, A. Bell, Journ. Ipswich Field Club, vol. iii, p. 9,
1911. Cardium et. decorticatum tenellum, S. V. Wood, Mon. Crag Moll., pt. ii,
p. 159, pi. xiv, fig. Id, 1850. [The above shell is decorticated as in Wood's figure, but the ribs are more
open = C. decorticatum of Lankester and Beid. ] Alfred Bell—Fossils of East Anglian Boxstones. Alfred Bell—Fossils of East Anglian Boxstones. Cardium cingulatum, Goldfuss. Cardium cingulatum,
Goldfuss, Petr. Germ., vol. ii, p. 222, pl. exlv, fig. 4,
1838. ,,
,,
HOrnes,
Foss. Moll. Tert. Wien, vol. ii, p. 177
pl. xxv, fig. 1, 1870. Mus York Ipswich ,
p
[ C venustum,
Lamk., non S. V. Wood, and C. umbonahim,
A. Bell,
non Sowerby.]
DECADE VI
VOL IV
NO IX
27 27 DECADE VI.—VOL. IV.—NO. IX. 27 https://doi.org/10.1017/S0016756800198899
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Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the 418 Cyprina tumida, Nyst. Cyprina tumida, Nyst, Coq. foss. Beige, p. 148, pi. x, fig. 1, 1843. Cyprina tumida, Nyst, Coq. foss. Beige, p. 148, pi. x, fig. 1, 1843. Cyprina rustica (tumida), S. V. Wood, Mon. Crag Moll., pt. ii, p. 197, pi. xviii,
fig. 1, 1850. Mus. York. Cardium Wbolnoughi, sp. nov. Cardium Wbolnoughi, sp. nov. [The species here referred to is not rare, but does not appear to have been
figured or described by any Continental writer. In shape it is roundly ovate,
tumid, and nearly equilateral, garnished with twenty-five to thirty narrow
rounded prominent ribs continued below the lower margin with rather wider
interspaces. The surface is much decorticated, leaving four or five ridges
marking probably stages of growth. Mus. Ipswich.] Donax minutus, Bronn. Donax minutus,
Sacco, Moll. Terr. terz. Piemonte, pt. xxix, p. 4, pi. i,
figs. 8, 9, 1901. Mus. Pract. Geol. London, Ipswich. Mactra miocmnica, Dollfus & Dautzenberg. Mactra miocmnica, Dollfus & Dautzenberg. Mactra miocainica, Dollfus & Dautzenberg, Mem. Soc. geol. France, vol. xi,
p. 109, pi. vi, figs. 10, 11, 1904. Mus. Praet. Geol. London, Ipswich. [M. podolica, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 62, pi. vii, fig. 5,
may be a variant of this species.] Solenocurtus Basteroti, Desmoulins. Solenocurtus Basteroti,
Sacco, Moll. Terr. terz. Piemonte, pt. xxix, p. 15,
pi. iv, fig. 1, 1901. p
g
,,
,,
Dollfus,
Cotter, & Gomes, Moll. tert. Portugal,
p. 27, pi. i, figs. 7-10, 1903. Mus. Pract. Geol. London. https://doi.org/10.1017/S0016756800198899
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Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Solen (Unsis) cf. Rollei (Homes). Ensis Rollei, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 15, pi. i, fig. 14, 1870. D llf
& D
b
M
S
l F
l
65 Ensis Rollei, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 15, pi. i, fig. 14, 1870
,,
,,
Dollfus & Dautzenberg, Mem. Soc. geol. France, vol. x, p. 65,
pi. ix, figs. 35-8, 1902. M
I
i h Mus. Ipswich. Meretrix (CaUista) fragilis
(Miinster). Meretrix (CaUista) fragilis
(Miinster). Meretrix (CaUista) fragilis
(Miinster). Venus fragilis, Goldfuss, Petr. Germ., vol. ii, p. 247, pi. cxlviii, fig. 8, 1840. Venus circularis, A. Bell, Journ. Ipswich Field Club, vol. iii, p. vii, 1911. Mus. Ipswich. Venus fragilis, Goldfuss, Petr. Germ., vol. ii, p. 247, pi. cxlviii, fig. 8, 1840. Venus fragilis, Goldfuss, Petr. Germ., vol. ii, p. 247, pi. cxlviii, fig. 8, 1840. Venus circularis, A. Bell, Journ. Ipswich Field Club, vol. iii, p. vii, 1911. Mus. Ipswich. Meretrix (CaUista) suborhicularis (Goldfuss). Meretrix (CaUista) suborhicularis (Goldfuss). Venus suborbictdaris, Goldfuss, Petr. Germ., vol. ii, p. 247, pi. cxlviii, fig. 7,
1840. Mus. Ipswich. [The shell quoted or figured by Koninck, Nyst, Eavn, and other writers as
Venus or Meretrix incrassata, Sow., does not seem to be the same as the
English shell of that name.] Tapes vetula
(Basterot). Meretrix
chione, Linne. Meretrix (Callista) chione elongata, Bucquoy, Dollfus, & Dautzenberg, Moll. du Boussillon, vol. ii, p. 328, pi. Hi, fig. 10, 1893. Meretrix {Callista) chione, Cerulli-Irelli, Pal. ital., vol. xiv, p. 43, pi. viii,
figs. 9, 10, 1908. M
C ll Moore Coll. [Major Moore has in his collection a fine mould of the interior of a shell,
corresponding to the above, found at Waldringfield.] [Major Moore has in his collection a fine mould of the interior of a shell,
corresponding to the above, found at Waldringfield.] https://doi.org/10.1017/S0016756800198899
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Boxstones. 419 Tapes vetula
(Basterot). Venus vetula, Basterot, Mem. geol. sur les Env. de Bordeaux, p. 89, pi. vi,
fig. 7, 1825. g
Tapes vetulus, Dollfus & Dautzenberg, Mem. Soc. geol. France, vol. xiv,
p. 176, pi. ii, figs. 1-6, 1906. Mus. Pract. Geol. London. Ventricola multilamella (Lamarck), var. Boryi, Deshayes Ventricola multilamella (Lamarck), var. Boryi, Deshayes. Ventricola multilamella (Lamarck), var. Boryi, Deshayes. Venus sp., Lankester, Quart. Journ. Geol. Soe., vol. xxvi, p. 502, pi. xxxiv,
fig. 7, 1870. g
,
Ventricola multilamella, Boryi, Sacco, Moll. Terr. terz. Piemonte, pt. xxviii,
p. 31, pi. viii, fig. 9, 1900. p
,
y
[The " boxstone " mould so closely approximates to the shell figured by
Sacco that it may be regarded as the same species ; the more so because
V. multilamella is somewhat variable in outline.] p
y
[The " boxstone " mould so closely approximates to the shell figured by
Sacco that it may be regarded as the same species ; the more so because
V. multilamella is somewhat variable in outline.] p
,
g
,
[Allied to L. oblonga, Chemnitz.] p
,
g
,
[Allied to L. oblonga, Chemnitz.] Mu3. Pract. Geol. London, Ipswich Mu3. Pract. Geol. London, Ipswich. Panopcea Gastaldi (Michel otti). Panopcea Gastaldi, Michelotti, Etud. Mioc. Inf. d'ltal., p. 54, pi. v, fig. 10,
1861. Glycimeris intermedia Gastaldi, Sacco, Moll. Terr. terz. Piemonte, pt. xxix,
p. 45, pi. x, fig. 4, 1901. Mus. Ipswich. Cofbidomya complanata, var. B, Jfyst. •Corbulomya complanata, Nyst, Coq. foss. Beige, p. 59, pi. ii, fig. ii, 1843. Stanley Coll. Lutraria sanna,t Basterot. Lutraria sanna, Basterot, Mem. geol. sur les Env. de Bordeaux, p. 94, pi. vii,
fig. 13, 1825. g
,
,,
„
Sacoo, Moll. Terr. terz. Piemonte, pt. xxix, p. 31, pi. viii,
fig. 5, 1901. l
d
i h Lutraria elliptica Jeffreysii, De Gregorio. Lutraria elliptica Jeffreysii, De Gregorio. Lutraria
elliptica Jeffreysi, De Gregorio, Boll. Soo. malac. ital., vol. x,
p. 143. p
Lutraria
lutraria Jeffreysi, Cerulli-Irelli, Pal. ital., vol. xv, p. 143, pi. xv,
fig. 9, 1909. Mus. Pract. Geol. London, Norwich, Ipswich. Panopcea (?) acutangula (Michelotti). Lutraria
acutangula,
Michelotti, Etud. Mioc. Inf. d'ltal., p. 57, pi. vi,
fig. 2, 1861. g
Glycimeris intermedia acutangula, Sacco, Moll. Terr. terz. Piemonte, pt. xxix,
p. 46, pi. xii, fig. 10, 1901. M
I
i h Mus. Ipswich. Mus. Pract. Geol. London. Panopcea Gastaldi (Michel otti). Panopma declivis, Michelotti. Lutraria declivis, Michelotti, Etud. Mioc. Inf. d'ltal., p. 57, pi. vi, fig. 1, 18
Gl
i
i
i
di
d
li i
S
M ll T
Pi
i Lutraria declivis, Michelotti, Etud. Mioc. Inf. d'ltal., p. 57, pi. vi, fig. 1, 1861. Glycimeris intermedia
declivis, Sacco, Moll. Terr. terz. Piemonte, pt. xxix,
p 45 pi
fig 6 1901 Lutraria declivis, Michelotti, Etud. Mioc. Inf. d'ltal., p. 57, pi. vi, fig. 1, 1861. Glycimeris intermedia
declivis, Sacco, Moll. Terr. terz. Piemonte, pt. xxix,
p. 45, pi. x, fig. 6, 1901. Panopcea Menardi, Deshayes. Panopcea Menardi, Homes, Foss. Moll. tert. Wien, vol. ii, p. 29, pi. ii,
figs. 1-3, 1870. g
Glycimeris Menardi, Sacco, Moll. Terr. terz. Piemonte, pt. xxix, p. 43, pi. xii,
fig. 4, 1901. ll
i Lutraria ovalis, sp. nov. Lutraria
sanna, Homes, Foss. Moll. Tert. Wien, vol. ii, p. 56, pi. v, fig. 5,
1870. ,,
,,
Dollfus, Cotter, & Gomes, Moll. tert. du Portugal, p. 30,
pi. iv, fig. 4, 1903. Mactra triangula, Renier. Mactra triangulata,
S. V. Wood, Mon. Crag Moll., 1850, pt. ii, p. 325,
pi. xxi, fig. 21. Stanley Coll. Mactra trinacria,
Speyer, Palteontographica, vol. xvi, p. 34, pi. iii, fig. 4,
1861. Mus. Pract. Geol. London, York. [The principal difference between M. triangulata and M. trinacria seems
to be that the latter forms a more equilateral triangle than the other. Both
are probably related to the recent M. elliptica.] https://doi.org/10.1017/S0016756800198899
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Boxstones. https://doi.org/10.1017/S0016756800198899
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Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Alfred Bell—Fossils of East Anglian Boxstones. 421 Alfred Bell—Fossils of East Anglian Boxstones. Lucina (Dentilucina) Barrandei, Mayer. Lucina Barrandei, Mayer, Journ. de Conch., vol. xix, p. 340, pi. x, fig. 1,
1871. Lucina Barrandei, Mayer, Journ. de Conch., vol. xix, p. 340, pi. x, fig. 1,
1871. Dentilucina Barrandei, var., Sacco, Moll. Terr. terz. Piemonte, pt. xxix, p. 83,
pi. xix, figs. 7-9, 1901. p
,
g
,
Lucina Carihami, A. Bell, Journ. Ipswich Field Club, vol. iii, p. 9, 1911. Mus Ipswich p
,
g
,
Lucina Carihami, A. Bell, Journ. Ipswich Field Club, vol. iii, p. 9, 1911. Sijndomnya sp. j
y
p
[Two or three species of this group are present in the "boxstones",
possibly the Erycina longicallis and E. similis, figured in Philippi, En. Moll. Sic, vol. ii, pi. xiii, figs. 7, 8, but they are not sufficiently definite for accurate
determination. Stanley Coll.] j
y
p
[Two or three species of this group are present in the "boxstones",
possibly the Erycina longicallis and E. similis, figured in Philippi, En. Moll. Sic, vol. ii, pi. xiii, figs. 7, 8, but they are not sufficiently definite for accurate
determination. Stanley Coll.] Cyrtodaria vagina (S. V. Wood). Cyrtodaria vagina (S. V. Wood). Glycimeris angusta, S. V. Wood, Mon. Crag Moll., pt. ii, p. 291, pi. xxix,
fig. 2, 1850. Mus. Pract. Geol. London. [I do not think this to be the same shell as the Glyc. angusta of Nyst's
memoir, pi. ii, fig. 1. The latter has a more pointed extremity. This I have
had from the Red Crag. Mr. Stanley has a small shell in his sandstone
collection from Bawdsey which may be the same.] https://doi.org/10.1017/S0016756800198899
Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. Downloaded from https:/www.cambridge.org/core. Cornell University Library, on 10 May 2017 at 15:10:11, subject to the Syndosmya prismatica (Montagu). Syndosmya prismatica (Montagu). Ligula donaciformis, Nyst, Coq. terr. Beige, p. 92, pi. iv, fig. 9, 1843. Ab
i
i
S V W
d M
C
M ll
ii
239
i
ii f Ligula donaciformis, Nyst, Coq. terr. Beige, p. 92, pi. iv, fig. 9, 1843. Abraprismatica S V Wood Mon Crag Moll
pt ii p 239 pi xxii f Ligula donaciformis, Nyst, Coq. terr. Beige, p. 92, pi. iv, fig. 9, 1843. Abraprismatica, S. V. Wood, Mon. Crag Moll., pt. ii, p. 239, pi. xxii, fig. 13
1850. Ligula donaciformis, Nyst, Coq. terr. Beige, p. 92, pi. iv, fig. 9, 1843. Abraprismatica, S. V. Wood, Mon. Crag Moll., pt. ii, p. 239, pi. xxii, fig. 13
1850. M
P
t G
l L
d
Y k Thracia ventricosa, Philippi. Thracia ventricosa, Philippi, En. Moll. Sic, vol. ii, p. 17, figured in vol. i,
pi. i, fig. 10 (as T. pubescens), 1844. p
,
g
(
p
),
Thracia ventricosa, S. V. Wood, Mon. Crag Moll., Suppl. 2, p. 48, pi. v,
fig. 3, 1879. Mus. Ipswich. Teredo borings in wood are not uncommon, but the shells have
entirely disappeared. [Certain shells of pre-Crag origin are found in the Oakleyan and Newbournian
zones of the Bed Crag, and as some of these also occur embedded in the box-
stones they are presumably of the same age. y
p
y
g
Most of these are figured by Mr. S. V. Wood in the Supplements to the Crag
Mollusca, and by Mr. F. W. Harmer in the Monograph on the Pliocene
Mollusca now in course of publication. f
lik
h
ll
l
ll
d
d p
A few like the Rimellm, Serpulce, Turritellce, and Venericardia occur
in profusion, but as a rule the majority are single specimens, as in the
following list:— Purpura derivata
h l Borsonia suffolciensis Borsonia suffolciensis p
Stenomphalus Weichmanni Pleurotoma denticulata interrupta. d f ,,
interrupta. dif Triton connectens. Ranella (?) anglica. S
i
i
b ,,
nodifer. l b i Semicassis saburon. ll
h ,,
plebeia. S l
ii ,,
p
S Bimella, two or three species. T
i ll
h
i ,,
Selysii. C
ll
l Cancellaria evulsa Turritella, two or three species Ancillaria glandiformis. Solarium, two or three species. g
f
Volutiliihes luctatrix. Ostrea, two or more species. nodosa. li ,,
nodosa. li Pecten Sceninghausii. ,,
nodosa. li suturalis. g
,,
Sollingensis. ,,
suturalis. ,,
suturalis. f
f
(?) ,,
f ,,
g
Venericardia, several varieties
d Mitra fusiformis (?). Lucina crassidens. Fusus abrasus. ,,
crispus. I have not seen any specimens of the typical Voluta Lamberti of the English
or Belgian Crags, or of Pyrula (Ficula) reticulata, or Cassidaria bicatenata in
the "boxstones". The latter, however, is said to occur sparingly in the
" Sables noirs d'Anvers ". Voluta Lamberti, Atractodon elegans, and Cassidaria bicatenata are occa-
sionally washed ashore on the coast, from Aldborough to Walton-on-the-Naze, https://doi.org/10.1017/S0016756800198899
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S l
t
P
t i hii D Flabelhim cuneata, Goldfuss, and another species. S l
P
i hii D Flabelhim cuneata, Goldfuss, and another species. S l
t
P
t i hii D Solenastrea Prestwichii, Duncan. T
h
h
li
D Solenastrea Prestwichii, Duncan. T
h
h
li
D Trochocyathus anglicus, Duncan. Trochocyathus anglicus, Duncan. Woods, fruits, and nuts are common in the Belgian Bupelien deposits, and
our sub-Crags are rich in these. Mr. W. Carruthers told me many years
ago that he had determined three Angiospermous Dicotyledons, one conifer,
and two palms. Certain plants or fruits retain their forms when phosphatized
both in exterior shape and internal structure, but whether these have any
relations to either of the woods present is not yet known. Mus. Ipswich,
Saffron Walden. Amber has been obtained from the Cromer Forest Bed, and Mr. C. Eeid
has referred to a variety of spiders, insects, etc., in amber washed up
on the East Anglian coast, Trans. Norfolk and Norwich Nat. Hist. Soc,
vols. iii-v. Mr. A. H. Foord, F.G.S., in vol. v, p. 92, figures many of these,
including bees, beetles, cockroaches, and spiders, submitted to, and partly
named by, Mr. C. 0. Waterhouse and the Eev. 0. P. Cambridge. Whether of
the same age as the above woods has yet to be determined. Crustacea. Cceloma sp. (? rupeliense, Strainer), and segments of a narrow lobster-like
species. p
Balanus inclusus (fide Lankester), B. unguiformis. Radiata. Cyphosoma tertiarium, Cotteau. Di d
A B ll Cyphosoma tertiarium, Cotteau
d
A
ll Diadema megastoma, A. Bell. S l
R
di Solaster Reedi, n.sp. [This unique example belongs to the Reed Collection in the York Museum. It exhibits the dorsal surface of a thick fleshy starfish, covered with bunches
of short fasciculate spines scattered over the surface, as they are in the recent
S. furcifer. f
f
Mr. W. K. Spencer, F.G.S., has kindly furnished me with the following
notes of dimensions : " Major radius 33 mm. (approx.), minor radius 13 mm.,
width of arm at base 14 mm., no. of arms six."] Thracia ventricosa, Philippi. Harmer
has in his collection a worn shell of the V. Lamberti group, snowing distinctly
broad and swollen ribs on the upper whorls obtained from the Felixstowe shore. pp
Very few invertebrate remains other than the Mollusca have been obtained
in the East Anglian area. I have only noticed, or found recorded :— 1 Abstract of a lecture delivered to the South-Eastern Union of Scientific
Societies at Burlington House, London, on June 7, 1917. N O T I C E S
O I F IMIEIVEOIIEJS- I . — O N
MAMMALIAN
BONES
FROM
EXCAVATIONS IN THE LONDON
DISTRICT. By ARTHUR SMITH WOODWAKD, LL.D., F.K.S.1
I I . — O N
MAMMALIAN
BONES
FROM
EXCAVATIONS IN THE LONDON
DISTRICT. By ARTHUR SMITH WOODWAKD, LL.D., F.K.S.1
I I IN an area so long populated as the London district the surface
deposits are naturally very varied, and those of the historic
period contain remains not only of the indigenous fauna but also of
man's accidental importations. Even so late as the twelfth century
"William Fitzstephen wrote that the woods close to the city were
well stocked with game—" stags, fallow-deer, boars, and wild bulls."
Their bones and teeth are often found, besides the remains of other
animals, perhaps partly of somewhat earlier date, amoug which the
beaver is especially interesting. Bones of the beaver are indeed so 1 Abstract of a lecture delivered to the South-Eastern Union of Scientific
Societies at Burlington House, London, on June 7, 1917.
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https://openalex.org/W3210110455
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https://link.springer.com/content/pdf/10.1007/s11225-021-09963-0.pdf
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English
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An Abductive Question-Answer System for the Minimal Logic of Formal Inconsistency $$\mathsf {mbC}$$
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Studia logica
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cc-by
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An Abductive
Question-Answer System for
the Minimal Logic of Formal
Inconsistency mbC Szymon Chlebowski
Andrzej Gajda
Mariusz Urba´nski Abstract. The aim in this paper is to define an Abductive Question-Answer System for
the minimal logic of formal inconsistency mbC. As a proof-theoretical basis we employ the
Socratic proofs method. The system produces abductive hypotheses; these are answers to
abductive questions concerning derivability of formulas from sets of formulas. We inte-
grated the generation of and the evaluation of hypotheses via constraints of consistency
and significance being imposed on the system rules. Keywords:
Abduction, Inferential erotetic logic, Minimal logic of formal inconsistency. Presented by Jacek Malinowski; Received September 30, 2020 1.
Introduction In abductive reasoning we aim at filling a certain gap between a knowledge
base Γ and a puzzling phenomenon A, unattainable from Γ (cf. [15,23]). The
commonly accepted schema is this: from an observation A and the known
rule if H, then A, infer H (see [21, 5.189]). However, this schema may be
and has been studied in detail in different ways, which leads to different
models of abduction [12,24]. From a computational point of view, it is of
particular appeal to consider an algorithmic perspective, according to which
an abductive hypothesis H “is legitimately dischargeable to the extent to
which it makes it possible to prove (or compute) from a database, a formula
not provable (or computable) from it, as it is currently structured” [13, p. 88]. A brief overview of procedures for generation of abductive hypotheses
defined in such a spirit can be found in [17]. There are four primary ingredients of the algorithmic account of abduc-
tion [17, p. 2]: (i) a basic logic (which determines the language of specification
of A, H and Γ), (ii) a proof method (which determines the exact mechanics
of the procedure of generation of abducibles), (iii) a hypotheses generation
mechanism (which determines the way the chosen proof method is applied Presented by Jacek Malinowski; Received September 30, 2020 Studia Logica (2022) 110: 479–509
https://doi.org/10.1007/s11225-021-09963-0 c⃝The Author(s) 2021 480 S. Chlebowski et al. S. Chlebowski et al. in order to generate abducibles), and (iv) an implementation of criteria for
comparative evaluation of different abducibles. in order to generate abducibles), and (iv) an implementation of criteria for
comparative evaluation of different abducibles. In this paper we seek to introduce a framework for automated genera-
tion and evaluation of abductive hypotheses in the form of an Abductive
Question-Answer System. Our proof-theoretical basis is set up by the So-
cratic proofs method [26]: we shall employ the concepts of an erotetic calcu-
lus and of a Socratic transformation of a question [28], which is proven to be
effective in an automated proof search [9,18,27,29]. As the reader will see,
there are close affinities between erotetic calculi and sequent calculi with
semantically reversible rules [28, p. 98]. The basic logic of choice is the min-
imal logic of formal inconsistency mbC, which is one of the logics of formal
inconsistency [5,6]. 1Although classical negation of a formula A, ¬A, can be defined in mbC by A →⊥,
where ⊥=df p ∧(∼p ∧◦p), we prefer to introduce classical negation as a primitive
connective. 1.
Introduction On the one hand, these logics, being paraconsistent, are
tools for reasoning under conditions which do not presuppose consistency
[20, p. 465]. On the other hand, they “have a remarkable way of reintro-
ducing consistency into the non-classical picture: they internalize the very
notions of consistency and inconsistency at the object-language level.” [6, p. 1]. Therefore, one can reconstruct classical logic inside paraconsistent logic. Moreover, more expressive language allows for formulation of such abductive
hypotheses that could not be obtained by means of classical logic. In light of
this arguments we can say that the abductive procedure we describe in this
paper does not contradict procedures based on classical logic but extends
them. We define an Abductive Question-Answer System for mbC in the form of
an erotetic calculus augmented with abductive rules, which allow for system-
atic search for answers to abductive questions, that is, abductive hypotheses. Consistency and significance constraints, imposed on abductive rules ap-
plications, warrants that generated abductive hypotheses meet those basic
proof-theoretical criteria. Thus in the case of our system comparative eval-
uation of hypotheses is embedded into the procedure for their generation. This is worth noticing, as separating hypotheses generation and evaluation
is by far more popular approach within the algorithmic perspective (cf. [13,
p. 47], [17]). We start with introducing the minimal logic of formal inconsistency, mbC
(Section 2) and its proof theory employing the Socratic proofs method (Sec-
tion 3). On this basis we define our abductive procedure (Section 4), includ-
ing an algorithm for generation of abductive hypotheses (p. 24). An Abductive Question-Answer System... 481 2.
Minimal Logic of Formal Inconsistency Logics of formal inconsistency (LFIs) are paraconsistent logics, which are able
to remodel classically valid reasoning, by means of some special operator ◦. A formula of the form ◦A should be read it is consistent that A or A behaves
classically. The main intuition is the following: when we reason with the
set of premises Γ = {A1, . . . , An} such that there is no Ai (1 ≤i ≤n)
which contains consistency operator ◦, we use deductive machinery of some
paraconsistent logic. But when we obtain an information that some of these
formulas are consistent, i.e. the ◦operator occurs somewhere in Γ, we can
use much stronger deductive machinery of classical logic to reason classically
about fragments of Γ. Suppose we have the following set of premises {p, ∼p},
where ∼is a paraconsistent negation. Using some paraconsistent logic, like
CLuN [2] for example, one cannot deduce an arbitrary formula from this set. But if we have an additional premise which says that p is safe or consistent,
formalized by the formula ◦p, we can deduce an arbitrary formula B, just
like in classical logic. We use the language LmbC of minimal logic of formal inconsistency, which
consists of a countably infinite set Var = {p1, p2, . . .} of propositional vari-
ables and ¬ (classical negation), 1 ∼(paraconsistent negation), ◦(consis-
tency operator), ∧(conjunction), ∨(disjunction), →(implication) as prim-
itive connectives. The set of well-formed formulas (wffs for short) is defined
as usual: A, B :: pi | ¬A | ∼A | ◦A | A ∧B | A ∨B | A →B By a literal we mean a propositional variable or its negation. Literals are
denoted by l, k, m an so on. If l = pi, then l means ¬pi and if l = ¬pi,
then l = pi. The literals l and l are called complementary literals. Naturally,
l = l. The Hilbert-style system for mbC consists of the following axioms and
rules [6]: S. Chlebowski et al. S. Chlebowski et al. 3The notion of mbC-valuation is defined in [8]. 2The notion of mbC-semivaluation is described in [8] and in [6] (but under the name
“bivaluation semantics for mbC”). The term semivaluation is sometimes used in a slightly
different sense, see for example [19].
3Th
ti
f
bC
l
ti
i d fi
d i
[8] 2.
Minimal Logic of Formal Inconsistency 482 (1) A →(B →A)
(2) (A →B) →(((A →(B →C)) →(A →C))
(3) A →(B →(A ∧B))
(4) (A ∧B) →A
(5) (A ∧B) →B
(6) A →(A ∨B)
(7) B →(A ∨B)
(8) (A →C) →((B →C) →(A ∨B →C))
(9) A ∨(A →B)
(10) A ∨¬A
(11) A →(¬A →B)
(12) A ∨∼A
(13) ◦A →(A →(∼A →B))
(MP) If ⊢mbC A and ⊢mbC A →B, then ⊢mbC B Definition 1. (mbC-semivaluation)2 An mbC-semivaluation is a function
v : FORmbC −→{0, 1} which behaves in a standard way in the case of
classical connectives and the following conditions are satisfied: (∼) if v(∼A) = 0, then v(A) = 1;
(◦) if v(◦A) = 1, then either v(A) = 0 or v(∼A) = 0. From a proof-theoretical point of view it is more convenient to work
with the notion of mbC-valuation instead of semivaluation for the following
reason. The notion of mbC-semivaluation has a drawback: the truth value
of some formulas is not determined by its subformulas (if v(A) = 1 then
v(∼A) is not determined). In order to assign values to formulas of the form
∼A and ◦A in a consistent manner, we introduce a new assignment function
λ. Using the notion of mbC-valuation we are able to give a simple soundness
and completeness theorems for our proof method. Definition 2. (mbC-valuation)3 Let FOR∼◦
mbC denote the set of all formulas
of FORmbC of the form ‘∼A’ or ‘◦A’. A function λ : FORmbC −→{0, 1} is
mbC-valuation iffλ behaves classically in the case of classical connectives
and there exists an assignment function λ : FOR∼◦
mbC −→{0, 1} such that
the following conditions hold: (1) λ(∼A) = 1 iffλ(A) = 0 or λ(∼A) = 1;
(2) λ(◦A) = 1 iff(λ(A) = 0 and λ(◦A) = 1) or (λ(∼A) = 0 and λ(◦A) = 1) For further reference let us state truth conditions for formulas of the form
‘¬ ∼A’ and ‘¬ ◦A’: (1*) λ(∼A) = 0 iffλ(A) = 1 and λ(∼A) = 0;
(2*) λ(◦A) = 0 iffλ(A) = λ(∼A) = 1 or λ(◦A) = 0. 2The notion of mbC-semivaluation is described in [8] and in [6] (but under the name
“bivaluation semantics for mbC”). The term semivaluation is sometimes used in a slightly
different sense, see for example [19]. 3 483 An Abductive Question-Answer System... 2.
Minimal Logic of Formal Inconsistency Now we define a new language L+
mbC which is an extension of the language
LmbC. For proof-theoretical reasons we add to the latter the symbol χ. The
set of well formed formulas of L+
mbC is defined in the following way: FOR+
mbC = FORmbC ∪{χA : A ∈FOR∼◦
mbC} ∪{¬χA : A ∈FOR∼◦
mbC} For the extended language L+
mbC we define an extension of mbC-valuation. Semantically, the introduced operator, χ, does not change the truth value
of a given formula. This operator is only a syntactic device for identifying
formulas preceded by consistency operator and paraconsistent negation, i.e. formulas whose truth value is not determined by its subformulas. Definition 3. (mbC-valuation for L+
mbC) An extended mbC-valuation is a
function λ# : FOR+
mbC −→{0, 1}, which behaves in the same manner on the
set FORmbC as λ and the following conditions are satisfied: (1) λ#(χ∼A) = λ(∼A);
(2) λ#(¬χ∼A) = λ(¬∼A);
(3) λ#(χ◦A) = λ(◦A);
(4) λ#(¬χ◦A) = λ(¬◦A). Note that in the extended language L+
mbC we are able to express normal
forms of formulas of the language LmbC. This fact has the following conse-
quences: it is relatively easy to design invertible sequent calculus rules for
non-classical connectives and the completeness theorem for the introduced
calculus can be based on the strategy of counter-model construction. These
advantages will be apparent in the next section on proof theory of mbC. 3.
Proof Theory of mbC There are several proof-theoretical descriptions of the logic mbC: there is
a standard tableau method for several LFIs (where rules operate on signed
formulas) [4], KE tableau method (a variant of standard tableau method, in
which some form of the cut rule is essential), which is also implemented [20]. Moreover there is a sequent calculus for mbC [10] and a system based on
resolution rule and grounded in Inferential Erotetic Logic [8]. Our approach
is based on Inferential Erotetic Logic as well and we use some techniques
and concepts introduced in [8], but we have to forgo the resolution rule in
order to obtain a simple and intuitive model of abductive reasoning. In fact,
our system is akin to some version of hypersequent calculus [27]. 484 S. Chlebowski et al. The language L? mbC is an object-level language in which our erotetic cal-
culi will be worded. The meaningful expressions of the language L? mbC belong
to two disjoint sets. The first one consists of declarative well-formed formulas
(d-wffs for short). The second one is a set of erotetic well-formed formulas
(e-wffs or simply questions). To obtain the vocabulary of L? mbC we add the following signs: ⊢(turnstile
which intuitively stands for a derivability relation in mbC), ? (a question
mark for constructing questions of L? mbC) and , (a comma), ; (a semicolon),
to the vocabulary of L+
mbC. Definition 4. Let Γ, Δ be finite, non-empty, sequences of formulas of L+
mbC. An atomic declarative formula or sequent of L? mbC is of the following form: Γ ⊢Δ Definition 5. Questions of L? mbC have the following form: ?(Φ) ?(Φ) where Φ is a finite, non-empty sequence of sequents of L? mbC. Let Φ = ⟨Γ1 ⊢Δ1, . . . , Γn ⊢Δn⟩be a sequence of sequents of L? mbC. The
question ?(Γ1 ⊢Δ1, . . . , Γn ⊢Δn) is interpreted as follows: is interpreted as follows: is interpreted as follows: Is it the case that Δ1 is entailed by Γ1 and . . . and Δn is entailed by Γn? Terms of Φ are called constituents of the question ?(Φ). 1
y
1
n
y
n
Terms of Φ are called constituents of the question ?(Φ). ? Terms of Φ are called constituents of the question ?(Φ). If Γ entails in mbC Δ then we say that the sequent Γ ⊢Δ of L? mbC is
closed, otherwise it is open. A sequent φ is basic iffφ is of one of the following forms (Γ, Γ′, Γ′′, Δ,
Δ′, Δ′′ may be empty): • Γ, B, Γ′ ⊢Δ, B, Δ′, • Γ, B, Γ′, ¬B, Γ′′ ⊢Θ, • Γ, ¬B, Γ′, B, Γ′′ ⊢Θ, • Θ ⊢Δ, B, Δ′, ¬B, Δ′′, • Θ ⊢Δ, B, Δ′, ¬B, Δ′′, • Θ ⊢Δ, ¬B, Δ′, B, Δ′′, • Θ ⊢Δ, ¬B, Δ′, B, Δ′′, where B ∈FOR+
mbC. Naturally, each basic sequent is closed. where B ∈FOR+
mbC. Naturally, each basic sequent is closed. C
The erotetic calculus EmbC for the logic mbC consists of the rules for
classical connectives and specific mbC rules. The erotetic calculus EmbC for the logic mbC consists of the rules for
classical connectives and specific mbC rules. 485 An Abductive Question-Answer System... Table 1. α/β—Formulas α
α1
α2
β
β1
β2
A ∧B
A
B
¬(A ∧B)
¬A
¬B
¬(A ∨B)
¬A
¬B
A ∨B
A
B
¬(A →B)
A
¬B
A →B
¬A
B
Table 2. Rules for classical connectives Table 2. Rules for classical connectives Table 2. Rules for classical connectives Table 3. Specific rules of mbC Table 3. Specific rules of mbC Table 3. Specific rules of mbC Table 3. Specific rules of mbC 486
S. Chlebowski et al. 486 S. Chlebowski et al. S. Chlebowski et al. Definition 6. (Socratic transformation) A finite sequence of questions s =
⟨s1, . . . , sn⟩is a Socratic transformation (s-transformation) of a question
?(Φ) by means of EmbC iffthe following conditions hold: 1. s1 =?(Φ). 1. s1 =?(Φ). 2. si results from si−1 (where i > 1) by an application of a rule of
EmbC. Definition 7. is interpreted as follows: (complexity) The complexity of a formula A ∈FOR+
mbC,
com(A) is defined inductively as follows: 1. com(A) = 0, where A ∈Var;
2. com(χ∼A) = com(χ◦A) = 0;
3. com(¬A) = com(A) + 1;
4. com(∼A) = com(A) + 2;
5. com(◦A) = com(A) + 3;
6. com(A ⊗B) = com(A) + com(B) + 1, where ⊗∈{∧, ∨, →}. 1. com(A) = 0, where A ∈Var;
2. com(χ∼A) = com(χ◦A) = 0;
3. com(¬A) = com(A) + 1;
4. com(∼A) = com(A) + 2;
5. com(◦A) = com(A) + 3;
6. com(A ⊗B) = com(A) + com(B) + 1, where ⊗∈{∧, ∨, →}. 1. com(A) = 0, where A ∈Var; 2. com(χ∼A) = com(χ◦A) = 0;
3. com(¬A) = com(A) + 1;
4. com(∼A) = com(A) + 2;
5. com(◦A) = com(A) + 3; 6. com(A ⊗B) = com(A) + com(B) + 1, where ⊗∈{∧, ∨, →}. This concept of formula complexity is not standard because it does not
measure the number of occurrences of propositional connectives (such as
items 2, 4, and 5) in the formula. At the semantic level, although connec-
tives ∼and ◦differ from the other ones by being slightly more complicated
(their truth value is not always determined by the truth values of their sub-
formulas), the introduced notion of complexity reflects this difference. Note
that if A is an unanalyzable formula then com(A) ≤1. Corollary 3.1. (reduction) For rule schemes Lα, Rα, Lβ, Lβ, R∼, R∼,
L¬∼, R¬∼, com(B) < com(A) and com(C) < com(A), where A is an
active formula of that rule and B and C are principal formulas of that
rule. For rule schemes L◦, R◦, L¬◦, R¬◦, com(B) < com(A), com(C) <
com(A), com(D) < com(A), where B, C, D are principal formulas of that
rule and A is an active formula of that rule. Note that the above corollary follows directly from the definition of the
measures of complexity. Lemma 1. (existence of atomic questions) Let Γ ⊢Δ be an arbitrary sequent
of L? mbC. There exists a finite s-transformation s = ⟨s1, . . . , sn⟩, where s1 =
?(Γ ⊢Δ) and sn is an atomic question. Proof. If Γ ⊢Δ is a sequent containing only unanalyzable formulas (atomic
sequent), then s1 =?(Γ ⊢Δ) is an atomic question and s = ⟨s1⟩is finite
s-transformation. is interpreted as follows: (Socratic proof ) A Socratic proof (s-proof) of a sequent Γ ⊢
Δ in EmbC is a finite s-transformation s of the question ?(Γ ⊢Δ), such that
each constituent of the last question of s is a basic sequent. An active sequent is specified in a premise of a given EmbC rule scheme. A principal sequent is specified in a conclusion of a given EmbC rule scheme. For each EmbC rule scheme exactly one sequent is active in the premise of
that rule. A formula which is specified in an active sequent of a given rule
scheme is called an active formula of that rule scheme. Formula(s) which is
(are) specified in the principal sequent of a given rule is (are) called principal
formula(s) of that rule. Definition 8. (unanalyzable formulas) The formulas of one of the following
forms: (i) pi; (ii) ¬pi; (iii) χ∼A; (iv) ¬χ∼A; (v) χ◦A; (vi) ¬χ◦A, and only
them, are mbC-unanalyzable. unanalyzable formulas are those that are not active formulas in any
premise of any EmbC rule. This means that these formulas cannot be further
decomposed by means of introduced rules; however they guarantee that the
rules for non-classical connectives are sound and invertible (see Lemma 2). If a sequent consists of unanalyzable formulas only, it is called an atomic
sequent. If each constituent of a question Q is atomic, then Q is called an
atomic question. An s-transformation s is called complete iffthe last term
of s is an atomic question. There are two kinds of unanalyzable formulas:
positive unanalyzable formulas are of the form (i), (iii), (v); negative unana-
lyzable formulas are of the form (ii), (iv), (vi). Complementary unanalyzable
formulas are pairs of formulas: (i) and (ii), (iii) and (iv), (v) and (vi), where
the negative unanalyzable formula is obtainable by addition of the classi-
cal negation to the positive unanalyzable formula, and similarly, the positive
unanalyzable formula is obtainable by removal of the classical negation from
the beginning of the negative unanalyzable formula. We will say that the sequent Γ ⊢Δ is valid iffthere is no valuation λ#
such that λ#(A) = 1 for every term A of Γ and λ#(B) = 0 for every term
B of Δ. An Abductive Question-Answer System... An Abductive Question-Answer System... 487 Definition 9. (complexity) The complexity of a formula A ∈FOR+
mbC,
com(A) is defined inductively as follows: Definition 9. is interpreted as follows: If the sequent Γ ⊢Δ is not atomic, then from Lemma 3.1 we know that
the rules which could be applied to ?(Γ ⊢Δ) reduce the complexity of some
formula in Γ or Δ. As both Γ and Δ are finite, by applying rules of EmbC
consecutively we obtain an atomic question. Lemma 2. For every EmbC rule scheme the active sequent of that rule is
valid iffthe principal sequent(s) is (are) valid. Lemma 2. For every EmbC rule scheme the active sequent of that rule is
valid iffthe principal sequent(s) is (are) valid. 488 S. Chlebowski et al. S. Chlebowski et al. S. Chlebowski et al. Proof. Proof goes by cases. Let us consider R◦rule scheme. Let us assume
that the sequent Γ ⊢Δ, ◦A, Δ′ is valid. The only non-trivial case is when
λ#(◦A) = 1. By the Definition 3 we have that (λ#(A) = 0 and λ#(χ◦A) =
1) or (λ#(∼A) = 0 and λ#(χ◦A) = 1). What follows, (λ#(A) = 0 or λ#(∼
A) = 0) and λ#(χ◦A) = 1. Principal sequents of the R◦rule scheme are:
Γ ⊢Δ, χ◦A, Δ′ and Γ ⊢Δ, ¬A, ¬∼A, Δ′. For the first principal sequent we
have that λ#(χ◦A) = 1 and for the second, λ#(¬A) = 1 or λ#(¬∼A) = 1. Similarly, it is easy to see (in the light of Definition 3) that the validity of
the principal sequents ensures the validity of the active sequent of R◦rule
scheme. The proof goes analogically for the rest of EmbC rule schemes. Lemma 3. (countermodel) Let Γ ⊢Δ be an atomic and not basic sequent. There exists an extended mbC-valuation λ# such that λ#(A) = 1, for each
term A of Γ and λ#(B) = 0, for each term B of Δ. Proof. Note that the following clauses define an assignment which deter-
mines an extended mbC-valuation which invalidates Γ ⊢Δ. 1. if D is a term of Γ (where D ∈Var), then λ#(D) = 1; 1. if D is a term of Γ (where D ∈Var), then λ#(D) = 1; 2. if ¬D is a term of Γ (where D ∈Var), then λ#(D) = 0; 3. if χ∼D is a term of Γ, then λ#(∼D) = 1; 3. if χ∼D is a term of Γ, then λ#(∼D) = 1; 4. if ¬χ∼D is a term of Γ, then λ#(∼D) = 0; 4. is interpreted as follows: Theorem 1. (completeness) If a sequent φ is valid, then φ is provable in
EmbC. Theorem 1. (completeness) If a sequent φ is valid, then φ is provable in
EmbC. Proof. Assume that φ is valid but not provable in EmbC. Therefore, by
Lemma 1 there exists a finite Socratic transformation s = ⟨s1, . . . , sn⟩of
the question ?(φ) such that at least one constituent ψ of the last question of
s is an atomic but not basic sequent. By Lemma 3 there exists an extended
mbC-valuation, which invalidates ψ. Thus at least one constituent of the
last question sn of s is not valid. Therefore, by Lemma 2 we know that at
least one constituent of the question sn−1 is not valid. By applying Lemma
2 consecutively we arrive at the conclusion that the sequent φ is not valid,
contrary to the assumption. is interpreted as follows: if ¬χ∼D is a term of Γ, then λ#(∼D) = 0; 5. if χ◦D is a term of Γ, then λ#(◦D) = 1; 5. if χ◦D is a term of Γ, then λ#(◦D) = 1; 6. if ¬χ◦D is a term of Γ, then λ#(◦D) = 0; 6. if ¬χ◦D is a term of Γ, then λ#(◦D) = 0; 7. if D is a term of Δ (D ∈Var), then λ#(D) = 0; 7. if D is a term of Δ (D ∈Var), then λ#(D) = 0; 8. if ¬D is a term of Δ (D ∈Var), then λ#(D) = 1; 8. if ¬D is a term of Δ (D ∈Var), then λ#(D) = 1; 9. if χ∼D is a term of Δ, then λ#(∼D) = 0;
10. if ¬χ∼D is a term of Δ, then λ#(∼D) = 1;
11. if χ◦D is a term of Δ, then λ#(◦D) = 0;
12. if ¬χ◦D is a term of Δ, then λ#(◦D) = 1. 13. if D is not a term of Γ nor Δ, then λ#(D) = 0. 9. if χ∼D is a term of Δ, then λ#(∼D) = 0; 13. if D is not a term of Γ nor Δ, then λ#(D) = 0. We will show that this assignment determines an extended mbC-valuation,
i.e. it is not the case that there is a formula A such that λ#(A) = 1 and
λ#(A) = 0. As is easily seen, it cannot happen when A is unanalyzable
formula. Assume it cannot happen in the case of formulas B and C and it
happens in the case of B ∧C, i.e. (i) λ#(B ∧C) = 1 and (ii) λ#(B ∧C) = 0. 489 An Abductive Question-Answer System... From (i) it follows that λ#(B) = 1 and λ#(C) = 1, and form (ii) it follows
that λ#(B) = 0 or λ#(C) = 0. In this case λ#(B) = 1 and λ#(B) = 0 or
λ#(C) = 1 and λ#(C) = 0, contrary to our assumption. A similar argument
applies in the case of other connectives. From (i) it follows that λ#(B) = 1 and λ#(C) = 1, and form (ii) it follows
that λ#(B) = 0 or λ#(C) = 0. In this case λ#(B) = 1 and λ#(B) = 0 or
λ#(C) = 1 and λ#(C) = 0, contrary to our assumption. A similar argument
applies in the case of other connectives. 4.
Abduction in mbC Following the algorithmic account of abduction, we interpret the abductive
problem as a requirement to fill the deductive gap between the premises and
the conclusion. In our Abductive Question-Answer System, such requests
will be expressed through abductive questions. Definition 10. (Abductive question) An abductive question (or abductive
problem) has the following form: 4Length(s) denotes the number of elements in sequence s. ?(Ψ) where Ψ is a non-empty sequence of sequents such that at least one term of
Ψ is an open sequent of L? mbC. where Ψ is a non-empty sequence of sequents such that at least one term of
Ψ is an open sequent of L? mbC. • If Ψ = ⟨φ⟩is an one-term sequence, then the question ?(Ψ) is called
simple abductive question. • If Ψ = ⟨φ1, . . . , φn⟩and for each i (1 ≤i ≤n), φi is an atomic sequent,
then the question ?(Ψ) is called a minimal abductive question. • If Ψ = ⟨φ1, . . . , φn⟩and for each i (1 ≤i ≤n), φi is an atomic sequent,
then the question ?(Ψ) is called a minimal abductive question. An atomic abductive question: An atomic abductive question: ?(Γ ⊢Δ)
(1) (1) ?(Γ ⊢Δ) 490 S. Chlebowski et al. can be read as follows: can be read as follows: Which formulas close ⌜Γ ⊢Δ⌝? (2) Which formulas close ⌜Γ ⊢Δ⌝? (2) Which formulas close ⌜Γ ⊢Δ⌝? (2) (2) A compound abductive question ?(Γ1 ⊢Δ1, . . . , Γn ⊢Δn)
(3) ?(Γ1 ⊢Δ1, . . . , Γn ⊢Δn) (3) can be read as follows: (4) Which formulas close every term of ⟨Γ1 ⊢Δ1, . . . , Γn ⊢Δn⟩? (4) Which formulas close every term of ⟨Γ1 ⊢Δ1, . . . , Γn ⊢Δn⟩? (4) Let VΓi⊢Δi = {pi
1, . . . , pi
ni} be the set of all propositional variables occurring
in wffs in sequences Γi or Δifrom (3), then VΦ = n
i=1(VΓi⊢Δi) is the set
of all propositional variables occurring in wffs in sequences from Φ, where
Φ = ⟨Γ1 ⊢Δ1, . . . , Γn ⊢Δn⟩. Definition 11. (Direct analytic answers) A wffB is a direct analytic an-
swer to the abductive question ?(Φ) if and only if each propositional variable,
which occurs in B belongs to VΦ. Definition 12. (Correct analytic answers) A wffB is a correct analytic
answer to the abductive question ?(Φ) if and only if • B is a direct analytic answer to ?(Φ), • B is a direct analytic answer to ?(Φ), • B is a direct analytic answer to ?(Φ), • B closes each open term of Φ. • B closes each open term of Φ. ?(Ψ) • B closes each open term of Φ • B closes each open term of Φ The fact that B is a correct analytic answer for a question Q will be denoted
as: B ∈c(Q). ( )
As an example let us consider the question: As an example let us consider the question: Q∗=?(p, ¬(q ∧r), ¬s ⊢z ; r →s, ¬s, p ⊢r)
(5) (5) • the set of all propositional variables occurring in Q∗: VQ∗= {p, q, r, s, z}, • exemplary direct analytic answers to Q∗: p, q, p →q,
• exemplary correct analytic answers to Q∗: ¬p, s, ¬p ∧z. Theorem 4.1. (Invertibility of the rules of EmbC) Let s = ⟨Q1, . . . , Qn⟩be
a complete Socratic transformation of the question Q1 in EmbC. Theorem 4.1. (Invertibility of the rules of EmbC) Let s = ⟨Q1, . . . , Qn⟩be
a complete Socratic transformation of the question Q1 in EmbC. ⋆For some wffC, if C ∈c(Qn), then C ∈c(Q1). ⋆For some wffC, if C ∈c(Qn), then C ∈c(Q1). Proof. Proof goes by induction on the length of the s-transformation s and
by an inspection of the rules of EmbC. y
p
The case of length(s) = 1 is trivial.4 The case of length(s) = 1 is trivial.4 An Abductive Question-Answer System... 491 Table 4. Examples of abductive rules Table 4. Examples of abductive rules Assume that the property holds for the arbitrary s-transformation s,
where length(s) = i. We will show that it is also valid for the s-transforma-
tion s′, where length(s′) = i+1. Let us also assume that the last rule applied
in s′ was Lα. Let formula C close each constituent of the last question of
s′ (Qi+1). Let Γ1, α1, α2, Γ2 ⊢Δ be the conclusion sequent of Lα. We know
from assumption that C closes this sequent, i.e. C, Γ1, α1, α2, Γ2 ⊢mbC
Δ. Since v(α) = 1 iffv(α1) = 1 and v(α2) = 1 the formula C closes the premise
sequent of the last applied rule, namely C, Γ1, α, Γ2 ⊢mbC
Δ. The length
of the s-transformation with the deleted last question equals i. A similar
argument applies for the other rules. Definition 13. (Partial answer) Let Q = ?(Γ1 ⊢Δ1, . . . , Γn ⊢Δn) be an
abductive question. Let us further assume that the sequent Γi ⊢Δi (for
some i, where 1 ≤i ≤n) is open. Partial answer for Q is such a formula
A that the addition of A to the Γi results in Γi ⊢Δi becoming a closed
sequent or a sequent which after transformation to the atomic sequent is
also a closed one. Note that it could be the case that a partial answer is also a correct
analytic answer, i.e. it closes all open sequents of Q. Definition 14. (Abductive rule) Let Q be a minimal abductive question
and A be a partial answer for Q. The premise of an abductive rule is Q and
the conclusion is A. Each rule in Table 4 has a question as the premise and a declarative
formula as a conclusion (which is a partial answer to the question-premise). A formula, which is a conclusion, when added to the antecedent of an active
sequent in an abductive rule, makes this antecedent inconsistent (in the
classical sense) or generates a link between antecedent and succedent. 492 S. Chlebowski et al. Most abductive procedures consist of two steps: abductive hypotheses
generation and subsequent evaluation of generated hypotheses against pre-
defined criteria [17]. There are several candidates for such criteria [1, 8]. In
this paper we are concerned with just two of them, which are of fundamental
importance from the proof-theoretical point of view. Table 4. Examples of abductive rules The first one is consistency: an abductive hypothesis should be consistent
with the initial data or knowledge base. Note that the notion of consistency
used here is relative to the logic mbC i.e. abductive hypothesis of the form
∼p is consistent with the knowledge base of the form Γ = {p, q, r}, but
not with the knowledge base Γ′ = {p, q, ◦p} for example. The reason for
introducing the consistency criterion is that we do not want a knowledge
base to become inconsistent or trivial in the sense that every formula could
be inferred from it. Consistency criterion may be also called non-triviality
criterion. The second one is significance: an abductive hypothesis should not allow
to derive Δ by itself, that is, in filling this deductive gap both abductive
hypothesis and the initial database should be significant. yp
g
Another point is that we do not want to carry out two separate steps for
the generation and evaluation of the generated abductive hypothesis, but
rather to build an abductive procedure that generates the good abductive
hypotheses. Therefore, we will not implement the evaluation criteria of the
abductive hypotheses, but we will implement rules that can make the con-
struction of the abductive hypotheses consistent and / or significant. These
rules are implemented as restrictions placed on the application of the rules. Abductive rules from Table 4 generate partial answers that can be in-
consistent with the knowledge base Γ or it could be the case, that such a
generated partial answer is itself sufficient to derive Δ. As we would like to
rule out such possibilities, we introduce downward (or Hintikka) and dual
downward saturated sets. Partial answers that are generated along with the
restriction concerning downward saturated set (we will call it consistency
constraints) will be consistent with the knowledge base Γ. Similarly, partial
answers that are generated with the restriction concerning dual downward
saturated set (we will call it significance constraints) will not be too strong,
i.e. Δ would not be obtainable from the partial answer alone. Another point is that we do not want to carry out two separate steps for
the generation and evaluation of the generated abductive hypothesis, but
rather to build an abductive procedure that generates the good abductive
hypotheses. (i) if A is a term of Γ, then A ∈UΓ, (ii) if α ∈UΓ, then α1 ∈UΓ and α2 ∈UΓ, Table 4. Examples of abductive rules Therefore, we will not implement the evaluation criteria of the
abductive hypotheses, but we will implement rules that can make the con-
struction of the abductive hypotheses consistent and / or significant. These
rules are implemented as restrictions placed on the application of the rules. Abductive rules from Table 4 generate partial answers that can be in-
consistent with the knowledge base Γ or it could be the case, that such a
generated partial answer is itself sufficient to derive Δ. As we would like to
rule out such possibilities, we introduce downward (or Hintikka) and dual
downward saturated sets. Partial answers that are generated along with the
restriction concerning downward saturated set (we will call it consistency
constraints) will be consistent with the knowledge base Γ. Similarly, partial
answers that are generated with the restriction concerning dual downward
saturated set (we will call it significance constraints) will not be too strong,
i.e. Δ would not be obtainable from the partial answer alone. Definition 15. (Downward saturated set) Let Γ be a sequence of formulas
of L+
mbC. By a downward saturated set (or Hintikka set) corresponding to
a sequence Γ we mean a set UΓ, which fulfils the following conditions: 493 An Abductive Question-Answer System... (iii) if β ∈UΓ, then β1 ∈UΓ or β2 ∈UΓ, (iii) if β ∈UΓ, then β1 ∈UΓ or β2 ∈UΓ, (iv) if ¬¬A ∈UΓ, then A ∈UΓ, (iv) if ¬¬A ∈UΓ, then A ∈UΓ, (iv) if ¬¬A ∈UΓ, then A ∈UΓ, (v) if ∼A ∈UΓ, then ¬A ∈UΓ or χ∼A ∈UΓ, (vi) if ¬ ∼A ∈UΓ, then A ∈UΓ and ¬χ∼A ∈UΓ, (vii) if ◦A ∈UΓ, then (¬A ∈UΓ and χ◦A ∈UΓ) or (¬ ∼A ∈UΓ and
χ◦A ∈UΓ), (vii) if ◦A ∈UΓ, then (¬A ∈UΓ and χ◦A ∈UΓ) or (¬ ∼A ∈UΓ and
χ◦A ∈UΓ), (viii) if ¬ ◦A ∈UΓ, then (A ∈UΓ and ∼A ∈UΓ) or ¬χ◦A ∈UΓ, (viii) if ¬ ◦A ∈UΓ, then (A ∈UΓ and ∼A ∈UΓ) or ¬χ◦A ∈UΓ, (ix) nothing more belongs to UΓ except those formulas which enter UΓ on
the grounds of conditions (i)–(viii). (ix) nothing more belongs to UΓ except those formulas which enter UΓ on
the grounds of conditions (i)–(viii). A Hintikka set UΓ is satisfied under extended mbC-valuation λ# (or is
consistent) iffeach element of UΓ is true under v. Table 4. Examples of abductive rules By a dual downward saturated set (or dual Hintikka set)
corresponding to a sequence Δ we mean a set WΔ, which fulfils the following
conditions: (i) if A is a term of Δ, then A ∈WΔ,
(ii) if α ∈WΔ, then α1 ∈WΔ or α2 ∈WΔ,
(iii) if β ∈WΔ, then β1 ∈WΔ and β2 ∈WΔ,
(iv) if ¬¬A ∈WΔ, then A ∈WΔ,
(v) if ∼A ∈WΔ, then ¬A ∈WΔ and χ∼A ∈WΔ,
(vi) if ¬ ∼A ∈WΔ, then A ∈WΔ or ¬χ∼A ∈WΔ,
(vii) if ◦A ∈WΔ, then χ◦A ∈WΔ or (¬A ∈WΔ and ¬∼A ∈WΔ),
(viii) if ¬◦A ∈WΔ, then (A ∈WΔ and ¬χ◦A ∈WΔ) or (∼A ∈WΔ and
¬χ◦A ∈WΔ), (i) if A is a term of Δ, then A ∈WΔ, (iii) if β ∈WΔ, then β1 ∈WΔ and β2 ∈WΔ, (iv) if ¬¬A ∈WΔ, then A ∈WΔ, (v) if ∼A ∈WΔ, then ¬A ∈WΔ and χ∼A ∈WΔ,
(vi) if ¬ ∼A ∈WΔ, then A ∈WΔ or ¬χ∼A ∈WΔ, ( )
,
χ
,
(vi) if ¬ ∼A ∈WΔ, then A ∈WΔ or ¬χ∼A ∈WΔ, (viii) if ¬◦A ∈WΔ, then (A ∈WΔ and ¬χ◦A ∈WΔ) or (∼A ∈WΔ and
¬χ◦A ∈WΔ), (ix) nothing more belongs to WΔ except those formulas which enter WΔ
on the grounds of conditions (i)–(viii). A dual Hintikka set WΔ is d-satisfied under extended mbC-valuation λ#
iffat least one element of WΔ is true under λ#. A dual Hintikka set WΔ is
d-satisfied by each extended mbC-valuation (WΔ is d-valid) iffthere is no
extended mbC-valuation λ# such that each formula in WΔ is false under
λ#. If WΔ = ∅, then WΔ is d-inconsistent. Corollary 4.3. A dual Hintikka set WΔ is d-satisfied by each extended
mbC-valuation (WΔ is d-valid) ifffor some unanalyzable formula A, A ∈
WΔ and ¬A ∈WΔ. Corollary 4.3. A dual Hintikka set WΔ is d-satisfied by each extended
mbC-valuation (WΔ is d-valid) ifffor some unanalyzable formula A, A ∈
WΔ and ¬A ∈WΔ. Definition 18. (Non-validity property) By a non-validity property corre
sponding to a sequence Δ we mean a finite set Wnv
Δ = {W1
Δ, . . . , Wn
Δ}, which
contains all dual Hintikka sets for Δ that do not contain complementary
unanalyzable formulas. Definition 18. (Non-validity property) By a non-validity property corre
sponding to a sequence Δ we mean a finite set Wnv
Δ = {W1
Δ, . . . Table 4. Examples of abductive rules A Hintikka set UΓ is
inconsistent ifffor every λ#, at least one formula in UΓ is false under λ#. If
UΓ = ∅, then UΓ is satisfied by each extended mbC-valuation (UΓ is valid). Definition 16. (Consistency property) By a consistency property corre-
sponding to a sequence Γ we mean a finite set Uc
Γ = {U1
Γ, . . . , Un
Γ}, which
contains all Hintikka sets for Γ that does not contain complementary unan-
alyzable formulas. Let us recall Hintikka’s well-known result: Lemma 4. (Hintikka’s Lemma) For arbitrary Γ, each set belonging to the
consistency property of Γ is satisfiable. Lemma 4. (Hintikka’s Lemma) For arbitrary Γ, each set belonging to the
consistency property of Γ is satisfiable. The idea in the proof is to construct a valuation which sends each unan-
alyzable formula to 1. The next step is to show by induction that it can be
extended to satisfy all formulas from Γ. For a detailed proof see for example
[11]. Corollary 4.2. A Hintikka set UΓ is inconsistent ifffor some unanalyz-
able formula A, A ∈UΓ and ¬A ∈UΓ. Corollary 4.2. A Hintikka set UΓ is inconsistent ifffor some unanalyz-
able formula A, A ∈UΓ and ¬A ∈UΓ. Corollary 4.2. A Hintikka set UΓ is inconsistent ifffor some unanalyz-
able formula A, A ∈UΓ and ¬A ∈UΓ. Lemma 5. If a non-empty sequence of formulas Γ is satisfiable, then at least
one downward saturated set corresponding to Γ belongs to consistency prop-
erty of Γ. Lemma 5. If a non-empty sequence of formulas Γ is satisfiable, then at least
one downward saturated set corresponding to Γ belongs to consistency prop-
erty of Γ. Proof. Assume no downward saturated set corresponding to Γ belongs
to consistency property of Γ. Thus all such sets contain complementary
unanalyzable formulas. Due to the fact that the construction of downward
saturated sets reflects mbC-valuation, Γ cannot be satisfiable. 494 S. Chlebowski et al. The notion of downward saturated set can be dualized in order to tackle
the problem of significance restriction. Detailed study of such sets in the
context of First-Order Logic can be found in [7]. Definition 17. (Dual downward saturated set) Let Δ be a sequence of
formulas of L+
mbC. 5Addition of the negation simulates the transfer of the formula from the antecedent
to the consequent of a sequent. Abductive hypotheses are always added to the knowledge
base, which is situated in the antecedent of a sequent. Table 4. Examples of abductive rules , Wn
Δ}, which
contains all dual Hintikka sets for Δ that do not contain complementary
unanalyzable formulas. Lemma 6. (Dual Hintikka’s Lemma) For an arbitrary Δ, each set belonging
to the non-validity property of Δ is not d-valid. Lemma 6. (Dual Hintikka’s Lemma) For an arbitrary Δ, each set belonging
to the non-validity property of Δ is not d-valid. The idea of the proof of dual Hintikka’s lemma is analogous to that of
Hintikka’s lemma. But now we want to construct a valuation which sends An Abductive Question-Answer System... 495 each unanalyzable formula to 0. Then we can easily extend such valuation
to falsify all formulas from Δ. each unanalyzable formula to 0. Then we can easily extend such valuation
to falsify all formulas from Δ. Table 5 contains constraints to rules from Table 4. The intuitions under-
lying those constraints are the following: in cases when we want to generate
abductive hypothesis that is consistent with the knowledge base Γ, we look
for those formulas, that are consistent with at least one Hintikka set. In
other words, we can say that we are looking for a formula that is true under
some mbC-valuation λ#, under which all formulas from Γ are also true. Constraints for significance of the abductive hypothesis reflect similar
notions. We are looking for those hypotheses that do not make at least one
Hinntika set d-valid. In other words, when we extend such dual Hintikka
set by the negation of a formula which is our hypothesis,5 and turn such
extended dual Hintikka set into a formula by linking all elements from this
set by disjunctions, we do not want to obtain a formula which is true under
every mbC-valuation λ#. Lemma 7. Let UΓ ∈Uc
Γ be a downward saturated set corresponding to some
Γ. If an unanalyzable formula l /∈UΓ, then the set UΓ ∪{l} is consistent. Lemma 7. Let UΓ ∈Uc
Γ be a downward saturated set corresponding to some
Γ. If an unanalyzable formula l /∈UΓ, then the set UΓ ∪{l} is consistent. Proof. UΓ is consistent by definition of the consistency property. Let us
assume that l /∈UΓ. If UΓ ∪{l} is inconsistent then l ∈UΓ ∪{l}, which
contradicts the assumption. Proof. UΓ is consistent by definition of the consistency property. Let us
assume that l /∈UΓ. If UΓ ∪{l} is inconsistent then l ∈UΓ ∪{l}, which
contradicts the assumption. Proof. Table 4. Examples of abductive rules The proof follows from Theorems 4.5 and 4.4. Table 4. Examples of abductive rules UΓ is consistent by definition of the consistency property. Let us
assume that l /∈UΓ. If UΓ ∪{l} is inconsistent then l ∈UΓ ∪{l}, which
contradicts the assumption. Lemma 8. Let UΓ ∈Uc
Γ be a downward saturated set corresponding to some
Γ. If l /∈UΓ or k /∈UΓ, then the set UΓ ∪{l →k} is consistent. Proof. The proof is analogous to the proof of Lemma 7. Now we are going to prove that abductive hypotheses generated by ab-
ductive rules used in accordance with the constraints are consistent with
the initial knowledge base and significant. For that reason we introduce an
algorithm 1 (see page 24) which creates s-transformation, consistency and
significance properties for an initial question Q =?(Γ ⊢Δ), and then uses
abductive rules along with restrictions to produce abductive hypotheses. Theorem 4.4. Each abductive hypothesis generated by Algorithm 1, where
each abductive rule is applied with a consistency constraint is consistent with
the initial knowledge base. Proof. The proof follows from Lemmas 7 and 8 and from the construction
f Uc+ Proof. The proof follows from Lemmas 7 and 8 and from the construction
of Uc+
Γ . 496 S. Chlebowski et al. Table 5. Consistency and significance restrictions for abductive rules
Abductive rule
Consistency restriction:
Significance restriction:
There exists a set UΓ ∈Uc
Γ such that. . . There exists a set WΔ ∈Wnv
Δ such that. . . R1
abd
l /∈UΓ
l /∈WΔ
R2
abd
l /∈UΓ or k /∈UΓ
l /∈WΔ or k /∈WΔ
R3
abd (R3∗
abd)
◦p /∈UΓ or ∼p /∈UΓ
p /∈WΔ
R4
abd (R4∗
abd)
◦p /∈UΓ or p /∈UΓ
∼p /∈WΔ
R5
abd (R5∗
abd)
p /∈UΓ or ∼p /∈UΓ
◦p /∈WΔ 497 An Abductive Question-Answer System... Lemma 9. Let WΔ ∈Wnv
Δ be a dual downward saturated set corresponding
to some Δ. If an unanalyzable formula l /∈WΔ, then the set WΔ ∪{l} is
not valid. Proof. We know that WΔ is not valid, i.e. there exists an extended mbC-
valuation λ# such that each formula in WΔ is false under λ#. Since l /∈WΔ
we can assume that λ#(l) = 0. It follows that WΔ is not valid. Lemma 10. Let WΔ ∈Wnv
Δ be a dual downward saturated set corresponding
to some Δ. If l /∈WΔ or k /∈WΔ, then the set WΔ ∪{l} is not valid or
WΔ ∪{k} is not valid. Proof. Table 4. Examples of abductive rules The proof is analogous to the proof of Lemma 9. Lemma 11 l ⊬
bC A1 ∨
∨A
(where each Ai (1 ≤i ≤n) is a literal) if Proof. The proof is analogous to the proof of Lemma 9. Lemma 11. l ⊬mbC A1 ∨. . . ∨An (where each Ai (1 ≤i ≤n) is a literal) if
and only if a dual Hintikka set W = {l, A1, . . . , An} is not valid. Proof. (→) Assume that l ⊬mbC A1 ∨. . . ∨An. There exists an extended
mbC-valuation λ# such that λ#(l) = 1 and λ#(A1 ∨. . . ∨An) = 0. In this
case λ#(l) = 0 and each formula in W is false under λ#. Therefore W is not
valid. (←) Assume W is not valid. There exists an extended mbC-valuation λ#,
such that each formula in W is false under λ#. In this case λ#(l) = 1 and
λ#(A1 ∨. . . ∨An) = 0. Therefore l ⊬mbC A1 ∨. . . ∨An. Lemma 12. l →k ⊬mbC A1 ∨. . . ∨An (where each Ai (1 ≤i ≤n) is a
literal) if and only if a dual Hintikka set W = {l, A1, . . . , An} is not valid
or W = {k, A1, . . . , An} is not valid. Proof. The proof is analogous to the proof of Lemma 11. Theorem 4.5. Each abductive hypothesis generated by Algorithm 1, where
each abductive rule is applied with a significance constraint, is significant. Proof. The proof is a consequence of Lemmas 9 and 10 and the construc-
tion of Wnv+
Γ
. Proof. The proof is a consequence of Lemmas 9 and 10 and the construc-
tion of Wnv+
Γ
. Proof. The proof is a consequence of Lemmas 9 and 10 and the construc-
tion of Wnv+
Γ
. Theorem 4.6. Each abductive hypothesis generated by Algorithm 1, where
each abductive rule is applied with a significance and consistency constraint
is significant and consistent. Theorem 4.6. Each abductive hypothesis generated by Algorithm 1, where
each abductive rule is applied with a significance and consistency constraint
is significant and consistent. Theorem 4.6. Each abductive hypothesis generated by Algorithm 1, where
each abductive rule is applied with a significance and consistency constraint
is significant and consistent. Proof. The proof follows from Theorems 4.5 and 4.4. Proof. 5.
Examples We shall provide two examples in order to explain how the Algorithm 1
generates abductive hypotheses. At the end of the section some remarks
about the way the algorithm works have been provided. 498 S. Chlebowski et al. S. Chlebowski et al. S. Chlebowski et al. Example 1. Let us first consider an abductive question Q = ?(Γ ⊢Δ),
where: Example 1. Let us first consider an abductive question Q = ?(Γ ⊢Δ),
where: • Γ = ⟨p →(q →r), ¬(q →∼s)⟩, • Δ = ⟨z⟩. The complete s-transformation of Q assigned to s is the following: ?(p →(q →r),¬(q →∼s)⊢z)
?(q, ¬∼s, p →(q →r) ⊢z)
Lα
?(q, s, ¬χ∼s, p →(q →r) ⊢z) L¬∼
?(¬p, q, s, ¬χ∼s ⊢z ; q →r, q, s, ¬χ∼s ⊢z) Lβ
?(¬p, q, s, ¬χ∼s ⊢z ; ¬q, q, s, ¬χ∼s ⊢z ; r, q, s, ¬χ∼s ⊢z) Lβ Open sequents from the last term of s are assigned to Φ: Open sequents from the last term of s are assigned to Φ: • ⟨¬p, q, s, ¬χ∼s ⊢z⟩,
• ⟨r, q, s, ¬χ∼s ⊢z⟩. • ⟨¬p, q, s, ¬χ∼s ⊢z⟩, • ⟨r, q, s, ¬χ∼s ⊢z⟩. The number of elements in Φ: x = 2, therefore Θ = {1, 2}. The consistency
property Uc
Γ = {U1
Γ, U2
Γ, U3
Γ}, where: The number of elements in Φ: x = 2, therefore Θ = {1, 2}. The consist
1
2
3 U1
Γ = {p →(q →r), ¬(q →∼s), q, s, ¬χ∼s, ¬p, q →r, r},
U2
Γ = {p →(q →r), ¬(q →∼s), q, s, ¬χ∼s, ¬p},
U3
Γ = {p →(q →r), ¬(q →∼s), q, s, ¬χ∼s, q →r, r}. The non-validity property contains one set Wnv
Δ = {W1
Δ}, where: The non-validity property contains one set Wnv
Δ = {W1
Δ}, where: W1
Δ = {z}. Let us assume that we randomly get j = 1. In that case: φ = ⟨¬p, q, s, ¬χ∼s ⊢z⟩. Let us further assume that we randomly get r = 1, therefore R = R1
abd, and
our partial answer generated by means of the rule R is the following: a = p. In the next step we have to cross out from consistency property those Hin-
tikka sets that are inconsistent with a, i.e. sets U1
Γ and U2
Γ. 5.
Examples After this step
consistency property looks as follows: Uc
Γ = {U3
Γ}. 499 An Abductive Question-Answer System... Similarly, we leave only those dual Hintikka set in non-validity property that
are not d-valid with a. In this case nothing changes, because W1
Δ is not d-
valid with a. The set Ω is enlarged by partial hypothesis a = p and j = 1 is
removed from Θ, therefore Θ = {2}. Θ still contains one element, which is now assigned to j = 2. In this case: φ = ⟨r, q, s, ¬χ∼s ⊢z⟩. At this stage the algorithm can randomly assign r = 1 again. However,
there is no partial hypothesis that could be generated by means of R1
abd
in accordance with the consistency constraint for R1
abd. The reason is that
there is only one Hintikka set in the consistency property, which contains
complementary unanalyzable formulas of all formulas that belong to the
antecedent of the sequent φ. The algorithm cannot execute instructions in
the if loop and the value for r is again randomly assigned. Let us assume that r = 2 this time. R = R2
abd and the generated partial
answer can be a = q →z, since it is consistent with the U3
Γ and not d-valid
with W1
Δ. The set Ω is enlarged by a and j = 2 is removed from Θ, leaving
Θ = ∅as a result. Therefore, the condition for breaking the while loop is
fulfilled. The set Ω is transformed into the abductive hypothesis by linking
all partial answers contained in it with conjunction: Ω = p ∧(q →z). The addition of Ω to the Γ from initial abductive question Q results in
obtaining a question Q∗= ?(p ∧(q →z), p →(q →r), ¬(q →∼s) ⊢z),
which is no longer an abductive one. Example 2. Let us now consider an abductive question Q′ = ?(Γ′ ⊢Δ′),
where: • Γ′ = ⟨(p ∨r) →¬ ◦q⟩, • Δ′ = ⟨∼z⟩. 5.
Examples The complete s-transformation of Q′ assigned to s is the following: ?((p ∨r) →¬◦q ⊢∼z)
?((p ∨r) →¬◦q ⊢¬z, χ∼z) R∼
?(¬(p ∨r) ⊢¬z, χ∼z ; ¬◦q ⊢¬z, χ∼z) L→
?(¬p, ¬r ⊢¬z, χ∼z ; ¬◦q ⊢¬z, χ∼z)
L¬∨
?(¬p, ¬r ⊢¬z, χ∼z ; q, ∼q ⊢¬z, χ∼z ; ¬χ◦q ⊢¬z, χ∼z) L¬◦
?(¬p, ¬r ⊢¬z, χ∼z ; q, ¬q ⊢¬z, χ∼z ; q, χ∼q ⊢¬z, χ∼z ; ¬χ◦q ⊢¬z, χ∼z) L∼ Open sequents from the last term of s are assigned to Φ: S. Chlebowski et al. 500 • ⟨¬p, ¬r ⊢¬z, χ∼z⟩,
• ⟨q, χ∼q ⊢¬z, χ∼z⟩,
• ⟨¬χ◦q ⊢¬z, χ∼z⟩. • ⟨¬p, ¬r ⊢¬z, χ∼z⟩,
• ⟨q, χ∼q ⊢¬z, χ∼z⟩,
• ⟨¬χ◦q ⊢¬z, χ∼z⟩. The number of elements in Φ: x = 3, therefore Θ = {1, 2, 3}. The consistency
property Uc
Γ = {U1
Γ, U2
Γ, U3
Γ, U4
Γ, U5
Γ, U6
Γ}, where: The number of elements in Φ: x = 3, therefore Θ = {1, 2, 3}. The consistency
property Uc
Γ = {U1
Γ, U2
Γ, U3
Γ, U4
Γ, U5
Γ, U6
Γ}, where: U1
Γ = {(p ∨r) →¬◦q, ¬(p ∨q), ¬◦q, ¬p, ¬r, q, ∼q, ¬χ◦q, ¬q, χ∼q},
U2
Γ = {(p ∨r) →¬◦q, ¬(p ∨q), ¬◦q, ¬p, ¬r, q, ∼q, χ∼q},
U3
Γ = {(p ∨r) →¬◦q, ¬(p ∨q), ¬◦q, ¬p, ¬r, ¬χ◦q},
U4
Γ = {(p ∨r) →¬◦q, ¬(p ∨q), ¬p, ¬r},
U5
Γ = {(p ∨r) →¬◦q, ¬◦q, q, ∼q, χ∼q},
U6
Γ = {(p ∨r) →¬◦q, ¬◦q, ¬χ◦q}. The non-validity property contains one set Wnv
Δ = {W1
Δ}, where: The non-validity property contains one set Wnv
Δ = {W1
Δ}, where: W1
Δ = {∼z, ¬z, χ∼z}. Let us assume that we randomly get j = 1. In that case: φ = ⟨¬p, ¬r ⊢¬z, χ∼z⟩. Let us further assume that we randomly get r = 2, therefore R = R2
abd, and
our partial answer generated by means of the rule R is the following: a = ¬p →¬z. In the next step we have to cross out from consistency property those Hin-
tikka sets that do not fulfil the consistency restriction for R. After this step
consistency property contains the same Hintikka sets: Uc
Γ = {U1
Γ, U2
Γ, U3
Γ, U4
Γ, U5
Γ, U6
Γ}. 5.
Examples Similarly, we leave only those dual Hintikka set in non-validity property that
are not d-valid with a. In this case nothing changes, because W1
Δ is not d-
valid with a. The set Ω is enlarged by partial hypothesis a = p →¬z and
j = 1 is removed from Θ, therefore Θ = {2, 3}. Θ still contains elements. Let us assume that we randomly get j = 2. In
this case: φ = ⟨q, χ∼q ⊢¬z, χ∼z⟩. An Abductive Question-Answer System... 501 501 An Abductive Question-Answer System... An Abductive Question-Answer System... Let us assume that r = 5 this time. R = R5
abd and the generated partial
answer can be: a = ◦q. The following Hintikka sets do not fulfil the consistency restriction for R:
U1
Γ, U2
Γ, U5
Γ, therefore they are removed from the consistency property: Uc
Γ = {U3
Γ, U4
Γ, U6
Γ}. Uc
Γ = {U3
Γ, U4
Γ, U6
Γ}. Similarly as in the case of the previous partial hypothesis, a in not d-valid
with W1
Δ and the non-validity property does not change. Similarly as in the case of the previous partial hypothesis, a in not d-valid
with W1
Δ and the non-validity property does not change. The set Ω is enlarged by a and j = 2 is removed from Θ, leaving Θ = {3}
as a result. Therefore, in the next step j = 3 and: φ = ⟨¬χ◦q ⊢¬z, χ∼z⟩. There are only two abductive hypotheses which can generate a partial
hypothesis for φ, namely R1
abd and R2
abd. Assuming that r = 1 the partial
hypothesis we obtain is of the following form: a = χ◦q. Hintikka sets U3
Γ and U6
Γ do not fulfil the consistency restriction for R
and are removed from the consistency property: Uc
Γ = {U4
Γ}. Since there is a Hintikka set left in the consistency property and a is nod
d-valid with the W1
Δ set form the non-validity property, constructed partial
hypothesis is significant and valid. Θ = ∅and the while loop is broken. As in the previous example, the set Ω
is transformed into the abductive hypothesis by linking all partial answers
contained in it with conjunction: Ω = (¬p →¬z) ∧◦q ∧χ◦q. The question ?(Γ′ ∪Ω ⊢Δ′) is not an abductive one. The question ?(Γ′ ∪Ω ⊢Δ′) is not an abductive one. 5.
Examples Our algorithm exhibits some weaknesses that should be mentioned. First
of all, the algorithm is just a scheme used to depict how the abductive
procedure works, rather than optimised implementation of an abductive
hypotheses generator. Another point is that the algorithm will not terminate
in case when it is impossible to generate partial answer by means of the
proposed abductive rules used along with the constraints. There are at least
two possible situations of this kind: the abductive goal is inconsistent with 502 S. Chlebowski et al. S. Chlebowski et al. the knowledge base, or already generated partial answers make it impossible
to generate further partial answers. The algorithm is also not optimised for finding the shortest possible ab-
ductive hypotheses, nevertheless it is possible that it will find them. It is
easy to see that in some cases the algorithm will not recognise, that a partial
answer for one open sequent can be a partial answer for other open sequents. p
q
p
p
q
Algorithm 1: Generation of a consistent and valid abductive hypothesis
Input: An abductive question Q =?(Γ ⊢Δ) of L? ⊢mbC
Output: An answer Ω to an abductive question Q (abductive
hypothesis)
1 begin
2
s ←a complete s-transformation of Q;
3
Φ ←open sequents from the last term of s;
4
x ←the number of terms in Φ;
5
Θ ←{1, . . . , x};
6
Uc
Γ ←{U1
Γ, . . . , Un
Γ} the consistency property based on Γ;
7
Wnv
Δ ←{W1
Δ, . . . , Wm
Δ} the non-validity property based on Δ;
8
Ω ←∅;
9
while Θ non-empty do
10
j ←random element from Θ;
11
φ ←the j-th term of Φ;
12
r ←random element from the set {1, 2, 3, 4, 5};
13
R ←abductive rule Rr
abd (Rr∗
abd);
14
if R can be applied to φ with constraint for R then
15
a ←partial answer from R;
16
Uc
Γ ←Uc
Γ \ {Ui
Γ ∈{U1
Γ, . . . , Un
Γ} | Ui
Γ is not compatible under
the consistency constraint for R with a as a partial answer};
17
Wnv
Δ ←Wnv
Δ \ {Wi
Δ ∈{W1
Δ, . . . 5.
Examples , Wm
Δ} | Wi
Δ is not
compatible under the validity constraint for R with a as a
partial answer};
18
Ω ←Ω ∪{a};
19
Θ ←Θ \ {j};
20
end
21
end
22
Ω ← Ω;
23 end Algorithm 1: Generation of a consistent and valid abductive hypothesis
Input: An abductive question Q =?(Γ ⊢Δ) of L? ⊢mbC
Output: An answer Ω to an abductive question Q (abductive
hypothesis) Algorithm 1: Generation of a consistent and valid abductive hypothesis
Input: An abductive question Q =?(Γ ⊢Δ) of L? ⊢mbC
Output: An answer Ω to an abductive question Q (abductive
hypothesis) 1 begin
2
s ←a complete s-transformation of Q;
3
Φ ←open sequents from the last term of s;
4
x ←the number of terms in Φ;
5
Θ ←{1, . . . , x};
6
Uc
Γ ←{U1
Γ, . . . , Un
Γ} the consistency property based on Γ;
7
Wnv
Δ ←{W1
Δ, . . . , Wm
Δ} the non-validity property based on Δ;
8
Ω ←∅; p y
10
j ←random element from Θ;
11
φ ←the j-th term of Φ;
12
r ←random element from the set {1, 2, 3, 4, 5};
13
R ←abductive rule Rr
abd (Rr∗
abd);
14
if R can be applied to φ with constraint for R then
15
a ←partial answer from R;
16
Uc
Γ ←Uc
Γ \ {Ui
Γ ∈{U1
Γ, . . . , Un
Γ} | Ui
Γ is not compatible under
the consistency constraint for R with a as a partial answer};
17
Wnv
Δ ←Wnv
Δ \ {Wi
Δ ∈{W1
Δ, . . . , Wm
Δ} | Wi
Δ is not
compatible under the validity constraint for R with a as a
partial answer};
18
Ω ←Ω ∪{a};
19
Θ ←Θ \ {j};
20
end
21
end
22
Ω ← Ω;
23 end if R can be applied to φ with constraint for R then Ω ←Ω ∪{a};
Θ ←Θ \ {j}; 503 An Abductive Question-Answer System... 6.
Discussion In this section we want to compare our model of abductive reasoning with
two other approaches. 6.1.
Carnielli’s System There was an earlier attempt, made by Carnielli, to model abductive rea-
soning in the context of paraconsistent logic. We will briefly compare his
system to ours (for details, see [3]). As we have mentioned at the beginning of the paper, four ingredients of
algorithmic approach to abduction can be distinguished: a basic logic (which
gives us a formal language and a system of formulas considered valid), proof
method (a way, in which this logic is given), hypotheses generation mecha-
nism and criteria which rule out hypotheses which are not good enough. The
logic used by Carnielli is LFI1 system, which is an extension of mbC for which
a simple 3-valued semantics exists. As a proof method, signed version of an-
alytic tableaux is used. Passing to the last two ingredients, the situation
becomes more complicated: it seems to us that the procedure of generat-
ing hypotheses and hypotheses evaluation mechanism are interrelated. Such
properties of hypotheses as consistency (non-triviality in Carnielli system),
analyticity or minimality are forced by the very definition of what abduc-
tive problem and abductive solution are (see definition 5.1 in [3]). It is an
approach very different from ours: we try to be neutral in the definition of
hypotheses generation mechanism with respect to properties one may think
of as desirable. But we also deliver some simple implementation of most
frequently accepted properties such as consistency and significance, but we
let the users to decide, which properties they want to deploy. Another major
difference between these systems is the form of hypotheses, which can be
generated. In Carnielli’s system, hypotheses are collections of atoms. This
is determined by the proof method used. One of the consequences of this
approach is that disjunctive hypotheses are impossible to obtain (we will
say more on this, when discussing some specific examples). Another is that
only analytic hypotheses are accepted. Our approach is more general: we
stipulate in what way an abductive rule, which enables hypotheses gener-
ation, has to function and we provide two examples, one of them enabling
law-like hypotheses (see [25]). This approach is, in a way, open ended: new
abductive rules can be added, which enable more interesting hypotheses, in
particular non-analytic ones, which is impossible in Carnielli’s system. 504 S. Chlebowski et al. S. Chlebowski et al. S. Chlebowski et al. Fq There is no rule which can be applied to simplify our problem further. In Carnielli’s system two abductive hypothesis can be generated: Fp and
Tq. The first one is (classically) inconsistent with the knowledge base. The
second one is certainly too strong: from Tq follows that q is true, but that
is exactly what we were trying to explain. In AQAS we start with the aforementioned question ?(p ⊢q) 6.1.
Carnielli’s System Let us consider an eminently simple abductive problem: we want to obtain
q from the knowledge base consisting solely of p. In the context of AQAS
one can pose an abductive question ?(p ⊢q) In Carnielli’s system we start by constructing a tableaux, where we list all
formulas from the knowledge base (and we assign to each of them symbol
T) and an abductive goal (with F assigned) in the root of a tree. 6.2.
Abductive Logic Programming The next abductive procedure that we want to compare our approach with
is Abductive Logic Programming (ALP) (details of the method can be found
in [16]). The ALP framework consists of three ingredients: a logic program
P (knowledge base), a set of abducibles A (i.e. potential abductive hypothe-
ses) and a set of integrity constraints IC, where we can express constraints
regarding our knowledge that are additional to the logic program P. ALP is
aimed at modeling the syllogistic perspective on abductive reasoning [12]. Logic used in ALP is a part of the first order logic called logic pro-
gramming where only universally quantified implications are used. The an-
tecedent of the implication is a set of literals, and the consequent of the
implication is an atom. In ALP all variables are substituted in a conse-
quent manner by constants from a finite set, therefore we use propositional
examples for ALP. The proof method is the standard SLD-resolution with
backward reasoning in SLD-fashion. The mechanisms for the generation and
evaluation of abductive hypotheses are mixed together. One of the starting
ingredients of ALP is a set of abducibles A, which is assumed to be given at
the start. In [16] set A contains all atoms that occur in logic program P or
atoms that occur in logic program P but only those that do not appear in the
consequent of any implication. Abductive hypotheses are defined as subsets
of A set. Therefore, the latter method for A set generation impose the mini-
mality restriction for abductive hypotheses. In addition, the proof procedure
accompanied by the above mentioned method for the set of abducibles gen-
eration guarantees that obtained abductive hypotheses are consistent with
the initial knowledge base represented by the the logic program P and the
set of integrity constraints IC. Differences between the approach described in this paper and the ALP
occur in the foundations of both methods. In ALP abductive goals and
hypotheses are restricted only to literals, while we do not have such re-
striction regarding abductive goals in our procedure and generated abduc-
tive hypotheses include also law-like statements. Furthermore, we generate
abductive hypotheses, while in ALP framework abductive hypotheses are
picked from the set of abducibles given from the start. which cannot be further simplified. which cannot be further simplified. By means of question-answer rules we can formulate three hypotheses: ¬p
(where ¬ denotes classical negation), q and p →q. The first two hypotheses
do not meet consistency and significance restriction, but the third one does. This simple example shows that AQAS is able to generate good (in the
above case the only good) hypotheses which are not reachable for Carnielli’s
system. In the next example we will show that AQAS produces more good hy-
potheses than other considered systems. Our knowledge base consists of
p →q and q →r, and we want to derive r. The initial step is the transfor-
mation of an abductive question: ?(p →q, q →r ⊢r)
?(¬p, q →r ⊢r ; q, q →r ⊢r)
?(¬p, ¬q ⊢r ; ¬p, r ⊢r ; q, q →r ⊢r)
?(¬p, ¬q ⊢r ; ¬p, r ⊢r ; q, ¬q ⊢r ; q, r ⊢r) There is only one open constituent of the last question, namely the se-
quent ¬p, ¬q ⊢r and it can be closed in AQAS (with consistency and signif-
icance constraints) by any of the following formulas: p, q, ¬p →r, ¬q →r. In Carnielli’s system only p and q can be obtained due to the fact that ab-
ductive hypothesis is considered there as a conjunction of literals, thus more 505 An Abductive Question-Answer System... complicated formulas are not reachable, which can result in a system not
producing any hypothesis despite the fact that there is one, as the previous
example has shown. 6.2.
Abductive Logic Programming As a consequence, we
are able to produce abductive hypotheses for abductive goals that contain
information that do not belong to the initial knowledge base, contrary to 506 S. Chlebowski et al. the ALP approach. There are many implementations of Abductive Logic
Programming, e.g. in Prolog [22] or in a neuro-symbolic system [14]. the ALP approach. There are many implementations of Abductive Logic
Programming, e.g. in Prolog [22] or in a neuro-symbolic system [14]. Let us consider the same two examples as in the previous subsection. For the first abductive problem, where we have p as our knowledge base
and q as the abductive goal, our procedure is able to generate three abduc-
tive hypotheses, i.e. ¬p, q and p →q, with one meeting both, consistency
and significance restrictions. In this case the ALP procedure is not able to
produce any hypothesis. Let us consider the same two examples as in the previous subsection. In the second example we have the following formulas as the knowledge
base: p →q, q →r and as the abductive goal we have r. Our approach generates the following
four abductive hypotheses that are consistent and significant: p, q, ¬p →q,
¬q →r. For the ALP procedure we assume that P = {q ←p, r ←q} and
the set of integrity constraints IC is empty. According to the two ways of
selecting the set of abducibles we have the following: A = {p, q} or A′ = {p}. In the first case ALP produces the following three hypotheses: {p}, {q} and
{p, q}. In the second case we have only one abductive hypothesis {p}. and as the abductive goal we have r. Our approach generates the following
four abductive hypotheses that are consistent and significant: p, q, ¬p →q,
¬q →r. For the ALP procedure we assume that P = {q ←p, r ←q} and
the set of integrity constraints IC is empty. According to the two ways of
selecting the set of abducibles we have the following: A = {p, q} or A′ = {p}. In the first case ALP produces the following three hypotheses: {p}, {q} and
{p, q}. In the second case we have only one abductive hypothesis {p}. 7.
Summary and Conclusion Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations. 7.
Summary and Conclusion In this paper we have introduced an Abductive Question-Answer System
for the minimal logic of formal inconsistency mbC. The system produces
abductive hypotheses, which are answers to abductive questions concern-
ing derivability of formulas from sets of formulas. We integrated generation
and evaluation of hypotheses via constraints of consistency and significance
being imposed on the system rules. Our further research will be concerned
with optimization issues. We also plan for modular implementation of more
diverse set of evaluation criteria, which would allow for producing hypothe-
ses exhibiting different characteristics, depending on particular choice of
criteria. Additionally, we have compared our procedure with two alternative ap-
proaches. Generally speaking, abductive hypotheses in ALP and Carnielli’s
system are conjunction of literals, where in AQAS each hypothesis can be
considered as a conjunctive normal form, which can consists of nonempty
disjunctions (due to the interdefinability of implication and disjunction in
the presence of classical negation). In both cases the model of abductive 507 An Abductive Question-Answer System... reasoning proposed in this paper is more flexible with regards to assum-
ing abductive goals and creation of abductive hypotheses. In addition, our
system clearly distinguishes between the generation and evaluation of ab-
ductive hypotheses, while in both other approaches this division is not plain
and simple. Funding This work has been supported by the Polish National Science Cen-
ter, grant no. 2012/04/A/HS1/00715 (first author) and DEC-2013/10/E/
HS1/00172 (second and third author). Funding This work has been supported by the Polish National Science Cen-
ter, grant no. 2012/04/A/HS1/00715 (first author) and DEC-2013/10/E/
HS1/00172 (second and third author). Open Access. This article is licensed under a Creative Commons Attribution 4.0 Interna-
tional License, which permits use, sharing, adaptation, distribution and reproduction in
any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were
made. The images or other third party material in this article are included in the article’s
Creative Commons licence, unless indicated otherwise in a credit line to the material. If
material is not included in the article’s Creative Commons licence and your intended use
is not permitted by statutory regulation or exceeds the permitted use, you will need to
obtain permission directly from the copyright holder. To view a copy of this licence, visit
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symbolic systems, Topoi 26(1):37–49, 2007. [15] Hintikka, J., Inquiry as Inquiry: A Logic of Scientific Discovery, Kluwer, Dor-
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of logic and computation 2(6):719–770, 1992. [17] Komosinski, M., A. Kups, D. Leszczy´nska-Jasion, and M. Urba´nski, Identifying
efficient abductive hypotheses using multicriteria dominance relation, ACM Transac-
tions on Computational Logic 15(4):28:1–28:20, 2014. [18] Leszczy´nska-Jasion, D., The Method of Socratic Proofs for Normal Modal Proposi-
tional Logics, Adam Mickiewicz University Press, Pozna´n, 2007. References [19] Loparic, A., Semantical study of some propositional calculi, Journal of Symbolic
Logic 43:358, 1978. [20] Neto, A.G.S.S., and M. Finger, Effective prover for minimal inconsistency logic, in
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Press, 1974. [22] Saptawijaya, A., and L. M. Pereira, Tabdual: a tabled abduction system for logic
programs, FLAP 2(1):69–124, 2015. [23] Thagard, P., Abductive inference: From philosophical analysis to neural mechanisms,
in A. Feeney, and E. Heit, (eds.), Inductive reasoning: Experimental, developmental,
and computational approaches, Cambridge University Press, 2007, pp. 226–247. [24] Urba´nski, M., and A. Klawiter, Abduction: Some conceptual issues, Logic and
Logical Philosophy 27(4):583–597, 2018. [25] Urba´nski, M., and A. Wi´sniewski, On search for law-like statements as abductive
hypotheses by socratic transformations, in C. Baskent, (ed.), Perspectives on Inter-
rogative Models of Inquiry. Developments in Inquiry and Questions, Springer, 2016,
pp. 111–127. [26] Wi´sniewski, A., The Posing of Questions: Logical Foundations of Erotetic Inferences,
Kluwer Academic Publishers, Dordrecht/Boston/London, 1995. [27] Wi´sniewski, A., Socratic Proofs, Journal of Philosophical Logic 33(3):299–326, 2004. 509 An Abductive Question-Answer System... [28] Wi´sniewski, A., Questions, Inferences and Scenarios, vol. 46 of Studies in Logic. Logic and Cognitive Systems, College Publications, London, 2013. [28] Wi´sniewski, A., Questions, Inferences and Scenarios, vol. 46 of Studies in Logic. Logic and Cognitive Systems, College Publications, London, 2013. [28] Wi´sniewski, A., Questions, Inferences and Scenarios, vol. 46 of Studies in Logic. Logic and Cognitive Systems, College Publications, London, 2013. [29] Wi´sniewski, A., and V. Shangin, Socratic Proofs for Quantifiers, Journal of Philo-
sophical Logic 35(2):147–178, 2006. [29] Wi´sniewski, A., and V. Shangin, Socratic Proofs for Quantifiers, Journal of Philo-
sophical Logic 35(2):147–178, 2006. [29] Wi´sniewski, A., and V. Shangin, Socratic Proofs for Quantifiers, Journal of Philo-
sophical Logic 35(2):147–178, 2006. S. Chlebowski, A. Gajda, M. Urba´nski
Department of Psychology and Cognitive Science
Adam Mickiewicz University
Wieniawskiego 1
Pozna´n
Poland
szymon.chlebowski@amu.edu.pl
A. Gajda
andrzej.gajda@amu.edu.pl
M. Urba´nski
murbansk@amu.edu.pl S. Chlebowski, A. Gajda, M. Urba´nski
Department of Psychology and Cognitive Science
Adam Mickiewicz University
Wieniawskiego 1
Pozna´n
Poland
szymon.chlebowski@amu.edu.pl
A. Gajda
andrzej.gajda@amu.edu.pl
M. Urba´nski
murbansk@amu.edu.pl
|
https://openalex.org/W2949242417
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https://www.biorxiv.org/content/biorxiv/early/2018/10/01/432187.full.pdf
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English
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Crystal structure of a<i>Thermus aquaticus</i>diversity-generating retroelement variable protein
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bioRxiv preprint retroelement variable protein Sumit Handa, Kharissa L Shaw, Partho Ghosh* Sumit Handa, Kharissa L Shaw, Partho Ghosh* Department of Chemistry & Biochemistry, University of California San Diego, La
Jolla, CA 92093, USA *Correspondence: pghosh@ucsd.edu *Correspondence: pghosh@ucsd.edu Abstract Diversity-generating retroelements (DGRs) are widely distributed in bacteria,
archaea, and microbial viruses, and bring about unparalleled levels of sequence
variation in target proteins. While DGR variable proteins share low sequence
identity, the structures of several such proteins have revealed the C-type lectin
(CLec)-fold as a conserved scaffold for accommodating massive sequence
variation. This conservation has led to the suggestion that the CLec-fold may be
useful in molecular surface display applications. Thermostability is an attractive
feature in such applications, and thus we studied the variable protein of a DGR
encoded by the thermophile Thermus aquaticus. We report here the 2.8 Å
resolution crystal structure of the variable protein from the T. aquaticus DGR,
called TaqVP, and confirm that it has a CLec-fold. Remarkably, its variable
region is nearly identical in structure to those of several other CLec-fold DGR
variable proteins despite low sequence identity among these. TaqVP was found
to be thermostable, which appears to be a property shared by several CLec-fold
DGR variable proteins. These results provide impetus for the pursuit of the DGR
variable protein CLec-fold in molecular display applications. 1 . CC-BY 4.0 International license
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ioRxiv preprint Introduction Diversity generating-retroelements (DGRs) are unique and unparalleled
generators of massive protein sequence diversity [1, 2]. At least 1020 sequences
are possible in proteins diversified by these retroelements [3]. This scale of
variation exceeds by several orders of magnitude the variation brought about by 2 2 . CC-BY 4.0 International license
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bioRxiv preprint the adaptive immune systems of jawed and jawless vertebrates, the only other
examples of natural massive protein sequence variation [4, 5]. In these immune
systems, massive sequence variation of immunoreceptors permits the
recognition of novel ligands and is a robust means for adaptation to dynamic
environments. Similarly, massive sequence variation by DGRs appears to enable
adaptation to dynamic environments for the ecologically diverse microbes –
bacteria, archaea, and microbial viruses – that encode them. These include
constituents of the human microbiome [2, 3, 6-12] as well as of the microbial
‘dark matter’ which constitutes a major fraction of microbial life [13-17]. Three fundamental components define DGRs: a reverse transcriptase
(RT) that has a unique sequence motif [1, 2, 18], a variable region (VR) that
forms part of the coding sequence of a DGR diversified protein, and a template
region (TR) that is nearly identical to VR and is located proximally to VR (Fig 1). The TR serves as an invariant store of amino acid coding information. This
information is transferred from TR to VR, and during this process adenines within
TR are specifically mutated to other bases. A recent study on the prototypical
DGR of Bordetella bacteriophage indicates that the DGR RT in association with a
second DGR protein, the accessory variability determinant (Avd), is necessary
and sufficient for mutagenesis of adenines in TR [19]. Adenine-specific
mutagenesis culminates in substitutions occurring only at amino acids that have
adenines in their codons in TR. Introduction AAY is the most recurrent adenine-containing
codon in the TR of a variety of DGRs [2]. As previously noted, adenine-
mutagenesis of Asn-encoding AAY can result in the encoding of 14 other amino 3 . CC-BY 4.0 International license
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bioRxiv preprint acids, which cover the gamut of amino acid chemical character, but cannot result
in a stop codon [20]. acids, which cover the gamut of amino acid chemical character, but cannot result
in a stop codon [20]. DGR variable proteins are divergent in sequence (roughly 20% identity)
[2, 20]. To date, structures of three DGR variable proteins have been determined
— Bordetella bacteriophage Mtd [20, 21], Treponema denticola TvpA [3], and
Nanoarchaeota AvpA [22]. Despite the sequence divergence of these proteins,
they all share a C-type lectin (CLec)-fold, which appears to be an evolutionarily
conserved scaffold among DGRs for accommodating massive protein sequence
variation. The CLec-fold, despite its nomenclature, is a general ligand-binding
fold [23]. Variable amino acids in these CLec-fold DGR variable proteins are
solvent-exposed and form ligand-binding sites. Some DGR variable proteins,
including those that exist in the human virome [6], are predicted instead to have
an immunoglobulin (Ig)-fold as a scaffold for variation. The β-strand body of the
Ig-fold appears to be the locus for variation in these proteins, rather than loop
regions as in antibodies and T cell receptors. Yet other DGR variable proteins
have folds that at present cannot be assigned by sequence alone to CLec- or Ig-
folds, or to other protein folds [2]. DGR variable proteins with characterized CLec-folds have the potential to
add to the existing toolbox of selectable variable protein scaffolds for molecular
display purposes, which includes affibodies, fibronectin type III (FN3) domains,
and designed ankyrin repeat proteins (DARPins) among others [24, 25]. As
thermostability is an attractive property of selectable variable proteins, we
focused on a DGR of the thermophile Thermus aquaticus [2]. The T. aquaticus 4 . CC-BY 4.0 International license
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ioRxiv preprint DGR has a genetic structure similar to that of that of the Bordetella
bacteriophage DGR (Fig. 1). The variable protein of the T. aquaticus DGR, which
we call TaqVP, is predicted to have a CLec-fold [2]. acids, which cover the gamut of amino acid chemical character, but cannot result
in a stop codon [20]. While a common theme in
DGR variable proteins is surface-display [12], TaqVP appears to lack a surface-
targeting signal sequence, suggesting that sequence variation in the protein may
have an intracellular function instead. We determined the 2.8 Å resolution crystal
structure of TaqVP and confirmed that it indeed has a CLec-fold. We also
characterized the thermostability of TaqVP, along with those of the previously
structurally characterized DGR variable proteins Mtd and TvpA, and found that
thermostability was a shared property of several DGR CLec-fold proteins. Structure of TaqVP TaqVP was overexpressed in Escherichia coli, purified, and crystallized. Single-wavelength anomalous dispersion (SAD) data from selenomethionine-
labeled crystals of TaqVP were collected and used to determine the structure of
TaqVP. The structure was determined and refined to 2.81 Å resolution limit
(Table 1), and the entire length of TaqVP, amino acids 1-381, was modeled. TaqVP appeared by gel filtration chromatography to be monomeric in solution
and was observed to be monomeric in the crystal (Fig. 2a and 2b). The structure of TaqVP revealed a single globular CLec-fold domain that
strongly resembles the CLec-fold of two previously determined bacterial DGR
variable proteins (Fig. 2c and 2d). Specifically, TaqVP closely resembles TvpA 5 5 . CC-BY 4.0 International license
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ioRxiv preprint (2.5 Å rmsd; 109 Cα; Z = 6.0; 15.8% sequence identity) and Mtd (2.6 Å rmsd;
102 Cα; Z = 5.4, 20.9% sequence identity) [3, 20]. Like TvpA and Mtd, TaqVP
has the formylglycine-generating enzyme (FGE) subtype of the CLec-fold and,
like these other two proteins, shares structural homology with human FGE (3.2 Å
rmsd; 116 Cα; Z = 6.2; 22% sequence identity) [26]. TaqVP is more distantly
related to the CLec-fold of the archaeal DGR variable protein AvpA (3.3 Å rmsd;
114 Cα; Z = 3.7, 14% sequence identity), which does not belong to the FGE
subtype [22]. The FGE-type CLec domain of TaqVP begins at amino acid 112 and
extends to its C-terminal amino acid 381. Preceding amino acid 112 is a region
composed of short β-strands and α-helices that wraps around the N-terminus of
the CLec domain. The characteristic CLec-fold features, including the N- and C-
termini forming anti-parallel β-strands (β1 and β5) and two roughly perpendicular
α–helices (α1 and α2), are found in TaqVP. Structure of TaqVP The second classic feature of the
CLec fold in DGR variable proteins is a four-stranded, anti-parallel β-sheet (β2 β3
β4 β4’). In TaqVP the β4’ strand is replaced by a loop. The sequence between
the β3 and β5 strands forms the putative ligand-binding site. TaqVP also has
short segments inserted between the secondary elements of the CLec fold (Fig. 2e), as also seen in Mtd, TvpA, and AvpA. Variable Region The variable region of TaqVP (amino acids 341-381) is located at the very
C-terminus of the protein, as in Mtd and TvpA. The TaqVP VR is 40 amino acids 6 6 . CC-BY 4.0 International license
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ioRxiv preprint in length — between the 45-amino acid VRs of Mtd and TvpA and the 23-amino
acid VR of AvpA. As shown previously for all structurally characterized DGR
variable proteins, the nine variable amino acids in TaqVP are solvent exposed
and form a potential binding site (Fig. 3a and 3b). Variable hydrophobic and
hydrophilic amino acids are segregated from each other at this site (Fig. 3b). TaqVP has two nonvariable aromatic amino acids (W349 and W371) within the
binding site, which might provide a constant hydrophobic contact to ligands. Similarly, Mtd, TvpA, and AvpA have one or two nonvariable aromatic acids
within their ligand-binding sites. Remarkably, the TaqVP variable region and those of Mtd and TvpA are
nearly identical in structure, despite their weak sequence relationship (rmsd 0.46
Å, 26 Cα, p<0.001, 28.9% sequence identity; and rmsd 1.10 Å, 30 Cα, p<0.001,
23.1% sequence identity, respectively) (Figs. 3c and 3d). However, the TaqVP
variable region does not share significant structural similarity with the variable
region of the more distantly related AvpA (rmsd, 2.28 Å; 22 Cα; p>0.1) (Fig. 3e). The nine variable amino acids in TaqVP VR support a potential diversity through
adenine-mutagenesis of 3 x 109. Seven of the 9 variable amino acids are
encoded by AAY codons in TR (D348, V354, Y361, N364, S368, and R370 by
AAC and N351 by AAT), enabling substitution by 14 other amino acids at each of
these positions. The remaining two variable amino acids are encoded by an ATC
(I344) or AGT (to G372) codon, which enables substitution by three other amino
acids. Inserts TaqVP has three inserts within the core of the CLec-fold. Insert 1’ (amino
acids 129-217) is located between α1 and α2; an equivalent to insert 1’ occurs in
TvpA. Insert 1’ in TaqVP appears to stabilize the VR through hydrogen bonding
(Fig. 3f), whereas insert 1’ in TvpA interacts with helix α1 instead. Insert 2 of
TaqVP is between α2 and β2 (amino acids 222-296). An equivalent occurs in all
DGR variable proteins structurally characterized to date, but unlike these others,
insert 2 in TaqVP does not interact with the VR. Insert 3 (amino acids 301-331) is
between β2 and β3 of the CLec-domain and is composed of loops and a short α-
helix; an equivalent for insert 3 occurs in AvpA. Variable Region All nine of the TaqVP variable amino acids have structural equivalents in
TvpA, while eight of the nine have structural equivalents in Mtd (Figs. 3c and 3d). 7 7 . CC-BY 4.0 International license
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oRxiv preprint The structural similarity among these VRs suggests that a composite VR having
maximal diversity may be designed from these. The last seven amino acids (375-381) of TaqVP VR are invariant and
located along the β5-strand, as in Mtd and TvpA. The corresponding DNA
sequence is likely to function as the initiation of mutagenic homing (IMH)
element, a critical component of DGRs that along with the IMH* element in TR
defines the directionality of cDNA transfer [18] (Fig. 1). Thermal Stability The thermal stability of TaqVP was determined by monitoring its
secondary structure as a function of temperature by circular dichroism. We
observed that TaqVP started to unfold at ~70 °C and was completely denatured 8 . CC-BY 4.0 International license
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bioRxiv preprint at ~90 °C, as monitored by the loss of ellipticity (Fig. 4a). The thermal unfolding
of TaqVP was irreversible. AvpA has previously been studied for its thermal
stability and it was found that this protein also adopts a thermostable fold,
starting to unfold at ~65 °C and becoming completely denatured at ~80 °C [10]. We also determined the thermal stabilities of Mtd-P1 and TvpA. Bordetella
bacteriophage Mtd-P1, which unlike the other DGR variable proteins studied here
has multiple domains, was found to start irreversibly unfolding at ~70 °C and was
completely denatured at ~80 °C (Fig. 4b). TvpA began unfolding at ~50 °C and
was completely denatured at ~70 °C (Fig. 4c). For TvpA, the ellipticity became
more negative upon unfolding. This shift to more negative ellipticity upon
unfolding has been seen previously in the unfolding of dihydrofolate reductase
due to the involvement of W47 and W74 forming an exciton pair [27]. TvpA has a
structurally similar pairing of tryptophans (W138 and W263) that could form an
exciton pair. These results suggest that thermostability is shared by several of the
structurally characterized CLec-fold DGR variable proteins (i.e., Mtd, AvpA, and
TaqVP), and that any of these may provide an advantageous scaffold for
molecular display applications. TaqVP expression and purification The coding sequence of TaqVP (accession no. CP010822.1) was
synthesized with codons optimized for expression in Escherichia coli (GENEWIZ, 9 . CC-BY 4.0 International license
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oRxiv preprint Inc.) and cloned into a modified pET28b expression vector encoding an N-
terminal His-tag followed by a PreScission protease cleavage site. The integrity
of the construct was confirmed by DNA sequencing. TaqVP was expressed in E. coli BL21-Gold (DE3). Bacteria were grown with shaking at 37 °C to an OD600 of
0.6–0.8 and then cooled to room temperature, followed by induction with 0.5 mM
isopropyl β-D-1-thiogalactopyranoside. Bacteria were grown with shaking at room
temperature for 4 h further, then harvested by centrifugation (30 min, 5,000 x g, 4
°C); the bacterial pellet was frozen at -80 °C. Cells were thawed and resuspended in buffer A (250 mM NaCl, 50 mM
Tris, pH 8, and 5 mM β-mercaptoethanol; 20 ml/L of bacterial culture)
supplemented with 1 mM phenylmethylsulfonyl fluoride. Bacteria were lysed
using an Emulsiflex (Manufacturer), and the lysate was centrifuged (30 min,
35,000 x g, 4 °C). The supernatant was incubated at 55 °C for 10 min, and the
sample was centrifuged (30 min, 35,000 x g, 4 °C). The supernatant was then
applied to a column containing His-Select Nickel affinity gel (Sigma, 1 ml of resin
per 20 ml of bacterial lysate), which had been equilibrated with buffer A. The
column was washed with 10 column volumes of buffer B (250 mM NaCl, 20 mM
Tris, pH 8, and 5 mM β-mercaptoethanol) containing 20 mM imidazole, and the
TaqVP was eluted with buffer B containing 250 mM imidazole. The His-tag was
removed by PreScission protease cleavage (1:50 mass ratio TaqVP:protease)
overnight at 4 °C. Cleaved TaqVP was separated from the non-cleaved protein
by applying the sample to a His-Select Nickel affinity gel column (Sigma) and
collecting the flow-through. TaqVP expression and purification TaqVP was further purified by gel filtration 10 . CC-BY 4.0 International license
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bioRxiv preprint chromatography (Superdex 75) in 150 mM NaCl, 20 mM Tris, pH 8, and 1 mM
dithiothreitol. Crystallization and structure determination Selenomethionine (SeMet)-substituted TaqVP was expressed by culturing
E. coli in synthetic minimal media supplemented with 200 mg/L L(+)-
selenomethionine (Sigma) [28]. Purified SeMet-labeled TaqVP was concentrated
to 50 mg/mL by ultrafiltration (10 kDa MWCO Amicon, Millipore); the
concentration of TaqVP was determined using a calculated molar extinction
coefficient at 280 nm of 80,900M
-1cm
-1. Crystals of SeMet-labeled TaqVP were grown by the hanging drop method
at 20 °C by mixing 1 μL of TaqVP (50 mg/mL) and 1 μL of 15 % (w/v) 2-methyl-
2,4-pentanediol, 20 mM CaCl2, 100 mM sodium acetate, pH 4.6. Crystals were Structural alignment of VR and equivalent regions The structure of the VR of TaqVP (amino acids 341–374) was compared to
that of the VR of Mtd (amino acids 337–381), TvpA (amino acids 285–329), and
AvpA (amino acids 181–210) using FATCAT [37]. cryoprotected by soaking in the precipitant solution supplemented with 20% glycerol. Single-wavelength anomalous dispersion (SAD) data were collected at
Advanced Photon Source (Argonne, IL) beamline 24-ID-E. Diffraction data were
indexed, integrated, and scaled with MOSFLM [29-31]. Se sites were located
from SAD data of SeMet-labeled TaqVP, and initial phases were determined
using SOLVE [32]. All five methionines (M1, M24, M112, M227, and M320) were
located, and the asymmetric unit was found to contain four molecules of TaqVP. An initial model of TaqVP was built by automatic means using Autobuild
(within Phenix). A total of 75 iterative rounds of manual model building and
maximum likelihood refinement were carried out with Refine (within Phenix) using 11 . CC-BY 4.0 International license
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bioRxiv preprint default parameters, with each refinement step consisting of 3 cycles [33, 34]. Each refinement step included manual model rebuilding with COOT, guided by
σA-weighted 2mFo-DFc and mFo-DFc difference maps [35]. One round of TLS
parameterization with default settings was then used, followed by the addition of
water, calcium, and acetate ions into ≥3σ mFo-DFc density. Structure validation
was carried out with Molprobity [36], and molecular figures were generated with
PyMOL (http://www.pymol.org/). The crystal structure and structure factors have
been deposited to the Protein Data Bank (accession no. 5VF4). Figure 1. T. aquaticus DGR. The T. aquaticus DGR contains a gene encoding a variable protein (taqvp). The 3’
end of taqvp contains the variable region (VR) and initiation-of-mutagenic homing
(IMH) sequence. The DGR also contains an accessory variability determinant
(avd) gene, followed by an invariant template region (TR), which differs from VR
mainly at adenines. A sequence similar but not identical to the VR IMH occurs at
the 3’ end of the TR and is called IMH*. Following these elements is a gene
encoding a reverse transcriptase (rt). TR is transcribed to produce TR-RNA, which
is reverse transcribed to produce TR-cDNA, with adenine-specific mutagenesis of
the sequence accompanying reverse transcription. Adenine-mutagenized TR-
cDNA homes to and replaces VR to yield a variant TaqVP. CD Spectroscopy CD spectra of Taq VP, Mtd-P1, and TvpA were collected between 195 and
260 nm at 24 °C with 1-nm intervals, and temperature denaturation scan was
carried out between 25 °C and 110 °C at 216 nm with 1° intervals, using a quartz
cell with a 1-mm path length on a model 202 spectrometer (Aviv Instruments)
equipped with thermoelectric temperature control. Measurements were collected
for Taq VP, Mtd-P1, and TvpA samples at 0.4 mg/mL, 0.3 mg/mL and 0.3
mg/mL, respectively. Protein samples were in 40 mM NaF, 10 mM NaPi buffer, 12 12 . CC-BY 4.0 International license
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bioRxiv preprint pH 7.5. The CD signal from buffer alone was subtracted from the data before
conversion to mean residue ellipticity. pH 7.5. The CD signal from buffer alone was subtracted from the data before
conversion to mean residue ellipticity. c. The core elements of the CLec-fold in TaqVP in ribbon representation (α-
helices red, β-strands and loops blue). The inserts are ghosted. c. The core elements of the CLec-fold in TaqVP in ribbon representation (α-
helices red, β-strands and loops blue). The inserts are ghosted. d. Topology diagram of the CLec-fold in TaqVP. e. Inserts of TaqVP in ribbon representation, with core elements of the CLec-fold
are ghosted (color coding same as in panel b). Figure 2. Structure of TaqVP. a. TaqVP in ribbon representation (α-helices gold, β-strands blue, loops grey, and
VR purple). The amino acid positions of the N- and C-termini of TaqVP are
indicated. b. TaqVP in ribbon representation with the core elements of the CLec-fold in red
(α-helices) and blue (β-strands). Insert 1’, amino acids 129-217, is magenta;
insert 2, amino acids 222-296, green; insert 3, amino acids 301-331, teal. 13 13 . CC-BY 4.0 International license
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ioRxiv preprint Figure 3. Variable region of TaqVP. a. VR of TaqVP in ribbon representation. The main chain is in gray, side chains
of variable amino acids are in green (sphere is glycine), and nonvariable
aromatic amino acids are in orange. b. Surface representation of TaqVP, with the VR facing the viewer. Variable
hydrophobic amino acids (I, V, and Y) are green, variable hydrophilic amino acids
(S, N, D, and R) blue, and variable glycine pale orange. c. Superposition of the VR of TaqVP (red) and Mtd-P1 (orange) in Cα
representation. The spheres represent the position of variable amino acids in
each protein. c. Superposition of the VR of TaqVP (red) and Mtd-P1 (orange) in Cα
representation. The spheres represent the position of variable amino acids in
each protein. d. Superposition of the VR of TaqVP (red) and TvpA (blue) in Cα representation. e. Superposition of the VR of TaqVP (red) and AvpA (magenta) in Cα
representation. f. Stabilization of the main chain of VR (gray, Cα of variable amino acids
indicated by spheres) by insert 1’ (magenta) in Cα representation. Dashed line
indicates hydrogen bonds. 14 . CC-BY 4.0 International license
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ioRxiv preprint Figure 4. Thermal stability of DGR variable proteins. Circular dichroism signal (mean residue ellipticity, MRE) at 216 nm for the
transition from 25 to 110 °C (green), and transition from 110 to 25 °C (blue) for
TaqVP (a), Mtd-P1 (b), and TvpA (c). Standard deviations from three separate
experiments are shown. aHighest resolution bin in parentheses here and other rows. 15 . CC-BY 4.0 International license
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oRxiv preprint Table 1. Data collection, phasing and refinement statistics
Data collection
Space group
P 32 2 1
Cell dimensions
a, b, c (Å)
155
155
202
α, β, γ(°)
90, 90, 120
Wavelength
0.979 Å
Resolution (Å)
134.27-2.81 (3.29-2.81)a
Rmerge
0.18 (1.00)
I / σI
12.5 (1.6)
Completeness (%)
100 (100)
Redundancy
7.4 (6.9)
cc1/2
0.98 (0.60)
Refinement
Resolution (Å)
80.81-2.81 (3.29-2.81)
No. reflections
132403 (12794)
Rwork / Rfree
0.18 (0.31)/0.23 (0.33)
No. atoms
Se
18
Ca
8
S
O
N
C
H
4
2384
2032
7223
90
Average B-factors
60.1
R.m.s deviations
Bond lengths (Å)
0.009
Bond angles (°)
1.22
MolProbity score
2.1 [98th]b
Ramachandran
% preferred
93.7
% allowed
5.8
% disallowed
0.5
Clashscore
7.6 [99th]b
aHighest resolution bin in parentheses here and other rows. bPercentile in brackets here and other rows. Table 1. Data collection, phasing and refinement statistics
Data collection
Space group
P 32 2 1
Cell dimensions
a, b, c (Å)
155
155
202
α, β, γ(°)
90, 90, 120
Wavelength
0.979 Å
Resolution (Å)
134.27-2.81 (3.29-2.81)a
Rmerge
0.18 (1.00)
I / σI
12.5 (1.6)
Completeness (%)
100 (100)
Redundancy
7.4 (6.9)
cc1/2
0.98 (0.60)
Refinement
Resolution (Å)
80.81-2.81 (3.29-2.81)
No. reflections
132403 (12794)
Rwork / Rfree
0.18 (0.31)/0.23 (0.33)
No. g
p
bPercentile in brackets here and other rows. 15 atoms
Se
18
Ca
8
S
O
N
C
H
4
2384
2032
7223
90
Average B-factors
60.1
R.m.s deviations
Bond lengths (Å)
0.009
Bond angles (°)
1.22
MolProbity score
2.1 [98th]b
Ramachandran
% preferred
93.7
% allowed
5.8
% disallowed
0.5
Clashscore
7.6 [99th]b
aHighest resolution bin in parentheses here and other rows. bPercentile in brackets here and other rows. Table 1. Data collection, phasing and refinement statistics 16 . CC-BY 4.0 International license
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|
https://openalex.org/W3098814405
|
https://ri.conicet.gov.ar/bitstream/11336/93840/2/CONICET_Digital_Nro.9571c940-ea48-4dec-b2e8-2ff0a635b864_A.pdf
|
English
| null |
Nonequilibrium critical behavior of magnetic thin films grown in a temperature gradient
|
Journal of statistical mechanics
| 2,012
|
cc-by
| 10,692
|
Abstract We investigate the irreversible growth of (2 + 1)−dimensional magnetic
thin films under the influence of a transverse temperature gradient, which is
maintained by thermal baths across a direction perpendicular to the direction
of growth. Therefore, different longitudinal layers grow at different temper-
atures between T1 and T2, where T1 < T hom
c
< T2 and T hom
c
= 0.69(1) is
the critical temperature of films grown in homogeneous thermal baths. We
find a far-from-equilibrium continuous order-disorder phase transition driven
by the thermal bath gradient. We characterize this gradient-induced critical
behavior by means of standard finite-size scaling procedures, which lead to
the critical temperature Tc = 0.84(2) and a new universality class consistent
with the set of critical exponents ν = 3/2, γ = 5/2, and β = 1/4. In order to
gain further insight into the effects of the temperature gradient, we also de-
velop a bond model that captures the magnetic film’s growth dynamics. Our
findings show that the interplay of geometry and thermal bath asymmetries
leads to growth bond flux asymmetries and the onset of transverse ordering
effects that explain qualitatively the shift observed in the critical tempera-
ture. The relevance of these mechanisms is further confirmed by a finite-size
scaling analysis of the interface width, which shows that the growing sites of
the system define a self-affine interface. Nonequilibrium critical behavior of magnetic thin
films grown in a temperature gradient Juli´an Candia1 and Ezequiel V. Albano1,2
1 - Instituto de F´ısica de L´ıquidos y Sistemas Biol´ogicos,
(CONICET, UNLP), 59 Nro 789, 1900 La Plata, Argentina
2 - Departamento de F´ısica (UNLP), La Plata, Argentina Juli´an Candia1 and Ezequiel V. Albano1,2
1 - Instituto de F´ısica de L´ıquidos y Sistemas Biol´ogicos,
(CONICET, UNLP), 59 Nro 789, 1900 La Plata, Argentina
2 - Departamento de F´ısica (UNLP), La Plata, Argentina July 10, 2012 1
Introduction The importance of thin film technology has been widely recognized in the realms
of experimental and applied science, from the manufacture of electronics (layers 1 of insulators, semiconductors, and conductors from integrated circuits) to optics
(reflective and anti-reflective coatings, self-cleaning glasses, etc) and packaging (e.g. aluminium-coated PET films). Indeed, the increasing role of thin films in basic and
applied research relies on the development and refinement of nanoscale deposition
techniques such as sputtering and molecular beam epitaxy, which allow a single layer
of atoms to be deposited at a time [1, 2, 3, 4]. Since the growth temperature is one of the critical parameters in the formation
of ordered thin films, several experiments have focused on the influence of a tem-
perature gradient during film growth. In an early experiment by Tanaka et al. [5],
magnetic Tb-Fe films were grown between two substrates with a temperature gra-
dient, reporting the observation of perpendicular magnetic anisotropies and other
gradient-driven structural features. More recently, Schwickert et al. [6] introduced
the “temperature wedge method” where a calibrated temperature gradient of sev-
eral hundred Kelvin was established across the substrate during co-deposition of Fe
and Pt on MgO(001) and MgO(110) substrates. These experiments generated the
L10 ordered phase of FePt, which is currently the leading candidate material for
ultrahigh density heat assisted magnetic recording (HAMR) and bit patterned mag-
netic recording (BPMR) media ([7, 8] and references therein). Other experiments
by Yongxiong et al. [9] have investigated the evolution of Fe oxide nanostructures on
GaAs(100) by using a multi-technique experimental setup that included transmission
and reflection high energy electron diffraction and scanning electron microscopy. In
these studies, nanoscale epitaxial Fe films were grown, oxidized, and annealed using
a gradient temperature method, which led to nanostripes with uniaxial magnetic
anisotropy. As a result of the experimental advances on this field, many techno-
logical applications have been envisioned as well. For instance, magneto-optical
recording studies of signal reproduction [10] have suggested that recording media
having multiple magnetic layers in a transverse temperature gradient may suppress
magnetic noise from tracks adjacent to the target track during information storage
and reproduction [11]. From a theoretical perspective, gradients have been studied extensively in the
context of diffusion processes and later extended to thermal conductivity and heat
conduction problems. 1
Introduction The so-called gradient percolation method was originally in-
troduced to study percolation transition models where the density is the control
parameter [12] and later applied to a variety of problems, such as fractal diffu-
sion fronts [13, 14, 15], overlapping disks in a concentration gradient [16], bond
percolation for the Kagom´e lattice [17], invasion percolation under gravity [18],
porous media [19], as well as in the study of vegetation distribution [20]. Very re-
cently, the gradient method has been extended as a powerful tool to study first- and
second-order irreversible phase transitions in far-from-equilibrium systems such as
the Ziff-Gulari-Barshad model and forest-fire cellular automata [21, 22]. In magnetic
systems, damage spreading processes in a temperature gradient [23] and studies of 2 several one-dimensional models [24, 25, 26, 27] have been followed by the inves-
tigation of the kinetic Ising model in two dimensions under a variety of dynam-
ics [28, 29, 30, 31, 32]. Within the broad context of these recent experimental and theoretical investiga-
tions, the aim of this paper is to study the irreversible growth of magnetic thin films
in a temperature gradient and to provide a full characterization of the gradient-
induced critical phase transition. The magnetic thin film growth process under
far-from-equilibrium conditions is investigated by using the so-called magnetic Eden
model (MEM) [33, 34, 35], an extension of the classical Eden model [36] in which
particles have a two-state spin as an additional degree of freedom. Earlier studies
have shown that, growing in (d + 1)-dimensional strip geometries in homogeneous
thermal baths, MEM films are noncritical for d = 1 [34]. In contrast, for d = 2 they
undergo an order-disorder phase transition that takes place at T hom
c
= 0.69(1) in the
thermodynamic limit. The critical exponents are νhom = 1.04(16), γhom = 2.10(36),
and βhom = 0.16(5), which intriguingly agree within error bars with the exact expo-
nents for the kinetic Ising model [34]. Since the MEM growth process is irreversible
and newly deposited particles are not allowed to flip and thermalize once they are
added to the growing cluster, the observed correspondence between the MEM and
the equilibrium Ising model remains puzzling. In this work, we focus on the critical case (i.e. 1
Introduction d = 2) and show that, when
applying a transverse temperature gradient maintained by thermal baths between
temperatures T1 and T2, where T1 < T hom
c
< T2, the system undergoes a continuous
phase transition at a higher critical temperature (Tc > T hom
c
) and with different
critical exponents. We also develop a growth bond model and show the existence of
bond flux asymmetries caused by the interplay of geometry and thermal bath asym-
metries, which shed some light on the growth dynamics and explain qualitatively
the shift observed in the critical temperature. The growth bond model analysis is
further supported by the fact that the growing interface is self-affine, thus ensuring
that the growing sites are correlated at all size scales. The rest of the paper is laid out as follows. In Section 2, we introduce the
model and describe the Monte Carlo algorithm used to simulate MEM thin films
in a temperature gradient. In Section 3, we present our results and a discussion. Finally, Section 4 consists of concluding remarks. 2
The Model and the Monte Carlo Simulation
Method The MEM in (2 + 1)−dimensions is studied in the square lattice by using a rectan-
gular geometry Lx × Ly × Lz, where Lz ≫Lx = Ly ≡L is the growth direction. The location of each spin on the lattice is specified through its coordinates (x, y, z) 3 (1 ≤x, y ≤L, 1 ≤z ≤Lz). The starting seed for the growing cluster is a plane of
L×L parallel-oriented spins placed at z = 1 and cluster growth takes place along the
positive longitudinal direction (i.e., z ≥2). Across one of the transverse directions
(the y−axis), a temperature gradient is applied by thermal baths at fixed tempera-
tures linearly varying between T1 and T2. Therefore, in our setup each layer at fixed y
is subjected to a constant temperature T(y) = T1+(T2−T1)(y−1)/(L−1) maintained
by a thermal bath. We adopt open boundary conditions along the y−direction, while
continuous boundary conditions are considered along the x−direction. Clusters are grown by selectively adding two-state spins (Sxyz = ±1) to perimeter
sites, which are defined as the nearest-neighbor (NN) empty sites of the already
occupied ones. Let us recall that the substrate is a 3D cubic lattice and therefore
each lattice site in the bulk has 6 NN sites. Considering a ferromagnetic interaction
of strength J > 0 between NN spins, the energy E of a given configuration of spins
is given by E = −J
2
! ⟨xyz,x′y′z′⟩
SxyzSx′y′z′ ,
(1) (1) where the summation ⟨xyz, x′y′z′⟩is taken over occupied NN sites. The Boltzmann
constant is set equal to unity throughout, and both temperature and energy are
measured in units of J. The probability for a perimeter site at (x, y, z) to be occupied
by a spin is proportional to the Boltzmann factor exp(−∆E/T), where ∆E is the
change of energy involved in the addition of the spin and T is the temperature at
the perimeter site. At each step, all perimeter sites have to be considered and the probabilities of
adding a new (either up or down) spin to each site must be evaluated. Using the
Monte Carlo simulation method, after all probabilities are computed and normal-
ized, the growth site and the orientation of the new spin are both simultaneously
determined by means of a pseudo-random number. 2
The Model and the Monte Carlo Simulation
Method Notice that the MEM’s growth
rules require updating the probabilities at each time step and lead to very slow al-
gorithms compared with analogous equilibrium spin models. Since the observables
of interest (e.g. the mean transverse magnetization along the x−direction and its
higher moments) require the growth of samples with a large number of transverse
planes of size L × L, clusters having up to 109 spins have typically been grown for
lattice sizes in the range 12 ≤L ≤96. Also, let us point out again that, although
Eq. (1) resembles the Ising Hamiltonian, the MEM is a nonequilibrium model in
which new spins are continuously added, while older spins remain frozen and are
not allowed to flip, detach, nor diffuse. As in the case of the classical Eden model, the magnetic Eden model leads to a
compact bulk and a self-affine growth interface [33] (see Sect. 3.4 for a detailed finite-
size scaling analysis of the interface width). The growth front may temporarily create
voids within the bulk, usually not far from the rough growth interface. However, 4 Figure 1: Snapshot showing a longitudinal slice for a fixed value of the transverse
coordinate x. A temperature gradient between T1 = 0.5 (bottom) and T2 = 1.5 (top)
is maintained along the transverse axis y. The system grows along the longitudinal
z > 0 direction in a semi-infinite (2 + 1)-dimensional strip substrate. Red (black)
sites represent up (down) spins, while empty sites are shown in white. Figure 1: Snapshot showing a longitudinal slice for a fixed value of the transverse
coordinate x. A temperature gradient between T1 = 0.5 (bottom) and T2 = 1.5 (top)
is maintained along the transverse axis y. The system grows along the longitudinal
z > 0 direction in a semi-infinite (2 + 1)-dimensional strip substrate. Red (black)
sites represent up (down) spins, while empty sites are shown in white. since the boundaries of these voids are also perimeter sites, they ultimately become
filled at some point during the growth process. Hence, far behind the active growth
interface, the system is compact and frozen, and the different quantities of interest
can thus be measured on defect-free transverse planes. Notice that the growth of magnetic Eden aggregates in (2 + 1)-strip geometries
is characterized by an initial transient length ℓT ∼L2 (measured along the growth
direction, i.e. 2
The Model and the Monte Carlo Simulation
Method the z−axis) followed by a nonequilibrium stationary state that is
independent of the initial configuration [34]. We considered starting seeds formed by
L×L up spins (i.e. Sxy1 = 1) but any choice for the seed leads to the same stationary
states for z ≫ℓT. By disregarding the transient region, all results reported in this
paper are obtained under stationary conditions. Also notice that, since the films are
effectively semi-infinite and the substrate length along the growth direction plays
no role, the only characteristic length is the transverse linear size L. 3.1
Gradient-Driven Continuous Pseudo-Phase Transitions
in Finite-Size Films Let us begin by considering a fixed gradient between temperatures T1 = 0.5 and
T2 = 1.5. The effect of changing this gradient will be discussed later. Figure 1 shows
the snapshot of a longitudinal slice for a fixed value of the transverse coordinate x. The temperature gradient is applied along the transverse y−direction, while the 5 -1
-0.5
0
0.5
1
m
0
0.5
1
1.5
2
2.5
P(m)
T=0.80
T=0.91
T=1.01
T=1.09
T=1.28
Figure 2: Symmetrized magnetization probability distributions for a system of linear
size L = 64 and different layer temperatures between T1 = 0.5 and T2 = 1.5. The
sharp peaks near m ≃±1 for T = 0.80 have been truncated. -1
-0.5
0
0.5
1
m
0
0.5
1
1.5
2
2.5
P(m)
T=0.80
T=0.91
T=1.01
T=1.09
T=1.28 0m Figure 2: Symmetrized magnetization probability distributions for a system of linear
size L = 64 and different layer temperatures between T1 = 0.5 and T2 = 1.5. The
sharp peaks near m ≃±1 for T = 0.80 have been truncated. system grows from left to right along the longitudinal z > 0 direction. Notice that
the bulk grows compact, because although voids and holes in the bulk may eventually
occur, they ultimately become filled at some point during the growth process. The
bottom layers grow in contact with thermal baths at cold temperatures, which favor
the formation of well-ordered spin domains. In contrast, the top layers grow in
contact with hot thermal baths that promote bulk disorder. As will be shown below,
the interplay of model growth dynamics, geometry, and thermal bath asymmetries
lead to the onset of gradient-driven order-disorder critical phase transitions that can
be quantitatively characterized. In order to take into account the asymmetries introduced by the temperature
gradient, we can quantify the degree of order in the system by considering the
magnetization of transverse columns at constant temperature (i.e. along the x-axis): m(y) = 1
L
! x
Sxyz . (2) (2) Figure 2 shows the probability distributions of m for a system of linear size
L = 64 growing in a temperature gradient between T1 = 0.5 and T2 = 1.5. Notice
that different plots correspond to different layers and, therefore, to different tem-
peratures within the gradient’s range, as indicated. 3.1
Gradient-Driven Continuous Pseudo-Phase Transitions
in Finite-Size Films As expected for a continuous 6 0.5
0.7
0.9
1.1
1.3
1.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=12
L=16
L=24
L=32
L=48
L=64
L=96
Figure 3: Mean absolute magnetization as a function of the layer temperature for
different system sizes, as indicated. 0.5
0.7
0.9
1.1
1.3
1.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=12
L=16
L=24
L=32
L=48
L=64
L=96 Figure 3: Mean absolute magnetization as a function of the layer temperature for
different system sizes, as indicated. order-disorder phase transition, the low-temperature distributions are bimodal and
peaked at the spontaneous magnetization m = ±msp (0 < msp < 1). As the temper-
ature is increased, the peaks approach each other and merge smoothly, ultimately
leading to a Gaussian distribution peaked at m = 0 for high temperatures, which is
characteristic of the disordered phase. Indeed, the smooth shift of the distribution
maxima across T ≃Tc(L), from the low-temperature nonzero spontaneous magne-
tization m = ±msp to the high-temperature Gaussian centered at m = 0, is the
signature of true thermally-driven continuous phase transitions [37]. Notice that the distributions in Figure 2 are symmetrical, since there exists a
finite probability for fluctuations to grow and switch the magnetization from m ≃
+msp to m ≃−msp and viceversa. Since Monte Carlo simulations are restricted to
finite samples, the standard procedure to avoid these shortcomings due to finite-size
effects is to average the absolute value of the order parameter [38]. In this context,
the appropriate order parameter is the mean absolute magnetization of transverse
columns at constant temperature, i.e. ⟨|m|⟩(y) = ⟨1
L|
! x
Sxyz|⟩z ,
(3) (3) where ⟨...⟩z denotes averages along the growth direction z > 0 within the stationary
region. Figure 3 shows plots of the mean absolute magnetization as a function of 7 0.5
0.7
0.9
1.1
1.3
1.5
T
0
100
200
300
400
r
L=12
L=16
L=24
L=32
L=48
L=64
L=96
Figure 4: Susceptibility as a function of the layer temperature for different system
sizes in the range 12 ≤L ≤96. As expected for a critical system, the peaks become
sharper and higher as L is increased. 0.5
0.7
0.9
1.1
1.3
1.5
T
0
100
200
300
400
r
L=12
L=16
L=24
L=32
L=48
L=64
L=96 Figure 4: Susceptibility as a function of the layer temperature for different system
sizes in the range 12 ≤L ≤96. 3.1
Gradient-Driven Continuous Pseudo-Phase Transitions
in Finite-Size Films As expected for a critical system, the peaks become
sharper and higher as L is increased. the layer temperature for different system sizes in the range 12 ≤L ≤96. For
any given system size, at low temperatures the system grows ordered and the mag-
netization is close to unity, while at higher temperatures the disorder sets on and
the magnetization becomes significantly smaller. However, fluctuations due to the
finite system size prevent the magnetization from becoming strictly zero above the
critical temperature, so the transition between the low-temperature ordered phase
and the high-temperature disordered phase becomes smoothed out and rounded. As
expected, larger systems are less affected by finite-size effects and display sharper
transitions. Strictly speaking, however, these results just show evidence of pseudo-phase tran-
sitions, which might be precursors of true phase transitions taking place in the
thermodynamic limit. In the following, we will characterize in more detail this
pseudo-critical phenomenon by measuring other observables on finite-size systems. In the next Subsection, we will use standard finite-size scaling procedures to estab-
lish the existence of a non-trivial critical temperature in the L →∞limit, as well
as to calculate critical exponents that describe the behavior of the infinite system
at criticality. 8 8 Let us now consider the magnetic susceptibility χ, given by Let us now consider the magnetic susceptibility χ, given by χ = L2
T
"
⟨m2⟩−⟨|m|⟩2#
. (4) (4) For equilibrium systems, the susceptibility is related to order parameter fluctua-
tions by the fluctuation-dissipation theorem. Although the validity of a fluctuation-
dissipation relation in the case of a nonequilibrium system is less evident, we will
assume Eq. (4) to hold also for the MEM. Indeed, as shown in earlier studies of
nonequilibrium spin models [39, 40], this definition of χ proves very useful for ex-
ploring critical phenomena under far-from-equilibrium conditions. In Section 3.2, we
will characterize the critical behavior in the thermodynamic limit through critical
exponents and finite-size scaling relations by applying the equilibrium theory to our
far-from-equilibrium model. Figure 4 shows plots of χ vs T for different system sizes, as indicated. As with
the thermal dependence of the order parameter shown in Figure 3, the peaks of the
susceptibility become rounded and shifted, indicating the existence of pseudo-phase
transitions in finite-size MEM thin films. Increasing the system size, the peaks
become sharper and higher, as expected for a critical system. 3.1
Gradient-Driven Continuous Pseudo-Phase Transitions
in Finite-Size Films Since the results presented thus far considered a fixed gradient between the
temperatures T1 = 0.5 and T2 = 1.5, let us now investigate the effects of changing
the gradient span ∆T ≡T2 −T1. With this aim, we keep the same temperature
for the thermal bath at the cold end (T1 = 0.5) and consider a substantially higher
temperature for the thermal bath at the hot end (T2 = 2.5). Figure 5 compares the mean absolute magnetization for these two different gra-
dient ranges (i.e. ∆T = 1, 2) for systems of size L = 12 and L = 96. We observe
that increasing the gradient span shifts the magnetization profiles towards higher
temperatures. That is, the temperature of a given layer does not uniquely deter-
mine its degree of order, since the mean magnetization of the layer also depends on
the overall gradient span under which the film grows. Similar shifts towards higher
temperatures are also seen in higher-order moments of the order parameter prob-
ability distributions, such as the susceptibility and Binder’s fourth-order cumulant
(not shown here for the sake of space). Alternatively, we can compare systems of
different sizes and gradient spans such that the local gradients δ ≡∆T/L are the
same. The inset to Figure 5 shows a comparison between a system of size L = 16
and gradient span ∆T = 1 (dashed lines) and another system of size L = 32 and
gradient span ∆T = 2 (dotted lines), both of which have the same local gradient
δ = 1/16. The solid line corresponds to the mixed case L = 32 and ∆T = 1 (i.e. δ = 1/32). We observe that the systems with the same local gradient have simi-
lar magnetization in layers at intermediate temperatures (i.e. approximately in the
range 0.8 ≤T ≤1.3). However, the magnetization profiles for equal-δ systems differ
noticeably in layers closer to the borders of the sample. 9 0.5
1
1.5
2
2.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=12, 6T=1
L=12, 6T=2
L=96, 6T=1
L=96, 6T=2
0.5
1
1.5
2
2.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=16, 6T=1
L=32, 6T=1
L=32, 6T=2
Figure 5: Comparison of magnetization profiles ⟨|m|⟩vs T for different gradient
spans (∆T = 1, 2) and system sizes (L = 12, 96). The arrows indicate the corre-
sponding shifts in the finite-size critical temperature Tc(L). 3.1
Gradient-Driven Continuous Pseudo-Phase Transitions
in Finite-Size Films Inset: Magnetization
profiles for systems with the same local gradient δ = 1/16, namely L = 16, ∆T = 1
(dashed line) and L = 32, ∆T = 2 (dotted line). For comparison, the mixed case
L = 32, ∆T = 1 (solid line) is also shown. 0.5
1
1.5
2
2.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=12, 6T=1
L=12, 6T=2
L=96, 6T=1
L=96, 6T=2
0.5
1
1.5
2
2.5
T
0.2
0.4
0.6
0.8
1
<|m|>
L=16, 6T=1
L=32, 6T=1
L=32, 6T=2 1.5
T Figure 5: Comparison of magnetization profiles ⟨|m|⟩vs T for different gradient
spans (∆T = 1, 2) and system sizes (L = 12, 96). The arrows indicate the corre-
sponding shifts in the finite-size critical temperature Tc(L). Inset: Magnetization
profiles for systems with the same local gradient δ = 1/16, namely L = 16, ∆T = 1
(dashed line) and L = 32, ∆T = 2 (dotted line). For comparison, the mixed case
L = 32, ∆T = 1 (solid line) is also shown. The arrows in Figure 5 show that the shifts for smaller systems are signifi-
cantly larger than the corresponding shifts for larger systems. Defining the finite-size
pseudo-critical temperature Tc(L) as the temperature corresponding to ⟨|m|⟩= 0.5,
the shift for L = 12 is ∆Tc = 0.18, while the corresponding shift for L = 96 is
∆Tc = 0.07. This observation suggests that differences arising from changing the
gradient span might just reflect finite-size effects that vanish in the L →∞limit. In the next Subsection, we study the critical behavior of MEM films and confirm
that, in fact, these differences are merely finite-size effects that become irrelevant in
the thermodynamic limit. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit So far, we have found evidence for the existence of a gradient-driven order-disorder
phase transition from the analysis of order parameter probability distributions, the
order parameter mean absolute value (magnetization) and its fluctuations (suscep- 10 0.5
0.7
0.9
1.1
1.3
1.5
T
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
U4
L=12
L=16
L=24
L=32
L=48
L=64
L=96
0.7
0.8
0.9
1
T
0.63
0.64
0.65
0.66
0.67
U4
Figure 6: Binder cumulant as a function of the layer temperature for different system
sizes, as indicated. The inset shows the cumulant intersections for the larger systems
(32 ≤L ≤96), which determine Tc = 0.84(2). 0.5
0.7
0.9
1.1
1.3
1.5
T
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
U4
L=12
L=16
L=24
L=32
L=48
L=64
L=96
0.7
0.8
0.9
1
T
0.63
0.64
0.65
0.66
0.67
U4 Figure 6: Binder cumulant as a function of the layer temperature for different system
sizes, as indicated. The inset shows the cumulant intersections for the larger systems
(32 ≤L ≤96), which determine Tc = 0.84(2). tibility) in the growth of finite-size magnetic films. In this Subsection, we apply
standard finite-size scaling techniques to show the existence of this phase transition
in the thermodynamic limit and to determine critical exponents that characterize
the system’s critical behavior and universality class. The Binder cumulant, defined by The Binder cumulant, defined by U4 = 1 −⟨m4⟩
3⟨m2⟩2 ,
(5) (5) is a fourth-order cumulant dependent on the variance and the kurtosis of the order
parameter probability distribution. One important property of the Binder cumu-
lant is that, for large system sizes, the low-temperature, ordered region tends to
the value 2/3, while the high-temperature, disordered region tends to 0. Thus, in
the thermodynamic limit, the function becomes discontinuous exactly at the critical
temperature. Moreover, since for second-order phase transitions, the scaling prefac-
tor of the cumulant is independent of the sample size, plots of U4 versus the control
parameter lead to a common (size-independent) intersection point that corresponds
to the location of the critical value of the order parameter in the thermodynamic
limit [41]. Figure 6 shows the Binder cumulant as a function of the layer temperature for
different system sizes in the range 12 ≤L ≤96. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit The Inset to Figure 6 shows 11 a detailed view of the same data for the largest lattices (32 ≤L ≤96), where the
intersection region is indicated by a grey vertical strip. Based on this observation, we
determine the critical temperature in the L →∞limit as Tc = 0.84(2). Interestingly,
this value is significantly higher than the corresponding critical temperature for the
MEM growing in an homogeneous thermal bath (i.e. in the absence of a temperature
gradient), namely T hom
c
= 0.69(1) [34]. In the next Subsection, we will explore the
growth dynamics and explain qualitatively this shift in the critical temperature as
due to ordering effects caused by a net transverse growth bond flux induced by
thermal asymmetries. Notice also that, by fixing the temperature range (i.e. the temperatures T1
and T2) and increasing L, we are effectively considering different gradients δ =
(T2−T1)/L that become smaller as L is increased. Figure 6, which shows a fixed point
in the Binder cumulants as the gradients are changed, provides therefore quantitative
evidence for the existence of a gradient-independent phase transition taking place
at the temperature Tc. According to the finite-size scaling theory, developed for the treatment of finite-
size effects at criticality under equilibrium conditions [42, 43], the difference between
the true critical temperature, Tc, and the effective pseudo-critical one, Tc(L), is given
by (6) |Tc −Tc(L)| ∝L−1/ν,
(6) where ν is the exponent that characterizes the divergence of the correlation length at
criticality. As mentioned above, we define the finite-size pseudo-critical temperature
Tc(L) as the temperature corresponding to ⟨|m|⟩= 0.5. Let us point out that, given the lack of a comprehensive theory of non-equilibrium
phase transitions, concepts and definitions developed in the context of equilibrium
phenomena are customarily borrowed and applied to far-from-equilibrium phenom-
ena as well. For a review of standard methods, see e.g. [44, 45, 46]. Indeed, although
this approach is ad-hoc and lacks the theoretical foundations of equilibrium systems,
it has been used extensively in the literature and has become a powerful means of
advancing our knowledge within the realm of non-equilibrium phenomena. For in-
stance, numerical methods such as Monte Carlo simulations or series expansions
are restricted to finite systems and it is therefore important to understand how
far finite-size effects influence the properties of the system. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit As known from equi-
librium statistical mechanics, finite-size effects are particularly strong close to the
critical point, where the spatial correlation length becomes comparable with the
linear dimensions of the system. By introducing the system size as an additional
parameter, finite-size scaling laws are used to characterize the steady state of finite
far-from-equilibrium systems through appropriate scaling exponents, such as, for in-
stance, the exponent ν in Eq.(6) above. Moreover, this procedure allows us to define
universality classes of non-equilibrium systems, as reviewed e.g. in Refs. [47, 48, 49]. Fi
7 h
l
l
l t
f th fiit
i
d
iti
l t
t
T (L) Figure 7 shows log-log plots of the finite-size pseudo-critical temperatures Tc(L) 12 10
-3
10
-2
10
-1
L
-1
0.9
1.0
1.1
1.2
1.3
1.4
1.5
Tc (L)
fit with Tc=0.82
fit with Tc=0.84
fit with Tc=0.86
0.1
1
10
|T-Tc| L
1/i
1
<|m|> L
`/i
L=32
L=48
L=64
L=96
10
-3
10
-2
10
-1
L
-1
0.9
1.0
1.1
1.2
1.3
1.4
1.5
Tc (L)
6T=1
6T=2
Figure 7: Log-log plots of the finite-size pseudo-critical temperatures Tc(L) as a
function of the inverse of the system linear size, L−1, for ∆T = 1 (filled circles)
and ∆T = 2 (open circles). By means of standard finite-size scaling analysis, we
obtain the critical exponent ν = 1.53(6) (see more details in the text). Inset: plot of
⟨|m|⟩× Lβ/ν vs |T −Tc| × L1/ν (with β = 0.26) showing a data collapse for ∆T = 1
and different system sizes in the range 32 ≤L ≤96. 10
-3
10
-2
10
-1
L
-1
0.9
1.0
1.1
1.2
1.3
1.4
1.5
Tc (L)
fit with Tc=0.82
fit with Tc=0.84
fit with Tc=0.86
0.1
1
10
|T-Tc| L
1/i
1
<|m|> L
`/i
L=32
L=48
L=64
L=96
10
-3
10
-2
10
-1
L
-1
0.9
1.0
1.1
1.2
1.3
1.4
1.5
Tc (L)
6T=1
6T=2 L
-1
L
-1 Figure 7: Log-log plots of the finite-size pseudo-critical temperatures Tc(L) as a
function of the inverse of the system linear size, L−1, for ∆T = 1 (filled circles)
and ∆T = 2 (open circles). By means of standard finite-size scaling analysis, we
obtain the critical exponent ν = 1.53(6) (see more details in the text). 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit Inset: plot of
⟨|m|⟩× Lβ/ν vs |T −Tc| × L1/ν (with β = 0.26) showing a data collapse for ∆T = 1
and different system sizes in the range 32 ≤L ≤96. as a function of the inverse of the system linear size, L−1, for different gradients and
system sizes, as indicated. By rewriting the finite-size scaling relation as Tc(L) = Tc + A × L−1/ν,
(7) (7) we performed different least-squares fits to the data using the mean, upper-bound
and lower-bound values for the critical temperature in the thermodynamic limit. The nonlinear least-squares fitting procedure was implemented using the Levenberg-
Marquardt minimization method [50] and the results from each independent fit are
reported in Table 1. The errors in the table are determined by the fitting algorithm
and take into account the statistical errors for each datapoint. Figure 7 shows that
the finite-size scaling relation fits the data very well within error bars for the range of
values for the critical temperature that was derived from the intersection of Binder’s
cumulants. From these fits, we obtain the critical exponent ν = 1.53(6), where the
error bars reported reflect the errors derived from the evaluation of Tc as well as the
statistical errors. Notice that the data for different gradients tends to converge in
the L →∞limit, therefore confirming that differences arising from changing the we performed different least-squares fits to the data using the mean, upper-bound
and lower-bound values for the critical temperature in the thermodynamic limit. The nonlinear least-squares fitting procedure was implemented using the Levenberg-
Marquardt minimization method [50] and the results from each independent fit are
reported in Table 1. The errors in the table are determined by the fitting algorithm
and take into account the statistical errors for each datapoint. Figure 7 shows that
the finite-size scaling relation fits the data very well within error bars for the range of
values for the critical temperature that was derived from the intersection of Binder’s
cumulants. From these fits, we obtain the critical exponent ν = 1.53(6), where the
error bars reported reflect the errors derived from the evaluation of Tc as well as the
statistical errors. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit Notice that the data for different gradients tends to converge in
the L →∞limit, therefore confirming that differences arising from changing the 13 ∆T
Tc
A
ν
1
0.82
2.86(3)
1.54(2)
1
0.84
2.90(3)
1.49(2)
1
0.86
2.78(3)
1.48(1)
2
0.82
3.70(3)
1.58(1)
2
0.84
3.65(3)
1.56(2)
2
0.86
3.66(4)
1.53(2)
Table 1: Results from fitting the data to the finite-size scaling relation, Eq.(7). Table 1: Results from fitting the data to the finite-size scaling relation, Eq.(7). 12
16
24
32
48
64
96
14
20
L
10
1
10
2
10
3
rmax
6T=1
6T=2
0.1
1
|T-Tc| L
1/i
0.1
r L
-a/i
0.1
1
10
|T-Tc| L
1/i
0.1
r L
-a/i
L=32
L=48
L=64
L=96
(a)
(b)
Figure 8: Log-log plots of the susceptibility maxima as a function of the system
linear size for ∆T = 1 (filled circles) and ∆T = 2 (open squares), where statistical
errors for each datapoint are smaller than the symbol size. The solid lines are finite-
size scaling fits that yield γ/ν = 1.66(3). The insets display plots of χL−γ/ν vs
|T −Tc|L1/ν (for the ∆T = 1 case) showing separately the data collapse for (a) the
low-temperature branch and (b) the high-temperature branch. 12
16
24
32
48
64
96
14
20
L
10
1
10
2
10
3
rmax
6T=1
6T=2
0.1
1
|T-Tc| L
1/i
0.1
r L
-a/i
0.1
1
10
|T-Tc| L
1/i
0.1
r L
-a/i
L=32
L=48
L=64
L=96
(a)
(b) Figure 8: Log-log plots of the susceptibility maxima as a function of the system
linear size for ∆T = 1 (filled circles) and ∆T = 2 (open squares), where statistical
errors for each datapoint are smaller than the symbol size. The solid lines are finite-
size scaling fits that yield γ/ν = 1.66(3). The insets display plots of χL−γ/ν vs
|T −Tc|L1/ν (for the ∆T = 1 case) showing separately the data collapse for (a) the
low-temperature branch and (b) the high-temperature branch. gradient are finite-size effects. On the other hand, finite-size scaling theory predicts
that plots of ⟨|m|⟩Lβ/ν vs |T −Tc|L1/ν for different lattice sizes should collapse near
the critical region. The inset to Figure 7 shows the data collapse obtained by using
β = 0.26 (that is determined from the hyperscaling relation, as explained below)
with two separate branches corresponding to the low- and high-temperature regions. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit An additional characterization of the critical behavior of this system can be 14 obtained by calculating the critical exponent γ, which describes the divergence of the
susceptibility at the critical point. Using again the finite-size scaling theory [42, 43],
the exponent ratio γ/ν is related to the peak of the susceptibility measured in finite
samples of size L by χmax ∝Lγ/ν . (8) (8) χmax ∝Lγ/ν . χmax ∝Lγ/ν . The symbols in Figure 8 correspond to the maxima of χ plotted against the
system linear size for different gradients, as indicated, while the solid lines are fits to
the data using the scaling relation from Eq.(8). Statistical errors for each datapoint
are smaller than the symbol size in the Figure. The fitting procedure (which, as
mentioned above, was implemented as a nonlinear least-squares algorithm using the
Levenberg-Marquardt minimization method [50]) yields γ/ν = 1.66(3), where the
error bars reflect the statistical errors from the fits. Using this ratio and the value
already obtained for ν, we determine γ = 2.54(11). The insets to Figure 8 display
plots of χL−γ/ν vs |T −Tc|L1/ν for ∆T = 1 and different lattice sizes in the range
32 ≤L ≤96. Using the critical temperature as determined by the susceptibility
peaks, the data collapse is shown separately for (a) the low-temperature branch and
(b) the high-temperature branch. In the former case, data from low-temperature
layers near T1 = 0.5 depart from the collapse and have been removed. However,
the collapse near the critical region is remarkable and agrees very well with the
expectations from the finite-size scaling theory. By replacing the exponents ν and γ
in the hyperscaling relation dν −2β −γ = 0 with d = 2, we determine the exponent
β = 0.26(8), where the error is determined from standard error propagation applied
to the hyperscaling relation. Recall that we anticipated this value of β when we
considered the data collapse of the scaled magnetization (see the inset to Figure 7
above). The excellent data collapse near the critical region confirms the consistency
and robustness of the obtained results. As a summary, Binder’s cumulant method and finite-size scaling analysis allowed
us to characterize quantitatively the critical behavior of nonequilibrium magnetic
films growing in a temperature gradient. We found that differences arising from
changing the gradient are due to finite-size effects that vanish in the thermody-
namic limit. 3.2
Characterization of Gradient-Driven Critical Behavior
in the Thermodynamic Limit The system’s critical temperature is Tc = 0.84(2), significantly higher
than the critical temperature for films grown in an homogeneous thermal bath,
T hom
c
= 0.69(1) [34]. The critical exponents are ν = 1.53(6), γ = 2.54(11), and
β = 0.26(8). Based on our findings, we conjecture that magnetic Eden films grow-
ing in a temperature gradient belong to a new universality class characterized by
critical exponents ν = 3/2, γ = 5/2, and β = 1/4. In contrast, the critical exponents
for magnetic Eden films grown in an homogeneous bath agree within error bars with
the exact exponents for the Ising model in d = 2 [34], namely ν = 1, γ = 7/4, and
β = 1/8. 15 0
0.5
1
1.5
2
2.5
6T
0
0.2
0.4
0.6
0.8
1
mean bond flux
<qx>
<qy>
<qz>
Figure 9: Mean growth bond flux components as a function of the gradient span
∆T for L = 32 and T1 = 0.5. Asymmetries due to the temperature gradient and the
substrate geometry are responsible for net bond fluxes along the y and z directions. Along the transverse direction x the system is fully symmetric, so no net bond fluxes
are observed regardless of ∆T. 0
0.5
1
1.5
2
2.5
6T
0
0.2
0.4
0.6
0.8
1
mean bond flux
<qx>
<qy>
<qz> Figure 9: Mean growth bond flux components as a function of the gradient span
∆T for L = 32 and T1 = 0.5. Asymmetries due to the temperature gradient and the
substrate geometry are responsible for net bond fluxes along the y and z directions. Along the transverse direction x the system is fully symmetric, so no net bond fluxes
are observed regardless of ∆T. 3.3
Growth Bond Model and Bond Flux Asymmetries In this Subsection, we explore the growth dynamics by means of a simple bond
representation. Let us recall that the MEM’s growth process adds new spins, which
are deposited one by one to the growing cluster. Although voids and holes may form
within the bulk, ultimately all sites become filled. Hence, to each pair of neighboring
sites, we can assign a directed bond that points from the earlier occupied site to the
later occupied one. The components of the bond flux field ⃗φ at a site (x, y, z) are
defined as: φx(x, y, z) = b[(x, y, z), (x + 1, y, z)] ,
φy(x, y, z) = b[(x, y, z), (x, y + 1, z)] ,
(9)
φz(x, y, z) = b[(x, y, z), (x, y, z + 1)] , (9) where b[s1, s2] = 1 if the bond points from s1 to s2, and b[s1, s2] = −1 if the bond
points from s2 to s1. ⃗ Figure 9 shows the x−, y−, and z−components of the mean bond flux ⟨⃗φ⟩as a
function of the gradient span ∆T for L = 32 and T1 = 0.5. As expected from the
symmetry along the transverse x−direction, there is no net bond flux in x: ⟨φx⟩= 0 16 regardless of ∆T. For ∆T = 0, the system is also symmetric along y, so no net bond
flux is observed. When a gradient is applied, however, this symmetry is broken. Since the growth probabilities depend on the Boltzmann factor exp(−∆E/T(y)),
where T(y) is the layer’s temperature, the thermal asymmetries introduced by the
gradient favor spin deposition on the colder layers. This phenomenon is captured
by the observed net bond flux ⟨φy⟩> 0. Indeed, as shown in Figure 9, the thermal
asymmetries cause ⟨φy⟩to grow steeply up to ⟨φy⟩max ≈0.75 followed by a moder-
ate decrease for larger gradients, which is due to the onset of bulk disorder within
the hotter layers. Since the net transverse growth bond flux is directed from the
ordered (cold) layers towards the disordered (hot) ones, this gradient-induced trans-
verse ordering mechanism causes the system’s critical temperature to increase from
T hom
c
= 0.69(1) to Tc = 0.84(2). On the other hand, for ∆T = 0, ⟨φz⟩= 1 due to
the longitudinal asymmetries in the substrate (i.e., the semi-infinite strip geometry
constrains the system to grow along the z > 0 direction). 3.3
Growth Bond Model and Bond Flux Asymmetries However, when the trans-
verse gradient is applied, two effects contribute to decrease ⟨φz⟩: (i) the onset of the
transverse bond flux, which creates transverse domains in the active perimeter and
causes some of the added spins to grow backwards; (ii) the bulk disorder induced
in the hotter layers (which also causes ⟨φy⟩to decrease, as discussed above). y
(
⟨φy⟩
,
)
The mean fluxes shown in Figure 9 were averaged over sites at different temper-
atures. In order to gain further insight, let us now investigate the dependence of the
bond fluxes on the layer temperature T(y) = T1 +(y −1)×(T2 −T1)/(L−1) (where
1 ≤y ≤L). Since we are considering different gradient spans for a fixed system size,
it is actually more convenient in this case to plot the bond fluxes as a function of the
transverse coordinate y. We already observed that the transverse bond flux along x
is null regardless of temperature, so we will focus on the growth bond fluxes along
the y−and z−directions. Figure 10(a) shows the upwards bond flux ⟨φy(y)⟩vs y
for L = 32, T1 = 0.5, and different gradient spans ∆T, as indicated. In the absence
of a gradient, the flux is directed downwards at the bottom and upwards at the
top, yielding zero net bond flux. Indeed, because of the open boundary conditions,
empty perimeter sites at the confinement walls experience a missing-neighbor effect
and the system grows preferentially along the center of the film as compared to the
walls. When a gradient is applied, the flux grows steeply in the upwards direction,
as expected. However, for larger gradients, the hotter thermal baths are capable
of inducing disorder in the bulk and partially break the upwards bond flux on the
upper layers. Indeed, this phenomenon causes the overall bond flux ⟨φy⟩(averaged
over all layers) to decrease for large values of ∆T, as discussed above. Similarly,
Figure 10(b) shows the forward bond flux ⟨φz(y)⟩vs y for L = 32, T1 = 0.5, and
different values of ∆T, as indicated. For ∆T = 0, there is a slight missing-neighbor
effect for the sites near the confinement walls. Since forward growth is mostly driven
by the substrate asymmetry, this effect is much less noticeable that in the flux along
y. 3.3
Growth Bond Model and Bond Flux Asymmetries When the gradient is applied, two effects contribute to reduce the longitudinal 17 0
0.2
0.4
0.6
0.8
1
y/L
-0.5
0
0.5
1
<qy(y)>
6T=0
6T=0.1
6T=0.2
6T=0.3
6T=0.5
6T=1
6T=2.5
(a)
0
0.2
0.4
0.6
0.8
1
y/L
0
0.2
0.4
0.6
0.8
1
<qz>
6T=0
6T=0.1
6T=0.2
6T=0.3
6T=0.5
6T=1
6T=2.5
(b)
Figure 10: Bond flux components as a function of the transverse coordinate y/L
for L = 32, T1 = 0.5, and different gradient spans, as indicated: (a) transverse flux
along y; (b) longitudinal flux along z. 0
0.2
0.4
0.6
0.8
1
y/L
-0.5
0
0.5
1
<qy(y)>
6T=0
6T=0.1
6T=0.2
6T=0.3
6T=0.5
6T=1
6T=2.5
(a) 0
0.2
0.4
0.6
0.8
1
y/L
0
0.2
0.4
0.6
0.8
1
<qz>
6T=0
6T=0.1
6T=0.2
6T=0.3
6T=0.5
6T=1
6T=2.5
(b) Figure 10: Bond flux components as a function of the transverse coordinate y/L
for L = 32, T1 = 0.5, and different gradient spans, as indicated: (a) transverse flux
along y; (b) longitudinal flux along z. flux, as discussed above. One of them, which is dominant for small gradients, is
due to the formation of transverse domains along y, causing some backwards depo-
sition when the bulk is filled in. The other mechanism, which is dominant for larger
gradients, is due to the onset of bulk disorder in the hotter layers. Previously, we pointed out the fact that the gradient-driven order-disorder phase
transition occurs at a temperature that is significantly higher than the corresponding
critical temperature for the MEM growing in an homogeneous thermal bath (i.e. in
the absence of a temperature gradient). The results presented in this Subsection 18 allow a qualitative explanation for the shift in the critical temperature. Indeed,
the temperature gradient breaks the transverse symmetry along the y−direction,
causing the onset of a net transverse growth bond flux. This flux is directed from
the ordered layers (that grow at T < Tc) towards the disordered layers (that grow at
T > Tc), thus expanding the low-temperature ordering effects across layers at higher
temperatures. This gradient-induced transverse ordering mechanism increases the
system’s critical temperature. 3.4
Scaling behavior of the growth interface This nearly-linear universal shape is
qualitatively consistent with the roughness exponent α = 1, as it has quantitatively 19 0
100
200
300
400
500
tlayer
0
50
100
150
200
interface width
L=12
L=16
L=20
L=32
L=48
L=64
L=96
10
100
L
10
100
wsat
Figure 11: Interface width as a function of time, where the time unit is the deposition
time of L2 spins. Inset: log-log plot of the saturation width, wsat, as a function of
system size. The statistical errors are smaller than the size of the symbols. The
fit to the data is shown by the solid line and agrees with a linear scaling wsat ∝L
(more details in the text). 0
100
200
300
400
500
tlayer
0
50
100
150
200
interface width
L=12
L=16
L=20
L=32
L=48
L=64
L=96
10
100
L
10
100
wsat 1
interface width Figure 11: Interface width as a function of time, where the time unit is the deposition
time of L2 spins. Inset: log-log plot of the saturation width, wsat, as a function of
system size. The statistical errors are smaller than the size of the symbols. The
fit to the data is shown by the solid line and agrees with a linear scaling wsat ∝L
(more details in the text). been determined. In passing, notice also that this universal profile shows a good
agreement with the instantaneous snapshot displayed in Figure 1. Thus, we con-
clude that the active growth interface is self-affine and has universal features: the
detailed analysis of bond flux asymmetries presented in Section 3.3 for a fixed lattice
size (L = 32) remains valid for larger systems. In particular, our analysis focused
on the influence exerted by the low-temperature layers into higher-temperature lay-
ers, which therefore is a gradient-induced growth mechanism still relevant in the
thermodynamic limit. In addition to the roughness exponent α, self-affine interfaces are also charac-
terized by a fractal dimension df. In fact, within short length-scales such that
∆z ≪ℓ, where ∆z is the longitudinal interface distance along the growth direction
between two points separated by a transverse distance ℓ, the fractal dimension is
df = 2 −α [52]. In the long length-scale limit, moreover, the fractal dimension of
the self-affine interface is df = 1, irrespective of its roughness [52]. 3.4
Scaling behavior of the growth interface According to the analysis presented in Section 3.3, the system’s critical temperature
is increased due to gradient-induced transverse ordering mechanisms that originate
in the cold layers. It could be argued, however, that, since the distance between
the cold layer at T1 and a layer at a fixed temperature T > T1 becomes larger as
L is increased (while keeping fixed the gradient span ∆T), then the transverse flux
effects may become weaker and eventually negligible in the large-L limit. In this
Subsection we show that the growth interface is self-affine and its shape is stable
and independent of size. Therefore, we confirm that the effects described in Section
3.3 are still relevant in the thermodynamic limit. In order to track the evolution of the growth interface, we compute the position
of the perimeter sites in the active region every time a monolayer of L2 spins is
deposited. The interface width at time t is defined by w(t) =
$
%
%
& 1
Np
Np
! i=1
(zi(t) −zc(t))2 ,
(10) (10) where the sum is taken over the Np perimeter sites in the active growth region, zi is
the longitudinal coordinate of the i−th perimeter site, and zc = (1/Np) '
i zi is the
center of the interface. Figure 11 shows the interface width as a function of time
for different lattice sizes in the range 12 ≤L ≤96, where the time unit corresponds
to the deposition of L2 spins. After a short transient period, the interface reaches a
stable saturation width, wsat, analogously to other surface growth phenomena [51,
52]. The Inset to Figure 11 shows the dependence of wsat on the system size L, where
the statistical errors are smaller than the size of the symbols. The fit to the data
(solid line) shows that wsat ∝Lα, where the roughness exponent is α = 1.01 ± 0.01. That is, the saturation width scales linearly with the system size. By subtracting the interface center, zc, we can compute the average interface
profile in the stationary regime, as shown in Figure 12. We find that, when scaled
by the mean interface width, interface profiles for different system sizes collapse
into a universal shape for the growth interface. 3.4
Scaling behavior of the growth interface Therefore, we
conclude that the growth interface of the MEM in a thermal gradient is df = 1 at
both short and long length-scales. Indeed, these conclusions are in full agreement
with the nearly-linear shape of the growing interface that is consistent with a unitary 20 -2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
(z-zc)/<w>
0.5
0.7
0.9
1.1
1.3
1.5
T(y)
L=12
L=16
L=24
L=32
L=48
L=64
L=96
Figure 12: Collapse of the scaled average growth profile in the stationary regime for
different lattice sizes, as indicated. Figure 12: Collapse of the scaled average growth profile in the stationary regime for
different lattice sizes, as indicated. fractal dimension at all length-scales, as seen in Figure 12. Here, it is useful to compare the obtained results with those from related, well-
studied growth models. For the standard MEM growing in a homogeneous tempera-
ture bath at high temperatures, the attachment of spins is a stochastic (random) pro-
cess that becomes independent of the interaction energy and the temperature [33]. Thus, in this limit, the growth interface of the standard MEM [33, 34, 35] agrees
with that of the classic Eden model [36], which is well known to belong to the
Kardar-Parisi-Zhang (KPZ) universality class [52]. The most accurate simulation
results for the KPZ model in (2+1)−dimensions yield α = 0.393±0.003 [53], which
agrees well with some of the formerly reported values for KPZ [54] and the Eden
model [55]. Using this value for the roughness, the fractal dimension of the growth
interface of the MEM in an homogeneous thermal bath at high temperatures crosses
over from df ≃1.6 (at short length-scales) to df = 1 (at long length-scales). More-
over, we can safely expect that the self-affine properties of the growth interface of
the standard MEM (in an homogeneous bath) be independent of the temperature
within a wide range around and below the critical temperature, at least insofar the
occurrence of a layering/roughening transition, in the sense of that observed in the
3−dimensional Ising model [56, 57], can be neglected. Therefore, we conclude that
the fractal and self-affine characteristics of the growth interface of the MEM in a
constant temperature bath are quite different than those of the same model growing 21 in a temperature gradient. 3.4
Scaling behavior of the growth interface p
g
On the other hand, due to the fact that the MEM grown under a temperature-
gradient constraint exhibits a second-order transition, one may also consider the
self-affine properties of the interface between the ordered and the disordered phases. Although for systems under equilibrium conditions a useful (alternative) approach
is the evaluation of the damaged interface [23], the damage spreading technique can
not straightforwardly be applied for the evaluation of an interface in an irreversible
growth model. Furthermore, the implementation and application of a cluster count-
ing algorithm [12, 15, 16, 18, 19, 21, 22, 58, 59] to our model would require formidable
computational task that is beyond the aim of this paper. Additional shortcomings
for this kind of calculations are the definition of the suitable cluster (e.g. Swendsen-
Wang vs physical clusters) and the occurrence of noticeable corrections to scaling
that one needs to evaluate in order to obtain reliable exponents [15], which is also a
task that lies beyond our computational capabilities. However, from heuristic argu-
ments based on the standard scaling relationship αord−dis = ν/(1 + ν) [12, 15, 23],
where αord−dis is the roughness exponent of the order-disorder interface, we can con-
jecture that αord−dis = 3/5, which yields a self-affine order-disorder interface with
short length-scale fractal dimension dord−dis
f
= 7/5. For comparison, by applying the
same scaling relationship to the standard MEM growing in an homogeneous thermal
bath, we obtain αord−dis = 0.51±0.09 and dord−dis
f
= 1.49±0.09. Thus, although the
growth interface is very significantly affected by the temperature gradient compared
to the thermally homogeneous system, the geometry of the order-disorder interface is
not so markedly affected by the gradient constraint and the results for both systems
agree within error bars. 4
Conclusions In this work, we studied magnetic thin films growing under far-from-equilibrium
conditions in (2 + 1)-dimensional strip geometries, where a temperature gradient is
applied across one of the transverse directions. We modeled the thin film growth
process by means of extensive Monte Carlo simulations performed on the magnetic
Eden model (MEM), in which spins are deposited on a growing cluster with proba-
bilities dependent on a ferromagnetic, Ising-like configuration energy. Firstly, we studied the thermal dependence of order parameter probability dis-
tributions, the order parameter mean absolute value (magnetization), the order
parameter fluctuations (susceptibility) and its higher moments (Binder cumulant)
on finite-size magnetic films, which showed the existence of gradient-driven pseudo-
phase transitions. Secondly, we applied Binder’s cumulant method and finite-size
scaling analysis in order to characterize quantitatively the critical behavior of MEM
films growing in a temperature gradient. The system’s critical temperature is 22 Tc = 0.84(2), significantly higher than the MEM’s critical temperature when grow-
ing in an homogeneous thermal bath, namely T hom
c
= 0.69(1) [34]. The critical
exponents are ν = 1.53(6), γ = 2.54(11), and β = 0.26(8), which also differ from
the MEM’s exponents in the absence of a temperature gradient [34]. By changing
the gradient span, we observed finite-size effects that vanish in the thermodynamic
limit. Hence, the critical temperature and exponents are universal for MEM films
growing in a temperature gradient. We also investigated the system’s growth dy-
namics by means of a bond model. We found that the interplay of geometry and
thermal bath asymmetries leads to growth bond flux asymmetries and the onset of
transverse ordering effects that explain qualitatively the shift observed in the critical
temperature. Finally, we analyzed the self-affine growth interface and obtained a
collapse of the scaled average growth profile in the stationary regime for different
lattice sizes, which shows that growth bond flux asymmetries play a relevant role in
the model’s growth dynamics even in the thermodynamic limit. In the context of a great experimental and theoretical interest in magnetic sys-
tems growing in temperature gradients, as well as a wide variety of technological
applications that benefit from these efforts, we hope that this work will contribute
to the progress of this research field and stimulate further work. Acknowledgments This work was financially supported by CONICET, UNLP, and ANPCyT (Ar-
gentina). The authors thank Nara Guisoni and Ernesto Loscar for useful discus-
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Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow
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Vol. 6, No. 4, 2024, 365–386
https://doi.org/10.1007/s42757-023-0184-8 Vol. 6, No. 4, 2024, 365–386
https://doi.org/10.1007/s42757-023-0184-8 Experimental and Computational Multiphase Flow Abstract The interaction and impact of solid particles from a dilute suspension with fixed spherical and
deformed bubbles (i.e., oblate spheroids) with rigid interface was analysed numerically, a situation
found for example in flotation or three-phase chemical reactors. The flow field about the bubbles
was computed for laminar flow and the particles were considered as point masses incorporating
all forces as there are drag, added mass, fluid inertia, transverse shear-lift, and gravity/buoyancy. Particle sizes were varied up to about 200 m allowing for a wide range of interaction Stokes
numbers. The impact efficiency was evaluated for a wide range of bubble Reynolds numbers
and bubbles having different shape and size, as well as eccentricity and orientation. The volume
equivalent diameter of the bubbles was between 2 and 4 mm. The bubble deformation was
varied up to an eccentricity of 1.8 and the bubble orientation was modified until 45 degrees. The effect of different forces on the impact efficiency was studied in detail. Added mass, fluid
inertia (part of the pressure term), and slip-shear transverse lift force cannot be neglected in
liquid environments, especially for larger particles. The obtained results were also compared to
the composite model of Schulze (1989), well established in the field of flotation. Finally, also the
particle impact statistics (i.e., location and velocity) was evaluated. Article History
Received: 21 September 2023
Revised: 22 December 2023
Accepted: 23 December 2023 In such numerical simulations, naturally, the interactions
between the fluid and both dispersed phases has to be
considered, the so-called two-way coupling. In a three-phase
bubble column, the injected bubbles constitute the energy
input and eventually induce the flow inside the column
through their buoyancy. The solid particles on the other
hand tend to sediment by gravity, but should be moved and
dispersed by the bubble-induced flow. In addition, a direct
interaction between particles and bubbles, namely, collisions,
particle attachment and detachment, as well as particle
motion along the bubble interface, are the relevant transport
processes. As a result, the buoyancy-induced bubble rise is
hindered by the solid particles, but additionally a lifting of
solid particles is occurring. Therefore, in both modelling
approaches for flotation processes (i.e., Eulerian or Lagrangian)
the particle/bubble scale transport processes need to be
described appropriately: particle–bubble collision rates and
efficiency (Dai et al., 2000), particle–bubble attachment martin.sommerfeld@ovgu.de Martin Sommerfeld (), Manuel A. Taborda Multiphase Flow Systems (MPS), Institute for Process Engineering, Otto-von-Guericke-University Magdeburg, Hoher Weg 7b, D-06120 Halle
(Saale) Germany Multiphase Flow Systems (MPS), Institute for Process Engineering, Otto-von-Guericke-University Magdeburg, Hoher Weg 7b, D-06120 Halle
(Saale), Germany 2 Impact efficiency 2 Impact efficiency In order to describe the direct interaction (collisions) of
particles with bubbles, the impact efficiency is an important
parameter. Considering a rising bubble in an almost
stagnant dilute suspension, the particles, depending on size
and density, may bypass the bubble with the relative flow to
a certain extent. Only particles arriving in the region of the
front stagnation point will hit the bubble and stick on the
surface. This impact efficiency is a result of several transport
processes, or may be connected with a number of influences,
which are normally, diffusion, inertia, and interception. Especially in column flotations and vertical bubble column
reactors, gravity as an external force will be driving particle
motion and influence impact efficiency wherefore it is very
often counted as a separate mechanism (Schulze, 1989;
Dai et al., 2000; Hassanzadeh et al., 2018). Such an impact,
capture, or deposition efficiency is not only relevant for
flotation processes (Dai et al., 2000) and three-phase chemical
reactors (Pan et al., 2016), but also for spray scrubbers
applied to separate fine particles from contaminated gas
streams by collecting the particles by the spray droplets
(Pieloth et al., 2013), particle separation on a fibre matrix
(Fotovati et al., 2010; Sommerfeld et al., 2021), the collision
between small and large particles in a dispersed two-phase
flow (Ho and Sommerfeld, 2002; Sommerfeld and Lain,
2009), and finally also fine particle deposition in confined
laminar or turbulent flows (Guha, 2008). All these processes
show a skewed S-shaped distribution of the capture efficiency
in dependence of the particle size or the relevant Stokes
number, mainly the result of the competition between In the pioneering work of Mitra-Majumdar et al. (1997)
using a multi-fluid continuum approach, the drag coefficients
of bubbles and particles were modified in order to mimic
this fluid dynamic particle/bubble interaction. Consequently,
the bubble drag was increased (hindered rise) and the
particle drag decreased (lifted upwards); both empirical
correction factors are depending on the solid particle volume
fraction. As a result, in bubbly suspension (or slurry) flows, the
collision and interaction of solid particles with a mobile or
rigid interface of the bubbles needs to be understood and
modelled properly in order to allow for a realistic numerical
simulation using both numerical frameworks. 1 Introduction Bubbly suspension flows are found in three-phase chemical
reactors, such as gas–liquid–solid fluidised beds, as well as
flotation processes in mineral treatment using agitated
flotations cells, flotation columns, and dissolved air flotation. Over the last decades increasingly numerical simulations of
such multiphase flows are conducted for process analysis,
design, and layout. With respect to flotation applications,
detailed reviews are presented by Pan et al. (2016), Wang
et al. (2018), and Wang et al. (2021). For such technically
relevant three-phase flows mostly multi-fluid approaches
are applied (Koh and Schwarz, 2006, 2008; Rabha et al.,
2013; Li et al., 2021; Mühlbauer et al., 2021). However,
there are also a few studies using point-particle Lagrangian
approaches for the dispersed phase particles and the bubbles
(Bourloutski and Sommerfeld, 2002, 2004; Zhang and
Ahmadi, 2005, 2012; Xu et al., 2013; Gruber et al., 2016). 366 M. Sommerfeld, M. A. Taborda As a first step of developing models for all these
elementary processes, the impact efficiency of fine particles
with a rigid and stationary bubble having different shapes
is considered. The assumption of rigid bubbles is justified
for contaminated systems. In the following part the relevant
parameters characterising impact efficiency and the well-known
Schulze (1989) model will be introduced and some expected
trends will be elucidated. Then the numerical approach
with the fundamental equations is presented, followed by a
description of the numerical grid discretisation, as well as
the initial and boundary conditions applied. Following that,
some typical flow field results will be shown for different
bubble shapes. The deposition pattern on the bubbles of
different shapes (spherical and ellipsoidal) will be presented
and the impact efficiency will be evaluated for different
conditions, especially, considering different force settings. Finally, the influence of bubble shape and orientation on
the capture efficiency will be highlighted. For allowing
model improvements also the impact properties over the
bubble surface are analyzed. based on interfacial forces (Omota et al., 2006), particle
motion along the surface of the bubbles and their accumulation
(Gao et al., 2015) as well as particle detachment from the
bubble surface (Schwarz et al., 2016). The interaction between particles and bubbles may be
also classified in terms of direct and indirect interactions:
Direct interactions are those phenomena associated
with contact between particles and bubbles and the
resulting momentum transfer as summarised above. Moreover, bubble oscillatory behaviour may be modified
due to the presence of surrounding particles. 1 Introduction
Indirect interactions are mainly associated with a
modification of the particle-laden flow around the
bubbles, such as boundary layer modification or wake
accumulation of particles, which will eventually modify
the flow resistance coefficients and especially drag and
added mass. Here the question is in as much drag, and may be
transverse lift forces, as well as added mass are modified in
dependence of particle material density and volume fraction. This summary of fluid dynamic effects already emphasises
the complexity of bubbly three-phase suspension flows,
which are complemented by interfacial effects and forces
governing the transport of the particles on the interface
of the bubble and also a possible detachment. th
m
bu
2
In
pa Here the question is in as much drag, and may be
transverse lift forces, as well as added mass are modified in
dependence of particle material density and volume fraction. This summary of fluid dynamic effects already emphasises
the complexity of bubbly three-phase suspension flows,
which are complemented by interfacial effects and forces
governing the transport of the particles on the interface
of the bubble and also a possible detachment. 2 Impact efficiency F
B
F
B
B
F
ρ D
Re
μ
-
=
u
u
(3) (3) In the numerical simulations conducted, a stationary and
rigid bubble was assumed and the inflow velocity was
assumed with a certain value to allow a variation of bubble
Reynolds number, so that
0
B
F
B
U
U
=
=
-
u
u . Since in
the present study also deformed rigid bubbles are considered,
the bubble size value used, is always the volume equivalent
diameter
B
D . The different mechanisms responsible for particle
collisions with bubbles are mostly added up to yield the
total impact efficiency, which however, strictly speaking, is
only valid if one of these mechanisms is dominant (Schulze,
1989) and there is no strong correlation between the different
transport processes: total
diff
inertia
inter
grav
E
E
E
E
E
=
+
+
+
(4) (4) where
diff
E
is the diffusional or fine-scale turbulence
contribution (being not considered in the present study),
inertia
E
is the inertia-based impact efficiency,
inter
E
accounts
for the interception effect, and
grav
E
is the additional
influence of gravity. Especially in the field of flotation,
intensive research has been conducted in the past for
deriving theoretically-based correlations for the different
contributions to the total impact efficiency as summarised
by Dai et al. (2000) and Hassanzadeh et al. (2018). In the
present study the correlations provided by Schulze (1989)
will be presented briefly, as they serve for comparison
with the present numerical simulations and also showed
a reasonable agreement with other simulation studies (Li
et al., 2019). 2 Impact efficiency The inertia-based impact efficiency developed
by Schulze (1989) was starting with the correlation introduced
by Schuch and Löffler (1978) and incorporates additional
terms relevant for flotation: where
diff
E
is the diffusional or fine-scale turbulence
contribution (being not considered in the present study), The characteristic non-dimensional number describing
this interaction is the relative Stokes number
rel
St
, defined
as the particle response time
P
τ over the time a particle will
need to pass the spherical collector bubble
F
T : 2
P
P
P
B
rel
F
F
B
18
ρ d
τ
U
St
T
μ D
=
=
(1) (1) where
P
d and
B
D are the particle and bubble diameters
respectively,
B
U is the bubble rise velocity, or better the
relative velocity with respect to the flow,
P
ρ the particle
material density, and
F
μ is the dynamic viscosity of the fluid,
mostly water in flotation applications. Here, the particle
response time is obtained for Stokes flow, i.e., a particle
Reynolds number smaller than one (
P
1.0
Re <
). This
definition is mostly used in publications related to the
impact efficiency in flotation processes. However, for
describing the particle response in a liquid flow, the added
mass contribution, being 50% of the fluid density (i.e.,
F
0.5ρ ), should to be also considered, yielding the effective
Stokes number: 2
P
rel
inertia
P
B
rel
B
1
1
1
b
d
St
E
V
D
St
a
U
æ
ö æ
ö
÷
÷
ç
ç
=
+
÷
÷
ç
ç
÷
÷
ç
ç
è
ø è
ø
+
+
(5) (5) where
P
V is the settling velocity of the particles and
B
U the
rise velocity of the bubbles. The velocity and size terms (the
1st and 2nd terms on the right-hand side) were introduced
to match the specific conditions for flotation processes. The
last term depends on the relative Stokes number
rel
St
(Eq. (1))
and was developed by Schuch and Löffler (1978) for fine
particles interacting with larger spray droplets for the
purpose of gas cleaning. The corresponding parameters a
and b in dependence of the bubble (collector) Reynolds
number were derived through numerical simulations (see
Table 1). 2 Impact efficiency Since the
particles may move around the bubble with the relative
flow in the case of smaller and lighter particles, the effective
collision rate of course strongly depends on the so-called
impact efficiency (Sommerfeld and Lain, 2009). The collisional
interaction between particles and bubbles will first result
in a possible momentum exchange, whereby the motion
of both dispersed phases is modified (Bourloutski and
Sommerfeld, 2004). Moreover, depending on the interfacial
conditions, different scenarios of the collision outcome
may be observed, namely rebound, penetration, or sliding
along the surface (Schulze, 1989). This also depends on the
wettability of the solid particles as well as the interfacial
forces relevant during this elementary process (Omota
et al., 2006). al and spheroidal bubbles in laminar flow
367 Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow
367 Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 367 the flow structure around the bubble: diffusion for small particles and inertia for large ones. It should be noted that gravity is counted separately only
in vertical flow situations such as flotation, however, will
cause an asymmetric impact efficiency distribution in
most other situations of dispersed two-phase flows (Galeev
and Zaripov, 2003). The principal definition of the impact
efficiency is the ratio of the circular cross-section from
where the particles are coming (i.e., farther away from the
bubble) and hit the bubble surface, in relation to the
cross-section of this collector bubble. Mostly, the bubbles
are assumed to be spherical for a theoretical analysis of
the impact efficiency (Li et al., 2019). Hence, the area of the
“hit-circle” is defined by the boundary trajectory line of a
point-wise particle just touching the bubble. This boundary
trajectory line naturally deviates from the flow streamline
due to particle inertia. An additional increase of impact
efficiency is caused by interception which accounts for the
effect of finite particle size where the particles are however
still completely following the flow streamlines. On the other
hand, the impact efficiency may be obtained from the number
of particles hitting the bubble as a fraction of those injected
upstream the bubble over the bubble cross-section. 2 Impact efficiency Such an addition is not
accounting for any coupling of the elementary mechanisms
and should be only done if one of the terms is dominant,
as this the case for either gravity dominating at low bubble
Reynolds number and inertia effects prevailing at higher
values: B
Re
< 5
5–25
25–50
50–100 100–250 250–500
> 500
a
0.65
1.24
1.03
0.56
0.4
0.3
0.25
b
3.70
1.97
2.06
1.84
2.0
2.0
2.00 from the work of Weber and Paddock (1983) depending on
velocity and size ratios, as well as the critical collision angle
C
θ of the grazing particle trajectory (i.e., in degree and
measured from the stagnation point) where the particle just
touches the bubble (Weber and Paddock, 1983): inter
total
inter
grav
inertia
2
P
B
1
1
E
E
E
E
E
d
D
é
ù
ê
ú
ê
ú
ê
ú
=
+
+
-
ê
ú
æ
ö
ê
ú
÷
ç +
÷
ç
÷
ç
ê
ú
è
ø
ë
û
(11) (11) P
2
P
B
2
gravity
C
P
B
B
1
sin
1
V
d
U
E
θ
V
D
U
æ
ö÷
ç
=
+
÷
ç
÷
çè
ø
+
(6) (6) In the inertia term an additional multiplier was introduced
(Schulze, 1989), probably to consider a coupling between
interception and inertia effects (Li et al., 2019). In this
equation the influence of diffusion is not considered, since
only larger particles were considered. Brownian diffusion of
particles becomes only of importance if sub-micron particles
are considered. For an immobile bubble with no-slip boundary condition
on the surface, this collision angle was specified in terms
of the bubble Reynolds number (Dobby and Finch, 1987)
using empirical fitting curves to experimental data (Dobby
and Finch, 1987): In order to demonstrate the tendencies in the particle
to bubble impact efficiency for a variation of flow conditions,
i.e., bubble Reynolds number and particle size, the individual
components of the composite correlation (Eq. (11)) are
compared in Figs. 1 and 2. The evaluation of the correlations
was conducted for a rigid 2.5 mm spherical bubble in water
(i.e.,
3
F
1000
,
kg/m
ρ =
F
1.0 mPa s
μ =
⋅). The particles were
spherical with a size between 10 and 200 μm. In Fig. 1 the
results are shown in dependence of particle diameter
whereas in Fig. 2 Impact efficiency 2 the dependence on bubble Reynolds number
for given particle diameters is considered. Naturally, impact
efficiency grows with particle size and will start with very
small values and approach one for large particles. Note that
here the particle size was limited to a maximum of less than
10% of the bubble diameter, since particles are considered as
point masses. When increasing the bubble Reynolds number
(i.e., cases with
B
100, 200, and 500
Re =
are considered), the
importance of the different contributions is continuously
shifted. For small bubble Reynolds numbers, the shares
from inertia and interception are very small over the entire
particle size spectrum (Fig. 1(a)). Gravity is the dominant
mechanism for the impact efficiency. When the bubble
Reynolds number increase, naturally the flow field around
the bubble is changing and so is the impact efficiency; the
importance of gravity falls and inertia effects are growing. At
B
500
Re =
inertia is the dominant collision mechanism C
B
85.0
2.50log
,
0.1
1
θ
Re
Re
=
-
<
<
C
B
85.5
12.49log
,
1
20
θ
Re
Re
=
-
<
<
(7)
C
B
78.1
7.37log
,
20
400
θ
Re
Re
=
-
<
< (7) Finally, the interception effect is considered, which becomes
of importance for larger particles with respect to the bubble
diameter. This finite-size particle effect yields an increase
of the impact efficiency and was specified in terms of the
axisymmetric formulation of the Stokes stream function
for the grazing trajectory
C
ψ (i.e., point particle completely
following the flow), giving the result for an immobile rigid
bubble as (Schulze, 1989): Finally, the interception effect is considered, which becomes
of importance for larger particles with respect to the bubble
diameter. 2 Impact efficiency The gravity-induced impact efficiency was taken (
)
2
P
F
P
B
AM
F
B
0.5
18
ρ
ρ
d U
St
μ
D
+
=
(2) (2) For scaling purposes, the impact efficiency is generally
described as a function of the standard Stokes number in
order to be generally applicable. However, as will be shown
below, the Stokes number seems not to be the only scaling
parameter relevant for the considered process. Also important
is of course the bubble Reynolds number which determines For scaling purposes, the impact efficiency is generally
described as a function of the standard Stokes number in
order to be generally applicable. However, as will be shown
below, the Stokes number seems not to be the only scaling
parameter relevant for the considered process. Also important
is of course the bubble Reynolds number which determines 368 M. Sommerfeld, M. A. Taborda For the case mostly at hand,
P
B
V
U
, the interceptional
impact efficiency is simplified to Table 1 Model parameters a and b for the inertia-based impact
efficiency (Eq. (5)) in dependence of the bubble Reynolds number
taken from Schulze (1989) which were based on the trajectory
simulation data of Schuch and Löffler (1978); it should be noted
that here the Stokes number (Eq. (1)) is defined different as in
Schulze (1989) so that the parameter a is halved *
inter
C
2
E
ψ
=
(10) (10) Eventually, according to Schulze (1989), the overall impact
efficiency is obtained simply as the sum of the above-
described individual effects. 2 Impact efficiency This finite-size particle effect yields an increase
of the impact efficiency and was specified in terms of the
axisymmetric formulation of the Stokes stream function
for the grazing trajectory
C
ψ (i.e., point particle completely
following the flow), giving the result for an immobile rigid
bubble as (Schulze, 1989): C
inter
2
P
B
B
B
2
1
ψ
E
V
U R
U
= æ
ö÷
ç +
÷
ç
÷
çè
ø
(8) (8) The equation for the stream function of the grazing particle
trajectory
C
ψ resulted from an approximation suggested by
Schulze (1989) for a rigid bubble in the case of the particle
diameter being smaller than that of the bubble and was
specified in dependence of the bubble Reynolds number: 2
C
B
P
*
C
2
0.56
B
B
B
3
3 /16
1
4
1
0.249
B
ψ
Re
d
ψ
D
U R
Re
æ
öæ
ö
÷
÷
ç
ç
=
=
+
÷
÷
ç
ç÷
÷
ç÷
ç
è
ø
è
ø
+
(9) (9) 369 Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow (Fig. 1(c)). Interception and gravity have the smallest share
and slightly grow with particle diameter. The overall impact
efficiency is however not necessarily growing with the bubble
Reynolds number as will be discussed in Fig. 2. The variation of the impact efficiency with
B
Re is
demonstrated in Fig. 2, considering again all impaction
components for district particle sizes, namely, 50, 100,
and 200 μm. Certainly, the overall impact efficiency rises Fig. 1 Impact efficiency for the different contributions according to Schulze (1989) at different (spherical) bubble Reynolds numbers:
(a)
B
100
Re =
, (b)
B
500
Re =
, (c)
B
1000
Re =
, in dependence of particle diameter; inertia with Eq. (5), gravity from Eq. (6), intercept with
Eq. (10), and total impact efficiency by Eq. (11) (water:
3
F
1000 kg/m
ρ =
,
F
1.0 mPa s,
μ =
⋅
spherical particles:
3
P
2500 kg/m )
ρ =
. Fig. 1 Impact efficiency for the different contributions according to Schulze (1989) at different (spherical) bubble Reynolds numbers:
(a)
B
100
Re =
, (b)
B
500
Re =
, (c)
B
1000
Re =
, in dependence of particle diameter; inertia with Eq. (5), gravity from Eq. (6), intercept with
Eq. 2 Impact efficiency (10), and total impact efficiency by Eq. (11) (water:
3
F
1000 kg/m
ρ =
,
F
1.0 mPa s,
μ =
⋅
spherical particles:
3
P
2500 kg/m )
ρ =
. Fig. 2 Impact efficiency for the different contributions according to Schulze (1989) for different particle diameters: (a)
P
50
d =
,
(b)
P
100
d =
, (c)
P
200
d =
, in dependence of bubble Reynolds number
B;
Re
inertia with Eq. (5), gravity from Eq. (6), interception with
Eq. (10), and total impact efficiency by Eq. (11) (water:
3
F
1000
,
kg/m
ρ =
F
1.0 mPa s,
μ =
⋅
spherical particles:
3
P
2500 kg/m
ρ =
). Fig. 2 Impact efficiency for the different contributions according to Schulze (1989) for different particle diameters: (a)
P
50
d =
,
(b)
P
100
d =
, (c)
P
200
d =
, in dependence of bubble Reynolds number
B;
Re
inertia with Eq. (5), gravity from Eq. (6), interception with
Eq. (10), and total impact efficiency by Eq. (11) (water:
3
F
1000
,
kg/m
ρ =
F
1.0 mPa s,
μ =
⋅
spherical particles:
3
P
2500 kg/m
ρ =
). 370 M. Sommerfeld, M. A. Taborda remarkably with growing particle diameter. Interestingly,
the overall capture efficiency has a distinct minimum for all
particle sizes, which stems from the competition between
gravity and inertia. Clearly, at small bubble Reynolds
number and hence low velocity magnitudes and gradients
near the bubble interface, gravity is dominating. At higher
B
Re inertia effects are most important for all particle sizes as
they are not able to follow the strong streamline curvature. The cross-over Reynolds number (i.e., where impact efficiency
resulting from gravity and inertia are identical) reduces
from 500 to 350 and 300 for a particle size decrease from
50 μm over 100 μm up to 200 μm (Fig. 2). Interception again
has the smallest contribution but of course grows with
particle diameter. This presentation shows the complexity
of particle collision mechanisms with bubbles, even though
only a laminar flow is considered. bubble shapes were considered. The influence of bubble
deformation (i.e., eccentricity) and orientation angle on the
solid particle collision rates were evaluated for different
bubble Reynolds numbers
B
Re and Stokes numbers
rel. 3 Numerical approach The considered flow domain for the standard case with
a 2.5 mm bubble was a pipe element with a diameter of
40 mm (16 bubble diameters) and a total length of 75 mm,
corresponding to 30 bubble diameters (Fig. 3). Hence, the
ratio between domain diameter and bubble size is 16. The
centroid of the bubble was positioned at 25 mm whereby
the wake region was captured over 50 mm. When considering
other bubble sizes, the computational domain was scaled
accordingly, so that all relevant scale ratios remained the
same. The entire computational domain was discretised by
3 million hexahedral elements with refinements around the
bubble and in the wake region (see Fig. 3). For analysing particle–bubble collisions and interactions
as well as validating the theoretical/empirical correlations
presented above, numerical simulations were conducted for
fixed bubbles exposed to a laminar dilute suspension flow
at various injection velocities. The interface of the bubbles
was, at the moment, assumed to be rigid, meaning a no-slip
condition is applied at the surface. This is for most technical
applications a valid assumption, since these are very often
contaminated and therefore the bubble interface will quickly
become immobile. In the simulations different bubble sizes
(i.e., volume equivalent diameters between 1 and 5 mm) and Fig. 3 Computational domain (left) for a bubble fixed in a stationary downflow (dimensions for a bubble of 2.5 mm volume equivalent
diameter), here the bubble with an eccentricity of 1.8 is inclined at 45° and exposed to a plug flow with
0
0.125 m/s
U =
(
B
312.5
Re =
) as
well as numerical grid with different magnifications (middle and right); middle cut through the entire domain with flow field around the
bubble; upper right: zoom of the region around the bubble; lower right: zoom of the bubble surface grid viewed from the top with grid of
the outlet cross-section in the background. Fig. 2 Impact efficiency St
The bubble Reynolds number not necessarily corresponds
to the steady-state rise Reynolds number for a considered
bubble size, but was varied in a wider range, since also in
a highly turbulent bubbly flow the instantaneous relative
velocity is strongly changing. In all cases considered,
the fluid was assumed to be water with a density of
Fρ =
3
1000 kg/m and a dynamic viscosity of
F
1.0 mPa s. μ =
⋅
The standard case was a bubble with a volume equivalent
diameter of 2.5 mm, which in practice exhibits already a
remarkable deformation (Sommerfeld and Bröder, 2009). The particles were assumed to be spherical glass beads
with a density of 2500 kg/m3 having diameters in the range of
10–200 m. With these conditions relative Stokes numbers
rel
St
up to a value of 2 could be reached. 3 Numerical approach 3 Computational domain (left) for a bubble fixed in a stationary downflow (dimensions for a bubble of 2.5 mm volume equivalent
diameter), here the bubble with an eccentricity of 1.8 is inclined at 45° and exposed to a plug flow with
0
0.125 m/s
U =
(
B
312.5
Re =
) as
well as numerical grid with different magnifications (middle and right); middle cut through the entire domain with flow field around the
bubble; upper right: zoom of the region around the bubble; lower right: zoom of the bubble surface grid viewed from the top with grid of
the outlet cross-section in the background. 371 Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow The inlet was assumed to be a laminar plug flow (i.e., a
laminar flow with constant velocity over the cross-section)
and the wall velocity was set to be identical to the inflow
velocity (i.e., moving wall) so that no boundary layer develops
in the pipe geometry. The outflow boundary conditions
were specified as zero gradients. At the bubble surface zero
velocity conditions were used which implies considering a
rigid “fully contaminated” bubble. A quasi-steady-state flow
solution of the flow field was reached typically after about
3000 fluid iterations, depending on the Reynolds number. Expectedly, at higher bubble Reynolds numbers fluctuations
of the wake may be observed. Fρ , and the fluid rotation obtained from
F
= ´
ω
u . The
relevant resistance coefficients are:
D
C the drag coefficient,
AM
C
the added mass coefficient,
LS
C
the transverse shear
lift coefficient. The gravity vector g is acting downwards
(Fig. 3) in the mainstream direction. For the spherical solid particles considered the standard
drag correlation by Schiller and Naumann (1933) is used: (
)
0.687
D
P
P
24 1
0.15
C
Re
Re
=
+
(14) (14) The particle Reynolds number is of course determined
with the magnitude of the instantaneous relative velocity
between particle and surrounding fluid: Such a frozen flow field was then used for tracking
many particles through the entire computational domain. In the present study 5 million particles were introduced at
random positions distributed over the entire inlet cross-
section. 3 Numerical approach The particles were injected with the fluid velocity
in the streamwise direction
0
U , but adding a small random
component (i.e., 0.5% of the injection velocity
0
U , randomly
selected from a normal distribution function). The lateral
particle mean velocities were assumed to be zero, but
again a random component of
0
0.005U was added. Particle
rotation was not considered in this study, since they
move in a viscous liquid so that they may be assumed to
rotate with the fluid. Therefore, also a rotational lift force
(Sommerfeld et al., 2008) was neglected in this study. The
particle tracking was conducted considering all relevant
forces such as, drag, added mass, slip shear lift force, fluid
inertia (part of the pressure term), and gravity/buoyancy
(Sommerfeld, 2019). The Basset force which may be important
in liquid–solid particle-laden flows (Sommerfeld and
Schmalfuß, 2020) was however at the moment neglected as
it is computationally quite expensive. Thus, particle tracking
is described by the set of ordinary differential equations
in Eqs. (12) and (13): F
P
F
P
P
F
ρ d
Re
μ
-
=
u
u
(15) (15) The applied added mass coefficient was assumed to be
fixed with
AM
0.5
C
=
. The applied added mass coefficient was assumed to be
fixed with
AM
0.5
C
=
. The calculation of the slip-shear lift force for freely
rotating single particles in an unbounded shear flow is based
on analytical results of Saffman (1965) which was extended
for high particle Reynolds number according to Mei (1992)
and generalised according to Sommerfeld (2019). The shear
lift coefficient depends on both the translational particle
Reynolds number (Eq. (15)) and the shear particle Reynolds
number
2
s
F
P
F
/
Re
ρ d
μ
=
ω
. 3 Numerical approach A. Taborda introduced. Subsequently, the impact efficiency for spherical
bubbles is evaluated and discussed. Then deformed bubbles
are considered and the difference in impact efficiency with
respect to spherical bubbles is evaluated. Finally, also impact
statistics including distributions of impact locations as well
as impact velocities are presented, which are important for
model development and for estimating particle sticking. is not moving and also has no dimension. This assumption
is consistent with the bubbles being treated as rigid, i.e., no
particle transport over the interface is considered. At the
outlet the particles are leaving the flow domain. The deposition fraction of particles is obtained from the
number of particles sticking on the bubble surface divided
by the number of particles injected over the circular area
corresponding to the volume equivalent diameter of the
bubbles
dves
A
. The injected particle number in this region
is calculated by 4.1 Flow field results The simulated water flow field about a rigid ellipsoidal
bubble is shown already in Fig. 3 for a volume equivalent
diameter of 2.5 mm, an eccentricity of 1.8, and an inclination
angle of 45°, which is roughly a maximum orientation a
bubble can take in a bubble column flow (Sommerfeld and
Bröder, 2009). With the inflow velocity of
0
0.125 m/s
U =
the bubble Reynolds number is
B
312.5
Re =
, so that the
bubble wake still shows a stationary behaviour, which is
especially the case for tilted bubbles. dves
inj
tot
pipe
A
N
N
A
=
(18) (18) where
pipe
A
is the entire circular inlet cross-section and
tot
N
is the total number of injected particles, in this study
5 million. The impact or capture efficiency is then obtained
from the number of particles hitting the bubble surface,
normalised by the injected number: capture
tot,CFD
inj
N
E
N
=
(19) A more detailed illustration of the flow field about a
spherical and an ellipsoidal rigid bubble with the same
volume equivalent diameter (i.e., 2.5 mm) is presented in
Figs. 4 and 5 illustrating vertical planes through the bubble
centroids (i.e., in y–z and x–z planes) based on colour
contours of the vertical velocity component
. z
U
The images
shown were captured after 3000 fluid iterations where a
converged solution was reached. Comparing the flow field
for a spherical bubble at lower and higher Reynolds number
(Fig. 4), it shows the wider flow deflection at lower
B
Re and
that at higher
B
Re the region of disturbance is much smaller
and consequently the extent of the front stagnation region (19) Additionally, from all particles hitting the bubble the impact
conditions, like velocity and impact angles, were stored, so
that the spatial number distribution of the deposit and other
correlations between impact conditions could be evaluated. 3 Numerical approach The resulting lift coefficient,
also conform with the Saffman (1965) formulation, is
defined as (
)
LS
P
S
P
2
4.1126
,
β
C
f Re Re
Re
=
(16) (16) where the non-dimensional shear rate
S
P
0.5
/
β
Re Re
=
and
the functional extension to higher particle Reynolds numbers
(Mei, 1992) is (
)
1
P
2
P
S
1
2
P
,
1
0.3314
exp
10
0.3314
,
40
Re
f Re Re
β
β
Re
æ
ö
æ
ö
÷
÷
ç
ç
=
-
-
÷
÷
ç
ç
÷
÷
ç
÷
ç
è
ø
è
ø
+
£
(17a)
(
)
(
)
1
2
P
S
P
P
,
0.0524
,
40
f Re Re
βRe
Re
=
³
(17b) P
P
d
dt =
x
u
(12) (12) (
)
(
)
[
]
{
}
p
L
p
p
D
F
P
F
P
p
p
F
F
P
AM
P
P
F
P
LS
P
F
P
P
P
F
F
F
P
P
P
P
d
3
d
4
D
d
D
d
3
4
D
1
D
ρ
m
m C
t
ρ d
ρ
C
m ρ
t
t
ρ m C
d
ρ d
ρ
ρ
m
m
ρ
t
ρ
=
-
-
æ
ö÷
ç
+
-
÷
ç
÷
çè
ø
+
-
´
æ
ö÷
ç
+
+
-
÷
ç
÷
çè
ø
u
u
u
u
u
u
u
u
u
ω
u
g
(3) (17a) (17b) Regarding the particle boundary conditions, a specular
reflection is prescribed at the “pipe” walls, so that no
particles are being lost in the system. For describing the
particle–bubble interaction, the finite size of the particles
is considered, implying that a contact is occurring if the
particle surface just touches the bubble interface (i.e., the
contact is not based on the centroid of the particles). In the
present studies all particles touching the bubble surface
were assumed to stick, building up a stationary deposit which (3) (3) in which,
P
x ,
P
u ,
P
m ,
P,
ρ
P
d are the particle position
and velocity vectors, the particle mass, the material density,
and their diameter, respectively. The fluid properties are the
velocity vector at the particle position
F
u , the fluid density 372 M. Sommerfeld, M. 4 Results and discussion In this section results of the laminar flow field simulations
for different bubble shapes and orientation angles are Fig. 4 Numerically obtained water flow field (vertical velocity component
z
U ) about a spherical 2.5 mm bubble at two different
bubble Reynolds numbers (left:
B
0
78,
0.03125 m/s
Re
U
=
=
; right:
B
0
625,
0.25 m/s
Re
U
=
=
) (note that the colour scale is different
for both cases). Fig. 4 Numerically obtained water flow field (vertical velocity component
z
U ) about a spherical 2.5 mm bubble at two different
bubble Reynolds numbers (left:
B
0
78,
0.03125 m/s
Re
U
=
=
; right:
B
0
625,
0.25 m/s
Re
U
=
=
) (note that the colour scale is different
for both cases). Fig. 4 Numerically obtained water flow field (vertical velocity component
z
U ) about a spherical 2.5 mm bubble at two different
bubble Reynolds numbers (left:
B
0
78,
0.03125 m/s
Re
U
=
=
; right:
B
0
625,
0.25 m/s
Re
U
=
=
) (note that the colour scale is different
for both cases). Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 373 is narrower, indicating that due to the stronger curvature of
the streamlines particle inertia will become more important
when particles interact with a rigid bubble. in this case to the right, and the flow becomes of course
asymmetric. The front stagnation point on the bubble
surface moves to the left and the region of disturbance
in front of the bubble is tilted to the right-hand side. The
particle deposition in these cases will be of course strongly
affected by the modification of the flow field in the front
of an inclined ellipsoidal bubble yielding eventually an
asymmetric deposition pattern. Considering the horizontally aligned ellipsoidal bubble
with eccentricity
1.8
χ =
at higher
B
Re , first of all, it shows
that the bubble wake region becomes wider compared to
the spherical bubble (compare Fig. 4 (right) and Fig. 5 (left,
upper and lower row)). The stagnation region is however
not very different in dimension. It was certainly noticed,
that due to the high bubble Reynolds number, the wake of
the spheroidal bubble is slightly fluctuating in the course of
the iteration process. 4 Results and discussion If the spheroidal bubble is inclined
(here in the x–z plane) the wake region in the y–z plane
becomes narrower when increasing the bubble tilting
angle (Fig. 5 (lower row)). Naturally, the wake region in the
inclination plane (x–z plane in Fig. 5 (upper row)) is shifted, 4.2 Rigid spherical collector in air flow However, it is known, that in an air flow the
pressure term and the added mass are of minor importance. Moreover, simulations have shown that the transverse shear
lift force was not very strong in this case. The simulation
results naturally include all mechanisms considered in the
composite Schulze (1989) model, namely gravity, inertia,
and interception. Of course, for considering interception,
the collisions of point-particles with the bubbles in the
present work accounts for the finite dimension of the
spherical particles in the contact detection. The simulated
impact efficiency in Fig. 6(a) shows the expected behaviour,
namely, at low
rel
St
one has small impact efficiencies as
these small particles move to a large extent around the
collector object with the relative flow. With increasing
rel
St
the impact efficiency is continuously growing in a kind of
skewed S-shaped way, approaching a value of near one at
high Stokes number. Due to interception, these values may
become even slightly larger than unity. Now, when increasing the collector Reynolds number (here from 10 to 500), the
curves for the impact efficiency are continuously shifted
to the right. This means with growing collector Reynolds
number; the total impact efficiency is decreasing. However,
the rate of change is becoming smaller. The total impact efficiency predicted by the Schulze
(1989) correlations shows at the first glance the same
behaviour as the simulations, except that the curves seem
to be shallower (Fig. 6(b)). Likewise, first the curves are
shifted to the right with increasing
B
Re values; however,
beyond
B
50
Re =
the curves again shift to the left. This
behaviour is associated with the minimum predicted for
total
E
when plotted over the collector Reynolds number
(see Fig. 2). This minimum depends on the particle size
and is the result of the competition between gravity at
small
B
Re and inertia prevailing at large
B. Re
In the
numerical simulations, such a minimum was also observed,
but it was less pronounced and the increase of the impact
efficiency in the inertia dominated regime (i.e., at larger
B
Re ) was less strong or even was not observed. A direct comparison of the total impact efficiencies
obtained from the simulations with the results of the Schulze
(1989) model is presented in Fig. 7 for two collector Reynolds
numbers, namely 10 and 50. 4.2 Rigid spherical collector in air flow For the particle tracking all forces summarised above were
considered. However, it is known, that in an air flow the
pressure term and the added mass are of minor importance. Moreover, simulations have shown that the transverse shear
lift force was not very strong in this case. The simulation
results naturally include all mechanisms considered in the
composite Schulze (1989) model, namely gravity, inertia,
and interception. Of course, for considering interception,
the collisions of point-particles with the bubbles in the
present work accounts for the finite dimension of the
spherical particles in the contact detection. The simulated
impact efficiency in Fig. 6(a) shows the expected behaviour,
namely, at low
rel
St
one has small impact efficiencies as
these small particles move to a large extent around the
collector object with the relative flow. With increasing
rel
St
the impact efficiency is continuously growing in a kind of
skewed S-shaped way, approaching a value of near one at
high Stokes number. Due to interception, these values may
become even slightly larger than unity. Now, when increasing by Schulze (1989). In order to cover a proper range of Stokes
numbers for the present geometry with 2.5 mm spherical
objects (i.e.,
int
St
between 0.01 and 50) only for this case
an air flow (
3
F
1.2 kg/m
ρ =
,
6
F
18.5
10
Pa s
μ
-
=
´
⋅) was
considered. Actually, for water as a fluid and a meaningful
upper particle diameter of 200 μm (
3
P
2500 kg/m
ρ =
) the
Stokes number at the highest Reynolds number
B
1250
Re =
reached only a value of 1.1, which is too small to cover the
entire inertia-dominated regime. When considering solid
particles larger than 200 μm interacting with a 2.5 mm
sphere, they may not anymore be treated as point masses. Moreover, in a liquid flow the question about the importance
of other forces on the solid particle motion and deposition,
such as, added mass and transverse lift forces, arises, which
will be discussed in Section 4.3. In an air flow these forces are
negligibly small. In the converged air flow field spherical
particles (
3
P
2500 kg/m
ρ =
) with diameters between 10 and
200 μm were tracked and the total deposition was determined. For the particle tracking all forces summarised above were
considered. 4.2 Rigid spherical collector in air flow Before moving to the analysis of particle deposition pattern
on the bubble surface for the different conditions, the
overall capture or deposition efficiency obtained from
the simulations will be compared in dependence of the
interaction Stokes number
int
St
with the model proposed Fig. 5 Numerically obtained water flow field (vertical velocity component
z
U ) about a spheroidal bubble (
1.8
χ =
, volume equivalent
diameter 2.5 mm) at different inclination (left:
0
α = ; middle:
15
α =
; right:
45
α =
) for a bubble Reynolds number of
B
625,
Re =
0
0.25 m/s
U =
, upper row x–z plane, lower row y–z plane. Fig. 5 Numerically obtained water flow field (vertical velocity component
z
U ) about a spheroidal bubble (
1.8
χ =
, volume equivalent
diameter 2.5 mm) at different inclination (left:
0
α = ; middle:
15
α =
; right:
45
α =
) for a bubble Reynolds number of
B
625,
Re =
0
0.25 m/s
U =
, upper row x–z plane, lower row y–z plane. 374 M. Sommerfeld, M. A. Taborda by Schulze (1989). In order to cover a proper range of Stokes
numbers for the present geometry with 2.5 mm spherical
objects (i.e.,
int
St
between 0.01 and 50) only for this case
an air flow (
3
F
1.2 kg/m
ρ =
,
6
F
18.5
10
Pa s
μ
-
=
´
⋅) was
considered. Actually, for water as a fluid and a meaningful
upper particle diameter of 200 μm (
3
P
2500 kg/m
ρ =
) the
Stokes number at the highest Reynolds number
B
1250
Re =
reached only a value of 1.1, which is too small to cover the
entire inertia-dominated regime. When considering solid
particles larger than 200 μm interacting with a 2.5 mm
sphere, they may not anymore be treated as point masses. Moreover, in a liquid flow the question about the importance
of other forces on the solid particle motion and deposition,
such as, added mass and transverse lift forces, arises, which
will be discussed in Section 4.3. In an air flow these forces are
negligibly small. In the converged air flow field spherical
particles (
3
P
2500 kg/m
ρ =
) with diameters between 10 and
200 μm were tracked and the total deposition was determined. 4.2 Rigid spherical collector in air flow Please remember that the
results are obtained for air as a carrier medium. Generally,
the simulations for these cases give a higher impact
efficiency compared to the model and also the slope for the
low-
B
Re case is slightly higher. It is clear that the numerical
simulations capture all physical effects and also any
coupling between the mechanisms. One effect which was
neglected in the simulations is the Basset force, which acts
as an unsteady drag force due to the delay of boundary
layer development around the solid particles. Thereby, the
particle velocity could be reduced when interacting with
the stagnation point region (i.e., particle deceleration). This
may reduce impact efficiency, whereby the simulations
could be shifted more towards the theory (Fig. 7). On the Fig. 6 Total impact efficiency
total
E
for solid particles interacting with a 2.5 mm collector sphere in an air flow obtained from laminar
flow simulations and Lagrangian particle tracking (a), and the well-accepted Schulze (1989) model (b), considering different collector
Reynolds numbers
B
Re and particle diameters between 10 and 200 μm (
3
P
2500 kg/m
ρ =
). Fig. 6 Total impact efficiency
total
E
for solid particles interacting with a 2.5 mm collector sphere in an air flow obtained from laminar
flow simulations and Lagrangian particle tracking (a), and the well-accepted Schulze (1989) model (b), considering different collector
Reynolds numbers
B
Re and particle diameters between 10 and 200 μm (
3
P
2500 kg/m
ρ =
). Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 375 Fig. 7 Total impact efficiency
total
E
for solid particles interacting with a 2.5 mm collector sphere in an air flow; comparison of laminar
flow simulations and Lagrangian particle tracking and the well-accepted Schulze (1989) model considering two collector Reynolds
numbers, left:
B
10
Re =
and right:
B
50
Re =
(particle diameters between 10 and 200 μm;
3
P
2500 kg/m
ρ =
). Fig. 7 Total impact efficiency
total
E
for solid particles interacting with a 2.5 mm collector sphere in an air flow; comparison of laminar
flow simulations and Lagrangian particle tracking and the well-accepted Schulze (1989) model considering two collector Reynolds
numbers, left:
B
10
Re =
and right:
B
50
Re =
(particle diameters between 10 and 200 μm;
3
P
2500 kg/m
ρ =
). Fig. 4.2 Rigid spherical collector in air flow 8 Numerically obtained deposition pattern for 50 m particles
(
3
P
2500 kg/m
ρ =
) on a 2.5 mm rigid spherical bubble in water
at different inflow velocities of 0.0625, 0.125, 0.25, and 0.5 m/s
(
B
156.25, 312.5, 625, and 1250
Re =
) viewed from the top (the
deposition counter per area has a colour scale from 0 to 1×108 m−2
for all four cases). other hand, the theoretical model is based on many
assumptions, among which the conjuncture of the critical
collision angle for the gravity effect is based on empirical
correlations (Dobby and Finch, 1987). Moreover, the typical
inertia term (Schuch and Löffler, 1976) was supplemented
by three additional terms, which were needed to match
flotation experiments and to allow for including gravity
effects separately in the total impact efficiency. Finally,
Schulze (1989) mentioned the neglection of centrifugal
effects on particles moving along curved streamlines in
their theoretical derivation. Such mechanisms are of course
automatically considered in the particle tracking simulations. The streamline curvature around the front stagnation
region of the bubble should yield an enhancement of
deposition, whereas the outwards bulged streamlines around
the bubble equator will cause a reduction of deposition
which is assumed to be less important. Hence, including
such effects in the theory would give a net enhancement
of deposition and resultingly a better agreement with the
simulations (Fig. 7). Fig. 8 Numerically obtained deposition pattern for 50 m particles
(
3
P
2500 kg/m
ρ =
) on a 2.5 mm rigid spherical bubble in water
at different inflow velocities of 0.0625, 0.125, 0.25, and 0.5 m/s
(
B
156.25, 312.5, 625, and 1250
Re =
) viewed from the top (the
deposition counter per area has a colour scale from 0 to 1×108 m−2
for all four cases). 4.3 Rigid spherical collector bubble in water flow (Fig. 9). Actually, this Reynolds number is located just
before the regime where bubble oscillation begins, namely,
for
B
400
Re »
(Clift et al., 1978). As before, in the case of
lower Reynolds number the fine particles produce a rather
sparce deposition pattern (Fig. 9 (upper block, left)), but
almost covering the entire front hemisphere. Expectedly,
with increasing particle size, the total deposition is growing
and the patterns are becoming more filled, however, still
having the maximum deposition number around the pole
of the bubble. Clearly, the region next to the equator for the
100 μm particles is less covered by particles. The very large
particles produce an almost complete coverage of the upper
hemisphere facing the inflow. Now comes a surprise, posing
the question on the relevant physical mechanism. Why
larger particles can deposit on the rear bubble hemisphere
downstream of the equator (Fig. 9 (lower block))? This is
not observed to occur for the smaller particles. The particles
are also not very strongly entrained into the bubble wake
flow which is illustrated by combining the side view of
the deposition pattern on the bubble surface with a vertical
slice through the bubble centroid for the particle concentration
field (Fig. 9). The concentration field indicates that probably
particles smaller than 50 μm (Stokes number
AM
0.021
St
=
)
will be more entrained into the bubble wake. With growing
particle size, more particles are entrained into the wake and
concentrate at the rim of the wake region, especially for the
largest particles considered, i.e.,
P
AM
200 μm,
0.33
d
St
=
=
. Such an accumulation may probably modify the bubble
added mass force in a suspension. The reason for particle deposition downstream of the
bubble equator is the shear-induced transverse lift force (see
Eq. (13)), which drives larger particles towards the bubble
surface. But of course, the direction of the shear-lift depends
on the direction of the slip velocity between particle and
fluid and the gradient of the flow velocity within the bubble
boundary layer (Sommerfeld et al., 2008; Sommerfeld, 2019). This lift force is also responsible for the stronger entrainment
of the larger particles into the wake of the bubble (Fig. 9
(lower block)). 4.3 Rigid spherical collector bubble in water flow The analysis of particle deposition on a spherical bubble
with 2.5 mm is first based on the observed pattern in
dependence of the collector bubble Reynolds number
B
Re
exposed to a laminar water suspension flow with small 50
μm particles and
3
P
2500 kg/m
ρ =
(Fig. 8). For such small
particles the overall deposition or impact efficiency defined
by Eqs. (18) and (19) is very low for all values of
B
Re
considered, namely, below about 5%. Even though a quite
large number of particles is injected over the entire inlet
area, the resulting deposition pattern looks quite sparce in
all cases (Fig. 8). Such a stochastic distribution of depositions
is associated with the spatially random injection of the
particles and the slight random variation of injection velocity
(see Section 3). At low Reynolds number (i.e.,
B
156.25)
Re = the particles are hitting the entire upper hemisphere mainly
due to gravity (see Fig. 2) and are rather homogeneously
distributed. When increasing the collector Reynolds
number, an interesting phenomenon is observed, namely,
the deposition region for the particles is shrinking in size,
indicating the transition to the inertia-dominated deposition
(see Fig. 2 (above)). Actually, the overall impact efficiency
in dependence of
B
Re (i.e., 156.25, 312.5, 625, and 1250)
shown in Fig. 8 decreases continuously, namely, 0.0412,
0.0242, 0.0193, and 0.024. Now the variation of the deposition pattern on a rigid
spherical bubble in water at
B
312.5
Re =
with an increase
in particle size from 50 to 200 μm will be considered 376 M. Sommerfeld, M. A. Taborda ,
Fig. 9 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm spherical collector bubble in
water at a Reynolds number of
B
0
312.5,
0.125 m/s
Re
U
=
=
and
different sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(
3
P
2500 kg/m
ρ =
) (upper rows: deposition pattern viewed from
the top (the deposition counter per area has a colour scale from
0 to 1×108 m−2) in the case of 50 and 100 μm particles and from
0 to 5×108 m−2 for the larger particles with 150 and 200 μm); lower
rows: vertical slice through the bubble centroid illustrating the
particle concentration field (kg/m3); please note the variable
colour scale, 50 μm: 0–5 kg/m3; 100 μm: 0–35 kg/m3; 150 μm:
0–120 kg/m3, 200 μm: 0–250 kg/m3). 4.3 Rigid spherical collector bubble in water flow 10 Calculated particle trajectories (
P
200 μm
d =
,
3
P
2500 kg/m
ρ =
) around a spherical bubble of 2.5 mm diameter in water at a
Reynolds number of
B
0
156.25 (
0.0625 m/s)
Re
U
=
=
(left: without shear lift force; right: with shear lift force); the back-ground colour
corresponds to the magnitude of flow velocity (velocity scale from 0 to 0.07 m/s). is reduced due to the lift as will be illustrated below. Such a
situation is occurring when the flow around the bubble is
accelerated by the defection and the heavy particles are not
able to follow immediately. force on the other hand, the particle trajectories entering
the boundary layer are bend towards the bubble surface
and deposit. Even particles passing the equator may deposit
on the lower hemisphere of the bubble (see Fig. 9). Other
particles are stronger entrained into the wake flow and
form a layer of very high particle concentration (see Fig. 9
(lower block)). Also, for the 100 m particles an observable
effect of the transverse lift force is identified, which is
eventually very small for 50 m particles. Hence, as expected,
the slip-shear lift force is considerably more important for
larger particles. The results presented so far clearly showed a strong
dependence of the deposition efficiency on the collector
Reynolds number and the forces considered to acting on
the particles. The importance of forces naturally is affected
by the environment, which is a liquid phase in the case
of flotation or chemical reactors and therefore all forces
like drag, pressure, added mass, and gravity/buoyancy are
important. For the moment the numerically quite expensive
Basset force was still neglected; however, it will have a similar
influence as the added mass. The drastic importance of
the transverse shear lift was already highlighted above. In
Fig. 12 the impact efficiency in dependence of
B
Re is shown
for small 50 m and larger 150 m particles. It should
be noted, that fixing the particle size at varying Reynolds
number still implies a change of the interaction Stokes
number. With increasing Reynolds number and considering
all forces, it shows for both particle sizes a decay of the
impact efficiency, approaching some plateau or limiting
value. Neglecting now only gravity, but keeping all other
forces (see Eq. 4.3 Rigid spherical collector bubble in water flow It should be noted that in a gas flow,
presented above, the transverse shear lift force was found
to be of minor importance for deposition, even though the
slip between 200 μm particles and the gas flow may be
higher compared to smaller particles. Fig. 9 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm spherical collector bubble in
water at a Reynolds number of
B
0
312.5,
0.125 m/s
Re
U
=
=
and
different sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(
3
P
2500 kg/m
ρ =
) (upper rows: deposition pattern viewed from
the top (the deposition counter per area has a colour scale from
0 to 1×108 m−2) in the case of 50 and 100 μm particles and from
0 to 5×108 m−2 for the larger particles with 150 and 200 μm); lower
rows: vertical slice through the bubble centroid illustrating the
particle concentration field (kg/m3); please note the variable
colour scale, 50 μm: 0–5 kg/m3; 100 μm: 0–35 kg/m3; 150 μm:
0–120 kg/m3, 200 μm: 0–250 kg/m3). The effect of the shear lift is better illustrated through
the visualisation of particle trajectories (Fig. 10). For that
purpose, 80 particles were introduced at the inlet along a
line corresponding to the vertical plane through the bubble
centroid. The particles were then tracked until deposition
occurs or they have passed the bubble. In Fig. 10 the
trajectories of large particles with 200 m are presented for
the cases without and with shear-lift. Neglecting the lift
force yields relative smooth particle trajectories, which are hitting the bubble in a straight way and particles passing
the equator of the bubble are moving further downwards
on almost straight paths (Fig. 10 (left)). With the shear lift Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 377 Fig. 10 Calculated particle trajectories (
P
200 μm
d =
,
3
P
2500 kg/m
ρ =
) around a spherical bubble of 2.5 mm diameter in water at a
Reynolds number of
B
0
156.25 (
0.0625 m/s)
Re
U
=
=
(left: without shear lift force; right: with shear lift force); the back-ground colour
corresponds to the magnitude of flow velocity (velocity scale from 0 to 0.07 m/s). Fig. 4.3 Rigid spherical collector bubble in water flow (13)) demonstrates again the strong importance
of gravity for low
B
Re in the present situation with the
gravity acting in flow direction. This behaviour is also
predicted by the theory presented in Fig. 2. When neglecting
gravity, for both particle sizes the simulated impact efficiency
is very small at low
B
Re and increases with growing
Reynolds number implying that inertia becomes more
important (Fig. 12). The process of particle interaction with the boundary
layer flow is illustrated in Fig. 11. First, due to the action of
the downward gravity the heavy particles should be faster
than the fluid. Moreover, inertial particles entering the
boundary layer from the topside with a higher velocity will
be faster than the fluid and therefore, the lift is pushing the
particles towards the bubble surface. In the case of particles
which lag the flow within the boundary layer, i.e., the
particle downward velocity is lower than the local fluid
velocity, the shear lift is driving the particles out of the
boundary layer and consequently, the deposition efficiency Fig. 11 Illustration of the action of the shear-induced lift on a
solid particle moving around a large rigid bubble (i.e., suspension
flow directed downwards) (left: fast solid particle moving from
outside into the boundary layer on the bubble surface yielding a
lift towards the bubble; right: the particle lags behind the flow and
the lift force is acting away from the bubble surface, this situation
is supported by the accelerative flow around the bubble which the
particles are not able to follow). Fig. 11 Illustration of the action of the shear-induced lift on a
solid particle moving around a large rigid bubble (i.e., suspension
flow directed downwards) (left: fast solid particle moving from
outside into the boundary layer on the bubble surface yielding a
lift towards the bubble; right: the particle lags behind the flow and
the lift force is acting away from the bubble surface, this situation
is supported by the accelerative flow around the bubble which the
particles are not able to follow). Expectedly, added mass and pressure term are less
important for small particles and lower
B,
Re
since they
increase fluid resistance against the direction of motion
and hence reduce particle downward velocity, yielding
eventually a reduction of impact efficiency. Disregarding
the shear-induced lift force in a liquid flow has a drastic 378 M. Sommerfeld, M. A. Taborda Fig. 4.3 Rigid spherical collector bubble in water flow 12 Total impact efficiency
total
E
for solid particles: (a)
P
50 μm
d =
; (b)
P
150 μm
d =
(
3
P
2500
)
kg/m
ρ =
interacting with a
spherical bubble (
B
2.5 mm
D =
) in water obtained from laminar flow simulations and Lagrangian particle tracking considering
different force combinations for varying Reynolds numbers
B. Re Fig. 12 Total impact efficiency
total
E
for solid particles: (a)
P
50 μm
d =
; (b)
P
150 μm
d =
(
3
P
2500
)
kg/m
ρ =
interacting with a
spherical bubble (
B
2.5 mm
D =
) in water obtained from laminar flow simulations and Lagrangian particle tracking considering
different force combinations for varying Reynolds numbers
B. Re influence on impact efficiency (Fig. 12). As mentioned above,
shear lift is more relevant for larger particles (see also
Sommerfeld (1996)) and enhances remarkably deposition
for lower
B
Re (i.e., consistent with the result presented
in Fig. 10), but interestingly reduces impact probability for
larger
B
Re (Fig. 12(b)). In the case of spherical bubbles
with 2.5 mm, this transition is found at
B
900
Re =
, from
where on transverse lift reduces deposition. This effect may
be again illustrated showing particle trajectories around
the bubble for the condition of
B
1250
Re =
(Fig. 13). Please note that for this high bubble Reynolds number the
predicted liquid flow showed slight asymmetries, i.e., the
wake is slightly diverted to the left. Without transverse lift
force, particles hit the bubble up to an angle of about 50°
from the front stagnation point and all other particles
injected at larger radial positions pass by the bubble on
smooth trajectories. They are also not decisively entrained
into the wake of the bubble. Accounting for the lift force
shows that particles are deposited only until an angle of
about 30° from the stagnation point. Particles approaching
the bubble further outward are sharply deflected away from the bubble surface within the boundary layer (i.e., mechanism
illustrated in Fig. 11(b)) and thereafter carried along with
the flow, bypassing the bubble. At the considered high bubble
Reynolds number the streamlines are strongly squeezed
towards the bubble surface so that in the region of the front
stagnation point very high velocity gradients are existing. 4.3 Rigid spherical collector bubble in water flow Particles will enter the boundary layer with relatively large
downward velocity, but the particle velocity component
tangential to the bubble surface will be considerably lower
than the fluid tangential velocity (condition illustrated in
Fig. 11 (right)) so that they are expelled out of the boundary
layer by the shear lift (Fig. 13). Moreover, particles coming
out of the bubble boundary layer just downstream of the
front stagnation point (i.e., deflected particles) with lower
velocity will enter the outer region of the boundary layer
with higher flow velocity and as a result the lift will act
outwards as shown in Fig. 11(b). When only drag and gravity are considered, just like in
the theory (Fig. 2), one obtains a similar behaviour with
increasing
B
Re ; initially the impact efficiency is high due to
gravity effects, around
B
300
Re »
a minimum is observed, Fig. 13 Calculated particle trajectories (
P
150 μm
d =
) around a rigid spherical bubble in water with 2.5 mm diameter at a Reynolds
number of
B
0
1250 (
0.5 m/s)
Re
U
=
=
(left: without shear lift force; right: with shear lift force); the back-ground colour corresponds to
the magnitude of flow velocity (velocity scale from 0 to 0.6 m/s). Fig. 13 Calculated particle trajectories (
P
150 μm
d =
) around a rigid spherical bubble in water with 2.5 mm diameter at a Reynolds
number of
B
0
1250 (
0.5 m/s)
Re
U
=
=
(left: without shear lift force; right: with shear lift force); the back-ground colour corresponds to
the magnitude of flow velocity (velocity scale from 0 to 0.6 m/s). Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 379 Fig. 4.4 Rigid ellipsoidal collector bubble in water flow This part of the results is devoted to deformed rigid bubbles
where the shape is assumed to be an oblate spheroid or
ellipsoid. Examining first the deposition pattern and the
particle concentration field around a spheroidal bubble with
an eccentricity of
1.8
χ =
(Fig. 14) gives basically the same
picture as for the spherical bubbles (Fig. 9). In this context
it should be remarked that all properties, like bubble
Reynolds number and the impact efficiency are determined
on the basis of the volume equivalent diameter, which in
this case is also 2.5 mm. The top view of the deposition
pattern shows that the small particles (i.e., 50 μm) have a
low impact efficiency, again the particles are covering the
entire upper part of the ellipsoidal bubble facing the flow,
however, also rather sparce. The deposition densities of
course increase with growing particle diameter, and they
also show a maximum around the front stagnation point
(Fig. 14). The side views depict the deposition pattern on
the bubble surface as well as a vertical plane of the particle
concentration going through the bubble centroid. This
concentration distribution clearly demarks the region of
the bubble wake (Fig. 14). Similar to the results for the
spherical bubble, the slip-shear lift on the particles causes
their deposition on the luff-side of the bubble, downstream
of the equator. Fig. 14 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm horizontally aligned and
deformed spheroidal bubble with eccentricity
1.8
χ =
at a
Reynolds number of
B
0
312.5,
0.125 m/s
Re
U
=
=
and different
sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(upper rows:
deposition pattern viewed from the top (the deposition counter
per area has different colour scales for better visualising the
distribution, upper row from 0 to 1×108 m−2 and lower row from
0 to 5×108 m−2), lower rows: vertical slice through the bubble
centroid illustrating the particle concentration field (kg/m3);
please note the variable colour scale, 50 μm: 0–5 kg/m3; 100 μm:
0–30 kg/m3; 150 μm: 0–200 kg/m3; 200 μm: 0–250 kg/m3). Interesting is the accumulation of particles in the
bubble wake, which strongly depends on the particle size
and hence the Stokes number. Very small particles (i.e.,
P
AM
50 μm,
0.02
d
St
<
<
) easily tend to be entrained over
the entire wake region (Figs. 4 and 5). 4.3 Rigid spherical collector bubble in water flow 14 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm horizontally aligned and
deformed spheroidal bubble with eccentricity
1.8
χ =
at a
Reynolds number of
B
0
312.5,
0.125 m/s
Re
U
=
=
and different
sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(upper rows:
deposition pattern viewed from the top (the deposition counter
per area has different colour scales for better visualising the
distribution, upper row from 0 to 1×108 m−2 and lower row from
0 to 5×108 m−2), lower rows: vertical slice through the bubble
centroid illustrating the particle concentration field (kg/m3);
please note the variable colour scale, 50 μm: 0–5 kg/m3; 100 μm:
0–30 kg/m3; 150 μm: 0–200 kg/m3; 200 μm: 0–250 kg/m3). and beyond this point the impact efficiency again increases
due to inertia (Fig. 12). With respect to considering all
relevant forces, the result only accounting for drag and gravity
yields a huge difference. For smaller
B
Re considering all
forces, higher deposition is obtained, whereas at larger
B
Re
simulations with all forces give lower deposition. This
demonstrates that the theory is not appropriate for large
particles. For smaller particles (here 50 m) there is no
large difference in the results obtained with the different
force settings (Fig. 12(a)), increasing however for growing
B
Re . Hence, the theory of Schulze (1989) has a limited
applicability and is more suitable for smaller particles, since
it was derived on the basis of simulations conducted for a
gas flow (Schuch and Löffler, 1978). 4.4 Rigid ellipsoidal collector bubble in water flow The largest particles
(i.e.,
P
AM
200 μm,
0.33
d
St
=
=
) clearly accumulate near the
rim of the wake region, whereas slightly smaller particles
(i.e.,
P
AM
150 μm,
0.19
d
St
=
=
) are also entrained into the
toroidal vortex structure established within the wake. In a
practical situation where bubbles and particles are moving
within the facility, such a particle accumulation in the wake of the bubbles will of course increase the added mass
force acting on the bubbles. Such a complex process may be
evaluated in more detail using numerical flow simulations
with resolved bubbles through for example a VOF
(volume-of-fluid) method. 380 M. Sommerfeld, M. A. Taborda Fig. 16 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm ellipsoidal and inclined
bubble (
1.8,
45
χ
α
=
=
) in water at a Reynolds number of
B
0
625,
0.25 m/s
Re
U
=
=
and different sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(
3
P
2500 kg/m
ρ =
) (upper rows:
deposition pattern viewed from the side (the deposition counter
per area has a colour scale from 0 to 1×108 m−2), lower rows:
deposition pattern viewed from the side perpendicular to the
incarnation plane; both include vertical slices through the bubble
centroid illustrating the particle concentration field (kg/m3);
please note the variable colour scale, 50 μm: 0–2.5 kg/m3; 100 μm:
0–20 kg/m3; 150 μm: 0–80 kg/m3; 200 μm: 0–200 kg/m3). For the horizontally aligned ellipsoidal bubble with
1.8
χ =
, also the capture or impact efficiency versus the
bubble Reynolds number was analysed for 150 μm particles
considering different force settings (Fig. 15). The general
trends are very similar to those observed for the spherical
bubble (Fig. 12), but the spheroidal bubble results show
higher impact efficiencies for all force settings considered,
except for the case without gravity. Moreover, the influence
of the shear-lift onto the particle motion is less pronounced
compared with the spherical bubble (compare Figs. 12 and
15) and the associated increase of deposition is lower. The
transition Reynolds number where the action of the lift force
is reversed (i.e., from increasing to reducing deposition)
already occurs at
B
600
Re »
. The added mass effect has
roughly the same impact for spherical and ellipsoidal bubbles
(Fig. 15). 4.4 Rigid ellipsoidal collector bubble in water flow Finally, the influence of bubble inclination on the
deposition pattern will be investigated. The measurements
of Sommerfeld and Bröder (2009) showed that the bubble
tilting angle in a laboratory bubble column is distributed
between ±45 at maximum. Hence, as an extreme case the
inclination angle of 45 is considered (Fig. 16), again with a
volume equivalent diameter of 2.5 mm and an eccentricity
of
1.8
χ =
, which is also near the maximum of the
measured eccentricities in a bubble column (Sommerfeld
and Bröder, 2009). The bubble Reynolds number is selected
to be
B
625
Re =
, located in the wobbling regime of bubbles
(Clift et al., 1978). As to be expected, the asymmetric flow
about the deformed bubble (Fig. 5) results in an asymmetric
and shifted deposition pattern (Fig. 16). For small particles
the deposition pattern is again quite sparse. Increasing
particle size of course results in growing impact or deposition
efficiency. The topology of deposition for the largest
particles again illustrates the negative effect of the shear lift, Fig. 15 Total impact efficiency
total
E
for solid particles (150 μm,
3
P
2500 kg/m
ρ =
) interacting with a horizontally aligned ellipsoidal
bubble (
B,ves
2.5 mm
D
=
) in water obtained from laminar flow
simulations and Lagrangian particle tracking considering different
force combinations for varying Reynolds numbers
B
Re . Fig. 16 Numerically obtained deposition pattern and particle
concentration fields for a 2.5 mm ellipsoidal and inclined
bubble (
1.8,
45
χ
α
=
=
) in water at a Reynolds number of
B
0
625,
0.25 m/s
Re
U
=
=
and different sizes of particles, i.e.,
P
50,100,150, and 200 μm
d =
(
3
P
2500 kg/m
ρ =
) (upper rows:
deposition pattern viewed from the side (the deposition counter
per area has a colour scale from 0 to 1×108 m−2), lower rows:
deposition pattern viewed from the side perpendicular to the
incarnation plane; both include vertical slices through the bubble
centroid illustrating the particle concentration field (kg/m3);
please note the variable colour scale, 50 μm: 0–2.5 kg/m3; 100 μm:
0–20 kg/m3; 150 μm: 0–80 kg/m3; 200 μm: 0–200 kg/m3). similar to the observation for spherical bubbles (see Figs. 12
and 13). There is only little deposition on the luff side of the
bubble. This was also observed on the graph for the total
impact efficiency (Fig. 15). 4.5 Comparison for different conditions in water flow 4.5 Comparison for different conditions in water flow For the first time bubble shape effect on the impact efficiency
for fine particles was numerically analysed. The main question
to answer was in as much bubble deformation enhances
capture efficiency and hence fine particle flotation. For the
comparison of spherical and ellipsoidal bubble flotation the
total impact efficiency according to Eqs. (18) and (19) was
determined from the simulations and plotted versus the
particle diameter as well as the relative Stokes number
AM
St
(Eq. (2)). In Fig. 17 the comparison of the capture
efficiency for both bubble shapes at various
B
Re is shown. Similar to the trends found for a collector in an air flow
(Fig. 6), the impact efficiency is reduced with growing
B,
Re
suggesting that in a flotation the relative velocity
between bubbles and suspension should be kept as small as
possible in order to make use of the strong dominance of
gravity for low
B
Re and for small particles (see also Fig. 2). It should be kept in mind, that due to the treatment of the
particles as point-masses an upper limit of
P
200 μm
d =
was a meaningful assumption. Therefore, in the present
configuration of relevance (i.e., bubble size
B
2.5 mm
D =
)
the efficiency curves in Fig. 17 do not show the typical
S-shape as in Fig. 6 for the airflow. Expectedly, the impact
efficiency grows with particle diameter and is enhanced for
the oblate spheroidal bubbles compared to the spherical
ones. This enhancement grows with the reduction of bubble
Reynolds number (Fig. 17). Plotting the capture efficiency
versus the Stokes number
AM
St
, the curves for spherical and
elliptical bubbles are very similar, again with higher
total
E
for the spheroidal bubbles. For the smallest bubble Reynolds
number at larger particle diameters, this increase is at
maximum about 10%. For smaller bubble eccentricities the The comparison of the capture efficiency in dependence
of particle diameter is depicted in Fig. 18 for a horizontally
aligned bubble and one inclined by 45. Since in this
configuration the effective bubble capturing cross-section
facing the flow is smaller, the values for the impact efficiency
are also slightly reduced. Although there is not a large
difference for the considered static situation, a dynamic
oscillating and tumbling bubble motion could give an
enhancement of impact efficiency. 4.4 Rigid ellipsoidal collector bubble in water flow Interesting is again the interaction
of the particles with the bubble wake structure, which shows Fig. 15 Total impact efficiency
total
E
for solid particles (150 μm,
3
P
2500 kg/m
ρ =
) interacting with a horizontally aligned ellipsoidal
bubble (
B,ves
2.5 mm
D
=
) in water obtained from laminar flow
simulations and Lagrangian particle tracking considering different
force combinations for varying Reynolds numbers
B
Re . Fig. 15 Total impact efficiency
total
E
for solid particles (150 μm,
3
P
2500 kg/m
ρ =
) interacting with a horizontally aligned ellipsoidal
bubble (
B,ves
2.5 mm
D
=
) in water obtained from laminar flow
simulations and Lagrangian particle tracking considering different
force combinations for varying Reynolds numbers
B
Re . Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 381 impact efficiency would of course lay between the spherical
bubble and the results for
1.8
χ =
. almost no entrainment and accumulation of particles. For
the large particles some particle braids are shedding off the
upper side of the bubble (Fig. 16 (lower block)). The dependence of the impact efficiency on the relative
Stokes number (Fig. 17) also demonstrates that it will not
be an easy task to establish a generalised correlation for the
impact efficiency in dependence of relative Stokes number
AM
St
and bubble Reynolds number
B
Re , similar to Eqs. (5)
and (11), due to the relative importance of the fluid forces
for different sized particles. 4.5 Comparison for different conditions in water flow 4.5 Comparison for different conditions in water flow A comparison of the capture efficiency obtained for the
different bubble sizes and shapes is presented in Fig. 19,
namely for a spherical bubble with 2.5 mm, and spheroidal
bubbles with
1.8
χ =
having volume equivalent diameters
of 2.5 mm as well as 4.0 mm. The impact efficiency for the
large deformed bubble is considerably higher, especially at
lower but identical
B. Re
Hence, the large bubble captures
much more particles, since for the same Reynolds number
the bubble vertical relative velocity is much smaller, which
strongly influences particle–bubble interaction. 4.6 Impact statistics for a spherical collector bubble in
water flow 18 Total particle capture efficiency
total
E
for ellipsoidal bubbles
(eccentricity=1.8,
B,ves
2.5 mm
D
=
) in water at two different
inclination angles (i.e., horizontally aligned bubble
0
α = and
45
α =
) in dependence of particle diameter (
3
P
2500 kg/m
ρ =
)
for three bubble Reynolds numbers
B
Re obtained from laminar
flow simulations and Lagrangian particle tracking considering
all force. p
(c)
(d)
(
(
)
)
a
p
p
a
Fig. 20 Relative probability (number of locally impinging particles
over injected number of particles given by Eq. (19)) divided by
cross-sectional area of solid particles hitting a 2.5 mm spherical
bubble at laminar water flow for different bubble Reynolds numbers
B
Re and particle diameters (
3
P
2500 kg/m
ρ =
): (a)
B
156.25
Re =
,
(b)
B
312.5
Re =
, (c)
B
625,
Re =
and (d)
B
1250
Re =
. Fig. 19 Total particle capture efficiency
total
E
for spherical and
ellipsoidal (eccentricity=1.8) bubbles in water with different
diameter (
B,ves
2.5 and 4.0 mm
D
=
) in dependence of relative
Stokes number
AM
St
for two bubble Reynolds numbers
B
Re
obtained from laminar flow simulations and Lagrangian particle
tracking considering all force (spherical solid particles with
3
P
2500 kg/m
ρ =
). (c)
(d)
(
)
a
p (c) Fig. 19 Total particle capture efficiency
total
E
for spherical and
ellipsoidal (eccentricity=1.8) bubbles in water with different
diameter (
B,ves
2.5 and 4.0 mm
D
=
) in dependence of relative
Stokes number
AM
St
for two bubble Reynolds numbers
B
Re
obtained from laminar flow simulations and Lagrangian particle
tracking considering all force (spherical solid particles with
3
P
2500 kg/m
ρ =
). (d) (d)
(
)
p
a and also to estimate a sticking probability considering the
relevant interfacial forces (Omota et al., 2006). Consequently,
in order to support the modelling of impact efficiencies and
a possible particle sticking on the bubble surface, the
distributions of all impact locations over the bubble radius
as well as scatter plots of the instantaneous particle impact
velocity are evaluated from the simulations for a spherical
rigid bubble in water flow. All the impact points over
the bubble surface are counted and classified with respect
to radius and subsequently normalised by the respective
projected annular area. 4.6 Impact statistics for a spherical collector bubble in
water flow Consequently,
in order to support the modelling of impact efficiencies and
a possible particle sticking on the bubble surface, the
distributions of all impact locations over the bubble radius
as well as scatter plots of the instantaneous particle impact
velocity are evaluated from the simulations for a spherical
rigid bubble in water flow. All the impact points over
the bubble surface are counted and classified with respect
to radius and subsequently normalised by the respective
projected annular area. The profiles presented in Fig. 20
for different bubble Reynolds numbers and a number of
particle diameters confirm the qualitative result presented
in Figs. 8 and 9. When increasing the bubble Reynolds
(a)
(b)
p
p
a
a
(
(
)
)
(c)
(d)
(
(
)
)
a
p
p
a
Fig. 20 Relative probability (number of locally impinging particles
over injected number of particles given by Eq. (19)) divided by
cross-sectional area of solid particles hitting a 2.5 mm spherical
bubble at laminar water flow for different bubble Reynolds numbers
B
Re and particle diameters (
3
P
2500 kg/m
ρ =
): (a)
B
156.25
Re =
,
(b)
B
312.5
Re =
, (c)
B
625,
Re =
and (d)
B
1250
Re =
. Fig. 18 Total particle capture efficiency
total
E
for ellipsoidal bubbles
(eccentricity=1.8,
B,ves
2.5 mm
D
=
) in water at two different
inclination angles (i.e., horizontally aligned bubble
0
α = and
45
α =
) in dependence of particle diameter (
3
P
2500 kg/m
ρ =
)
for three bubble Reynolds numbers
B
Re obtained from laminar
flow simulations and Lagrangian particle tracking considering
all force. (a)
(b)
p
p
a
a
(
(
)
) (a)
(b)
p
a
(
) (a)
(b)
p
p
a
a
(
(
)
)
(c)
(d)
(
(
)
)
a
p
p
a
g. 20 Relative probability (number of locally impinging particle
ver injected number of particles given by Eq. (19)) divided b
oss-sectional area of solid particles hitting a 2.5 mm spherica
ubble at laminar water flow for different bubble Reynolds number
Be and particle diameters (
3
P
2500 kg/m
ρ =
): (a)
B
156.25
Re =
)
B
312.5
Re =
, (c)
B
625,
Re =
and (d)
B
1250
Re =
. (b) (b)
p
a
(
) Fig. 4.6 Impact statistics for a spherical collector bubble in
water flow 4.6 Impact statistics for a spherical collector bubble in
water flow 4.6 Impact statistics for a spherical collector bubble in
water flow Besides the presented results on global impact or capture
efficiencies, the numerical simulations allow to extract much
more information for each individual impact, such as impact
velocities and impact angles of the particles. From these data
it is possible to evaluate appropriate probability distributions Fig. 17 Total particle capture efficiency
total
E
for spherical and ellipsoidal (eccentricity=1.8) bubbles in water (
B,ves
2.5 mm
D
=
), in
dependence of (a) particle diameter (
3
P
2500 kg/m
ρ =
) and (b) relative Stokes number
AM
St
for a range of bubble Reynolds numbers
B
Re , obtained from laminar flow simulations and Lagrangian particle tracking considering all force. Fig. 17 Total particle capture efficiency
total
E
for spherical and ellipsoidal (eccentricity=1.8) bubbles in water (
B,ves
2.5 mm
D
=
), in
dependence of (a) particle diameter (
3
P
2500 kg/m
ρ =
) and (b) relative Stokes number
AM
St
for a range of bubble Reynolds numbers
B
Re , obtained from laminar flow simulations and Lagrangian particle tracking considering all force. 382 M. Sommerfeld, M. A. Taborda M. Sommerfeld, M. A. Taborda
382
Fig. 18 Total particle capture efficiency
total
E
for ellipsoidal bubbles
(eccentricity=1.8,
B,ves
2.5 mm
D
=
) in water at two different
inclination angles (i.e., horizontally aligned bubble
0
α = and
45
α =
) in dependence of particle diameter (
3
P
2500 kg/m
ρ =
)
for three bubble Reynolds numbers
B
Re obtained from laminar
flow simulations and Lagrangian particle tracking considering
all force. Fig. 19 Total particle capture efficiency
total
E
for spherical and
ellipsoidal (eccentricity=1.8) bubbles in water with different
diameter (
B,ves
2.5 and 4.0 mm
D
=
) in dependence of relative
Stokes number
AM
St
for two bubble Reynolds numbers
B
Re
obtained from laminar flow simulations and Lagrangian particle
tracking considering all force (spherical solid particles with
3
P
2500 kg/m
ρ =
). and also to estimate a sticking probability considering the
relevant interfacial forces (Omota et al., 2006). 4.6 Impact statistics for a spherical collector bubble in
water flow This is caused by the shear lift whereby
the particle trajectories are deflected towards the bubble by
the mechanism illustrated in Fig. 11 (right)) and obvious
from the trajectories in Fig. 10. From these results it is
clear, that modelling the particle to bubble impact
velocity in the frame of large-scale numerical simulations
of gas–liquid–solid three phase flows is not a simple task. Assuming constant values over the bubble cross-section,
for example being equivalent to the relative velocity between
particles and bubbles, seems to be a rather crude assumption
(Bourloutski and Sommerfeld, 2004; Gruber et al., 2016). number or free stream inlet velocity, the profiles change
from roughly flat (i.e., almost constant over the bubble
surface) to a kind of parabolic shape with the highest impact
probability near the stagnation point of the bubble. This
trend is of course the result of increasing particle inertia
with growing
B
Re due the flow being more compressed
towards the bubble. Overall, however, the impact probability
increases with bubble Reynolds number. For a given bubble
Reynolds number an increase of the total impact probability
(i.e., integration of the profiles) with particle size is of course
expected (see Fig. 1). Very interesting is again the role of
the shear lift force as discussed above (Fig. 11), which
is highlighted through a simulation without transverse lift
for the 150 μm particles (dashed lines in Fig. 20). Except
for
B
625
Re =
the shear lift is very important and both
mechanisms illustrated in Fig. 11 may be identified. Naturally,
the importance of the lift also grows with particle diameter. In the case of the lowest bubble Reynolds number, i.e.,
B
156.25
Re =
, the shear lift tends to transport the solid
particles towards the outer rim of the bubble (mechanism
Fig. 11 (right)), yielding high collection in this region
whereas in the inner bubble cross-section region particle
collection is reduced (Fig. 20(a)). At
B
312.5
Re =
a similar
effect is observed and for
B
625
Re =
(Fig. 20(c)) the
transverse lift seems to have the smallest influence. Finally,
for the highest bubble Reynolds number considered, i.e.,
B
1250
Re =
, the lift effect reverses and causes in average a
strong transport of the particles towards the core region
of the bubble projected cross-section (mechanism Fig. 11
(left)), illustrated in Fig. 20(d)). As mentioned above in all
results shown in Fig. 4.6 Impact statistics for a spherical collector bubble in
water flow The profiles presented in Fig. 20
for different bubble Reynolds numbers and a number of
particle diameters confirm the qualitative result presented
in Figs. 8 and 9. When increasing the bubble Reynolds Fig. 20 Relative probability (number of locally impinging particles
over injected number of particles given by Eq. (19)) divided by
cross-sectional area of solid particles hitting a 2.5 mm spherical
bubble at laminar water flow for different bubble Reynolds numbers
B
Re and particle diameters (
3
P
2500 kg/m
ρ =
): (a)
B
156.25
Re =
,
(b)
B
312.5
Re =
, (c)
B
625,
Re =
and (d)
B
1250
Re =
. Collision rates of small solid particles with rigid spherical and spheroidal bubbles in laminar flow 383 response and their deceleration of course strongly depend
on their size. The 50 μm particles are expectedly quickly
decelerated in the bubble stagnation point. Others, released
more laterally, begin to move around the bubble and
hence, maintain a higher downward velocity (Fig. 21(a)). Consequently, the impact velocity profile has a parabolic
shape. The impact angle rapidly decreases from about 90
(at the north pole of the bubble) to 0 for lateral impacts
(Fig. 21(a) (right)). When the particle size is increased, they
are less strongly decelerated within the bubble stagnation
point region. Hence, at the bubble north pole the impact
velocity continuously increases, namely: −0.01, −0.02, −0.065,
and −0.11 for particle diameters of 50, 100, 150, and 200 μm
(Fig. 21 (left column)). For the considered larger particles
the radial profiles of the vertical particle velocity have rather
complex shapes caused by particles moving almost straight
downwards and others passing around the stagnation point
and hitting the bubble at more lateral surface locations. Interesting is the result for the 200 μm particles (Fig. 21(d))
showing at the outer edge of the bubble some events with
upward vertical velocities which comes from particles being
entrained in the wake flow. Such an effect is again associated
with the slip-shear lift force. Naturally, the particle impact
angle is also linked with their motion history (Fig. 21 (right
column)). Again, an interesting effect is observed, for the
larger particles (i.e.,
P
50 μm
d >
) no grazing particle-bubble
collisions are observed (i.e., there are no impact angles
below about 30). 4.6 Impact statistics for a spherical collector bubble in
water flow 20, the shear lift force importance
decreases when reducing particle diameter (see also Fig. 12). In order to model the impact of solid particles on the
bubble surface also the impact velocity and the impingement
angle are relevant. Therefore, these data were extracted from
the simulations and presented in the form of scatter plots
exemplarily for a bubble Reynolds number of
B
625
Re =
which roughly corresponds to the terminal velocity of a
2.5 mm bubble, being about 0.25 m/s. The result in Fig. 21
was obtained for four particle diameters and shows in the
left column the vertical component of the particle velocity. The right column presents the impact angle with the bubble
surface, corresponding to 90 for a normal impingement,
found mainly around the front stagnation point of the
bubble, and 0 for a grazing collision observed near the
equator of the bubbles. For the considered bubble Reynolds
number, the fluid inlet velocity is 0.25 m/s; however, the
particles, due to gravity, will become slightly faster than the
liquid. When approaching the bubble surface, the particles
will respond to the velocity change induced by the bubble,
namely, near the front stagnation point, the flow deflection
by the bubble and the bubble boundary layer. The particle 5 Conclusions For a laminar flow condition and rigid spherical and
ellipsoidal bubbles (i.e., corresponding to fully contaminated
bubbles) the impact efficiency of fine suspension particles
was evaluated based on numerical simulations. The predicted
laminar flow fields obtained for a range of inflow velocities
or bubble Reynolds numbers were used to inject and track
a large number of particles considering various sizes in a
Lagrangian fashion. Particle tracking was done considering
drag, added mass, fluid inertia, transverse shear-lift, and
gravity/buoyancy. It was clearly demonstrated that for a
flotation condition with water as a continuous phase, the 384 M. Sommerfeld, M. A. Taborda se shear-lift cannot be neglected. For smaller bubble
ds numbers (spherical bubbles:
B
900;
Re <
ellipsoidal
with
1.8
χ =
:
B
700
Re <
) and larger particles this
elds a remarkable increase of capture efficiency. When increasing bubble Reynolds number be
transition point, the shear-induced lift has th
effect, namely a reduction of deposition efficien
case of only considering drag and gravity a clear
Scatter plots of the vertical component of the particle velocity upon impact on a spherical bubble (2.5 mm) surface (l
icle impact angle with respect to the tangent on the bubble surface (right column), both plotted versus the normal
.5 mm spherical bubble in laminar water flow for a bubble Reynolds number of
B
0
625,
0.25 m/s,
Re
U
=
=
and f
s: (a)
P
50 μm
d =
, (b)
P
100 μm
d =
, (c)
P
150 μm
d =
, (d)
P
200 μm
d =
(
3
P
2500 k
)
g/m
. ρ = Fig. 21 Scatter plots of the vertical component of the particle velocity upon impact on a spherical bubble (2.5 mm) surface (left column)
and particle impact angle with respect to the tangent on the bubble surface (right column), both plotted versus the normalised bubble
radius (2.5 mm spherical bubble in laminar water flow for a bubble Reynolds number of
B
0
625,
0.25 m/s,
Re
U
=
=
and four particle
diameters: (a)
P
50 μm
d =
, (b)
P
100 μm
d =
, (c)
P
150 μm
d =
, (d)
P
200 μm
d =
(
3
P
2500 k
)
g/m
. ρ = When increasing bubble Reynolds number beyond this
transition point, the shear-induced lift has the opposite
effect, namely a reduction of deposition efficiency. References Bourloutski, E., Sommerfeld, M. 2002. Transient RANS/Lagrange
calculations of two- and three-phase flows in bubble columns. In:
Engineering Turbulence Modelling and Experiments 5. Rodi, W.,
Fueyo, N. Eds. Amsterdam: Elsevier Science Ltd., 969–978. Bourloutski, E., Sommerfeld, M. 2004. Euler/Lagrange calculations of
gas–liquid–solid-flows in bubble columns with phase interaction. In: Bubbly Flows. Heat and Mass Transfer. Sommerfeld, M. Ed. Springer Berlin Heidelberg, 243–259. Naturally, the composite theory of Schulze (1989) does
not account for added mass and slip-shear lift effects. Therefore, the theory of Schulze (1989) has a limited
applicability and it was shown that it is more suitable for
smaller particles. Therefore, further studies need to be
conducted for improving the correlations of Schulze (1989)
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relevant to the content of this article. The author Martin
Sommerfeld is an Editorial Board Member of this journal. For the first time also bubble shape and orientation
effects on impact efficiency were analysed through numerical
computations. For a rather strong bubble deformation with
an eccentricity of 1.8 (i.e., typically found in bubble columns
for bubbles larger than about 2 mm) the increase of impact
efficiency becomes more pronounced for lower bubble
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B
80
Re »
at larger particle sizes between about
50 and 200 μm . In bubble columns normally bubbles are
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Reynolds numbers (spherical bubbles:
B
900;
Re <
ellipsoidal
bubbles with
1.8
χ =
:
B
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Re <
) and larger particles this
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opened the possibility of conducting interesting research. of the capture efficiency in dependence of bubble Reynolds
number is observed for all particle sizes due to the
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B
Re ) and
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B
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licenses/by/4.0/. Sommerfeld, M., Bröder, D. 2009. Analysis of hydrodynamics and
microstructure in a bubble column by planar shadow image
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Content Development for a Physical Activity and Sedentary Behaviour e-Learning Module for Early Childhood Education Students: A Delphi Study
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Content Development for a Physical Activity and
Sedentary Behaviour e-Learning Module for Early
Childhood Education Students: A Delphi Study Trish Tucker
(
ttucker2@uwo.ca
) Research article DOI: https://doi.org/10.21203/rs.2.22496/v3 License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License Version of Record: A version of this preprint was published on October 23rd, 2020. See the published
version at https://doi.org/10.1186/s12889-020-09670-w. Page 1/18 Abstract Background: Early childhood educators play a prominent role in promoting healthy activity behaviours in
childcare. However, they have expressed that they lack the appropriate pre-service training to confidently
lead physical activity (PA), and minimize sedentary behaviour (SB), in childcare. As such, the purpose of
this Delphi study was to generate and reach agreement on content areas for inclusion in a PA and SB e-
Learning module for Early Childhood Education (ECE) students. Methods: Purposeful sampling of Canadian/international researchers was used to form two expert
panels: a PA/SB expert panel (n = 26), and a Canadian ECE panel. The PA/SB experts suggested their top
12 PA/SB topics for the module via online survey. These topics were then pooled to generate a list of 19
content areas. In a second online survey, both panels of experts rated the importance of each content
area (0 = unimportant to 5 = very important). Mean ratings (M) were ranked separately for each panel,
and then ratings were pooled to create an overall ranking of the 19 content areas. Inter-panel agreement
of importance rankings was visually represented as a scatterplot and quantified using Spearman’s rho
(rs). Results: The top-rated content area was Outdoor Play (M = 4.77 ± 0.64), followed by Benefits of PA in the
Early Years (M = 4.75 ± 0.66), and Factors Influencing PA and SB in Childcare (M = 4.71 ± .74). Monitor PA
and Sedentary Time Within Your Classroom had the lowest combined score (M = 3.77 ± 1.44). There was
moderate-to strong inter-panel agreement for content area importance rankings (rs = 0.60, 95% CI: 0.20 to
0.83). The majority of the ECE expert panel considered this training important for ECE students (94.3%),
aligning with ECE curriculum objectives (91.4%) and accreditation standards (78.8%), and
complementary to the present ECE curriculum (88.6%). Conclusions: Providing PA and SB training to ECE students is a proactive way to ensure healthy
movement behaviours are prioritized in childcare programming. With the PA/SB expert-developed content
areas, and endorsement by the ECE expert panel, implementing this training within ECE programs is a
necessary next step. Background For young children (<5 years), regular participation in physical activity is key to healthy physical,
psychosocial, and cognitive development.(1) Specifically, increased duration and frequency of physical
activity in early childhood positively influences executive function and language,(2) while higher intensity
physical activity has been associated with improved motor skill development.(3) Further, limiting
prolonged sedentary time, particularly in front of screens, is critical; in young children, television-viewing
has been linked to decreased attention and disruptive sleep,(4) as well as decreased cognitive
development (including literacy and numeracy).(5) As such, establishing healthy physical activity and
sedentary behaviour habits in early childhood is highly important, and the childcare environment, where Page 2/18 Page 2/18 two-thirds of young Canadian children spend the majority of their weekdays,(6) has been identified as a
prime setting to target these health behaviours. Background Early childhood educators are influential role models in the childcare setting, and with respect to
programming, they control a substantial portion of young children’s days.(7–9) However, research has
shown that both educator values and self-efficacy relating to physical activity, as well as their level of
training in this area, influence the amount of physical activity they incorporate in their programming.(10–
13) Early childhood educators have acknowledged their limited pre-service training in physical activity
and sedentary behaviour,(12,14) and have associated this with their low self-efficacy to promote and lead
physical activity opportunities in childcare.(10) A recent Canadian study found that only 32.2% and 26.7%
of Canadian Early Childhood Education (ECE) students reported receiving physical activity and screen-
viewing-related training in their post-secondary ECE programs, respectively.(15) Further, in Canada, only 3
provinces/territories specifically reference physical activity, and 1 references screen-viewing, in their
childcare regulation,(16) and few childcare centres have adopted physical activity (30%) and screen-
viewing (29%) policies of their own.(17) Given such limited regulations, it is often early childhood
educators who are responsible for determining the duration and frequency of physical activity
opportunities and screen use in their classroom.(11,12) With the strong curricular focus placed on
preparing children in their care for school, educators may not consider opportunities for physical activity
as integral programming components.(18,19) Providing educators with proper training in physical activity
has been introduced as a possible solution to ensure children are afforded appropriate daily opportunities
to be active.(20) Both early childhood educators(21) and ECE students(22) have expressed their desire for additional
training in physical activity and sedentary behaviour, and the provision of such learning opportunities is
essential to assist educators in promoting the development of healthy movement behaviours among
children in childcare. Methods The Non-Medical Research Ethics Board at the University of Western Ontario provided ethical approval
(REB# 114435) for the conduct of this research. Study Design The Delphi method, developed by Dalkey and Helmer (1963), was adopted as the study design, as it is
appropriate in cases where the subjective opinion of a group of experts is needed to reach consensus on
a topic, but these individuals cannot meet to discuss in-person (due to constraints such as distance and
time).(30,31) The Delphi technique involves multiple rounds of surveys with controlled feedback, allowing
participants to reassess their answers based on their review of other panelists’ responses (30). Further,
this method allows for anonymity, which mitigates challenges associated with traditional group
consensus methods, where dominant individuals and pressure to conform can be confounding factors
(32). The study design and procedures were loosely modeled after Gillis and colleagues’(33) Delphi study,
which aimed to achieve consensus on research priorities for children’s and adolescents’ physical activity
and sedentary behaviours. Background Recent efforts to better support educators in promoting and leading physical
activity, and minimizing excessive sedentary time in childcare environments, have shown promising
results.(23–27) For example, interventions that have provided early childhood educators with physical
activity training have resulted in preschoolers accumulating increased moderate-to vigorous-intensity
physical activity (MVPA; +0.5 min/day and +1.28 min/day)(23,25), and decreased sedentary time (-2.13
min/day) while in childcare.(25) Early childhood educators’ receptiveness to both of these interventions
was positive, and they communicated that they would continue to use the knowledge gained from the
training after the interventions ceased.(24,28) While professional development in physical activity and
sedentary behaviour for educators is essential to support ongoing learning and scaffold their physical
activity-related teaching self-efficacy,(23,27) there is a need for this supplementary education at the post-
secondary level (i.e., within ECE programs). This initiative will ensure ECE graduates are well-prepared to
support healthy movement behaviours among young children upon entering a childcare-based
profession.(29) Given the success of physical activity training programs for early childhood educators,(23,25) and the
importance of providing this training to all early childhood educators pre-employment (where physical Page 3/18 Page 3/18 Page 3/18 activity-related education is lacking),(15) the next step is to narrow down key physical activity and
sedentary behaviour content areas to include in training at the pre-service level. Further, there is a need to
introduce more educator outcome measures (e.g., physical activity-related knowledge, self-efficacy, and
teaching behaviours) in order to find out what content best supports educators’ knowledge acquisition
and retention, as well as their development of self-efficacy to lead physical activity and minimize
prolonged sedentary time in childcare. As such, the goal of the Training EArly CHildhood educators in
physical activity study (i.e., the TEACH study), is to develop, implement, and evaluate the impact of a
physical activity and sedentary behaviour e-Learning module for students in Canadian post-secondary
ECE programs. As a first step, the current study aimed to identify and reach agreement on physical
activity and sedentary behaviour content areas that are necessary for early childhood educators to be
trained in. Study Procedures hysical activity/sedentary behaviour experts completed two online surveys. The first survey gathered their
top 12 physical activity and sedentary-behaviour-related content areas they felt should be included in an
e-Learning module for ECE students (with a brief justification for each topic). Two study investigators
(BAB, PT) reviewed the topics generated in the first round of surveys and pooled them together. Similar
topics were merged, and a list of unique content areas was created. Content areas that were only
mentioned by one participant were excluded from the final list. In the second round of surveys, experts were provided the pooled list of content areas (along with a brief
description of what would be included in that section of the module). They were asked to rate the
importance of each content area on a 5-point Likert scale (0 = unimportant to 5 = very important). In order
to ensure all proposed content areas were captured in the pooled list, experts were asked to indicate
whether the topics they proposed in the first survey were accurately represented. Occupational positions
for physical activity experts were retrieved by the research team via their institutional websites. The ECE expert panel completed a version of the second online survey, which, in addition to gathering
their importance ratings of the content areas generated by the physical activity/sedentary behaviour
expert panel, also captured: 1. demographics (occupational position, years of experience); 2. suggestions
for topics not already proposed; 3. how important they felt this type of training was for ECE students; and,
4. whether they felt the module content aligned with ECE curriculum objectives and accreditation
criteria/vocational learning outcomes, and complemented current ECE curriculum. Experts were assigned a unique participant code to use when filling out each online survey so that study
investigators could determine which panel (i.e., Canadian, international, or ECE) each expert belonged to,
and who had participated (in order to determine the need for subsequent survey dissemination). Participants and Recruitment In order to ensure module content was appropriate and contextually relevant to integrate into Canadian
ECE curricula, 46 Canadian ECE experts were identified by the research team and invited via email to
participate. Experts were selected based on their: 1. occupational position (i.e., ECE university professor,
board/executive member of a relevant ECE organization, dean or program head/instructor of a post-
secondary ECE program); 2. years of experience in the ECE field (5 years minimum); 3. In order to ensure module content was appropriate and contextually relevant to integrate into Canadian
ECE curricula, 46 Canadian ECE experts were identified by the research team and invited via email to
participate. Experts were selected based on their: 1. occupational position (i.e., ECE university professor,
board/executive member of a relevant ECE organization, dean or program head/instructor of a post-
secondary ECE program); 2. years of experience in the ECE field (5 years minimum); 3. provincial/territorial location (i.e., to ensure appropriate representation); and, 4. online email address
availability. Additional experts (n = 14), referred to the research team by the initial group of ECE experts,
were also invited to participate. Recruitment took place in November 2019 and a total of 35 ECE experts
agreed to participate (58% response rate). See Figure 1 for the full recruitment process of physical
activity/sedentary behaviour and ECE experts. provincial/territorial location (i.e., to ensure appropriate representation); and, 4. online email address
availability. Additional experts (n = 14), referred to the research team by the initial group of ECE experts,
were also invited to participate. Recruitment took place in November 2019 and a total of 35 ECE experts
agreed to participate (58% response rate). See Figure 1 for the full recruitment process of physical
activity/sedentary behaviour and ECE experts. Participants and Recruitment Canadian (n = 13) and international (n = 18) early years physical activity and sedentary behaviour experts
were identified by the research team and invited via email to participate in two online surveys through
QualtricsÓ. Experts were selected based on: 1. their established research in the field; and, 2. Canadian (n = 13) and international (n = 18) early years physical activity and sedentary behaviour experts
were identified by the research team and invited via email to participate in two online surveys through
QualtricsÓ. Experts were selected based on: 1. their established research in the field; and, 2. provincial/geographic location (i.e., to ensure appropriate representation within and outside of Canada). Additional experts (n = 17), referred to the research team by the initial group of study participants, were
then invited as national (n = 2) and international (n = 15) experts. If no response was received within 2
weeks, a reminder email was circulated. Recruitment took place in October 2019 and a total of 25
physical activity and sedentary behaviour experts agreed to participate prior to the first round of surveys. One additional expert agreed to participate prior to the second round of surveys (53% response rate). provincial/geographic location (i.e., to ensure appropriate representation within and outside of Canada). Additional experts (n = 17), referred to the research team by the initial group of study participants, were
then invited as national (n = 2) and international (n = 15) experts. If no response was received within 2
weeks, a reminder email was circulated. Recruitment took place in October 2019 and a total of 25
physical activity and sedentary behaviour experts agreed to participate prior to the first round of surveys. One additional expert agreed to participate prior to the second round of surveys (53% response rate). Page 4/18 Page 4/18 Page 4/18 In order to ensure module content was appropriate and contextually relevant to integrate into Canadian
ECE curricula, 46 Canadian ECE experts were identified by the research team and invited via email to
participate. Experts were selected based on their: 1. occupational position (i.e., ECE university professor,
board/executive member of a relevant ECE organization, dean or program head/instructor of a post-
secondary ECE program); 2. years of experience in the ECE field (5 years minimum); 3. Demographics Physical activity and sedentary behaviour expert panel. Physical activity/sedentary behaviour experts
represented 6 different countries (Canada [n = 13], Australia [n = 5], the United States [n = 4], the
Netherlands [n = 2], the United Kingdom [n = 1], and New Zealand [n = 1]). All experts held positions in
academia (including 2 post-doctoral fellows, 5 assistant professors, 10 associate professors, and 9 full
professors). See Figure 2a for geographical representation of the physical activity/sedentary behaviour
expert panel. ECE expert panel. ECE experts represented 10 Canadian provinces/territories (Ontario [n = 11], Quebec [n =
6], Saskatchewan [n = 6], British Columbia [n = 3], Alberta [n = 2], Newfoundland and Labrador [n = 2],
Nova Scotia [n = 2], Manitoba [n = 1], New Brunswick [n = 1], and Yukon [n = 1]; Figure 2b). Experts held a
wide range of ECE occupational positions, including 6 as university professors (3 assistant professors, 1
associate professor, 1 full professor, and 1 professor emerita), 11 as board/executive members of ECE-
related organizations, and 18 as faculty/staff within ECE programs (1 dean, 4 program/department
heads/coordinators, 1 curriculum writer, and 12 instructors). On average, these experts had 23.11 ±
11.43[1] years of experience in the ECE field. Data Analysis Descriptive statistics of demographics, content area importance ratings, representation of panel-
suggested topics, and perspectives regarding the importance of this type of training were completed in Page 5/18 SPSS (version 25). Within each panel of experts (i.e., physical activity/sedentary behaviour and ECE),
mean (M) scores on each of the 19 content areas was generated. Pearson product-moment correlation
coefficient was then calculated between the means of the two panels, and the 19 content areas were
ranked within each panel. Similarity in rankings between the two panels was assessed using Spearman’s
rho (rs). Analyses were conducted in R version 3.6.1.(34) Physical Activity and Sedentary Behaviour Content Areas A total of 22 content areas were generated by the physical activity/sedentary behaviour expert panel. Three content areas were excluded due to not being relevant to other panelists’ topics; as such, 19 content
areas were carried forward. The majority (90.5%) of panelists reported their suggested topics were
appropriately represented in the final list of content areas. See Supplementary Table 1 for a detailed list
and description of the content areas. Physical activity and sedentary behaviour expert panel. On average, physical activity/sedentary behaviour
experts (n = 21[2]) rated all content areas as important to include in the e-learning module (M range =
3.76 to 4.81). These experts rated Benefits of Physical Activity in the Early Years as the most important
content area (M = 4.81 ± 0.40), and Monitor Physical Activity and Sedentary Time in Your Classroom as
the least important content area (M = 3.76 ± 1.14]), to include in the e-Learning module. See Table 1 for
content area importance rankings. Page 6/18 Table 1. Ranked Content Areas in Physical Activity and Sedentary Behaviour Suggested for Inclusion in an e-
Learning Training Module for Canadian Early Childhood Education Students. Table 1. Ranked Content Areas in Physical Activity and Sedentary Behaviour Suggested for Inclusion in an e-
Learning Training Module for Canadian Early Childhood Education Students. Table 1. Ranked Content Areas in Physical Activity and Sedentary Behaviour Suggested for Inclusion in an e-
Learning Training Module for Canadian Early Childhood Education Students. Physical Activity and Sedentary Behaviour Content Areas Content Area
PA/SB
Panel
(n =
21)
M (SD)
PA/SB
Panel
Rank
ECE
Panel
(n =
35)
M (SD)
ECE
Panel
Rank
Both
Panels
M
(SD)
Final
Ranka
Outdoor Play
4.71
(.46)
4
4.83
(.45)
1
4.77
(.64)
1
Benefits of Physical Activity in the Early Years
4.81
(.40)
1
4.69
(.53)
3
4.75
(.66)
2
Factors Influencing Physical Activity and Sedentary
Behaviour in Childcare
4.76
(.44)
2.5
4.66
(.59)
5
4.71
(.74)
3
Defining Physical Activity and Sedentary Behaviour
4.57
(.60)
8
4.74
(.44)
2
4.66
(.74)
4
Promote Physical Activity and Minimize Sedentary Time
through Instruction and Interaction
4.76
(.44)
2.5
4.51
(.66)
8
4.64
(.79)
5
Create and Make Use of Environments to be Supportive
of Physical Activity
4.57
(.68)
8
a4.68
(.48)
4
4.63
(.83)
6
Become a Role Model and Champion for Physical
Activity
4.62
(.74)
5.5
4.40
(.74)
10.5
4.51
(1.05)
7
Program Time for Physical Activity and Active Breaks to
Limit Sitting Time
4.62
(.67)
5.5
4.37
(1.03)
12
4.50
(1.23)
8
The Canadian 24-Hour Movement Guidelines for the
Early Years (<5 years)
4.38
(.81)
12.5
4.60
(.60)
7
4.49
(1.01)
9
Risky Play
4.24
(.83)
15.5
4.63
(.60)
6
4.44
(1.02)
10
Get Parents/Guardians On Board! 4.43
(1.03)
10.5
4.40
(.78)
10.5
4.41
(1.29)
11
Physical Literacy and Fundamental Movement Skills
4.38
(.81)
12.5
4.43
(.78)
9
4.41
(1.12)
11
Incorporate Physical Activity into Other Educational
Objectives
4.24
(1.00)
15.5
a4.35
(.65)
13
4.30
(1.19)
13
Resources and Professional Development
4.33
(.80)
14
4.26
(.78)
15
4.30
(1.12)
13
Suggest the Creation of Physical Activity and Screen-
Viewing Policies at Your Centre
4.43
(.60)
10.5
a4.06
(.92)
16.5
4.25
(1.10)
15
Example Activities
4.57
(.75)
8
3.91
(1.10)
18
4.24
(1.33)
16
Risks of Excessive Sedentary Behaviour and Screen-
Viewing
4.10
(.94)
17
4.34
(.68)
14
4.22
(1.16)
17
Prevalence of Physical Activity, Sedentary Behaviour,
and Screen-Viewing among Young Children
3.95
(.92)
18
b4.06
(.85)
16.5
4.01
(1.25)
18
Monitor Physical Activity and Sedentary Time in Your
Classroom
3.76
(1.14)
19
3.77
(.88)
19
3.77
(1.44)
19
Note. PA = physical activity; SB = sedentary behaviour; ECE = Early Childhood Education; M = mean; SD =
standard deviation; a Final rank was determined by the highest combined mean score between panels; b Only 34
respondents for this question. ECE expert panel. Page 7/18
ECE expert panel. ECE experts (n = 35) also had moderate to high ratings of the importance of the content
areas (M range = 3.77 to 4.83). They rated Outdoor Play as the most important content area to include in
the e-Learning module (M = 4.83 ± 0.45]) and Monitor Physical Activity and Sedentary Time in Your Physical Activity and Sedentary Behaviour Content Areas ECE experts (n = 35) also had moderate to high ratings of the importance of the content
areas (M range = 3.77 to 4.83). They rated Outdoor Play as the most important content area to include in
the e-Learning module (M = 4.83 ± 0.45]) and Monitor Physical Activity and Sedentary Time in Your Classroom as the least important content area (M = 3.77 ± 0.88]). See Table 1 for content area
importance rankings by panel. Classroom as the least important content area (M = 3.77 ± 0.88]). See Table 1 for content area
importance rankings by panel. Final ranking and inter-panel agreement. In the final ranked list of content areas, Outdoor Play (M = 4.77 ±
0.64), Benefits of PA in the Early Years (M = 4.75 ± 0.66), and Factors Influencing PA and SB in Childcare
(M = 4.71 ± 0.74) had the highest combined scores. Monitor PA and Sedentary Time in Your Classroom
had the lowest combined score (M = 3.77 ± 1.44). There was moderate-to-strong inter-panel agreement
across the 19 content areas, with mean scores correlating 0.63 (95% CI: 0.25 to 0.84) and ranked scores
demonstrating an association (rs) of 0.60 (95% CI: 0.20 to 0.83). See Figure 3 for a graphical
representation of the associations between panels for each content area ranking. [2] Five members of the panel did not respond to the second round of surveys. [2] Five members of the panel did not respond to the second round of surveys. ECE Panel Perspectives on the e-Learning Module The majority of ECE experts (94.3%) rated this type of training as ‘Important’ or ‘Very Important’ for ECE
students to receive. Most experts (91.4%) reported they agreed that the physical activity and sedentary
behaviour e-Learning module aligned with the objectives of the current post-secondary ECE curriculum,
and 88.6% reported they agreed that the training would complement this curriculum. The majority of ECE
experts (78.8%) also communicated their agreement that this type of training aligned with ECE
professional accreditation standards. Discussion (35) This review of correlates is critical within the module, as it will highlight to ECE students the varying
aspects of the childcare environment, and educator behaviours, that act as facilitators/barriers to
children’s physical activity and that influence their sedentary behaviours.(13,36) Stemming from the
review of correlates, eight additional content areas suggested by the panel related to providing ECE
students with practical strategies on how to promote physical activity and minimize sedentary time in
their classroom (noted as important within childcare educator training interventions). (26,37) In addition,
two content areas focused on helpful resources and training, and practical video example activities, to
further aid ECE students in this respect. The focus of the content suggested for the module on these
strategies and resources is encouraging, as educators have reported they lack the appropriate training on
how to lead skill-based physical activities in childcare.(38) Further, early childhood educator training
interventions have noted the benefit of this type of practical support in scaffolding educators’ physical
activity-related self-efficacy,(27) and both increasing physical activity(39) and decreasing sedentary
time(26) among children in their care. Offering video examples may teach ECE students how to engage
children in physical activity, and promises to support their self-efficacy in this pursuit via vicarious
reinforcement and modeling.(40) While both expert panels expressed their views of the importance of all proposed content areas for the e-
Learning module, the top-rated content areas (i.e., Outdoor Play, Benefits of Physical Activity in the Early
Years, Factors Influencing Physical Activity and Sedentary Behaviour in Childcare) were logical. While both expert panels expressed their views of the importance of all proposed content areas for the e-
Learning module, the top-rated content areas (i.e., Outdoor Play, Benefits of Physical Activity in the Early
Years, Factors Influencing Physical Activity and Sedentary Behaviour in Childcare) were logical. Considering outdoor time is a required component of all childcare in Canada, coupled with the knowledge
that children accumulate the majority of their daily MVPA outdoors while attending childcare,(41) the high
prioritization of Outdoor Play by both expert panels is reassuring and important to educate ECE students
about. The introductory content area regarding benefits of physical activity stresses the need to provide
ECE students with solid foundational knowledge of physical activity and sedentary behaviour. Further,
overviewing the factors influencing children’s movement behaviours in the childcare environment was
considered very important. Discussion This was the first study to employ the Delphi method to generate physical activity and sedentary
behaviour content to be included in training for ECE students. The use of two field-specific expert panels
to offer their insights on this training provided a unique perspective on module content development, and
their general consensus on important rankings of the content areas provides helpful direction regarding
areas of foci for the e-Learning module. A number of important findings from this study are discussed
below. Six content areas proposed by the experts focused on giving ECE students necessary background
information on physical activity and sedentary behaviour, ranging from definitions and benefits/risks of
these behaviours to guidelines and current prevalence rates. These content areas are essential to include,
as ECE students have noted the lack of physical activity and sedentary behaviour-specific training in their
program.(15) Bruijns et al. (2019) surveyed 1,292 ECE students, and while the majority of students
reported that their courses covered gross motor development (86.6%), few covered concepts such as
physical literacy (46.2%), screen-viewing (47.3%), or sedentary behaviour (41.5%).(15) Without a proper Page 8/18 introduction to these concepts and their importance to consider when programming, it is unlikely that ECE
students will be receptive to strategies to promote physical activity and minimize sedentary time.(22) As
evidenced by Bruijns et al. (under review), ECE students felt it was more important and their responsibility
to teach physical activity-related skills (such as fitness activities, locomotor skills, and play skills) in
childcare if they reported receiving training in physical activity.(22) As such, if ECE students are
introduced to these concepts during their pre-service schooling, it is likely that they will promote healthy
movement behaviours among the children they care for upon entering the ECE profession. Physical activity/sedentary behaviour experts also suggested including training related to factors that
influence young children’s physical activity and sedentary behaviour in the childcare environment, with
specific attention paid to outdoor and risky play (receiving heightened attention in the ECE field as of late. Research Implications and Future Directions This research study has a number of important implications. First, the results of this study will be used to
generate a physical activity and sedentary behaviour e-Learning course that is tailored specifically to ECE
students, the first study globally to focus this training within early childhood educators’ pre-service
education. Having educators who are well-trained in physical activity and sedentary behaviour will ensur
children in childcare are provided sufficient movement opportunities daily, which is vital for their healthy
development. Second, the recruitment of top international experts in the field to generate the content for
the module ensures that this training covers the most important and relevant information for ECE
students to promote healthy movement behaviours in childcare-based professions upon graduation. In
addition, having a diverse panel of ECE experts review the content proposed by the physical
activity/sedentary behaviour panel confirmed the applicability of this training to ECE, and will ease its
receptivity by post-secondary ECE programs. The implementation of the e-Learning course across Canada will shed light on whether this training is
successful in ECE programs in multiple locations. In Canada, ECE curricula and professional
accreditation standards are governed at the provincial/territorial level; as such, testing the effectiveness
of this educational tool nationwide will determine the versatility of the e-Learning course to be
implemented in multiple educational environments. If successful, the e-Learning course can be adapted
(e.g., changing country-specific movement guidelines) for use in other countries, which would maximize
the reach and global public health impact of this training. Given the global call for physical activity and
sedentary behaviour training to be made available within early childhood educators’ pre-service
schooling,(20,29,44) international collaborations are warranted to support this initiative. Discussion Specifically, early childhood educator behaviours, known to influence
children’s movement behaviours in childcare,(42) was highlighted as critical for targeted education. Taken
together, the top-rated content areas represent topics in need of focus within training interventions for
early childhood educators, and are pertinent to include in the e-Learning module for ECE students. Page 9/18 Page 9/18 The moderate-to-strong inter-panel agreement, both in terms of content area mean score and rank-order,
demonstrates general consensus regarding the importance of each topic for inclusion within the module. While select content areas were rated higher by one panel than the other (e.g., Creation of Physical
Activity/Screen-Viewing Policies was favoured by the physical activity/sedentary behaviour experts, and
Risky Play was favoured by the ECE experts), most content areas were similarly rated and ranked by both
panels. Given the overarching goal of the TEACH study is to implement this e-Learning module in ECE
post-secondary programs, it is critical that the content created for the module is pertinent to the ECE field. It is reassuring, then, that the large majority of ECE experts rated this training module as both in line with
objectives of, and of added benefit to, the current post-secondary ECE curriculum. Hnatiuk and
colleagues(43) stress the importance of tailoring early years physical activity interventions to community
needs (in this case, lack of physical activity and sedentary behaviour training in the present ECE
curriculum). With the overwhelming support of the ECE expert panel (nearly 100% of ECE experts reported
this training was important for ECE students to receive), the creation of the e-Learning module using the
content areas generated from this Delphi study is likely to be well-received by ECE programs within
Canadian post-secondary institutions. ECE = Early Childhood Education
TEACH = Training EArly CHildhood educators in physical activity ECE = Early Childhood Education
TEACH = Training EArly CHildhood educators in physical activity ECE = Early Childhood Education Conclusion Using the Delphi method to identify and reach agreement on physical activity and sedentary behaviour-
related topics to include in supplementary training for post-secondary ECE students provided a unique
perspective on e-Learning module content development. The high importance ratings of all 19 content
areas, coupled with the moderate-to-strong inter-panel agreement across these topics, suggest the need
for this tailored education. Further, the agreement by the ECE expert panel regarding the appropriateness
of incorporating this type of training within ECE programs demonstrated that there is a desire for physical
activity and sedentary behaviour-related education at the post-secondary level, and that the addition of
this content would support curriculum objectives and accreditation standards. Moving forward, creating
an e-Learning module with evidence-based and expert-developed content, endorsed by those working in a
wide range of ECE professions, will ensure that ECE graduates receive the necessary and most relevant
education to be able to promote children’s healthy development of movement behaviours in childcare
settings. Integrating such physical activity and sedentary behaviour training within ECE programs is a
population-level approach to public health that has the potential to benefit a vast number of young
children. Limitations Page 10/18 Page 10/18 Although this study has many strengths, including a high online survey response rate (53% for physical
activity experts, 58% for ECE experts) and the use of the Delphi technique with two field-specific expert
panels, it is not without limitations. First, the purposeful sampling method may have introduced selection
bias. While efforts were made by the research team to overcome this bias (e.g., ensuring sufficient
recruitment of international/provincial experts, allowing participants to suggest researchers to recruit), the
selection of experts by the research team may have included experts with similar ideals and values
regarding the importance of this training in ECE; this may limit the generalizability of the findings. Second, despite the anonymous nature of the online surveys, participants may have been subject to
social desirability bias, as they may have felt that higher importance ratings were ‘expected’ of someone
in their profession. Third, as is the case in any Delphi study, data gathered were based upon availability
and the subjective opinion and expertise of participants. Although this study has many strengths, including a high online survey response rate (53% for physical
activity experts, 58% for ECE experts) and the use of the Delphi technique with two field-specific expert
panels, it is not without limitations. First, the purposeful sampling method may have introduced selection
bias. While efforts were made by the research team to overcome this bias (e.g., ensuring sufficient
recruitment of international/provincial experts, allowing participants to suggest researchers to recruit), the
selection of experts by the research team may have included experts with similar ideals and values
regarding the importance of this training in ECE; this may limit the generalizability of the findings. Second, despite the anonymous nature of the online surveys, participants may have been subject to
social desirability bias, as they may have felt that higher importance ratings were ‘expected’ of someone
in their profession. Third, as is the case in any Delphi study, data gathered were based upon availability
and the subjective opinion and expertise of participants. Declarations Ethics Approval and Consent to Participate Funding The Social Sciences and Humanities Research Council of Canada funded this research (ref #: 435-2019-
1008). BAB was funded by an Ontario Graduate Scholarship (2019-20). PT holds an Ontario Ministry of
Research and Innovation Early Researcher Award. Authors’ Contributions BAB and PT were responsible for study inception, online survey creation, and pooling of content areas. BAB and AMJ conducted the analyses. BAB led manuscript writing while all authors provided substantive
feedback. All authors read and approved the final manuscript. Availability of Data and Materials The dataset generated and analyzed during the present study is available from the corresponding author
upon reasonable request. Consent for Publication Participants gave consent for their data to be published prior to completing the online surveys. Participants gave consent for their data to be published prior to completing Acknowledgements The authors would like to thank all of the physical activity/sedentary behaviour and early childhood
education experts who participated in this study. The authors would like to thank all of the physical activity/sedentary behaviour and early childhood
education experts who participated in this study. Ethics Approval and Consent to Participate The Non-Medical Research Ethics Board at the University of Western Ontario provided ethical approval
(REB# 114435) for the conduct of this research, and implied consent was received via participants’ Page 11/18 Page 11/18 voluntary completion of the online surveys. voluntary completion of the online surveys. Competing Interests The authors declare that they have no competing interests. References 1. Carson V, Lee E-Y, Hewitt L, Jennings C, Hunter S, Kuzik N, et al. Systematic review of the
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105. Figures Page 15/18 Page 15/18 Figure 1
Purposeful sampling process undertaken to recruit physical activity/sedentary behaviour and
Early
Childhood Education experts. Figure 3 Scatterplot of the associations between panels’ rankings for each content area. Scatterplot of the associations between panels’ rankings for each content area. Figure 1 Purposeful sampling process undertaken to recruit physical activity/sedentary behaviour and
Early
Childhood Education experts. Purposeful sampling process undertaken to recruit physical activity/sedentary behaviour and
Early
Childhood Education experts. Page 16/18 igure 2
a) Geographical representation of participating physical activity/sedentary behaviour e
ndicates how many experts were from that region). (b) Provincial/territorial representat
articipating Early Childhood Education experts (number indicates how many experts w
rovince/territory) Figure 2
(a) Geographical representation of participating physical activity/sedentary behaviour experts
(number
indicates how many experts were from that region). (b) Provincial/territorial representation of
participating Early Childhood Education experts (number indicates how many experts were from that
province/territory). Figure 2 (a) Geographical representation of participating physical activity/sedentary behaviour experts
(number
indicates how many experts were from that region). (b) Provincial/territorial representation of
participating Early Childhood Education experts (number indicates how many experts were from that
province/territory). Page 17/18 Page 17/18 Figure 3 Supplementary Files This is a list of supplementary files associated with this preprint. Click to download. This is a list of supplementary files associated with this preprint. Click to download. SupplementaryTable1MergedContentAreas.docx Page 18/18
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https://www.frontiersin.org/articles/10.3389/fphy.2013.00028/pdf
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Linear field demagnetization of artificial magnetic square ice
|
Frontiers in physics
| 2,013
|
cc-by
| 7,441
|
Reviewed by: Dong-Hyun Kim, Chungbuk National
University, South Korea
Dario A. Arena, Brookhaven National
Laboratory, USA Dong-Hyun Kim, Chungbuk National
University, South Korea
Dario A. Arena, Brookhaven National
Laboratory, USA *Correspondence:
Christopher H. Marrows, School of
Physics and Astronomy, University
of Leeds, Leeds LS2 9JT, UK
e-mail: c.h.marrows@leeds.ac.uk Keywords: artificial spin ice, nanomagnetism, magnetic force microscopy, frustrated systems, statistical
mechanics Keywords: artificial spin ice, nanomagnetism, magnetic force microscopy, frustrated systems, statistical
mechanics 1. INTRODUCTION early stages of material deposition when the moment volumes
were small [3, 17]. As their thickness increased, thermal dynam-
ics of the macrospin lattice slowed down and ultimately blocked,
locking-in order [29, 30]. Applied fields are hence required to
promote any subsequent reconfiguration of such frozen systems
following this single-shot anneal. Artificial spin ices are patterned nanomagnet arrays designed
to act as analogs of bulk geometrically frustrated materials
[1, 2]. They realize two-dimensional (2D) Ising and vertex ice
models [3–5], in which each single domain element forms an
anisotropic macrospin which can be directly imaged via mag-
netic microscopy. As they are built via nanolithography and
thin film deposition, it is possible to engineer system parame-
ters such as lattice geometry [6], inter-elemental dipolar coupling
strength [2, 3], moment switching behavior [7], and (to an extent)
quenched disorder (QD) [3, 8]. They have hence presented a fam-
ily of systems in which to explore a myriad of phenomena, such as
collective ordering, competing interactions, and fractionalization
[9–13]. Rotating field protocols have proved a reliable and repeat-
able method for experimentally controlling magnetic states via
“effective thermodynamics” [4]. Whilst ac field profiles were
reported as superior [31], only short range GS correlations could
be produced in quasi-infinite patterns [2, 14]. Although this is
the most commonly employed protocol, the parameter space is
large and has not been extensively and systematically explored. Constant magnitude rotating fields have recently helped eluci-
date reconfiguration processes at work during such protocols
[22, 32] and emphasize the crucial influence of QD [23, 33, 34]:
unlike the Ising systems they mimic, such patterned systems
possess an intrinsic distribution of macrospin properties due to
unavoidable random variations imparted by the fabrication pro-
cesses employed. Non-rotating fields have also generated varying
amounts of GS order [35, 36]. For all field profiles, a critical win-
dow exists in which non-trivial dynamics are allowed, defined by
the interplay between QD and dipolar coupling. PHYSICS PHYSICS PHYSICS ORIGINAL RESEARCH ARTICLE published: 18 December 2013
doi: 10.3389/fphy.2013.00028 Linear field demagnetization of artificial magnetic
square ice Jason P. Morgan 1,2, Alexander Bellew 1, Aaron Stein 3, Sean Langridge 4 and Christopher H. Marrows 1*
1 School of Physics and Astronomy, University of Leeds, Leeds, UK
2 Department of Physics, University of Cambridge, Cambridge, UK
3 Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY, USA
4 ISIS, STFC Rutherford Appleton Laboratory, Didcot, UK Jason P. Morgan 1,2, Alexander Bellew 1, Aaron Stein 3, Sean Langridge 4 and Christopher H. Marrows 1*
1 School of Physics and Astronomy, University of Leeds, Leeds, UK
2 Department of Physics, University of Cambridge, Cambridge, UK
3 Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY, USA
4 ISIS, STFC Rutherford Appleton Laboratory, Didcot, UK Jason P. Morgan 1,2, Alexander Bellew 1, Aaron Stein 3, Sean
1 School of Physics and Astronomy, University of Leeds, Leeds, UK
2 Department of Physics, University of Cambridge, Cambridge, UK
3 Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY, USA
4 ISIS, STFC Rutherford Appleton Laboratory, Didcot, UK We have studied experimentally the states formed in artificial square ice nanomagnet
systems following demagnetization in a rotating in-plane applied magnetic field that
reduces to zero in a manner that is linear in time. The final states are found to be controlled
via the system’s lattice constant, which determines the strength of the magnetostatic
interactions between the elements, as well as the field ramping rate. We understand
these effects as a requirement that the system undergoes a sufficiently large number of
active rotations within the critical field window in which elements may be reversed, such
that the interactions are allowed to locally exert their influence if the ground state is to be
approached. On the other hand, if quenched disorder is too strong when compared to the
interaction strength, any close approach to the ground state is impossible. These results
show that it is not necessary for there to be any ac component to the field amplitude that
is applied to the system during demagnetization, which is the method almost exclusively
employed in field protocols reported to date. Furthermore, by optimizing the parameters
of our linear demagnetization protocol, the largest field-generated ground state domains
yet reported are found. www.frontiersin.org Edited by: y
Peter Fischer, Lawrence Berkeley
National Laboratory, USA
Reviewed by:
Dong-Hyun Kim, Chungbuk National
University, South Korea
Dario A. Arena, Brookhaven National
Laboratory, USA
*Correspondence:
Christopher H. Marrows, School of
Physics and Astronomy, University
of Leeds, Leeds LS2 9JT, UK
e-mail: c.h.marrows@leeds.ac.uk Peter Fischer, Lawrence Berkeley
National Laboratory, USA
Reviewed by:
Dong-Hyun Kim, Chungbuk National
University, South Korea
Dario A. Arena, Brookhaven National
Laboratory, USA
*Correspondence:
Christopher H. Marrows, School of
Physics and Astronomy, University
of Leeds, Leeds LS2 9JT, UK
e-mail: c.h.marrows@leeds.ac.uk Peter Fischer, Lawrence Berkeley
National Laboratory, USA Peter Fischer, Lawrence Berkeley
National Laboratory, USA Reviewed by: Naturally, ground state (GS) access has been a prominent area
of interest [14, 15]: one wishes to know whether or not a system
behaves as designed. Furthermore, the square ice GS, shown in
Figure 1A, provides a background for energetically well-defined
magnetic charge defects [16, 17], hence the reliable generation
of GS order could lead to studies of defect creation and manip-
ulation. More generally, the repeatable experimental access of
well-defined states is of its own interest and is further com-
plementary to numerous current studies, e.g., of ferromagnetic
resonance in nanopatterned magnetic structures [18–20] and
numerical simulations of ordering processes [21–25]. Here we apply a simple rotating linearly-decreasing field pro-
tocol to square ice systems similar to those discussed. Results of
such a protocol have been previously reported, but not in exten-
sive detail [31]. Using magnetic force microscopy (MFM), we look Until recently [26–28] the most successful route to GS ordering
in square ice involved the thermalization of NiFe islands during December 2013 | Volume 1 | Article 28 | 1 Demagnetization of artificial square ice Morgan et al. fashion from ≈1300 Oe to 0 Oe, at a rate r = dHa
dt , whilst the
sample rotated around an axis normal to the sample plane at
close to f = 42 Hz. A schematic of the protocol as well as an
example of an experimentally measured field profile are shown
in Figure 2. As for previous studies [2, 21], this protocol oper-
ates within a regime in which the micromagnetic response of the
system’s constituent nano elements to the time-varying field they
experience is expected to occur on time scales significantly faster
than the utilized rotational period, hence the dynamic response of
an island’s magnetization occurs effectively instantaneously. For
clarity, note that the following results will be discussed from the
sample reference frame. Such a protocol ensures states are ini-
tially reset with each application, with bulk array coercive fields
of Hc ≈600 Oe, and a switching window of ≈100 Oe (hys-
teresis measurements for the a = 500 nm sample of batch 1 have
previously been presented [37]; such values are typical for nano-
magnets of the dimensions used here [21, 31] and vary little with
a [38]). These values are also indicated in Figure 2. Magnetic
states were imaged using MFM over ∼5 evenly spaced areas each
of ≈13 µm ×13 µm. 2.1. SAMPLE FABRICATION AND FIELD PROTOCOL The black
solid line indicates the coercive field of such samples, Hc ≈600 Oe, and
the dashed black lines indicate the estimated intrinsic macrospin switching
field distribution width of ≈±100 Oe centered about Hc. FIGURE 1 | (A) The square ice ground state. Each magnetic nano-element
possesses an Ising-like moment, as indicated by arrows. The dashed box
indicates a structural unit cell (with lattice constant a) containing a single
vertex, which possesses an area of a2. An example of a pair of 1st nearest
neighbor moments is emboldened. Cartesian axes are also defined with
reference to the sample frame. (B) The 16 vertex model of square ice. Vertices can be arranged into four types Ti in order of increasing energy,
i = 1–4, respectively. 2.2. VERTEX MODEL INTERPRETATION The square ice system is well-described by a 16 vertex model,
Figure 1B. Four degenerate configuration types can be formed by
the four moments converging at a vertex, Ti for i = 1–4 in order
of increasing energy [2]. The GS is defined by a chess-board tiling FIGURE 2 | Applied field protocol example. (Inset) A sample is rotated
about an out-of-plane axis at f = 42 Hz whilst and in-plane field Ha is
applied. Ha is ramped down from 1300 to 0 Oe in a linear fashion, as shown
in the main plot for a ramping rate of r = 6 Oe/s (red solid line). The black
solid line indicates the coercive field of such samples, Hc ≈600 Oe, and
the dashed black lines indicate the estimated intrinsic macrospin switching
field distribution width of ≈±100 Oe centered about Hc. FIGURE 1 | (A) The square ice ground state. Each magnetic nano-element
possesses an Ising-like moment, as indicated by arrows. The dashed box
indicates a structural unit cell (with lattice constant a) containing a single
vertex, which possesses an area of a2. An example of a pair of 1st nearest
neighbor moments is emboldened. Cartesian axes are also defined with
reference to the sample frame. (B) The 16 vertex model of square ice. Vertices can be arranged into four types Ti in order of increasing energy,
i = 1–4, respectively. FIGURE 1 | (A) The square ice ground state. Each magnetic nano-element
possesses an Ising-like moment, as indicated by arrows. The dashed box
indicates a structural unit cell (with lattice constant a) containing a single
vertex, which possesses an area of a2. An example of a pair of 1st nearest
neighbor moments is emboldened. Cartesian axes are also defined with
reference to the sample frame. (B) The 16 vertex model of square ice. Vertices can be arranged into four types Ti in order of increasing energy,
i = 1–4, respectively. FIGURE 2 | Applied field protocol example. (Inset) A sample is rotated
about an out-of-plane axis at f = 42 Hz whilst and in-plane field Ha is
applied. Ha is ramped down from 1300 to 0 Oe in a linear fashion, as shown
in the main plot for a ramping rate of r = 6 Oe/s (red solid line). 2.1. SAMPLE FABRICATION AND FIELD PROTOCOL Samples were fabricated by electron beam lithography using a
JEOL 6300 system and evaporative metallization, as described
previously [17]. Elements were 86 nm by 280 nm in area, pos-
sessing a thin film structure of Ti(3 nm)/NiFe(26 nm)/Al(2.5 nm). Each element forms a single domain anisotropic macrospin, with
a bistable dipolar moment. Samples each spanned total areas of
2.5 mm × 2.5 mm. Two sample batches were studied: batch 1
consisted of five arrays with lattice constants of a = 500 nm to
900 nm in steps of 100 nm, and batch 2 consisted of two arrays
with a = 400 nm and 500 nm. Magnetic states were prepared by the application of an in-
plane magnetic field of magnitude Ha which decreased in a linear FIGURE 1 | (A) The square ice ground state. Each magnetic nano-element
possesses an Ising-like moment, as indicated by arrows. The dashed box
indicates a structural unit cell (with lattice constant a) containing a single
vertex, which possesses an area of a2. An example of a pair of 1st nearest
neighbor moments is emboldened. Cartesian axes are also defined with
reference to the sample frame. (B) The 16 vertex model of square ice. Vertices can be arranged into four types Ti in order of increasing energy,
i = 1–4, respectively. so twa e [39]) suc
t at eac
a o
ag et appea s as a du
b
bell of red and blue contrast, as drawn in Figure 1, indicating the
north and south magnetic poles, respectively, allowing moment
configurations to be fully inferred. Unless stated otherwise, sta-
tistical error bars presented are calculated as the standard error
over the collection of images for a given sample and field protocol
realization. 2.2. VERTEX MODEL INTERPRETATION
The square ice system is well-described by a 16 vertex model,
Figure 1B. Four degenerate configuration types can be formed by
the four moments converging at a vertex, Ti for i = 1–4 in order
of increasing energy [2]. The GS is defined by a chess-board tiling
FIGURE 2 | Applied field protocol example. (Inset) A sample is rotated
about an out-of-plane axis at f = 42 Hz whilst and in-plane field Ha is
applied. Ha is ramped down from 1300 to 0 Oe in a linear fashion, as shown
in the main plot for a ramping rate of r = 6 Oe/s (red solid line). Reviewed by: Our images are colored (using the WSxM
software [39]) such that each nanomagnet appears as a dumb-
bell of red and blue contrast, as drawn in Figure 1, indicating the
north and south magnetic poles, respectively, allowing moment
configurations to be fully inferred. Unless stated otherwise, sta-
tistical error bars presented are calculated as the standard error
over the collection of images for a given sample and field protocol
realization. in detail at the effects of varying both the system’s lattice constant
and the protocol ramping rate on the magnetic states achieved. We observe effective control of GS ordering strength without the
need for an oscillating field and produce the strongest GS order
yet reported for field-driven dynamics. 3.1. MAGNETIC STATES vs. LATTICE CONSTANT Figure 3 shows a series of MFM images of states prepared for
r = 6 Oe/s, with a shown in each case. For clarity, regions con-
tinuously tiled with T1 vertices are boxed and tinted red or blue,
indicating whether they belong to one possible GS phase or
the other. What is immediately apparent is the variety of states
achieved. For largest a, states appear magnetically disordered. As
a decreases, small GS-ordered regions emerge, becoming clear
to the eye at a = 700 nm, existing within a disordered-looking
matrix of higher energy vertices. By a = 500 nm, the order is typ-
ified by sizeable continuous GS domains spanning many vertices
and separated by narrow domain wall structures the width of a Figure 4 shows the corresponding vertex type populations, ni
for i = 1–4, as a function of a. Populations are non-random over
all a, as ni are not given by their multiplicities qi, plotted as dashed
lines in Figure 4A. Throughout this series, vertex populations
mainly shift from n3 to n1, being respectively, equal to 0.36 ±
0.01 and 0.24 ± 0.02 for a = 900 nm, and 0.073 ± 0.003 and
0.628 ± 0.009 for a = 400 nm. n2,4 stay approximately constant
at n2 ≈0.33 and n4 ≈0. It is clear that the observed behavior FIGURE 3 | MFM images of square ice states prepared by a linearly
decreasing rotating in-plane field. Scale bars represent 2 µm. Samples
were rotated at f = 42 Hz, and the field was ramped down at
r = 6 Oe/s. As the lattice constant decreases from a = 900 nm to
400 nm, strong ground state order emerges in the form of well-defined
domains, which are boxed and tinted red or blue to indicate the two
GS phases. The normalized digital magnetization components mx,y are
quoted and standard errors are expressed in brackets at their
corresponding significant figures. Note, all images are of samples from
batch 1 except for a = 400 nm. domains, which are boxed and tinted red or blue to indicate the two
GS phases. The normalized digital magnetization components mx,y are
quoted and standard errors are expressed in brackets at their
corresponding significant figures. Note, all images are of samples from
batch 1 except for a = 400 nm. FIGURE 3 | MFM images of square ice states prepared by a linearly
decreasing rotating in-plane field. 3. RESULTS 3.1. MAGNETIC STATES vs. LATTICE CONSTANT 2.2. VERTEX MODEL INTERPRETATION The black
solid line indicates the coercive field of such samples, Hc ≈600 Oe, and
the dashed black lines indicate the estimated intrinsic macrospin switching
field distribution width of ≈±100 Oe centered about Hc. FIGURE 2 | Applied field protocol example. (Inset) A sample is rotated
about an out-of-plane axis at f = 42 Hz whilst and in-plane field Ha is
applied. Ha is ramped down from 1300 to 0 Oe in a linear fashion, as shown
in the main plot for a ramping rate of r = 6 Oe/s (red solid line). The black
solid line indicates the coercive field of such samples, Hc ≈600 Oe, and
the dashed black lines indicate the estimated intrinsic macrospin switching
field distribution width of ≈±100 Oe centered about Hc. December 2013 | Volume 1 | Article 28 | 2 Frontiers in Physics | Condensed Matter Physics Demagnetization of artificial square ice Morgan et al. single vertex, much like those observed following thermal order-
ing [3, 17, 26–29, 32] and in square ice simulations [24]. For
a = 400 nm, these features are only enhanced. Here interaction
strength is being varied against a close-to-constant intrinsic island
property distribution (assuming little variation in patterning as a
is changed). of T1 vertices, Figure 1, which, crucially, is twofold degenerate. This state presents a background for well-defined magnetic chain
defects consisting of magnetically charged “monopole” excita-
tions in the form of T3,4 vertices, which possess an excess of
north or south polarity, connected by energetic strings of T2 ver-
tices. Such chain defects can exist as isolated excitations flipped
out of the GS background [40], or as part of domain wall struc-
ture separating two continuous regions of opposite GS phase
[3, 17, 32]. Whilst both T1,2 obey the 2-in/2-out ice rules, they
are energetically split by the square ice geometry. Also quoted in Figure 3 are the normalized digital magneti-
zation components mx,y along the respective x−, y−directions
as defined in Figure 1A. Here we assume identical point Ising
dipoles. Previous discussion of a similar linear protocol reported
a large variation in the net magnetization of states achieved for
similar samples and protocol parameters, however, this observa-
tion was never explained or understood [31]. Here we observe
a tendency for demagnetization to improve as a decreases,
attributable to stronger interactions promoting the formation of
zero-moment T1 vertices. 3.1. MAGNETIC STATES vs. LATTICE CONSTANT Scale bars represent 2 µm. Samples
were rotated at f = 42 Hz, and the field was ramped down at
r = 6 Oe/s. As the lattice constant decreases from a = 900 nm to
400 nm, strong ground state order emerges in the form of well-defined December 2013 | Volume 1 | Article 28 | 3 www.frontiersin.org Demagnetization of artificial square ice Morgan et al. FIGURE 4 | (A) Vertex populations ni for i = 1–4 vs. lattice constant a. Dashed lines represent the corresponding random-state values, as given by multiplicities
qi. (B) The corresponding mean areal domain size Nd. Data points for batch 1(2) are open(filled). FIGURE 4 | (A) Vertex populations ni for i = 1–4 vs. lattice constant a. Dashed lines represent the corresponding random-state values, as given by multiplicities
qi. (B) The corresponding mean areal domain size Nd. Data points for batch 1(2) are open(filled). ons ni for i = 1–4 vs. lattice constant a. Dashed lines represent the corresponding random-state values, as given by multiplicitie
n areal domain size Nd. Data points for batch 1(2) are open(filled). with a is qualitatively similar to that of thermally annealed square
ice systems: the GS domains are comparable in form [3, 41]. Furthermore, the data for a = 400 nm shows the strongest GS
order yet reported following field-driven dynamics. non-interacting system in the limit of a →∞(This was calcu-
lated by averaging the statistics of pseudo-randomly generated
square ice states, 200 × 200 vertices in size, over 30,000 real-
izations). Note, we follow recent studies of dipole domains in
nanomagnet arrays [5], neglecting the finite field of view in the
calculation, which will act to reduce the measured size of edge-
straddling domains. While our domains could be interpreted in
terms of dipoles which belong to either phase of the GS, the ver-
tex picture is more appealing as the T1 vertex is the natural object
of interest in this study. The maximum n1 population yet reported following ac
demagnetization of quasi-infinite square ice is 0.35 [2]. Whilst
the ac demagnetization protocol was further optimized in later
studies [14], this work addressed exclusively pairwise correlation
between elemental magnetizations. 3.1. MAGNETIC STATES vs. LATTICE CONSTANT If a correlator C is defined
as ±1 depending on whether two first-nearest-neighbor elements
(as illustrated in Figure 1A) are favorably or unfavorably aligned,
respectively, at a = 400 nm we find a value of ⟨C⟩= 0.618 ±
0.009, averaged over all such pairs imaged. This compares with
roughly 0.5 ± 0.02 for the previously reported ac demagnetiza-
tion study [14]. Furthermore, whilst rotating and non-rotating
field demagnetization experiments on finite area square ice pat-
terns have also been shown to generate significant n1 populations
[21, 35, 42], finite size edge effects are expected to have played a
significant role in the onset of coherent ordering [22], which will
be absent from our “bulk” measurements. It is interesting to consider the means by which the observed
order should form during the field protocol. The evolution of
order will be governed by whether or not the net local field
experienced by a given macrospin overcomes its intrinsic switch-
ing barrier as Ha evolves in time. This is indeed a non-trivial
many-body problem requiring the attention of simulations or
“real-time” microscopy studies, beyond the scope of our present
report. Despite this, we can make general inferences based on the
state-of-the-art. As we will discuss, this is a problem involving
the balance of three magnetic field scales defined by interaction
strength (controlled by a), QD, and r. For completeness, note that our two a = 500 nm samples
possess similar statistics, however, they are statistically distinct,
indicating the subtle difference between sample batches as men-
tioned in previous reports [17]. The protocol was also repeated
two or three times for each sample, yielding consistent results (not
shown in Figure 4 for clarity). Two trivial field regimes must exist: one where Ha is so large
that all macrospins track it, the other where Ha is too low to allow
any dynamics at all. In the crossover between these two regimes
the non-trivial regime of interest exists, both interactions and
QD influencing its width. This region is illustrated in the plot
of Figure 2. The most influential interaction is that between first
nearest neighbors, as indicated in Figure 1A. The field strength
H1 can be calculated assuming point Ising dipoles with moments
μ = VMs, a prismatic volume V and the saturation magnetiza-
tion of NiFe Ms = 860 × 103 A/m. 3.2. MAGNETIC STATES vs. FIELD RAMPING RATE To further study these ideas we explore the effects of parameter r
on the states formed. We test this for two samples from batch 1,
the densest and sparsest patterns, with a = 500 nm and 900 nm,
respectively. The crucial difference between these two samples is
the interaction strength. Both should, however, possess a simi-
lar intrinsic distribution of moment properties, hence, the effects
of QD should be much more prominent for the latter sample,
in which interelemental coupling is relatively weaker. Rates of
r = 0.3 Oe/s, 3 Oe/s, 6 Oe/s, 60 Oe/s, 300 Oe/s, and 600 Oe/s were
used. In dc field reversal, a picture of propagation of defected vertices
across a background state via the sequential flipping of underlying
moments is often invoked [12, 35, 36, 43]. In our protocol, we can
consider there to be a background of “loose” spins which track
the field. As Ha drops through the critical field window, increas-
ing numbers of moments will lock out due to local stabilization. Initial nucleation of order will occur at random sites defined by
QD. Correlated order can then form around such nucleation sites
due to dipolar interactions. Simulations have showed that at opti-
mal values of Ha spin flip dynamics increment every 1/4 turn
in constant-magnitude rotating field protocols [21, 22], proceed-
ing via the creation, propagation and annihilation of oppositely
charged T3 vertex pairs, and the same is anticipated for our lin-
early decreasing field profile. The field step every 1/4 turn, Ha,
is hence a third relevant scale, influencing which moments might
or might not freeze. For r = 6 Oe/s and f = 42 Hz, Ha =
0.036 Oe. Tuning r is hence expected to be a means of control-
ling the order in a given sample, crudely defining an “annealing
time.” Figure 5 shows MFM images for a selection of four values of r
for the a = 500 nm sample, and two images for the a = 900 nm
sample with smallest and largest r, respectively. All states were
found to be adequately demagnetized, as quoted, with a con-
sistently higher moment for a = 900 nm. Again, a shorter a has
resulted in better demagnetization. Figure 6 shows (A) ni and (B)
Nd for both samples. 3.1. MAGNETIC STATES vs. LATTICE CONSTANT H1 varies from ≈40 to 4 Oe
as a increases from 400 to 900 nm, respectively. For QD, recently
a width σ = 1.25H1 was estimated for a Gaussian distribution
of intrinsic switching fields in similar patterns with a = 400 nm
[21], hence σ ≈50 Oe. This estimation is expected to be repre-
sentative of all a studied, as similarly fabricated patterns studied To directly characterize the observed domain structure, we
define the normalized mean areal domain size, Nd, as the aver-
age number of T1 vertices in continuous contact within a domain
(calculated cumulatively over all MFM images for a given param-
eter set, along with a standard error). A vertex contributes a unit
area a2 to a domain, as shown by a box in Figure 1A. Shown in
Figure 4B, Nd steadily increases from 1.9 ± 0.1 at a = 900 nm
to 11.3 ± 0.9 at a = 400 nm. The value of Nd for a random
state equals 1.32 to 3 significant figure, as indicated in Figure 4B
by a dotted line, which would be expected for a demagnetized December 2013 | Volume 1 | Article 28 | 4 Frontiers in Physics | Condensed Matter Physics Demagnetization of artificial square ice Morgan et al. by MOKE magnetometry were reported to show little variation in
the width of the field range over which their net magentizations
reversed as a function of a [38], implying that extrinsic perturba-
tions to magnetic reversal of the constituent nanoelements, such
as pairwise interaction disorder, are a much lesser contribution to
this width. 4. DISCUSSION
l d
h To conclude, this rotating linearly-ramped applied field protocol
has been shown to produce effective and repeatable formation of
GS ordered domains in square ice systems. It is simpler to imple-
ment than the ac rotational demagnetization method [31], but
can yield superior results in terms of approaching the GS. Whilst field-driven demagnetization is not as effective at larger
a, we have shown here that the field ramping rate is crucial, which
determines how many active rotations a system undergoes whilst
the applied field lies within a critical dynamical window. Whilst
this is also true of ac field profiles applied to rotating systems, an
oscillation of the applied field (as observed in the laboratory ref-
erence frame) is unnecessary in forming well-demagnetized states
possessing strong GS-order. The extent of GS domains, as quanti-
fied by an average GS domain size, is the strongest yet achieved by
field-driving reported in experimental literature, attributable to a
significant degree to sufficiently high ratio of interaction strength
to QD. For the a = 900 nm sample only very weak effects are
observed. For all r, GS order is weak. Whilst there is some evi-
dence of GS order enhancement on reducing r, this is far from
conclusive. At r = 600 Oe/s, Ha = 3.6 Oe which is ≈H1(a =
900 nm) hence local variations in field due to interactions may
not be allowed to play a significant role in ordering. Interactions
are, however, not irrelevant as n4 is suppressed for all values
of r. Below r = 6 Oe/s, even though Ha ≪H1, QD must dom-
inate the behavior via the local variation in macrospin properties
as σ ≫H1. The effect of QD can be emphasized by compar-
ing states for parameters sets (a = 500 nm and r = 3 Oe/s) and
(a = 900 nm and r = 0.3 Oe/s). Ha/H1 are very similar in these
two cases, however, the final states achieved are clearly very differ-
ent. Neither state is random, however, the relative scale of QD is
much greater in the latter. The observed tuning of domain structure in the final states
achieved by relative levels of QD is consistent with the results of
numerical simulations [24]. Finding a means of influencing the
levels of QD present [3, 8] is hence important for future studies
of field- and thermally-driven systems. 3.2. MAGNETIC STATES vs. FIELD RAMPING RATE For r = 0.3 Oe/s and a = 500 nm, the strongest GS order
and largest average domain size are observed, again with nar-
row domain walls. Here n1 = 0.62 ± 0.09 and Nd = 11.3 ± 1.4
vertices (statistically similar to the state of a = 400 nm and r =
6 Oe/s discussed previously). As r is increased, the domains
shrink in size. Whilst continuous T1 domains are never fully
suppressed to a random-state size, a messy matrix of T2,3 FIGURE 5 | MFM image series of square ice states for varying
ramping rates r for the a = 500 nm and a = 900 nm samples of
batch 1 (as quoted). Scale bars represent 2 µm. The two GS phases
are indicated by boxes tinted red or blue. For a = 500 nm, decreasing
r enhances the formation of GS-ordered domains, whilst increasing r
promotes more disorder and T2,3 vertices. For a = 900 nm, little
variation is observed with r, indicating the relative strength of QD in
the system. r enhances the formation of GS-ordered domains, whilst increasing r
promotes more disorder and T2,3 vertices. For a = 900 nm, little
variation is observed with r, indicating the relative strength of QD in
the system. FIGURE 5 | MFM image series of square ice states for varying
ramping rates r for the a = 500 nm and a = 900 nm samples of
batch 1 (as quoted). Scale bars represent 2 µm. The two GS phases
are indicated by boxes tinted red or blue. For a = 500 nm, decreasing December 2013 | Volume 1 | Article 28 | 5 www.frontiersin.org Demagnetization of artificial square ice Morgan et al. FIGURE 6 | (A) Vertex populations ni vs. ramping rate r for samples with a = 500 nm (filled symbols) and a = 900 nm (open symbols). (B) The corresponding
average domain size Nd. Dashed lines represent the limiting random-state values. FIGURE 6 | (A) Vertex populations ni vs. ramping rate r for samples with a = 500 nm (filled symbols) and a = 900 nm (open symbols). (B) The corresponding
average domain size Nd. Dashed lines represent the limiting random-state values. structure develops by r ≈600 Oe/s. Here, n1 = 0.41 ± 0.01 and
Nd = 3.4 ± 0.2. can also be understood by considering the effects of QD. 3.2. MAGNETIC STATES vs. FIELD RAMPING RATE The
samples used in our current study which have the strongest GS
order possess less QD relative to the interaction strength, mean-
ing that stronger coherent ordering has been allowed. Evidence
for this can be found by comparing various electron microscopy
images of experimental square ice patterns previously reported
[41, 44]. This observation is consistent with the picture that more active
rotations within the critical field window allows for increased
incremental propagation of T3 vertices, which has allowed them
to travel further and find opposite charges with which to anni-
hilate, increasingly forming coherent GS domains in their wake. Once domains are established, they may further evolve or coarsen
by motion and annihilation of T3 vertices along their walls
[23, 32]. As r increases, there is less opportunity for T3 ver-
tices to travel before becoming trapped by the decreasing of Ha. Interactions are still clearly important at r = 600 Oe/s, as few T4
vertices are found, however, the system is simply not active for
long enough to allow for strong GS order formation. This state is
not dissimilar to the a = 600 nm and 700 nm states for r = 6 Oe/s
discussed previously. Tuning Ha appears to influence the extent
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Phys. (2012) 14:035017. doi: 10.1088/1367-2630/14/3/035017 7. REFERENCES Wysin GM, Moura-Melo WA, Mól LAS, Pereira AR. Magnetic anisotropy of
elongated thin ferromagnetic nano-islands for artificial spin ice arrays. J Phys
Condens Matt. (2012) 24:296001. doi: 10.1088/0953-8984/24/29/296001 31. Wang RF, Li J, McConville W, Nisoli C, Ke X, Freeland JW, et al. Demagnetization protocols for frustrated interacting nanomagnet arrays. J
Appl Phys. (2007) 101:09J104. doi: 10.1063/1.2712528 8. Daunheimer S, Petrova O, Tchernyshyov O, Cumings, J. Reducing dis-
order in artificial kagome ice. Phys Rev Lett. (2011) 107:167201. doi:
10.1103/PhysRevLett.107.167201 32. Budrikis Z, Livesey K, Morgan JP, Akerman J, Stein A, Langridge S, et al. Domain dynamics and fluctuations in artificial square ice at finite tempera-
tures. New J Phys. (2012) 14:035014. doi: 10.1088/1367-2630/14/3/035014 9. Branford WR, Ladak S, Read DE, Zeissler K, Cohen LF. Emerging chirality in
artificial spin ice. Science (2012) 335:1597–600. doi: 10.1126/science.1211379 33. Davidovi´c D, Kumar S, Reich DH, Siegel J, Field SB, Tiberio RC, et al. Correlations and disorder in arrays of magnetically coupled superconducting
rings. Phys Rev Lett. (1996) 76:815–8. doi: 10.1103/PhysRevLett.76.815 10. Braun HB. Topological effects in nanomagnetism: from superparam-
agnetism
to
chiral
quantum
solitons. Adv. Phys. (2012)
61:1. doi:
10.1080/00018732.2012.663070 34. Davidovi´c D, Kumar S, Reich DH, Siegel J, Field SB, Tiberio RC, et al. Magnetic correlations, geometrical frustration, and tunable disorder in
arrays of superconducting rings. Phys Rev B (1997) 55:6518–40. doi:
10.1103/PhysRevB.55.6518 11. Farhan A, Derlet PM, Kleibert A, Balan A, Chopdekar RV, Wyss M, et al. Exploring hyper-cubic energy landscapes in thermally active finite spin-ice
systems. Nat Phys. (2013) 9:375–82. doi: 10.1038/nphys2613 12. Mengotti E, Heyderman LJ, Fraile Rodríguez A, Nolting F, Hügli RV, Braun
HB. Real-space observation of emergent magnetic monopoles and associated
Dirac strings in artificial kagome spin ice. Nat Phys. (2011) 7:68–74. doi:
10.1038/nphys1794 35. Phatak C, Pan M, Petford-Long AK, Hong S, De Graef, M. Magnetic interac-
tions and reversal of artificial square spin ices. New J Phys. (2012) 14:075028. doi: 10.1088/1367-2630/14/7/075028 36. Pollard SD, Volvok V, Zhu, Y. Propagation of magnetic charge monopoles
and Dirac flux strings in an artificial spin-ice lattice. Phys Rev B (2012)
85:180402(R). doi: 10.1103/PhysRevB.85.180402 13. Möller G, Moessner, R. Artificial square ice and related dipolar nanoarrays. Phys Rev. Lett. (2006) 96:237202. doi: 10.1103/PhysRevLett.96.237202 14. Ke X, Li J, Nisoli C, Lammert PE, McConville W, Wang RF, et al. Energy mini-
mization and ac demagnetization in a nanomagnet array. Phys Rev Lett. (2008)
101:037205. doi: 10.1103/PhysRevLett.101.037205 37. 4. DISCUSSION
l d
h Further work is needed to
better compare the various protocols employed, and understand
the subtle difference between their driven dynamics. This can be
further supported by numerical simulations, to understand how
final states and “effective equilibrium” are approached. It is further interesting to compare these results with previ-
ous reports of ac demagnetized square ice states. It was reported
that ac demagnetization was notably superior to linearly ramped
field demagnetization [31], despite few details of state statis-
tics being given. Here, using a linear field, we report a closer
approach to the GS than those reported for ac demagnetization
[2, 3, 14]. Whilst this at first appears to be contradictory, this Further work could also involve studies of the effects of field
profile parameters, as well as the synchronization of field step with
sample rotation. Furthermore, in our samples, the domain size is
large enough and the domain walls are narrow enough to further December 2013 | Volume 1 | Article 28 | 6 Frontiers in Physics | Condensed Matter Physics Demagnetization of artificial square ice Morgan et al. study how GS ordered regions and defects respond to applied
fields. 15. Qi Y, Brintlinger T, Cumings, J. Direct observation of the ice rule
in an artificial kagome spin ice. Phys Rev B (2008) 77:094418. doi:
10.1103/PhysRevB.77.094418 y
16. Mól LA, Moura-Melo WA, Pereira AR. Conditions for free magnetic
monopoles in synthetic square ice dipolar nanoarrays. Phys Rev B (2010)
82:054434. doi: 10.1103/PhysRevB.82.054434 AUTHOR CONTRIBUTIONS The experiments were designed by Jason P. Morgan. Experimental
measurements were conducted by Alexander Bellew. Data analysis
was conducted by Jason P. Morgan and Alexander Bellew. Sample
fabrication was conducted by Jason P. Morgan and Aaron Stein. The manuscript was written by Jason P. Morgan and Christopher
H. Marrows. The work was supervised by Jason P. Morgan, Sean
Langridge, and Christopher H. Marrows. 17. Morgan JP, Stein A, Langridge S, Marrows CH. Thermal ground state ordering
and elementary excitations in artificial magnetic square ice. Nat Phys. (2011)
7:75–9. doi: 10.1038/nphys1853 18. Gliga S, Kákay A, Hertel R, Heinonen OG. Spectral analysis of topological
defects in an artificial spin-ice lattice. Phys Rev Lett. (2013) 110:117205. doi:
10.1103/PhysRevLett.110.117205 19. Sklenar J, Bhat VS, DeLong LE, Ketterson JB. Broadband ferromagnetic reso-
nance studies on an artificial square spin-ice island array. J Appl Phys. (2013)
113:17B530. doi: 10.1063/1.4800740 ACKNOWLEDGMENTS 20. Verba R, Melkov G, Tiberkevich V, Slavin, A. Fast switching of a ground
state of a reconfigurable array of magnetic nano-dots. Appl Phys Lett. (2012)
100:192412. doi: 10.1063/1.4714772 Funding: The authors thank the UK EPSRC, the STFC Centre for
Material Physics and Chemistry, the Nuffield Foundation and the
Institute of Physics for financial support. Research was carried out
in part at the Center for Functional Nanomaterials, Brookhaven
National Laboratory, which is supported by the U.S. Department
of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. 21. Budrikis Z, Morgan JP, Akerman J, Stein A, Politi P, Langridge S, et al. Disorder
strength and field-driven ground state domain formation in artificial spin ice:
experiment, simulation and theory. Phys Rev Lett. (2012) 109:037203. doi:
10.1103/PhysRevLett.109.037203 22. Budrikis
Z,
Politi
P,
Stamps
RL. Vertex
dynamics
in
finite
two-
dimensional square spin ices. Phys Rev Lett. (2010) 105:017201. doi:
10.1103/PhysRevLett.105.017201 23. Libál A, Reichhardt C, Reichhardt CJO. Hysteresis and return-point mem-
ory in colloidal artificial spin ice system. Phys Rev E (2012) 86:021406. doi:
10.1103/PhysRevE.86.021406 REFERENCES Morgan JP, Kinane CJ, Charlton TR, Stein A, Sánchez-Hanke C, Arena DA,
et al. Magnetic hysteresis of an artificial square ice studied by in-plane December 2013 | Volume 1 | Article 28 | 7 www.frontiersin.org Demagnetization of artificial square ice Morgan et al. 44. Wang, R. Geometrical Magnetic Frustration and Demagnetization of Artificial
Spin Ice. Ph.D. thesis, Department of Physics, The Graduate School, The
Pennsylvania State University, (2007). 44. Bragg x-ray resonant magnetic scattering. AIP Adv. (2012) 2:022163. doi:
10.1063/1.4732147 Bragg x-ray resonant magnetic scattering. AIP Adv. (2012) 2:022163. doi:
10.1063/1.4732147 38. Kohli K, Balk AL, Li J, Zhang S, Gilbert I, Lammert P, et al. Magneto-optical
Kerr effect studies of artificial spin ice. Phys Rev B (2011) 84:180412(R). doi:
10.1103/PhysRevB.84.180412 Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest. 39. Horcas I, Fernández R, Gómez-Rodríguez JM, Colchero J, Gómez-Herrero
J, Baro AM. WSxM: a software for scanning probe microscopy and a
tool for nanotechnology. Rev Sci Instrum. (2007) 78:013705. doi: 10.1063/
1.2432410 Received: 17 August 2013; accepted: 23 November 2013; published online: 18
December 2013. 40. Mól LA, Silva RL, Silva RC, Pereira AR, Moura-Melo WA, Costa BV. Magnetic
monopole and string excitations in two-dimensional spin ice. J Appl Phys. (2009) 106:063913. doi: 10.1063/1.3224870 Citation: Morgan JP, Bellew A, Stein A, Langridge S and Marrows CH (2013)
Linear field demagnetization of artificial magnetic square ice. Front. Physics 1:28. doi: 10.3389/fphy.2013.00028 Citation: Morgan JP, Bellew A, Stein A, Langridge S and Marrows CH (2013) Linear field demagnetization of artificial magnetic square ice. Front. Physics 1:28. doi: 10.3389/fphy.2013.00028 41. Morgan JP. Ordering and Defects in Artificial Magnetic Square Ice: thermody-
namic and Field-Driven Processes. Ph.D. thesis, University of Leeds (2011). This article was submitted to Condensed Matter Physics, a section of the journal
Frontiers in Physics. 42. Phatak C, Petford-Long AK, Heinonen O, Tanase M, De Graef, M. Nanoscale
structure of the magnetic induction at monopole defects in artificial
spin-ice lattices. Phys Rev B (2011) 83:174431. doi: 10.1103/PhysRevB.83. 174431 Copyright © 2013 Morgan, Bellew, Stein, Langridge and Marrows. This is an
open-access article distributed under the terms of the Creative Commons Attribution Copyright © 2013 Morgan, Bellew, Stein, Langridge and Marrows. This is an
open-access article distributed under the terms of the Creative Commons Attribution
License (CC BY). December 2013 | Volume 1 | Article 28 | 8 Frontiers in Physics | Condensed Matter Physics REFERENCES The use, distribution or reproduction in other forums is permitted,
provided the original author(s) or licensor are credited and that the original publica-
tion in this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these terms. 43. Morgan JP, Stein A, Langridge S, Marrows CH. Magnetic reversal of an arti-
ficial square ice: dipolar correlation and charge ordering. New J Phys. (2011). 13:105002. doi: 10.1088/1367-2630/13/10/105002 December 2013 | Volume 1 | Article 28 | 8 Frontiers in Physics | Condensed Matter Physics
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Evaluating the impact of healthcare interventions using routine data
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Evaluating the impact of healthcare interventions using
routine data OPEN ACCESS Geraldine M Clarke senior data analyst
1, Stefano Conti senior statistician
2, Arne T Wolters senior
analytics manager
1, Adam Steventon director of data analytics
1 1The Health Foundation, London, UK; 2NHS England and NHS Improvement, London, UK 1The Health Foundation, London, UK; 2NHS England and NHS Improvement, London, UK Correspondence to G Clarke Geraldine.clarke@health.org.uk PRACTICE PRACTICE What you need to know Assessing the impact of healthcare interventions is critical to inform future
decisions
Compare observed outcomes with what you would have expected if the
intervention had not been implemented
A wide range of routinely collected data is available for the evaluation of
healthcare interventions A health intervention is a combination of activities or strategies
designed to assess, improve, maintain, promote, or modify health
among individuals or an entire population. Interventions can
include educational or care programmes, policy changes,
environmental improvements, or health promotion campaigns. Interventions that include multiple independent or interacting
components are referred to as complex.5 The impact of any
intervention is likely to be shaped as much by the context (eg,
communities, work places, homes, schools, or hospitals) in
which it is delivered, as the details of the intervention itself.6-9 Interventions to transform the delivery of health and social care
are being implemented widely, such as those linked to
Accountable Care Organizations in the United States,1 or to
integrated care systems in the UK.2 Assessing the impact of
these health interventions enables healthcare teams to learn and
to improve services, and can inform future policy.3 However,
some healthcare interventions are implemented without high
quality evaluation, in ways that require onerous data collection,
or may not be evaluated at all.4 Interventions to transform the delivery of health and social care
are being implemented widely, such as those linked to
Accountable Care Organizations in the United States,1 or to
integrated care systems in the UK.2 Assessing the impact of
these health interventions enables healthcare teams to learn and
to improve services, and can inform future policy.3 However,
some healthcare interventions are implemented without high
quality evaluation, in ways that require onerous data collection,
or may not be evaluated at all.4 An impact is a positive or negative, direct or indirect, intended
or unintended change produced by an intervention. An impact
evaluation is a systematic and empirical investigation of the
effects of an intervention; it assesses to what extent the outcomes
experienced by affected individuals were caused by the
intervention in question, and what can be attributed to other
factors such as other interventions, socioeconomic trends, and
political or environmental conditions. Evaluations can be
categorised as formative or summative (table 1). A range of routinely collected administrative and clinically
generated healthcare data could be used to evaluate the impact
of interventions to improve care. Open Access: Reuse allowed Page 1 of 7 BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) Subscribe: http://www.bmj.com/subscribe What you need to know However, there is a lack of
guidance as to where relevant routine data can be found or
accessed and how they can be linked to other data. A diverse
array of methodological literature can also make it hard to
understand which methods to apply to analyse the data. This
article provides an introduction to help clinicians,
commissioners, and other healthcare professionals wishing to
commission, interpret, or perform an impact evaluation of a
health intervention. We highlight what to consider and discuss
key concepts relating to design, analysis, implementation, and
interpretation. A range of routinely collected administrative and clinically
generated healthcare data could be used to evaluate the impact
of interventions to improve care. However, there is a lack of
guidance as to where relevant routine data can be found or
accessed and how they can be linked to other data. A diverse
array of methodological literature can also make it hard to
understand which methods to apply to analyse the data. This
article provides an introduction to help clinicians, Approaches such as the Plan, Do, Study, Act cycle11, which is
part of the Model for Improvement, a commonly used tool to
test and understand small changes in quality improvement work12
may be used to undertake formative evaluation. commissioners, and other healthcare professionals wishing to
commission, interpret, or perform an impact evaluation of a
health intervention. We highlight what to consider and discuss
key concepts relating to design, analysis, implementation, and
interpretation. With either type of evaluation, it is important to be realistic
about how long it will take to see the intended effects. Assessment that takes place too soon risks incorrectly
concluding that there was no impact. This might lead
stakeholders to question the value of the intervention, when
later assessment might have shown a different picture. For
example, in a small case study of cost savings from proactively
managing high risk patients, the costs of healthcare for the Subscribe: http://www.bmj.com/subscribe Open Access: Reuse allowed BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) Page 2 of 7 PRACTICE eligible intervention population initially increased compared
with the comparison population, but after six months were
consistently lower.14 be assumed that the control group outcomes are representative
of those that the treated group would have experienced if nothing
had changed, ie, the counterfactual. What are the right evaluation questions? An effective impact evaluation begins with the formulation of
one or more clear questions driven by the purpose of the
evaluation and what you and your stakeholders want to learn. For example, “What is the impact of case management on
patients’ experience of care?” Observational studies are often referred to as natural (for natural
or unplanned interventions), or quasi (for planned or intentional
interventions) experiments. Natural experiments are discussed
to evaluate population health interventions.41 Formulate your evaluation questions using your understanding
of the idea behind your intervention, the implementation
challenges, and your knowledge of what data are available to
measure outcomes. Review your theory of change or logic
model21 22 to understand what inputs and activities were planned,
and what outcomes were expected and when. Once you have
understood the intended causal pathway, consider the practical
aspects of implementation, which include the barriers to change,
unexpected changes by recipients or providers, and other
influences not previously accounted for. Patient and public
involvement (PPI) in setting the right question is strongly
recommended for additional insights and meaningful results. For example, if evaluating the impact of case management, you
could engage patients to understand what outcomes matter most
to them. Healthcare leaders may emphasise metrics such as
emergency admissions, but other aspects such as the experience
of care might matter more to patients.5 23 What’s wrong with a simple
before-and-after study? Before-and-after studies compare changes in outcomes for the
same group of patients at a single time point before and after
receiving an intervention without reference to a control group. These differ from interrupted time series studies, which compare
changes in outcomes for successive groups of patients before
and after receiving an intervention (the interruption). Before-and-after studies are useful when it is not possible to
include an unexposed control group, or for hypothesis
generation. However, they are inherently susceptible to bias
since changes observed may simply reflect regression to the
mean (any changes in outcomes that might occur naturally in
the absence of the intervention), or influences or secular trends
unrelated to the intervention, eg, changes in the economic or
political environment, or a heightened public awareness of
issues. What you need to know For example, an evaluation
of alternative elective surgical interventions for primary total
hip replacement on osteoarthritis patients in England and Wales
used genetic matching to compare patients across three different
prosthesis groups, and reported that the most prevalent type of
hip replacement was the least cost effective.29 This article focuses on impact evaluation, but this can only ever
address a fraction of questions.15 Much more can be
accomplished if it is supplemented with other qualitative and
quantitative methods, including process evaluation. This
provides context, assesses how the intervention was
implemented, identifies any emerging unintended pathways,
and is important for understanding what happened in practice
and for identifying areas for improvement.16 The economic
evaluation of healthcare interventions is also important for
healthcare decision making, especially with ongoing financial
pressures on health services.17 Assessing similarity is only possible in relation to observed
characteristics, and matching can result in biased estimates if
the groups differ in relation to unobserved variables that are
predictive of the outcome (confounders). It is rarely possible to
eliminate this possibility of bias when conducting observational
studies, meaning that the interpretation of the findings must
always be sensitive to the possibility that the differences in
outcomes were caused by a factor other than the intervention. Methods that can help when selection is on unobserved
characteristics include difference-in-difference,30 regression
discontinuity,31 instrumental variables,18 or synthetic
controls.32Table 2 gives a summary of selected observational
study designs. What methods can be used to perform an
impact evaluation? Randomised control designs, where individuals are randomly
selected to receive either an intervention or a control treatment,
are often referred to as the “gold standard” of causal impact
evaluation.24 In large enough samples, the process of
randomisation ensures a balance in observed and unobserved
characteristics between treatment and control groups. However,
while often suitable for assessing, for example, the safety and
efficacy of medicines, these designs may be impractical,
unethical, or irrelevant when assessing the impact of complex
changes to health service delivery. For example, a before-and-after study of the impact of a care
coordination service for older people tracked the hospital
utilisation of the same patients before and after they were
accepted into the service. They found that the service resulted
in savings in hospital bed days and attendances at the emergency
department.42 Reduced hospital utilisation could have reflected
regression to the mean here rather than the effects of the
intervention; for example, a patient could have had a specific
health crisis before being invited to join the service and then
reverted back to their previous state of health and hospital
utilisation for reasons unconnected with the care coordination
service. Observational studies are an alternative approach to estimate
causal effects. They use the natural, or unplanned, variation in
a population in relation to the exposure to an intervention, or
the factors that affect its outcomes, to remove the consequences
of a non-randomised selection process.25 The idea is to mimic
a randomised control design by ensuring treated and control
groups are equivalent—at least in terms of observed
characteristics. This can be achieved using a variety of well
documented methods, including regression control and
matching,26 eg, propensity scoring27 or genetic matching.28 If
the matching is successful at producing such groups, and there
are also no differences in unobserved characteristics, then it can Various tools are available to evaluate the risk of bias in
non-randomised designs due to confounding and other potential
biases.43 44 Open Access: Reuse allowed Are there any additional considerations? It is essential to consider threats to validity when designing and
evaluating an impact evaluation; validity relates to whether an
evaluation is measuring what it is claiming to measure. See
Rothman et al55 for further discussion. Provenance and peer review: This article is part of a series commissioned by The
BMJ based on ideas generated by a joint editorial group with members from the
Health Foundation and The BMJ, including a patient/carer. The BMJ retained full
editorial control over external peer review, editing, and publication. Open access
fees and The BMJ’s quality improvement editor post are funded by the Health
Foundation. Internal validity refers to whether the effects observed are due
to the intervention and not some other confounding factor. Selection bias, which results from the way in which subjects
are recruited, or from differing rates of participation due, for
example, to age, gender, cultural or socioeconomic factors, is
often a problem in non-randomised designs. Care must be taken
to account for such biases when interpreting the results of an
impact evaluation. Sensitivity analyses should be performed to
provide reassurance regarding the plausibility of causal
inferences. Patient and/or members of the public were not involved in the creation of this article. 1
Davis K, Guterman S, Collins S, Stremikis G, Rustgi S, Nuzum R. Starting on the path to
a high performance health system: Analysis of the payment and system reform provisions
in the Patient Protection and Affordable Care Act of. The Commonwealth Fund, 2010,
https://www.commonwealthfund.org/publications/fund-reports/2010/sep/starting-path-
high-performance-health-system-analysis-payment. 2
NHS NHS Long Term Plan. 2019. https://www.england.nhs.uk/long-term-plan/
3
Djulbegovic B. A framework to bridge the gaps between evidence-based medicine, health
outcomes, and improvement and implementation science. J Oncol Pract 2014;10:200-2. 10.1200/JOP.2013.001364 24839282
4
Bickerdike L, Booth A, Wilson PM, etal . Social prescribing: less rhetoric and more reality. A systematic review of the evidence. BMJ Open 2017;7:e013384. 5
Campbell M, Fitzpatrick R, Haines A, etal . Framework for design and evaluation of
complex interventions to improve health. BMJ 2000;321:694-6. 10.1136/bmj.321.7262.694 10987780
6
Rickles D. Causality in complex interventions. Med Health Care Philos 2009;12:77-90. 10.1007/s11019-008-9140-4 18465202
7
Hawe P. Lessons from complex interventions to improve health. Annu Rev Public Health
2015;36:307-23. 10.1146/annurev-publhealth-031912-114421 25581153
8
Greenhalgh T, Papoutsi C. Studying complexity in health services research: desperately
seeking an overdue paradigm shift. BMC Med 2018;16:95. 1
Davis K, Guterman S, Collins S, Stremikis G, Rustgi S, Nuzum R. Starting on the path to
a high performance health system: Analysis of the payment and system reform provisions
in the Patient Protection and Affordable Care Act of. The Commonwealth Fund, 2010,
https://www.commonwealthfund.org/publications/fund-reports/2010/sep/starting-path-
high-performance-health-system-analysis-payment.
2
NHS NHS Long Term Plan. 2019. https://www.england.nhs.uk/long-term-plan/
3
Djulbegovic B. A framework to bridge the gaps between evidence-based medicine, health
outcomes, and improvement and implementation science. J Oncol Pract 2014;10:200-2.
10.1200/JOP.2013.001364 24839282
4
Bickerdike L, Booth A, Wilson PM, etal . Social prescribing: less rhetoric and more reality.
A systematic review of the evidence. BMJ Open 2017;7:e013384.
5
Campbell M, Fitzpatrick R, Haines A, etal . Framework for design and evaluation of
complex interventions to improve health. BMJ 2000;321:694-6.
10.1136/bmj.321.7262.694 10987780
6
Rickles D. Causality in complex interventions. Med Health Care Philos 2009;12:77-90.
10.1007/s11019-008-9140-4 18465202
7
Hawe P. Lessons from complex interventions to improve health. Annu Rev Public Health
2015;36:307-23. 10.1146/annurev-publhealth-031912-114421 25581153
8
Greenhalgh T, Papoutsi C. Studying complexity in health services research: desperately
seeking an overdue paradigm shift. BMC Med 2018;16:95.
10.1186/s12916-018-1089-4 29921272
9
Pawson R Tilley N Realistic evaluation Sage 1997 Education into practice • What interventions have you designed or experienced aimed at
transforming your service? Have they been evaluated? • What interventions have you designed or experienced aimed at
transforming your service? Have they been evaluated? • What interventions have you designed or experienced aimed at
transforming your service? Have they been evaluated? Healthcare records can often be linked across different sources
as a single patient identifier is commonly used across a
healthcare system, eg, the use of an NHS number in the UK. Using a common pseudonym across different data sources can
support linkage of pseudonymised records. Linking into publicly
available sources of administrative data and surveys can further
enrich healthcare records. Commonly used administrative data
available for UK populations include measures of GP practice
quality and outcomes from the Quality and Outcomes
Framework (QOF),52 deprivation, rurality, and demographics
from the 2011 Census,53 and patient experience from the GP
Patient Survey.54 • What types of routine data are collected about the care you deliver? Do you know how to access them and use them to evaluate care
delivery? • What resources are available to you to support impact evaluations for
interventions? Contributors GMC, SC, ATW and AS designed the structure of the report. GMC
wrote the first draft of the manuscript. SC wrote table 2. ATW wrote table 3. AS
and GMC critically revised the manuscript for important intellectual content. All
authors approved the final version of the manuscript. Competing interests We have read and understood BMJ policy on declaration
of interests. All authors work in the Improvements Analytics Unit, a joint project
between NHS England and the Health Foundation, which provided support for
work reported in references of this report. 13 37 60 Further Resources See The Health Foundation. Evaluation: what to consider. 201560 for a list of
websites, articles, webinars and other guidance on various aspects of impact
evaluation, which may help locate further information for the planning,
interpretation, and development of a successful impact evaluation.5 23 55 Where can I find suitable routine data? Healthcare systems generate vast amounts of data as part of
their routine operation. These datasets are often designed to Subscribe: http://www.bmj.com/subscribe BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) Page 3 of 7 PRACTICE support direct care, and for administrative purposes, rather than
for research, and use of routinely collected data for evaluating
changes in health service delivery is not without pitfalls. For
example, any variation observed between geographical regions,
providers, and sometimes individual clinicians may reflect real
and important variations in the actual healthcare quality
provided, but can also result from differences in measurement.45
However, routine data can be a rich source of information on a
large group of patients with different conditions across different
geographical regions. Often, data have been collected for many
years, enabling construction of individual patient histories
describing healthcare utilisation, diagnoses, comorbidities,
prescription of medication, and other treatments. Clear and transparent reporting using established guidelines
(eg, STROBE58 or TREND59)to describe the intervention, study
population, assignment of treatment, and control groups, and
methods used to estimate impact should be followed. Limitations
arising as a result of inherent biases, or validity, should be
clearly acknowledged. Around the world, many interventions designed to improve
health and healthcare are under way. An evaluation is an
essential part of understanding what impact these changes are
having, for whom and in what circumstances, and help inform
future decisions about improvement and further roll out. There
is no standard, ‘‘one size fits all’’ recipe for a good evaluation:
it must be tailored to the project at hand. Understanding the
overarching principles and standards is the first step towards a
good evaluation. Some of these data are collected centrally, across a wider system,
and routinely shared for research and evaluation purposes, eg,
secondary care data in England (Hospital Episode Statistics),
or Medicare Claims data in the United States. Other sources,
such as primary care data, are often collected at a more local
level, but can be accessed through, or on behalf of, healthcare
commissioners, provided the right information governance
arrangements are in place. Pseudonymised records, where any
identifying information is removed or replaced by an artificial
identifier, are often used to support evaluation while maintaining
patient confidentiality. See table 3 for commonly used routine
datasets available in England. Open Access: Reuse allowed Are there any additional considerations? 10.1186/s12916-018-1089-4 29921272
9
Pawson R Tilley N Realistic evaluation Sage 1997 External validity refers to the extent to which the results of a
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2010;25:1-21. 10.1214/09-STS313 20871802 Published by the BMJ Publishing Group Limited. For permission to use (where not already
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2007;15:199-23610.1093/pan/mpl013. by guest. Protected by copyright. Open Access: Reuse allowed Subscribe: http://www.bmj.com/subscribe Page 5 of 7 BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) PRACTICE Open Access: Reuse allowed Tables |
p
Examples
Summative
Formative
A formative evaluation of the Whole Systems Integrated Care (WSIC) programme,
aimed at integrating health and social care in London, found that difficulties in
establishing data sharing and information governance, and differences in
professional culture were hampering efforts to implement change
10
Conducted after the intervention’s
completion, or at the end of a programme
cycle
Conducted during the development
or implementation of an intervention
A summative impact evaluation of an NHS new care model vanguard initiative found
that care home residents in Nottinghamshire who received enhanced support had
substantially fewer attendances at emergency departments and fewer emergency
admissions than a matched control group. 13 This evidence supported the decision
by the NHS to roll out the Enhanced Health in Care Homes Model across the
country. 2
Aims to render judgment, or make
decisions about the future of the
intervention
Aims to fine tune or reorient the
intervention Method Matching
33 Aims to find a subset of control group units (eg, individuals or hospitals)
with similar characteristics to the intervention group units in the pre-intervention period. For example, impact of enhanced support in care homes in Rushcliffe,
Nottinghamshire
13 Can be combined with other methods, eg, difference-in-differences and
regression. Enables straightforward comparison between intervention and
control groups. Methods include propensity score matching and genetic
matching Regression control
34 Refers to use of regression techniques to estimate association
between an intervention and an outcome while holding the value of the other variables
constant, thus adjusting for these variables Can be beneficial to pre-process the data using matching in addition to
regression control. This reduces the dependence of the estimated treatment
effect on how the regression models are specified
35 Difference-in-differences (DiD)
30 Compares outcomes before and after an intervention
in intervention and control group units. Controls for the effects of unobserved
confounders that do not vary over time, eg, impact of hospital pay for performance on
mortality in England
36 Simple to implement and intuitive to interpret. Depends on the assumption
that there are no unobserved differences between the intervention and control
groups that vary over time, also referred to as the “parallel trends” assumption Synthetic controls
32 Typically used when an intervention affects a whole population
(eg, region or hospital) for whom a well matched control group comprising whole
control units is not available. Builds a “synthetic” control from a weighted average of
the control group units, eg, impact of redesigning urgent and emergency care in
Northumberland
37 Allows for unobserved differences between the intervention and control
groups to vary over time. The uncertainty of effect estimates is hard to
quantify. Produces biased estimates over short pre-intervention periods Regression discontinuity design
31 Uses quasi-random variations in intervention
exposure, eg, when patients are assigned to comparator groups depending on a
threshold. Outcomes of patients just below the threshold are compared with those
just above, eg, impact of statins on cholesterol by exploiting differences in statin
prescribing
38 There is usually a strong basis for assuming that patients close to either side
of the threshold are similar. Open Access: Reuse allowed Formative Produces biased estimates over short pre-intervention periods
Synthetic controls
32 Typically used when an intervention affects a whole population
(eg, region or hospital) for whom a well matched control group comprising whole
control units is not available. Builds a “synthetic” control from a weighted average of
the control group units, eg, impact of redesigning urgent and emergency care in
Northumberland
37
There is usually a strong basis for assuming that patients close to either side
of the threshold are similar. Because the method only uses data for patients
near the threshold, the results might not be generalisable
Regression discontinuity design
31 Uses quasi-random variations in intervention
exposure, eg, when patients are assigned to comparator groups depending on a
threshold. Outcomes of patients just below the threshold are compared with those
just above, eg, impact of statins on cholesterol by exploiting differences in statin
prescribing
38
Ensures limited impact of selection bias and confounding as a result of
population differences but does not generally control for confounding as a
result of other interventions or events occurring at the same time as the
intervention
Interrupted time-series
39 Compares outcomes at multiple time points before and
after an intervention (interruption) is implemented to determine whether the intervention
has an effect that is statistically significantly greater than the underlying trend, eg, to
examine the trends in diagnosis for people with dementia in the UK
40
Explicitly addresses unmeasured confounding but conceptually difficult and
easily misused. Identification of instrumental variables is not straightforward. Estimates are imprecise (large standard error), biased when sample size is
small, and can be biased in large samples if assumptions are even slightly
violated
20
Instrumental variables
18 An instrumental variable is a variable that affects the outcome
solely through the effect on whether the patient receives the treatment. An instrumental
variable can be used to counteract issues of measurement error and unobserved
confounders, eg, used to assess delivery of premature babies in dedicated v hospital
intensive care units
19 Table 2| Observational study designs for quantitative impact evaluation Formative A formative evaluation of the Whole Systems Integrated Care (WSIC) programme,
aimed at integrating health and social care in London, found that difficulties in
establishing data sharing and information governance, and differences in
professional culture were hampering efforts to implement change
10 A summative impact evaluation of an NHS new care model vanguard initiative found
that care home residents in Nottinghamshire who received enhanced support had
substantially fewer attendances at emergency departments and fewer emergency
admissions than a matched control group. 13 This evidence supported the decision
by the NHS to roll out the Enhanced Health in Care Homes Model across the
country. 2 Open Access: Reuse allowed Subscribe: http://www.bmj.com/subscribe Page 6 of 7 BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) PRACTICE Table 2| Observational study designs for quantitative impact evaluation
Strengths and limitations
Method
Can be combined with other methods, eg, difference-in-differences and
regression. Enables straightforward comparison between intervention and
control groups. Methods include propensity score matching and genetic
matching
Matching
33 Aims to find a subset of control group units (eg, individuals or hospitals)
with similar characteristics to the intervention group units in the pre-intervention period. For example, impact of enhanced support in care homes in Rushcliffe,
Nottinghamshire
13
Can be beneficial to pre-process the data using matching in addition to
regression control. This reduces the dependence of the estimated treatment
effect on how the regression models are specified
35
Regression control
34 Refers to use of regression techniques to estimate association
between an intervention and an outcome while holding the value of the other variables
constant, thus adjusting for these variables
Simple to implement and intuitive to interpret. Depends on the assumption
that there are no unobserved differences between the intervention and control
groups that vary over time, also referred to as the “parallel trends” assumption
Difference-in-differences (DiD)
30 Compares outcomes before and after an intervention
in intervention and control group units. Controls for the effects of unobserved
confounders that do not vary over time, eg, impact of hospital pay for performance on
mortality in England
36
Allows for unobserved differences between the intervention and control
groups to vary over time. The uncertainty of effect estimates is hard to
quantify. Method Because the method only uses data for patients
near the threshold, the results might not be generalisable Ensures limited impact of selection bias and confounding as a result of
population differences but does not generally control for confounding as a
result of other interventions or events occurring at the same time as the
intervention Interrupted time-series
39 Compares outcomes at multiple time points before and
after an intervention (interruption) is implemented to determine whether the intervention
has an effect that is statistically significantly greater than the underlying trend, eg, to
examine the trends in diagnosis for people with dementia in the UK
40 Instrumental variables
18 An instrumental variable is a variable that affects the outcome
solely through the effect on whether the patient receives the treatment. An instrumental
variable can be used to counteract issues of measurement error and unobserved
confounders, eg, used to assess delivery of premature babies in dedicated v hospital
intensive care units
19 Explicitly addresses unmeasured confounding but conceptually difficult and
easily misused. Identification of instrumental variables is not straightforward. Estimates are imprecise (large standard error), biased when sample size is
small, and can be biased in large samples if assumptions are even slightly
violated
20 Subscribe: http://www.bmj.com/subscribe Open Access: Reuse allowed Page 7 of 7 BMJ 2019;365:l2239 doi: 10.1136/bmj.l2239 (Published 20 June 2019) PRACTICE Table 3| Commonly used routine datasets available in the NHS in England Dataset Hospital episode statistics (HES). 46 HES is a database containing details of all
admissions, accident and emergency attendances, and outpatient appointments
at NHS England hospitals and NHS England funded treatment centres. Information
captured includes clinical information about diagnoses and operations, patient
demographics, geographical information, and administrative information such as
the data and method of admissions and discharge HES is available through the Data Access Request Service (DARS),
47 a service
provided by NHS Digital. Commissioners, providers in the NHS, and analytics
teams working on their behalf, can also access hospital data directly via the
Secondary Use Service (SUS). 48 These data are very similar to HES, processed
by NHS Digital, and are available for non-clinical uses, including research and
planning health services Commissioners, and analytics teams working on their behalf, can work with an
intermediary service called Data Service for Commissioning Regional Office to
request access to anonymised patient level general practice data (possibly linked
to SUS, described above) for the purpose of risk stratification, invoice validation,
and to support commissioning. Anonymised UK primary care records for a
representative sample of the population are available for public health research
through, for instance, the Clinical Practice Research Datalink. 49 Primary care data is collected by general practices. Although there is no national
standard on how primary care data should be collected and/or reported, there are
a limited number of commonly used software providers to record these data. Information captured includes clinical information about diagnoses, treatment,
and prescriptions, patient demographics, geographical information, and
administrative information on booking and attendance of appointments, and
whether appointments relate to a telephone consultation, an in-practice
appointment, or a home visit ONS mortality data are routinely processed by NHS Digital, and can be linked
to HES data. These data can be requested through the DARS service. When deaths occur in hospital this is typically recorded as part of discharge
information Mortality data
50 The Office for National Statistics (ONS) maintains a dataset of
all registered deaths in England. These data can be linked to routine health data
to record deaths that occur outside of hospital ONS mortality data are routinely processed by NHS Digital, and can be linked
to HES data. These data can be requested through the DARS service. Like HES, MHSDS is available through the DARS service. Like HES, MHSDS is available through the DARS service. Mental health data
from before April 2016 have been recorded in the Mental Health Minimum Dataset
also disseminated through NHS Digital
The Mental Health Services Data Set (MHSDS)
51 contains record level data
about the care of children, young people, and adults who are in contact with mental
health, learning disabilities, or autism spectrum disorder services. These data
cover data from April 2016 Open Access: Reuse allowed Dataset Mental health data
from before April 2016 have been recorded in the Mental Health Minimum Dataset
also disseminated through NHS Digital
The Mental Health Services Data Set (MHSDS)
51 contains record level data
about the care of children, young people, and adults who are in contact with mental
health, learning disabilities, or autism spectrum disorder services. These data
cover data from April 2016 Open Access: Reuse allowed Subscribe: http://www.bmj.com/subscribe
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https://openalex.org/W1974751543
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https://europepmc.org/articles/pmc4416445?pdf=render
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Pro-social 50-kHz ultrasonic communication in rats: post-weaning but not post-adolescent social isolation leads to social impairments—phenotypic rescue by re-socialization
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Frontiers in behavioral neuroscience
| 2,015
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cc-by
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Edited by:
Regina Marie Sullivan,
Nathan Kline Institute and New York
University School of Medicine, USA
Reviewed by:
Mu Yang,
University of California Davis School of
Medicine, USA
Piotr Popik,
Polish Academy of Sciences, Poland
*Correspondence:
Dominik Seffer and Markus Wöhr,
Behavioral Neuroscience,
Experimental and Biological
Psychology, Faculty of Psychology,
Philipps-University of Marburg,
Gutenbergstr. 18, 35032 Marburg,
Germany
seffer@staff.uni-marburg.de;
woehrm@staff.uni-marburg.de Edited by:
Regina Marie Sullivan,
Nathan Kline Institute and New York
University School of Medicine, USA Edited by:
Regina Marie Sullivan,
Nathan Kline Institute and New York
University School of Medicine, USA Reviewed by:
Mu Yang,
University of California Davis School of
Medicine, USA
Piotr Popik,
Polish Academy of Sciences, Poland Reviewed by:
Mu Yang,
University of California Davis School of
Medicine, USA
Piotr Popik,
Polish Academy of Sciences, Poland Reviewed by:
Mu Yang,
University of California Davis School of
Medicine, USA
Piotr Popik,
Polish Academy of Sciences, Poland *Correspondence:
Dominik Seffer and Markus Wöhr,
Behavioral Neuroscience,
Experimental and Biological
Psychology, Faculty of Psychology,
Philipps-University of Marburg,
Gutenbergstr. 18, 35032 Marburg,
Germany seffer@staff.uni-marburg.de;
woehrm@staff.uni-marburg.de Received: 06 March 2015
Accepted: 07 April 2015
Published: 01 May 2015 Pro-social 50-kHz ultrasonic
communication in rats: post-weaning
but not post-adolescent social
isolation leads to social
impairments—phenotypic rescue by
re-socialization
Dominik Seffer*, Henrike Rippberger, Rainer K. W. Schwarting and Markus Wöhr*
Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Marburg, Germany Rats are highly social animals and social play during adolescence has an important role
for social development, hence post-weaning social isolation is widely used to study
the adverse effects of juvenile social deprivation and to induce behavioral phenotypes
relevant to neuropsychiatric disorders, like schizophrenia. Communication is an important
component of the rat’s social behavior repertoire, with ultrasonic vocalizations (USV)
serving as situation-dependent affective signals. High-frequency 50-kHz USV occur
in appetitive situations and induce approach behavior, supporting the notion that
they serve as social contact calls; however, post-weaning isolation effects on the
behavioral changes displayed by the receiver in response to USV have yet to be
studied. We therefore investigated the impact of post-weaning isolation on socio-affective
information processing as assessed by means of our established 50-kHz USV radial
maze playback paradigm. We showed that post-weaning social isolation specifically
affected the behavioral response to playback of pro-social 50-kHz but not alarm 22-kHz
USV. While group-housed rats showed the expected preference, i.e., approach, toward
50-kHz USV, the response was even stronger in short-term isolated rats (i.e., 1 day),
possibly due to a higher level of social motivation. In contrast, no approach was
observed in long-term isolated rats (i.e., 4 weeks). Importantly, deficits in approach
were reversed by peer-mediated re-socialization and could not be observed after
post-adolescent social isolation, indicating a critical period for social development during
adolescence. Together, these results highlight the importance of social experience for
affiliative behavior, suggesting a critical involvement of play behavior on socio-affective
information processing in rats. Citation: Seffer D, Rippberger H, Schwarting
RKW and Wöhr M (2015) Pro-social
50-kHz ultrasonic communication in
rats: post-weaning but not
post-adolescent social isolation leads
to social impairments—phenotypic
rescue by re-socialization. Front. Behav. Neurosci. 9:102. doi: 10.3389/fnbeh.2015.00102 Keywords: juvenile social isolation, affiliative behavior, rough-and-tumble play, schizophrenia, negative symptoms ORIGINAL RESEARCH
published: 01 May 2015
doi: 10.3389/fnbeh.2015.00102 Introduction This could possibly be due
to adverse effects on social information processing, such as
attention to social cues, consequently leading to inappropriate
regulation of both negative affect and aggression (Dodge et al.,
1990; Shackman and Pollak, 2014). For instance, children
exposed to an extreme form of social deprivation while being
raised in an orphanage have an increased risk for delayed
cognitive and socio-affective development, along with mental
health disorders. Specifically, they display attention deficits,
hyperactivity, and increased anxiety, together with impaired
emotional regulation and social attachment (Nelson et al., 2007;
Bos et al., 2011). Moreover, their language development is
delayed, with particular deficits in verbal skills (Frank et al.,
1996). For rats, communication is an important component in the
social behavior repertoire. Rats produce and perceive calls in
the ultrasonic range (so called ultrasonic vocalizations, USV). Based on their acoustic features, various USV types can be
differentiated which serve distinct communicative functions, as
situation-dependent affective signals (Portfors, 2007; Brudzynski,
2013; Wöhr and Schwarting, 2013). In juvenile and adult rats,
a distinction is made between 22- and 50-kHz USV. Low-
frequency 22-kHz USV occur in aversive situations, such as
predator exposure, social defeat, and fear learning, and are
thought to be reflecting a negative affective state of the sender. They serve as an alarm function and induce freezing behavior
in the recipient. In contrast, high-frequency 50-kHz USV occur
in appetitive situations, mostly social ones, such as rough-and-
tumble play (Knutson et al., 1998), tickling (Panksepp and
Burgdorf, 2000; Burgdorf and Panksepp, 2001), and sexual
behavior (Sales, 1972), and are thought to be reflecting a positive
affective state. In support for a communicative function, evidence
was recently provided that juvenile 50-kHz USV promote and
maintain playful social interactions (Himmler et al., 2014), while
play behavior is reduced in pairs of devocalized rats (Kisko et al.,
2015). Furthermore, it was repeatedly shown that playback of 50-
kHz USV induces approach behavior in the recipient, supporting
the notion that they serve as social contact calls (Wöhr and
Schwarting, 2007, 2009, 2012; Willuhn et al., 2014). Interestingly, there is evidence that post-weaning isolation
affects USV production in rats. For instance, the rate of
50-kHz USV emission during social play and tickling is
increased following isolation, possibly due to an increase
in social motivation (Knutson et al., 1998; Panksepp and
Burgdorf, 2000; Burgdorf and Panksepp, 2001). Furthermore,
Inagaki et al. Introduction (2013) found a strong decrease in 50-kHz
USV in male rats exposed to a sexually receptive female
after
prolonged
isolation,
likely
reflecting
their
inability
to recognize social cues and/or to respond appropriately. Finally, von Frijtag et al. (2002) observed that, in the
presence of an aggressive resident, socially isolated male
rats display impaired suppression of play behavior, suffer
more harming attacks, and emit more 22-kHz USV than their
group-housed counterparts. They suggested that 22-kHz USV
production was dissociated from the sender’s behavioral pattern
and therefore lost its aggression-reducing communicative
function. )
In rats, maternal separation and post-weaning social isolation
are widely used to study the adverse effects of early social
deprivation. Importantly, rats are highly social animals and
live in groups (Whishaw and Kolb, 2005) with a distinct
hierarchy (Baenninger, 1966), offering optimal experimental
conditions to investigate social behavior and communication. For instance, rats engage in social play (Panksepp, 1981) and
cooperative behavior (Willner et al., 1989; Łopuch and Popik,
2011), display direct (Rutte and Taborsky, 2008) and generalized
reciprocity (Rutte and Taborsky, 2007), and, as recently shown,
prefer mutual rewards in a pro-social choice test, resulting
in benefits not only for themselves but also for conspecifics
(Hernandez-Lallement et al., 2015). Similarly, evidence for
helping behavior and empathy has been provided (Ben-Ami
Bartal et al., 2011; but see Silberberg et al., 2014). Play with
peers emerges as one of the earliest forms of social behavior
that is not directed to the mother. In rats, social play behavior
(also called rough-and-tumble play or play fighting) mainly
occurs after weaning and reaches its peak during the middle
of the juvenile stage (Panksepp, 1981). Lack of play during the
critical developmental period, due to post-weaning isolation,
leads to a behavioral phenotype characterized by prominent
social impairments in adulthood (Hol et al., 1999; van den
Berg et al., 1999a). Most notably, long-term changes in behavior
with relevance to various neuropsychiatric disorders can be
observed, including hyperactivity in a novel environment, altered
responses to drugs of abuse, impaired sensorimotor gating,
cognitive inflexibility, increased aggressive behavior, and social
withdrawal (Hall, 1998; Lapiz et al., 2003; Fone and Porkess,
2008). In contrast, post-weaning isolation effects on the behavioral
changes displayed by the receiver in response to USV have
yet to be studied. Introduction In social species, like humans and other mammals, early life experiences are crucial for the
development of social and cognitive skills. Positive relationships between parent and child, as well May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 Post-weaning isolation induces communication deficits Seffer et al. as among peers promote appropriate acquisition of adult
social competency. In contrast, disruptions of social attachment
during critical developmental periods can lead to various
behavioral alterations, including deficits in emotional regulation
and social impairments, and are considered as non-specific
risk factors for developing psychopathologies (Cicchetti and
Toth, 1995; Veenema, 2009; Braun and Bock, 2011). In fact,
child maltreatment, such as sexual/physical abuse and social
neglect, contribute to various forms of impaired functioning
characterized by social withdrawal, like the development of
anxiety and depressive disorders, but also psychosis and
schizophrenia (Brown et al., 1999; Lansford et al., 2002; Read
et al., 2005; Gilbert et al., 2009; Spinhoven et al., 2010; Varese
et al., 2012; DeRosse et al., 2014). This could possibly be due
to adverse effects on social information processing, such as
attention to social cues, consequently leading to inappropriate
regulation of both negative affect and aggression (Dodge et al.,
1990; Shackman and Pollak, 2014). For instance, children
exposed to an extreme form of social deprivation while being
raised in an orphanage have an increased risk for delayed
cognitive and socio-affective development, along with mental
health disorders. Specifically, they display attention deficits,
hyperactivity, and increased anxiety, together with impaired
emotional regulation and social attachment (Nelson et al., 2007;
Bos et al., 2011). Moreover, their language development is
delayed, with particular deficits in verbal skills (Frank et al.,
1996). as among peers promote appropriate acquisition of adult
social competency. In contrast, disruptions of social attachment
during critical developmental periods can lead to various
behavioral alterations, including deficits in emotional regulation
and social impairments, and are considered as non-specific
risk factors for developing psychopathologies (Cicchetti and
Toth, 1995; Veenema, 2009; Braun and Bock, 2011). In fact,
child maltreatment, such as sexual/physical abuse and social
neglect, contribute to various forms of impaired functioning
characterized by social withdrawal, like the development of
anxiety and depressive disorders, but also psychosis and
schizophrenia (Brown et al., 1999; Lansford et al., 2002; Read
et al., 2005; Gilbert et al., 2009; Spinhoven et al., 2010; Varese
et al., 2012; DeRosse et al., 2014). General Overview To assess the impact of post-weaning social isolation on approach
behavior induced by pro-social 50-kHz USV, we used our 50-
kHz USV radial maze playback paradigm (Seffer et al., 2014). In
total, three experiments were conducted, all using a 3 × 3 design
with the factors experimental housing condition and acoustic
stimulus (Figure 1A). Nine experimental groups of N = 12 rats
per experimental housing/acoustic stimulus combination were
used. Rats were exposed to one of the following three acoustic
stimuli: (I) pro-social 50-kHz USV; (II) alarm 22-kHz USV; or
(III) background noise (NOISE). 22-kHz USV and NOISE were
used to assure specificity of the effects of isolation on approach Animals Male
Wistar
rats
(HsdCpb:WU,
Harlan,
Venray,
The
Netherlands) served as subjects and were housed in an animal
room with a 12:12 h light/dark cycle (lights on 8–20 h) where
the environmental temperature was maintained between 20 and
23◦C (humidity: 30–50%). Lab chow (Altromin, Lage, Germany)
and water (0.0004% HCl-solution) were available ad libitum. Rats were handled for three consecutive days prior to testing
in a standardized way for 5 min. All experimental procedures
were performed according to legal requirements of Germany
and approved by the ethical committee of the local government
(Regierungspräsidium Gießen, Germany). Materials and Methods behavior induced by 50-kHz USV. Of note, Wistar rats were
shown to have the ability to perceive acoustic stimuli in the
audible and ultrasonic range (Borg, 1982). Introduction Therefore, we investigated the impact
of
post-weaning
isolation
on
socio-affective
information
processing as assessed by means of our established 50-
kHz USV radial maze playback paradigm that allows to
study
pro-social
ultrasonic
communication
in
a
reliable
and highly standardized manner (Seffer et al., 2014). It was
hypothesized that (I) post-weaning social isolation will impair
approach behavior in response to playback of pro-social
50-kHz USV, that (II) this phenotype can be rescued by peer-
mediated re-socialization, and that (III) isolation-induced
deficits depend on the time period of isolation during
development. May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org Frontiers in Behavioral Neuroscience | www.frontiersin.org 2 Post-weaning isolation induces communication deficits Seffer et al. Experiment 1: Post-weaning Social
Isolation—Effects In Experiment 1, we exposed rats to one of the following three
experimental housing conditions for 4 weeks: (I) group housing
(NO ISO), with rats being housed in groups of six; (II) short-term
social isolation (SHORT ISO), with rats housed in groups of six,
but isolated 24 h prior testing; or (III) long-term social isolation
(LONG ISO), with rats being isolated for 28 days prior testing. Rats were isolated as weanlings at about 3 weeks of age. At about 7
weeks of age (body weight: 246.44 ± 1.43 g; range: 208.5–276.5 g),
they were exposed to (I) 50-kHz USV, (II) 22-kHz USV, or (III)
NOISE. Experiment 2: Post-weaning Social
Isolation—Rescue In Experiment 2, we tested for phenotypic rescue by adding one
additional week of peer rearing after being housed under one
of the three experimental housing conditions for 4 weeks, i.e.,
(I) NO ISO, (II) SHORT ISO, or (III) LONG ISO, since recent
findings demonstrated that social deficits displayed by a well-
established autism model can be improved by peer intervention
(Yang et al., 2011). As in Experiment 1, rats were isolated
as weanlings at about 3 weeks of age. After one additional FIGURE 1 | Experimental design of the three studies to assess
the impact of post-weaning social isolation on approach
behavior induced by pro-social 50-kHz USV. (A) Experimental
designs: Experiment 1: Post-weaning Social Isolation—Effects;
Experiment 2: Post-weaning Social Isolation—Rescue; and Experiment
3: Post-adolescent Social Isolation—Effects. (B) Schematic illustration
of the rat developmental profile, highlighting the rough-and-tumble
play period. FIGURE 1 | Experimental design of the three studies to assess
the impact of post-weaning social isolation on approach
behavior induced by pro-social 50-kHz USV. (A) Experimental
designs: Experiment 1: Post-weaning Social Isolation—Effects; FIGURE 1 | Experimental design of the three studies to assess
the impact of post-weaning social isolation on approach
behavior induced by pro-social 50-kHz USV. (A) Experimental
designs: Experiment 1: Post-weaning Social Isolation—Effects; Experiment 2: Post-weaning Social Isolation—Rescue; and Experiment
3: Post-adolescent Social Isolation—Effects. (B) Schematic illustration
of the rat developmental profile, highlighting the rough-and-tumble
play period. Frontiers in Behavioral Neuroscience | www.frontiersin.org May 2015 | Volume 9 | Article 102 3 Post-weaning isolation induces communication deficits Seffer et al. week of peer rearing, at about 8 weeks of age (body weight:
280.88 ± 2.01 g; range: 236.5–326.0 g), they were exposed to
(I) 50-kHz USV, (II) 22-kHz USV, or (III) NOISE, as in
Experiment 1. FIGURE 2 | Setup of the 50-kHz USV radial maze playback paradigm. (A) Elevated eight arm radial maze equipped with two ultrasonic microphones
and two ultrasonic loudspeakers positioned opposite to each other (only one
ultrasonic microphone and the active loudspeaker are shown). The rat’s
behavioral responses during playback of acoustic stimuli were recorded with a
video camera positioned above the radial maze. (B) Schematic illustration of
the radial maze, depicting area definitions to assess approach behavior, with
arms close to the loudspeaker denoted as proximal, central arms as neutral,
and opposite arms as distal. Experiment 2: Post-weaning Social
Isolation—Rescue (C) Acoustic stimuli were presented by an
ultrasonic loudspeaker (sampling rate: 192 kHz; 16 bit), with accurate
playback of acoustic stimuli being confirmed by means of ultrasonic
microphones. (D) Testing was performed under dim red light. Acoustic Stimuli Rats were exposed to 5 min of playback of one of the following
three acoustic stimuli: (I) pro-social 50-kHz USV, (II) alarm
22-kHz USV, and (III) background noise (NOISE; for details
see (Wöhr and Schwarting, 2007, 2009, 2012; Seffer et al.,
2014; Willuhn et al., 2014; Figures 3A–C, Supplementary Figures
2A–C, 3A–C). Briefly, playback of 50-kHz USV consisted of 1105
calls, including flat and frequency-modulated calls, recorded
from an adult male Wistar rat during exploration of a cage
containing scents from a recently separated cage mate (for
setting and recording see Wöhr et al., 2008). This recording
context had been chosen since playback of 50-kHz USV recorded Experiment 3: Post-adolescent Social
Isolation—Effects In Experiment 3, we tested for the existence of a critical window
for developing social deficits induced by post-weaning social
isolation. To this aim, post-adolescent young adult rats at about
7 weeks of age, and after going through the rough-and-tumble
play period (Figure 1B; Panksepp, 1981), were exposed to one
of the three experimental housing conditions for 4 weeks, i.e.,
(I) NO ISO, (II) SHORT ISO, or (III) LONG ISO. At about 11
weeks of age (body weight: 383.93±1.91 g; range: 349.0–444.0 g),
they were exposed to (I) 50-kHz USV, (II) 22-kHz USV, or (III)
NOISE, as in Experiment 1. Experimental Setting Playback of acoustic stimuli was conducted under dim red light
(∼10 lux) on a radial eight arm maze made of black plastic,
elevated 52 cm above the floor (Figures 2A–D). The arms (9.8 ×
40.5 cm) extend radially from a central platform (diameter:
24 cm). Acoustic stimuli were presented through an ultrasonic
loudspeaker (ScanSpeak, Avisoft Bioacoustics, Berlin, Germany)
using an external sound card with a sampling rate of 192 kHz
(Fire Wire Audio Capture FA-101, Edirol, London, UK). The
loudspeaker had a frequency range of 1–120 kHz with a relatively
flat frequency response (±12 dB) between 15 and 80 kHz and it
was placed 20 cm away from the end of one arm. An additional,
but inactive ultrasonic loudspeaker was arranged symmetrically
at the opposite arm as visual control. Rats were tested in a testing
room with no experimenter or other rats present. Stimulus
application and animal observation was performed in a separate
control room. Behavioral tests were conducted between 8 and
18 h. Before each test, behavioral equipment was cleaned (0.1%
acetic acid solution) and dried. during tickling or exploration of an empty cage had no or only
very moderate effects on the behavior displayed by the receiver
(Burman et al., 2007; Endres et al., 2007). Average acoustic call
parameters were (mean ± SEM): call duration: 0.07 ± 0.01 s; peak
frequency: 61.24 ± 1.75 kHz; frequency modulation: 31.68 ±
4.62 kHz. Besides 50-kHz USV, playback contained background
noise, produced by the rat while exploring the cage. Playback of
22-kHz USV consisted of 145 calls recorded from a male Wistar
rat which had received electric foot-shocks before, but not during
recording (for setting and recording see Wöhr et al., 2005). Average acoustic call parameters were: call duration: 1.18 ± 0.06
s; peak frequency: 23.61 ± 0.07 kHz; frequency modulation: 1.90
± 0.09 kHz. To control for background noise as present in the 50-
kHz USV stimulus, background noise was added to the 22-kHz
USV stimulus. Background noise alone (NOISE), i.e., without
USV, served to control for unspecific effects, i.e., novelty-induced
changes in behavior not linked to the communicative function
of 50-kHz USV. All stimuli were presented with a sampling rate
of 192 kHz in 16 bit format at ∼69 dB, with the exception of
NOISE that was presented at ∼50 dB (measured from a distance
of 40 cm). Experimental Housing FIGURE 2 | Setup of the 50-kHz USV radial maze playback paradigm. FIGURE 2 | Setup of the 50-kHz USV radial maze playback paradigm. (A) Elevated eight arm radial maze equipped with two ultrasonic microphones
and two ultrasonic loudspeakers positioned opposite to each other (only one
ultrasonic microphone and the active loudspeaker are shown). The rat’s
behavioral responses during playback of acoustic stimuli were recorded with a
video camera positioned above the radial maze. (B) Schematic illustration of
the radial maze, depicting area definitions to assess approach behavior, with
arms close to the loudspeaker denoted as proximal, central arms as neutral,
and opposite arms as distal. (C) Acoustic stimuli were presented by an
ultrasonic loudspeaker (sampling rate: 192 kHz; 16 bit), with accurate
playback of acoustic stimuli being confirmed by means of ultrasonic
microphones. (D) Testing was performed under dim red light. FIGURE 2 | Setup of the 50-kHz USV radial maze playback paradigm. (A) Elevated eight arm radial maze equipped with two ultrasonic microphones
and two ultrasonic loudspeakers positioned opposite to each other (only one
ultrasonic microphone and the active loudspeaker are shown). The rat’s
behavioral responses during playback of acoustic stimuli were recorded with a
video camera positioned above the radial maze. (B) Schematic illustration of
the radial maze, depicting area definitions to assess approach behavior, with
arms close to the loudspeaker denoted as proximal, central arms as neutral,
and opposite arms as distal. (C) Acoustic stimuli were presented by an
ultrasonic loudspeaker (sampling rate: 192 kHz; 16 bit), with accurate
playback of acoustic stimuli being confirmed by means of ultrasonic
microphones. (D) Testing was performed under dim red light. Group housing was conducted in polycarbonate Macrolon type
IV cages (380 × 200 × 590 mm, plus high stainless steel covers)
and isolation rearing in Macrolon type III cages (265 × 150 ×
425 mm, plus high stainless steel covers), both filled with Tapvei
peeled aspen bedding (indulab ag, Gams, Switzerland). Experimental Procedure Rats were placed onto the central platform of the radial maze
with their body axis at an angle of 90◦to the two ultrasonic
loudspeakers. After an initial habituation phase of 15 min where May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 4 Seffer et al. Post-weaning isolation induces communication deficits FIGURE 3 | Post-weaning social isolation induces behavioral
inhibition in response to pro-social 50-kHz USV similar to alarm
22-kHz USV and NOISE. (A–C) Exemplary spectrograms of acoustic
stimuli used for playback, namely (A) 50-kHz USV, (B) 22-kHz USV, and (C)
background noise (NOISE). (A′–C′) Bar graphs depicting changes in
locomotor activity as assessed by means of total arm entries per min
[entries/min] displayed by rats exposed to 4 weeks of NO ISO (left), SHORT
ISO (middle), and LONG ISO (right), post-weaning, in response to (A′) 50-kHz
USV, (B′) 22-kHz USV, and (C′) NOISE, in Experiment 1: Post-weaning
Social Isolation—Effects. (A′′–C′′) Pie charts depicting changes in
stimulus-directed locomotor activity as assessed by means of numbers of
proximal (black), neutral (gray), and distal (white) arm entries displayed as
percentages by rats exposed to 4 weeks of NO ISO (left), SHORT ISO
(middle), and LONG ISO (right), post-weaning, during the baseline period
(5 min; upper row; PRE) and during playback (1 min; lower row; DUR) in
response to (A′′) 50-kHz USV, (B′′) 22-kHz USV, and (C′′) NOISE, in
Experiment 1: Post-weaning Social Isolation—Effects. The red dashed circles
represent 100% of the total number of arm entries during the baseline period
(average over all nine experimental groups). The sizes of the circles depicting
proximal (black), neutral (gray), and distal (white) arm entries represent total
number of arm entries as percentage of 100%. *p < 0.050 compared to
LONG ISO; #p < 0.050 compared to baseline locomotor activity. FIGURE 3 | Post-weaning social isolation induces behavioral
inhibition in response to pro-social 50-kHz USV similar to alarm
22-kHz USV and NOISE. (A–C) Exemplary spectrograms of acoustic
stimuli used for playback, namely (A) 50-kHz USV, (B) 22-kHz USV, and (C)
background noise (NOISE). (A′–C′) Bar graphs depicting changes in
locomotor activity as assessed by means of total arm entries per min
[entries/min] displayed by rats exposed to 4 weeks of NO ISO (left), SHORT
ISO (middle), and LONG ISO (right), post-weaning, in response to (A′) 50-kHz
USV, (B′) 22-kHz USV, and (C′) NOISE, in Experiment 1: Post-weaning
Social Isolation—Effects. Experimental Procedure (A′′–C′′) Pie charts depicting changes in
stimulus-directed locomotor activity as assessed by means of numbers of proximal (black), neutral (gray), and distal (white) arm entries displayed as
percentages by rats exposed to 4 weeks of NO ISO (left), SHORT ISO
(middle), and LONG ISO (right), post-weaning, during the baseline period
(5 min; upper row; PRE) and during playback (1 min; lower row; DUR) in
response to (A′′) 50-kHz USV, (B′′) 22-kHz USV, and (C′′) NOISE, in
Experiment 1: Post-weaning Social Isolation—Effects. The red dashed circles
represent 100% of the total number of arm entries during the baseline period
(average over all nine experimental groups). The sizes of the circles depicting
proximal (black), neutral (gray), and distal (white) arm entries represent total
number of arm entries as percentage of 100%. *p < 0.050 compared to
LONG ISO; #p < 0.050 compared to baseline locomotor activity. USV Recording and Analysis no acoustic stimuli were presented, the rat was exposed to one of
the three acoustic stimuli for 5 min. Accurate playback of acoustic stimuli was confirmed by means
of two UltraSoundGate Condenser Microphones (CM16; Avisoft
Bioacoustics) placed opposite to each other, 20 cm away from
the radial maze (Seffer et al., 2014). For acoustical analysis,
recordings (sampling rate: 250 kHz; format: 16 bit) were
transferred to SASLab Pro (version 4.38; Avisoft Bioacoustics)
and a fast Fourier transform was conducted (512 FFT-length,
100% frame, Hamming window and 75% time window overlap;
Seffer et al., 2014). Importantly, no substantial USV production
(<1/min on average) by the rats under study was detected (data
not shown). Behavioral Recording and Analysis Behavior was monitored by a video camera (Panasonic WV-
BP 330/GE, Hamburg, Germany) from about 150 cm above
the radial maze, which fed into an external multimedia hard
drive (ScreenPlay Pro HD, Iomega, San Diego, CA, USA). For
behavioral analysis, a trained observer scored the videos for
the following parameters (Seffer et al., 2014): (I) total number
of arm entries, (II) number of entries into the three arms
proximal to or distal from the active ultrasonic loudspeaker,
and (III) the time spent on proximal and distal arms. An
arm entry was counted when all four paws were in the arm. Total number of arm entries served as measure for general
locomotor activity. Proximal vs. distal arm entries and the
time spent thereon served as measures for stimulus-directed
locomotor activity. Behavioral analysis was focused on the first
min of acoustic stimulus exposure, since behavioral changes in
response to 50-kHz USV are short-lasting, with most prominent
changes occurring during the first min of playback (Wöhr
and Schwarting, 2012; Willuhn et al., 2014; Supplementary
Figures 1A,B). Statistical Analysis General locomotor activity during the baseline period (PRE:
total arm entries 5 min prior playback; average per min)
was analyzed using ANOVAs with the between-subject factor
experimental housing condition (NO ISO, SHORT ISO, vs. LONG ISO). To assess the effects of experimental housing
conditions on stimulus-induced locomotor activity, ANOVAs
for repeated measurements were calculated with the within-
subject factor stimulus presentation before and during playback;
average per min) and the between-subject factor experimental May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 5 Post-weaning isolation induces communication deficits Seffer et al. housing condition (NO ISO, SHORT ISO, vs. LONG ISO) for
50-kHz USV, 22-kHz USV, and NOISE. To directly compare
the latter, ANOVAs with the between-subject factor stimulus
type were used. ANOVAs were followed by LSD post-hoc or
paired t-tests when appropriate (p
<
0.050). Paired t-tests
were also used to compare proximal and distal arm entries
and the time spent thereon before and during playback. Three
rats had to be excluded from data analysis due to technical
problems (Experiment 1: N = 1 from the NO ISO/22-kHz USV
combination; Experiment 2: N = 1 from the SHORT ISO/50-
kHz USV combination; Experiment 3: N = 1 from the NO
ISO/NOISE combination). Data are presented as mean ± SEM. A p-value of < 0.050 was considered statistically significant. behavioral inhibition [t(11) = 0.924; p = 0.375 and t(11) = 9.544;
p < 0.001, respectively; Figure 3A′′]. In general, locomotor
activity during the baseline period was increased in rats exposed
to LONG ISO [main effect housing: F(2, 104) = 6.816; p = 0.002;
LONG ISO vs. NO ISO: p < 0.001; LONG ISO vs. SHORT ISO:
p = 0.059; SHORT ISO vs. NO ISO: p = 0.076]. This effect was
also detectable in the subset of rats exposed to the 50-kHz USV
stimulus condition, as reflected in the size of the pie charts [main
effect housing: F(2, 33) = 3.702; p = 0.035; LONG ISO vs. NO
ISO: p = 0.011; LONG ISO vs. SHORT ISO: p = 0.355; SHORT
ISO vs. NO ISO: p = 0.091]. Approach behavior induced by 50-kHz USV was not only
reflected by proximal and distal arm entries but also by the time
spent thereon. Experiment 1: Post-weaning Social
Isolation—Effects To assess the impact of post-weaning isolation on approach
behavior induced by 50-kHz USV, we used our 50-kHz USV
radial maze playback paradigm (Seffer et al., 2014) and assessed
approach in post-weaning rats exposed to (I) NO ISO, (II)
SHORT ISO, or (III) LONG ISO. In response to all three acoustic stimuli presented, i.e., pro-
social 50-kHz USV, alarm 22-kHz USV, and NOISE, changes in
locomotor activity, as assessed by means of total arm entries,
were detected (Figures 3A′–C′). While 22-kHz USV and NOISE
led to behavioral inhibition irrespective of experimental housing
condition [main effect stimulus presentation: F(1, 32) = 82.719;
p < 0.001; interaction housing × stimulus presentation: NS; and
main effect stimulus presentation: F(1, 32) = 52.538; p < 0.001;
interaction housing × stimulus presentation: NS, respectively],
the behavioral response to 50-kHz USV was strongly affected by
post-weaning isolation [main effect stimulus presentation: NS;
interaction housing × stimulus presentation: F(1, 32) = 12.147;
p < 0.001]. Specifically, rats exposed to LONG ISO displayed
behavioral inhibition in response to 50-kHz USV [t(11) = 6.680;
p
<
0.001], whereas NO ISO or SHORT ISO maintained
their level of locomotor activity [t(11) = 0.526; p = 0.609
and t(11) = 1.358; p = 0.202, respectively], with both being
significantly different from LONG ISO (p < 0.001 and p <
0.001, respectively). Importantly, LONG ISO rats displayed a
level of behavioral inhibition in response to 50-kHz USV that was
similar to the one seen in rats exposed to 22-kHz USV or NOISE
(main effect stimulus type: NS). Together, Experiment 1 shows that post-weaning isolation has
a strong impact on approach behavior elicited by 50-kHz USV. Consistent with previous studies (Wöhr and Schwarting, 2007,
2009, 2012; Willuhn et al., 2014), approach is seen in NO ISO and
SHORT ISO rats. Rats exposed to LONG ISO, however, respond
to 50-kHz USV by behavioral inhibition, similar to the one seen
in response to 22-kHz USV or NOISE, resulting in a complete
lack of approach behavior. Importantly, post-weaning isolation
specifically affected the behavioral response to 50-kHz USV and
did not change the responses seen in rats exposed to 22-kHz USV
or NOISE. Statistical Analysis In NO ISO rats, the proximal time increased
[t(11) = 2.920; p = 0.014], while the distal time decreased
[t(11) = 2.450; p = 0.032], resulting in a significant preference
toward the stimulus source during 50-kHz USV playback [t(11) =
3.621; p = 0.004; Figure 4A]. Likewise, in SHORT ISO rats the
proximal time increased [t(11) = 2.526; p = 0.028], while the
distal time decreased [t(11) = 5.947; p < 0.001], again resulting
in a significant preference toward the stimulus source during
50-kHz USV playback [t(11) = 5.641; p < 0.001; Figure 4B]. However, this response pattern was not seen in LONG ISO rats
when exposed to 50-kHz USV, since they displayed avoidance
behavior and spent less time on both, proximal and distal arms
[t(11) = 2.889; p = 0.015 and t(11) = 14.581; p < 0.001,
respectively], and no significant preference toward the stimulus
source during 50-kHz USV playback [t(11) = 2.040; p = 0.066;
Figure 4C]. No significant preferences were seen before playback
(all p-values > 0.050). Experiment 2: Post-weaning Social
Isolation—Rescue To test whether it is possible to revert the deficits in approach
behavior induced by post-weaning isolation, we assessed
approach in post-weaning rats exposed to (I) NO ISO, (II)
SHORT ISO, or (III) LONG ISO, followed by an additional week
of peer rearing. Behavioral inhibition in response to 22-kHz USV and NOISE
was typically reflected by a reduction in both, proximal and distal
arm entries (not shown in detail; Figures 3B′′,C′′). In contrast,
locomotor activity displayed by NO ISO and SHORT ISO rats in
response to 50-kHz USV was clearly directed toward the sound
source, as reflected by an increase in the number of proximal arm
entries [t(11) = 2.820; p = 0.017 and t(11) = 3.336; p = 0.007,
respectively], often paralleled by a decrease in distal arm entries
[t(11) = 0.527; p = 0.609 and t(11) = 3.960; p = 0.002,
respectively], whereas in LONG ISO rats proximal arm entries
did not increase, with distal arm entries being reduced due to As in Experiment 1, changes in locomotor activity were
detected in response to all three acoustic stimuli presented
(Supplementary Figures 2A′–C′). Alarm 22-kHz USV led to
behavioral inhibition, irrespective of experimental housing
condition [main effect stimulus presentation: F(1, 33) = 35.597;
p < 0.001; interaction housing × stimulus presentation: NS]. Behavioral inhibition was also seen in response to NOISE in
all experimental housing conditions, yet most prominently in May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 6 Post-weaning isolation induces communication deficits Seffer et al. FIGURE 4 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social
50-kHz USV that can be reversed by re-socialization: within-group
comparisons. (A–C)
Line graphs depicting changes in side preferences
as assessed by the time spent [s/min] on proximal (black) and distal
(white) arms displayed by rats exposed to 4 weeks of (A) NO ISO, (B)
SHORT ISO, and (C) LONG ISO, post-weaning, during the baseline
period (5 min; PRE) and during playback (1 min; DUR) in response to
50-kHz USV in Experiment 1: Post-weaning Social Isolation—Effects. Experiment 2: Post-weaning Social
Isolation—Rescue (A–C)
Line graphs depicting changes in side preferences
as assessed by the time spent [s/min] on proximal (black) and distal
(white) arms displayed by rats exposed to 4 weeks of (A) NO ISO, (B)
SHORT ISO, and (C) LONG ISO, post-weaning, during the baseline
period (5 min; PRE) and during playback (1 min; DUR) in response to
50-kHz USV in Experiment 1: Post-weaning Social Isolation—Effects. (D–F) Line graphs depicting changes in side preferences as assessed by
the time spent [s/min] on proximal (black) and distal (white) arms comparisons. (A–C)
Line graphs depicting changes in side preferences
as assessed by the time spent [s/min] on proximal (black) and distal
(white) arms displayed by rats exposed to 4 weeks of (A) NO ISO, (B)
SHORT ISO, and (C) LONG ISO, post-weaning, during the baseline
period (5 min; PRE) and during playback (1 min; DUR) in response to
50-kHz USV in Experiment 1: Post-weaning Social Isolation—Effects. (D–F) Line graphs depicting changes in side preferences as assessed by
the time spent [s/min] on proximal (black) and distal (white) arms to the one seen in rats exposed to 22-kHz USV or NOISE [main
effect stimulus type: F(1, 34) = 12.710; p < 0.001; p = 0.055 and
p < 0.001, respectively]. Such a behavioral inhibition was shown
by LONG ISO rats in Experiment 1 not exposed to an additional
week of group housing. LONG ISO rats [main effect stimulus presentation: F(1, 32) =
100.938; p < 0.001; interaction housing × stimulus presentation:
F(1, 32) = 5.704; p = 0.008; as compared to NO ISO: p = 0.003;
and SHORT ISO: p = 0.014]. Also, the behavioral response to
pro-social 50-kHz USV was affected by post-weaning isolation
[main effect stimulus presentation: NS; interaction housing ×
stimulus presentation: F(1, 32) = 4.968; p = 0.013]. Specifically,
rats exposed to NO ISO slightly increased their locomotor activity
in response to 50-kHz USV [t(11) = 1.987; p = 0.072], whereas,
after one additional week of group housing, SHORT ISO but
not LONG ISO rats slightly decreased their locomotor activity
[t(10) = 2.191; p = 0.053 and t(11) = 0.685; p = 0.508,
respectively], with LONG ISO not being significantly different
from both, NO ISO and SHORT ISO, anymore (p = 0.072 and
p = 0.199, respectively). Experiment 2: Post-weaning Social
Isolation—Rescue (D–F) Line graphs depicting changes in side preferences as assessed by
the time spent [s/min] on proximal (black) and distal (white) arms
displayed by rats exposed to 4 weeks of (D) NO ISO, (E) SHORT ISO,
and (F) LONG ISO, post-weaning, plus one additional week of peer
rearing, during the baseline period (5 min; PRE) and during playback
(1 min; DUR) in response to 50-kHz USV in Experiment 2: Post-weaning
Social Isolation—Rescue. (G–I) Line graphs depicting changes in side
preferences as assessed by the time spent [s/min] on proximal (black)
and distal (white) arms displayed by rats exposed to 4 weeks of (G) NO
ISO, (H) SHORT ISO, and (I) LONG ISO, post-adolescent, during the
baseline period (5 min; PRE) and during playback (1 min; DUR) in
response to 50-kHz USV in Experiment 3: Post-adolescent Social
Isolation—Effects. *p < 0.050 compared to distal arm time. displayed by rats exposed to 4 weeks of (D) NO ISO, (E) SHORT ISO,
and (F) LONG ISO, post-weaning, plus one additional week of peer
rearing, during the baseline period (5 min; PRE) and during playback
(1 min; DUR) in response to 50-kHz USV in Experiment 2: Post-weaning
Social Isolation—Rescue. (G–I) Line graphs depicting changes in side
preferences as assessed by the time spent [s/min] on proximal (black)
and distal (white) arms displayed by rats exposed to 4 weeks of (G) NO
ISO, (H) SHORT ISO, and (I) LONG ISO, post-adolescent, during the
baseline period (5 min; PRE) and during playback (1 min; DUR) in
response to 50-kHz USV in Experiment 3: Post-adolescent Social
Isolation—Effects. *p < 0.050 compared to distal arm time. FIGURE 4 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social
50-kHz USV that can be reversed by re-socialization: within-group
i
(A C)
Li
h
d
i ti
h
i
id
f FIGURE 4 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social
50-kHz USV that can be reversed by re-socialization: within-group
comparisons. Comparison across Experiments p
p
In Experiment 1 (effects of post-weaning social isolation), NO
ISO and SHORT ISO rats displayed approach behavior in
response to playback of pro-social 50-kHz USV, as reflected in
an increase in the time spent on proximal arms, whereas LONG
ISO rats displayed social avoidance, as reflected in a decrease in
proximal arm times, resulting in a significant difference between
experimental housing conditions [main effect housing: F(1, 35) =
8.770; p
=
0.001; Figure 5A]. Specifically, LONG ISO rats
differed from NO ISO and SHORT ISO rats (p = 0.003 and
p
<
0.001, respectively), with the latter ones not differing
from each other (p = 0.478). Importantly, when comparing
LONG ISO rats between the three experiments, LONG ISO rats
exposed to post-weaning isolation displaying social avoidance
differed from the LONG ISO rats of the other two experiments
[main effect housing: F(1, 35) = 7.997; p = 0.001; Figure 5B],
namely LONG ISO rats exposed to post-weaning isolation after
one additional week of group housing (p = 0.028; one-tailed)
and LONG ISO rats exposed to post-adolescent social isolation
(p < 0.001; one-tailed), both displaying approach behavior. However, approach tended to be stronger in LONG ISO rats
exposed to post-adolescent isolation than in LONG ISO rats
exposed to post-weaning isolation after one additional week of
group housing (p = 0.055). This indicates that the rescue by
social peer intervention was only partial. Of note, the trend
for stronger approach behavior in LONG ISO rats exposed to
post-adolescent isolation is unlikely to be explained by age-
differences, as approach behavior diminishes with age (Wöhr and
Schwarting, 2007). As before, changes in locomotor activity were detected
in response to alarm 22-kHz USV and NOISE, yet, in
Experiment 3, no effect of pro-social 50-kHz USV was detected
(Supplementary Figures 3A′–C′). Again, 22-kHz USV and
NOISE led to behavioral inhibition irrespective of experimental
housing condition [main effect stimulus presentation: F(1, 33) =
53.598; p < 0.001; interaction housing × stimulus presentation:
NS and main effect stimulus presentation: F(1, 32) = 30.517;
p
<
0.001; interaction housing × stimulus presentation:
NS, respectively], while no change in locomotor activity in
response to 50-kHz USV was detected (main effect stimulus
presentation: NS; interaction housing × stimulus presentation:
NS). Experiment 2: Post-weaning Social
Isolation—Rescue of proximal arm entries, in post-adolescent rats of all three
experimental housing conditions, namely NO ISO [t(11) = 2.871;
p = 0.015], SHORT ISO [t(11) = 3.490; p = 0.005], and LONG
ISO [t(11) = 3.874; p = 0.003], typically paralleled by a decrease
in distal arm entries [t(11) = 3.442; p = 0.006, t(11) = 3.149; p =
0.009, and t(11) = 1.590; p = 0.140, respectively; Supplementary
Figure 3A′]. Furthermore, in NO ISO rats the proximal time increased
[t(11) = 3.088; p = 0.010], while the distal time decreased [t(11) =
4.894; p < 0.001], resulting in a significant preference toward
the stimulus source during 50-kHz USV playback [t(11) = 3.874;
p = 0.003; Figure 4D]. Likewise, SHORT ISO rats, after one
additional week of group housing, displayed a preference toward
the stimulus source during 50-kHz USV playback [preference:
t(10) = 3.448; p = 0.006; proximal time: t(10) = 1.063; p =
0.313; distal time: t(11) = 5.287; p < 0.001; Figure 4E). Most
importantly, however, LONG ISO rats, after one additional week
of group housing, also displayed a preference toward 50-kHz
USV playback [preference: t(11) = 5.957; p = 0.009; proximal
time: t(10) = 0.879; p = 0.398; distal time: t(11) = 4.014;
p = 0.002; Figure 4F]. No significant preferences were seen
before playback (all p-values >0.050). Furthermore, in post-adolescent NO ISO rats the proximal
time increased [t(11) = 3.336; p = 0.007], while the distal
time decreased [t(11)
=
6.416; p
<
0.001], resulting in a
significant preference toward the stimulus source during 50-kHz
USV playback [t(11) = 5.957; p < 0.001; Figure 4G]. Likewise,
post-adolescent SHORT ISO rats displayed a preference toward
the stimulus source during 50-kHz USV playback [preference:
t(11)
=
5.566; p
<
0.001; proximal time: t(11)
=
1.063;
p = 0.313; distal time: t(11) = 5.287; p < 0.001; Figure 4H]. Most importantly, however, post-adolescent LONG ISO rats also
displayed a preference toward 50-kHz USV playback [preference:
t(11) = 4.726; p = 0.001; proximal time: t(11) = 3.709; p = 0.003;
distal time: t(11) = 3.903; p = 0.002; Figure 4I]. No significant
preferences were seen before playback (all p-values >0.050). Together, Experiment 2 shows that deficits in approach
behavior induced by post-weaning isolation can be rescued by
additional exposure to 1 week of peer rearing. Experiment 2: Post-weaning Social
Isolation—Rescue This is in line
with recent findings demonstrating that social deficits can be
improved by peer intervention in a well-established autism model
(Yang et al., 2011). Together, Experiment 3 shows that post-adolescent isolation
did not affect approach behavior elicited by 50-kHz USV. This
indicates that the deficits in approach induced by post-weaning
isolation is specific for the juvenile period, while no such
effects are seen in post-adolescents, i.e., young adults after their
rough-and-tumble play period (Panksepp, 1981). Experiment 2: Post-weaning Social
Isolation—Rescue Importantly, after the additional week
of group housing, prior LONG ISO rats did not display a level of
behavioral inhibition in response to 50-kHz USV that is similar LONG ISO rats [main effect stimulus presentation: F(1, 32) =
100.938; p < 0.001; interaction housing × stimulus presentation:
F(1, 32) = 5.704; p = 0.008; as compared to NO ISO: p = 0.003;
and SHORT ISO: p = 0.014]. Also, the behavioral response to
pro-social 50-kHz USV was affected by post-weaning isolation
[main effect stimulus presentation: NS; interaction housing ×
stimulus presentation: F(1, 32) = 4.968; p = 0.013]. Specifically,
rats exposed to NO ISO slightly increased their locomotor activity
in response to 50-kHz USV [t(11) = 1.987; p = 0.072], whereas,
after one additional week of group housing, SHORT ISO but
not LONG ISO rats slightly decreased their locomotor activity
[t(10) = 2.191; p = 0.053 and t(11) = 0.685; p = 0.508,
respectively], with LONG ISO not being significantly different
from both, NO ISO and SHORT ISO, anymore (p = 0.072 and
p = 0.199, respectively). Importantly, after the additional week
of group housing, prior LONG ISO rats did not display a level of
behavioral inhibition in response to 50-kHz USV that is similar As in Experiment 1, behavioral inhibition in response to 22-
kHz USV and NOISE was typically reflected by a reduction
in both, proximal and distal arm entries (not shown in detail;
Supplementary Figures 2B”,C”). In contrast, locomotor activity
displayed by NO ISO and SHORT ISO rats, after one additional
week of group housing, in response to 50-kHz USV was clearly
directed toward the sound source, as typically reflected by an
increase in the number of proximal arm entries [t(11) = 2.721;
p = 0.020 and t(10) = 0.593; p = 0.566, respectively], paralleled
by a decrease in distal arm entries [t(11) = 4.750; p = 0.001
and t(10) = 5.043; p = 0.001, respectively]. Most importantly,
LONG ISO rats, after one additional week of group housing, also May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 7 Post-weaning isolation induces communication deficits Seffer et al. displayed a slight increase in proximal arm entries [t(11) = 1.984;
p = 0.073], paralleled by a decrease in distal arm entries [t(11) =
4.899; p < 0.001; Supplementary Figure 2A′′]. Experiment 3: Post-adolescent Social
Isolation—Effects To test whether the deficits in approach behavior induced
by post-weaning social isolation occur specifically during the
juvenile developmental period, we repeated the experiment and
assessed approach in post-adolescent rats exposed to (I) NO ISO,
(II) SHORT ISO, or (III) LONG ISO. Comparison across Experiments during the baseline period (5 min), displayed by rats exposed to 4 weeks of
LONG ISO, post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects (left), 4 weeks of LONG ISO, post-weaning, plus one
additional week of peer rearing in Experiment 2: Post-weaning Social
Isolation—Rescue (middle), 4 weeks of LONG ISO, post-adolescent, in
Experiment 3: Post-adolescent Social Isolation—Effects (right). *p < 0.050
compared to EXP 1. FIGURE 5 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social 50-kHz
USV that can be reversed by re-socialization: between-group FIGURE 5 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social 50-kHz
USV that can be reversed by re-socialization: between-group
comparisons. (A) Bar graphs depicting changes in side preferences as
assessed by the time spent [s/min] on proximal arms during playback in
response to 50-kHz USV (1 min) vs. during the baseline period (5 min),
displayed by rats exposed to 4 weeks of NO ISO (left), SHORT ISO (middle),
and LONG ISO (right), post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects. *p < 0.050 compared to LONG ISO. (B) Bar graphs
depicting changes in side preferences as assessed by the time spent [s/min]
on proximal arms during playback in response to 50-kHz USV (1 min) vs. during the baseline period (5 min), displayed by rats exposed to 4 weeks of
LONG ISO, post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects (left), 4 weeks of LONG ISO, post-weaning, plus one
additional week of peer rearing in Experiment 2: Post-weaning Social
Isolation—Rescue (middle), 4 weeks of LONG ISO, post-adolescent, in
Experiment 3: Post-adolescent Social Isolation—Effects (right). *p < 0.050
compared to EXP 1. g
Our present finding that post-weaning long-term isolation
results in a complete lack of approach behavior in the receiver
when exposed to 50-kHz USV, is in line with a number of
studies reporting isolation-induced social deficits in rats, like
reduced social activity, including approach, anogenital sniffing,
and reciprocal interaction (Meaney and Stewart, 1979; Hol et al.,
1999; van den Berg et al., 1999a,b,c; Kokare et al., 2010; Möller
et al., 2011, 2013; but see Ferdman et al., 2007; Han et al.,
2011), as well as heightened aggression (Wongwitdecha and
Marsden, 1996; Vale and Montgomery, 1997; Meng et al., 2010;
Wall et al., 2012; Grotewold et al., 2014), which is possibly
due to impaired communication (Tóth et al., 2008). Comparison across Experiments Importantly, post-adolescent LONG ISO rats did not display
a level of behavioral inhibition in response to 50-kHz USV that is
similar to the one seen in rats exposed to 22-kHz USV or NOISE
[main effect stimulus type: F(1, 35) = 4.663; p = 0.016; p = 0.029
and p = 0.007, respectively]. Such a behavioral inhibition was
shown by LONG ISO rats in Experiment 1 after post-weaning
isolation. Again, as in Experiments 1 and 2, behavioral inhibition in
response to 22-kHz USV and NOISE was typically reflected by
a reduction in both, proximal and distal arm entries (not shown
in detail; Supplementary Figures 3B′,C′). In contrast, locomotor
activity in response to 50-kHz USV was clearly directed toward
the sound source, as reflected by an increase in the number May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 8 Post-weaning isolation induces communication deficits Seffer et al. FIGURE 5 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social 50-kHz
USV that can be reversed by re-socialization: between-group
comparisons. (A) Bar graphs depicting changes in side preferences as
assessed by the time spent [s/min] on proximal arms during playback in
response to 50-kHz USV (1 min) vs. during the baseline period (5 min),
displayed by rats exposed to 4 weeks of NO ISO (left), SHORT ISO (middle),
and LONG ISO (right), post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects. *p < 0.050 compared to LONG ISO. (B) Bar graphs
depicting changes in side preferences as assessed by the time spent [s/min]
on proximal arms during playback in response to 50-kHz USV (1 min) vs. during the baseline period (5 min), displayed by rats exposed to 4 weeks of
LONG ISO, post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects (left), 4 weeks of LONG ISO, post-weaning, plus one
additional week of peer rearing in Experiment 2: Post-weaning Social
Isolation—Rescue (middle), 4 weeks of LONG ISO, post-adolescent, in
Experiment 3: Post-adolescent Social Isolation—Effects (right). *p < 0.050
compared to EXP 1. with other studies reporting hyperactivity in response to a novel
environment after post-weaning isolation (Hall, 1998; Lapiz et al.,
2003; Fone and Porkess, 2008; Gaskin et al., 2014). Therefore,
deficits in approach behavior cannot be due to a general lack of
locomotor activity. Comparison across Experiments In fact,
besides social behavior, post-weaning long-term isolation was
also shown to affect communication. Specifically, male rats were
found to emit fewer 50-kHz USV when exposed to a sexually
receptive female, probably reflecting their inability to recognize
social cues and/or to respond appropriately (Inagaki et al.,
2013). Furthermore, it was reported that isolation-rearing leads
to a dissociation of 22-kHz USV production from the sender’s
behavioral pattern, possibly resulting in a loss of its aggression-
reducing communicative function (von Frijtag et al., 2002). In
contrast, the receiver’s response to 22-kHz USV was not affected
by social isolation in our experiments, suggesting that they Comparison across Experiments Most notably, as shown in Experiments 2 and
3, respectively, such impairments could be rescued by exposure
to one additional week of peer rearing and were not seen after
post-adolescent social isolation. Importantly, post-weaning isolation specifically affected the
behavioral response to 50-kHz USV and did not change the
responses to 22-kHz USV or NOISE. Playback of 22-kHz USV
consistently led to behavioral inhibition in all three experiments,
irrespective of experimental housing condition, i.e., in nine
independent groups of rats. This is in line with previous studies,
supporting the notion that they serve an alarm function (Burman
et al., 2007; Endres et al., 2007; Wöhr and Schwarting, 2007,
2010). However, what appears surprising is that NOISE also led
to behavioral inhibition, challenging the view that 22-kHz USV
specifically induce behavioral inhibition as background noise
was also present during 22-kHz USV playback. Future studies
specifically focusing on behavioral inhibition induced by 22-kHz
USV, thus appear requisite. In particular, a detailed analysis of
freezing behavior might allow a more sensitive assessment of
minor differences in the level of behavioral inhibition induced
by 22-kHz USV and NOISE, as compared to the measure applied
here, namely total number of arm entries. In the present context,
however, it needs to be emphasized that 50-kHz USV playback
consistently led to approach behavior, despite the presence
of background noise, with only one exception, namely rats
exposed to post-weaning long-term isolation. In future studies,
it would be interesting to assess whether deficits in approach
behavior following post-weaning social isolation are also seen in
response to related acoustic stimuli, such as artificially/computer-
generated 50-kHz sine wave tones. FIGURE 5 | Post-weaning but not post-adolescent social isolation
leads to a lack of approach behavior in response to pro-social 50-kHz
USV that can be reversed by re-socialization: between-group
comparisons. (A) Bar graphs depicting changes in side preferences as
assessed by the time spent [s/min] on proximal arms during playback in
response to 50-kHz USV (1 min) vs. during the baseline period (5 min),
displayed by rats exposed to 4 weeks of NO ISO (left), SHORT ISO (middle),
and LONG ISO (right), post-weaning, in Experiment 1: Post-weaning Social
Isolation—Effects. *p < 0.050 compared to LONG ISO. (B) Bar graphs
depicting changes in side preferences as assessed by the time spent [s/min]
on proximal arms during playback in response to 50-kHz USV (1 min) vs. Discussion Post-weaning social isolation had a strong impact on approach
behavior elicited by pro-social 50-kHz USV, as shown in
Experiment 1. Approach was seen in group-housed and short-
term isolated rats, which is consistent with previous studies
(Wöhr and Schwarting, 2007, 2009, 2012; Willuhn et al., 2014). Rats exposed to long-term isolation, however, responded to 50-
kHz USV by behavioral inhibition, similar to that seen in rats
exposed to alarm 22-kHz USV or NOISE, resulting in a complete
lack of approach behavior. General locomotor activity during the
baseline period was increased in long-term isolated rats, in line May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 9 Post-weaning isolation induces communication deficits Seffer et al. were either innately recognized as alarm calls or had gained
alarm signal value through autoconditioning prior to isolation
(Parsana et al., 2012), which is potentially facilitated by biological
preparedness (Wöhr and Schwarting, 2010). While deficits in approach behavior were induced by post-
weaning isolation, no such effects were seen in young adults
reared in post-adolescent isolation, i.e., after going through the
rough-and-tumble play period. This is also in line with other
studies that could not find behavioral deficits in rats that were at
least partially reared in groups during this critical period, before
being isolated (Wright et al., 1991; Hol et al., 1999). There is some
evidence that additional playful experience during the course of
isolation may, to some extent, prevent impaired development of
social competencies (Potegal and Einon, 1989; Einon and Potegal,
1991; but see van den Berg et al., 2000), further suggesting that
there is a critical involvement of play behavior on socio-affective
information processing in rats. Most importantly, however, our findings demonstrate for
the first time that post-weaning isolation not only induces
behavioral changes displayed by the sender, but also by the
receiver in response to 50-kHz USV. This is in line with a
study on scent marking behavior where post-weaning long-term
isolation increased the time spent investigating conspecific odors,
but reduced the amount of urine counter-marking, together
with an alteration in odor preferences (Brown, 1991). Lack
of approach behavior during 50-kHz USV playback following
long-term isolation could be interpreted in terms of increased
anxiety and/or reduced social motivation, possibly resembling a
depression-like behavioral phenotype (Wright et al., 1991; van
den Berg et al., 1999b; Lukkes et al., 2009; Kokare et al., 2010;
Meng et al., 2010). Discussion The idea that social isolation affects the
level of social motivation in the receiver is supported by our
bidirectional modulation of approach behavior in response to 50-
kHz USV through short- and long-term isolation. While group-
housed rats showed a clear preference toward 50-kHz USV, this
response was enhanced after short-term isolation, whereas it was
absent in long-term isolated rats. In fact, there is evidence that
increased social motivation in the sender is reflected by higher
rates of 50-kHz USV emission, e.g., during social play or tickling
(Knutson et al., 1998; Panksepp and Burgdorf, 2000; Burgdorf
and Panksepp, 2001). In support of this notion, it was shown in a well-established
autism model that social deficits can be improved by peer
intervention (Yang et al., 2011). In our study, deficits in approach
induced by post-weaning isolation were partially rescued by
1 week of group housing. Yet, other studies investigating
behavioral changes following re-socialization are inconsistent. For instance, it was shown that increased anxiety, abnormal
aggression, and defense behavior, as well as reduced social
interaction were not alleviated by re-socialization (Potegal and
Einon, 1989; Einon and Potegal, 1991; Wright et al., 1991; van
den Berg et al., 1999a; Lukkes et al., 2009; Tulogdi et al., 2014). In
line with our results, however, beneficial effects of re-socialization
could be demonstrated, like attenuation of anxiety-like behavior,
depression-like behavior, and isolation-induced aggression (Vale
and Montgomery, 1997; Kokare et al., 2010; Meng et al., 2010),
as well as recovery of sleep-related huddling (Tulogdi et al., 2014)
and social interaction (Kokare et al., 2010). There is also evidence
for restored social cooperation by re-socialization after isolation
during adulthood (Willner et al., 1989). Data from human
adoption studies further support a re-socialization effect insofar
as placement of children in a beneficial family environment was
shown to reverse deficits in cognitive development, as compared
to children remaining in institutional care (Nelson et al., 2007;
Bos et al., 2011). A further explanation for the lack of approach behavior
following post-weaning long-term isolation, is a deficit in
socio-affective information processing, induced by withholding
social play. Importantly, play behavior reaches its peak during
the middle of the juvenile stage (Panksepp, 1981; Thor and
Holloway, 1984), exactly during the period of isolation. Discussion Play
fighting differs from serious fighting in regards to the target
of attack (Takahashi and Lore, 1983; Pellis and Pellis, 1987),
and consists of various behavioral components which appear
to be programmed during development, promoting reciprocity,
i.e., comparable outcome of successful play encounters within
a pair, by reducing the behavioral control over the partner
(Pellis, 2002; Pellis et al., 2005). It is assumed that social play
facilitates neural and behavioral development by equipping an
individual adequately for the needs in adulthood (Vanderschuren
et al., 1997). In support of the critical period hypothesis (Scott,
1962; Hol et al., 1999; van den Berg et al., 1999a), a full
manifestation of isolation-induced behavioral alterations is only
observed when the intervention takes place during this sensitive
developmental period (Fone and Porkess, 2008). During play,
juveniles frequently experience a loss of control by exposing
themselves to unpredictable events. Training for the unexpected
allows rats to develop flexible responses to cope with rapidly
changing environments (Spinka et al., 2001; Pellis et al., 2010). Most notably, physical interactions during adolescence are
important to acquire social competency. This includes social,
emotional, and cognitive skills; such as the ability to express and
understand communicative signals from conspecifics (Wöhr and
Schwarting, 2013). Apparently, efficacy of rat re-socialization depends both on
isolation duration (Hol et al., 1999) and re-socialization duration,
with at least 3 days of social housing being required to attenuate
certain behavioral deficits (Kokare et al., 2010). Regarding our
results, 1 week of group housing might still not be sufficient to
completely rescue the adverse effects caused by 4 weeks of post-
weaning isolation in this paradigm. Also, it appears possible that
social experiences made by the peers before peer intervention
play an important role (Hol et al., 1999; Tulogdi et al., 2014). In
the future it would therefore be interesting to assess the effects of
longer peer intervention periods and previous social experiences
made by the peers. Importantly, behavioral alterations following post-weaning
isolation, such as deficits in the social behavior repertoire,
mimic negative symptoms typically observed in schizophrenia
(Hall, 1998; Lapiz et al., 2003; Fone and Porkess, 2008). Our present finding that post-weaning long-term isolation
results in a complete lack of approach behavior in the
receiver when exposed to 50-kHz USV is in line with that
view. Discussion In fact, in schizophrenia patients, several domains of May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 10 Post-weaning isolation induces communication deficits Seffer et al. social behavior are impaired (Penn et al., 2008), including
theory of mind (Brüne, 2005; Biedermann et al., 2012),
emotional perception (Schneider et al., 2006; Irani et al.,
2012), and verbal and non-verbal communication (Couture
et al., 2006; Lavelle et al., 2013). According to the DSM-
5 (American Psychiatric Association, 2013), patients display
severe disorganized and/or reduced speech output (alogia)
that substantially impairs effective communication, as well as
diminished emotional expression and a lack of interest in social
interactions (asociality). social behavior are impaired (Penn et al., 2008), including
theory of mind (Brüne, 2005; Biedermann et al., 2012),
emotional perception (Schneider et al., 2006; Irani et al.,
2012), and verbal and non-verbal communication (Couture
et al., 2006; Lavelle et al., 2013). According to the DSM-
5 (American Psychiatric Association, 2013), patients display
severe disorganized and/or reduced speech output (alogia)
that substantially impairs effective communication, as well as
diminished emotional expression and a lack of interest in social
interactions (asociality). 2008). Consistently, by means of the post-weaning isolation
paradigm applied here, we recently induced alterations in
regulators of neuronal development and synaptic plasticity, such
as ubiquitin ligase and microRNAs (Valluy et al., 2015). In future
studies, it would therefore be interesting to assess changes in
neurotransmission and synaptic plasticity that specifically occur
in response to post-weaning, but not post-adolescent isolation,
and to test which of them can be reversed by peer intervention. This approach would likely lead to the identification of promising
targets for novel pharmacological treatment approaches, the
efficacy of which could be tested in rodent models for negative
symptoms of schizophrenia. (
y)
Consistently,
pharmacological
treatments,
including
antipsychotics, were shown to rescue isolation-induced deficits
in rats. Sub-chronic, but not acute administration of the
antipsychotic drug clozapine or N-acetyl cysteine, a modulator
of
glutamatergic
transmission,
restores
social
interaction
and deficits in other domains linked to schizophrenia, such
as sensorimotor gating and memory (Möller et al., 2011,
2013). Also, acute treatment with the selective MC4 receptor
antagonist HS014 reverses social deficits, as well as anxiety- and
depression-like symptoms (Kokare et al., 2010). Supplementary Material The Supplementary Material for this article can be found
online
at:
http://journal.frontiersin.org/article/10.3389/fnbeh. 2015.00102/abstract Acknowledgments This work was supported by grants from the Deutsche
Forschungsgemeinschaft to RS (SCHW 559/10-1 and SCHW
559/14-1) and MW (WO 1732/4-1). The authors wish to thank
Karl-Alexander Engelhardt, Katharina Günther, Kerstin Haas,
Clara Krzikalla, Andrea Lörwald, Christoph Renninger, Verena
Schuster, and Laura Wendt for their help in this project. The
authors further wish to thank Karl-Alexander Engelhardt for his
help with Figure 1, Theresa Kisko for reading the manuscript,
and the reviewers for their helpful comments. Besides the systems targeted in these pharmacological studies,
behavioral alterations observed following post-weaning isolation
are further accompanied by various neuromorphological changes
and neurochemical imbalances, including neurotransmitter
systems implicated in schizophrenia, such as dopamine and
serotonin (Hall, 1998; Lapiz et al., 2003; Fone and Porkess, Conclusion We showed that post-weaning social isolation specifically affected
the behavioral response to playback of pro-social 50-kHz but
not alarm 22-kHz USV. While group-housed rats showed the
expected preference toward 50-kHz USV, the response was
even stronger in short-term isolated rats, possibly due to a
higher level of social motivation. In contrast, no approach
behavior to 50-kHz USV was observed in long-term isolated
rats. Importantly, deficits in approach behavior were reversed by
peer-mediated re-socialization and could not be observed after
post-adolescent social isolation, indicating a critical period for
social development during adolescence. Together, these results
highlight the importance of social experience for affiliative
behavior, suggesting a critical involvement of play behavior on
socio-affective information processing in rats. Discussion In contrast,
benzodiazepines attenuate increased aggression but the effects
on social interaction are inconsistent, thus challenging the
notion that isolation-induced abnormal social behavior is
anxiety-related (Wongwitdecha and Marsden, 1996; Vale and
Montgomery,
1997). Furthermore,
chronic
application
of
the antidepressants imipramine or fluoxetine, after isolation
during adulthood, was demonstrated to re-establish cooperative
behavior (Willner et al., 1989). Importantly, chronic morphine
treatment counteracts reduced social activity, accompanied by
a reversal of upregulated µ-opioid-receptor binding sites (van
den Berg et al., 1999c, 2000). Since it was shown that social
play induces the release of opioids in specific brain regions
(Vanderschuren et al., 1997), alterations in social behavior due to
deprivation of play might be the result of reduced opioid release
during this critical developmental period. Morphine treatment
appears to substitute for the lack of play-induced opioid peptide
release. Consistently, knocking-out µ-opioid-receptors in mice
(Wöhr et al., 2011) or administering a µ-opioid-receptor-
antagonist in rats (Wöhr and Schwarting, 2009) negatively
affects approach behavior during USV playback, suggesting that
endogenous opioids are not only involved in social behavior but
also in socio-affective information processing (Oddi et al., 2013). Besides the systems targeted in these pharmacological studies,
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article distributed under the terms of the Creative Commons Attribution License (CC
BY). The use, distribution or reproduction in other forums is permitted, provided the
original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution
or reproduction is permitted which does not comply with these terms. Wöhr, M., and Schwarting, R. K. W. (2012). Testing social acoustic memory in
rats: effects of stimulus configuration and long-term memory on the induction
of social approach behavior by appetitive 50-kHz ultrasonic vocalizations. Neurobiol. Learn. Mem. 98, 154–164. doi: 10.1016/j.nlm.2012.05.004 May 2015 | Volume 9 | Article 102 Frontiers in Behavioral Neuroscience | www.frontiersin.org 14
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Научная статья
УДК 004.09 Научная статья
УДК 004.09 Peter the Great Saint Petersburg Polytechnic University, 29 Polytechnicheskaya St., St. Petersburg 195251,
Russia Russia
Oksana Yu. Iliashenko, ioy120878@gmail.com, https://orcid.org/0000-0001-9292-7759, AuthorID:
331642
Ekaterina L. Lukyanchenko, lukyanchenko@mail.ru, https://orcid.org/0000-0003-2738-5513, AuthorID:
1090381 Russia
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331642
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1090381 Ekaterina L. Lukyanchenko, lukyanchenko@mail.ru, https://orcid.org/0000-0003-2738-5513, AuthorID:
1090381 Abstract. This article discusses the possibilities of using artificial intelligence technologies,
namely computer vision, in the field of medicine. The relevance of the topic is due to the growing
burden on medical personnel and medical institutions due to an increase in the number of elderly
people, an increase in the number of patients with chronic diseases, as well as unforeseen
circumstances, such as the SARS-CoV-2 pandemic in 2019–2021. In addition, many medical
institutions are interested in providing high-quality services, increasing loyalty, and increasing the
number of regular patients, and therefore feel the need to introduce the latest technologies and
follow strategic development trends. The article describes how the physician can use the solutions
offered by artificial intelligence in the course of his work to obtain a more accurate diagnosis
and save time spent on the patient’s history review. The authors propose an IT and technological
architecture of a medical organization that uses computer vision in its work, created on the
basis of the IT and the technological architecture reference model of a medical organization. The
architecture implies the use of cloud infrastructure and specialized software and provides for both
the introduction of new types of equipment, for example, 3D cameras, imaging sensors, and the
use of traditional equipment: an ultrasound machine, X-ray equipment, an MRI machine.i words: artificial intelligence, computer vision, enterprise architecture, IT architectur
cine For citation: Iliashenko O. Yu., Lukyanchenko E. L. Possibilities of using computer vision for
data analytics in medicine. Izvestiya of Saratov University. Mathematics. Mechanics. Informa-
tics, 2022, vol. 22, iss. 2, pp. 224–232. https://doi.org/10.18500/1816-9791-2022-22-2-224-232
This is an open access article distributed under the terms of Creative Commons Attribution 4.0
International License (CC-BY 4.0) Научная статья
УДК 004.09 О. Ю. Ильяшенко, Е. Л. Лукьянченко https://doi.org/10.18500/1816-9791-2022-22-2-224-232 Статья опубликована на условиях лицензии Creative Commons Attribution 4.0 International
(CC-BY 4.0) О. Ю. Ильяшенко, Е. Л. Лукьянченко Санкт-Петербургский политехнический университет Петра Великого, Россия, 195251, г. Санкт-
Петербург, ул. Политехническая, д. 29 c○Iliashenko O. Yu., Lukyanchenko E. L., 2022 O. Yu. Iliashenko, E. L. Lukyanchenko. Possibilities of using computer vision for data analytics Ильяшенко Оксана Юрьевна, кандидат педагогических наук, доцент Высшей школы бизнес-инжи-
ниринга, https://orcid.org/0000-0001-9292-7759, AuthorID: 331642, ioy120878@gmail.com
Лукьянченко Екатерина Леонидовна, магистрант Высшей школы бизнес-инжиниринга, https://orcid. org/0000-0003-2738-5513, AuthorID: 1090381, lukyanchenko@mail.ru Ильяшенко Оксана Юрьевна, кандидат педагогических наук, доцент Высшей школы бизнес-инжи-
ниринга, https://orcid.org/0000-0001-9292-7759, AuthorID: 331642, ioy120878@gmail.com
Лукьянченко Екатерина Леонидовна, магистрант Высшей школы бизнес-инжиниринга, https://orcid. org/0000-0003-2738-5513, AuthorID: 1090381, lukyanchenko@mail.ru Ильяшенко Оксана Юрьевна, кандидат педагогических наук, доцент Высшей школы бизнес-инжи-
ниринга, https://orcid.org/0000-0001-9292-7759, AuthorID: 331642, ioy120878@gmail.com
Лукьянченко Екатерина Леонидовна, магистрант Высшей школы бизнес-инжиниринга, https://orcid. org/0000-0003-2738-5513, AuthorID: 1090381, lukyanchenko@mail.ru Аннотация. В статье рассматриваются возможности использования технологий искусствен-
ного интеллекта, а именно компьютерного зрения, в сфере медицины. Актуальность темы
обусловлена растущей нагрузкой на медицинский персонал и на медицинские учреждения
в связи с увеличением числа пожилых людей и пациентов с хроническими заболевания-
ми, а также непредвиденными обстоятельствами, как, например, пандемия коронавируса
SARS-CoV-2 в 2019–2021 гг. Кроме того, многие медицинские учреждения заинтересованы в
предоставлении услуг высокого качества, повышении лояльности и увеличении числа постоян-
ных пациентов, в связи с чем ощущают необходимость во внедрении новейших технологий и
хотят следовать трендам стратегического развития. В статье описывается, как лечащий врач
может использовать предлагаемые искусственным интеллектом решения в процессе своей
работы для получения более точного диагноза и экономии времени на ознакомление с анам-
незом пациента. Предложена ИТ- и технологическая архитектура медицинской организации,
использующей компьютерное зрение в своей работе, созданная на основе референтной модели. Архитектура подразумевает использование облачной инфраструктуры, специализированно-
го ПО и предусматривает как внедрение новых типов оборудования, например 3D камер,
датчиков визуализации, так и использование традиционного оборудования: аппарата УЗИ,
рентген-оборудования, аппарата МРТ. Ключевые слова: искусственный интеллект, компьютерное зрение,архитектура предприятия,
ИТ-архитектура, медицина Для цитирования: Iliashenko O. Yu., Lukyanchenko E. L. Possibilities of using computer
vision for data analytics in medicine [Ильяшенко О. Ю., Лукьянченко Е. Л. Возможности
применения компьютерного зрения для аналитики данных в медицине] // Известия Саратов-
ского университета. Новая серия. Серия: Математика. Механика. Информатика. 2022. Т. 22,
вып. 2. С. 224–232. https://doi.org/10.18500/1816-9791-2022-22-2-224-232 Для цитирования: Iliashenko O. Yu., Lukyanchenko E. L. Possibilities of using computer
vision for data analytics in medicine [Ильяшенко О. Ю., Лукьянченко Е. Л. Возможности
применения компьютерного зрения для аналитики данных в медицине] // Известия Саратов-
ского университета. Новая серия. Серия: Математика. Механика. Информатика. 2022. Т. 22,
вып. 2. С. 224–232. Introduction The concept of artificial intelligence (AI) has evolved since 1950 when Alan Turing
described the use of computers to develop critical thinking and human decision-making. Currently, artificial intelligence is an integral part of the development of the digital
world and is used in all spheres of activity from medicine to industry and production [1]. Initially, AI was represented by a number of simple algorithms such as “if this, then that”,
then the algorithms rapidly became more complex, mimicking the neural connections of
the human brain. The result of the development of the concept is the appearance of such
classes of artificial intelligence as machine learning, deep learning, natural language
processing, and computer vision [2]: – machine learning is a field of artificial intelligence, which implies the “training”
of computer algorithms to make decisions on their own. Machine learning is
the driving force behind the intelligence of modern systems. Thus, the system
learns independently (learning without a teacher) or with reinforcement from
the environment, analyzing and classifying large amounts of data to identify the
detected patterns and use them for further insights; Информатика 225 Изв. Сарат. ун-та. Нов. сер. Сер.: Математика. Механика. Информатика. 2022. Т. 22, вып. 2 – deep learning is represented by machine learning methods that allow training a
system not with algorithms, but with representations. Deep learning has proven
to be effective after the increase in computing power has allowed the creation of
complex neural network architectures. The use of deep learning made it possible
to solve problems using computer vision, speech recognition, machine translation,
etc.; ;
– natural language processing is a field of AI used to convert a natural language into
a format understandable for computer systems for further analysis. It is used for
speech recognition; handwritten and typewritten notes recognition;i – natural language processing is a field of AI used to convert a natural language into
a format understandable for computer systems for further analysis. It is used for
speech recognition; handwritten and typewritten notes recognition; – computer vision is an area of AI that deals with the identification of video and
photographic images by raw pixels. Computer vision allows performing tasks such
as detecting, classifying, and interpreting various objects to categorize predefined
analysis results [3]. Introduction The purpose of this article is to study the application of computer vision methods in
the field of medicine: areas of use, advantages and possible difficulties; development of
an IT model and technological architecture of a medical organization that uses computer
vision in its work, based on the reference architecture model, as well as the workflow of
the physician using the opinion of artificial intelligence to make medical decisions. Materials and methods This study is based on the concept of an enterprise architecture. Currently, there are
several standards and methodologies for modeling an enterprise architecture, but one
of the most commonly used is the TOGAF (The Open Group Architecture Framework)
standard, developed by The Open Group consortium. The TOGAF standard is based on the Architecture Development Method (ADM),
which describes a cyclical, phased plan for developing an enterprise architecture. In this
study, ADM phases C and D were used. Also, the authors use in their work the reference model presented in [4]. The reference
model describes the IT and technology architecture of a healthcare organization, following
the concept of value-based, personalized medicine and Health 4.0. Results In the last decade, in the field of medicine the most urgent problem is appeared to be
the insufficient provision of medical institutions with personnel: general practitioners,
specialist doctors, and junior medical personnel. The current medical staff bears the
burden associated with examination, admission, counseling, prescribing treatment, and
maintaining medical records, which affects the quality and quantity of work performed
by them [5]. In addition, the population of most countries is aging rapidly, which in the
near future will mean an increase in the flow of patients and the demand for medical
services and examinations. Controversial yet important is the issue of medical error in the process of making
decisions about the further treatment of the patient. Telemedicine is actively used in
Russia and around the world, which makes it possible to quickly assemble a medical
consultation of highly qualified specialists and conduct it in a remote format. Patients
also have access to solutions that allow them to remotely consult with their doctor,
automatically collect, store and process data on medical indicators, for example, blood
pressure, pulse, blood sugar level, etc. 226 Научный отдел Научный отдел O. Yu. Iliashenko, E. L. Lukyanchenko. Possibilities of using computer vision for data analytics Currently, the possibilities of using AI and machine learning in medicine are beginning
to actively develop. The use of technologies such as computer vision, deep learning, and
natural language processing will make it possible to fully implement such concepts as
personalized, value-based, and predictive medicine [6]. Machine learning algorithms can
be used to improve the accuracy of diagnosis, the efficiency of medical personnel and
increase patient flow, therapeutic follow-up and clinical operations, the experience of
interaction between the patient, and the medical organization as a whole. The use of the latest technologies in medical data analytics is relevant because the
volume of medical data already available is large and continues to grow daily. Medical
data include data from electronic and paper medical records, results of clinical studies,
and visual results of studies: MRI, X-ray, ultrasound, ECG, etc. [7]. In addition to the
variety of types and sources of medical data, it is also characterized by high requirements
for data confidentiality and security, anonymity, and medical secrecy. Until recently, the healthcare industry could rely on small open source datasets or
data collected by commercial companies. Results However, the dynamics of data exchange and
data availability are already affecting and will continue to influence the development and
availability of the use of big data analytics and artificial intelligence technologies [8]. These changes are stimulating research in the field of computer vision in medicine,
which is reflected in the growth of research in areas such as multimodal education that
combines computer vision and language recognition; 3D vision used in intensive care
units, as well as work with videos-activity recognition, understanding of the ongoing
movements to detect adverse events and respond to them [9]. In general, the process of computer vision operation consists of three stages: – image acquisition — the basic stage, which consists of obtaining a photo or video
image from hardware, for example, cameras of various types; – image acquisition — the basic stage, which consists of obtaining a photo or video
image from hardware, for example, cameras of various types; – image processing — the stage at which software is used for image processing:
quality improvement, compression, reduction or increase in size and noise removal. At this stage, primitive operations are performed, which allow faster and better
image processing and obtain the necessary analysis results in the future; – image analysis and decision-making — the most important stage at which image
segmentation or object identification occurs, and then the obtained characteristics
are transferred to machine learning algorithms or other artificial intelligence
technologies. Thus, computer vision can be implemented using traditional machine learning
algorithms, for example, hidden Markov models, random forest or random tree algorithms,
or deep learning algorithms — convolutional neural networks, recurrent neural networks,
and multilayer perceptron [10]. Deep learning is preferred because it allows the processing
of large amounts of data without sacrificing hardware performance. In medical practice, computer vision based on deep learning algorithms can be
successfully applied in such areas as: – gastroenterology [1]; – pulmonology [3]; – cardiology; – dermatology; – ophthalmology; – clinical and imaging studies; – surgery, etc. The workflow implemented by a medical institution that uses computer vision The workflow implemented by a medical institution that uses computer vis 227 Информатика Изв. Сарат. ун-та. Нов. сер. Сер.: Математика. Механика. Информатика. 2022. Т. 22, вып. 2 algorithms in its activities may look like this (Fig. 1). Results Possibilities of using computer vision for data analytics – insufficient amount of data available for training algorithms in the field of computer
vision in medicine — despite the increased interest in this topic and the growing
number of works devoted to research in the field of computer vision, the amount
of high-quality and balanced data available for evaluating various computer vision
techniques is not sufficient yet. – insufficient amount of data available for training algorithms in the field of computer
vision in medicine — despite the increased interest in this topic and the growing
number of works devoted to research in the field of computer vision, the amount
of high-quality and balanced data available for evaluating various computer vision
techniques is not sufficient yet. The use of computer vision by a medical institution unambiguously affects its
IT architecture [12]. The medical institution must be mature enough to implement
deep learning concepts: have transparent business processes described, have sufficient
computing power and technological equipment, have sufficient funding, etc. To build the IT and technological architecture of a medical organization using
computer vision in its activities, the authors will rely on the reference model of IT and
technological architecture of a medical organization presented in the study [4]. The model
is performed in Archi software using the ArchiMate language supported by the TOGAF
standard, which is actively used by international companies and institutions. The reference model (Fig. 2) at the technological architecture level represents a
cluster of servers, medical equipment, and personal gadgets used by patients to monitor
vital medical indicators. Fig. 2. Reference model of IT and technological architecture of a medical organization [4] Fig. 2. Reference model of IT and technological architecture of a medical organization [4 Fig. 2. Reference model of IT and technological architecture of a medical organization [4] Fig. 2. Results AI algorithms at the current
stage of their development and application in medical practice cannot be the final link
in making medical decisions. This means that the physician must familiarize himself
with the results of the algorithms and, on their basis, make a diagnosis and prescribe
treatment for the patient. For example, a system developed by the Californian company
Gauss Surgical allows to accurately assess a patient’s blood loss during surgery or
childbirth by visualizing bloodied medical supplies — surgical sponges. The algorithms
are able to distinguish between blood and non-blood fluids and trigger alerts about
bleeding and critical blood loss in a patient, which allows them respond as quickly as
possible and start a blood transfusion [11]. Nevertheless, the final decision, in this case,
is made by the operating doctor, and the observation of artificial intelligence algorithms
is a tool in the work of medical personnel and not a decision-making tool. Fig. 1. An example of a medical institution workflow improved by computer
vision algorithms Fig. 1. An example of a medical institution workflow improved by computer
vision algorithms The use of computer vision technologies in the process of carrying out diagnostic
procedures has a number of specific features, for example:i The use of computer vision technologies in the process of carrying out diagnostic
procedures has a number of specific features, for example: – the need to find a balance in the accuracy of the interpretation of the results —
minimization of false warnings, but sufficient accuracy is needed, not to miss the
detection of the desired element on the image;i – the need to find a balance in the accuracy of the interpretation of the results —
minimization of false warnings, but sufficient accuracy is needed, not to miss the
detection of the desired element on the image; – the complexity of the configuration of the IT infrastructure of the solution, especially
in the case of multifunctional use; – the complexity of the configuration of the IT infrastructure of the solution, especially
in the case of multifunctional use; – features of working with medical images: the problem of transparency when
visualizing the location of body organs — special instructions are needed to
determine the location of organs in the image; high image resolution, which can
exceed 100 thousand square pixels and several gigabytes of memory; Научный отдел 228 Научный отдел O. Yu. Iliashenko, E. L. Lukyanchenko. Results Reference model of IT and technological architecture of a medical organization [4] The application layer of the reference model is represented by a set of information
systems used by a medical organization [13]: The application layer of the reference model is represented by a set of information
systems used by a medical organization [13]: – ERP — used by the organization to manage all types of resources; financial,
operational, strategic, and tactical planning; marketing activities; etc.; – MIS is a medical information system, used in work with patients to automate
document flow, maintain electronic medical records, store and analyze clinical trials,
manage bed funds, etc.; – BI system in a medical organization is used for advanced analytics, predictive
analytics and forecasting, visualization of the results. Based on the reference architecture from [4], the authors propose a model of IT
and technological architecture of a medical organization that uses computer vision
technologies (Fig. 3). Based on the reference architecture from [4], the authors propose a model of IT
and technological architecture of a medical organization that uses computer vision
technologies (Fig. 3). Информатика 229 Изв. Сарат. ун-та. Нов. сер. Сер.: Математика. Механика. Информатика. 2022. Т. 22, вып. 2 Fig. 3. Proposed model of IT and technological architecture for a medical organization using
computer vision technology in its activities
The architecture model proposed by the authors consists of the following elements Fig. 3. Proposed model of IT and technological architecture for a medical organization using
computer vision technology in its activities The architecture model proposed by the authors consists of the following elements
depicted on the technology layer: – a server cluster located in the cloud infrastructure. The choice was made in favor of
cloud technologies since training and testing machine learning algorithms requires
large amounts of data and infrastructure flexibility [14]. For a medical organization,
it will be more profitable and more convenient to use cloud resources, rather than
maintain its own hardware infrastructure; – in the cloud infrastructure, there is a LAN network, in which servers for the
operation of MIS and BI systems, and software for the implementation of computer
vision are located. The ERP system is not reflected in this diagram, since it is not
directly related to the use of machine learning in the situation considered by the
authors. Nevertheless, the ERP system of a medical organization can and should
be used for more efficient business and resource management; – load Balancer, an application that balances the load on servers to increase their
performance and fault tolerance, has been added to the diagram in the cloud
infrastructure. In addition, since the organization has to deal with medical data, a
secure VPN connection to avoid leakage of especially sensitive data is provided; – the diagram shows medical equipment that provides visual information for the use
of machine learning. The type of equipment depends on the requirements and work
of the medical organization: it can be either an X-ray machine or an MRI machine
that is already available in the clinic, or cameras and sensors that are not used in
traditional procedures. The application layer has undergone changes in the part of Medical Equipment
Software — it is presented by the use of software for the implementation of computer
vision technology. As the deep learning model is trained on the provided medical data, Научный отдел Научный отдел 230 O. Yu. Iliashenko, E. L. Lukyanchenko. Информатика Possibilities of using computer vision for data analytics it will not be able to access the server and the database, but offer its opinion to the
attending physician directly using the software on the application layer. Thus, the proposed architecture can be used to implement computer vision technology
in the work of medical clinics if they are ready to incur financial, time, and resource costs. The use of computer vision will relieve the medical staff, providing them with more time
for important actions; will increase the accuracy of diagnosis and treatment prescription,
which will affect the patient’s attitude and loyalty to this medical institution [15]. The
use of machine learning algorithms will reduce mortality in intensive care units and
predict the deterioration of the patient’s condition. All these advantages are especially
relevant in our time since we see the impact of the SARS-CoV-2 pandemic on healthcare
institutions around the world: the load on bed funds and medical personnel at the peak
of the incidence rate was so high that it was not possible to provide adequate and
high-quality medical care. Despite the fact that the use of computer vision in medicine is a promising direction,
in the field of medical imaging, some difficulties hinder the scaling of such solutions [16]. Firstly, testing the concept and conducting research, and introducing it into the work of
the clinic, is characterized by high financial and time costs and requires the involvement
of highly qualified specialists, which not many medical institutions can do. In addition,
collecting data for training and testing a system can be time-consuming and expensive,
as a particularly large volume of medical data is required, which must be collected,
stored, protected, and anonymized. The introduction of a new medical practice requires mandatory validation and
certification, which is also costly for a medical institution both in terms of time and
finances. Finally, compliance with international and local laws, policies, and practices is
required, which can be a deterrent to implementation. At the same time, integrating new
services with traditional research, familiar to patients, can be expensive and difficult,
and the likelihood of sabotaging and ignoring the latest services using AI technology by
patients of a medical institution is very high. Ilin I. V., Lepekhin A. A., Ershova A. S., Borremans A. D. IT and technological architect Conclusion In this paper, the main areas of artificial intelligence are considered, the prerequisites
for the popularization of machine learning and computer vision in the field of medicine
are determined, and the areas of application of computer vision in medicine are considered. The authors studied the reference model based on the source [4], and proposed a modified
model of IT and technological architecture of a modern medical organization, using
computer vision algorithms in its work. The article briefly described the advantages and
possible difficulties that may prevent the introduction of computer vision into the main
processes of hospitals. References
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5157020 Поступила в редакцию / Received 25.11.2021 Принята к публикации / Accepted 27.12.2021 232 Научный отдел Научный отдел
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&lt;i&gt;Trichodesmium&lt;/i&gt; physiological ecology and phosphate reduction in the western Tropical South Pacific
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WP 042155018 Ppm Planktothrix agardhii
Q84G06 PphA Variovorax
WP 054215137 Ppm Actinobacteria bacterium
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WP 024094158 PphA Paenibacillus larvae
P33182 Ppm Tetrahymena pyriformis
P29247 Ppm Streptomyces hygroscopicus
WP 003988636 Ppm Streptomyces viridochromogenes
WP 070393116 Ppm Moorea producens
NATL scaffold 145228 1
WP 083624119 Ppm Planktothrix serta
OUTPACE Trichodesmium scaffold 3391 1
NATL scaffold 44888 2
NATL scaffold 7659 3
WP 036654131 Ppm Paenibacillus larvae
WP 003474429 Ppm Gracilibacillus halophilus
OUTPACE microbiome scaffold 53475 1
P56839 Ppm Mytilus edulis
O86937 Ppm Streptomyces
WP 066506643 Ppm Clostridiales bacterium
A0A0M3WN97 BcpB Streptomyces hygroscopicus
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WP 045869133 Ppm Tolypothrix sp.
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Q84G06 PphA Variovorax
WP 054215137 Ppm Actinobacteria bacterium
NATL scaffold 997 9
WP 024094158 PphA Paenibacillus larvae
P33182 Ppm Tetrahymena pyriformis
P29247 Ppm Streptomyces hygroscopicus
WP 003988636 Ppm Streptomyces viridochromogenes
WP 070393116 Ppm Moorea producens
NATL scaffold 145228 1
WP 083624119 Ppm Planktothrix serta
OUTPACE Trichodesmium scaffold 3391 1
NATL scaffold 44888 2
NATL scaffold 7659 3
WP 036654131 Ppm Paenibacillus larvae
WP 003474429 Ppm Gracilibacillus halophilus
OUTPACE microbiome scaffold 53475 1
P56839 Ppm Mytilus edulis
O86937 Ppm Streptomyces
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In silico Analyses of Skin and Peripheral Blood Transcriptional Data in Cutaneous Lupus Reveals CCR2-A Novel Potential Therapeutic Target
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In silico Analyses of Skin and
Peripheral Blood Transcriptional Data
in Cutaneous Lupus Reveals CCR2-A
Novel Potential Therapeutic Target Cutaneous lesions feature prominently in lupus erythematosus (LE). Yet lupus and its
cutaneous manifestations exhibit extraordinary clinical heterogeneity, making it imperative
to stratify patients with varying organ involvement based on molecular criteria that
may be of clinical value. We conducted several in silico bioinformatics-based analyses
integrating chronic cutaneous lupus erythematosus (CCLE)-skin and blood expression
profiles to provide novel insights into disease mechanisms and potential future therapy. In addition to substantiating well-known prominent apoptosis and interferon related
response in both tissue environments, the overrepresentation of GO categories in the
datasets, in the context of existing literature, led us to model a “disease road-map”
demonstrating a coordinated orchestration of the autoimmune response in CCLE
reflected in three phases: (1) initiation, (2) amplification, and (3) target damage in skin. Within this framework, we undertook in silico interactome analyses to identify significantly
“over-connected” genes that are potential key functional players in the metabolic
reprogramming associated with skin pathology in CCLE. Furthermore, overlapping and
distinct transcriptional “hot spots” within CCLE skin and blood expression profiles
mapping to specified chromosomal locations offer selected targets for identifying
disease-risk genes. Lastly, we used a novel in silico approach to prioritize the receptor
protein CCR2, whose expression level in CCLE tissues was validated by qPCR analysis,
and suggest it as a drug target for use in future potential CCLE therapy. Edited by:
Katja Bieber,
Universität zu Lübeck, Germany Reviewed by:
Carlo Riccardi,
University of Perugia, Italy
Claudia Günther,
University Hospital Carl Gustav Carus,
Germany *Correspondence:
Rama Dey-Rao
dey@buffalo.edu
Animesh A. Sinha
aasinha@buffalo.edu *Correspondence:
Rama Dey-Rao
dey@buffalo.edu
Animesh A. Sinha
aasinha@buffalo.edu *Correspondence:
Rama Dey-Rao
dey@buffalo.edu
Animesh A. Sinha
aasinha@buffalo.edu Specialty section:
This article was submitted to
Autoimmune and Autoinflammatory
Disorders,
a section of the journal
Frontiers in Immunology
Received: 22 October 2018
Accepted: 08 March 2019
Published: 29 March 2019 Specialty section:
This article was submitted to
Autoimmune and Autoinflammatory
Disorders,
a section of the journal
Frontiers in Immunology Keywords: CCLE, cutaneous lupus, skin, autoimmune, therapeutic, bioinformatics, expression profiles Keywords: CCLE, cutaneous lupus, skin, autoimmune, therapeutic, bioinformatics, expression profiles INTRODUCTION Lupus erythematosus (LE) is a complex (1) autoimmune disease that spans a tremendous variety
of forms, degrees, and phenotype expressions ranging from relatively well-defined cutaneous
manifestations to a rapidly progressive, lethal, multi-organ involvement in the systemic disease
(SLE) (2, 3). Cutaneous features represent a major and medically significant component of LE
and are evidenced as a wide range of clinical manifestations, some of which are disfiguring and
debilitating. CCLE, which encompasses discoid lupus erythematosus (DLE), represents the most
common category of cutaneous lupus erythematosus (CLE). While it is clear that CLE pathogenesis
is multifactorial, with distinct roles for genetic, environmental, immunologic as well as epigenetic
factors, large gaps in knowledge remain regarding the exact causes, mechanisms and biological ORIGINAL RESEARCH
published: 29 March 2019
doi: 10.3389/fimmu.2019.00640 Abbreviations: C/C/LE, chronic/cutaneous/lupus erythematosus; SLE, systemic
lupus erythematosus; DLE, Discoid lupus erythematosus; HLA, human leukocyte
antigen; DEGs, differentially expressed genes; DAVID, Database for Annotation,
Visualization and Integrated Discovery; MHC, major histocompatibility complex;
DC, dendritic cells; IFN, interferon; CTL, cytotoxic T-lymphocytes; IC, immune
complex, GO, gene ontology; FC, fold change, NF-kB, nuclear factor kappa-
light-chain-enhancer of activated B cells; qPCR/RT-qPCR, quantitative polymerase
chain reaction/ real-time quantitative polymerase chain reaction. Differentially Expressed Genes (DEGs) y
p
(
)
For the present study, we re-analyzed the CCLE-blood expression
dataset to define a new DEGs list based on statistical criteria
identical to our previously published CCLE-skin (21) thus
allowing a more direct comparison. Briefly, we controlled the p-
value at ≤0.05 and fold change (FC) ≥±1.1 and identified 783
non-redundant CCLE- peripheral blood DEGs (337 UP and 446
DOWN), that distinguished patients from healthy controls. The
low FC cut offwas chosen for this study because: (1) minimal
expression differences may be biologically significant (27) and (2)
it allowed us to start with a larger pool of significant genes from
both transcriptional profiles with which to perform downstream
statistical analyses with high stringencies, in order to streamline
our search to only “over-connected” DEGs. g
p
In the present study, gene enrichment analyses of the CCLE
skin and blood transcriptional datasets were conducted to
illuminate shared, over-represented, disease-related pathways
and processes across both tissue environments. Our findings
corroborate
the
involvement
of
a
generalized
immune
dysregulation and altered apoptosis as central drivers of the
cutaneous lupus phenotypes (21, 22). Through our integrative
analytical approach we propose a detailed “disease road-map”
tethered upon functional enrichments that illuminate a potential
orchestration from initiation, amplification to tissue targeting in
skin as linked steps in the autoimmune response of CCLE. This
framework allowed us to assign existing and emerging therapies
within the “disease road-map” based on mechanism of action
of specific medications. In silico based interactome analysis
identified 3 “over-connected” genes as potential key functional
players in the metabolic reprogramming associated with skin
pathology in CCLE. Subsequently, drug target analyses allowed
us to narrow the search and prioritize CCR2 as the druggable
target receptor that needs further research to test viability in
potential future disease therapy. Bioinformatics tools in DAVID (28), (https://david.ncifcrf. gov/) and MetaCoreTM v6.21 (Thomson Reuters, St Joseph, MI)
were used (http://www.genego.com) to analyze and compare the
two gene expression profiles (29). Unique gene symbols from
the DEGs lists were mapped to “network objects” and used to
probe the MetaCore database (metabase) (30). Using the disease
terms “lupus” or “cutaneous lupus” we were able to generate
and analyze several disease–associated canonical pathway maps
followed by similar investigations in the Gene Ontology (GO)
and KEGG databases. This allowed us to dissect each known
overlapping disease-related biological pathway/process between
the two tissue environments. Differentially Expressed Genes (DEGs) We compiled lists of interferon (IFN) inducible genes and
those linked to apoptosis related pathways as described earlier
(22). We also consolidated one hundred and five potential
SLE susceptibility loci from genome–wide association studies
(GWAS) recorded (31–44) in the National Human Genome
Research Institute (NHGRI-EBI) catalog (http://www.ebi.ac.uk/
gwas/search?query=lupus) and the SLEGEN study as well as
susceptibility loci for CLE in a recent GWAS study (16)
for comparison. Citation: Thus, an enhanced understanding of the
molecular and genetic basis of disease is a requisite to advance
the search for novel therapeutic targets, particularly those that are
more targeted and even personalized. Citation: Dey-Rao R and Sinha AA (2019) In
silico Analyses of Skin and Peripheral
Blood Transcriptional Data in
Cutaneous Lupus Reveals CCR2-A
Novel Potential Therapeutic Target. Front. Immunol. 10:640. doi: 10.3389/fimmu.2019.00640 March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 1 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha interactions leading to the development of autoimmune attack
on the skin. A number of trigger factors have been reported to
influence the course and prognosis of cutaneous lupus including,
UV light, medication, and smoking. Additional factors such as
race, sex, age of onset and genetic predisposition, among others
also impact disease manifestation (4–9). Although susceptibility
to CCLE has been linked to genes within the HLA (HLA-DQ
and/or DR), as well as outside the HLA region (HSP70-1, TNF–
α/β, C4 null, C2, IL-1, and IL10) (10–19) the molecular and
genetic basis of disease initiation, progression, and response to
treatment is poorly understood. interactions leading to the development of autoimmune attack
on the skin. A number of trigger factors have been reported to
influence the course and prognosis of cutaneous lupus including,
UV light, medication, and smoking. Additional factors such as
race, sex, age of onset and genetic predisposition, among others
also impact disease manifestation (4–9). Although susceptibility
to CCLE has been linked to genes within the HLA (HLA-DQ
and/or DR), as well as outside the HLA region (HSP70-1, TNF–
α/β, C4 null, C2, IL-1, and IL10) (10–19) the molecular and
genetic basis of disease initiation, progression, and response to
treatment is poorly understood. used by any of the patients for 2 months prior to sampling. The procedures for blood and tissue handling, peripheral blood
mononuclear cell extractions, total RNA preparation, cDNA
synthesis and microarray processing have also been described
previously (21, 22, 25, 26). The transcriptional data analyzed
was from skin of 6 lesional and 4 non-lesional biopsies from
patients with CCLE and blood from 3 CCLE patients and 3
healthy controls. There was an overlap of 2 patients (1008 and
1009) between blood and skin analysis. The range of sample size
reflects the limited human samples that were available for the rare
autoimmune disorder CCLE/DLE. In large part due to the gap in knowledge regarding disease
susceptibility and pathomechanisms, the current therapeutic
armamentum in cutaneous LE does not include any approved
systemic drugs (20) and needs to be empirically determined for
individual patients. MATERIALS AND METHODS Recruitment of CCLE/CLE (more specifically the most common
subtype, discoid LE DLE), age- and sex-matched patients, and
healthy control individuals, tissue procurement and handling
has been described in detail along with IRB approval number,
consent, demographic data and raw data in our earlier reports
(21–24). None of the patients were positive for ANA or met any
criteria for SLE. No systemic or topical medications had been The DEG lists were analyzed for their chromosomal
enrichment by leveraging the gene expression data to detect
regions of the chromosomes with a statistically significant
proportion of DEGs (called transcriptional “hot spots”) (45–49). We used DNA–Chip Analyzer (dCHIP) (www.dchip.org) for the
purpose of gene mapping using the “genome” tool with masked
duplicate probe sets. P-value ≤0.001 was calculated for all
stretches of chromosomes (“hot spots”) that contained ≥5 DEGs
(CCLE-blood DEGs used for this analysis) (50). We overlaid a
similar map generated from our previous site-matched lesional March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 2 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha vs. non-lesional skin analysis (from CCLE patients) (21) on the
CCLE –blood chromosomal map. We explored the overlapping
and unique genes that were significantly associated or not with
systemic or cutaneous disease in previous gene expression and
GWAS studies. transcriptional profiles. Finally, we were able to prioritize one
DEG CCR2 based on several analytical criteria discussed above. Network generating algorithms in MetaCore were based on auto-
expand by one interaction including both up- and downstream
reactions. We further categorized the genes by their association
with SLE-genes (either expressed or as susceptibility loci). A
“drug target analysis” was performed via MetaCore along with a
literature search on all three receptor proteins, to discover novel
drug/target combinations that offer the best potential to be used
in the treatment of CLE. Interactome and Drug Target Analysis g
g
y
We started out with the broadest pool of statistically significant
genes, and subsequently employ downstream bioinformatics-
based statistical tools with high stringency to assign disease
relevance. To go beyond simply cataloging disease-related
molecules we subjected our DEGs from CCLE skin and blood
to an interactome analysis by protein function” (52). The
relative connectivity of a gene (encoded protein) mirrors its
functional significance to the disease under investigation (53)
and is calculated by the number of interactions between the
experimental gene with the genes on the experimental list
normalized to the number of interactions it has with all genes in
the human database (in MetaCore). The ranking of importance
is related to the “knowledge based” analysis that takes into
consideration experimental DEGs in the context of their known
interactions in complex gene/protein and molecular networks. The localization of receptors in membranes that allows the
extracellular domains to be targeted by specific ligands and
drugs was key to narrowing the search to the “over-connected”
3 receptors that were shared between the skin and blood Quantifying Gene Expression
Using RT-qPCR Total RNA was isolated as described previously (22, 26)
using TRIzol reagent (Invitrogen, San Diego, CA, USA) per
manufacturer’s protocol and treated with DNase, purified
and quantified by Nanodrop ND-1000. We used reverse
transcription quantitative real-time PCR (RT-qPCR) to quantify
gene expression from peripheral blood of an entirely different
set of 5 CCLE patients (LE 1013, 1014, 1016, 1017, and
1018) and 5 healthy controls (CR, 221, 220, 231, 1042,
and 1032). cDNA was synthesized from 400 ng total RNA
using Promega Kit (Promega Corp., Madison, WI, USA) and
quantitative real-time PCR was subsequently carried out using
the FastStart Universal SYBR Green Master (ROX) from Roche
(Roche Diagnostics,Mannheim, Germany) according to carefully
standardized protocols. Intron-spanning primers were designed
using Primer3 v. 4.0.0 (http://bioinfo.ut.ee/primer3/) for the
following selected DEGs: CCR2, IFI30, OAS1, OAS2, STAT1
TNFAIP3, ERBB3, and FGFR2, based on published human
gene sequences in the Ensemble Genome Browser (http://useast. ensembl.org/index.html). Primers were checked with a BLAT
search (http://genome.ucsc.edu/cgi-bin/hgBlat). Amplicons were
designed to be <150 bp in most cases (Table 1). Duplicate
experiments were run for the 5 biological replicates in each of the
patient and control group. The resulting qPCR cycle times (Ct)
were normalized against the β-actin (ACTB) housekeeping gene
to obtain 1Ct. Fold changes in expression were calculated using
the 2−11Ct method (51) relative to one control sample taken as
unity (Figure 6). The fold changes in gene expression obtained by
qPCR were compared to those observed by microarray analysis. in the treatment of CLE. RESULTS
Differentially Expressed Genes (DEGs) and
Ontology Enrichment Analysis
We
generated
a
blood
gene
expression
profile
of
783
non-redundant DEGs (Supplementary Table 1) for comparison
with the skin profile (776 DEGs) described previously (21). Both
FIGURE 1 | Gene expression analysis in CCLE blood and lesional skin. (A)
Differentially expressed genes (DEGs) were generated from blood (CCLE vs. healthy control) and skin (lesional vs. non-lesional) of CCLE patients and
healthy controls that were able to distinguish between compared phenotypes
via hierarchical clustering. (B) An overlap of 11% (87 DEGs) between the two
lists is shown by the Venn diagram. The majority of genes in both lists are
distinct to the respective environment (skin and blood) from which they are
generated. Differentially Expressed Genes (DEGs) and
Ontology Enrichment Analysis Differentially Expressed Genes (DEGs) and
Ontology Enrichment Analysis gy
y
We
generated
a
blood
gene
expression
profile
of
783
non-redundant DEGs (Supplementary Table 1) for comparison
with the skin profile (776 DEGs) described previously (21). Both Frontiers in Immunology | www.frontiersin.org FIGURE 1 | Gene expression analysis in CCLE blood and lesional skin. (A)
Differentially expressed genes (DEGs) were generated from blood (CCLE vs. healthy control) and skin (lesional vs. non-lesional) of CCLE patients and
healthy controls that were able to distinguish between compared phenotypes
via hierarchical clustering. (B) An overlap of 11% (87 DEGs) between the two
lists is shown by the Venn diagram. The majority of genes in both lists are
distinct to the respective environment (skin and blood) from which they are
generated. March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 3 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha DEGs shared between blood and skin that are statistically “over-
connected” to objects within the two CCLE datasets as well as the
larger human database in MetaCore (Supplementary Table 6). Three (CCR2, ERBB3, and FGFR2) of the seven “over-connected”
shared DEGs coding for receptor proteins (localized at the cell
membrane) were selected for further investigations. All three
were found to be interactive hubs by interactome and network
analysis (Figure 5). A literature- and Metabase- search with the
term “discoid lupus erythematosus” allowed an investigation
into existing as well as emerging therapies in CLE/DLE. A drug
analysis on all three receptors revealed CCR2 to be targeted
by drugs that are currently in clinical trials for treatment of
other related diseases. see Supplementary Table 7 for a list
of existing, emerging, and experimental as well as the newly
proposed therapeutic agents, along with relevant literature and
source documentation. lists were generated using the same fold change and p-value
cut off(Figure 1A). Of the 87 DEGs (Figure 1B) common
between the blood and skin transcriptional profiles, 65 were
dysregulated in the same direction in both tissues (upregulated
= UP or down-regulated = DOWN) and 22 were in the opposite
direction (Supplementary Table 2). Validation Studies We further evaluated the expression of 8 genes shown to be
dysregulated by microarray analysis in CCLE/DLE by RT-qPCR
(qPCR) (Table 1 and Figure 6). Included among the 8 was CCR2,
which we propose as a potential drug target in CCLE therapy. The
qPCR experiments demonstrate a relative level of gene expression
consistent with our microarray data for all eight DEGs. Genes
such as CCR2, IFI30, OAS1, OAS2, and STAT1 and TNFAIP3 are
over-expressed in CCLE/DLE patients as compared to healthy
controls. While ERBB3 and FGFR2 exhibited overall low levels of
expression, the trend in downward expression (case vs. controls)
was also similar to our microarray analysis. Integration
and
synthesis
of
CCLE
blood
and
skin
transcriptional data in the context of existing literature
regarding SLE/CCLE-related processes suggests a coordinated
orchestration of the autoimmune response leading to organ-
specific tissue damage in the skin that can be viewed in 3 phases:
(1) initiation, (2) amplification of immune response, and (3)
target damage in skin (Figure 3). DISCUSSION We leveraged the blood transcriptional profile to locate genomic
regions in which the 783 CCLE-DEGs cluster more frequently
than would be expected by chance.(47, 49) 16 transcriptional “hot
spots” were identified on chromosomes 1, 3, 5, 6, 11 (2), 12 (2), 14,
15, 16, 19, 20, 21, 22, and X, harboring 177 CCLE-blood DEGs. We had previously described 13 CCLE-skin specific “hot spots”
on chromosomes (21). Seven transcriptionally active regions
(chromosome 1, 3, 6, 11, 19, 22, and X) overlapped between
skin and blood profiles (Figure 4A). Twelve dysregulated genes
including AIM2, ANP32E, CD48, EFNA1, CCR2, CAP2, PSMB8,
FEN1, ECH1, LGALS2, TST, and APOBEC3G were common to
skin and blood within the overlapping “hot spots” (Figure 4B). See Supplementary Table 3 for details on the 177 DEGs
contained within the sixteen CCLE-blood “hot spots.” Development of a Disease Roadmap
Our new in silico analyses reveal a more enhanced composite of
disease pathomechanisms operative in CCLE. In the proposed
disease road-map schema (Figure 3), the three phases are
not necessarily mutually exclusive, with specific components
potentially operative in two, or all three phases across the
spectrum. Below, we break down the three broad phases: (1)
initiation, (2) amplification, (3) target damage, and dissect the
linked disease relevant biological pathway/process (Figure 2) to
discuss a model for pathobiology in the context of recognized
systemic (blood) and local (skin) disturbances. Enrichment Analyses Ontology enrichment analysis was processed through two
different analytical platforms (DAVID and MetaCore) to identify
enriched disease-related biological functions, pathways and
processes. We uncovered prominent apoptotic and type I
interferon (IFN) signatures in both tissue environments. The
overall number of DEGs in the activated immune response
related pathways and processes are consistently higher in
lesional skin than in peripheral blood. However, processes
associated with lysome/proteasome related breakdown were
more pronounced in peripheral blood than in skin. The
differences and similarities in the two tissue environments forms
the basis of our present analysis aimed at elucidating specific local
and systemic disturbances linked to pathomechanisms related to
CCLE (Figure 2). Frontiers in Immunology | www.frontiersin.org Apoptosis numbers of upregulated DEGs (93%) associated with cytokine-
chemokine related processes in lesional skin as opposed to blood
(70% DOWN), perhaps reflecting an influx of cytokine producing
cells at the local site of pathology. This may be particularly
important as these mediators are short lived and local effects
could be tissue specific and different from systemic effects (74). The potential significance of apoptosis in CLE is underscored by
several observations including an increase in the number of UV
induced apoptotic keratinocytes found in lesional skin (54, 67). In our analysis, a larger number of dysregulated genes were
associated with apoptosis in lesional skin (117 with 75% UP) as
compared to peripheral blood (81 with 61% UP), emphasizing
enhanced apoptosis (particularly in the skin) as a prominent
signature of the disease. Both pro- and anti-apoptotic molecules
are dysregulated simultaneously in both environments (21, 22),
underscoring the complex and epistatic nature of the apoptotic
cascade. It might also indicate redundancies of contributors to
apoptosis, perhaps including involvement of diverse cell types
(e.g., keratinocytes and lymphocytes) relevant to lupus pathology. Amplification of Immune Response p
p
CCLE is characterized by an increase in local mediators
of inflammation in the skin. These effects in turn induce
changes which include induction of adhesion molecules that
are needed for the migration and sequestration of activated
lymphocytes and leukocytes to the skin (76). Accumulating
apoptotic debris may also bolster autoantigen presentation
by
Langerhans
cells
(LCs)
to
T
cells
(77). Binding
of
autoantibodies to keratinocytes could then further expose
self-antigens
and
promote
cytokine
release
to
continue
and amplify the autoimmune response. T cell reactivity
may in turn promote B cell activation and production Pattern Recognition Receptor
(PRR) Signaling We discovered 19 genes (100% UP) related to PRR to be activated
in lesional skin, as opposed to 7 (71% UP) in peripheral blood. Upregulation of TLR-4 expression was previously demonstrated
in affected tissue of CLE patients (75). PRRs participate in the
recognition of both extrinsic and endogenous danger-associated
conserved molecular patterns, and thus bridge innate and
adaptive immune responses. Initiation Several well-known trigger factors e.g., UV light, medications,
smoking are associated with cutaneous lupus (4, 9, 54–57),
all of which could contribute to enhanced autoantigen display
to the immune system. Theoretically, this could occur via
increased keratinocyte apoptosis, autoantigen translocation to
the keratinocyte cell surface, and/or a decreased clearance
of apoptotic debris as in SLE (58), causing self-antigens
(e.g., nucleosomes) to persist in the extracellular environment,
enabling recognition by autoreactive cells (59–65). The skin has
been speculated to be the site of autoimmune initiation for
both cutaneous and systemic disease in genetically susceptible
individuals (56, 57, 66). Identification of a Novel Therapeutic Target
Using our transcriptional datasets, CCLE-specific gene regulation
was evaluated through enrichment by “protein function”
revealing a significantly high number of ligands, proteases,
receptors and other protein classes (Supplementary Table 4). Overall interaction topology reveals a high level of incoming
and outgoing connections within the CCLE-experimental dataset
as well as to and from the CCLE-datasets to the metabase
(Supplementary Table 5). We leveraged our expression dataset to search for key drivers
of mechanisms underlying CCLE pathogenesis. We reveal 44 March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 4 Dey-Rao and Sinha
Interactome Analysis: Cutaneous Lupus
FIGURE 2 | Functional annotation and pathway analysis of the DEGs from CCLE-blood and lesional skin. The two transcriptional profiles reveal several enriched
disease-related Gene Ontology (GO) biological processes. We break down the number of DEGs (up- and down-regulated) included in some of the shared disease
related processes such as: apoptosis, oxidation: reduction, cytokine chemokine, leukocyte chemotaxis, TLR signaling, cell adhesion, dendritic cells, T cell, B cell, type
I interferon, NK cells and lysosome/proteasome. The most prominent signatures for interferon and apoptosis in both profiles are marked with a star (*). Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha FIGURE 2 | Functional annotation and pathway analysis of the DEGs from CCLE-blood and lesional skin. The two transcriptional profiles reveal several enriched
disease-related Gene Ontology (GO) biological processes. We break down the number of DEGs (up- and down-regulated) included in some of the shared disease
related processes such as: apoptosis, oxidation: reduction, cytokine chemokine, leukocyte chemotaxis, TLR signaling, cell adhesion, dendritic cells, T cell, B cell, type
I interferon, NK cells and lysosome/proteasome. The most prominent signatures for interferon and apoptosis in both profiles are marked with a star (*). Oxidation: Reduction Increased upregulation (71% of the 28 DEGs) in oxidative and
nitrosative stress related processes in CCLE peripheral blood
demonstrated in our dataset is similar to past observations in
both SLE and CLE (68–71), underscoring the possibility of post-
translational modification of auto-proteins/peptides, rendering
them altered and able to provoke the autoimmune reaction. HLA Region Progression of lupus is facilitated by the local generation
of
adhesion
molecules
and
expression
of
their
ligands
in inflammatory cells (78, 79). In the present study, we
demonstrate nearly equal numbers of dysregulated genes
linked to cell adhesion in both skin and blood, but observe
59% UP in lesional skin as compared to 76% DOWN in
peripheral blood. CLE susceptibility (in patients positive for anti-Ro) is linked to
the major histocompatibility complex (MHC) on chromosome
6, including genes for human leukocyte antigens (HLA),
complement components, and tumor necrosis factor (TNF)
(12, 21, 82–84). We found the top enriched KEGG pathway
associated with the 87 DEGs overlapping between CCLE-skin
and blood profiles to be antigen processing and presentation
(Supplementary Table 8) skewed toward activation in both skin
(92% UP) and blood (79% UP). Of the twelve DEGs mapping
to chromosome 6, CSNK2B, and CDKN1A are reported as
potential CLE-associated susceptibility locus (16) and associated
with SLE (85), respectively (Supplementary Table 3). The precise
influence of the HLA region on CCLE is not clear as of yet, but is of
autoantibodies
specific
to
previously
sequestered
or
altered molecules. of
autoantibodies
specific
to
previously
sequestered
or
altered molecules. Cytokines, Chemokine, and
Leukocyte Chemotaxis UV radiation is known to induce the production of numerous
pro-inflammatory cytokines in the skin and contributes to the
marked photosensitivity observed in CCLE (56, 72). These
cytokines can promote translocation of intracellular autoantigens
to the surface of epidermal keratinocytes (13, 73). We find higher March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 5 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha FIGURE 3 | Disease Road Map. Enriched disease-related pathways and processes found in skin and blood profiles underlie three distinct phases in the autoimmune
response in CCLE: (i) initiation, (ii) amplification of the immune response, and (iii) target damage in the skin, that are not mutually exclusive. The shared disease-related
processes over-represented in skin and blood are as follows: apoptosis, oxidation reduction, cell adhesion, cytokine chemokine activity, leukocyte chemotaxis, NK
cell, TLR signaling, dendritic cells, T cell, B cell activation, Interferon signature, lysosome and proteasome, antigen processing and presentation, complement cascade
among others (see also Figure 2). Potential molecular targets of some of the existing and emerging drugs R (n) have been identified in the schematic according to
mechanism of action presently used for CLE/DLE treatment. Some experimental drugs have also been included (see inserted box). Drugs used in CLE/DLE treatment
R(n) (teal hexagons): Topical agents: R1 = corticosteroids fluocinonide, R-salbutamol sulfate (anti-inflammatory, acting upon cytokines and leukocytes) Systemic
agents: R1 = glucocorticoids, R2 = hydroxychloroquine (antimalarial) (acting upon MHC presentation and lysosome pH, anti-inflammatory), R3 = thalidomide,
lenalidomide, CC 11050 (TNF-α inhibitors, apoptosis), R4 = methotrexate MTX (acts on T cell proliferation), R5 = pimecrolimus (calcineurin inhibitor, down-regulating
T cell activity) TRX-1, AMG 557 (humanized mAbs act as T cell regulators), R6 = humanized mAbs AMG 811 (anti-IFNα) and sirukumab (acts on pro-inflammatory
cytokines such as IL-6). Ds, double stranded; UV, ultraviolet; PAMP, pathogen–associated molecular pattern; HMGB1, high mobility group protein B1; ICs, nucleic
acid containing immune complexes; NMDAR, N-methyl-D-aspartate receptor; C1q, complement component 1; q subcomponent; C2, complement component 2; C4,
complement component 4; DC, dendritic cells; pDC, plasmacytoid DC; LC, Langerhans cells; T, T cells; B, B cells; Th, T helper cells; Th0, T helper cells 0; CTL,
cytotoxic T lymphocytes; IgG, immunoglobulin G; NK, natural killer cells; IFN, interferon; TLR, toll-like receptor; PDE4, phosphodiesterase-4; TNF, tumor necrosis
factor. FIGURE 3 | Disease Road Map. Cytokines, Chemokine, and
Leukocyte Chemotaxis Enriched disease-related pathways and processes found in skin and blood profiles underlie three distinct phases in the autoimmune
response in CCLE: (i) initiation, (ii) amplification of the immune response, and (iii) target damage in the skin, that are not mutually exclusive. The shared disease-related
processes over-represented in skin and blood are as follows: apoptosis, oxidation reduction, cell adhesion, cytokine chemokine activity, leukocyte chemotaxis, NK
cell, TLR signaling, dendritic cells, T cell, B cell activation, Interferon signature, lysosome and proteasome, antigen processing and presentation, complement cascade
among others (see also Figure 2). Potential molecular targets of some of the existing and emerging drugs R (n) have been identified in the schematic according to
mechanism of action presently used for CLE/DLE treatment. Some experimental drugs have also been included (see inserted box). Drugs used in CLE/DLE treatment
R(n) (teal hexagons): Topical agents: R1 = corticosteroids fluocinonide, R-salbutamol sulfate (anti-inflammatory, acting upon cytokines and leukocytes) Systemic
agents: R1 = glucocorticoids, R2 = hydroxychloroquine (antimalarial) (acting upon MHC presentation and lysosome pH, anti-inflammatory), R3 = thalidomide,
lenalidomide, CC 11050 (TNF-α inhibitors, apoptosis), R4 = methotrexate MTX (acts on T cell proliferation), R5 = pimecrolimus (calcineurin inhibitor, down-regulating
T cell activity) TRX-1, AMG 557 (humanized mAbs act as T cell regulators), R6 = humanized mAbs AMG 811 (anti-IFNα) and sirukumab (acts on pro-inflammatory
cytokines such as IL-6). Ds, double stranded; UV, ultraviolet; PAMP, pathogen–associated molecular pattern; HMGB1, high mobility group protein B1; ICs, nucleic
acid containing immune complexes; NMDAR, N-methyl-D-aspartate receptor; C1q, complement component 1; q subcomponent; C2, complement component 2; C4,
complement component 4; DC, dendritic cells; pDC, plasmacytoid DC; LC, Langerhans cells; T, T cells; B, B cells; Th, T helper cells; Th0, T helper cells 0; CTL,
cytotoxic T lymphocytes; IgG, immunoglobulin G; NK, natural killer cells; IFN, interferon; TLR, toll-like receptor; PDE4, phosphodiesterase-4; TNF, tumor necrosis
factor. DEGs (63% DOWN) in the peripheral blood, underscoring clear
patho-mechanistic differences in the two environments. Frontiers in Immunology | www.frontiersin.org Dendritic Cells (DC) Thirteen “hot spots” associated with CCLE lesional skin signature
(blue boxes) from our previous study, have been overlaid on the blood chromosomal map revealing seven regions of overlap (bold). (B) Twelve genes in the
overlapping “hot spots” (including CCR2) were shared between the skin and blood profiles. The seven overlapping “hot spots” also include 14 DEGs from skin (blue),
blood (red) and both milieus (purple), which have been previously reported as potential disease loci in SLE. TNF is a skin-DEG that is previously described as a
putative disease locus for both SLE as well as CLE. CSNK2B is a blood-DEG that has been described as a disease locus in CLE. likely related to its well-defined role in antigen presentation and
activation/selection of T cells in the pathogenesis of LE (86–91). amplification of the immune response in CCLE. A prominent
IFN-α signature in dermal lesions of SLE patients, suggests
that the skin acts as a reservoir for IFN producing cells with
the ability to promote autoimmunity (96–98). This appears to
be a central theme in cutaneous lupus as well (99). In this
analysis, we demonstrate a stronger IFN signature in CCLE skin
(that is predominantly upregulated) as compared to peripheral
blood. This may indicate a potential shift in the engagement of
this key cytokine pathway as a pathogenic mediator from the
blood to the skin in CCLE patients. Supplementary Figure 1
demonstrates one such over-represented and activated canonical
pathway linked to IFN signaling, with more upregulated genes
in the skin than from blood. A more comprehensive picture of
the role of various IFN family members in disease pathogenesis
will emerge as detailed demographics such as disease onset, age,
organs involved, and therapy are taken into consideration. Target Damage The pathology in CLE is one of inflammatory lichenoid reaction
in which basal keratinocytes that express surface self-antigens are
the chief center of damage (100). Global gene expression data
revealing dysregulated apoptosis, inflammation, complement
system as well as lysosome and proteasome associated breakdown
processes in skin and blood from CCLE patients serves to support
the model for the creation, accumulation and presentation of Dendritic Cells (DC) Antigen presentation by immature DCs may lead to T cell anergy
due to lack of co-stimulation, a mechanism by which certain
(self) antigens may evade immune responsiveness (80, 81). We
observe much higher numbers of activated genes associated with
skin-dendritic cells (94% UP of 63 DEGs), as compared to only 8 March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 6 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha FIGURE 4 | Chromosomal locations of transcriptional “hot spots” found in CCLE-associated blood and lesional skin signatures. (A) CCLE blood gene expression data
is leveraged to identify transcriptional “hot-spots” in chromosomes where DEGs map with statistically increased frequency. Each horizontal line corresponds to one
chromosome. Chromosomal locations of CCLE blood molecular signature are colored in bold black vertical bars vs. the non-differentially expressed genes which are
gray. The vertical bars above and below the horizontal lines represent genes either on the forward or reverse strand. Sixteen significant stretches at p-value ≤0.001
are considered to be transcriptionally active “hot spots” using the CCLE blood profile (red boxes). Thirteen “hot spots” associated with CCLE lesional skin signature
(blue boxes) from our previous study, have been overlaid on the blood chromosomal map revealing seven regions of overlap (bold). (B) Twelve genes in the
overlapping “hot spots” (including CCR2) were shared between the skin and blood profiles. The seven overlapping “hot spots” also include 14 DEGs from skin (blue),
blood (red) and both milieus (purple), which have been previously reported as potential disease loci in SLE. TNF is a skin-DEG that is previously described as a
putative disease locus for both SLE as well as CLE. CSNK2B is a blood-DEG that has been described as a disease locus in CLE. FIGURE 4 | Chromosomal locations of transcriptional “hot spots” found in CCLE-associated blood and lesional skin signatures. (A) CCLE blood gene expression data
is leveraged to identify transcriptional “hot-spots” in chromosomes where DEGs map with statistically increased frequency. Each horizontal line corresponds to one
chromosome. Chromosomal locations of CCLE blood molecular signature are colored in bold black vertical bars vs. the non-differentially expressed genes which are
gray. The vertical bars above and below the horizontal lines represent genes either on the forward or reverse strand. Sixteen significant stretches at p-value ≤0.001
are considered to be transcriptionally active “hot spots” using the CCLE blood profile (red boxes). T Cell Response Our analysis uncovered 60 DEGs (95% UP) in skin and 18
(56% UP) in blood (Figure 2) that are involved in T cell
related processes such as -activation, -differentiation, -selection,
-proliferation, -receptor signaling and -thymic selection, thus
implicating a similarly activated T cell mediated autoimmune
reaction in CCLE as well. B Cells Although
B
cell
hyperactivity
and
the
production
of
autoantibodies in LE appears to be T cell driven (92, 93),
breaking of B cell tolerance without the support of T cells has
been reported as well (94). Given that 55–75 % of B cell receptors
on human immature B cells are self-reactive, maintenance
of B cell tolerance is vital for thwarting the production of
autoantibodies with potential disease causing specificities (95). We observed 32 DEGs (100% UP) in lesional skin and 13 (62%
UP) in blood associated with B cell antigen receptor engagement. Interferon Cytokines play a crucial role in modulating the immune
response to foreign and self-antigens, both in the initiation and March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 7 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha FIGURE 5 | Interactive receptor proteins CCR2, ERBB3 and FGFR2. (A) We focused on three receptor proteins (CCR2, ERBB3, and FGFR2) that were considered
“over-connected” when the number of observed interactions (actual) was greater than the number of expected interactions accompanied by (significant) low p-values
(*) and high z-scores (B) Algorithms in MetaCore are used to generate networks using the expand by single interaction in both upstream and downstream directions. Interactions within the network reveal all 3 receptors as central hubs connected to each other as well as with a large number of curated interactions with both positive
(green) and negative effect (red) to and from (arrow direction) several objects in the CCLE-skin profile as well the larger human proteome database. The individual
CCLE-DEGs and proteins in the metabase are representated as nodes of different shapes (see legend) with connections/interactions to one another. Drug target
analysis revealed 4 drugs (teal box) that target one of the receptor proteins CCR2, (yellow). All 4 drugs are currently being used in the clinic to treat other closely
related diseases (see Supplementary Table 7). Explanation of columns: Actual, number of network objects in the activated signatures which interact with the chosen
object; n, number of network objects in experimental datasets; R, number of network objects in the activated background list which interact with the chosen object;
N, total number of protein-based objects in the activated background list; Expected, mean of hypergeometric distribution; Ratio, connectivity ratio (Actual/Expected);
z-score, (Actual-Expected)/(standard deviation); p-value: probability to have the value of Actual by chance under null hypothesis of no over-connectivity. Star (*)
denotes significant p-values. FIGURE 5 | Interactive receptor proteins CCR2, ERBB3 and FGFR2. (A) We focused on three receptor proteins (CCR2, ERBB3, and FGFR2) that were considered
“over-connected” when the number of observed interactions (actual) was greater than the number of expected interactions accompanied by (significant) low p-values
(*) and high z-scores (B) Algorithms in MetaCore are used to generate networks using the expand by single interaction in both upstream and downstream directions. Interferon Interactions within the network reveal all 3 receptors as central hubs connected to each other as well as with a large number of curated interactions with both positive
(green) and negative effect (red) to and from (arrow direction) several objects in the CCLE-skin profile as well the larger human proteome database. The individual
CCLE-DEGs and proteins in the metabase are representated as nodes of different shapes (see legend) with connections/interactions to one another. Drug target
analysis revealed 4 drugs (teal box) that target one of the receptor proteins CCR2, (yellow). All 4 drugs are currently being used in the clinic to treat other closely
related diseases (see Supplementary Table 7). Explanation of columns: Actual, number of network objects in the activated signatures which interact with the chosen
object; n, number of network objects in experimental datasets; R, number of network objects in the activated background list which interact with the chosen object;
N, total number of protein-based objects in the activated background list; Expected, mean of hypergeometric distribution; Ratio, connectivity ratio (Actual/Expected);
z-score, (Actual-Expected)/(standard deviation); p-value: probability to have the value of Actual by chance under null hypothesis of no over-connectivity. Star (*)
denotes significant p-values. autoantigens to the immune system to be at the heart of
the disease (101–103). Dysregulated apoptosis and clearance
processes might be significant for both initiating the autoimmune
response as well as for the ultimate damage to the skin,
demonstrating how various phases of the disease might be
mutually non-exclusive. related) and intrinsic pathway (stress related) in blood and skin. An understanding of the molecular events that regulate cell death
at both the skin and systemic level is essential for clarification of
pathogenesis in the disease. In addition to UV induction of apoptosis, cellular cytotoxic
mechanisms involving CTLs, and natural killer (NK) cells have
also been implicated in CLE (4, 104–107). Our analysis finds
several more NK cell associated genes (65 DEGs, mostly UP)
in the CCLE lesional skin than in the blood profile (14 DEGs,
mostly UP), with 7 DEGs shared between the two environments. Inflammatory response also included more activated genes in
the skin (90% of 144 DEGs UP) than in the blood (78% of 14
DEGs UP). Apoptosis/NK Cells and Inflammation The role of defects in the apoptotic pathway has been discussed
previously in the context of disease initiation, but may be relevant
for ultimate target damage as well. Multiple apoptotic pathways
are involved in both CCLE skin and blood. We observed
upregulated markers from both the extrinsic (death receptor March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 8 Dey-Rao and Sinha Interactome Analysis: Cutaneous Lupus FIGURE 6 | Quantifying gene expression by RT-qPCR. Gene expression for the eight DEGs: CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, within
both the CCLE skin and blood signatures were quantified using RT-qPCR. Data is normalized to the housekeeping gene β-actin (ACTB). Fold change in gene
expression in peripheral blood (presented as bar graphs with S.E.M) is calculated using the 2−11Ct method and represent duplicate runs of 5 biological replicates
each of CCLE (DLE)-patients and healthy control individuals. Fold change in expression (between case and controls) of CCR2 and STAT1 trended toward significant
(*p-value = 0.055 and 0.053, respectively). CCLE, chronic cutaneous lupus erythematosus/discoid lupus erythematosus; S.E.M., standard error of the mean. FIGURE 6 | Quantifying gene expression by RT-qPCR. Gene expression for the eight DEGs: CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, within
both the CCLE skin and blood signatures were quantified using RT-qPCR. Data is normalized to the housekeeping gene β-actin (ACTB). Fold change in gene
expression in peripheral blood (presented as bar graphs with S.E.M) is calculated using the 2−11Ct method and represent duplicate runs of 5 biological replicates
each of CCLE (DLE)-patients and healthy control individuals. Fold change in expression (between case and controls) of CCR2 and STAT1 trended toward significant
(*p-value = 0.055 and 0.053, respectively). CCLE, chronic cutaneous lupus erythematosus/discoid lupus erythematosus; S.E.M., standard error of the mean. Complement could lead back to amplification of the immune response and
serve as a feedback mechanism in the disease. The complement cascade is known to be involved in opsonization
of apoptotic cells for efficient clearance by phagocytosis, in the
absence of which apoptotic cells may remain longer in the system
to stimulate autoantibody production (108). This aberration in
the clearing mechanism could be associated with both initiation
as well as the target damage stage of the autoimmune reaction. In the present study, we observe many more dysregulated
genes related to the complement cascade in lesional skin (such
as C2, C1R, C1QB, C3AR1, C4A /// C4B, CD59, CFB, CFD,
ERCC6 /// PGBD3, and ITGB2 among others; 89% UP) than
in blood (C4BPB, CFHR3, FANCC PLAU, IGHG1. and ITGB2;
83% DOWN). Another effect of complement activation can be
apoptosis through cellular events (109), and could be yet another
explanation of the increased apoptosis observed in lesional skin
over blood (described earlier). Overall, our investigations offer a global comprehensive
viewpoint of CCLE-associated transcriptional changes that may
be particularly relevant for understanding disease mechanisms
and identification of biomarkers relevant to disease progression. Genetics We have reported a significant, but not complete overlap
between our CCLE expression data and previously reported SLE
transcriptional data, indicating that while these two conditions
are related, they are also clearly distinct (110). Five of the twelve
shared DEGs (described above) in the overlapping CCLE skin
and blood “hot spot” regions (AIM2, CD48, CCR2, FEN1, and
LGALS2) also overlap with previously reported SLE associated
genes expression or GWAS studies. The remaining seven
common DEGs in the two profiles (ANP32E, EFNA1, CAP2,
PSMB8, ECH1, TST, and APOBEC3G) that do not overlap with
SLE may thus represent CCLE specific genes. CSNK2B (casein
kinase 2, beta polypeptide), in the CCLE-blood “hot spot” within
the MHC region of chromosome 6, and APOC1, mapping to the
“hot spot” on chromosome 19 in CCLE-skin have also previously
been reported as potential gene markers of CLE (16, 111). Frontiers in Immunology | www.frontiersin.org Therapeutic Considerations—Current
and Future Currently, no consensus or evidence based therapeutic regimen
exists for CCLE. Moreover, very few well-controlled trials have
systematically evaluated commonly used treatments for CLE
(114–118). Disease management in CCLE begins with precise
diagnosis and a treatment plan that can only be decided upon
after comprehensive evaluation and recording of patient clinical
and laboratory data. This includes immunological, clinical
presentation, race, sex, age of onset, disease flares history, family
history, past therapy failures, and histopathology of a skin biopsy
among others. Topical
and
systemic
glucocorticoids,
antimalarials,
methotrexate and thalidomide are the standard of care in
SLE, and are used in cutaneous disease as well. All treatments
must be accompanied by intermittent re-evaluation of the
patients to screen disease prognosis. The overall choices in
therapy are discussed very briefly. Tacrolimus (calcineurin inhibitor), may be a good substitute
for those patients who respond poorly to topical corticosteroids
(119). Antimalarial drugs (oral) such as chloroquine and
quinacrine are also considered the first line of systemic CLE
therapy (120–122). In refractory CLE that does not respond
well to antimalarial therapy, the addition of medications that
generally suppress the immune system is required. These
include: methotrexate (123), mycophenolate mofetil (124), oral
retinoids such as acitretin (125, 126), dapsone (127), as well
as intravenous immunoglobulin (IVIG) (128, 129), Thalidomide
and its structural analogs have also been used to treat recalcitrant
CLE, with success in some cases (130). Trials assessing
monoclonal antibodies such as sifalimumab and belimumab in
CLE are on-going but mostly found to be effective in SLE with
mucocutaneous involvement (131, 132). We have mapped many of the drugs that are currently
in clinical use for CCLE to their targets of influence in
the “disease road map” based on mechanism of action
(please refer to Figure 3). GO enrichment analyses of our
transcriptional profiles reveal enhanced and activated leukocyte
chemotaxis and B cell activation in skin more so than blood. This might explain the observed efficacy of the preventive
topical corticosteroids (CS) treatments (114), since they bind
to specific cytoplasmic receptors resulting in the inhibition
of leukocyte infiltration at the site of inflammation. CS
are equally effective in both humoral- and T cell mediated
diseases (133). peripheral blood measured by RT-qPCR. Intron-spanning primers were chosen for CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, which are dysregulated genes within the CCLE skin and
is normalized to the housekeeping gene β-actin (ACTB). Fold changes in expression (with S.E.M) are calculated using the 2−∆∆Ct method relative to one sample of the control taken as unity and represent
eplicates each of CCLE (DLE)-patients and healthy controls. Fold change in expression (between case and control blood samples) of CCR2 and STAT1 trended toward significance with p-values = 0.055
ed). Gene expression values from the microarray data are included as fold change in gene expression in skin and blood associated with p ≤0.05. CCLE, chronic cutaneous lupus erythematosus/Discoid
standard error of the mean (see also Figure 6) CCLE, chronic cutaneous lupus erythematos
lupus erythematosus; S.E.M., standard error of the mean (see also Figure 6). Lysosome/Proteasome Ubiquitin-mediated proteasomal proteolysis constitutes the
intracellular protein-degradation apparatus involved in several
cellular functions such as cell cycle, cell differentiation, immune
and inflammatory response, stress signaling and apoptosis among
others. Upregulated genes (CTSB, CTSC, CTSH, CTSZ, and
CTSL) from the cathepsin related protease family, as well as
15 other members of the proteasome family (all involved in
proteolysis), were skewed toward the blood than in skin. The
evidence supporting enhanced activation of proteolytic markers
in peripheral blood over skin of CCLE patients indicates effective
processing of peptides in the systemic milieu to enable MHC I
and II mediated autoantigen presentation in the disease, which Although the pathogenetic relationship between DLE and
SLE is still unclear, our comparative CCLE skin and blood
analyses supports the existence of both overlapping as well as
distinct genetic susceptibilities and mechanisms relevant to the
development of systemic as well as cutaneous LE as discussed
previously (4, 21, 22, 110, 112, 113). Furthermore, the DEGs
mapping to the “hot spots” which do not overlap with SLE and/or March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 9 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha are previously identified as CLE susceptibility loci potentially
represent specific association to the cutaneous disease. peripheral blood measured by RT-qPCR. Intron-spanning primers were chosen for CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, which are dysregulated genes within the CCLE skin and
is normalized to the housekeeping gene β-actin (ACTB). Fold changes in expression (with S.E.M) are calculated using the 2−∆∆Ct method relative to one sample of the control taken as unity and represent
eplicates each of CCLE (DLE)-patients and healthy controls. Fold change in expression (between case and control blood samples) of CCR2 and STAT1 trended toward significance with p-values = 0.055
ed). Gene expression values from the microarray data are included as fold change in gene expression in skin and blood associated with p ≤0.05. CCLE, chronic cutaneous lupus erythematosus/Discoid
standard error of the mean (see also Figure 6) #
Gene
symbol
Forward primer sequence
Reverse primer sequence
Prod
size
Microarray (fold change)
qPCR (fold change) (Blood)
Skin
p-value
Blood
p-value
Control
±S.E.M
CCLE/DLE
±S.E.M
1
CCR2*
GAGGCATAGGGCAGTGAGAG
GCAATCCTACAGCCAAGAGC
269
1.8
0.031
1.6
0.006
2.64
0.49
5.98
2.19
2
IFI30
TGACCATTGTCTGCATGGAA
TCCATGATAGTGTCTGGCGA
100
3.9
0.0006
2
0.027
1.72
0.21
3.02
0.46
3
OAS1
CAACTCTGCATCTACTGGACAAAG
AAGTTTCCTGTAGGGTCCGC
125
2.6
0.0001
6
0.001
2.3
0.47
15.42
6.44
4
OAS2
TTGACAACCGTCCTGGAAAA
GTAAGCAGCTCCAGGGCATA
121
2.6
0.007
1.9
0.007
1.71
0.17
8.84
3.52
5
STAT1*
TCAGAAGTGCTGAGTTGGCA
GTCCACGGAATGAGACCATC
125
4.2
0.002
2.2
0.043
4.05
0.78
9.94
2.34
6
TNFAIP3
TCAACTGGTGTCGAGAAGTCC
ACGCCCCACATGTACTGAGA
97
2.1
0.003
1.5
0.048
1.81
0.41
6
3.06
7
ERBB3
GAACATTCGCCCAACCTTTA
ACGTGGCCGATTAAGTGTTC
279
−2.3
0.003
−1.2
0.041
0.29
0.22
0.22
0.07
8
FGFR2
CAGAATGGATAAGCCAGCCA
GCTTGAACGTTGGTCTCTGG
95
−2
0.016
−1.3
0.049
0.12
0.12
0.1
0.03
Differential gene expression in peripheral blood measured by RT-qPCR. Intron-spanning primers were chosen for CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, which are dysregulated genes within the CCLE skin and
blood signatures. Q-PCR data is normalized to the housekeeping gene β-actin (ACTB). Fold changes in expression (with S.E.M) are calculated using the 2−∆∆Ct method relative to one sample of the control taken as unity and represent
duplicate runs of 5 biological replicates each of CCLE (DLE)-patients and healthy controls. Fold change in expression (between case and control blood samples) of CCR2 and STAT1 trended toward significance with p-values = 0.055
and 0.053, respectively (*starred). Gene expression values from the microarray data are included as fold change in gene expression in skin and blood associated with p ≤0.05. CCLE, chronic cutaneous lupus erythematosus/Discoid Differential gene expression in peripheral blood measured by RT-qPCR. Intron-spanning primers were chosen for CCR2, IFI30, OAS1, OAS2, STAT1, TNFAIP3, ERBB3, and FGFR2, which are dysregulated genes within the CC
blood signatures. Q-PCR data is normalized to the housekeeping gene β-actin (ACTB). Fold changes in expression (with S.E.M) are calculated using the 2−∆∆Ct method relative to one sample of the control taken as unity an
duplicate runs of 5 biological replicates each of CCLE (DLE)-patients and healthy controls. Fold change in expression (between case and control blood samples) of CCR2 and STAT1 trended toward significance with p-valu
and 0.053, respectively (*starred). Gene expression values from the microarray data are included as fold change in gene expression in skin and blood associated with p ≤0.05. Frontiers in Immunology | www.frontiersin.org Therapeutic Considerations—Current
and Future Over-represented disease-related processes such
as lysosome/proteasome degradation in blood, as well as NK
cells, and antigen processing and presentation in both skin
and blood are expected to be the target of antimalarials
(hydroxychloroquine or chloroquine), that are known to alter
pH in lysosomes (134), modify TLR activation (135) and
inhibit antigen presentation. We observe activated T cell related
processes in CLE skin and blood analyses which are the
predicted targets for several immunosuppressant medications March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 10 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha with “interactome-” “network-” “drug target-” analyses. The
data is integrated and synthesized within the milieu of current
literature on SLE/CCLE. We hypothesize a “disease road-map”
demonstrating a coordinated orchestration of the autoimmune
response in CCLE reflected in three phases: (1) initiation,
(2) amplification, and (3) target damage in skin. In -silico
interactome analyses was conducted to identify potential key
functional players associated with the skin disease. Our careful
and systematic downstream analyses of the CCLE skin and blood
transcriptional data not only allowed us to uncover potential
crucial contributors to the metabolic changes linked to the skin
disease, but to select the best potential target candidate for
future therapy. such as methotrexate, a T cell proliferation inhibitor used
in the treatment of recalcitrant CLE (123). Thalidomide and
analog lenalidomide effectively target TNF-α in UV-induced
apoptosis, thus decreasing inflammation. Prominent apoptotic
signatures in both skin and blood presumably indicate effective
use of these drugs, but they are not the drug of choice
in cutaneous lupus due to potential serious side effects. Experimental therapeutic agents include azathropine, (anti-
purine metabolite); apremilast, (phosphodiesterase-4 inhibitor);
R333 (topical JAK/spleen tyrosine kinase inhibitor acting
as an anti-inflammatory molecule), and etanercept (TNF-α
inhibitor). Many of these agents are linked to clinical trials
(Supplementary Table 7). Clearly,
healthcare
is
moving
toward
tailoring
medicines/therapy targeting specific molecules in individual
patients whose expression profiles are known. Our genome-wide
transcriptome study is a representation of gene regulation in a
highly balanced system of networks and pathways underlying
CCLE. Disruption of any of the pathways by primary or
secondary drug targeting offers unique treatment opportunities
(136). Overall, our new in silico analyses identified a novel target,
CCR2 which is a key link to prominent disease related pathways
and processes that merits further investigation for potential use
in future therapy of CLE. Therapeutic Considerations—Current
and Future Chemokine (C-C motif) receptor2 (CCR2) is the only molecule
within the scope of our bioinformatics-guided analyses that fits
all criteria we used to prioritize it as a potential drug target:
(a) included as CCLE-DEG (blood and skin) by microarray
analysis. The observed upregulation in case vs. control (blood)
and lesional vs. non-lesional (skin) were accompanied by
low e-values of ≤0.05, (b) overexpressed in disease vs. control peripheral blood by RT-qPCR analysis, in a separate
set of samples as those used in the microarray analysis, (c)
enriched in lupus-related pathways and processes by ontology
enrichment analyses, (d) “over-connected” functional molecule
by interactome analysis, (e) a reaction hub by network analysis,
(f) mapped to chromosome 3 in an overlapping skin/blood
transcriptional “hot spot” by chromosome mapping analysis, and
(g) targeted by drugs that are currently being used to treat other
diseases such as inflammatory and immune diseases by drug
target analysis. py
Chemokine (C-C motif) receptor2 (CCR2) encodes two
isoforms of a receptor for monocyte chemoattractant protein-1
(MCP-1), which specifically mediates monocyte chemotaxis
in inflammatory diseases such as rheumatoid arthritis. CCR2
maps to the overlapping CCLE skin (FC = 1.8) and blood (FC
= 1.6) “hot spot” on chromosome 3. Additionally, previous
reports have found a positive correlation with increased gene
expression in SLE (137, 138). This makes CCR2 (implicated
in the damaging inflammation underlying autoimmune and
inflammatory diseases) a good potential therapeutic target
candidate in cutaneous lupus as well. We discovered three
xenobiotics: CCX915, CCX140 (clinical trials- phase I and II),
and TAK779 (preclinical) that have been used to target the
extracellular region of CCR2. CCX915 is a highly selective
inhibitor of the CCR2 chemokine receptor in multiple sclerosis
and other autoimmune and inflammatory diseases. Preclinical
data show that CCX140 selectively inhibits CCR2-mediated
migration of monocytes and does not inhibit migration mediated
by other chemokine receptors, even when the compound
is given at high doses. This high degree of target specificity
is an important safety feature that may allow CCX140 to
be effective while avoiding unwanted side effects. We also
discovered one highly specific humanized monoclonal antibody
MLN1202 (clinical trial-Phase II) that interrupts MCP-1
binding to CCR2. These drugs (CCX915, CCX140-B, TAK779,
and MLN 1202) have been used in the past in treatment of
rheumatoid arthritis, diabetes mellitus, multiple sclerosis (139)
and cardiovascular diseases with a modicum of success (140, 141)
(Supplementary Table 7). DATA AVAILABILITY The raw data associated with this study can be accessed associated
with our two previous “Data in Brief” publications which are
from skin (doi: 10.1016/j.dib.2015.02.024; PMID: 26217761) and
blood (doi: 10.1016/j.dib.2014.11.006; PMID: 26217703). Therapeutic Considerations—Current
and Future In summary, the present study, based on genome-wide gene
expression aims to integrate clinical, genetic and bioinformatics
data to bridge the gap between the laboratory and clinical
management of patients. Information and evidence garnered
from this report potentially impacts future clinical decision-
making through the definition of actionable diagnostic and
prognostic markers of the disease and the illumination of
disease related pathways relevant to therapeutic response. Finally,
we
present
the
exciting
possibility
of
designing
potential
new
clinical
trials
(with
a
shorter
cycle
time
due to pre-resolved regulatory issues) in the treatment of
CCLE using repurposed drugs that target the CCLE related
receptor, CCR2. Frontiers in Immunology | www.frontiersin.org REFERENCES 14. Fowler JF, Callen JP, Stelzer GT, Cotter PK. Human histocompatibility
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Weill Cornell Medical College Institutional Review Board: WCM
IRB# 0998-398. Signed consent forms were obtained from all Overall, the present study represents the first comparative
analyses of CCLE skin and blood transcriptional profile along March 2019 | Volume 10 | Article 640 Frontiers in Immunology | www.frontiersin.org 11 Interactome Analysis: Cutaneous Lupus Dey-Rao and Sinha Weill-Cornell Medical College; and the Colgate-Palmolive, Co. to AS. patient and healthy control individuals before obtaining punch
biopsies or performing blood draws. FUNDING The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fimmu. 2019.00640/full#supplementary-material This work was supported in part by grants from the Mary
Kirkland Center for Lupus Research; Colleck Research Fund, ACKNOWLEDGMENTS RD-R contributed to experimentation, data analyses, research,
conceptualizing, and writing of the manuscript and editing. AS contributed to design and procurement of samples for
microarray and editing of manuscript. We thank Birendra Kumar Sinha, Asha Sinha, and Mita Sinha for
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67:e123–6. doi: 10.1016/j.jaad.2011.10.030 Copyright © 2019 Dey-Rao and Sinha. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is permitted, provided the original
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in this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these terms. 127. Klebes M, Wutte N, Aberer E. Dapsone as second-line treatment
for cutaneous lupus erythematosus? a retrospective analysis of 34
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Association between diabetes and causes of dementia: Evidence from a clinicopathological study
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Dementia & Neuropsychologia
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Evidence from a clinicopathological study Maria Niures Pimentel dos Santos Matioli1, Claudia Kimie Suemoto2,3,
Roberta Diehl Rodriguez1,3, Daniela Souza Farias3, Magnólia Moreira da Silva3,
Renata Elaine Paraizo Leite2,3, Renata Eloah Lucena Ferretti-Rebustini3,4,
Carlos Augusto Pasqualucci3, Wilson Jacob Filho2,3, Lea Tenenholz Grinberg3, Ricardo Nitrini1,3 ABSTRACT. Background: Diabetes mellitus is a risk factor for dementia, especially for vascular dementia (VaD), but there
is no consensus on diabetes as a risk factor for Alzheimer’s disease (AD) and other causes of dementia. Objective:
To explore the association between diabetes and the neuropathological etiology of dementia in a large autopsy study. Methods: Data were collected from the participants of the Brain Bank of the Brazilian Aging Brain Study Group between
2004 and 2015. Diagnosis of diabetes was reported by the deceased’s next-of-kin. Clinical dementia was established
when CDR ≥ 1 and IQCODE > 3.41. Dementia etiology was determined by neuropathological examination using
immunohistochemistry. The association of diabetes with odds of dementia was investigated using multivariate logistic
regression. Results: We included 1,037 subjects and diabetes was present in 279 participants (27%). The prevalence of
dementia diagnosis was similar in diabetics (29%) and non-diabetics (27%). We found no association between diabetes
and dementia (OR = 1.22; 95%CI = 0.81-1.82; p = 0.34) on the multivariate analysis. AD was the main cause of
dementia in both groups, while VaD was the second-most-frequent cause in diabetics. Other mixed dementia was the
second-most-common cause of dementia and more frequent among non-diabetics (p = 0.03). Conclusion: Diabetes
was not associated with dementia in this large clinicopathological study. Key words: Alzheimer’s disease, Diabetes mellitus, vascular dementia, neuropathology, clinicopathologic study. 1Department of Neurology, University of São Paulo Medical School , São Paulo, SP, Brazil. 2Division of Geriatrics, University of São Paulo Medical School, São Paulo,
SP, Brazil. 3Aging Brain Study Group from the University of São Paulo Medical School - LIM/22, São Paulo, SP, Brazil. 4Medical-surgical Nursing Department, Univer
sity of São Paulo School of Nursing, São Paulo, SP, Brazil. This study was conducted at the Department of Neurology, University of São Paulo Medical School, São Paulo, SP, Brazil. Original Article Original Article Dement Neuropsychol 2017 December;11(4):406-412 DOI: 10.1590/1980-57642016dn11-040010 Received October 11, 2017. Accepted in final form November 16, 2017. Maria Niures Pimentel dos Santos Matioli. Avenida Doutor Arnaldo 455 / room 1353 – 01246-903 São Paulo SP – Brazil. E-mail: matioli@kingnet.com.br
Disclosure: The authors report no conflits of interest.
Received October 11, 2017. Accepted in final form November 16, 2017. SP, Brazil. 3Aging Brain Study Group from the University of São Paulo Medical School - LIM/22, São Paulo, SP, Brazil. 4Medical-surgical Nursing Department, Univer
sity of São Paulo School of Nursing, São Paulo, SP, Brazil.
Maria Niures Pimentel dos Santos Matioli. Avenida Doutor Arnaldo 455 / room 1353 – 01246-903 São Paulo SP – Brazil. E-mail: matioli@kingnet.com.br
Disclosure: The authors report no conflits of interest.
Received October 11, 2017. Accepted in final form November 16, 2017. Maria Niures Pimentel dos Santos Matioli. Avenida Doutor Arnaldo 455 / room 1353 – 01246-903 São Paulo SP – Brazil. E-mail: matioli@kingnet.com.br Maria Niures Pimentel dos Santos Matioli. Avenida Doutor Arnaldo 455 / room 1353 – 01246-903 São Paulo SP – Brazil. E-mail: matioli@kingnet.com.br
Di l
Th
h
fli
f i INTRODUCTION were selected from 2004 to 2015, but incomplete
interview or neuropathological data were found in 46
deceased. Therefore, the final sample comprised 1,037
deceased. Signed informed consent obtained from the
deceased’s next-of-kin (NOK) allowed autopsy and
brain donation. The local ethics committee approved
this study. T
he number of people affected by diabetes mellitus
has been growing worldwide.1 In 2015, the Inter
national Diabetes Federation estimated that 415 mil
lion people aged 20-79 years had diabetes worldwide,
and nearly 75% lived in low-to-middle-income coun
tries (LMIC).1 The number of diabetics will continue to
rise with diabetes set to affect 642 million people by
2040, and this will take place especially in regions where
economies are transitioning from low-income to middle-
income levels.1 The World Alzheimer Report 2015 esti
mated that 46.8 million people worldwide had dementia
in 2015, and 58% of these lived in LMIC.2 The propor
tion of people with dementia living in LMIC will reach
63% in 2030 and 68% in 2050.2 Dementia and type 2
diabetes are more prevalent with aging.1,2 T Clinical information. A skilled team of gerontolo
gist nurses applied the structured interview to the
deceased’s NOK. The NOK had to have at least weekly
contact with the deceased during the six months prior
to death. This structured interview provided informa
tion about demographics (age, sex, race, and educa
tion) and socioeconomic status, previous diagnosis of
diseases (hypertension, dyslipidemia, heart failure,
coronary artery disease, and stroke), lifestyle (alco
holism, smoking, sedentary lifestyle), medication
intake, as well as cognitive and functional status.33 A
Brazilian scale classifying subjects into five socioeco
nomic strata34 was applied. Stratum A is the highest
income and stratum E the lowest, and this scale was
grouped into high (stratum A+B), middle (stratum C)
and low (stratum D+E) socioeconomic status for statis
tical analysis. Diabetes was defined based on the NOK
report of diabetes diagnosis during life or the use of any
antidiabetic medication. Cognitive status was evalu
ated by the Clinical Dementia Rating scale (CDR)35 and
the Informant Questionnaire on Cognitive Decline in
the Elderly.36 The clinical diagnosis of dementia was
established in the presence of CDR ≥ 1 and IQCODE
score > 3.41.37 The cause of dementia was determined
following neuropathological criteria. INTRODUCTION Diabetes is a known risk factor for dementia and
vascular dementia (VaD), but the association between
diabetes and Alzheimer’s disease (AD) needs to be bet
ter clarified.3 Several longitudinal studies have shown
that diabetes was associated only with VaD, but not with
AD.4-9 Meanwhile, some studies have shown that DM is
associated with increased risk of dementia and AD,10-17
while others have found a positive association only in
the presence of the apolipoprotein E ε4 allele (APOE
ε4).18,19 However, Akomolafe et al.20 showed diabetes
was a risk factor for AD, especially when three known
AD risk factors were absent: elevated plasma homocys
teine level, the APOE ε4 allele, or age 75 years or older. There are fewer autopsy studies than epidemiologi
cal investigations. Despite the positive evidence linking
diabetes and cerebrovascular neuropathology,21-27 most
autopsy studies have not supported the same conclu
sion regarding the association between diabetes and AD
neuropathology22,24,26-30 and some authors described a
positive association only in individuals carrying the
APOE ε4 allele.21,23,31,32 Studies from LMIC regarding the
association between diabetes and dementia are scarce.2
We recently showed that diabetes was not associated
with AD-neuropathology in a large sample from Brazil.30
Here, we aimed to expand this finding by examining the
association between diabetes and causes of dementia in
a large autopsy study. Neuropathological assessment. The brain was collected
within 24 hours of death. One hemisphere was coro
nally sectioned and snap frozen and the other hemi
sphere was fixed in 4% buffered paraformaldehyde. Samples from the fixed hemisphere were embedded in
paraffin and sectioned to produce slides of following
regions: hippocampus and parahippocampal gyrus at
the level of the lateral geniculate body, amygdala at
the level of mammillary bodies (including the ambiens
gyrus), basal ganglia at the level of the anterior commis
sure, thalamus, midbrain, pons, medulla oblongata, and
cerebellum, middle frontal gyrus, middle and anterior
temporal gyri, angular gyrus, superior frontal gyrus and
anterior cingulate gyrus, and visual cortex. Hematox
ylin & eosin (H&E) staining was applied to all sampled
regions. Selected sections were immunostained with
antibodies against phosphorylated tau (PHF-1, dilu ASSOCIAÇÃO ENTRE DIABETES E CAUSAS DE DEMÊNCIA: EVIDÊNCIA DE UM ESTUDO CLÍNICO-PATOLÓGICO RESUMO. Introdução: Diabetes mellitus é um fator de risco para a demência, especialmente para a demência vascular
(DV), mas ainda não há consenso sobre diabetes como fator de risco para a doença de Alzheimer (DA) e outras causas
de demência. Objetivo: Verificar a associação entre diabetes e demência e sua etiologia neuropatológica em um grande
estudo de autópsia. Métodos: Os dados foram coletados do Banco de Encéfalos Humanos do Grupo de Estudos em
Envelhecimento Cerebral da FMUSP entre 2004 e 2015. O diagnóstico de diabetes foi relatado por pelos parentes do
falecido. A demência clínica foi estabelecida quando CDR ≥ 1 e IQCODE > 3,41. A etiologia da demência foi determinada
pelo exame neuropatológico com imuno-histoquímica. A associação de diabetes com probabilidades de demência foi
investigada usando regressão logística multivariada. Resultados: Foram incluídos 1.037 sujeitos, diabetes esteve
presente em 279 participantes (27%). A frequência de diagnóstico de demência foi semelhante entre diabéticos (29%)
e não diabéticos (27%). Não encontramos associação entre diabetes e demência (OR = 1,22; IC 95% = 0,81-1,82;
p = 0,34) na análise multivariada. DA foi a principal causa de demência em ambos os grupos, DV foi a segunda causa
em diabéticos. A frequência de outra demência mista foi a segunda causa de demência e mais frequente entre os não
diabéticos (p = 0,03). Conclusão: A diabetes não foi associada à demência neste grande estudo clínico-patológico. Palavras-chave: doença de Alzheimer, diabetes mellitus, demência vascular, neuropatologia, estudo clinicopatológico. 406
Diabetes and causes of dementia 406
Diabetes and causes of dementia
Matioli et al. Dement Neuropsychol 2017 December;11(4):406-412 407
Matioli et al. Diabetes and causes of dementia RESULTS We analyzed data from 1,037 subjects, of which 758
(72%) were non-diabetics and 279 (27%) diabetics. Dementia was determined in 80 diabetics (29%)
and 205 (27%) non-diabetics, and no difference was
found regarding dementia frequency between these
groups (p = 0.24). First, the total sample were strati
fied by diabetes status, and compared for frequency of
dementia diagnosis regarding sociodemographic and
clinical variables (Table 1). Participants with dementia,
with and without diabetes, were mostly female, had
lower educational level, and were older compared to
non-demented groups. Black and admixed races were
more frequent in diabetics with dementia than diabetics
without dementia. A higher frequency of stroke and
physical inactivity were found in both demented groups. Hypertension and current smoking were more frequent
in non-diabetics without dementia compared to non-
diabetics with dementia. AD-type pathology was scored using the Braak and
Braak staging system38 and the Consortium to Estab
lish a Registry for AD (CERAD)39 criteria. Diagnosis of
AD dementia was made in cases that had at least Braak
stage III and CERAD moderate score.40 AD-type pathology was scored using the Braak and
Braak staging system38 and the Consortium to Estab
lish a Registry for AD (CERAD)39 criteria. Diagnosis of
AD dementia was made in cases that had at least Braak
stage III and CERAD moderate score.40 The presence of diffuse small-vessel disease in the
white matter, of hippocampal sclerosis, and of lacunae,
microinfarcts, and infarcts were analyzed semi-quanti
tatively by H&E staining. Cerebral amyloid angiopathy
was investigated using anti β-amyloid immunostaining. The diagnosis of VaD was defined in cases with one large
chronic infarct (> 1 cm) or three lacunae in strategic areas
(thalamus, frontocingular cortex, basal forebrain and
caudate, medial temporal area, and angular gyrus).37 AD
plus VaD was considered as mixed dementia only when
the criteria for AD and VaD were concomitantly present. Second, only diabetics and non-diabetics with
dementia data were compared. Similar frequencies were
found between them regarding age (p = 0.12), sex (p =
0.79), education (p = 0.88), race (p = 0.17), socioeco
nomic status (p = 0.70), coronary artery disease (p =
0.72), stroke (p = 0.52), heart failure (p = 0.83), physical
inactivity (p = 0.90), current smoking (p = 0.60), and
alcohol use (p = 0.90). Hypertension (p < 0.01) and dys
lipidemia (p < 0.01) were more frequent in demented
diabetics than in non-diabetics with dementia. METHODSh Participants. This cross-sectional study included subjects
aged 50 years and older from the Brain Bank of the
Brazilian Aging Brain Study Group of the University of
São Paulo Medical School (BB-BABSG-FMUSP). Exclu
sion and inclusion criteria for the BB-BABSG-FMUSP
were previously described.33 Initially, 1,083 subjects Dement Neuropsychol 2017 December;11(4):406-412 employed for statistical analyses. The significance level
was set at 0.05 in two-tailed tests. tion 1:2.000; gift of Prof. Peter Davies, NY), β-amyloid
(4G8, dilution 1:10.000; Signet Pathology Systems,
Dedham, MA), α-synuclein (EQV, 1:10.000, gift of Kenji
Ueda, Tokyo, Japan), and transactivation response
DNA-binding protein of 43 kDA (TDP-43; 1:500,
Proteintech, Chicago, IL).33 Internationally accepted
neuropathological criteria and guidelines were used
for diagnosing and staging the causes of dementia.33 408
Diabetes and causes of dementia Matioli et al. RESULTS There was
a higher frequency of individuals with severe dementia
(CDR = 3) among non-diabetics (p = 0.03), and with mild
(CDR = 1) and moderate dementia (CDR = 2) among dia
betics. Non-diabetics with dementia died with highest
mean IQCODE scores (4.43; SD:0.48; p = 0.04) (Table 2). Lewy body disease was diagnosed based on criteria
described by McKeith et al.41 To define dementia sec
ondary to Parkinson’s disease, a criterion described by
Braak et al.42 was applied. The diagnosis of Frontotem
poral lobar degeneration was established using the cri
teria of Mackenzie et al.43 The diagnosis of argyrophilic
grain disease was established according to Saito et al.44
Undefined cause was defined when there was no agree
ment between the clinical diagnosis of dementia and the
neuropathological findings. Other mixed dementia was
considered in presence of two or more neuropathologies
of dementia, except when AD + VaD were present. Statistical analysis. We used the unpaired t-test or
Mann-Whitney test for quantitative variables, and the
Chi-square or Fisher’s exact tests for categorical vari
ables, to investigate the association of demographic and
clinical variables with dementia stratified by diabetes
status. The association between diabetes and dementia
was investigated using multivariate ordinal logistic
regression with results adjusted for age, sex, education,
hypertension, dyslipidemia, smoking, alcohol use and
physical inactivity. We also described the frequency of
neuropathological diagnosis by diabetes status among
participants with dementia, and compared these
frequencies using Chi-square or Fisher’s exact tests. Stata 13.0 (College Station, TX: StataCorp LP) was Diabetes was not associated with dementia (OR:1.22;
95%CI:0.81-1.82; p = 0.34) on multivariate ordinal logis
tic regression adjusted for age, sex, race, education,
hypertension, dyslipidemia, smoking, physical inactiv
ity and alcohol use (Table 3). Among participants with dementia, AD was the main
neuropathological cause of dementia in both groups
(Table 4). Only other mixed dementia was more frequent
in non-diabetics with dementia (p = 0.03). The distribu
tion of causes of dementia differed between diabetics
and non-diabetics. The second-most-common cause of
dementia in diabetics was VaD, but in non-diabetics was
other mixed dementia. Undefined cause of dementia was
similar between diabetics and non-diabetics (Table 4). 408
Diabetes and causes of dementia Matioli et al. Dement Neuropsychol 2017 December;11(4):406-412 Table 1. Sociodemographic and clinical data from diabetics and non-diabetics with and without dementia (n=1,037). RESULTS Variable
Non-diabetics
P
Diabetics
p
Without dementia
With dementia
Without dementia
With dementia
(N = 553)
(N = 205)
(N = 199)
(N = 80)
Female, n (%)*
260 (47.0)
128 (62.4)
< 0.01
101 (50.8)
52 (65.0)
0.03
Age (years), mean (SD)†
72.6 (11.8)
80.3 (9.7)
< 0.01
71.5 (10.9)
78.5 (9.4)
< 0.01
Education (years), mean (SD)£
4.4 (3.7)
3.2 (3.4)
< 0.01
4.6 (3.8)
3.2 (3.4)
< 0.01
Race, n (%)#
0.09
0.03
• White
336 (60.8)
120 (58.5)
132 (66.3)
40 (50)
• Black
104 (18.8)
53 (25.9)
33 (16.6)
20 (25.0)
• Admixed
99 (17.9)
30 (14.6)
31 (15.6)
20 (25.0)
• Yellow
14 (2.5)
2 (1.0)
3 (1.5)
0 (0)
Socioeconomic class, n (%)#
0.41
0.22
• High
162 (29.3)
73 (35.6)
57 (28.6)
26 (32.5)
• Middle
260 (47.1)
86 (42.0)
106 (53.3)
38 (47.5)
• Low
130 (23.6)
46 (22.4)
36 (18.1)
16 (20.0)
Hypertension, n (%)*
354 (64.0)
102 (49.8)
< 0.01
165 (82.9)
59 (73.8)
0.08
Dyslipidemia, n (%)*
37 (6.7)
6 (2.9)
0.05
41 (20.6)
9 (11.3)
0.06
Coronary artery disease, n (%)*
118 (21.3)
33 (16.1)
0.11
59 (29.6)
15 (18.8)
0.06
Heart failure, n (%)*
94 (17.0)
27 (13.2)
0.20
43 (21.6)
12 (15.0)
0.21
Stroke, n (%)*
57 (10.3)
52 (25.4)
< 0.01
34 (17.1)
24 (30.0)
0.02
Physical inactivity, n (%)*
243 (49.4)
136 (82.4)
< 0.01
107 (57.8)
53 (88.3)
< 0.01
Current smoking, n (%)*
169 (30.6)
39 (19.0)
< 0.01
40 (20.1)
18 (22.5)
0.78
Current alcohol use, n (%)*
139 (25.1)
39 (19.0)
0.10
41 (20.6)
14 (17.5)
0.67
*Chi
t
t #Fi h ’
t t
t †St d
t´ t t
t £M
Whit
T t phic and clinical data from diabetics and non-diabetics with and without dementia (n=1,037). Table 1. Sociodemographic and clinical data from diabetics and non-diabetics with and without dementia (n=1,037). Table 2. CDR and IQCODE in diabetics and non-diabetics with dementia (n = 285). Variables
Non-diabetics with dementia
n = 205
Diabetics with dementia
n = 80
p
CDR, n (%)#
0.03
• 1
45 (22.0)
26 (32.5)
• 2
42 (20.5)
22 (27.5)
• 3
118 (57.5)
32 (40.0)
IQCODE, mean (SD)*
4.43 (0.48)
4.30 (0.45)
0.04
SD: standard deviation; CDR: Clinical Dementia Rating; IQCODE: Informant Questionnaire on Cognitive Decline in the Elderly; *Mann-Whitney
test; #Chi-square test. Table 2. hi-square test; #Fisher’s exact test †Student´s t-test; £Mann-Whitney Test. 409
Matioli et al. Diabetes and causes of dementia DISCUSSION dementia in the non-diabetic group (p < 0.01) of 31% in
non-diabetics and 21% in diabetics, but with a mean age
similar to the present study. Peila et al.21 described an
increased risk for the development of dementia in dia
betics, whereas the study by Ahtiluoto et al.26 reported
double the incidence of dementia in this group. This study did not find an association between diabetes
and dementia in a large sample of subjects submitted to
autopsy. All diabetics and non-diabetics with dementia
were older, predominantly women, had lower educa
tion, and a higher frequency of stroke and physical
inactivity. Older age, low education, female sex, phys
ical inactivity and stroke have been considered risk
factors for dementia.2,45-48 Participants with diabetes
died at mild and moderate stages of dementia. They had
more comorbidities, exhibiting more hypertension and
dyslipidemia; therefore, they might have died before
dementia had reached more advanced clinical stages. AD was the main cause of dementia in both groups,
showing the importance of this neurodegenerative
disease in older people even in the presence of vascu
lar risk factors. VaD was the second-most-common
cause only in diabetics. Other mixed neuropathology
of dementia was more frequent and the second-most-
frequent cause of dementia in non-diabetics. The differ
ence in cause of dementia distribution can probably be
explained by diabetics being a group with more vascular
risk factors, showing the important role of diabetes in
cerebrovascular disease. DM was not associated with
increased frequency of any particular type of demen
tia in the present study, unlike cohort studies that have
shown an increased risk for AD,10-17,19,49 VaD,5-9,18 AD
and VaD,11,21,26,50 or for mixed AD and VaD11,21 in dia
betic patients Diabetes increases the risk for cerebral
small-vessel disease, cerebral infarcts, vascular cognitive
decline and VaD.3,51,52 The role of diabetes with regard The prevalence of dementia among non-diabetics
(27%) and diabetics (29%) was lower in our study com
pared with other reports.22,26,27 Arvanitakis et al.22 found
dementia in 44.2% of non-diabetics and in 50% of dia
betics (p = 0.52). Ahtiluoto et al.26 reported a very high
frequency of dementia, present in 65.9% of non-diabet
ics and 60.0% of diabetics (p = 0.381) with mean age
of 88 years. Abner et al.27 reported dementia in 38.2%
of non-diabetics and 39.1% of diabetics (p = 0.69), also
with a mean sample age of 88.7 years. RESULTS CDR and IQCODE in diabetics and non-diabetics with dementia (n = 285). Dement Neuropsychol 2017 December;11(4):406-412 Table 3. Association between clinical dementia and diabetes mellitus status (n = 1,037). DM
Clinical dementia n (%)
Simple regression
OR (95% CI)
Multivariate regression*
OR (95% CI)
No
Yes
No
553 (73.0)
205 (27.0)
1.00 (reference)
1.00 (reference)
Yes
199 (71.3)
80 (28.7)
1.08 (0.80-1.47)
1.22 (0.81-1.82)
p
0.602
0.340
OR: odds ratio; CI: confidence interval. *Multivariate ordinal logistic regression adjusted for age, sex, race, education, hypertension, dyslipidemia, physical inactivity, smok
ing, and alcohol use. Table 3. Association between clinical dementia and diabetes mellitus status (n = 1,037). DM
Clinical dementia n (%)
Simple regression
OR (95% CI)
Multivariate regression*
OR (95% CI)
No
Yes
No
553 (73.0)
205 (27.0)
1.00 (reference)
1.00 (reference)
Yes
199 (71.3)
80 (28.7)
1.08 (0.80-1.47)
1.22 (0.81-1.82)
p
0.602
0.340
OR: odds ratio; CI: confidence interval. *Multivariate ordinal logistic regression adjusted for age, sex, race, education, hypertension, dyslipidemia, physical inactivity, smok
ing, and alcohol use. Table 4. Neuropathological causes of dementia in diabetics and non-diabetics (n = 285). Neuropathology, n %
Non-diabetics with dementia, n (%)
N = 205
Diabetics with dementia, n (%)
N = 80
P
AD**
52 (25.4)
24 (30.0)
0.52
VaD**
22 (10.7)
14 (17.5)
0.65
Mixed dementia (AD +VaD)*
15 (7.3)
03 (3.8)
0.30
Other Mixed NP**
46 (22.4)
09 (11.3)
0.03
Other single NP**
27 (13.2)
11 (13.8)
0.95
Undefined**
43 (21.0)
19 (23.8)
0.73
AD: Alzheimer’s disease; NP: neuropathology; VaD: vascular dementia. **Chi-square test; *Fisher’s exact test. Table 3. Association between clinical dementia and diabetes mellitus status (n = 1,037). Table 4. Neuropathological causes of dementia in diabetics and non-diabetics (n = 285). Neuropathology, n %
Non-diabetics with dementia, n (%)
N = 205
Diabetics with dementia, n (%)
N = 80
P
AD**
52 (25.4)
24 (30.0)
0.52
VaD**
22 (10.7)
14 (17.5)
0.65
Mixed dementia (AD +VaD)*
15 (7.3)
03 (3.8)
0.30
Other Mixed NP**
46 (22.4)
09 (11.3)
0.03
Other single NP**
27 (13.2)
11 (13.8)
0.95
Undefined**
43 (21.0)
19 (23.8)
0.73
AD: Alzheimer’s disease; NP: neuropathology; VaD: vascular dementia. **Chi-square test; *Fisher’s exact test. Table 4. Neuropathological causes of dementia in diabetics and non-diabetics (n = 285). 410
Diabetes and causes of dementia Matioli et al. REFERENCES Diabetes Mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53(9):1937-42. 1. International Diabetes Federation, 2015. IDF Diabetes Atlas seventh
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disease in relation to diabetes: a population-based cohort study. Neuro
epidemiology. 2012;38:237-44. 7. Hassing LB, Johansson B, Nilson SE, Berg S, Pedersen NL, Gatz M,
McClearn G. Diabetes Mellitus is a risk factor for vascular dementia, but
not for Alzheimer1s disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14(3):239-48. 18. Xu WL, Qui CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes Mellitus and
risk of dementia in the Kungsholmen project. Neurology 2004;63:1181-6. 8. DISCUSSION However, the
study by Alafuzoff et al.23 found a higher frequency of 410
Diabetes and causes of dementia Matioli et al. Matioli et al. Dement Neuropsychol 2017 December;11(4):406-412 to AD remains controversial, where cerebrovascular dis
ease is likely the main mechanism involved and diabetes
possibly decreases brain resilience, but does not directly
cause AD.3 Author contribution. Maria Niures Pimentel dos Santos
Matioli and Claudia Kimie Suemoto: preparation and
statistical calculation of the study. Ricardo Nitrini:
study conception, and writing and reviewing the paper. Roberta Diehl Rodriguez and Lea Tenenholz Grinberg:
responsible for the neuropathological diagnosis. The
other authors contributed to the research and revision
of the paper. The present study has several strengths: a) the
large sample size from a LMIC with low educational
level among subjects, in contrast with other studies;
b) autopsy studies allow for the direct measurement of
neuropathological lesions, untangling the pure asso
ciation between DM and dementia neuropathology; c)
neuropathologists were blinded to clinical information. However, our study has some limitations: a) this is a
cross-sectional study and therefore limited in determin
ing causality of diabetes for dementia; b) all clinical data,
including diabetes diagnoses, were obtained in NOK; c)
the clinical diagnosis of dementia was established only
after death based on NOK information. However, the
accuracy of our clinical interview was tested previously
and showed good reliability.53 Acknowledgements/Funding. The authors are grateful to
the families of the brain donors and to the São Paulo
City Autopsy Service physicians and staff for their
unconditional support, and to the Brazilian Aging Brain
Study Group participants. Study funding. Support for this work was provided
by grants the from Fundação de Apoio a Pesquisa do
Estado de São Paulo – FAPESP (grant 2009/01934-4
and scholarship to R.E.P.L.), LIM22 of the Department
of Pathology of the University of São Paulo Medical
School, Albert Einstein Education and Research Insti
tute, São Paulo (grant 240/07), and the Coordenadoria
de Apoio ao Pessoal de Nivel Superior – CAPES, Brazil
(scholarship to students of the BABSG). In conclusion, we did not find an association
between diabetes and dementia frequency or any neu
ropathological cause in a large sample with low educa
tional level in a LMIC. Further studies are necessary to
better clarify these questions, especially longitudinal
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Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004–2007 as an example of the potential and pitfalls of using routinely collected electronic patient data
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BioMed Central BioMed Central Published: 25 June 2008 Received: 14 November 2007
Accepted: 25 June 2008 Published: 25 June 2008 BMC Health Services Research 2008, 8:138
doi:10.1186/1472-6963-8-138 BMC Health Services Research 2008, 8:138
doi:10.1186/1472-6963-8-138 This article is available from: http://www.biomedcentral.com/1472-6963/8/138 © 2008 Wong et al; licensee BioMed Central Ltd. © 008 Wo g et a ; ce see
o e Ce t a
t . This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. BMC Health Services Research Open Access Health services research in the public healthcare system in Hong
Kong: An analysis of over 1 million antihypertensive prescriptions
between 2004–2007 as an example of the potential and pitfalls of
using routinely collected electronic patient data Health services research in the public healthcare system in Hong
Kong: An analysis of over 1 million antihypertensive prescriptions
between 2004–2007 as an example of the potential and pitfalls of
using routinely collected electronic patient data
Martin CS Wong1, Johnny Y Jiang1, Jin-ling Tang1, Augustine Lam1, Address: 1Department of Community and Family Medicine and School of Public Health, Chinese University of Hong Kong, Hong Kong SAR,
China. 4/F, School of Public Health, Prince of Wales Hospital, Shatin, HKSAR, PR China and 2General Practice and Primary Care, Division of
Community-Based Sciences, Faculty of Medicine, University of Glasgow, 1 Horselethill Road, Glasgow G12 9LX, UK Email: Martin CS Wong - wong_martin@cuhk.edu.hk; Johnny Y Jiang - jiangyu@cuhk.edu.hk; Jin-ling Tang - jltang@cuhk.edu.hk;
Augustine Lam - lamt@ha.org.hk; Hong Fung - fungh@ha.org.hk; Stewart W Mercer* - sm83z@clinmed.gla.ac.uk Data Source and Subjects Clinical and demographic information were retrieved
from CDARS for all patients who attended HA primary
care clinics in the New Territory East (NTE) cluster of
Hong Kong, during the period from January 2004 to June
2007. We chose this time period because although e-CMS
was initiated in 2000, its implementation was gradual and
was severely interrupted by the SARS outbreak in 2003. There was no requirement for doctors to enter the ICPC
codes into the CMS until post-SARS, which is also when
CDARS became operationalised. Thus January 2004 is the
earliest time point for the availability of both CDARS and
e-CMS data including ICPC codes. In many western countries these databases have been con-
structed in a systematic manner and influential study
results have been published [12-15]. There is a growing
trend for these evolving information systems to imple-
ment regional networks [16] and allow physician- or
patient- access to clinical information, as well as integra-
tion of a broader spectrum of patient data. Hong Kong ini-
tiated the operation of a comprehensive computerized
recording and management system in the public sector in
2000. All patient information, drug prescription details
and laboratory investigation results are routinely entered
into the electronic Clinical Management System (e-CMS)
for every consultation by health care professionals,
backed up by the Clinical Data Analysis Reporting System
(CDARS). Paper records will only be used during rare
occasions where computer systems are unexpectedly not
operational. These computerized databases thus far con-
sist of seven million patient records, one million annual
admissions and 13 million ambulatory visits, with medi-
cal research as one of the stated purposes of their imple-
mentation [17]. Nevertheless, the usefulness of these
clinical electronic databases in Hong Kong for high qual-
ity health services research has been little explored [17]. The NTE cluster serves a population of around 1.3 million
in Hong Kong, representing 17.2% of the Hong Kong
population [31]. This cluster is further divided into 3 sep-
arate regions, namely Shatin, Tai-Po and the North Dis-
trict, from the most urbanized to the most rural regions
respectively. Their median monthly household incomes
in 2006 were US$2,510, US$2,338 and US$2,078 for
these three regions respectively, compared to the Hong
Kong-wide figure of US$2,240 [31]. These three regions
have similar median ages (38–39 years), comparable with
the median age of 39 years for Hong Kong. http://www.biomedcentral.com/1472-6963/8/138 BMC Health Services Research 2008, 8:138 http://www.biomedcentral.com/1472-6963/8/138 Background sent an important area of health service research [26-30],
but there is a paucity of reports on health care utilization
patterns of this disease among Chinese patients. In the
present study we evaluated the completeness of the demo-
graphic and prescription details of patients recorded in
the e-CMS database of the HA in Hong Kong. Also we
examined the patterns and independent predictors of dis-
ease coding using antihypertensive drug prescriptions in
primary care as an example. g
The use of electronic patient records within healthcare sys-
tems has important implications for health services
research. When used within a comprehensive computer-
ized data management system such records can support
research into the aetiology of disease [1,2], the predictive
value of symptoms in diagnosis [3], the clinical effective-
ness and cost effectiveness of interventions [4], and in
evaluating whole-system approaches to the organization
and delivery of care [5]. The databases invariably contain
a large number of subjects, may provide almost complete
population coverage (depending on the healthcare and
data collection systems), often provide reliable informa-
tion on variables such as demographic characteristics, pre-
scribing patterns and diagnoses, and in theory allow for
quick and efficient data retrieval [6]. Notable examples
include the UK General Practice Research Database
(GPRD) [7], the Health Search Database in Italy [8], and
Ontario Drug Benefit (ODB) database [9]. Some data-
bases include almost all residents of a province [10,11],
thus enhancing the applicability and generalizability of
findings. Page 2 of 9
(page number not for citation purposes) Abstract Background: Increasing use is being made of routinely collected electronic patient data in health services research. The aim of
the present study was to evaluate the potential usefulness of a comprehensive database used routinely in the public healthcare
system in Hong Kong, using antihypertensive drug prescriptions in primary care as an example. Methods: Data on antihypertensive drug prescriptions were retrieved from the electronic Clinical Management System (e-
CMS) of all primary care clinics run by the Health Authority (HA) in the New Territory East (NTE) cluster of Hong Kong
between January 2004 and June 2007. Information was also retrieved on patients' demographic and socioeconomic
characteristics, visit type (new or follow-up), and relevant diseases (International Classification of Primary Care, ICPC codes). Results: 1,096,282 visit episodes were accessed, representing 93,450 patients. Patients' demographic and socio-economic
details were recorded in all cases. Prescription details for anti-hypertensive drugs were missing in only 18 patients (0.02%). However, ICPC-code was missing for 36,409 patients (39%). Significant independent predictors of whether disease codes were
applied included patient age ≥ 70 years (OR 2.18), female gender (OR 1.20), district of residence (range of ORs in more rural
districts; 0.32–0.41), type of clinic (OR in Family Medicine Specialist Clinics; 1.45) and type of visit (OR follow-up visit; 2.39). In the 57,041 patients with an ICPC-code, uncomplicated hypertension (ICPC K86) was recorded in 45,859 patients (82.1%). The characteristics of these patients were very similar to those of the non-coded group, suggesting that most non-coded patients
on antihypertensive drugs are likely to have uncomplicated hypertension. Conclusion: The e-CMS database of the HA in Hong Kong varies in quality in terms of recorded information. Potential future
health services research using demographic and prescription information is highly feasible but for disease-specific research
dependant on ICPC codes some caution is warranted. In the case of uncomplicated hypertension, future research on pharmaco-
epidemiology (such as prescription patterns) and clinical issues (such as side-effects of medications on metabolic parameters)
seems feasible given the large size of the data set and the comparability of coded and non-coded patients. Page 1 of 9
(page number not for citation purposes) (page number not for citation purposes) http://www.biomedcentral.com/1472-6963/8/138 http://www.biomedcentral.com/1472-6963/8/138 Data Source and Subjects Eligible subjects were those having received at least one
prescription of antihypertensive drugs in any of these pri-
mary care visits. Only visits which result in prescription of
antihypertensive drugs were included (hereafter named
"antihypertensive drug visits"). Since CDARS does not
have disease coding, we further obtained a list of patient
identity card (ID) numbers from CMS for various relevant
codes of the International Classification of Primary Care
(ICPC), including uncomplicated hypertension (K86)
and other conditions which could potentially affect the
prescription choice of antihypertensive drugs, which we
therefore refer to as "exclusion codes" (Table 1). These
codes were then merged with the information from
CDARS using the patients' ID as the unique identifier. Patients were considered 'coded' if they had at least one
relevant ICPC code entered in the CMS during the study
period. The study was approved by the NTE cluster of HA, Hypertension is a good example of a common and impor-
tant condition which can be successfully researched using
comprehensive computerized patient records [8,18-21]. The prevalence of hypertension in Hong Kong has been
reported to exceed 27% and is one of the most common
conditions seen in public health sector [22], comparable
to the worldwide figure of 26% [23]. Data Source and Subjects The public health
costs of hypertension are substantial [24,25] and repre- Page 2 of 9
(page number not for citation purposes) Page 2 of 9
(page number not for citation purposes) http://www.biomedcentral.com/1472-6963/8/138 BMC Health Services Research 2008, 8:138 Table 1: Distribution of International Classification of Primary Care (ICPC) codes among patients with ≥ 1 code (N = 57,041)
ICPC codes
Disease entity
Reasons for exclusion
number
%
K87
Complicated hypertension
The presence of unknown complications may favor or preclude
prescription of a particular drug class
3310
5.8%
T90
Diabetes Mellitus
Favors the choice of ACEIs
15560
27.3%
T901
Impaired glucose tolerance
353
0.6%
T92
Gout
Contraindication of thiazide diuretics
635
1.1%
T93
Lipid disorders
Favor the exclusion of thiazide diuretics and β-blockers
1186
2.1%
K90
Stroke/cerebrovascular accident
Favor the choice of β-blockers
1920
3.4%
K91
Cerebrovascular disease
130
0.2%
K74
Ischemic Heart Disease with angina
348
0.6%
K76
Ischemic Heart Disease without angina
1099
1.9%
K75
Acute Myocardial Infarction
213
0.4%
K77
Heart Failure
Favor the choice of ACEIs
794
1.4%
K84
Heart Disease, other
Favor the choice of β-blockers or ACEIs
168
0.3%
K99
Cardiovascular disease, other
113
0.2%
R79
Chronic Bronchitis
Contraindication of β-blockers
436
0.8%
R95
Chronic Obstructive Pulmonary Disease
2199
3.9%
R96
Asthma
1083
1.9%
U14
Kidney symptoms/complaints
Either favor or a contraindication of ACEIs
312
0.5%
U88
Glomerulonephritis/nephrosis
36
0.1%
Y85
Benign Prostatic Hypertrophy
Favor the prescription of α-blockers
2917
5.1%
U78
Benign Neoplasm Urinary Tract
30
0.1%
Y79
Benign/unspecified neoplasm, male genital
1
0.0%
(ACEIs: Angiotensin Converting Enzyme Inhibitors. There were a total of 46,859 patients (82.1%) Apart from K86 these conditions are influencing
factors for antihypertensive drug prescription and were named "exclusion codes" (ACEIs: Angiotensin Converting Enzyme Inhibitors. There were a total of 46,859 patients (82.1%) Apart from K86 t
factors for antihypertensive drug prescription and were named "exclusion codes" and the Survey and Behavioural Research Ethics Commit-
tee, Chinese University of Hong Kong one ICPC code, as those listed in Table 1, by physicians
using bivariate analysis, followed by multivariable analy-
sis by entering predictors with statistically significance
into a binary logistic regression equation. A forward step-
wise model was adopted and only those significant inde-
pendent predictors were reported. All p values <0.05 were
regarded as statistically significant. Variables and Statistical Analysis All retrieved data were transformed and analyzed by the
Statistical Package for Social Sciences (SPSS) version 13.0. The proportions of four distinct, mutually exclusive
patient groups were reported. These consist of (1). Those
coded with K86 and with exclusion coding ("combined
group"); (2). Those coded with K86 without any exclusion
coding ("K86-only group"); (3). Those not coded with
K86 but with at least one exclusion coding ("Exclusion
only group"); and (4). Those without K86 nor any exclu-
sion coding ("Non-coded group"). Among patients with
at least one code, the distribution of each coding was stud-
ied. The basic demographic and health service characteris-
tics of these different coding groups were compared using
χ2 tests of homogeneity and Analysis of Variance
(ANOVA) for categorical and continuous variables,
respectively. These include patient age, gender, payment
status (fee-waivers or service payers), district of residence,
service type (general out-patient, Family Medicine Spe-
cialist Clinic (FMSC), staff clinics) and appointment type
(new or subsequent visits) All these data were routinely
entered by clinic staffs when patients attended for consul-
tation, apart from service type. We further analyzed the
independent predictors of patients having received at least Page 3 of 9
(page number not for citation purposes) Discussion
Main findings g
The present study shows that the public clinical databases
on antihypertensive drugs in Hong Kong are complete in
demographic and socio-economic data, and 99.98% com-
plete in prescription details. Among patients receiving
antihypertensive prescription in the primary care system,
the proportion having any relevant disease code was rela-
tively modest (61.0%) when compared with other prac-
tices in Western countries. About one third (32.9%) of
patients were identified as uncomplicated hypertensive
(K86-only) patients with no exclusion conditions. There
was similarity however between the K86-only group and
non-coded groups in age and gender distribution, pay-
ment status as well as service types, suggesting that most
non-coded patients probably had uncomplicated hyper-
tension. The important independent positive predictors of
having an ICPC code were advanced age, female gender,
residence in urbanized district, service type being family
medicine specialty, and follow-up case. Distribution of codes and morbidities Out of the 57,041 patients (61.0%) with at least one ICPC
disease code, the majority (82.1%) had uncomplicated
hypertension (K86) followed by diabetes mellitus (T90,
27.3%), complicated hypertension (K87, 5.8%) and
benign prostatic hypertrophy (Y85, 5.1%) (Table 1). The
coding proportions of other relevant diseases were low. Among patients with at least one coded condition, 66.7%
had one code (or one condition) and 27.8% two or more
from the list of conditions shown in Table 1. Among
patients coded with K86, the figures are similar (65.5%
K86 only and 29.5% K86 coded with exclusion codes,
respectively). Factors associated with disease coding Multi-regression logistic regression was used to determine
the independent predictors of disease coding, i.e., the fac-
tors associated with whether a patient receiving antihyper-
tensive drugs had an ICPC disease code or not. Younger
patients (< 50 years) were less likely to be coded than
older patients (Table 3). Female patients were more likely
to be coded (aOR = 1.202, 95% C.I. 1.168, 1.238, p <
0.001). Patients living in Shatin district were more likely
to receive a code when compared to other less urbanized
regions (aOR range from 0.316 to 0.405). Patients visiting
family medicine specialist clinics were more likely to be
coded when compared to general out-patient clinics (aOR
= 1.448, 95% C.I. 1.362, 1.539, p < 0.001). Follow-up
cases were more likely to have a code (aOR = 2.394, 95%
C.I. 2.324, 2.467, p < 0.001). No significant association
was found between payment status and physician coding. resulting in 30,704 patients (32.9% of total) with uncom-
plicated hypertension (K86) without associated co-mor-
bidity (i.e., no exclusion codes). Most of the patients were receiving calcium channel
blockers (49%) and β-blockers (46%), followed by angi-
otensin converting enzyme inhibitors (19%) and thiazide
diuretics (13%). http://www.biomedcentral.com/1472-6963/8/138 http://www.biomedcentral.com/1472-6963/8/138 BMC Health Services Research 2008, 8:138 The breakdown of disease coding relevant to antihyperten-
sive (anti-HT) drug prescriptions
Figure 1
The breakdown of disease coding relevant to antihy-
pertensive (anti-HT) drug prescriptions. 1,096,282 visit episodes
(93,450 patients)
(patients on anti
(patients on anti--HT for unknown reasons)
HT for unknown reasons)
Received
> 1 anti-HT
In 2004-2007
No K86
and no
exclusion
coding
36,409
Patients with > 1 coding
(57,041 patients)
Patients coded K86,
AND without exclusion coding
(30,704 patients)
(425,324 anti-HT drug visit episodes)
No K86
but with
Exclusion
Codes
10,182
All Patients with K86 coding
(46,859 patients)
K86 coded +
exclusion
codes
16,155
Total
61.0%
50.1%
32.9%
of
total groups. Almost half of all patients lived in the Shatin
region, which is the most urbanized area in the NTE clus-
ter (Table 2). More patients from the K86-only group lived
in the Shatin district than the other groups. The non-
coded group had the smallest proportion of patients resid-
ing in Shatin (33%). 1,096,282 visit episodes
(93,450 patients)
(patients on anti
(patients on anti--HT for unknown rea
HT for unknown rea Most patients attended the primary care general out-
patient clinics for antihypertensive drugs, but the exclu-
sion group had more patients who attended FMSC. The
distribution of service types was similar between the K86-
only group and the non-coded group. Overall more than
half of the patients were 'new' in terms of antihypertensive
drug visits during the study period. The non-coded group
had the greatest proportion of new visits (66%), almost
twice as high as in the combined group (34.0%). Patients coded K86,
AND without exclusion coding
(30,704 patients)
(425,324 anti-HT drug visit episode The break
sive (anti-H
Figure 1 The break
sive (anti-H
Figure 1 The breakdown of disease coding relevant to antihyperten-
sive (anti-HT) drug prescriptions
Figure 1
The breakdown of disease coding relevant to antihy-
pertensive (anti-HT) drug prescriptions. The breakdown of disease coding relevant to antihyperten-
sive (anti-HT) drug prescriptions
Figure 1
The breakdown of disease coding relevant to antihy-
pertensive (anti-HT) drug prescriptions. Overall patient breakdown A total of 1,096,282 antihypertensive drug visits were
retrieved from January 2004 to June, 2007, representing
93,450 patients. Demographic and socio-economic
details were recorded for all patients. Prescription details
for anti-hypertensive drugs were missing in only 18
patients (0.02%), including drug dosage, frequency, or
prescription period, and a combination of these. Figure 1
shows the breakdown of disease coding relevant to anti-
hypertensive (anti-HT) drug prescriptions. Relevant ICPC-
codes were absent in 36,409 patients (39% of the total
sample); i.e., these patients had neither K86 nor any
exclusion code. The remaining 57,041 (61% of total)
patients had at least one relevant disease identified by an
ICPC code. Of these, 46,859 (50.1% of the total sample)
had uncomplicated hypertension (K86) coding, and
among these K86-coded patients, 16,155 patients
(17.2%) also had at least one additional (exclusion) code, Page 3 of 9
(page number not for citation purposes) Comparing patient characteristics among different coding
groups (SD) (95%
C.I.)
63.87(13.06)
68.22 (11.61)
68.45 (12.46)
61.77 (14.26)
64.30 (13.51)
<0.001
(63.73, 64.02)
(68.04, 68.40)
(68.21, 68.69)
(61.62, 61.91)
(64.21, 64.39)
Gender (No./%)
Male
11,323 (36.9)
7,442 (46.1)
6,153 (60.4)
15,412 (42.3)
40330 (43.2)
<0.001
Female
19,381 (63.1)
8,713 (53.9)
4,029 (39.6)
20,997 (57.7)
53120 (56.8)
Payment status
Fee-waivers
7,949 (25.9)
4,379 (27.1)
3,147 (30.9)
9,696 (26.6)
25,171 (26.9)
<0.001
Non- waivers
22,755 (74.1)
11,776 (72.9)
7,035 (69.1)
26,713 (73.4)
68,279 (73.1)
District of
residence
Shatin
18,510 (60.3)
8,817 (54.6)
5,524 (54.3)
12,120 (33.3)
44,971 (48.1)
<0.001
Taipo
6,780 (22.1)
2,883 (17.8)
1,773 (17.4)
11,156 (30.6)
22,592 (24.2)
North
4,068 (13.2)
3,721 (23.0)
2,206 (21.7)
10,684 (29.3)
20,679 (22.1)
Others
1,346 (4.4)
734 (4.5)
679 (6.7)
2,449 (6.7)
5,208 (5.6)
Service type
General
28,946 (94.3)
13,881 (85.9)
7,523 (73.9)
34,524 (94.8)
84,874 (90.8)
<0.001
FMSC/IC
1,625 (5.3)
2,260 (14.0)
2,618 (25.7)
1,673 (4.6)
8,176 (8.7)
Staff clinic
133 (0.4)
14 (0.1)
41 (0.4)
212 (0.6)
400 (0.4)
Appointment
type (no./%)
New case
14,705 (47.9)
5,485 (34.0)
4,784 (47.0)
23,831 (65.5)
48,805 (52.2)
<0.001
Old case
15,999 (52.1)
10,670 (66.0)
5,398 (53.0)
12,578 (34.5)
44,645 (47.8)
(*: Pearson Chi Square tests) Table 2: Patient characteristics according to K86 & exclusion coding The finding that older patients are more likely to be coded
can perhaps be explained by the presence of more mor-
bidities in the elderly group and perhaps more frequent
consulting (and hence likelihood of ICPC code being
entered on at least one occasion) which would also be the
case for the higher coding rates in the follow-up patients. The coding difference in different districts of residence
may possibly be explained by the concentration of train-
ing centres and teaching clinics in Shatin. The similarly
higher coding rate in FMSC can also be explained by the
more stringent coding requirement of specialty clinics. That higher likelihood of the female patients receiving a
code is also of interest and further exploration of the rea-
sons is needed. Interpretation of findings The completeness of the demographic, socio-economic,
and prescribing details relate to the way in which this
information is organized and documented within the e-
CMS. Patient must register at first attendance and the
demographic and socio-economic data is entered directly
into the computer system by administrative staff in the
reception office. Prescriptions can only be issued via the
CMS, including private prescriptions. Comparing patient characteristics among different coding
groups The whole study cohort had an average age of 64 years,
with the majority (61.2%) being 60 years old or over
(Table 2). Patients with uncomplicated hypertension
(K86-only group) had a similar age distribution to the
non-coded group. Overall there were more female than
male patients (Table 2). The K86-only and non-coded
groups had more female patients than the other two Page 4 of 9
(page number not for citation purposes) Page 4 of 9
(page number not for citation purposes) BMC Health Services Research 2008, 8:138 http://www.biomedcentral.com/1472-6963/8/138 Table 2: Patient characteristics according to K86 & exclusion coding
Coding
K86 coded &
without exclusion
codes (n = 30,704)
K86 coded with
exclusion codes (n
= 16,155)
No K86 but with
exclusion codes (n
= 10,182)
No K86 & no
exclusion codes
(36,409)
All cases (n =
93,450)
p value*
Patient
"K86 only group"
"combined group"
"Exclusion group"
"Non-coded group"
Age on appt. (no.%)
<50
4550(14.8)
1,073 (6.6)
791 (7.8)
7,484 (20.6)
13898(14.9)
<0.001
50–59
8116(26.4)
2,814 (17.4)
1,804 (17.7)
9,704 (26.7)
22438(24.0)
60–69
6954(22.6)
4,191(25.9)
2,421 (23.8)
7,516 (20.6)
21082(22.6)
≥70
11084(36.1)
8,077 (50.0)
5,166 (50.7)
11,705 (32.1)
36032(38.6)
Mean Age on
appt. Comparing patient characteristics among different coding
groups Thus we would
expect such data to be complete. ICPC codes on the other
hand are entered by the attending physicians during the
consultation. Most primary care clinics are extremely busy
(each doctor needs to handle 70–80 patients a day), and
short consultations are the norm rather than the exception
Thus it is perhaps unsurprising that ICPC codes were often
not entered into the e-CMS. Audit work has shown that
diagnoses are often entered into the hand written notes
rather than given an ICPC code (MCS Wong, unpublished
data). Since completion of the current study, the NTEC, HA has
reinforced its ICPC coding policy and the coding rate for
all diseases as of July, 2007 has been reported to be 87.7%
[information provided by statistics team of the Hospital
Authority Head Office, November 2007]. Thus in future Page 5 of 9
(page number not for citation purposes) Page 5 of 9
(page number not for citation purposes) BMC Health Services Research 2008, 8:138 http://www.biomedcentral.com/1472-6963/8/138 Table 3: Associated factors of coding by physicians
Coding
Coded* (n = 57,041)
Non-coded(n = 36,409)
Adjusted Odds Ratios** (95% C.I.)
p value
Patient
Age on appt. (no.%)
<50
6,414(11.2)
7,484(20.6)
1.000 (reference)
50–59
12,735(22.3)
9,704(26.7)
1.364(1.302, 1.429)
<0.001
60–69
13,566(23.8)
7,516(20.6)
1.774(1.692, 1.861)
<0.001
≥70
24,327(42.6)
11,705(32.1)
2.180(2.088, 2.277)
<0.001
Gender
Male
24,918(43.7)
15,412(42.3)
1.000 (reference)
Female
32,123(56.3)
20,997(57.7)
1.202(1.168,1.238)
<0.001
Payment status
Fee-waivers
15,475(27.1)
9,696(26.6)
Payers
41,566(72.9)
26,713(73.4)
Not significant
District of residence
Shatin
32,851(57.6)
12,120(33.3)
1.000 (reference)
Taipo
11,436(20.0)
11,156(30.6)
0.316(0.304, 0.327)
<0.001
North
9,995(17.5)
10,684(29.3)
0.330(0.318, 0.343)
<0.001
Others
2,759(4.8)
2,449(6.7)
0.405(0.381, 0.432)
<0.001
Service type
General
50,350(88.3)
34,524(94.8)
1.000 (reference)
FMSC
6,503(11.4)
1,673(4.6)
1.448(1.362, 1.539)
<0.001
Staff clinic
188(0.3)
212(0.6)
0.940(0.760, 1.162)
0.565
Appointment type (no./%)
New case
24,974(43.8)
23,831(65.5)
1.000 (reference)
Old case
32,067(56.2)
12,578(34.5)
2.394(2.324, 2.467)
<0.001
(FMSC: Family Medicine Specialist Clinic. *Coded group refers to patients having at least one code, either K86 or exclusion coding. **represent
odds ratios after controlling for all the predictor variables) Table 3: Associated factors of coding by physicians cialist Clinic. *Coded group refers to patients having at least one code, either K86 or exclusion coding. **represent
for all the predictor variables) (FMSC: Family Medicine Specialist Clinic. *Coded group refers to patients having at least one code, either K86 or ex
odds ratios after controlling for all the predictor variables) ers. Comparing patient characteristics among different coding
groups The GPRD in UK consists of information from prac-
tices which are up to standard, requiring the practice to
record a minimum of 95% of prescribing and relevant
patient-encounter events [45]. Also data from practices are
routinely under internal checks for validity [34], and each
practice will be sent a validation report after data collec-
tion. work using this database substantially higher percentages
of disease coded data for patients with hypertension and
other chronic conditions seems likely. Relationship to published literature p
p
Many studies have used different diseases to validate local
databases. For the GPRD database in the UK, hospital
investigations and death certificates have been adopted to
support the validity of disease codes for deep vein throm-
bosis and pulmonary embolism [32]. Questionnaires
posted to general practitioners have been used to verify
the diagnosis and severity of chronic obstructive pulmo-
nary diseases for validation of the OXMIS codes of GPRD
[33]. Both studies found good agreement between data-
base disease codes and the tools used for validation, and
concluded that GPRD is of sufficiently high quality for
epidemiological research. Other methods for database
validation include the use of morbidity surveys and
national data to compare with database information
[34,35], which reported similar database usefulness. Many studies on GPRD mainly focused on the complete-
ness and quality of computer recorded data [36,37]. GPRD has been used to address a variety of clinical issues,
including pharmaco-epidemiology and medication safety
[38], rheumatoid diseases [39,40], gout [41,42], diabetes
[43], and sexually transmitted infections [44], among oth- We are unaware of any published work on validation of
the accuracy of disease codes in the HA e-CMS in Hong
Kong, but clearly this would be an important area for
future work if more rigorous health services research is
planned. However, a first step is the need for implementa-
tion of a quality control system and the necessary organi-
zational changes to ensure more complete data entry in
terms of ICPC disease codes. Page 6 of 9
(page number not for citation purposes) Authors' contributions MCSW has contributed to the conception, design, data
acquisition, analysis of data and prepared the first draft of
this paper. JYJ and J–LT contributed to refining the meth-
odology, data analysis, and intellectual input to data
interpretation; AL, HF and SWM contributed to amend-
ment of initial study design, analysis of data, and critically
revising the manuscript. All authors have read and
approved the final manuscript. SWM is guarantor for the
study. http://www.biomedcentral.com/1472-6963/8/138 BMC Health Services Research 2008, 8:138 However, this study also has some weaknesses. Firstly,
there are no external data to support the validity of the
database. We regarded the ICPC code as the 'gold stand-
ard' in categorizing our study cohort. The accuracy of
these codes however, has not been formally validated
against data from case notes or those from the secondary
care sector (which uses International Classification of Dis-
eases (ICD) codes). However, given the relatively straight-
forward diagnosis of uncomplicated hypertension we
believed the biases may be minimal. Secondly, these data
apply only to the NTE cluster, which represents only one
of seven organisational units within the HA in Hong
Kong. Thus we cannot know if the issues raised in the
study apply across the public healthcare system in Hong
Kong, although we have no reason to suspect that NTE is
different organizationally that other clusters. Thirdly, due
to gradual implementation of the e-CMS system and the
disruption of SARS in 2003 the present study could not
evaluate ICPC coding before 2004, and some of the 'un-
coded' patients in the present study could have been
coded by physicians pre-2004 into hand-written records
or free text space. However, since January 2004, all doctors
in the clinics are required to use the computer system as
the sole portal of information entry and patients with
ICPC codes in hand-written notes or free text before Janu-
ary 2004 should have had that information re-entered
into the e-CMS at consultations during the study period. However, the ICPC code need only be entered once to be
counted as a 'coded patient' (not re-coded at every consul-
tation). ers where data recording protocols are more stringently
managed and implemented. Further studies are needed to
validate the accuracy and completeness of CDARS and
CMS in Hong Kong by more rigorous testing. These
include comparison of cluster-representative surveys with
data generated for each disease entity to ensure they are
representative, and exploration of the disease status of
uncoded patients by case-note reviews to test whether the
uncoded group is likely to have uncomplicated hyperten-
sion only. Since prescription details are virtually complete, this data-
base has the potential to study the patterns of antihyper-
tensive prescription, profiles of drug discontinuation and
switching, and the association of antihypertensive drug
class to clinical outcomes like mortality. Work is under-
way currently on all these areas of enquiry. Acknowledgements The authors would like to acknowledge the support of the Hospital
Authority, Hong Kong and the input by colleagues in the Primary Care
research Group of the School of Public Health, Chinese University of Hong
Kong for their generous support to this project. SW Mercer conducted this
work as Visiting Professor in Primary Care Research at the School of Public
Health, Chinese University of Hong Kong. Conclusion
h
d The e-CMS database of the HA in Hong Kong varies in
quality in terms of recorded information. Potential future
health services research using demographic and prescrip-
tion information is highly feasible but for disease-specific
research dependant on ICPC codes some caution is war-
ranted. In the case of uncomplicated hypertension, future
research on pharmaco-epidemiology (such as prescrip-
tion patterns) and clinical issues (such as side-effects of
medications on metabolic parameters) seems feasible
given the large size of the data set and the comparability
of coded and non-coded patients. Implications for policy and practice Hypertension is an important chronic disease globally
and locally in Hong Kong. The large numbers of electronic
patient records and completeness of some information
could potentially serve to help addressing this condition
in important areas of health services research, such as drug
prescription profiles and health service utilization pat-
terns. The scale of the database also has potential in clini-
cal epidemiological research with linkage between the
needs of the populations served, their geographical loca-
tion, and the availability of high quality primary care on
the basis of such needs. Data protection issues should
however be observed by researchers; the present database
is anonymized having only identity numbers without
patient contact details hence enhancing its data safety. In
practical terms, there are simple steps that can be initiated
at minimal cost, to enhance the quality of the e-CMS data. For example, guidelines on ICPC coding for the clinical
staff may be helpful, and system changes which require
the entry of ICPC codes as compulsory rather than
optional. Our finding that more family medicine special-
ist clinics are likely to have coding supports the effective-
ness of routine data protocols in enhancing disease
coding rates, because these clinics are doctor training cent- The authors declare that they have no competing interests. The authors declare that they have no competing interests. Strengths and weaknesses of current study The major strength of this study was the availability of a
large amount of electronic patient data on antihyperten-
sive medication over a three and a half year period from
which we could ascertain the potential and pitfalls of
using such data in health services research in the public
healthcare system in Hong Kong. We have done this in a
systematic way, and included robust statistical analysis to
aid interpretation. Page 6 of 9
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Nolfo MA, Del Poggio P, Benvegnu L, Rapaccini G, Farinati F, Zoli M,
Borzio F, Giannini EG, Caturelli E, Bernardi M, Italian Liver Cancer 1. Trevisani F, Magini G, Santi V, Morselli-Labate AM, Cantarini MC, Di
Nolfo MA, Del Poggio P, Benvegnu L, Rapaccini G, Farinati F, Zoli M,
Borzio F, Giannini EG, Caturelli E, Bernardi M, Italian Liver Cancer Page 7 of 9
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KG: Gout epidemiology: results from the UK General Prac-
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Database. Lancet 1997, 350:1097-99. Pre-publication history The pre-publication history for this paper can be accessed
here: The pre-publication history for this paper can be accessed
here: http://www.biomedcentral.com/1472-6963/8/138/pre
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|
https://openalex.org/W3109510654
|
https://pubs.rsc.org/en/content/articlepdf/2021/ra/d1ra05451a
|
English
| null |
X-ray excited luminescence spectroscopy and imaging with NaGdF<sub>4</sub>:Eu and Tb
|
RSC advances
| 2,021
|
cc-by
| 9,649
|
X-ray excited luminescence spectroscopy and
imaging with NaGdF4:Eu and Tb† Meenakshi Ranasinghe,
a Md. Arifuzzaman,
a Apeksha C. Rajamanthrilage,
a
W. R. Willoughby,b Ashley Dickey,a Colin McMillen,a Joseph W. Kolis,a Mark Boldingb
and Jeffrey N. Anker
*a Meenakshi Ranasinghe,
a Md. Arifuzzaman,
a Apeksha C. Rajamanthrilage,
a
W. R. Willoughby,b Ashley Dickey,a Colin McMillen,a Joseph W. Kolis,a Mark Boldingb
and Jeffrey N. Anker
*a X-ray excited optical luminescence from nanophosphors can be used to selectively generate light in tissue
for imaging and stimulating light-responsive materials and cells. Herein, we synthesized X-ray scintillating
NaGdF4:Eu and Tb nanophosphors via co-precipitate and hydrothermal methods, encapsulated with
silica, functionalized with biotin, and characterized by X-ray excited optical luminescence spectroscopy
and imaging. The nanophosphors synthesized by co-precipitate method were 90 and 106 nm in
diameter, respectively, with hydrothermally synthesized particles showing the highest luminescence
intensity. More importantly, we investigated the effect of thermal annealing/calcination on the X-ray
excited luminescence spectra and intensity. At above 1000 C, the luminescence intensity increased, but
particles fused together. Coating with a 15 nm thick silica shell prevented particle fusion and enabled
silane-based chemical functionalization, although luminescence decreased largely due to the increased
mass of non-luminescent material. We observed an increase in luminesce intensity with temperature
until at 400 C. At above 600 C, NaGdF4:Eu@SiO2 converts to NaGd9Si6O26:Eu, an X-ray scintillator
brighter than annealed NPs at 400
C and dimmer than NPs synthesized using the hydrothermal
method. The particles generate light through tissue and can be selectively excited using a focused X-ray
source for imaging and light generation applications. The particles also act as MRI contrast agents for
multi-modal localization. Received 15th July 2021
Accepted 16th September 2021
DOI: 10.1039/d1ra05451a
rsc.li/rsc-advances Received 15th July 2021
Accepted 16th September 2021 DOI: 10.1039/d1ra05451a
rsc.li/rsc-advances subatomic particles) and emit UV, visible and/or NIR light.1,2
These materials are widely used in radiation detection3 and
imaging applications,4–6 and occasionally in external power-free
light generation applications (e.g., old luminescent watches,
emergency lighting and gun sites).7 Recently, researchers have
been developing scintillator nanophosphors for improved X-ray
luminescence
imaging,8–10
radiation
imaging,9,11,12
and
as
a potential light source for photochemistry and photobiology
(e.g., X-ray excited optogenetics13). aDepartment of Chemistry, Center for Optical Materials Engineering and Technology
(COMSET), Clemson University, Clemson, SC, USA. E-mail: janker@clemson.edu
bDepartment of Radiology, University of Alabama at Birmingham School of Medicine,
Birmingham, AL, USA
† Electronic
supplementary
information
(ESI)
available.
See
DOI:
10.1039/d1ra05451a RSC Advances Cite this: RSC Adv., 2021, 11, 31717
Received 15th July 2021
Accepted 16th September 2021
DOI: 10.1039/d1ra05451a
rsc.li/rsc-advances
PAPER
Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online
View Journal | View Issue Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Introduction Light can be a powerful tool for studying biochemistry in cells
and tissue and for stimulating responses from genetically
engineered light-sensitive neurons (optogenetics) or photo-
released drugs. The challenge for delivering or retrieving light
from deep tissue is that scattering in the tissue prevents light
from travelling ballistically, and the point spread function is
typically >1 cm through 1 cm of tissue, also the light is atten-
uated by the tissue.1,2 One approach that circumvents these
problems is to use selectively generate light using focused X-ray
beams to generate visible luminescence from scintillators
implanted or injected in the tissue. Since X-rays are far less
scattered than visible and near-infrared light, the X-ray beam
focus can be maintained through the tissue and generate visible
light locally aer absorption by scintillator particles. Scintilla-
tors are luminescent materials that absorb high-energy radia-
tion (g- and X-ray photons, high energy ions, neutrons, or other Rare-earth doped materials (NaGdF4:Eu14,15 and Tb,16 GdO2-
S2:Eu and Tb,10 YAG:Nd, LuAG:Tm, Lu2SiO5:Ce17) have inter-
esting
properties
including
narrow
and
distinct
spectral
emission peaks, large optical penetration depth, negligible
autouorescence background, photochemical stability and low
toxicity.6 Among them, rare-earth uorides (NaGdF4) are
considered excellent host matrices for luminescent rare earth
elements (e.g., Eu and Tb). They usually have high refractive
indices and low phonon energies, which cause a low probability
of nonradiative decay and higher luminescent quantum yields
compared to oxide hosts and other inorganic matrices.18 Herein, we synthesize 100 nm diameter NaGdF4:Eu and
NaGdF4:Tb nanophosphors for X-ray excited luminescence. This diameter is in a good range for long circulation as nano-
particles smaller than 5.5 nm undergo relatively fast blood RSC Adv., 2021, 11, 31717–31726 | 31717 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online View Article Online RSC Advances RSC Advances Paper Fig. 1
(A) Schematic illustration of nanophosphors synthesis accord-
ing to co-precipitate method. (i) Mixture of Gd(NO3)3 and Eu(NO3)3 or
Tb(NO3)3, (ii) Ln3+–citrate3 complex appears as a clear solution, (iii)
formation of NaGdF4:Ln3+ nanophosphors. Zoom out TEM images of
(B1) NaGdF4:Eu and (C1) NaGdF4:Tb nanophosphors. Zoom in TEM
images of (B2) NaGdF4:Eu and (C2) NaGdF4:Tb nanophosphors. Histograms of the average diameter of (B3) NaGdF4:Eu and (C3)
NaGdF4:Tb. Powder XRD pattern compared to PDF cards 27-0699 of
(B4) NaGdF4:Eu and (C4) NaGdF4:Tb. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. We also compared X-ray excited optical luminescence
(XEOL)
spectra
from
hydrothermal
and
co-precipitation
synthesis methods and the effect of thermal annealing. Nano-
particle annealing at high temperature is a widespread method
in upconversion nanophosphors to enhance luminescence10,23,24
by reducing crystal defect, increasing crystal domain size and
removing
trapped
water
and
carbon
dioxide. However,
enhancing luminescence of X-ray excited nanophosphors using
annealing techniques is still under investigation. Here, we
synthesized both NaGdF4:Tb and NaGdF4:Eu, which have
distinct spectra. The nanophosphors were functionalized with
biotin and attach to streptavidin in vitro. They could be selec-
tively excited in a solution using a focused X-ray source to obtain
XEOL spectroscopy and to image through tissue; here we
focused on the NaGdF4:Eu because their red emission has
deeper penetration through tissue than the largely green emit-
ting NaGdF4:Tb.25,26 Additionally, the particles serve as T1 and T2
MRI contrast agents which would be useful for multi-modal
imaging applications. Results and discussion We synthesized NaGdF4:Eu and NaGdF4:Tb nanophosphors via
co-precipitation and hydrothermal methods and studied the
effect of dopant concentration on their optical spectra and
crystal diffraction patterns. Next, we encapsulated the nano-
phosphors in silica to prevent thermal sintering and studied the
effect of thermal treatment. We functionalized the nano-
phosphors with biotin and showed that we could excite
colloidal suspensions of particles with a focused X-ray beam
and image the luminescence through tissue. Finally, we
explored the possibility of multimodal imaging based on spec-
trally distinct features of the nanophosphors as well as MRI
contrast. Fig. 1
(A) Schematic illustration of nanophosphors synthesis accord-
ing to co-precipitate method. (i) Mixture of Gd(NO3)3 and Eu(NO3)3 or
Tb(NO3)3, (ii) Ln3+–citrate3 complex appears as a clear solution, (iii)
formation of NaGdF4:Ln3+ nanophosphors. Zoom out TEM images of
(B1) NaGdF4:Eu and (C1) NaGdF4:Tb nanophosphors. Zoom in TEM
images of (B2) NaGdF4:Eu and (C2) NaGdF4:Tb nanophosphors. Histograms of the average diameter of (B3) NaGdF4:Eu and (C3)
NaGdF4:Tb. Powder XRD pattern compared to PDF cards 27-0699 of
(B4) NaGdF4:Eu and (C4) NaGdF4:Tb. synthesized using the co-precipitate method at room tempera-
ture were approximately spherical in shape (Fig. 1B1 and C1). The Eu-doped and Tb-doped nanophosphors respective had
average diameters of 90 nm (Fig. 1A2) and 106 nm (Fig. 1C2). The powder X-ray diffraction (powder-XRD) peaks displayed the
presence of hexagonal (b-phase) NaGdF4 (Fig. 1B3 and C3)
indexed to the standard data (JCPDS 00-027-0699), with rela-
tively large peak with indicating small crystal domain sizes (55
˚A NaGdF4:Eu and 53 ˚A NaGdF4:Tb according to the Scherrer
equation based on peak at 16.8 degrees). TEM images and Introduction clearance
by
renal
ltration,
nanoparticles
smaller
than
70 nm lter through fenestrae of hepatic sinusoids,19–21 while
nanoparticles between 200–500 nm are endocytosed by phago-
cytic or non-phagocytic cells and nanoparticles larger than
500 nm are likely to remove form cells by phagocytosis.19,22 Thus
nanoparticles with 100 nm diameter have shown the minimum
effect on blood clearance mechanisms (ex. renal, liver ltration)
and prolonged circulation time.20,21 These intermediate size
nanoparticles tend to accumulate in perivascular spaces of
permeable tissues (ex. liver and spleen, tumour, site of inam-
mation and angiogenesis)19,20 allowing bicomponent imaging. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. The optical properties of rare-earth doped nanophosphors
depend upon the doping ions and crystalline matrix. Fig. 2
shows the X-ray excited optical luminescence spectrum of
NaGdF4:Eu. There are three characteristic peaks in the visible
range of the electromagnetic spectrum, at around 589 nm,
615 nm and 691 nm that corresponding to 5D0 / 7F1, 5D0 /
7F2, 5D0 / 7F4 transitions.10,14 Tb doped NaGdF4 have four
characteristic peaks in the visible range, at around 489 nm,
543 nm, 585 nm and 620 nm that corresponding to 5D4 / 7F6,
5D4 / 7F5, 5D4 / 7F4, 5D4 / 7F3 transitions.10,29 Since the
luminescence
intensity
depends
upon
dopant
concentra-
tion,30,31 we varied the amount of Eu and Tb compared to Gd3+
in the reaction mixture. Fig. 2A and B show the luminescence
spectra for Eu- and Tb-doped nanophosphors, respectively. The
dopant:Gd molar concentration ratios in the NaGdF4 synthesis
reaction were 0.1% (bottom), 1%, 15%, 20% and 100% (top). A
base value has been added to each spectrum to avoid spectral
overlapping. At low and high molar ratios of both Eu and Tb
doped NaGdF4 nanophosphors showed low luminescence
intensity due to lack of luminescence centres and self-
quenching
(cross
relaxation
between
two
neighbouring
Eu3+),30 respectively. Intermediate concentrations, 1%, 15% and
20% in Eu-doped NaGdF4 showed the highest although similar
luminescence intensities. In Tb-doped NaGdF4 20% showed the
highest intensity. Fig. 3
(A) Schematic illustration of nanophosphors synthesis accord-
ing to co-precipitate method. (i) Mixture of Gd(NO3)3 and Eu(NO3)3 or
Tb(NO3)3, (ii) Ln3+–citrate3 complex appears as a clear solution, (iii)
formation of NaGdF4:Ln3+ nanophosphors, (iv) hydrothermally treated
NaGdF4:Ln3+ nanophosphors. TEM images of hydrothermally treated
(B1) NaGdF4:Eu and (B2) NaGdF4:Tb nanophosphors. (B3) Powder XRD
pattern
compared
to
PDF
cards
27-0699
of
NaGdF4:Eu
and
NaGdF4:Tb. nanophosphors recrystallize to rearrange the crystal structure. nanophosphors recrystallize to rearrange the crystal structure. The
nanophosphors
synthesized
using
the
co-precipitate
method at room temperature were hydrothermally treated to
increase the crystallinity and thereby, enhance the X-ray lumi-
nescence intensity. The hydrothermally treated nanophosphors
were irregularly shaped (Fig. 3B1 and B2) as nanophosphors are
starting to aggregate and fuse at high temperature. However,
narrow peaks in the powder XRD pattern (Fig. 3B3) conrmed
the
increased
crystallinity
compared
to
nanophosphors
synthesized at room temperature. (179 ˚A NaGdF4:Eu and 128
˚A NaGdF4:Tb according to the Scherrer equation based on peak
at 17 degrees). NaGdF4:Eu and NaGdF4:Tb nanoparticle synthesis In the NaGdF4 nanophosphor synthesis, citrate acts as a com-
plexing and dispersing agent that forms a La3+–Cit3 complex
and disperse in deionized (DI) water. Upon addition of excess
NaF, La3+ released from the complex reacts with Na+ and F to
form NaGdF4 nuclei. Aer the formation of NaGdF4:Eu and Tb,
the citrate serves as a surfactant which controls nanoparticle
growth and prevents aggregation.15,27 Co-precipitate
synthesis
method. The
co-precipitate
synthesis process is presented in Fig. 1A. The nanophosphors © 2021 The Author(s). Published by the Royal Society of Chemistry 31718 | RSC Adv., 2021, 11, 31717–31726 View Article Online Paper RSC Advances powder-XRD patterns of Eu- and Tb-dopped NaGdF4 (0.1, 1, 15,
20 and 100%) are included in ESI S1.† The synthesized nano-
phosphors show powder-XRD peak shicompared to standard
peak positions (ex. peaks at around 53). This observation is
common in most powder-XRD patterns due to changes in
stoichiometric composition by doping (size and amount of
dopant), microstructure parameters (crystallite size and lattice
strain).28 X-ray luminescence nanophosphors with low emission
intensity are used in X-ray luminescence computer tomography
(XLCT) and focused X-ray luminescence tomography (FXLT).11 Fig. 3
(A) Schematic illustration of nanophosphors synthesis accord-
ing to co-precipitate method. (i) Mixture of Gd(NO3)3 and Eu(NO3)3 or
Tb(NO3)3, (ii) Ln3+–citrate3 complex appears as a clear solution, (iii)
formation of NaGdF4:Ln3+ nanophosphors, (iv) hydrothermally treated
NaGdF4:Ln3+ nanophosphors. TEM images of hydrothermally treated
(B1) NaGdF4:Eu and (B2) NaGdF4:Tb nanophosphors. (B3) Powder XRD
pattern
compared
to
PDF
cards
27-0699
of
NaGdF4:Eu
and
NaGdF4:Tb. Silica-coating NaGdF4:Eu and Tb nanophosphors NaGdF4:Eu nanophosphors, synthesized at room temperature,
were coated with silica before further experiments. The silica
can protect nanophosphors from aggregation and facilitate
functionalization for biological applications. Fig. 5A presents
the NaGdF4 silica coating process. In electron microscopy
images (Fig. 6B1) the silica coating appeared as a 15 nm thick
shell around the nanophosphors. The average diameter of
NaGdF4:Eu@SiO2 nanophosphors was about 120 nm (Fig. 5B2). Both Tb-doped
and Eu-doped nanophosphors
showed
reduced X-ray luminescence aer coating with silica for the
same mass of material. Aer coating, the NaGdF4:Eu nano-
phosphors reduced intensity by 42% (Fig. 7A). This is largely
explained by the additional silica which increased the mass by
65% (based on particle diameter, coating thickness, and density
of NaGdF4 core and silica shell), while not providing any addi-
tional luminescent material. NaGdF4:Eu nanophosphors, synthesized at room temperature,
were coated with silica before further experiments. The silica
can protect nanophosphors from aggregation and facilitate
functionalization for biological applications. Fig. 5A presents
the NaGdF4 silica coating process. In electron microscopy
images (Fig. 6B1) the silica coating appeared as a 15 nm thick
shell around the nanophosphors. The average diameter of
NaGdF4:Eu@SiO2 nanophosphors was about 120 nm (Fig. 5B2). Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. 7
XEOL spectra of silica-coated (A) NaGdF4:Eu and (B) NaGdF4:Tb
compared to NaGdF4:Eu and NaGdF4:Tb synthesized using co-
precipitate method. Paper
View Article Online View Article Online View Article Online Paper RSC Advances Fig. 5
Metal composition of nanophosphors calculated using ICP-
OES measurements. The graph of percent metal ratio of nano-
phosphor vs. percent molar fraction of dopant added of NaGdF4:Eu
synthesized by (A1) co-precipitate and (A2) hydrothermal methods and
NaGdF4:Tb synthesized by (B1) co-precipitate and (B2) hydrothermal
methods. Note, the amount of Tb in NaGdF4:0.1%Tb was not calcu-
lated as it is lower than the limit of detection of the instrument. Fig. 7
XEOL spectra of silica-coated (A) NaGdF4:Eu and (B) NaGdF4:Tb
compared to NaGdF4:Eu and NaGdF4:Tb synthesized using co-
precipitate method. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Fig. 7
XEOL spectra of silica-coated (A) NaGdF4:Eu and (B) NaGdF4:Tb
compared to NaGdF4:Eu and NaGdF4:Tb synthesized using co-
precipitate method. (i.e., nanophosphors incorporated 20% more Eu than was
added to the reagent mixture) and 1.3 for the NaGdF4:Tb (i.e.,
nanophosphors incorporated 30% more Eu than was added to
the reagent mixture), suggesting increases in thermodynamic
stability or kinetic reaction rates during synthesis. Fig. 5
Metal composition of nanophosphors calculated using ICP-
OES measurements. The graph of percent metal ratio of nano-
phosphor vs. percent molar fraction of dopant added of NaGdF4:Eu
synthesized by (A1) co-precipitate and (A2) hydrothermal methods and
NaGdF4:Tb synthesized by (B1) co-precipitate and (B2) hydrothermal
methods. Note, the amount of Tb in NaGdF4:0.1%Tb was not calcu-
lated as it is lower than the limit of detection of the instrument. Inductive coupled plasma-optical emission spectroscopy (ICP-
OES) metal analysis ICP-OES analysis was performed for Gd, Eu and Tb to determine
the Eu/Gd and Tb/Gd ratios of the synthesized nanophosphors,
which determine X-ray luminescence intensity. All four types of
samples
(NaGdF4:Eu
and
NaGdF4:Tb
synthesized
by
co-
precipitate
and
hydrothermal
methods)
show
increased
percent metal ratio as the fraction of dopant added increases. The amount of dopant in the nal systems was directly
proportional to amount added to the reagent mix, with a slope
of 1.2 for both the coprecipitated and hydrothermal NaGdF4:Eu Both Tb-doped
and Eu-doped nanophosphors
showed
reduced X-ray luminescence aer coating with silica for the
same mass of material. Aer coating, the NaGdF4:Eu nano-
phosphors reduced intensity by 42% (Fig. 7A). This is largely
explained by the additional silica which increased the mass by
65% (based on particle diameter, coating thickness, and density
of NaGdF4 core and silica shell), while not providing any addi-
tional luminescent material. Fig. 6
(A) Schematic illustration of nanoparticle coating with silica. (i)
NaGdF4:Ln3+ nanophosphors, (ii) silica-coated NaGdF4:Ln3+ nano-
particles. (B1) TEM images of silica-coated NaGdF4 nanophosphors
Eu-doped. (B2)
Histograms
of
the
diameter
of
silica-coated
NaGdF4:Eu. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. TEM images and powder-XRD patterns of 0.1–
100% Eu- and Tb-dopped NaGdF4 are included in ESI S2.† Hydrothermally treated nanophosphors showed enhanced
X-ray luminescence intensity by a factor of 2–2.5 compared to
nanophosphors synthesized at room temperature. 15% Eu
doped NaGdF4 showed the highest intensity however, 1% and
20% Eu doped NaGdF4 showed high values close to the highest
intensity (Fig. 4A). The X-ray luminescence intensity of 15% Tb
doped NaGdF4 had the highest intensity and 20% Tb doped
NaGdF4 showed an intensity close to the highest value (Fig. 4B) Hydrothermal
synthesis
method. The
hydrothermal
synthesis process is presented in Fig. 3A. The crystallinity of
inorganic crystals plays an important role in X-ray luminescence
intensity where large crystal domain size results in high lumi-
nescence
intensity.10
During
the
hydrothermal
process, Fig. 2
X-ray excited optical luminescence (XEOL) of (A) NaGdF4:Eu
and (B) NaGdF4:Tb nanophosphors. Eu and Tb dopant fraction (mol%
added to reagents vs. Gd) of NaGdF4 nanophosphors varied from 0.1%
to 100%. X-ray luminescence intensities of nanophosphors were
normalized to the 620 nm peak intensity from commercial GOS:Eu
and Tb microphosphors. Spectra have been vertically displaced for
ease of comparison. Fig. 4
XEOL of hydrothermally treated (A) NaGdF4:Eu and (B)
NaGdF4:Tb nanophosphor. Mol fraction of Eu and Tb dopant vs. Gd in
regent mixture varied from 0.1% to 100%. X-ray luminescence inten-
sities of nanophosphors were normalized to the height of 620 nm peak
of commercial GOS:Eu and Tb microparticles. Spectra have been
vertically displaced by adding a baseline for ease of comparison. Fig. 2
X-ray excited optical luminescence (XEOL) of (A) NaGdF4:Eu
and (B) NaGdF4:Tb nanophosphors. Eu and Tb dopant fraction (mol%
added to reagents vs. Gd) of NaGdF4 nanophosphors varied from 0.1%
to 100%. X-ray luminescence intensities of nanophosphors were
normalized to the 620 nm peak intensity from commercial GOS:Eu
and Tb microphosphors. Spectra have been vertically displaced for
ease of comparison. Fig. 4
XEOL of hydrothermally treated (A) NaGdF4:Eu and (B)
NaGdF4:Tb nanophosphor. Mol fraction of Eu and Tb dopant vs. Gd in
regent mixture varied from 0.1% to 100%. X-ray luminescence inten-
sities of nanophosphors were normalized to the height of 620 nm peak
of commercial GOS:Eu and Tb microparticles. Spectra have been
vertically displaced by adding a baseline for ease of comparison. © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2021, 11, 31717–31726 | 31719 Fig. Thermal analysis The stability of the nanophosphors towards heat was studied by
thermal gravimetric analysis (TGA) and differential scanning
calorimetry (DSC) thermograms as in Fig. 8A and B. NaGdF4:Eu
and
NaGdF4:Tb
synthesized
using
co-precipitate
method Fig. 8
(A) TGA and (B) DSC of NaGdF4:Eu and NaGdF4:Tb nano-
phosphors
synthesized
using
co-precipitate
and
hydrothermal
methods and NaGdF4:Eu@SiO2. Fig. 6
(A) Schematic illustration of nanoparticle coating with silica. (i)
NaGdF4:Ln3+ nanophosphors, (ii) silica-coated NaGdF4:Ln3+ nano-
particles. (B1) TEM images of silica-coated NaGdF4 nanophosphors
Eu-doped. (B2)
Histograms
of
the
diameter
of
silica-coated
NaGdF4:Eu. Fig. 8
(A) TGA and (B) DSC of NaGdF4:Eu and NaGdF4:Tb nano-
phosphors
synthesized
using
co-precipitate
and
hydrothermal
methods and NaGdF4:Eu@SiO2. © 2021 The Author(s). Published by the Royal Society of Chemistry 31720 | RSC Adv., 2021, 11, 31717–31726 RSC Advances
View Article Online View Article Online Paper RSC Advances showed total weight loss of 12.5% and 12.1% respectively. Their
highest weight loss appeared at 62.5 C is attributed to the loss
of trapped H2O, and weight loss above 250 C may cause by the
decomposition of citrate. The nanophosphors synthesized
using the hydrothermal method indicated 3.10% (NaGdF4:Eu)
and 5.17% (NaGdF4:Tb) total weight loss. There is no signicant
weight loss caused by vaporization of trapped H2O. Also, the
weight loss above 250 C is less intense than the weight loss of
co-precipitate method. Silica coated-NaGdF4:Eu has total weight
loss of 17.4%. Its weight loss at 65.5 C is attributed to the loss
of trapped H2O and ethanol. The peaks above 250 C are more
intense than for uncoated nanophosphors and likely caused by
decomposition of citrate and PVP organic materials (ESI
Fig. S4B and C†). Further, a DSC thermogram shows that
vaporization and decomposition are both exothermic processes. The TGA thermogram shows that nanophosphors synthesized
by the hydrothermal method contain less trapped water and
organic materials, which may result in high X-ray luminescence
intensity. Fig. 10
TEM images of NaGdF4:Eu@SiO2 nanophosphors annealed at
(A) 400 C, (B) 600 C (C) 1000 C. Fig. 10
TEM images of NaGdF4:Eu@SiO2 nanophosphors annealed at
(A) 400 C, (B) 600 C (C) 1000 C. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. (Fig. 10C) caused the nanophosphors to aggregate, although not
to the extent of forming the large porous structures observed
without coating (Fig. 7C). Thermal analysis Annealing at 400 C and 1000 C increased the luminescence
intensity by a factor of 1.5 and 3 compared to unannealed
silica-coated nanophosphors. Among the three annealing
temperatures, 1000 C showed the highest intensity (Fig. 11A). We also observed that XEOL spectrum red-shied at high
temperature (600 C and 1000 C). This spectral shicould
potentially be useful for generating nanophosphors with
distinguishable spectra for multi-modal imaging, and likely
arises from changes in composition and crystal eld. (XEOL
graphs of synthesized, annealed and silica coated NPs are
included in ESI Fig. S3† to compare). Indeed, powder-XRD data
conrmed
the
formation
of
sodium
gadolinium
silicate
compound by reacting with the silica layer: XRD spectra display
the presence of NaGd9Si6O26:Eu (Fig. 11B) indexed to the stan-
dard data (JCPDS 00-056-0184). Additionally, we observed that
the 1000 C annealed samples have sharper diffraction peaks
indicating
larger
crystal
domains,
which
likely
reduces
quenching from the surface and defects.10 Also, at 1000 C, the
nanophosphors have started to aggregate. On balance, the
1000 C annealing appeared to give the best performance, albeit
with a spectral shi. XEOL graphs of NaGdF4:15%Eu annealed
at 150, 400 and 1000 C for 12 h are included in ESI S5.† Annealing NaGdF4:Eu nanophosphors Nanophosphors synthesized using the co-precipitate method
and coated with silica have relatively low luminescence inten-
sity which hinders most in vivo applications such as deep tissue
imaging
and
implantable
biosensors. High
temperature
annealing could enhance luminescence by removing crystal
defects, increasing crystal domain size and removing trapped
water and carbon dioxide.23,24 Unfortunately, when we annealed
our nanophosphors at temperatures above 700 C, we found
that the particles aggregated. For example, Fig. 9A shows that
aer thermal annealing at 1000
C, the NaGdF4:Eu nano-
phosphors aggregated and fused making a structure too large
for many biological applications. However, the luminescence
intensity was increased by a factor of 7 compared to nano-
phosphors synthesized by the co-precipitate method. Biotin functionalized NaGdF4:Eu@SiO2 Exposure time
was 10 s without tissue and 60 s through tissue. dispersion of surface-modied
physiological pH and high ion
biotin-functionalization was dem
streptavidin-functionalized
bu
(Fig. 12). X-ray excited optical luminescen
of capillaries lled with NaGdF4
XEOL spectroscopy and imagin
strate the ability to excite the n
and show that the luminescence
regions using a focused X-ray sou
breast because 5 mm is suffici
Fig. 12
Schematic illustration of (
functionalized with biotin (i) silica-co
(ii) amine-functionalized nanophos
nanophosphors. Biotin is connecte
phosphors via sulfo-NHS groups,
phosphors attach to streptavidin
streptavidin-coated
silica
microbu
nanophosphors attached to strepta
(C)
SEM
image
showing
biotin
attached to streptavidin-coated mic
Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Fig. 12
Schematic illustration of (A) silica coated nanophosphors
functionalized with biotin (i) silica-coated NaGdF4:Eu nanophosphors,
(ii) amine-functionalized nanophosphors, (iii) biotin-functionalized
nanophosphors. Biotin is connected to amine-functionalized nano-
phosphors via sulfo-NHS groups, (B) biotin functionalized nano-
phosphors attach to streptavidin coated silica microbubbles. (i)
streptavidin-coated
silica
microbubbles,
(ii)
biotin-functionalized
nanophosphors attached to streptavidin-coated silica microbubbles. (C)
SEM
image
showing
biotin-functionalized
nanophosphors
attached to streptavidin-coated microbubbles. Fig. 12
Schematic illustration of (A) silica coated nanophosphors
functionalized with biotin (i) silica-coated NaGdF4:Eu nanophosphors,
(ii) amine-functionalized nanophosphors, (iii) biotin-functionalized
nanophosphors. Biotin is connected to amine-functionalized nano-
phosphors via sulfo-NHS groups, (B) biotin functionalized nano-
phosphors attach to streptavidin coated silica microbubbles. (i)
streptavidin-coated
silica
microbubbles,
(ii)
biotin-functionalized
nanophosphors attached to streptavidin-coated silica microbubbles. (C)
SEM
image
showing
biotin-functionalized
nanophosphors
attached to streptavidin-coated microbubbles. Fig. 13
Schematic illustration of measuring XEOL of NaGdF4:Eu filled
in capillaries (A1) without tissue (B1) sandwiched with two 5 mm
porcine tissues. XEOL of NaGdF4:Eu filled in capillaries (A2) without
tissue (B2) sandwiched with two 5 mm porcine tissues. Exposure time
was 10 s without tissue and 60 s through tissue. dispersion of surface-modied nanophosphors in water at
physiological pH and high ionic strength (PBS buffer). The
biotin-functionalization was demonstrated by attachment to
streptavidin-functionalized
buoyant
silica
microbubbles
(Fig. 12). To demonstrate focused X-ray excited light generation and
collection through tissue, we loaded 1 mm diameter glass
capillaries with NaGdF4:Eu nanophosphor dispersions, and
placed the capillaries beneath 5 mm porcine tissue for imaging
(Fig. 14). Three capillaries were used, with NaGdF4 concentra-
tions of 0, 50 and 100 mg mL1, respectively. Biotin functionalized NaGdF4:Eu@SiO2 Silica coating can act as a protective layer, preventing parti-
cles
from
aggregating
and
fusing
during
the
annealing
process.24 Annealed nanophosphors at 400 C (Fig. 10A) showed
separate particles with a thin silica coating. Annealing at 600 C
(Fig. 10B) showed single and separate nanophosphors with
a silica shell, and nanophosphor core, but the core compressed,
and some void space was apparent. Annealing at 1000
C Functionalizing rare-earth doped nanophosphors are important
in in vivo labelling and imaging, biological assays and sensor
applications
with
specic
targets
such
as
proteins
and
DNA.12,32,33
We
functionalized
NaGdF4:Eu@SiO2
nano-
phosphors (not annealed) with a mixture of PEG-phosphate and
biotin-PEG. The PEG-phosphate was chosen to improve good Fig. 9
(A) SEM image and (B) XEOL of NaGdF4:Eu annealed at 1000 C
for 6 h compared to NaGdF4:Eu nanophosphors synthesized using co-
precipitate and hydrothermal methods. Fig. 11
(A) XEOL of NaGdF4:Eu@SiO2 annealed at 400 C, 600 C and
1000 C for 6 h. (B) Powder XRD pattern of annealed NaGdF4:Eu@SiO2
at 600 C and 1000 C compared to PDF cards 00-056-0184 and 00-
027-0699 biotin functionalized NaGdF4:Eu@SiO2. Fig. 9
(A) SEM image and (B) XEOL of NaGdF4:Eu annealed at 1000 C
for 6 h compared to NaGdF4:Eu nanophosphors synthesized using co-
precipitate and hydrothermal methods. Fig. 11
(A) XEOL of NaGdF4:Eu@SiO2 annealed at 400 C, 600 C and
1000 C for 6 h. (B) Powder XRD pattern of annealed NaGdF4:Eu@SiO2
at 600 C and 1000 C compared to PDF cards 00-056-0184 and 00-
027-0699 biotin functionalized NaGdF4:Eu@SiO2. Fig. 11
(A) XEOL of NaGdF4:Eu@SiO2 annealed at 400 C, 600 C and
1000 C for 6 h. (B) Powder XRD pattern of annealed NaGdF4:Eu@SiO2
at 600 C and 1000 C compared to PDF cards 00-056-0184 and 00-
027-0699 biotin functionalized NaGdF4:Eu@SiO2. Fig. 9
(A) SEM image and (B) XEOL of NaGdF4:Eu annealed at 1000 C
for 6 h compared to NaGdF4:Eu nanophosphors synthesized using co-
precipitate and hydrothermal methods. RSC Adv., 2021, 11, 31717–31726 | 31721 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online View Article Online RSC Advances Paper Fig. 13
Schematic illustration of measuring XEOL of NaGdF4:Eu filled
in capillaries (A1) without tissue (B1) sandwiched with two 5 mm
porcine tissues. XEOL of NaGdF4:Eu filled in capillaries (A2) without
tissue (B2) sandwiched with two 5 mm porcine tissues. X-ray excited optical luminescence spectroscopy and imaging
of capillaries lled with NaGdF4:Eu through tissue XEOL spectroscopy and imaging were performed to demon-
strate the ability to excite the nanophosphors through tissue
and show that the luminescence could be generated in specic
regions using a focused X-ray source. We chose 5 mm of chicken
breast because 5 mm is sufficient for many applications in
a mouse model where the “radius” is <1 cm, and we used
chicken breast because it is a common tissue material that
scatters light. Optical scattering in chicken breast is highly
anisotropic and has larger transport mean free path (the length
over which the direction of photon propagation is randomized)
than scattering mean free path.34 Fig. 14
XELCI images of NaGdF4:Eu dispersion in capillaries (A) XELCI
images without tissue (i) image of 620 nm intensity (counts) vs. posi-
tion. (ii) Image of 700 nm intensity (counts) vs. position (iii) XELCI ratio
image (intensity ratio of 620 nm and 700 nm). (B) XELCI images of the
same capillaries sandwiched between two 5 mm porcine tissue slices
(i) 620 nm image (ii) 700 nm image (iii) XELCI ratio image. (iv) Super-
imposed 620 nm image and X-ray transmittance images. Current was
200 mA without tissue and 600 mA through tissue. 1 mm scale bar is
same for all images. XEOL spectroscopy of colloidal NaGdF4:Eu nanophosphors
in capillaries were measured with and without being sand-
wiched between two 4 mm porcine tissue. Fig. 13A1 and B1
show a schematic illustration of the experimental setup. The
glass slide carrying capillaries (1 mm diameter) lled with
a nanoparticle solution (0, 50, 100 mg mL1) is placed on the
microscope stage. The light generated in X-ray irradiated
nanophosphors was collected through a microscope lens and
send to a spectrograph. Spectra generated without tissue
(Fig. 13A2) shows intensity higher than capillaries sandwiched
between porcine tissues (Fig. 11B2). Also, as the concentration
of nanophosphors increase in the capillary intensity increases
in both scenarios. Fig. 14
XELCI images of NaGdF4:Eu dispersion in capillaries (A) XELCI
images without tissue (i) image of 620 nm intensity (counts) vs. posi-
tion. (ii) Image of 700 nm intensity (counts) vs. position (iii) XELCI ratio
image (intensity ratio of 620 nm and 700 nm). (B) XELCI images of the
same capillaries sandwiched between two 5 mm porcine tissue slices
(i) 620 nm image (ii) 700 nm image (iii) XELCI ratio image. (iv) Super-
imposed 620 nm image and X-ray transmittance images. Biotin functionalized NaGdF4:Eu@SiO2 Our 0.7500 diameter
collection optics and coupled acrylic light guide collected light
from a large eld of view (100), but the focused X-ray beam
irradiated only a small region (250 mm spot size). We found
a relatively sharp image showing luminescence only from the
lled region of the capillaries, and excellent agreement with the X-ray excited optical luminescence spectroscopy and imaging
of capillaries lled with NaGdF4:Eu through tissue X-ray excited optical luminescence spectroscopy and imaging
of capillaries lled with NaGdF4:Eu through tissue Current was
200 mA without tissue and 600 mA through tissue. 1 mm scale bar is
same for all images. 31722 | RSC Adv., 2021, 11, 31717–31726 © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Advances
View Article Online RSC Advances
View Article Online Paper Paper X-ray transmission image. The capillary with DI water (0 mg
mL1) produced dim luminescence, as glass displays a weak X-
ray luminescence signal35 with a broad spectrum roughly
peaking at 430 nm (ESI Fig. S6†). The signal at 50 mg mL1 and
100 mg mL1 are clearly much larger and increase proportion-
ally to concentration. Importantly, although the signal through
tissue was 9.6 times weaker than with no tissue (mainly due to
optical attenuation and partly from X-ray attenuation), the
observed spatial resolution was very similar demonstrating
local radioluminescence excitation through tissue. MR imaging of NaGdF4:Eu and Tb NaGdF4:Eu and Tb nano-
phosphors were synthesized by the citrate method with slight
modications.14,15,40 Sodium citrate (12 mL of 0.2 M) was added to
a clear aqueous solution containing 4 mL of GdNO3 (0.2 M) and
TbNO3/EuNO3 (X mol%) and stirred for 30 min. Then, 16 mL of
sodium uoride (1 M) solution was combined with the above
mixture and stirred vigorously for another 15 minutes which result
in a white solution. This solution was transferred to a Teon-lined
autoclave and heated at 180 C for 6 hours. The synthesized
nanophosphors were centrifuged and washed three times before
further experiments. The synthesized nanophosphors were stored
in either DI water or 0.1% citrate solution. (TbNO3/EuNO3 X mol%
¼ 0.1%, 1%, 15% 20%, 100% of Gd3+ moles). pen Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Annealing NaGdF4:Eu nanoparticles NaGdF4:Eu nanoparticles prepared using the co-precipitate
method were dried at 80 C to form a white powder. It was
transferred to a crucible and heated (10 C min1) at 1000 C for
6 hours in a muffle furnace which results in a solid, aggregated
structure. Aer cooling down to room temperature, it was
crushed into a ne powder using mortar and pestle. NaGdF4:Eu@SiO2 nanophosphors were dried at 80 C to
form a white powder and divide into three portions and trans-
ferred to crucibles. The samples were heated at 400 C, 600 C
and 1000 C for 6 hours to anneal them. Fig. 15
Magnetic
resonance
images
(MRI)
of
NaGdF4:Eu
and
NaGdF4:Tb nanoparticle suspensions in water. (A) T1 weighted and (B)
T2 weighted images with various nanoparticle concentrations. 0 mM ¼
DI water. 1 cm scale bar is for both T1 and T2 weighted images. (C)
Longitudinal
relaxation
rate
vs. concentration
for
nanoparticle
suspensions. (D) Transverse relaxation rate vs. concentration. Dashed
lines are linear fits to data. Silica coating NaGdF4:Eu and Tb nanoparticles Synthesized nanophosphors were coated with silica using
previously described methods41–43 with slight modications
(certain reagents were scaled up). Eu doped and Tb doped
NaGdF4 nanoparticles prepared at room temperature were
resuspended in 8 mL of water and combined with 200 mL
ethanol solution containing PVP (1.2 g) and ammonium
hydroxide (6 mL). Then, TEOS (160 mL) was added aer the
solution was stirred for 20 min. The particles were aged another
3 hours before centrifuged and washed using DI water. Fig. 15
Magnetic
resonance
images
(MRI)
of
NaGdF4:Eu
and
NaGdF4:Tb nanoparticle suspensions in water. (A) T1 weighted and (B)
T2 weighted images with various nanoparticle concentrations. 0 mM ¼
DI water. 1 cm scale bar is for both T1 and T2 weighted images. (C)
Longitudinal
relaxation
rate
vs. concentration
for
nanoparticle
suspensions. (D) Transverse relaxation rate vs. concentration. Dashed
lines are linear fits to data. MR imaging of NaGdF4:Eu and Tb NaGdF4:Eu and Tb may also potentially be T1 and T2 weighted
MRI contrast agents as previously reported.36,37 To demonstrate
this, varying concentrations of NaGdF4:Eu and Tb were prepared
in DI water and imaged using a 3T Siemens MAGNATOM Prisma
MRI (Fig. 15A and B). As expected, T1 weighted images became
brighter, and T2 weighted images became darker as [Gd]
increased up to 0.4 mM. Fig. 13C and D show longitudinal and
transverse 1H relaxation rates, r1 and r2, measured at 20 C
plotted against concentration of the nanoparticle suspensions. Relaxivities were calculated by linear regression of this data. The
longitudinal relaxivities for NaGdF4:Eu and NaGdF4:Tb were 4.0
0.15 and 2.7 0.16 mM1 s1, and the transverse relaxivities
were 58 1.0 and 110 10 mM1 s1, respectively. The observed
differences between Tb and Eu doped particles, especially at high
concentrations, are likely from variation in sample preparation
since Tb and Eu doping is at a low concentration compared to the
Gd in the host crystal. The values are in the range of prior liter-
ature and the relaxivities provide clear contrast.36 The reported
relaxivity values 0.27 (minimum r1) and 160 (maximum r2) mM1
s1 depends on eld strength,36,38 size and morphology36,38 and
coating.39 MRI imaging would allow for deep tissue imaging and
would be complementary to X-ray luminescence imaging and
stimulation, allowing for non-invasive localization of nano-
phosphors in vivo. Hydrothermal synthesis method. NaGdF4:Eu and Tb nano-
phosphors were synthesized by the citrate method with slight
modications.14,15,40 Sodium citrate (12 mL of 0.2 M) was added to
a clear aqueous solution containing 4 mL of GdNO3 (0.2 M) and
TbNO3/EuNO3 (X mol%) and stirred for 30 min. Then, 16 mL of
sodium uoride (1 M) solution was combined with the above
mixture and stirred vigorously for another 15 minutes which result
in a white solution. This solution was transferred to a Teon-lined
autoclave and heated at 180 C for 6 hours. The synthesized
nanophosphors were centrifuged and washed three times before
further experiments. The synthesized nanophosphors were stored
in either DI water or 0.1% citrate solution. (TbNO3/EuNO3 X mol%
¼ 0.1%, 1%, 15% 20%, 100% of Gd3+ moles). Hydrothermal synthesis method. NaGdF4:Eu and NaGdF4:Tb nanoparticle synthesis 15
Magnetic
resonance
images
(MRI)
of
NaGdF4:Eu
a
NaGdF4:Tb nanoparticle suspensions in water. (A) T1 weighted and
T2 weighted images with various nanoparticle concentrations. 0 mM
DI water. 1 cm scale bar is for both T1 and T2 weighted images. Longitudinal
relaxation
rate
vs. concentration
for
nanoparti
suspensions. (D) Transverse relaxation rate vs. concentration. Dash
lines are linear fits to data. © 2021 The Author(s). Published by the Royal Society of Chemistry
Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. NaGdF4:Eu and NaGdF4:Tb nanoparticle synthesis NaGdF4:Eu and NaGdF4:Tb nanoparticle synthesis We synthesized particles using either the co-precipitation or
hydrothermal synthesis methods. Co-precipitate synthesis method. NaGdF4:Eu and Tb nano-
phosphors were synthesized by the citrate method with slight modi-
cations.14,40 Sodium citrate (12 mL of 0.2 M) was added to a clear
aqueous solution containing 4 mL of GdNO3 (0.2 M) and TbNO3/
EuNO3 (X mol%) and stirred vigorously for 30 min at room temper-
ature. Then, 16 mL of sodium uoride (1 M) solution was combined
with the above mixture and stirred vigorously for another 2 hours
which result in a white solution. The synthesized nanophosphors
were centrifuged and washed three times before further experiments. (TbNO3/EuNO3 X mol% ¼ 0.1%, 1%, 15% 20%, 100% of Gd3+ moles). ally to concentration. Importantly, although the signal throu
tissue was 9.6 times weaker than with no tissue (mainly due
optical attenuation and partly from X-ray attenuation), t
observed spatial resolution was very similar demonstrati
local radioluminescence excitation through tissue. MR imaging of NaGdF4:Eu and Tb
NaGdF4:Eu and Tb may also potentially be T1 and T2 weight
MRI contrast agents as previously reported.36,37 To demonstra
this, varying concentrations of NaGdF4:Eu and Tb were prepar
in DI water and imaged using a 3T Siemens MAGNATOM Prism
MRI (Fig. 15A and B). As expected, T1 weighted images becam
brighter, and T2 weighted images became darker as [G
increased up to 0.4 mM. Fig. 13C and D show longitudinal a
transverse 1H relaxation rates, r1 and r2, measured at 20
plotted against concentration of the nanoparticle suspension
Relaxivities were calculated by linear regression of this data. T
longitudinal relaxivities for NaGdF4:Eu and NaGdF4:Tb were 4
0.15 and 2.7 0.16 mM1 s1, and the transverse relaxivit
were 58 1.0 and 110 10 mM1 s1, respectively. The observ
differences between Tb and Eu doped particles, especially at hi
concentrations, are likely from variation in sample preparati
since Tb and Eu doping is at a low concentration compared to t
Gd in the host crystal. The values are in the range of prior lit
ature and the relaxivities provide clear contrast.36 The report
relaxivity values 0.27 (minimum r1) and 160 (maximum r2) mM
s1 depends on eld strength,36,38 size and morphology36,38 a
coating.39 MRI imaging would allow for deep tissue imaging a
would be complementary to X-ray luminescence imaging a
stimulation, allowing for non-invasive localization of nan
phosphors in vivo. Fig. ICP-OES metal analysis The percentage of metals (Gd, Eu and Tb) in the nal systems
were measured using iCAP 7200 MSC ICP-OES analyser. Nano-
phosphors were dissolved in 2% HNO3 to prepare nitrates of the
metals. The standard metal solutions were prepared from 0.1 to
100 ppm range. The samples and the standards were injected to
ICP-OES and quantied the amount of metal using instrument
soware (Qtegra ISDS soware). The wavelengths of the corre-
sponding spectrometric lines that used for the analysis were Gd:
335 nm, Eu: 381 nm, Tb: 350 nm. The metal percentages (Eu/Gd
and Tb/Gd) from the dissolved samples were calculated using
standard curves. Imaging capillaries lled with NaGdF4:Eu through tissue A series of concentration of NaGdF4:Eu (100, 50 and 0 mg mL1)
was prepared and lled in 1 mm (inner diameter) capillaries. X-ray excited optical luminescence of all the samples in
capillaries were measured by irradiating with a Mini-X Ag-target X-
ray source at 40 kV and 99 mA. Spectral data of capillaries were
obtained at 10 s exposure time and capillaries sandwiched in
between 4 mm porcine tissue were obtained at 60 s exposure time. X-ray excited luminescence chemical imaging (XELCI) of
these capillaries was done without tissue and with 5 mm
porcine tissue. The capillaries were scanned with 250 mm step
size and 1 mm s1 for a high-resolution scan. For imaging
without tissue, the X-ray source was set to 50 kV and 200 mA; 50
kV and 600 mA was used for imaging with porcine tissue. Data
were analysed and plotted using custom MATLAB scripts. X-ray luminescence of all the nanoparticles was measured by
irradiating with an X-ray beam. A 96 well plate containing dried
and powdered nanoparticles was places on the stage of an
inverted microscope and irradiated with an X-ray beam gener-
ated using a Mini-X (Ag) X-ray source (Amptek, Bedford, MA) set
at 40 kV and 99 mA. The emission of nanoparticles was collected
by 5 objective and focused to a spectrograph (DNS 300, Del-
taNu, Laramie, WY, USA), equipped with a cooled CCD camera
(iDUS-420BV, Andor, South Windsor, CT, United States). A series of concentration of NaGdF4:Eu (100, 50 and 0 mg mL1)
was prepared and lled in 1 mm (inner diameter) capillaries. X-ray excited optical luminescence of all the samples in
capillaries were measured by irradiating with a Mini-X Ag-target X-
ray source at 40 kV and 99 mA. Spectral data of capillaries were
obtained at 10 s exposure time and capillaries sandwiched in
between 4 mm porcine tissue were obtained at 60 s exposure time. X-ray excited luminescence chemical imaging (XELCI) of
these capillaries was done without tissue and with 5 mm
porcine tissue. The capillaries were scanned with 250 mm step
size and 1 mm s1 for a high-resolution scan. For imaging
without tissue, the X-ray source was set to 50 kV and 200 mA; 50
kV and 600 mA was used for imaging with porcine tissue. Data
were analysed and plotted using custom MATLAB scripts. MR imaging of NaGdF4:Eu and Tb Solutions of NaGdF4:Eu and Tb nanophosphors at a series of
concentrations from 0 to 0.4 mM were prepared by dissolving in
DI water. MR imaging and relaxometry was done on a 3T
Siemens
MAGNATOM
Prisma
MRI
instrument
(Siemens
Healthineers, Erlangen, Germany). T1-weighted images were
acquired using a 2D spin echo sequence with repetition time
(TR) 25 ms and echo time (TE) 5.9 ms. T2-weighted images were
acquired using a turbo spin echo sequence with TR ¼ 3200 ms
and TE ¼ 29 ms. T1 was measured with an inversion recovery
experiment using a spin echo pulse sequence. Inversion times
(TI) were 25, 50, 400, 1100, and 2500 ms. To calculate T1, the
model from ref. 46 was t to MR signal magnitude vs. TI using
the qMRLab package for MATLAB.47 T2 was measured with
a multi-echo spin echo sequence using 32 TEs ranging from 15
to
960
ms. To
calculate
T2,
a
monoexponential
model
SðTEÞ ¼ M0 exp
TE
T2
was t to MR signal magnitude vs. TE. Functionalization of NaGdF4:Eu@SiO2 with biotin NaGdF4:Eu@SiO2 nanophosphors were resuspended in ethanol
(100 mL) with APTES (300 mL) and stirred for 3.5 h. The amine- RSC Adv., 2021, 11, 31717–31726 | 31723 © 2021 The Author(s). Published by the Royal Society of Chemistry Paper
View Article Online View Article Online Paper
Article Online RSC Advances Relaxivities were calculated by linear regression of R1 ¼ 1/T1, R1
¼ 1/T2 vs. nanoparticle concentration. functionalized nanophosphors were collected and washed three
times using DI water. Relaxivities were calculated by linear regression of R1 ¼ 1/T1, R1
¼ 1/T2 vs. nanoparticle concentration. g
98 mL of MES buffer (0.1 M, pH 6.0) was taken in a 500 mL
round bottom ask. 100 mg of water-soluble carbodiimide
(EDC) and sulfo-NHS was added to it and stirred for 15 minutes
at room temperature. H2PO4–PEG–COOH (5000 Da) (500 mL,
10 mg mL1) and biotin–PEG–COOH (1000 Da) (250 mL, 10 mg
mL1) was added to the above solution and stirred for 1 hour at
room temperature to activate COOH groups. Then, the solution
pH was adjusted to pH 7.4 using PBS buffer. Previously
prepared NH2 functionalized NaGdF4:Eu@SiO2 nanoparticles
were added to the mixture and it could react for 12 h at room
temperature with continuous stirring. Lastly, biotin-conjugated
NPs were washed with PBS three times and stored in DI water. Biotin functionalized aqueous nanophosphors suspension
(10 mg mL1, 20 mL) was transferred into a centrifuge tube con-
tained PBS (10, 380 mL) solution. Streptavidin-coated micro-
bubbles (100 mL) were mixed with the previous solution and
vortexed to allow particle adhesion on the surface of the micro-
bubble. Aer waiting a 10–15 minutes, suspended microbubbles
were pipetted out and washed three times with DI water.44,45 98 mL of MES buffer (0.1 M, pH 6.0) was taken in a 500 mL
round bottom ask. 100 mg of water-soluble carbodiimide
(EDC) and sulfo-NHS was added to it and stirred for 15 minutes
at room temperature. H2PO4–PEG–COOH (5000 Da) (500 mL,
10 mg mL1) and biotin–PEG–COOH (1000 Da) (250 mL, 10 mg
mL1) was added to the above solution and stirred for 1 hour at
room temperature to activate COOH groups. Then, the solution
pH was adjusted to pH 7.4 using PBS buffer. Previously
prepared NH2 functionalized NaGdF4:Eu@SiO2 nanoparticles
were added to the mixture and it could react for 12 h at room
temperature with continuous stirring. Functionalization of NaGdF4:Eu@SiO2 with biotin Lastly, biotin-conjugated
NPs were washed with PBS three times and stored in DI water. Transmission electron microscopy The synthesized, silica-coated and annealed nanoparticles were
deposited on a formvar/carbon-coated copper grids from
a water solution and dried before taking the transmission
electron micrographs from Hitachi HT7800 operating at 20–120
keV and 8 mA. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024 6:33:05 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Powder X-ray diffraction (XRD) The phases of the NaGdF4:Eu powders, nanoparticles, and
annealed nanoparticles were characterized by Rigaku Ultima IV
powder diffractometer, using Cu Ka radiation. Powdered
samples were spread on a low background glass slide and data
are collected in 0.02 increments at a rate of 0.5–1 per minute
from 10 to 70 at room temperature. Annealed particles were
measured at 0.2–0.5 per minute. Biotin functionalized aqueous nanophosphors suspension
(10 mg mL1, 20 mL) was transferred into a centrifuge tube con-
tained PBS (10, 380 mL) solution. Streptavidin-coated micro-
bubbles (100 mL) were mixed with the previous solution and
vortexed to allow particle adhesion on the surface of the micro-
bubble. Aer waiting a 10–15 minutes, suspended microbubbles
were pipetted out and washed three times with DI water.44,45 Paper RSC Advances 2 P. Lecoq, in Detectors for Particles and Radiation. Part 1:
Principles and Methods, ed. C. W. Fabjan and H. Schopper,
Springer Berlin Heidelberg, Berlin, Heidelberg, 2011, vol. 21B1, pp. 45–71. Conflicts of interest 15 F. He, P. Yang, D. Wang, N. Niu, S. Gai and X. Li, Inorg. Chem., 2011, 50, 4116–4124. There are no conicts to declare. 16 Y. Ren, H. Winter, J. G. Rosch, K. Jung, A. N. Duross,
M. R. Landry, G. Pratx and C. Sun, ACS Appl. Nano Mater.,
2019, 2, 3718–3727. Author contributions 11 M. C. Lun, W. Cong, M. Arifuzzaman, M. Ranasinghe,
S. Bhattacharya, J. Anker, G. Wang and C. Li, in Optics and
Ionizing Radiation, International Society for Optics and
Photonics, 2020, vol. 11224, p. 112240F. J. N. Anker conceptualisation, funding acquisition, supervision,
writing-review and editing; M. Ranasinghe data curation,
investigation, methodology, validation, writing – original dra
preparation; M. Arifuzzaman, A. C. Rajamathrilage, W. R. Wil-
loughby,
and
A. Dickey
investigation,
validation;
Colin
McMillen data curation; J. W. Kolis supervision, M. Bolding
supervision. 12 F. Wang, D. Banerjee, Y. Liu, X. Chen and X. Liu, Analyst,
2010, 135, 1839–1854. 13 R. Berry, M. Getzin, L. Gjesteby and G. Wang, Photonics,
2015, 2, 23–39. 14 L. Sudheendra, G. K. Das, C. Li, D. Stark, J. Cena, S. R. Cherry
and I. M. Kennedy, Chem. Mater., 2014, 26, 1881–1888. Acknowledgements 17 T. Yanagida, Opt. Mater., 2013, 35, 1987–1992. This work was funded by NSF Track II EPSCoR OIA-1632881 for
the synthesis by the NIH NIBIB R01EB026646 for the X-ray
luminescence imaging, and P30 GM131959 for the electron
microscopy. Electron microscopy images were acquired with in
the Electron Microscope Facility, Clemson University, Clemson
Research Park, AMRL building. MR images were taken in the
Civitan International Neuroimaging Laboratory, University of
Alabama at Birmingham. We would like to acknowledge Dr
Sriparna Bhattachrya for helping acquire some of the TEM
images and Dr Rakesh Sachdeva for helping us run the ICP-OES
and TGA/DSC instruments. 18 H. Guan, G. Liu, J. Wang, X. Dong and W. Yu, Dalton Trans.,
2014, 43, 10801–10808. 19 S. Mitragotri and J. Lahann, Nat. Mater., 2009, 8, 15–23. 20 J. C. Stendahl and A. J. Sinusas, J. Nucl. Med., 2015, 56, 1469–
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41, 7116–7122. 24 E. A. Sagaydachnaya, V. I. Kochubey and J. G. Konyukhova, J. Phys. Conf. Ser., 2017, 917, 032006. Open Access Article. Published on 24 September 2021. Downloaded on 10/24/2024
This article is licensed under a Creative Commons Attribution 3.0 Un 6 H. Chen, B. Qi, T. Moore, D. C. Colvin, T. Crawford,
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V20.9 Build 20 thermal gravimetric by TA instruments. Nano-
phosphor samples in alumina crucibles were heated up to
700 C at a rate of 20 C minute1 under N2 gas ow. At 700 C
samples were kept under isothermal conditions and ushed
with
air. TGA
and
DSC
measurements
were
collected
simultaneously. © 2021 The Author(s). Published by the Royal Society of Chemistry 31724 | RSC Adv., 2021, 11, 31717–31726 View Article Online View Article Online RSC Advances
View Article Online Paper Conclusions In summary, we described two methods to synthesis Eu- and Tb
doped NaGdF4 X-ray luminescence nanophosphors. The co-
precipitation method is a simple method that synthesized
spherical-shaped nanoparticles at room temperature. The
hydrothermal method generated irregular particles that yielded
higher X-ray excited luminescence intensity. Our investigation
on annealing nanoparticles revealed that nanoparticles without
a silica coating resulted in high luminescence intensity yet
aggregated particles. The silica coating act as a protection layer
to prevent aggregation and increase X-ray luminescence during
the annealing process. However, at high temperature, it trans-
formed NaGdF4:Eu into sodium gadolinium silicate which also
shows X-ray luminescence. Then, we functionalized NaGdF4:-
Eu@SiO2 nanophosphors with biotin and conrmed attaching
to streptavidin in vitro. Importantly, we selectively excited
scintillator nanophosphors using a focused X-ray source to
generate light and collect them through the tissue to generate
XELCI images and XEOL was measured through tissue. We also
showed that the particles could serve as MRI contrast agents. Future work will investigate the spectral shiby changing host
materials for multi-analyte imaging through tissue. 3 M. D. Birowosuto, P. Dorenbos, C. W. E. van Eijk,
K. W. Kr¨amer and H. U. G¨udel, J. Appl. Phys., 2006, 99,
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North
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Treaty
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Springer,
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English
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A comprehensive collection of annotations to interpret sequence variation in human mitochondrial transfer RNAs
|
BMC bioinformatics
| 2,016
|
cc-by
| 7,182
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A comprehensive collection of annotations
to interpret sequence variation in human
mitochondrial transfer RNAs Maria Angela Diroma, Paolo Lubisco and Marcella Attimonelli* From Twelfth Annual Meeting of the Italian Society of Bioinformatics (BITS)
Milan, Italy. 3-5 June 2015 From Twelfth Annual Meeting of the Italian Society of Bioinformatics (BITS)
Milan, Italy. 3-5 June 2015 © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338
DOI 10.1186/s12859-016-1193-4 The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338
DOI 10.1186/s12859-016-1193-4 Abstract Background: The abundance of biological data characterizing the genomics era is contributing to a comprehensive
understanding of human mitochondrial genetics. Nevertheless, many aspects are still unclear, specifically about the
variability of the 22 human mitochondrial transfer RNA (tRNA) genes and their involvement in diseases. The complex
enrichment and isolation of tRNAs in vitro leads to an incomplete knowledge of their post-transcriptional modifications
and three-dimensional folding, essential for correct tRNA functioning. An accurate annotation of mitochondrial tRNA
variants would be definitely useful and appreciated by mitochondrial researchers and clinicians since the most of
bioinformatics tools for variant annotation and prioritization available so far cannot shed light on the functional role of
tRNA variations. Results: To this aim, we updated our MToolBox pipeline for mitochondrial DNA analysis of high throughput and Sanger
sequencing data by integrating tRNA variant annotations in order to identify and characterize relevant variants not only in
protein coding regions, but also in tRNA genes. The annotation step in the pipeline now provides detailed information
for variants mapping onto the 22 mitochondrial tRNAs. For each mt-tRNA position along the entire genome, the relative
tRNA numbering, tRNA type, cloverleaf secondary domains (loops and stems), mature nucleotide and interactions in the
three-dimensional folding were reported. Moreover, pathogenicity predictions for tRNA and rRNA variants were retrieved
from the literature and integrated within the annotations provided by MToolBox, both in the stand-alone version and
web-based tool at the Mitochondrial Disease Sequence Data Resource (MSeqDR) website. All the information available in
the annotation step of MToolBox were exploited to generate custom tracks which can be displayed in the GBrowse
instance at MSeqDR website. Conclusions: To the best of our knowledge, specific data regarding mitochondrial variants in tRNA genes were
introduced for the first time in a tool for mitochondrial genome analysis, supporting the interpretation of genetic
variants in specific genomic contexts. * Correspondence: marcella.attimonelli@uniba.it
Department of Biosciences, Biotechnologies and Biopharmaceutics,
University of Bari, Bari 70126, Italy Data collection from known databases, web-based
resources and literature All the information collected in this work and those
previously collected and already implemented in the
MToolBox pipeline [16], come from several resources
and the literature about human mtDNA genomics and
variation (Table 1). Nucleotide variability scores calculated
by applying SiteVar algorithm [18] on 22,691 complete ge-
nomes from healthy individuals in the Human Mitochon-
drial Database, HmtDB (May 2014 update) [19], were
reported for each position of the entire human mitochon-
drial genome; amino acid scores, calculated by MitVarProt
algorithm [20] on the same dataset, were obtained for
coding regions. Conservation scores calculated by PhyloP
[21] and PhastCons [22] algorithms were retrieved from
UCSC Genome Browser [23]. Somatic mutations and germline variants with reports
of disease-associations were available in MITOMAP [4],
with corresponding annotation of heteroplasmic/homo-
plasmic status (July 20, 2015 update of coding and con-
trol regions variants; July 29, 2015 update of somatic
mutations and RNA genes variants). Other resources
were exploited in order to facilitate clinical interpret-
ation of variants, although they are not specialized for
mitochondrial genome variant analysis, including OMIM
[24], the Online Mendelian Inheritance in Man (August
4, 2015 update), dbSNP [25], a database for short genetic
variations (release 144, May 26, 2015), and ClinVar [26],
a public archive of reports of human variations and phe-
notypes reporting annotations of variants found in pa-
tient samples (January 21, 2015 update). Some features are shared among human and other
mammalian mt-tRNAs, such as the low number of G–C
pairs within stems of the 14 tRNAs encoded by the light
DNA strand, due to a strong bias in nucleotide content
(A, U and C-rich tRNAs), variable D-loop and T-loop
sizes, and lack of conserved and semi-conserved signature
motifs [13], thus the difficulties linked to the complex
process of human tRNA purification and identification of
modified nucleotides are often overpassed through predic-
tions based on bovine models [2]. Moreover, specific annotations for tRNA variants were
gathered from databases, such as Mamit-tRNA [13],
mitotRNAdb [27] and MODOMICS [28], as well as from
the literature. Specifically, a scoring system developed for
207 variants in tRNA genes considering functional evi-
dence, conservation, frequency and heteroplasmy status in
mutations reported in MITOMAP as “pathogenic”, was
retrieved [29, 30] and normalized to a 0–1 range (Table 2). Recently published predictions of pathogenicity for DNA
variants involving 12S mitochondrial rRNA (mt-rRNA)
[31] were considered and adapted, too. Background in order to identify relevant variants not only in protein
coding regions but also in tRNA genes. Pathogenicity
predictions retrieved from the literature were added
both for tRNA and rRNA gene variants, when available. These information were also provided as custom tracks
which can be visualized in the GBrowse at the Mito-
chondrial Disease Sequence Data Resource (MSeqDR)
website [17], conveniently allowing a deep insight into
mitochondrial genomics. The abundance of biological data characterizing the ge-
nomics era is contributing to a comprehensive under-
standing of human mitochondrial genetics. To date more
than 30,000 complete human mitochondrial genomes have
been sequenced [1] and lots of tools and databases are
publicly available allowing to gather large amounts of infor-
mation about mitochondrial DNA (mtDNA). Nevertheless
many aspects are still unclear, specifically about the 22
human mitochondrial transfer RNAs (mt-tRNA). Thanks to the “four-way wobble rule” and post tran-
scriptional modifications at the first letters of tRNA anti-
codons [2], only 22 mt-tRNAs are sufficient in humans,
as well as in other mammals, to translate all sense co-
dons into 13 subunits of respiratory chain complexes
encoded in each single copy of mtDNA [2]. mt-tRNAs
could be considered hot spots of mutations [3]: among
more than 600 disease associated mutations compiled to
date, about 240 were mapped on mt-tRNA genes [4]. However, it is well known that clinical phenotypes appear
only when the mutation load exceeds a certain threshold
[5], considering the possible co-existence of different
mtDNA genotypes within the same cell, tissue or indivi-
dual, a condition known as heteroplasmy. Thus, if a mu-
tation in an mt-tRNA gene has no consequences on
mtDNA replication or transcription, it may instead affect
biogenesis and functioning of tRNAs after their transcrip-
tion [6]. For instance, post-transcriptional modifications
by nuclear-encoded enzymes [7, 8] often occur in key po-
sitions for a correct tRNA functioning, including folding
and codon-anticodon interaction [6, 9, 10]. As a conse-
quence, the lack of a correct post-transcriptional process
could cause pathological effects [11, 12]. Abstract Keywords: Mitochondrial genomics, tRNA sequence variation, Annotation and prioritization tools, Bioinformatics
analysis, NGS Abbreviations: AS, Acceptor stem; CL, Anticodon loop; CS, Anticodon stem; DL, Dihydrouridine loop; DS, Dihydrouridine
Stem; GFF3, General feature format version 3; HGVS, Human genome variation society; HmtDB, Human mitochondrial
database; MSeqDR, Mitochondrial disease sequence data resource; mtDNA, Mitochondrial DNA; mt-rRNA, Mitochondrial
ribosomal RNA; mt-tRNA, Mitochondrial transfer RNA; rCRS, Revised Cambridge Reference Sequence; TL, TΨC Loop;
TS, TΨC stem; VL, Variable loop * Correspondence: marcella.attimonelli@uniba.it
Department of Biosciences, Biotechnologies and Biopharmaceutics,
University of Bari, Bari 70126, Italy © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 146 of 212 Page 146 of 212 Page 146 of 212 Table 1 Annotations by MToolBox pipeline (Continued)
AC/AN 1000 Genomes
Previously y
Variant annotation
Locus
HF
CI_lower;CI_upper
RSRS
MHCS
rCRS
Haplogroup
Other Haplogroups
Nt Variability
Codon Position
Aa Change
Aa variability
tRNA Annotation
Disease Score
RNA predictions
MutPred Pred
MutPred Prob
PolyPhen-2 HumDiv Pred
PolyPhen-2 HumDiv Prob
PolyPhen-2 HumVar Pred
PolyPhen-2 HumVar Prob
PANTHER Pred
PANTHER Prob
PhD-SNP Pred
PhD-SNP Prob
SNPs&GO Pred
SNPs&GO Prob
MITOMAP Associated Disease(s)
MITOMAP Homoplasmy
MITOMAP Heteroplasmy
Somatic Mutations
SM Homoplasmy
SM Heteroplasmy
ClinVar
OMIM
dbSNP
Mamit-tRNA
PhastCons20Way
PhyloP20Way Previously provided
Previously provided
Previously provided All the annotations provided by MToolBox pipeline are shown. In the latest
update, new fields, mainly regarding tRNA gene variants, were added for a
more accurate variant annotation in analyzed samples: structural information
for tRNA variants (“tRNA annotation”), pathogenicity predictions for tRNA and
rRNA genes (“RNA predictions”), disease reports in ClinVar database (“ClinVar”),
conservation scores (“PhastCons20Way”, “PhyloP20Way”). tRNA annotation, in
turn, includes five semi-colon separated annotations: position numbering in
tRNA, tRNA type, cloverleaf secondary region, mature nucleotide and involvement
of the specific position in tRNA folding (Y for yes or N for no). Moreover, data
from HmtDB (“Nt variability”, “Aa variability”), MITOMAP (“MITOMAP Associated
Disease(s)”, “MITOMAP Homoplasmy”, “MITOMAP Heteroplasmy”, “Somatic
Mutations”, “SM Homoplasmy”, “SM Heteroplasmy”), OMIM links (“OMIM”)
and dbSNP identifiers (“dbSNP”) were updated. All the remaining annotations
were Previously provided by MToolBox Variant annotators
h
d Variant annotators
Both generic and mitochondrial-oriented tools were
used for a comparison of variant annotation processes. The command line tools ANNOVAR (version date
2015-03-22) [35], dbNSFP (version 3.0b1a) [14], and
SnpEff (version 4.1b) [36], although not specific for
mtDNA analysis, were used to provide annotations for
three mitochondrial mutations involving genes coding
for an rRNA, a tRNA and a protein, respectively. Web-
based versions of mit-o-matic [37], MitoBamAnnotator
[38] and MitImpact 2.0 [15] tools were also applied to
the same mutations to compare their performance in
variant annotation. MToolBox MToolBox [16] is a bioinformatics pipeline recently devel-
oped for accurate and complete analysis of mitochondrial
genome from high throughput sequencing. The tool in-
cludes several steps in the data analysis process, such as
variant annotation and prioritization by exploiting several
annotation resources, such as biological databases [4, 19]
and pathogenicity prediction software [32–34], proving to
be very useful especially in the characterization of mis-
sense variants (Table 1). The pipeline was also developed
as a web-based tool, hosted at MSeqDR website [17], a
portal recently developed for supporting mitochondrial
disease studies by providing both data and user-friendly
tools specifically for mtDNA analysis. Data collection from known databases, web-based
resources and literature The availability of information about mt-tRNA genes
and variants would support the interpretation of mtDNA
variants and improve the understanding of molecular
mechanisms of disease. However, most bioinformatics tools
for variant annotation and prioritization available so far
cannot shed light on the functional role of mt-tRNA varia-
tions, often focusing only on characterization of missense
variants [14, 15]. To this aim, we updated our MToolBox pipeline [16]
for mtDNA analysis of high throughput and Sanger se-
quencing data by integrating tRNA variants annotations The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 147 of 212 Table 1 Annotations by MToolBox pipeline
Variant annotation
Status
Locus
Previously provided
HF
Previously provided
CI_lower;CI_upper
Previously provided
RSRS
Previously provided
MHCS
Previously provided
rCRS
Previously provided
Haplogroup
Previously provided
Other Haplogroups
Previously provided
Nt Variability
Updated
Codon Position
Previously provided
Aa Change
Previously provided
Aa variability
Updated
tRNA Annotation
New
Disease Score
Previously provided
RNA predictions
New
MutPred Pred
Previously provided
MutPred Prob
Previously provided
PolyPhen-2 HumDiv Pred
Previously provided
PolyPhen-2 HumDiv Prob
Previously provided
PolyPhen-2 HumVar Pred
Previously provided
PolyPhen-2 HumVar Prob
Previously provided
PANTHER Pred
Previously provided
PANTHER Prob
Previously provided
PhD-SNP Pred
Previously provided
PhD-SNP Prob
Previously provided
SNPs&GO Pred
Previously provided
SNPs&GO Prob
Previously provided
MITOMAP Associated Disease(s)
Updated
MITOMAP Homoplasmy
Updated
MITOMAP Heteroplasmy
Updated
Somatic Mutations
Updated
SM Homoplasmy
Updated
SM Heteroplasmy
Updated
ClinVar
New
OMIM
Updated
dbSNP
Updated
Mamit-tRNA
Previously provided
PhastCons20Way
New
PhyloP20Way
New Results and discussion Annotations for mitochondrial DNA variants in RNA genes
by MToolBox pipeline and data update The MToolBox pipeline [16] was updated and enhanced
with specific annotations regarding tRNA genes, introduced
for the first time in a tool specific for mtDNA analysis. p
y
New fields were added in the latest version of the
MToolBox pipeline (Table 1): specific annotations for
tRNA and rRNA genes, annotations from ClinVar data-
base for disease-associated variants [26] and conservation
scores for each site produced by PhyloP [21] and Phast-
Cons [22] algorithms. Specifically, tRNA genes were char-
acterized in each position with reports about tRNA
structure including i) position in tRNA, following the
Sprinzl standard nomenclature [27]; ii) tRNA type [40]; iii)
cloverleaf-shaped secondary structure regions [27]; iv)
mature nucleotide [2, 7, 28]; v) involvement of the specific
position in tRNA folding [2, 7, 41] (Fig. 1). Each tRNA
nucleotide was numbered from 1 to 73, CCA-ending
excluded; the anticodon triplet was marked with nucleo-
tides 34 to 36. The tRNA type indicates one of the four
possible groups ranking human mt-tRNAs for their struc-
tural diversity and different tertiary interactions: type 0,
the quasi-canonical cloverleaf structure, with standard D-
loop/T-loop interaction; type II, the most common among
mt-tRNAs, characterized by loss of D/T-loop interaction;
type I and type III, each accounting one single tRNA with
an atypical anticodon stem and lack of D-stem, respect-
ively. The annotation of the typical cloverleaf pattern
includes abbreviations of four loops (TL-TΨC Loop, VL-
Variable Loop, CL-Anticodon Loop, DL-Dihydrouridine
Loop), four stems (AS-Acceptor Stem, TS-TΨC Stem,
CS-Anticodon Stem, DS-Dihydrouridine Stem), 3′ end (E)
and junctions (-). The mature nucleotide is meant as the nucleotide found
in the tRNA molecule after post-transcriptional processes,
predicted based on information of bovine and model or-
ganisms (bacteria, yeast, nematode) mt-tRNAs, and con-
firmed in 8 human mt-tRNAs [2, 8]. As a result of our
data collection, we annotated 110 residues in the human
mt-tRNA set involved in post-transcriptional modifica-
tions, with 16 different types of modified nucleotides. All
the post-transcriptional modifications in mt-tRNAs and
resulting mature nucleotides are listed in Table 3. Indication of the involvement of a specific residue in
tRNA folding could be now recovered through variant an-
notation by our updated version of MToolBox. GBrowse tracks at MSeqDR website GBrowse instance at MSeqDR website [17] allows
visualization and analysis of variations and other gen-
omics data in a classic genome browser interface by
hosting mtDNA specific annotation tracks containing
data from some of the major mtDNA genomics resources,
such as HmtDB_rCRSvariants and HmtDB_RSRSvariants,
provided by our group [17]. Data collection for new tracks The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 148 of 212 Page 148 of 212 Page 148 of 212 generation was manually curated in order to produce tab-
delimited text files, then converted in the required format
(General Feature Format version 3, GFF3). Variants were
d
i
h
H
G
V i i
S
i
Table 2 RNA pathogenicity predictions in MToolBox with
corresponding scores
rRNA
prediction
rRNA
Score
RNA pathogenicity
score in MToolBox
tRNA
Score
tRNA prediction
Proven
pathogenic
5
1.000
20
Definitely
pathogenic
0.950
19
Definitely
pathogenic
0.900
18
Definitely
pathogenic
0.850
17
Definitely
pathogenic
Expectedly
pathogenic
4
0.800
16
Definitely
pathogenic
0.750
15
Definitely
pathogenic
0.700
14
Definitely
pathogenic
0.650
13
Possibly/definitely
pathogenic
Likely
pathogenic
3
0.600
12
Possibly/definitely
pathogenic
0.550
11
Possibly/definitely
pathogenic
0.500
10
Possibly
pathogenic
0.450
9
Possibly
pathogenic
Not enough
evidence
2
0.400
8
Possibly
pathogenic
0.350
7
Possibly
pathogenic
0.300
6
Neutral
0.250
5
Neutral
Undetermined 1
0.200
4
Neutral
0.150
3
Neutral
0.100
2
Neutral
0.050
1
Neutral
Unlikely
pathogenic
0
0.000
0
Neutral
RNA pathogenicity scores provided by MToolBox pipeline, shown in the
central column of the table, derived from two different scoring systems for
rRNA and tRNA genes, respectively. Original predictions and scores, reported
on the right and the left of MToolBox scores, were retrieved from the
literature and normalized to a 0–1 range. Thresholds of 0.600 for rRNA and
0.350 for tRNA sequence variations (in bold) were set according to original
scores. Damaging effects could be observed for variants with a score above
or equal to the chosen thresholds, while neutral variants should be
associated with lower values Results and discussion The three-
dimensional structure of mt-tRNA has a typical L-shape,
due to the molecule folding back in itself forming two
double helix segments through base pairing between T and
D loop. Triplet interactions also occur in position 10-25-
45, 9-23-12 and 13-22-46 in order to increase stability [7]. The strength of folding is also affected by base stacking
interactions, interesting almost all the nucleotides [42]. generation was manually curated in order to produce tab-
delimited text files, then converted in the required format
(General Feature Format version 3, GFF3). Variants were
reported using the Human Genome Variation Society
(HGVS) nomenclature [39]. The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 149 of 212 Fig. 1 Schematic representation of the four types of human mitochondrial tRNAs. The four types of human mt-tRNAs are shown. Green circles represent all
the nucleotide positions involved in post-transcriptional modifications in each tRNA. Blue circles indicate nucleotide positions involved in tertiary folding
with interactions represented by lines. Red circles represent nucleotide positions involved in tertiary folding and subject to post-transcriptional modifications. All the stems (A-stem, T-stem, C-stem, D-stem) and loops (T-loop, V-loop, C-loop, D-loop) of cloverleaf secondary regions are also shown Fig. 1 Schematic representation of the four types of human mitochondrial t
h
l
id
i i
i
l
d i
i i
l
difi
i
i
h NAs The four types of human mt-tRNAs are shown Green circles represent all Fig. 1 Schematic representation of the four types of human mitochondrial tRNAs. The four types of human mt-tRNAs are shown. Green circles represent all
the nucleotide positions involved in post-transcriptional modifications in each tRNA. Blue circles indicate nucleotide positions involved in tertiary folding
with interactions represented by lines. Red circles represent nucleotide positions involved in tertiary folding and subject to post-transcriptional modifications. All the stems (A-stem, T-stem, C-stem, D-stem) and loops (T-loop, V-loop, C-loop, D-loop) of cloverleaf secondary regions are also shown pathogenicity predictions and scores. Original scores were
normalized to a 0–1 range, with derived thresholds of
0.600 and 0.350 for rRNA and tRNA sequence variations,
respectively (Table 2). Damaging effects could be observed
for variants with a score above or equal to the chosen
thresholds, while neutral variants should be associated
with lower values. Results and discussion Glu
50
pseudouridine
P
Met
54
5-methyluridine
T
Leu(UUR), Pro
55
pseudouridine
P
Leu(UUR), Pro
Glu, Gln, Ser(UCN), Tyr
58
1-methyladenosine
”
Ser(AGY), Leu(UUR)
Cys, Ser(UCN)
Glu
72
5-methylcytidine
? Thr
All the post-transcriptional modifications confirmed or predicted in human mt-tRNAs are listed. The full name of modifications, Modomics symbols and positions affected
are shown for each tRNA species. Modifications reported include those confirmed by crystallographic data in eight human mt-tRNAs, those predicted using bovine model,
which has similar structure and sequence in mt-tRNAs, and those predicted based on model organisms, such as bacteria, yeast and nematode bol
Human mt-tRNAs
Bovine mt-tRNAs
Model organisms tRNAs
Asp, Leu(CUN), Lys, Pro
Ala, Glu, Phe, Gly,
His, Asn, Arg, Thr,
Val, Trp
Ile, Leu(UUR)
Cys, Gln, Tyr
Leu(UUR), Leu(CUN),
Lys, Asp
Ala, Phe, Gly, His,
Asn, Val, Trp, Tyr
Leu(UUR)
Ala, Glu
Ile
Asp, Ile, Leu(UUR),
Leu(CUN),
Lys, Met, Pro
Cys, His
Ile, Lys, Leu(CUN), Pro
Cys, Glu, Asn,
Ser(UCN), Tyr
Ser(UCN)
Leu(CUN)
Ser(UCN), Thr
Pro
Cys
Leu(UUR)
Glu, Gln, Trp
Asp
His, Asn, Tyr
Lys
Glu, Gln
Met
Ile, Lys, Ser(AGY)
Asn, Thr
Cys, Phe, Ser(UCN),
Trp, Tyr
Phe, Ser(UCN),
Trp, Tyr
Leu(CUN), Pro
Gln
Pro
Ala, Cys, Phe, Gly,
His, Gln, Arg, Tyr
Glu, Gln
Leu(UUR)
Glu
Met
Leu(UUR), Pro
Leu(UUR), Pro
Glu, Gln, Ser(UCN), Tyr
Ser(AGY), Leu(UUR)
Cys, Ser(UCN)
Glu
Thr
RNAs are listed. The full name of modifications, Modomics symbols and positions affected
ed by crystallographic data in eight human mt-tRNAs, those predicted using bovine model,
ed on model organisms such as bacteria yeast and nematode All the post-transcriptional modifications confirmed or predicted in human mt-tRNAs are listed. The full name of modifications, Modomics symbols and positions affected
are shown for each tRNA species. Modifications reported include those confirmed by crystallographic data in eight human mt-tRNAs, those predicted using bovine model,
which has similar structure and sequence in mt-tRNAs, and those predicted based on model organisms, such as bacteria, yeast and nematode All the post-transcriptional modifications confirmed or predicted in human mt-tRNAs are listed. The full name of modifications, Modomics symbols and positions affected
are shown for each tRNA species. Results and discussion As expected, we observed a relatively low frequency of
disease associated mutations within the anticodon triplet
(11/394 mutations) since its high conservation is required
for a correct recognition of the messanger RNA. Specific-
ally, position 36, corresponding to the third base within
anticodon, is more subject to pathogenic mutations (7/11). Moreover we observed a quite homogeneous distribution
of mutations with a deleterious effect in other tRNA re-
gions, in line with an almost consistent involvement of all
the regions in the three-dimensional folding. Finally, several annotations previously collected [16] were
accurately revised to provide users the most possible up-
to-date pipeline for mitochondrial genome analysis, includ-
ing updated variability data from HmtDB database [19],
dbSNP identifiers [25], OMIM links to known variants
[24], novel disease associated variants and somatic muta-
tions reported in MITOMAP [4] (Table 1). Fortynine variants in rRNA genes [31] and 207 variants
in tRNA genes [29, 30] were retrieved from the literature
as validated mutations, hence inserted within the annota-
tion mechanism used by MToolBox and integrated with The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 150 of 212 All h
d
i
MT
lB
il bl b
h i
h
A
i
/
i
i i
i
l
i
Table 3 Post-transcriptional modifications in mt-tRNAs
Position
Modified base name
Modomics symbol
Human mt-tRNAs
Bovine mt-tRNAs
Model organisms tRNAs
9
1-methyladenosine
”
Asp, Leu(CUN), Lys, Pro
Ala, Glu, Phe, Gly,
His, Asn, Arg, Thr,
Val, Trp
9
1-methylguanosine
K
Ile, Leu(UUR)
Cys, Gln, Tyr
10
N2-methylguanosine
L
Leu(UUR), Leu(CUN),
Lys, Asp
Ala, Phe, Gly, His,
Asn, Val, Trp, Tyr
20
dihydrouridine
D
Leu(UUR)
26
N2-methylguanosine
L
Ala, Glu
26
N2,N2-dimethylguanosine
R
Ile
27
pseudouridine
P
Asp, Ile, Leu(UUR),
Leu(CUN),
Lys, Met, Pro
Cys, His
28
pseudouridine
P
Ile, Lys, Leu(CUN), Pro
Cys, Glu, Asn,
Ser(UCN), Tyr
29
pseudouridine
P
Ser(UCN)
31
pseudouridine
P
Leu(CUN)
32
3-methylcytidine
’
Ser(UCN), Thr
32
pseudouridine
P
Pro
Cys
34
5-taurinomethyluridine
Ê
Leu(UUR)
Glu, Gln, Trp
34
queuosine
Q
Asp
His, Asn, Tyr
34
5-taurinomethyl-2-thiouridine
Ǝ
Lys
Glu, Gln
34
5-formylcytidine
>
Met
37
N6-threonylcarbamoyladenosine
6
Ile, Lys, Ser(AGY)
Asn, Thr
37
N6-isopentenyladenosine
+
Cys, Phe, Ser(UCN),
Trp, Tyr
37
2-methylthio-N6-isopentenyladenosine
*
Phe, Ser(UCN),
Trp, Tyr
37
1-methylguanosine
K
Leu(CUN), Pro
Gln
38
pseudouridine
P
Pro
39
pseudouridine
P
Ala, Cys, Phe, Gly,
His, Gln, Arg, Tyr
40
pseudouridine
P
Glu, Gln
48
5-methylcytidine
? Leu(UUR)
49
5-methylcytidine
? Results and discussion Modifications reported include those confirmed by crystallographic data in eight human mt-tRNAs, those predicted using bovine model,
which has similar structure and sequence in mt-tRNAs, and those predicted based on model organisms, such as bacteria, yeast and nematode All the updates in MToolBox are available both in the
command line version [43] and in the web-based re-
source at MSeqDR website [44]. New options to better
manage input files are described in the readme file in
the package. Moreover a summary is now produced
reporting all the parameters chosen for the analysis and
some basic statistics. Annotation/prioritization tools comparison In recent years lots of tools for variant prioritization were
produced in order to help clinicians and researchers to
recognize a few relevant mutations among the huge
amount of variations detectable by NGS technologies. However, the annotation and prioritization processes car-
ried out by these tools are often focused on missense Page 151 of 212 The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 151 of 212 Table 4 Variant annotators comparison for a tRNA gene
mutation
MToolBox Annotation
Example
Locus
MT-TM
RSRS
Yes
MHCS
Yes
rCRS
Yes
Haplogroup
Other Haplogroups
Nt Variability
0.00E+00
tRNA Annotation
53;II;TS;G;N
Patho-prediction RNA coding genes 0.65
MITOMAP Associated Disease(s)
Myopathy
MITOMAP Homoplasmy
N
MITOMAP Heteroplasmy
Y
Mamit-tRNA
http://mamit-trna.u-strasbg.fr/
mutations.asp?idAA=19
PhastCons20Way
0.889764
PhyloP20Way
0.797921
SnpEff Annotation
Example
Annotation
non_coding_exon_variant
Annotation_Impact
MODIFIER
Gene_Name
MT-TM
Gene_ID
ENSG00000210112
Feature_Type
Transcript
Feature_ID
ENST00000387377
Transcript_BioType
Mt_tRNA
Rank
1/1
HGVS.c
n.49G>A
MitoBamAnnotator
Example
pos
4450
ref
G
from
G
to
A
gene
MT-TM
coding for
tRNA
coding region
0
is mutated
1
triplet position
NA
mutation type
NA
has_overlap
0
CI
NA
mit-o-matic
Example
Variant
4450
Ref allele
G Table 4 Variant annotators comparison for a tRNA gene
mutation Table 4 Variant annotators comparison for a tRNA gene
mutation (Continued)
Alt allele
A
Gene
MT-TM
Disease
Myopathy
Among tools providing annotations for a specific variant in a tRNA gene
(m.4450G>A) chosen for its potential damaging effect, MToolBox showed the
widest range of useful features provided in the final annotation step allowing
users to prioritize the variant. Empty fields were omitted. Tested tools which
do not provide annotations for tRNA variants were not reported Table 4 Variant annotators comparison for a tRNA gene
mutation (Continued) Among tools providing annotations for a specific variant in a tRNA gene
(m.4450G>A) chosen for its potential damaging effect, MToolBox showed the
widest range of useful features provided in the final annotation step allowing
users to prioritize the variant. Empty fields were omitted. Tested tools which
do not provide annotations for tRNA variants were not reported variant characterization by providing pathogenicity predic-
tions, dbSNP identifiers, frequency in known datasets
such as the 1000 Genomes, conservation scores and re-
gion annotations (see Additional file 1). Among the most
popular tools for variant prioritization, ANNOVAR [35],
SnpEff [36] and dbNSFP [14] are commonly used both
for nuclear DNA and mtDNA variations. Annotation/prioritization tools comparison Moreover
mitochondrial-oriented tools have been recently devel-
oped, such as mit-o-matic [37], MitImpact [15] and
MitoBamAnnotator [38] to ensure appropriate annota-
tions mindful of mitochondrial genetics peculiarities,
such as heteroplasmy. A comparison was performed
among the aforementioned tools, showing pros and
cons of each of them (Additional file 1). A few generic
annotations regarding mt-tRNA variants were provided
by some of the tested tools, while the MToolBox pipe-
line showed a wide range of annotations proving to be
useful for any variant evaluation and not only missense
variants (Table 4). Moreover, several input file formats can
be used by MToolBox, proving a great efficiency for both
high throughput sequencing and traditional FASTA data. Last but not least, the web-based version of the tool [44]
ensures large usability also by non-expert users interested
in mitochondrial genome analysis. Additional file Additional file 1: Variant annotation by 7 different tools. All the annotations
provided by MToolBox, ANNOVAR, SnpEff, dbNSFP, MitImpact 2.0,
MitoBamAnnotator and mit-o-matic are shown. Three variants were
considered (m.879T>C, m.3436G>C, m.4450G>A), one for an rRNA gene
(MT-RNR1), one for a tRNA gene (MT-TM) and one for a protein coding
gene (MT-ND1). ANNOVAR and SnpEff tools use dbNSFP databases. Generally, all the tools provided an accurate annotation for the missense
variant, although we were not able to obtain any information by mit-o-matic
web-based software. MToolBox provided the most complete annotation for
non protein coding regions. (XLSX 44 kb) Additional information from MITOMAP [4], ClinVar
[26], Mamit-tRNA [13] dbSNP [25] and OMIM [24]
databases were shown, when available, for all the four
tracks, as well as variability data from HmtDB database
[19] and conservation scores from UCSC Genome
Browser [21, 22]. The tracks, can be uploaded in the “Custom Tracks”
section of the MSeqDR website, selected, totally or par-
tially (only transitions, transversions, insertions or dele-
tions) and visualized in the GBrowse (Fig. 2). Conclusions The second track collects all the 1740 possible stop-
gain and 77 possible stop-loss mutations, which could
be damaging in the generation of the 13 human mito-
chondrial proteins. To the best of our knowledge, specific data regarding
mitochondrial variants in tRNA genes were introduced for
the first time in a tool for mitochondrial genome analysis
and then reported in custom tracks, which could be dis-
played at MSeqDR GBrowse. The availability of such data
could be useful to support the interpretation of genetic
variants in specific genomic contexts. The third track (“MT-patho.RNA”) is useful to show
all the information currently available about pathoge-
nicity of 392 variants in tRNA and 337 in rRNA genes,
while the fourth track (“MT-RNA”) includes generic
annotations reported for all the 1505 positions in genes
encoding tRNAs and 2513 positions in genes encoding
rRNAs, respectively. All the tracks were produced using
the revised Cambridge Reference Sequence, rCRS (Gen-
Bank: J01415.2), as reference sequence. Mitochondrial variations tracks at MSeqDR In order to facilitate the interpretation of genetic vari-
ants in a specific genomic context, four different custom
tracks were produced in GFF3 file format displayable at
MSeqDR GBrowse [45] (Fig. 2). The tracks included all
the data used for the annotation step carried out by the
MToolBox pipeline, providing users the possibility to
analyze only variants or genomic positions with no need
to provide input files. A track previously provided,
called “Mitochondrial Pathogenicity Predictions” [17],
was updated and split into two different tracks, “MT-
patho.CDS” and “MT-patho.STOP” tracks. The first
collects all the 24,202 possible non-synonymous vari-
ants within the 13 human mitochondrial protein encod-
ing genes, identified using mtDNA-GeneSyn software
[46]. Predictions and probabilities of pathogenicity were
produced using five different software [16] and an over-
all disease score was also provided [47]. The Author(s) BMC Bioinformatics 2016, 17(Suppl 12):338 Page 152 of 212 Fig. 2 Overview of the usage of mitochondrial tracks at MSeqDR GBrowse. MSeqDR website provides access to a GBrowse useful to visualize
genomics data. Users can upload the four tracks generated in this work in the “Custom Tracks” section of the browser (a). For the sake of
simplicity, the only “MT-patho.RNA” track is here shown, including data about pathogenic variants in mt-tRNA and mt-rRNA genes. The
custom track can be selected, totally or partially (only transitions, transversions, insertions or deletions, b) and then visualized in the browser
(c) where users can search for a specific genomic region of interest. Eventually, detailed information can be shown by clicking on a specific
variant site (d) Fig. 2 Overview of the usage of mitochondrial tracks at MSeqDR GBrowse. MSeqDR website provides access to a GBrowse useful to visualize
genomics data. Users can upload the four tracks generated in this work in the “Custom Tracks” section of the browser (a). For the sake of
simplicity, the only “MT-patho.RNA” track is here shown, including data about pathogenic variants in mt-tRNA and mt-rRNA genes. The
custom track can be selected, totally or partially (only transitions, transversions, insertions or deletions, b) and then visualized in the browser
(c) where users can search for a specific genomic region of interest. Eventually, detailed information can be shown by clicking on a specific
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variants of clinical interest. Hum Genet. 2016;135:121–36. References • We accept pre-submission inquiries
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Genetic and environmental components of female depression as a function of the severity of the disorder
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Brain and behavior
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cc-by
| 5,097
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K E Y W O R D S additive and dominance estimates, homozygotic and heterozygotic alleles, major depression,
mood disorders, twin studies Received: 3 March 2016 | Revised: 17 May 2016 | Accepted: 25 May 2016
DOI: 10.1002/brb3.519 Received: 3 March 2016 | Revised: 17 May 2016 | Accepted: 25 May 2016
DOI: 10.1002/brb3.519 d: 3 March 2016 | Revised: 17 May 2016 | Accepted: 25 May 2016 Revised: 17 May 2016 | Accepted: 25 May 2016 DOI: 10.1002/brb3.519 Genetic and environmental components of female depression
as a function of the severity of the disorder James S. M. Rusby1 | Fiona Tasker1 | Lynn Cherkas2 1Department of Psychological
Sciences, Birkbeck University of London,
London, UK
2Department of Twin Research and Genetic
Epidemiology, King’s College London,
London, UK Brain Behav 2016; 6: e00519 Abstract Background: Both clinical care and genome-wide studies need to account for levels
of severity in the etiology of depression. The purpose of the study is to estimate
the genetic and environmental components of female depression as a function of
the severity of the disorder. Correspondence
James S. M. Rusby, Department of
Psychological Studies, Birkbeck University of
London, London, UK. Email: jsrusby@btinternet.com Correspondence
James S. M. Rusby, Department of
Psychological Studies, Birkbeck University of
London, London, UK. Email: jsrusby@btinternet.com Methods: A genetic and environmental model analysis of depression incidence was
made using the IOP Depression Severity Measure (IDSM). Details of lifetime depres-
sion incidence were obtained by questionnaire from twins on the DTR registry. Data from 1449 matched female twin pairs in the age range 19–85 years in four
ordinal categories of increasing severity were employed in the analysis. Results: Estimates of additive and dominance genetic components of 27% and
25% were found when all three levels of depression were included, and near zero
and 33% when the recurrent/severe level was excluded. Shared environmental
effects were not significant in either case, but the estimate for random environ-
mental effects was greater when the severe level was excluded. Conclusions: These results suggest that the incidence of severe depression is asso-
ciated with homozygotic alleles and the less severe with heterozygotic alleles. This
is in accord with the finding that the hereditary component of severe depression
is relatively high and that milder forms are more dependent on life-time environ-
mental factors. Such conclusions have clinical implications for the diagnosis and
treatment of the disorder by practicing psychiatrists. They also lead to the impor-
tance of focusing future genome-wide and linkage studies on those females with
severe levels of depression if progress in identifying genetic risk loci is to be
made. 2.1 | Subjects Subjects were volunteer female monozygotic (MZ) and dizygotic
(DZ) twins enrolled in the TwinsUK Adult Twin Registry held in
the Department of Twin Research (DTR) at St Thomas’ Hospital,
London (Spector & Williams, 2006). All twins were recruited through
national media campaigns and from other twin registers. The twins
in the registry are not selected for any particular trait and they
volunteer to take part in studies that cover a wide range of traits
and common medical conditions. The study was approved by the
St Thomas’ Hospital Research Ethics Committee and all twins in
the study provided their consent. Twins from this registry have
been shown to be comparable to the age-matched general popula-
tion of singletons for a broad variety of medical and behavioral
traits (Andrew, Hart, Sneider, & De Lange, 2001). In 2006, the IOP Depression Severity Measure (IDSM) was
included in the annual questionnaire sent to 8,990 registered twins
by the Department of Twin Research. A total of 5,097 replied giving
a response rate of 57% of which 91% were females (Nf = 4,638). MZ
and DZ twins accounted for 57% and 42% of the respondents and
in 1% zygosity was undetermined. Age ranged from 19 to 85 years. After including only the paired female twins, reared together, of
known zygosity and white ethnicity, 1,740 twin pairs were available
(NF = 3,480, or 75%), 973 monozygotic, and 767 dizygotic twin pairs. In order to equalize the numbers of MZ and DZ pairs, this number was
then reduced to 1,449 twin pairs for the model genetic analysis. These past, inconclusive, GWAS and linkage results based on the
dichotic selection of control and incidence groups, and in which sex
and age are usually pooled, will need to be better focused in future if
progress is to be made in locating the genetic loci contributing to the
etiology of depression. As a contribution in this direction, the analysis
described in the present paper is limited to female cases to investigate
whether genetic and environmental variance components of depres-
sion may vary as a function of the severity of this disorder. Any analysis such as this which attempts to clarify the etiology
of clinical depression as a function of the severity of the disorder will
also be of value to practicing clinicians as they try to assess the pos-
sible origins of individual cases and the treatment required. 2.1 | Subjects For those
who may be unfamiliar with such genetic analyses, it is worth clari-
fying and defining the terms used. In this study, the classic genetic
model is employed in a structural analysis to estimate both the genetic
and environmental variance components related to the phenotype,
depression incidence. The genetic components may be additive or
dominant in form. If additive, the responsible genes have two dichotic
alleles which are identical or homozygotic. If dominant, then one allele
is responsible for the effect, and the other, recessive, allele does not
contribute, and the gene is heterozygotic. Dominance may be com-
plete, in which case the effect on the phenotype is the same as the
additive effect, or partial, leading to an intermediate dosage. Heredi-
tary influence is largely due to the additive component. The variance
of the environmental components estimated by the analysis is also in e00519 (2 of 7) Rusby et al. Rusby et al. confirmed by a large study from Sweden (Kendler, Gatz, Gardner, &
Pedersen, 2006; Sullivan, Neale, & Kendler, 2000). These studies have
also concluded that the figure may be higher for those with severe
or recurrent forms of the illness. The shared or family environmental
components have been found to be of little significance, but lifetime
environmental factors are important. It is well known that women are
at a greater risk of depression and there is increasing evidence that
this is partly due to the higher genetic component found for female
depression, where research evidence estimates genetic components
of some 40%–44% for women and 21%–31% for men (Bierut et al.,
1999; Jansson et al., 2004; Kendler, Gardner, Neale, & Prescott, 2001). These substantive results from twin analyses have encouraged inter-
national groups of researchers to use both GWAS and linkage studies
to try to ascertain which candidate genes might contribute to the eti-
ology of depression. However, as Flint and Kendler (2014) conclude
from their extensive review of these complex and ambitious inves-
tigations, many articles have been generated but no robust findings
or positive replications made. In addition, parallel research progress
based on the original monoamine hypothesis has been limited now
that certain aspects of its explanatory performance have been found
to be inadequate (Hirschfeld, 2000; Krishnan & Nestler, 2008). Flint
and Kendler believe that the mega-analysis of GWAS studies reported
by Ripke et al. (2013) totaling some 9,000 cases of clinical depression
that failed to find robust evidence for loci that exceeded genome-
wide significance levels implies that genetic variance may be due to
the joint effect of large numbers of loci of small effect. This suggests
that clinical depression may be diverse in origin and so unlikely to be
dichotomous in outcome. two forms: the first is due to shared or family factors and the second
to random factors during development and in adult life. In practice,
the effect on the phenotype is very likely to be due to the aggregated
influence of a number of contributing genetic loci and also on a range
of environmental effects. The classic structural genetic analysis has
been shown to be valid for such multiple effects (Neale & Cardon,
1992). 1 | INTRODUCTION Clinical depression is one of the most common psychiatric disorders,
particularly in Europe and America with a lifetime prevalence rate
between 10% and 20% where it is a major cause of morbidity and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited. Brain Behav 2016; 6: e00519
wileyonlinelibrary.com/brb3
© 2016 The Authors. Brain and Behavior published | 1 Brain Behav 2016; 6: e00519 e00519 (2 of 7) e00519 (2 of 7) 2.3 | Twin analysis The genetic and environmental analysis proceeded from the use
of the classic structural path model for data from monozygotic
and dizygotic twins reared together (Neale & Cardon, 1992). The
layout of this path coefficients model is shown in Fig. 1. In the
model, the latent additive genetic factors A1 and A2, the dominant
genetic factors D1 and D2, the shared environmental factors C1
and C2, and the random environmental factors E1 and E2, cause
the phenotypes P1 and P2 in twins 1 and 2. It is not expected
that the values of the genetic or environmental effects, a, c, e,
and d, as free parameters will vary between twins, and these
constraints are included in the running of the analysis. In addition,
the variance of the latent factors are standardized to unity. Classical
covariance values from genetic theory linking the factors for both
types of zygosity are included in the figure. Two genetic analyses were carried out: in the first, all three levels
of depression incidence were included, and in the second, the severe
level was omitted and only the mild and moderate levels retained. In order to equalize case numbers for the analyses, the numbers of
MZ twin pairs were reduced randomly by SPSS from 973 to 726 to
be equal to the number of DZ twin pairs in the first model analysis
and from 767 to 520 in the second analysis, giving a total of 1,449
and 1,052 twin pairs, respectively. This follows the recommendation
given by Neale and Cardon when a two-group analysis is run which
combines the data from both sets of twin pairs, MZ and DZ (Neale &
Cardon, 1992). The model fitting results obtained are listed in Table 1 for the five
nested models evaluated for each depression severity analysis, exclud-
ing the ACDE model which is not identified in the classical twin model. In both analyses, the shared environment effect, C, is not significant
and the models with the highest probability of fitting the observed
covariance are the ADE models. Both of these ADE model are satu-
rated, that is, there are only one set of values for the three parameters
for each of the ADE models which will produce expected values of the
covariance–variance matrix that match the observed values (Purcell,
2013). 3 | RESULTS As described above, the depression incidence data generated by
the IDSM measure was defined by four ordinal categories. In terms
of incidence, 63% reported no depression, 8% mild depression,
14% moderate depression, and 15% severe levels of depression. Twin pair correlations were 0.40 and 0.14 for the MZ and DZ
pairs, respectively, resulting in a heritability estimate of 52%. If
the severe category is omitted, the correlations were 0.18 and
0.06 giving a reduced heritability of 24%. to question 3 or 4. The final, severe/recurrent, level is scored if
the respondent has received defined medication from a general
practitioner or psychiatrist, that is ‘yes’ to question 6c, and/or
had more than one episode of depression that required some form
of treatment, that is ‘yes’ to question 8. In order to avoid any
experimenter bias leading to spurious linkage between individual
twin pairs scoring was automatically carried out by STATA software
using the IDSM depression level scoring algorithm described above. For the genetic analysis, these levels were scored in one of four
ordinal categories, from 0, no depression, through to 3, severe/
recurrent depression. likelihood ratio χ2 between the nested models and observed variance–
covariance matrices. This is the method recommended by Neale and
Cardon (1992) for obtaining such goodness-of-fit criteria. e00519 (3 of 7) Rusby et al. 2.2 | Assessment of depression The IDSM depression measure used was developed at the Institute
of Psychiatry (IOP) and assessed for content validity by Professors
David Collier and Anne Farmer of IOP (see Appendix 1). The
measure has been employed by Rusby, Harris, and Tasker (2013)
to study the association between personal dependency and levels
of depression and by Davies et al. (2014) to examine the relation-
ship between epigenetic methylation effects and depression. Three
levels of depression of increasing severity are assessed by the
design. The first or mild depression, is self-diagnostic and is scored
by those who answer ‘yes’ to question 1, but excludes those
women who only had depression following the birth of a baby. The second or moderate level, is scored if, in addition, a general
practitioner or psychiatrist had diagnosed depression, that is ‘yes’ 2.3 | Twin analysis However, little account was taken in these analyses of
any contribution due to a possible dominant genetic component. In the case of the first Virginia Twin Registry analysis with 1,033
twin pairs, a 13% dominant component was estimated, and in the
Australian study, the AE model was chosen rather than the ADE
model for reasons of parsimony. The other studies did not include
the ADE model in their analyses. So, the finding from this study that 25% of the variance is estimated
to be due to a dominant component, in addition to the 27% additive com-
ponent, is a significant factor in understanding the form of the genetic
association of depression, and is in contrast to these earlier results. against the results for the more parsimonious DE model, which also
has a low value of χ2, to check if the additive component in the ADE
model is significant. The difference in χ2 between the models is 2.6
with df = 1, giving a probability p = .11 which is not significant at the
.05 level. This suggests that the more parsimonious DE model is to
be preferred since it does not show a reduction in fit and so provides
evidence that the additive genetic component in the ADE model is not
likely to be significant. against the results for the more parsimonious DE model, which also
has a low value of χ2, to check if the additive component in the ADE
model is significant. The difference in χ2 between the models is 2.6
with df = 1, giving a probability p = .11 which is not significant at the
.05 level. This suggests that the more parsimonious DE model is to
be preferred since it does not show a reduction in fit and so provides
evidence that the additive genetic component in the ADE model is not
likely to be significant. The minimal contribution found in earlier studies for any dominance
component may be partly explained by a lack of statistical power. These
studies treated depression as a dichotomous trait using varying DSM
and other threshold criteria with different prevalence rates. 2.3 | Twin analysis In the case of the second analysis, in which the severe level
of depression has been excluded, the ADE model needs to be tested The EQS structural program employed was run as a two-group
analysis in which the results from each MZ and DZ modeling analy-
sis were combined in order to determine the best-fitting genetic and
environmental estimates (Bentler, 1995). Since the data are categori-
cal with four ordinal levels, arbitrary generalized least squares (AGLS)
estimation was used in which the correlations between the depression
level scores were estimated by polychoric and polyserial coefficients
(Lee, Poon, & Bentler, 1994). The EQS program allows an estimation
of the goodness-of-fit in the model analysis to be made based on the P1
P2
a
c
e
d
a
c
e
d
A1 C1
E1 D1 A2 C2 E2 D2
1
1 1
1 1 1 1 1
1.0 (MZ) or 0.5 (DZ) 1.0 (MZ, DZ) 1.0 (MZ) or 0.25 (DZ)
FIGURE 1 Basic genetic path model for
data from monozygotic (MZ) and dizygotic
(DZ) twins reared together P1
P2
a
c
e
d
a
c
e
d
A1 C1
E1 D1 A2 C2 E2 D2
1
1 1
1 1 1 1 1
1.0 (MZ) or 0.5 (DZ) 1.0 (MZ, DZ) 1.0 (MZ) or 0.25 (DZ) P1
P2
a
c
e
d
a
c
e
d
A1 C1
E1 D1 A2 C2 E2 D2
1
1 1
1 1 1 1 1
1.0 (MZ) or 0.5 (DZ) 1.0 (MZ, DZ) 1.0 (MZ) or 0.25 (DZ) d A2 D2 1 FIGURE 1 Basic genetic path model for
data from monozygotic (MZ) and dizygotic
(DZ) twins reared together FIGURE 1 Basic genetic path model for
data from monozygotic (MZ) and dizygotic
(DZ) twins reared together 1.0 (MZ, DZ) e00519 (4 of 7)
are additive
TABLE 1
Model fitting results for female depression Rusby et al. TABLE 1 Model fitting results for female depression
Model (df)
Severe level included
(1,449 twin pairs)
Severe level excluded
(1,052 twin pairs)
χ2
p
χ2
p
ADE (3)
0.0
1.00
0.00
1.00
ACE (3)
18.6
<.001
>1,000
<.001
AE (4)
18.6
<.001
29.6
<.001
CE (4)
293.6
<.001
546.3
<.001
DE (4)
25.7
<.001
2.6
.27 TABLE 1 Model fitting results for female depression are additive genetic estimates with the remaining variance due to
the random environment and with no shared environmental com-
ponent. 2.3 | Twin analysis Analytical
studies by Neale, Eaves, and Kendler (1994) have confirmed that the
power to detect genetic dominance is low in the classical twin model
and this is particularly the case with dichotomous data when the thresh-
old is set at a high level with a low incidence, or prevalence rate. As an
example, Neale et al. calculated if the true world variation is 30% addi-
tive, 30% dominance, and 40% random environmental, then, in excess
of 20,000 twin pairs would be required to reject a false AE model with
a power of 80%, if the prevalence rate for the disorder is only 10%. Following their analysis, this study has gained power in two ways: by
setting a low initial threshold relating to the incidence of depression, it
has resulted in a relatively high overall prevalence rate of 37%, as well
as by the gain received from having four ordinal levels rather than being
dichotomous in form. According to the Neale et al. analysis, even with
these gains, some 3,000 twin pairs would be required for a power of
80% to reject the AE model in favor of the real world ADE model. With
1,449 pairs in this study, the power is only about 50% although exam-
ination of Table 1 shows that this has proved sufficient to reject the AE
model in favor of the ADE one. Table 2 lists the estimated values of the path coefficients with their
confidence intervals and the variances of the two conditions analyzed. The total additive, a2, plus d2, dominant, genetic variance estimated
from the analysis which includes the severe category of depression is
52% which falls to 33% due to the dominant variance alone when only
the two nonsevere ordinal levels of depression are included. In both
cases, the remaining variance is accounted for by random environmen-
tal effects including residual error (e2 values) and none by shared or
family effects (c2 values). FUNDING INFORMATION TwinsUK is funded by the Welcome Trust, Medical Research Council,
European Union (EU), and the National Institute for Health Research
(NIHR)-funded
BioResource,
Clinical
Research
Facility,
and
Biomedical Research Centre based at Guy’s and St Thomas’ NHS
Foundation Trust in partnership with King’s College London. In view of the weakness of the classical twin analysis to reject the
AE model in favor of the ADE model, and the fact that this study is lim-
ited in power, it is important to replicate these estimates using a larger
sample. If it is confirmed that severe forms of female depression are
largely associated with the additive genetic component and the more
moderate forms with a dominance deviation component plus a larger
random environmental variance, then this has implications for the
design of GWAS and linkage surveys. Such surveys should be sex spe-
cific and recruit those with the severest, more heritable, forms of the
disability in order to attempt to detect significant homozygotic genetic
loci. In this context, a recent large-scale study, named CONVERGE, has
recruited some 5,000 Chinese women with recurrent major depression
in order to reduce such heterogeneity and to identify specific genes
through whole-genome sequencing (CONVERGE Consortium, 2015). 5 | CONCLUSION 5 The particular contribution of this study is that it has attempted to
gain some insight into whether the form and magnitude of the genetic
and environmental variance depends on the severity of the disorder
using ordinal data. The results suggest that the genetic element of
the severe level of depression is largely due to the additive com-
ponent and that when this depression level is excluded, the origin
of the more moderate, broader, forms of the disorder is due to the
dominance deviation component combined with a larger random
environmental component. If this is correct, then the severe level
is dependent on defined homozygosis, which is the presence of
certain identical alleles at corresponding multiple loci on homologous
chromosomes. The more moderate forms would then be dependent
on heterozygosis, or dissimilar alleles at corresponding multiple het-
erozygotic loci. The mathematical analysis of additive and dominance
deviation variance which led to the generation of the classic genetic
structural path model has been shown to apply to such multiple
loci and also to unequal gene frequencies (Mather & Jinks, 1982;
Neale & Cardon, 1992). This is important since the review by Flint
and Kendler (2014) suggests that it is likely that a large number of
loci, possibly of small effect, are involved in this disorder. ACKNOWLEDGMENTS The authors thank the twins for their voluntary contribution to
this research project. They also thank the staff of the DTR for
their work in distributing the questionnaire and collating the results. The design of the IDSM depression measure was the work of a
number of colleagues at the Institute of Psychiatry, including David
Collier and Anne Farmer and we thank them and DTR for the
use of the data. Our thanks also to Juliette Harris of DTR who
liaised with us and answered our queries so promptly. e00 this present study, if the contribution of the dominance component is
excluded then the narrow-sense heritability due only to any additive
component is 27% when the severe level of depression is included and
approximately 0% when it is excluded. The corollary of these estimates
is that the milder forms of the disorder are more dependent on lifetime
environmental influences than genetic effects. environmental influences on the outcome since twins and siblings may
vary in their susceptibility to the vagaries of family upbringing. More
research needs to be done to clarify this result and the developmental
and lifetime environmental risks associated with depression. Aside from the above limitation imposed by the number of twin
pairs in this study, there is also the question of self-report reliability
and the validity of the questionnaire used. The reliability concern is
mitigated to some extent by the checks inherent in the measure. In
the case of validity, it would be valuable to repeat this study with an
alternative form of ordinal measure. e00519 (5 of 7) Rusby et al. 4 | DISCUSSION The finding that the total genetic variance of depression for women
is estimated to lie between 30% and 52%, depending on the
severity of the disorder, is in general agreement with previous
results which did not account for severity levels. These include
two studies by researchers using the Virginia Twin Registry (Kendler
et al., 1992, 2001), two studies using the National Swedish Twin
Registry (Jansson et al., 2004; Kendler et al., 2006), and one
employing the Australian Volunteer Twin Registry (Bierut et al.,
1999), which all estimated the genetic component for women to
be around 40%. There is also agreement that the equivalent figure
for men is considerably less, lying between 21% and 31%. These The importance of the dominance contribution can be inferred
directly from the depression data where the MZ correlations were
found to be more than twice those of the DZ values. This data leads
to broad-sense heritability values of 52% when the severe level is
included and 24% when it is excluded using Falconer’s formula based
on the difference in MZ and DZ correlation values (Falconer, 1965). The higher value of 52% may be compared to that of 58% from the
equivalent correlation values reported from the large Swedish National
twin study using modified DSM-IV criteria (Kendler et al., 2006). In TABLE 2 Path coefficients and variance estimates for ADE model from MZ and DZ two-group analyses
Depression
Path coefficients
Variance estimates
a (CI.95)
d (CI.95)
e (CI.95)
a2
d2
e2
With severe
0.52 (0.16)
0.50 (0.18)
0.69 (0.02)
0.27
0.25
0.48
Nonsevere
0
0.58 (0.16)
0.82 (0.09)
0
0.33
0.67 TABLE 2 Path coefficients and variance estimates for ADE model from MZ and DZ two-group analyses mates for ADE model from MZ and DZ two-group analys e00519 (6 of 7) e00519 (6 of 7) 7) Rusby et al. Hirschfeld, R. M. (2000). History and evolution of the monoamine hypoth-
esis of depression. The Journal of Clinical Psychiatry, 61, (suppl.6): 4–6 Neale, M. C., Eaves, L. J., & Kendler, K. S. (1994). The power of the classical
twin study to resolve variation in threshold traits. Behavior Genetics,
24, 239–258. Jansson, M., Gatz, M., Berg, S., Johansson, B., Malmberg, B., McClearn, G. E., ... Pedersen, N. L. (2004). Gender differences in heritability of de-
pressive symptoms in the elderly. Psychological Medicine, 34, 471–479.t Purcell, S. (2013). Statistical methods in behavioural genetics. In R. Plomin,
J. C. DeFries, V. S. Knopik, & J. M. Neiderhiser (Eds.), Behavioural genet-
ics (pp. 357–411). New York, NY: Worth. Kendler, K. S., Gardner, C. O., Neale, M. C., & Prescott, C. A. (2001). Ge-
netic risk factors for major depression in men and women: Similar or
different heritabilities and same or partly distinct genes? Psychological
Medicine, 31, 605–616. Ripke, S., Wray, N. R., Lewis, C. M., Hamilton, S. P., Weissman, M. M., Breen,
G., ... Blackwood, D. H. (2013). A mega-analysis of genome-wide asso-
ciation studies for major depressive disorder. Molecular Psychiatry, 18,
497–511. Kendler, K. S., Gatz, M., Gardner, C. O., & Pedersen, N. L. (2006). A Swedish
national twin study of lifetime major depression. American Journal of
Psychiatry, 163, 109–114. Rusby, J. S. M., Harris, J. M., & Tasker, F. (2013). Female interpersonal
dependency: Genetic and environmental components and its rela-
tionship to depression as a function of age. Aging & Mental Health, 17,
1044–1051. Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves , L. J. (1992). A population-based twin study of major depression in women. Archives
of General Psychiatry, 49, 257–266. Rutter, M. L. (1997). Nature-nurture integration: The example of antisocial
behaviour. American Psychologist, 52, 390–398. Krishnan, V., & Nestler, E. J. (2008). The molecular neurobiology of depres-
sion. Nature, 455, 894–902. Spector, T. D., & Williams, F. M. (2006). The UK adult twin registry (Twin-
sUK). Twin Research and Human Genetics, 9, 899–906.i Lee, S.-Y., Poon, W.-Y., & Bentler, P. M. (1994). Covariance and correlation
structure analyses with continuous and polytomous variables. In T. W. Anderson, K.-T. Fang & I. Olkin (Eds.), Multivariate analysis and its appli-
cations (pp. 347–358), Vol 24. Hayward, CA: Institute of Mathematical
Statistics.ii Sullivan, P. F., Neale, M. C., & Kendler, K. e00519 (6 of 7) S. (2000). Genetic epidemiolo-
gy of major depression: Review and meta-analysis. American Journal of
Psychiatry, 157, 1552–1562. Mather, K., & Jinks, J. L. (1982). Biometrical genetics: The study of continuous
variation. London, UK: Chapman and Hall.i How to cite this article: Rusby, J. S. M., Tasker, F. and Cherkas, L. (2016), Genetic and environmental components of female
depression as a function of the severity of the disorder. Brain and
Behavior, 6: 1–7. e00519, doi: 10.1002/brb3.519 Neale, M. C., & Cardon, L. R. (1992). Methodology for genetic studies of twins
and families. Dordrecht, Netherlands: Kluwer Academic. REFERENCES Andrew, T., Hart, D. J., Sneider, H., & De Lange, M. (2001). Are twins and
singletons comparable? A study of disease-related and lifestyle charac-
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CA: Multivariate Software. Bierut, L. J., Heath, A. C., Bucholz, K.K., Dinwiddie, S. H., Madden, P. A.,
Statham, D. J., ... Martin, N. G. (1999). Major depressive disorder in
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557–563.ii CONVERGE Consortium (2015). Sparse whole-genome sequencing identi-
fies two loci for major depressive disorder. Nature, 523, 588–591. Davies, M. N., Krause, L., Bell, J. T., Gao, F., Ward, K. J., Wu, H., ... Wang J. (2014). Hypermethylation in the ZBTB20 gene is associated with ma-
jor depressive disorder. Genome Biology, 15, R56. http//genomebiology. com/2014/15/4/R56. Confirmation of these present results would, in addition, be of
clinical importance in confirming that the severe level of the disor-
der has a greater hereditary component while the milder forms are
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vious studies (Bierut et al., 1999; Jansson et al., 2004; Kendler et al.,
2006). However, Michael Rutter (1997) has warned that low, or negli-
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29, 51–76.i Flint, J., & Kendler, K. S. (2014). The genetics of major depression. Neuron,
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Foxp3+ Regulatory T Cells Control Persistence of Viral CNS Infection
|
PloS one
| 2,012
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cc-by
| 7,394
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Foxp3+ Regulatory T Cells Control Persistence of Viral
CNS Infection Dajana Reuter1, Tim Sparwasser2, Thomas Hu¨ nig1, Ju¨ rgen Schneider-Schaulies1*
1 Institute for Virology and Immunobiology, University of Wu¨rzburg, Wu¨rzburg, Germany, 2 Institute of Infection Immunology, TWINCORE, Dajana Reuter1, Tim Sparwasser2, Thomas Hu¨ nig1, Ju¨ rgen Schneider-Schaulies1*
1 Institute for Virology and Immunobiology, University of Wu¨rzburg, Wu¨rzburg, Germany, 2 Institute of Infection Immunology, TWINCORE, Centre for Experimental and
Clinical Infection Research, Hannover, Germany Dajana Reuter1, Tim Sparwasser2, Thomas Hu¨ nig1, Ju¨ rgen Schneider-Schaulies1* 1 Institute for Virology and Immunobiology, University of Wu¨rzburg, Wu¨rzburg, Germany, 2 Institute of Infection Immunology, TWINCORE, Centre for Experimental and
Clinical Infection Research, Hannover, Germany Abstract Funding: The authors thank the Deutsche Forschungsgemeinschaft for financial support
decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jss@vim.uni-wuerzburg.de of viral persistence as subacute sclerosing panencephalitis (SSPE). Epidemiological studies indicated that the primary MV infection
of SSPE patients takes place predominantly below the age of two
years, when the immune system of the host is still immature and
residual maternal antibodies may be absent or not sufficient for
complete virus neutralization [20,21]. For intracerebral MV
infection of mice, a transgenic human receptor for MV is not
necessarily required, and various infection models exist depending
on the age of the mice, the virus strain, and the infectious dose
[22,23,24,25,26]. As found in genetically unmodified and MV-
receptor transgenic mice, T cells and IFN-c have a critical role for
protection and clearance of virus from the brain [27,28,29,30]. Transient immunosuppression during MV-infection enhanced
virus replication and facilitated persistence [31]. After intranasal
infection of MV-receptor CD150-transgenic mice, a specific
antiviral
cellular
immune
response
including
an
increased
proportion of Foxp3+ Tregs in the spleen was observed [32]. Although the presence and activity of Tregs has been demon-
strated, their actual role in viral immunosuppression or immuno-
pathogenesis in the brain remains to be elucidated. Foxp3+ regulatory T cells control
persistence of viral CNS infection. Item Type
Article
Authors
Reuter, Dajana; Sparwasser, Tim; Hünig, Thomas; Schneider-
Schaulies, Jürgen
Citation
Foxp3+ regulatory T cells control persistence of viral CNS
infection. 2012, 7 (3):e33989 PLoS ONE
DOI
10.1371/journal.pone.0033989
Journal
PloS one
Download date
24/10/2024 04:42:30
Link to Item
http://hdl.handle.net/10033/595526 PLoS ONE | www.plosone.org Abstract We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically
unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T
cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be
modulated by manipulation of Tregs in the periphery. CD4+ CD25+ Foxp3+ Tregs were expanded or depleted during the
persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of
persistent infection were analyzed. Virus-specific CD8+ T cells predominantly recognising the H-2Db-presented viral
hemagglutinin epitope MV-H22–30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after
intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression
caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in
DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8+ effector T cells in the brain and
caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be
utilized to regulate virus persistence in the CNS. Citation: Reuter D, Sparwasser T, Hu¨nig T, Schneider-Schaulies J (2012) Foxp3+ Regulatory T Cells Control Persistence of Viral CNS Infection. PLoS ONE 7(3):
e33989. doi:10.1371/journal.pone.0033989 Editor: Tian Wang, University of Texas Medical Branch, United States of America Received January 16, 2012; Accepted February 22, 2012; Published March 20, 2012 Received January 16, 2012; Accepted February 22, 2012; Published March 20, 2012 uter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
tion, and reproduction in any medium, provided the original author and source are credited. Copyright: 2012 Reuter et al. This is an open-access article distributed under the terms of the Creative Commons Attributi
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: 2012 Reuter et al. This is an open-access article distributed under the
unrestricted use, distribution, and reproduction in any medium, provided the original au Funding: The authors thank the Deutsche Forschungsgemeinschaft for financial support. The funder had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript. Introduction The role of CD4+ CD25+ regulatory T cells (Tregs) in
autoimmune and pathogen-induced immune responses has been
studied intensively during recent years. An important tool was
provided by the discovery of the transcription factor Foxp3
(forkhead box P3) as a marker for Tregs and their suppressive
activity [1,2,3,4]. During acute viral infections depletion of Tregs
was found to prevent the development of exhausted T cells and to
improve the immune response. In addition, transient depletion of
Tregs in several persistent viral infections led to reactivation of
virus-specific T cells and reduction of the virus load [5,6,7,8,9]. The important protective role of Tregs against an overshooting
immune response in the CNS became obvious in animal models of
stroke and experimental autoimmune encephalitis [10,11], and
human immunodeficiency virus-1 (HIV-1)-associated neuro-de-
generation, where they reduce astrogliosis and microglia-mediated
inflammation [12]. Interestingly, some viruses even developed the
strategy to support the expansion of Tregs in order to suppress
anti-viral cytotoxic T cell (CTL) responses and to limit viral
immunopathogenesis [13,14,15,16,17,18]. Defects in regulation of
numbers or the activity of Tregs are also involved in a number of
human autoimmune diseases such as type 1 diabetes, rheumatoid
arthritis, and multiple sclerosis [19]. Here we investigated the role of Tregs for virus persistence in
the CNS. According to our model, two week old C57BL/6 mice
(an age in which these mice survive infection, while the immune
system is still not fully matured) were intracerebrally infected and
virus persists in a limited number of neurons in most animals for
more than 10 weeks [33]. We expanded and depleted Tregs in the
periphery during the persistent phase of the viral infection, and
investigated whether this can be exploited to modulate the Viral
infections
of
the
brain
mostly
represent
clinically
important, often life-threatening complications of systemic viral
infections. For example, after acute measles, CNS complications
may occur early as acute post-infectious encephalitis, or after years PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 1 March 2012 | Volume 7 | Issue 3 | e33989 Tregs Control Persistence of Viral CNS Infection Figure 1. Detection of regulatory T cells in secondary lymphoid
organs and the brain of C57BL/6 and DEREG mice. Mice were i.c. infected and analyzed at 3, 7, 10, 14, and 28 dpi as indicated. Persistent CNS infection is controlled by the immune
system y
In order to find out whether Tregs have an influence on the
persistent CNS infection we first expanded and functionally
activated Tregs using the superagonistic anti-CD28 monoclonal
antibody clone D665 (mAb D665) [36]. This mAb, while causing a
transient expansion of the total lymph node and splenic T cell
population, predominantly expands functional CD4+ Tregs without
causing systemic cytokine release [37]. In order to test the efficiency
of mAb D665 in young mice, we measured Tregs in a preliminary
experiment in uninfected mice 3 days after a single i.p. injection of
100 mg D665 by flow cytometry. The proportion of CD4+Foxp3+
Tregs increased in the spleen and lymph nodes approximately 2-
fold (Fig. 2 A; n = 4; P,0.01). This result indicated that mAb D665
can be used for expansion of Tregs also in young mice. Figure 1. Detection of regulatory T cells in secondary lymphoid
organs and the brain of C57BL/6 and DEREG mice. Mice were i.c. infected and analyzed at 3, 7, 10, 14, and 28 dpi as indicated. The
percentages of regulatory CD4+ Foxp3+ T cells all lymphocytes in spleen
(A) and draining cervical lymph nodes (CLN) (B) of rMV-green-infected
and PBS-injected (ctrl) animals were determined using C57BL/6 mice. Foxp3+ T cells were quantified by flow cytometry after staining with
antibodies to CD25, CD4, and Foxp3, and gating on positive cells. In
brains (C), total cell numbers of Foxp3-GFP+ Tregs were determined
using of rMV-infected and PBS-injected (ctrl) DEREG mice. Mean values
6 SEM are presented (n = 3). p
doi:10.1371/journal.pone.0033989.g001 treatment. Large clusters and groups of bright GFP-positive
(directly reflecting virus replication) infected neurons emerged in
the brains of these mice (Fig. 3 A). This was in striking contrast to
the brains of untreated mice at 28 dpi, which contain only a
limited number of infected neurons (Fig. 3 B). It is also strikingly
different from brains at 14 dpi, when the treatment with D665
begins. At this time point areas with weak (vanishing) GFP
expression are observed, that represent areas from which virus is
being eliminated (Fig. 3 C). The quantification demonstrated For the following experiments, to investigate the effect of mAb
D665 on the persistent viral infection, we applied 100 mg at day 14
and 21 post infection, and analyzed the brains at 28 dpi (Fig. 2 B). Regulatory T cells are present predominantly in spleen
and lymph nodes, but at a low frequency also in the
brain Regulatory T cells are present predominantly in spleen
and lymph nodes, but at a low frequency also in the
brain Two week old mice were intracerebrally (i.c.) infected with
103 PFU recombinant MV expressing the rodent brain-adapted
haemagglutinin CAMH and eGFP, or, when indicated, the
recombinant MV without eGFP. Both recombinant viruses
(rMVEdtagEGFP-CAMH and rMVEdtagCAMH) have the same
distinct tropism for mouse neurons, and infections cause similar
acute
and
persistent
CNS
infections
[24,33,34,35]. These
recombinant viruses were designated throughout the manuscript
as rMV-green and rMV. To determine the number of Tregs present in our infection
model in secondary lymphoid organs and the brain, C57BL/6
mice were infected with rMV-green and analyzed 3, 7, 10, 14 and
28 days post infection. Lymphocytes were isolated from 6 draining
cervical lymph nodes (LN), the spleen, and the brain of MV-
infected and control (i.c. injected PBS) animals. The fraction of
CD4+ CD25+ Foxp3+ T cells of all lymphocytes was determined to
be 1.5–3% in the spleen and 4–6% in LN (Fig. 1 A, B) with no
significant difference between infected and control animals. This
corresponds to a total number of Tregs of approximately 16106 in
the spleen and 26105 in the prepared LN at day 28 post infection. Only a small statistically not significant number of Foxp3+ T cells
was detected in the brain, irrespective of the infection (data not
shown). To obtain statistically significant results and to reduce
standard errors caused by the staining procedure, we used
DEREG mice, which express GFP in Foxp3+ cells. After infection
of these mice with rMV (not expressing GFP), a small but
significant number of GFP+ cells, approximately 800 per brain,
was detected in the brains, whereas almost no GFP+ cells were
detected in controls (Fig. 1 C; n = 3, P,0.05, two way ANOVA). Introduction The
percentages of regulatory CD4+ Foxp3+ T cells all lymphocytes in spleen
(A) and draining cervical lymph nodes (CLN) (B) of rMV-green-infected
and PBS-injected (ctrl) animals were determined using C57BL/6 mice. Foxp3+ T cells were quantified by flow cytometry after staining with
antibodies to CD25, CD4, and Foxp3, and gating on positive cells. In
brains (C), total cell numbers of Foxp3-GFP+ Tregs were determined
using of rMV-infected and PBS-injected (ctrl) DEREG mice. Mean values
6 SEM are presented (n = 3). doi:10.1371/journal.pone.0033989.g001 ‘‘hidden’’ CNS infection. Our data indicate that this is indeed the
case and that manipulation of Tregs can be utilized to regulate
virus-specific CD8+ effector T cells and virus persistence in the
brain. PLoS ONE | www.plosone.org Persistent CNS infection is controlled by the immune
system Under these conditions the total number of lymphocytes increased
significantly after D665 treatment in spleen and LN, but not in the
brain (Fig. 2 C). Furthermore, the proportion of Foxp3+ Tregs
increased significantly (approximately 2-fold, P,0.01) in spleen in
LN (Fig. 2 D). Interestingly, histological analyzes revealed that the
extent of the viral infection increased considerably after D665 March 2012 | Volume 7 | Issue 3 | e33989 PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 2 Tregs Control Persistence of Viral CNS Infection Figure 2. Expansion of T lymphocytes with the superagonistic CD28 antibody D665. (A) Two week old uninfected C57BL/6 mice were i.p. injected with 100 mg mAb D665 or PBS (control) and analyzed 3 days later. Lymphocytes were isolated from the spleen and lymph nodes (12 per
mouse; 6 cervical, 4 axillary and 2 inguinal lymph nodes). FACS dot plot examples for CD4+ Foxp3+ T cells in the lymph nodes are shown (left panels:
ctrl and +mAb D665 with percentages of all gated lymphocytes). Right panel: quantitative evaluation of the proportion of Foxp3+ T cells (percent of
all CD4+ T cells) in spleen and lymph nodes of D665-treated and control animals (mean values 6 SEM, n = 4, P,0.01). (B) Experimental setup used for
the treatment of MV-infected mice with mAb D665. As a control an appropriate volume of PBS was injected. (C) The total number of lymphocytes in
the spleen and draining lymph nodes (LN) (n = 3; P,0.01), and total number of percoll-isolated cells in brains of D665-treated and control animals
(n = 3). (D) Quantitative evaluation of CD4+ Foxp3+ Tregs in the spleen and LN of D665-treated and control animals (percent CD4+Foxp3+ cells of all
CD4+ T cells; n = 3, P,0.002 and P,0.02, respectively). doi:10.1371/journal.pone.0033989.g002 Figure 2. Expansion of T lymphocytes with the superagonistic CD28 antibody D665. (A) Two week old uninfected C57BL/6 mice were i.p. injected with 100 mg mAb D665 or PBS (control) and analyzed 3 days later. Lymphocytes were isolated from the spleen and lymph nodes (12 per
mouse; 6 cervical, 4 axillary and 2 inguinal lymph nodes). FACS dot plot examples for CD4+ Foxp3+ T cells in the lymph nodes are shown (left panels:
ctrl and +mAb D665 with percentages of all gated lymphocytes). Persistent CNS infection is controlled by the immune
system Right panel: quantitative evaluation of the proportion of Foxp3+ T cells (percent of
all CD4+ T cells) in spleen and lymph nodes of D665-treated and control animals (mean values 6 SEM, n = 4, P,0.01). (B) Experimental setup used for
the treatment of MV-infected mice with mAb D665. As a control an appropriate volume of PBS was injected. (C) The total number of lymphocytes in
the spleen and draining lymph nodes (LN) (n = 3; P,0.01), and total number of percoll-isolated cells in brains of D665-treated and control animals
(n = 3). (D) Quantitative evaluation of CD4+ Foxp3+ Tregs in the spleen and LN of D665-treated and control animals (percent CD4+Foxp3+ cells of all
CD4+ T cells; n = 3, P,0.002 and P,0.02, respectively). doi:10.1371/journal.pone.0033989.g002 approximately 100-fold more infected cells per brain in D665-
treated animals in comparison to control animals at 28 dpi (Fig. 3
D, compare lanes 3 and 5; differences were highly significant:
P,0.0001). Two weeks later, at 42 dpi, the number of infected
cells was reduced, but still higher than in control animals (Fig. 3 D,
compare lanes 4 and 6). The data indicate that CD28-mediated
expansion of Tregs in the periphery during the persistent phase of
the viral infection induced a transient release of the viral infection
from immunological control resulting in a dramatic increase of
virus replication and spread in the CNS. Foxp3-promoter, which can be treated with DT to eliminate
specifically Foxp3+ Tregs (DEREG-mice) [38]. To test the activity
of the DT-batch used, adult DEREG mice were in a pilot
experiment treated with DT under standard conditions (1 mg DT
i.p. injected at 6 consecutive days) and analyzed the next day. Lymphocytes isolated from the spleen and lymph nodes were
analyzed by flow cytometry to demonstrate the successful
depletion of Foxp3+GFP+ Tregs by more than 90% (Fig. 4 A). In order to assess the effect of Treg depletion on virus persistence
in young mice, persistently infected mice were treated at 3
consecutive days (at day 17, 18, and 20 post infection) with 1 mg
DT and analyzed at day 28 post infection (Fig. 4 B). In these mice,
the viral infection was again quantified histologically in subsequent
brain slices through the complete cerebrum as described earlier
[33]. Persistent CNS infection is controlled by the immune
system Treg depletion in DEREG2/+ mice (compared to DT- approximately 100-fold more infected cells per brain in D665-
treated animals in comparison to control animals at 28 dpi (Fig. 3
D, compare lanes 3 and 5; differences were highly significant:
P,0.0001). Two weeks later, at 42 dpi, the number of infected
cells was reduced, but still higher than in control animals (Fig. 3 D,
compare lanes 4 and 6). The data indicate that CD28-mediated
expansion of Tregs in the periphery during the persistent phase of
the viral infection induced a transient release of the viral infection
from immunological control resulting in a dramatic increase of
virus replication and spread in the CNS. Transient depletion of Tregs stimulates infiltration of
virus-specific T cells into the brain and virus elimination For the depletion of Tregs we used transgenic mice expressing
the human diphtheria toxin (DT) receptor under the control of the PLoS ONE | www.plosone.org PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 March 2012 | Volume 7 | Issue 3 | e33989 3 Tregs Control Persistence of Viral CNS Infection Figure 3. Expansion of T lymphocytes with the superagonistic
CD28 antibody D665 induces virus replication and spread. Consecutive coronal brain sections (100 mm sections) were prepared
from complete rMV-green-infected mouse cerebra and analyzed using
the UV microscope. Overviews and details of a typical section of an
infected brain of a mouse treated with mAb D665 and analyzed at
28 dpi (A), and sections of infected control animals in the absence of
mAb D665 at 28 dpi (B), and 14 dpi (C) are shown. The numbers of
infected eGFP+ cells per brain (sections through the complete cerebrum
of each animal were evaluated as described [33]) were determined
microscopically in infected control C57BL/6 mice at 7, 14, 28 and 42 dpi
(D, lanes 1–4) and in D665-treated mice at 28 and 42 dpi (D, lanes 5 and
6). The difference between control and D665-treated mice at 28 dpi was
highly significant (P,0,0001). treated DEREG2/2 mice as control animals) led to a significant
reduction of the number of infected neurons from brains of
persistently infected animals (n = 6, P = 0.0098; Fig. 4 C). treated DEREG2/2 mice as control animals) led to a significant
reduction of the number of infected neurons from brains of
persistently infected animals (n = 6, P = 0.0098; Fig. 4 C). reduction of the number of infected neurons from brains of
persistently infected animals (n = 6, P = 0.0098; Fig. 4 C). In order to investigate whether this increase in virus clearance
correlates with the presence of higher numbers of virus-specific
CD8+ T cells, we first identified T cell receptor recognized
peptides presented by MHC class I of C57BL/6 mice (H-2b). Two
recognized peptides, DbMV-H22–30 (RIVINREHL) and DbMV-
H446–454 (SNHNNVYWL), were identified as effective in stimu-
lating IFN-c synthesis using the ELISPOT assay (data not shown). MV-specific CD8+ T cells were then identified by flow cytometry
using MHC class I (H-2Db) pentamers loaded with the most
effective peptide MV-H22–30. Transient depletion of Tregs stimulates infiltration of
virus-specific T cells into the brain and virus elimination The percentages of DbMV-H22–30-
specific CD8+ T cells in spleen, LN, and the brain were
determined after 3, 7, 10, 14 and 28 days post infection. Considerable
proportions
of
DbMV-H22–30-pentamer-positive
CD8+ T cells were detected in the brain at 7, 10, 14, and
28 dpi (Fig. 5 A). Interestingly, high percentages of DbMV-H22–30-
specific CD8+ T cells are present in the brain during the persistent
phase of the infection (at 28 dpi approximately 18% of all CD8+ T
lymphocytes). Mock-treated animals (i.c. PBS injection; ctrl) did
not contain virus-specific CD8+ T cells. After treatment of
DEREG mice with DT, the number of Tregs decreased by
approximately 95%, while the number of CD8+ T cells in brains
slightly increased (Fig. 5 B). Interestingly, after depletion of Tregs,
the fraction and absolute number of DbMV-H22–30-specific CD8+
T cells increased from 2,000 to 8,000 cells per brain, or 5% to
23% of CD8+ T cells (n = 3, P = 0,05; Fig. 5 C). Thus, depletion of
Tregs during the persistent phase of infection led to an increase of
virus-specific CD8+ T cells and a significant reduction of the
persistent infection in the brain. Discussion Depletion of Tregs leads to a reduction of the CNS infection. (A) Adult DEREG (DEREG2/+) mice were i.p. injected with 1 mg
diphtheria toxin (DT) or with an appropriate volume of PBS (ctrl) at 6 consecutive days and analyzed the next day. Lymphocytes were isolated from
the spleen and LN (6 cervical, 4 axillary, and 2 inguinal). FACS dot plot examples for regulatory CD4+ Foxp3-GFP+ T cells in the lymph nodes (left
panels), and a quantitative evaluation of Foxp3-GFP+ T cells (percentage of all lymphocytes, right panel) from spleen and LN (mean values 6 SEM,
n = 4, P,0.01) are shown. (B) Experimental setup for the treatment of young MV-infected DEREG mice with DT at day 17, 18, and 20 post infection
and analysis at 28 dpi. (C) Quantitative evaluation of the number of infected eGFP+ cells at 28 dpi in DEREG (DEREG2/+) and control (DEREG2/2) mice
both infected i.c. with rMV-green and treated with DT. The reduction of mean values from 50 to 8 was significant, with P = 0,0098. The number of Figure 4. Depletion of Tregs leads to a reduction of the CNS infection. (A) Adult DEREG (DEREG2/+) mice were i.p. injected with 1 mg
diphtheria toxin (DT) or with an appropriate volume of PBS (ctrl) at 6 consecutive days and analyzed the next day. Lymphocytes were isolated from
the spleen and LN (6 cervical, 4 axillary, and 2 inguinal). FACS dot plot examples for regulatory CD4+ Foxp3-GFP+ T cells in the lymph nodes (left
panels), and a quantitative evaluation of Foxp3-GFP+ T cells (percentage of all lymphocytes, right panel) from spleen and LN (mean values 6 SEM,
n = 4, P,0.01) are shown. (B) Experimental setup for the treatment of young MV-infected DEREG mice with DT at day 17, 18, and 20 post infection
and analysis at 28 dpi. (C) Quantitative evaluation of the number of infected eGFP+ cells at 28 dpi in DEREG (DEREG2/+) and control (DEREG2/2) mice
both infected i.c. with rMV-green and treated with DT. The reduction of mean values from 50 to 8 was significant, with P = 0,0098. The number of
infected eGFP+ cells per brain was determined by microscopic evaluation of 100 mm sections through the complete cerebrum as described [33]. doi:10.1371/journal.pone.0033989.g004 was found to spread more transneuronally than in brains of normal
mice [41]. Discussion These findings indicated that infected neurons are target
cells of CD8+ lymphocytes, and that brain infections to some extent
can be inhibited by CTL activity. Further investigations revealed
that CD4+ T cells are able to protect either alone (in resistant mouse
strains), or through cooperation with CD8+ T cells (in mice with
intermediate susceptibility), and that CD8+ T cells are able to
protect alone after immunization of the mice [42,43]. Using CD46-
transgenic Rag-deficient mice, adoptive transfer of lymphocytes
revealed that the combined activity of CD4+ T lymphocytes with
CD8+ T cells or B cells is required to control the intracerebral
infection [44]. Thus, most findings support the view that CD8+ T
cells play an important role in the control of transneuronal virus
spread, and our findings suggest that MV-specific CD8+ T cells are
involved in maintaining the steady state and control of infection
during the persistent phase of CNS infection. expressing Foxp3+ cells in infected DEREG mice. These findings
suggest that only very few Tregs, if any at all, are required within the
brain for the regulation of effector immune cells, and that this
regulation predominantly takes place in secondary lymphoid
organs. Sellin et al. observed an increase of Foxp3+ Tregs as a
consequence of MV infection of CD150-transgenic mice in spleen
and brain [32], which suggests that also the MV-infection itself
supports the expansion and migration of Tregs, and that these
infection-induced Tregs may be part of the multifactorial MV-
induced immunosuppression [3,4]. Tregs can restrain effector T cell
responses through the production of immunomodulatory cytokines,
such as TGF-b, IL-10, and IL-35, expression of inhibitory ligands,
such as CTLA-4 and LAG-3, cytokine consumption, and direct
cytolysis. It remains to be elucidated which of these mechanisms are
involved in the persistent brain infection with MV. Several reports support the view that T cells play a decisive role in
control of viral CNS infections. Using primary human lymphocytes,
in vitro experiments demonstrated that CD8+ T lymphocytes control
the dissemination of MV [39]. In resistant mouse strains the
depletion of the CD4+ T cell subset by monoclonal antibodies led to
a breakdown of resistance to the infection, whereas depletion of
CD8+ T cells had no effect [23,40]. In TAP-transporter deficient
mice, which cannot present antigen on MHC class I molecules, MV PLoS ONE | www.plosone.org Discussion Our results indicate that the immune system keeps the ‘‘hidden’’
persistent viral CNS infection under permanent control. Manip-
ulation of Tregs in the periphery had significant consequences for
the fate of the viral infection in the brain, although only few
infected neurons are present during the persistent phase of the
infection. Expanding the number of Tregs by superagonistic CD28
antibody D665 led to an activation of virus replication and
dramatic increase of the number of infected neurons, whereas
transient depletion of Tregs by DT led to a significant reduction of
the number of infected neurons. Interestingly, complete elimina-
tion of virus and clearance of the infection was not achieved by
transient depletion of Tregs suggesting that additional means of an
antiviral immune response are required for complete clearance. Looking for Tregs in the brain, we did not detect a significant
number of CD4+ Foxp3+ Tregs by FACS-analysis after staining
with Foxp3-specific antibodies, and only a small number of GFP- PLoS ONE | www.plosone.org PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 March 2012 | Volume 7 | Issue 3 | e33989 4 Tregs Control Persistence of Viral CNS Infection Figure 4. Depletion of Tregs leads to a reduction of the CNS infection. (A) Adult DEREG (DEREG2/+) mice were i.p. injected with 1 mg
diphtheria toxin (DT) or with an appropriate volume of PBS (ctrl) at 6 consecutive days and analyzed the next day. Lymphocytes were isolated from
the spleen and LN (6 cervical, 4 axillary, and 2 inguinal). FACS dot plot examples for regulatory CD4+ Foxp3-GFP+ T cells in the lymph nodes (left
panels), and a quantitative evaluation of Foxp3-GFP+ T cells (percentage of all lymphocytes, right panel) from spleen and LN (mean values 6 SEM,
n = 4, P,0.01) are shown. (B) Experimental setup for the treatment of young MV-infected DEREG mice with DT at day 17, 18, and 20 post infection
and analysis at 28 dpi. (C) Quantitative evaluation of the number of infected eGFP+ cells at 28 dpi in DEREG (DEREG2/+) and control (DEREG2/2) mice
both infected i.c. with rMV-green and treated with DT. The reduction of mean values from 50 to 8 was significant, with P = 0,0098. The number of
infected eGFP+ cells per brain was determined by microscopic evaluation of 100 mm sections through the complete cerebrum as described [33]. doi:10.1371/journal.pone.0033989.g004 Figure 4. Animal infection and manipulation of the frequency of
Tregs This study was carried out in strict accordance with the
recommendations in the Guide for the Care and Use of March 2012 | Volume 7 | Issue 3 | e33989 PLoS ONE | www.plosone.org 5 Tregs Control Persistence of Viral CNS Infection Figure 5. Treg depletion causes an increase in virus-specific CD8+ T cells in the brain. (A) The proportion of virus-specific DbMV-H22–30-
pentamer+ CD8+ T cells of all CD8+ T cells was determined in spleen, lymph nodes, and brains of MV-infected C57BL/6 mice at days 3, 7, 10, 14, and 28
post infection (n = 3). MV-specific cells were gated as CD19-negative lymphocytes to exclude pentamer+ CD19+ cells. The total number of CD8+ T cells
(B) and the number and proportion of DbMV-H22–30-pentamer+ CD8+ T cells (C) was determined in brains of 28 days infected control (DEREG2/2) and
DEREG (DEREG2/+) mice, both treated with DT (Values 6 SEM; n = 3). doi:10.1371/journal.pone.0033989.g005 Figure 5. Treg depletion causes an increase in virus-specific CD8+ T cells in the brain. (A) The proportion of virus-specific DbMV-H22–30-
pentamer+ CD8+ T cells of all CD8+ T cells was determined in spleen, lymph nodes, and brains of MV-infected C57BL/6 mice at days 3, 7, 10, 14, and 28
post infection (n = 3). MV-specific cells were gated as CD19-negative lymphocytes to exclude pentamer+ CD19+ cells. The total number of CD8+ T cells
(B) and the number and proportion of DbMV-H22–30-pentamer+ CD8+ T cells (C) was determined in brains of 28 days infected control (DEREG2/2) and
DEREG (DEREG2/+) mice, both treated with DT (Values 6 SEM; n = 3). doi:10.1371/journal.pone.0033989.g005 described [33,35]. Slices were analyzed directly by UV microsco-
py. Photomicrographs were taken with a digital camera (Leica). Numbers of infected eGFP-positive neurons were counted and
statistical analyzes done using the student’s t test and the program
Prism (GraphPad, Inc.). Laboratory Animals of the National Institutes of Health. The
protocol was approved by the Committee on the Ethics of Animal
Experiments of the University of Wu¨rzburg (Permit Number:
55.2-2531.01-67/06). Specific pathogen free C57BL/6 mice were
purchased from Harlan-Winkelmann, Germany. DEREG mice
[38] were breeded in the animal facilities of the Institute for
Virology and Immunobiology and the Centre for Experimental
Medicine, Wu¨rzburg. Mice were anesthetized using isofluran and
infected intracerebrally (i.c.) into the left hemisphere with 20 ml
virus suspension containing 16103 PFU at an age of two weeks. Animal infection and manipulation of the frequency of
Tregs To expand Tregs, mice were treated intraperitoneally (i.p.) with
100 mg superagonistic anti-CD28 monoclonal antibody (mAb)
D665 [36], and to deplete Tregs, DEREG mice were treated i.p. with 1 mg diphtheria toxin (DT; Merck) [38]. Histology For analyzes, animals were anesthetized with CO2 and perfused
with 4% (w/v) paraformaldehyde (PFA). Brains were fixed in 4%
PFA at least 18 h, and free-floating sections (100 mm) were
prepared using a vibratome (Technical Products International) as Isolation of lymphocytes from lymph nodes, the spleen,
and the brain Draining cervical lymph nodes and the spleen were pressed
through a steel sieve in 4 ml HBSS and homogenized in a total
volume of 13 ml HBSS. After a centrifugation step at 310 g for
10 min the cell pellets were resuspended in an adequate volume of
HBSS (approximately 107/cells/ml). Spleen cells were additionally
treated with erythrocyte lysis buffer (155 mM NH4Cl, 10 mM
KHCO3, 0.1 mM EDTA) and washed with HBSS. Brains were
pressed through a steel sieve in 5 ml HBSS 3% FCS and
homogenized in a total volume of 20 ml HBSS 3% FCS. After a
centrifugation step at 170 g for 10 min the cell pellet was
resuspended
in
1.4 ml
dissociation
buffer
(23 mM
CaCl2,
50 mM KCl, 42 mM MgCl2, 153 mM NaCl) containing 0.4 U
collagenase (Serva) and 50 U Benzonase (Novagen) and incubated
at 37uC for 1 h. Afterwards the cells were washed with HBSS and
applied on a percoll density gradient to separate the lymphocytes
from the rest like myelin debris or neuronal cells as described [46]. The lymphocytes were isolated and washed to remove the percoll
for subsequent analyzes. Cell lines and viruses Vero cells (African green monkey; ATCC CRL 6318) were
cultured in Eagle’s minimal essential medium (MEM) containing
5% fetal calf serum (FCS), 100 U/mL penicillin and 100 mg/mL
streptomycin. Recombinant measles viruses expressing the rodent
adapted haemagglutinin of the strain CAM/RB (CAMH) and/or
not the enhanced green fluorescent protein (eGFP) rMVEdtag
EGFP-CAMH (rMV-green) and rMVEdtagCAMH (rMV) [35,45]
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interleukin-12-, and gamma interferon-driven viral clearance in measles virus-
infected brain tissue. J Virol 85: 3664–3676. 13. Acknowledgments For identification of peptides presented by MHC class I that can
be used in ELISPOT and pentamer staining experiments we used
the software programs SYFPEITHI (University of Tu¨bingen,
Germany) and BIMAS (BioInformatics and Molecular Analysis
Section, National Health Instituts, Bethesda, USA) to establish a
ranking of potential peptides. From 12 potential H-2 Kb and Db–
presented peptides of MV-N and MV-H with the highest
probability scores, we found that DbMV-H22–30 and DbMV-
H446–454 (RIVINREHL and SNHNNVYWL, respectively) were We thank S. Kendl and C. Strasheim for technical assistance and Dr. M. Kaymer, Beckman Coulter, for helpful advice concerning the tetramer
technology. Antibodies and flow cytometry Monoclonal fluorescein-isothiocyanat (FITC)-, phycoerythrin
(PE)- or peridinin chlorophyll protein (PerCP)-conjugated anti- PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 PLoS ONE | www.plosone.org 6 Tregs Control Persistence of Viral CNS Infection mouse CD3 (clone 145-2C11)-, CD4 (clone RM4-5)-, CD8 (clone
Ly-2)-, CD19 (clone 1D3)- and CD25 (clone 7D4)-antibodies were
purchased from Becton Dickinson. PE-conjugated anti-mouse
Foxp3 (clone FJK-16s)-antibody was purchased from NatuTec. Lymphocytes were stained in FACS buffer (PBS containing 0.4%
BSA and 0.02% sodium azide) at 4uC for 20 min. Intracellular
staining of Foxp3 was performed using the Foxp3 Staining Buffer
Set (NatuTec) according to the manufacture’s protocol. Briefly,
cells were fixed and permeabilized in 500 ml fixation/permeabi-
lization buffer (Concentrate/Diluent 1:4) at RT for 1 h and
stained afterwards in permeabilization buffer at RT for 30 min. Flow cytometric analysis was performed on a FACSCalibur
(Becton Dickinson). most efficiently recognized. ELISPOT experiments were per-
formed using the Mouse IFN-c ELISPOT set (BD Biosciences)
according to the manufacture’s protocol. most efficiently recognized. ELISPOT experiments were per-
formed using the Mouse IFN-c ELISPOT set (BD Biosciences)
according to the manufacture’s protocol. Author Contributions Conceived and designed the experiments: JSS. Performed the experiments:
DR. Analyzed the data: DR TH JSS. Contributed reagents/materials/
analysis tools: TS TH. Wrote the paper: DR JSS. Conceived and designed the experiments: JSS. Performed the experiments:
DR. Analyzed the data: DR TH JSS. Contributed reagents/materials/
analysis tools: TS TH. Wrote the paper: DR JSS. Pentamer staining MHC class I (H-2Db) pentamers presenting the selected peptide
MV-H22–30
(DbMV-H22–30–pentamers)
were
ordered
from
ProImmune Ltd (Oxford, UK). Cells were washed with FACS
buffer and stained with 5 mL pentamer-solution diluted in 100 ml
FACS buffer at 4uC for 30 min. After one washing step the cells
were analyzed using the FACSCalibur. MV-specific cells were
gated as CD8+ and CD19-negative lymphocytes to exclude
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in coronavirus-induced acute encephalitis. Virology 385: 358–367. 14. Dittmer U, He H, Messer RJ, Schimmer S, Olbrich AR, et al. (2004) Functional
impairment of CD8(+) T cells by regulatory T cells during persistent retroviral
infection. Immunity 20: 293–303. J
31. Oldstone MBA, Dales S, Tishon A, Lewicki H, Martin L (2005) A role for dual hits
in causation of subacute sclerosing panencephalitis. J Exp Med 202: 1185–1190. 32. Sellin CI, Jegou JF, Renneson J, Druelle J, Wild TF, et al. (2009) Interplay
between virus-specific effector response and Foxp3 regulatory T cells in measles
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induction of an immunosuppressive regulatory T cell response during acute
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A mouse model of persistent brain infection with recombinant measles virus. J Gen Virol 87: 2011–2019. 16. Iwashiro M, Messer RJ, Peterson KE, Stromnes IM, Sugie T, et al. (2001)
Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral
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semimature dendritic cells that induce regulatory T cells in HIV-infected
subjects. J Infect Dis 193: 494–504. PLoS ONE | www.plosone.org March 2012 | Volume 7 | Issue 3 | e33989 7 March 2012 | Volume 7 | Issue 3 | e33989 Tregs Control Persistence of Viral CNS Infection 35. Ludlow M, Duprex WP, Cosby SL, Allen IV, McQuaid S (2008) Advantages of
using recombinant measles viruses expressing a fluorescent reporter gene with
vibratome slice technology in experimental measles neuropathogenesis. Neuropathol Appl Neurobiol 34: 424–434. 42. Weidinger G, Czub S, Neumeister C, Harriott P, ter Meulen V, et al. (2000)
Role of CD4+ and CD8+ T cells in the prevention of measles virus-induced
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regulatory T-cell response prevents cytokine storm in CD28 superagonist treated
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cell control primary measles virus infection of the CNS: regulation is dependent
on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B
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depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med
204: 57–63. 45. Duprex WP, McQuaid S, Hangartner L, Billeter MA, Rima BK (1999)
Observation of measles virus cell-to-cell spread in astrocytoma cells by using a
green fluorescent protein-expressing recombinant virus. J Virol 73: 9568–9575. 39. de Vries RD, Yuksel S, Osterhaus AD, de Swart RL (2009) Specific CD8(+) T-
lymphocytes control dissemination of measles virus. Eur J Immunol. 46. Schwender S, Imrich H, Dorries R (1991) The pathogenic role of virus-specific
antibody-secreting cells in the central nervous system of rats with different
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74: 533–538. 40. Finke D, Liebert UG (1994) CD4+ T cells are essential in overcoming
experimental murine measles encephalitis. Immunology 83: 184–189. . Finke D, Liebert UG (1994) CD4+ T cells are essential in experimental murine measles encephalitis. Immunology 83: 184– 41. Urbanska EM, Chambers BJ, Ljunggren HG, Norrby E, Kristensson K (1997)
Spread of measles virus through axonal pathways into limbic structures in the
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Survival of Esophageal Cancer in China: A Pooled Analysis on Hospital-Based Studies From 2000 to 2018
|
Frontiers in oncology
| 2,019
|
cc-by
| 6,528
|
Haifeng Hou 1*†, Zixiu Meng 1†, Xuan Zhao 1†, Guoyong Ding 1, Ming Sun 2, Wei Wang 1,3 and
Youxin Wang 2* 1 School of Public Health, Taishan Medical University, Taian, China, 2 Beijing Key Laboratory of Clinical Epidemiology, School
of Public Health, Capital Medical University, Beijing, China, 3 School of Medical and Health Sciences, Edith Cowan University,
Perth, WA, Australia Edited by:
Jianguang Ji,
Lund University, Sweden
Reviewed by:
Zhijun Dai,
Zhejiang University, China
Shun He,
Cancer Hospital (CAMS), China
*Correspondence:
Haifeng Hou
hfhou@163.com
Youxin Wang
wangy@ccmu.edu.cn
†These authors have contributed
equally to this work Edited by:
Jianguang Ji,
Lund University, Sweden Background: Esophageal cancer (EC) causes more than 400 thousand deaths per year,
and half of them occur in China. There are discrepancies regarding the survival of EC
patients between population-based surveillance studies and hospital-based studies. Reviewed by:
Zhijun Dai,
Zhejiang University, China
Shun He,
Cancer Hospital (CAMS), China Objectives: We aimed to synthesize the survival data from hospital-based EC studies
in the Chinese population from 2000 to 2018 and to compare the survival rates between
EC patients with different clinical classifications. *Correspondence:
Haifeng Hou
hfhou@163.com
Youxin Wang
wangy@ccmu.edu.cn Methods:
The protocol of this systematic review was registered in PROSPERO
(CRD-42019121559). We searched Embase, PubMed, CNKI, and Wanfang databases
for studies published between January 1, 2000 and December 31, 2018. We calculated
the pooled survival rates and 95% confidence intervals (CIs) by Stata software (V14.0). Results: Our literature search identified 933 studies, of which 331 studies with 79,777
EC patients met the inclusion criteria and were included in meta-analyses. The pooled
survival rates were 74.1% (95% CI: 72.6–75.7%) for 1-year survival, 49.0% (95% CI:
44.2–53.8%) for 2-years survival, 46.0% (95% CI: 42.6–49.5%) for 3-years survival,
and 40.1% (95% CI: 33.7–46.4%) for 5-years survival. An increased tendency toward
EC survival was verified from 2000 to 2018. In addition, discrepancies were observed
between EC patients with different clinical classifications (e.g., stages, histologic types,
and cancer sites). Specialty section:
This article was submitted to
Cancer Epidemiology and Prevention,
a section of the journal
Frontiers in Oncology Specialty section:
This article was submitted to
Cancer Epidemiology and Prevention,
a section of the journal
Frontiers in Oncology Received: 23 February 2019
Accepted: 05 June 2019
Published: 27 June 2019 Keywords: esophageal cancer, survival, meta-analysis, hospital-based study, China SYSTEMATIC REVIEW
published: 27 June 2019
doi: 10.3389/fonc.2019.00548 Survival of Esophageal Cancer in
China: A Pooled Analysis on
Hospital-Based Studies From 2000 to
2018 Haifeng Hou 1*†, Zixiu Meng 1†, Xuan Zhao 1†, Guoyong Ding 1, Ming Sun 2, Wei Wang 1,3 and
Youxin Wang 2* Haifeng Hou 1*†, Zixiu Meng 1†, Xuan Zhao 1†, Guoyong Ding 1, Ming Sun 2, Wei Wang 1,3 and
Youxin Wang 2* Literature Search Strategy Esophageal cancer (EC) is among the top causes of cancer-
related mortality globally, resulting in more than 400 thousand
deaths each year (1). Because its incidence is increasing, EC
remains a global concern, especially in under-developed regions
(2). Annually, more than half of new cases are diagnosed in
China, where a so-called EC belt permanently exists around
Taihang Mountain (3, 4). EC ranks fifth in incidence (21.17 per
100,000), and fourth in mortality (15.58 per 100,000) among all
malignant tumors in China (5, 6). Carcinogen exposure (e.g.,
nitrosamines and their precursors, fungi, trace minerals, and
polycyclic hydrocarbons), nutritional deficiency, lifestyles, and
genetics contribute to the multistage development of EC through
(1) localized injury, (2) inflammation, (3) mutagenesis, and (4)
carcinogenesis (7, 8). Selection Criteria and Quality Assessment
First, two authors (XZ and ZM) independently reviewed the
titles and abstracts of the retrieved publications. Second, the
full text and online supplementary data were read to determine
the eligibility and quality of the literature (Table S3). Any
uncertainties and discrepancies were resolved by the third
investigator (HH) through discussion. The inclusion criteria
were (1) EC was diagnosed by pathological examination; (2) the
following data were available: number of included EC patients,
number of survived cases, or survival rates of EC patients; (3)
the survival data were obtained from hospital-based studies that
assessed the prognosis of hospitalized inpatients; (4) the ethnicity
of all EC patients was Chinese. For studies reporting on both
Chinese and other populations, only the data for the Chinese
population were included. The exclusion criteria were as follows:
(1) in vitro studies or animal studies; (2) reviews; (3) studies
that did not refer to a Chinese population; (4) studies without
survival data; (5) studies on community-based populations; (6)
low-quality studies. Although strategies for preventing EC are necessary, measures
to reduce morbidity or improve survival are also extremely
important. Therefore,
a
national
screening
program
was
launched in 2005 in areas in China with a high prevalence
of EC, especially rural regions (9). This program includes
endoscopic examination for high-risk individuals and early
surgery in the treatment of patients with EC (5). Several
studies have reported a 50% decrease in EC deaths among
subjects served in this healthcare program (9, 10). Also, a
nationwide population-based cancer registry system was initiated
to collect cancer data across China in 2002 (11, 12). Statistical Analysis The pooled survival rate and 95% confidence interval (CI) of
EC were calculated by Stata V14.0 (Stata Corp, College Station,
TX, USA). Cochran’s Q-test for heterogeneity, complemented
by the I2 statistic, was implemented to measure the level of
heterogeneity across original studies. A P > 0.10 and I2 < 50%
indicated no significant heterogeneity, and a fixed effect model
was utilized to calculate the pooled survival rate. Otherwise,
significant heterogeneity was assumed, then the random effect
model was carried out subsequently by the DerSimonian-
Laird method (17). Subgroup analyses on gender, cancer site,
clinical type, and stage, temporal trend, and study design were
conducted, respectively. To assess the strength and stability Citation: Conclusions:
Our findings showed a higher survival rate in hospital-based studies
than population-based surveillance studies. Although this hospital-based study is subject
to potential representability and publication bias, it offers insight into the prognosis of
patients with EC in China. Hou H, Meng Z, Zhao X, Ding G,
Sun M, Wang W and Wang Y (2019)
Survival of Esophageal Cancer in
China: A Pooled Analysis on
Hospital-Based Studies From 2000 to
2018. Front. Oncol. 9:548. doi: 10.3389/fonc.2019.00548 June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org Survival of Esophageal Cancer in China Hou et al. Literature Search Strategy These
population-based survival databases enable both temporal and
spatial surveillance of the overall state of different cancers (13). However, incomplete follow-up for registered individuals can
bias survival estimates in population-based surveillance studies. When the registered data do not cover all eligible cancer
deaths, the survival statistics might be overestimated, particularly
for cancers with high fatality rates (14). Meanwhile, many
clinical investigations have reported the prognosis of patients
with cancer within hospitals according to clinical research
criteria. These hospital-based survival investigations can reflect
comprehensive treatment effectiveness with relatively lower loss
to follow-up than population-based studies (15). Discrepancies
exist regarding the survival of EC patients between reports
from the national cancer registry system and hospital-based
studies, as well as between hospital-based studies. The present
study aimed to systematically synthesize all eligible survival
data reported in hospital-based clinical studies in the Chinese
population in order to estimate the prognosis of hospitalized
patients with EC. Data Extraction The following data were extracted from included studies: (1) first
author’s name, publication year, characteristics of EC patients
(e.g., age, gender, region, cancer site, clinical stage, and clinical
type), survival rate or number of survival cases, and study design. If data of a specific population were reported in several studies
or published more than once, the most recently published or the
largest sampled study was included. Data in each subgroup (study
design, gender, regions, cancer site, clinical type, and stage) were
also extracted for subgroup analyses. INTRODUCTION Literature Search Strategy
We searched Embase, PubMed, and Web of Science for
English language literature, as well as CNKI and Wanfang
for Chinese literature published between January 1, 2000 and
December 31, 2018. The combination of “China,” “Chinese,”
“survival,”
“hospital,”
“esophageal
cancer,”
“carcinoma
of
esophagus,” “esophageal carcinoma,” “esophagus cancer,” “cancer
of esophagus,” “esophageal cancer,” “carcinoma of esophagus,”
“esophageal carcinoma,” “esophagus cancer,” and “cancer of
esophagus” in English or Chinese were used in the literature
search. References cited in the included articles were further
reviewed. The detailed search strategy is shown in Table S2. MATERIALS AND METHODS The systematic review and meta-analyses were conducted in
accordance with the criteria of the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) (16). The reported PRISMA Checklist is available in the online
Table S1. As a systematic review, the protocol was registered
in PROSPERO (No. CRD-42019121559, https://www.crd.york. ac.uk/PROSPERO/). June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 2 Hou et al. Survival of Esophageal Cancer in China FIGURE 1 | Flow diagram of literature screening. FIGURE 1 | Flow diagram of literature screening. that met the predefined criteria were included in our study. The flow diagram for screening articles is shown in Figure 1. The distributions of the studies included are shown in Figure 2
and additional details are provided in Table S4. There were 104
prospective studies and 227 retrospective studies. A total of 118
studies reported survival of patients with esophageal squamous
cell carcinoma (ESCC), eight reported survival of patients with
esophageal small cell carcinoma (SCC), two reported survival of
patients with esophageal adenocarcinoma (EAC), 119 reported
the combined data of more than one histologic type, and 84
studies did not mention the histologic classifications. Of the 331
studies, 210 were conducted in the high prevalence areas of China
(e.g., Fujian, Guangdong, Henan, Jiangsu, Shandong, Shanxi,
Shaanxi, and Sichuan provinces). of pooled results, sensitivity analyses were also conducted by
successive removal of an eligible study each time. The publication
bias was estimated by funnel plot asymmetry and Begg’s adjusted
rank correlation test. A P-value < 0.05 was considered to
represent statistical significance. RESULTS Systematic Review and Eligible Studies
Our literature search identified 933 publications, of which 289
were from CNKI, 451 were from Wanfang, 42 were from Embase,
58 were from PubMed, and 93 were from Web of Science. Two authors (ZM and ZX) reviewed the retrieved literature
independently and then excluded 378 reduplicate publications. Among the 555 publications involved in the abstract and full-
text review, 26 were not original studies, 19 were not human-
based research, 52 were not in reference to EC, seven were
not designed as hospital-based studies, 16 were not conducted
among a Chinese population, 51 were not investigations on
survival or prognosis, and 53 did not provide appropriate survival
data. Finally, 331 publications with 79,777 EC patients (52,273
males/21,874 females/5,630 unavailable; mean age 51.8 years) Pooled Results of EC Survival Subgroup analysis on study design (Figure 4 and Table S8)
indicated that the pooled survival rates in retrospective studies June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 4 Survival of Esophageal Cancer in China Hou et al. TABLE 2 | Pooled survival and 95% CI of esophageal cancer in different
clinical stages. Categories
Stage
N
SR (%)
1-year survival
T1
6
95.6 (93.5–97.7)
T2
8
84.7 (79.3–90.0)a
T3
12
74.6 (68.8–80.4)a
T4
17
52.8 (39.9–65.7)abc
Overall
43
71.7 (66.5–76.9)
2-years survival
T1
3
87.0 (71.0–103.0)
T2
3
51.4 (39.9–62.9)a
T3
4
34.5 (28.8–40.2)a
T4
2
11.4 (2.2–25.1)abc
Overall
12
41.8 (13.7–69.8)
3-years survival
T1
10
81.0 (75.5–86.4)
T2
13
61.5 (53.6–69.3)a
T3
17
45.0 (36.9–53.1)ab
T4
11
36.3 (21.8–50.7)ab
Overall
51
53.3 (46.5–60.1)
5-years survival
T1
13
75.2 (68.4–82.0)
T2
14
51.6 (43.3–59.9)a
T3
16
38.5 (30.6–46.4)a
T4
10
25.4 (14.9–36.0)ab
Overall
53
48.4 (41.6–55.1)
SR, survival rate; CI, confidence interval; N, number of included studies. Between-group
comparisons: aP < 0.05 compared with T1 group; bP < 0.05 compared with T2 group;
cP < 0.05 compared with T3 group. TABLE 2 | Pooled survival and 95% CI of esophageal cancer in different
clinical stages. FIGURE 3 | Temporal trends of survival of esophageal cancer from 2000 to
2018. Between-group comparisons: the 1-year survival rates are significantly
higher than 2-, 3-, and 5-years survival rates between 2000 and
2018 (P < 0.05). FIGURE 3 | Temporal trends of survival of esophageal cancer from 2000 to
2018. Between-group comparisons: the 1-year survival rates are significantly
higher than 2-, 3-, and 5-years survival rates between 2000 and
2018 (P < 0.05). FIGURE 3 | Temporal trends of survival of esophageal cancer from 2000 to
2018. Between-group comparisons: the 1-year survival rates are significantly
higher than 2-, 3-, and 5-years survival rates between 2000 and
2018 (P < 0.05). FIGURE 4 | Forest plot of meta-analysis of retrospective and
prospective studies. SR, survival rate; CI, confidence interval; N, number of included studies. Between-group
comparisons: aP < 0.05 compared with T1 group; bP < 0.05 compared with T2 group;
cP < 0.05 compared with T3 group. SR, survival rate; CI, confidence interval; N, number of included studies. Between-group
comparisons: aP < 0.05 compared with T1 group; bP < 0.05 compared with T2 group;
cP < 0.05 compared with T3 group. Pooled Results of EC Survival showed a decreasing linear trend of survival (including 1-, 2-, 3-,
and 5-years survival) for patients with T1, T2, T3, and T4 stage
EC. A decreased trend was found in accordance with the TNM
stage classifications. The 5-years survival of patients with stage
T4 EC was 25.4% (95% CI: 14.9–36.0%), which was significantly
lower than the survival for patients with stage T1 EC (75.2%, 95%
CI: 68.4–82.0%). FIGURE 4 | Forest plot of meta-analysis of retrospective and
prospective studies. The major histologic type of EC in China is ESCC, which
accounts for 90% of new cases, while adenocarcinoma is more
common in Western countries (18–20). The pooled results
(Table 3) show that the 5-years survival rate of SCC (15.5%,
95% CI: 12.4–18.6%) was significantly lower than that of ESCC
(41.7%, 95% CI: 32.4–51.0%). The 1- and 3-years survival rates of
SCC were significantly lower as well. However, only two studies
reported survival of EAC, for which the pooled 1- and 3-years
survival rates were 80.9% (95% CI: 62.3–99.5%) and 45.7 (95%
CI: 23.2–68.2%), respectively. than for those of men, while the differences were not statistically
significant (Tables S6, S7). We also synthesized survival rates in the high prevalence areas
of China (e.g., Fujian, Guangdong, Henan, Jiangsu, Shandong,
Shanxi, Shaanxi, and Sichuan provinces), where the incidence
rates of EC are higher than other provinces. The pooled survival
rates in these high prevalence areas were 74.2% (95% CI: 71.8–
76.5%) for 1-year survival, 50.4% (95% CI: 45–55.8%) for 2-years
survival, 46.2% (95% CI: 42.5–49.9%) for 3-years survival, and
37.1% (95% CI: 29.3–45.0%) for 5-years survival (Table 1). The
prognosis of EC in high prevalence areas was similar with low
prevalence areas. We performed a subgroup meta-analysis on four sites of the
original tumors. As shown in Table 4, 1-, 3-, and 5-years survival
rates were lower among patients with hypopharynx and cervical
EC than patients with thoracic EC. Pooled Results of EC Survival As shown in Table 1, the observed survival rates in all eligible
studies were synthesized by a random effect model. The overall
pooled results were 74.1% (95% CI: 72.6–75.7%) for 1-year
survival, 49.0% (95% CI: 44.2–53.8%) for 2-years survival, 46.0%
(95% CI: 42.6–49.5%) for 3-years survival, and 40.1% (95% CI:
33.7–46.4%) for 5-years survival. June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 3 Hou et al. Survival of Esophageal Cancer in China FIGURE 2 | Distribution of included studies. FIGURE 2 | Distribution of included studies. TABLE 1 | Pooled survival and 95% CI of esophageal cancer in low and high prevalence areas. Survival
Low prevalence areas
High prevalence areas
Overall
N
SR (%)
N
SR (%)
N
SR (%)
1-year
115
74.1 (72.0–76.3)
117
74.2 (71.8–76.5)
232
74.1 (72.6–75.7)
2-years
62
47.6 (40.2–55.0)a
63
50.4 (45.0–55.8)a
125
49.0 (44.2–53.8)a
3-years
107
45.8 (40.2–51.5)a
104
46.2 (42.5–49.9)a
211
46.0 (42.6–49.5)a
5-years
47
41.3 (33.0–49.6)a
26
37.1 (29.3–45.0)ab
73
40.1 (33.7–46.4)a
SR, survival rate; CI, confidence interval; N, number of included studies; Between-group comparisons: aP < 0.05 compared with 1-year survival; bP < 0.05 compared with
2-years survival. TABLE 1 | Pooled survival and 95% CI of esophageal cancer in low and high prevalence areas. were 75.3% (95% CI: 73.5–77.2%) for 1-year survival, 49.6% (95%
CI: 43.3–55.9%) for 2-years survival, 45.5% (95% CI: 41.4–49.6%)
for 3-years survival, and 39.8% (95% CI: 33.0–46.7%) for 5-years
survival. Meanwhile, the pooled survival rates in prospective
studies were 71.9% (95% CI: 68.6–75.2%) for 1-year survival,
48.1% (95% CI: 41.5–54.8%) for 2-years survival, 47.6% (95%
CI: 42.8–52.3%) for 3-years survival, and 42.6% (95% CI: 34.7–
50.4%) for 5-years survival. Moreover, subgroup analyses by sex
showed higher rates of 2-, 3-, and 5-years survival among women To examine the survival profiles from 2000 to 2018, we
conducted analyses on time-trend survival of patients with EC. As shown in Figure 3 and Table S5, a tendency for increased
survival was evidenced by the pooled survival rates from 2006
to 2018. The same trends were found in both men and women
(Tables S6, S7), except that the 5-years survival rates among men
decreased from 2006 to 2015. Subgroup Analyses of EC Survival by
Clinical Classifications Categories
Sites
N
SR (%)
1-year survival
Hypopharynx and cervical
6
76.5 (68.7–84.4)
Upper thoracic
15
79.3 (73.7–84.8)
Mid thoracic
19
77.6 (72.1–83.0)
Lower thoracic
15
73.3 (66.2–80.3)
Overall
55
77.1 (73.9–80.3)
2-years survival
Hypopharynx and cervical
2
69.4 (45.0–93.7)
Upper thoracic
3
49.1 (25.9–72.3)
Mid thoracic
8
44.5 (35.4–53.6)
Lower thoracic
5
34.9 (6.4–63.5)
Overall
18
44.7 (36.2–53.1)
3-years survival
Hypopharynx and cervical
9
40.4 (30.2–50.6)
Upper thoracic
16
48.1 (42.3–54.0)
Mid thoracic
20
44.5 (35.2–53.8)
Lower thoracic
16
46.8 (39.7–53.9)
Overall
61
45.6 (41.0–50.1)
5-years survival
Hypopharynx and cervical
3
10.7 (0.1–21.4)
Upper thoracic
11
32.6 (24.8–40.4)a
Mid thoracic
12
37.4 (24.9–49.9)a
Lower thoracic
12
39.6 (31.0–48.1)a
Overall
38
35.2 (28.8–41.5)a
SR, survival rate; CI, confidence interval; N, number of included original studies. Between-
group comparisons: aP < 0.05 compared with hypopharynx group. TABLE 3 | Pooled survival and 95% CI of esophageal cancer of different
histologic types. SR, survival rate; CI, confidence interval; N, number of included original studies. Between-
group comparisons: aP < 0.05 compared with hypopharynx group. SR, survival rate; CI, confidence interval; N, number of included studies; ESCC,
esophageal squamous cell carcinoma; SCC, esophageal small cell carcinoma; EAC,
esophageal adenocarcinoma; Combined, esophageal cancer patients not classified by
histology; N, number of included original studies. Between-group comparisons: aP < 0.05
compared with ESCC group. pooled survival of EAC might not be representative. Moreover,
TNM stage is also a crucial determinant for EC survival (26). Our findings showed a decreased trend of survival for patients
with T1, T2, T3, and T4 stage EC. The 5-years survival rate of
patients with stage T4 EC was nearly three times lower than
that of patients with T1 EC. About half of ECs locate in the
middle thoracic esophagus, followed by lower thoracic, higher
thoracic, and hypopharyngeal parts of the esophagus (27). Our
subgroup analyses showed lower survival rates among patients
with hypopharynx and cervical EC, except for 2-years survival
rates that were obtained from two published studies. These
findings verify the relatively poorer prognosis of hypopharynx
and cervical EC. To address the strength and stability of the pooled results, we
conducted sensitivity analysis by omitting one study at a time. The estimates of pooled survival were not significantly affected by
any individual study that was included in our meta-analyses (see
Figures S1–S4), indicating that our results had relative strength
and stability. Subgroup Analyses of EC Survival by
Clinical Classifications As shown in Figure 5, the funnel plot analyses and Begg’s tests
indicated no publication bias in the meta-analyses of 3- and 5-
years survival. However, significant publication bias was detected
in both 1- and 2-years survival analyses. Thirty-five studies that involved 13,055 patients reported the
TNM stage of ED. As shown in Table 2, the pooled analyses June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 5 Survival of Esophageal Cancer in China Hou et al. TABLE 3 | Pooled survival and 95% CI of esophageal cancer of different
histologic types. Categories
Types
N
SR (%)
1-year survival
Combined
145
74.1 (72.1–76.0)
ESCC
80
75.3 (72.7–78.0)
SCC
5
55.6 (40.4–70.8)a
EAC
2
80.9 (62.3–99.5)
Overall
232
74.1 (72.6–75.7)
2-years survival
Combined
79
50.40 (44.5–56.2)
ESCC
41
48.70 (39.9–57.6)
SCC
4
24.40 (4.6–44.2)
EAC
1
–
Overall
125
49.00 (44.2–53.8)
3-years survival
Combined
127
47.8 (43.2–52.3)
ESCC
78
44.6 (39.4–49.7)
SCC
4
18.8 (2.6–35.0)a
EAC
2
45.7 (23.2–68.2)
Overall
210
46.0 (42.6–49.5)
5-years survival
Combined
37
41.30 (31.7–50.9)
ESCC
31
41.70 (32.4–51.0)
SCC
4
15.50 (12.4–18.6)a
EAC
1
–
Overall
72
40.10 (33.7–46.4)
SR, survival rate; CI, confidence interval; N, number of included studies; ESCC,
esophageal squamous cell carcinoma; SCC, esophageal small cell carcinoma; EAC,
esophageal adenocarcinoma; Combined, esophageal cancer patients not classified by
histology; N, number of included original studies. Between-group comparisons: aP < 0.05
compared with ESCC group. To address the strength and stability of the pooled results, we
conducted sensitivity analysis by omitting one study at a time. The estimates of pooled survival were not significantly affected by
any individual study that was included in our meta-analyses (see
Figures S1–S4), indicating that our results had relative strength
d
bili
TABLE 4 | The pooled survival and 95% CI of esophageal cancer at different sites. Subgroup Analyses of EC Survival by
Clinical Classifications Categories
Sites
N
SR (%)
1-year survival
Hypopharynx and cervical
6
76.5 (68.7–84.4)
Upper thoracic
15
79.3 (73.7–84.8)
Mid thoracic
19
77.6 (72.1–83.0)
Lower thoracic
15
73.3 (66.2–80.3)
Overall
55
77.1 (73.9–80.3)
2-years survival
Hypopharynx and cervical
2
69.4 (45.0–93.7)
Upper thoracic
3
49.1 (25.9–72.3)
Mid thoracic
8
44.5 (35.4–53.6)
Lower thoracic
5
34.9 (6.4–63.5)
Overall
18
44.7 (36.2–53.1)
3-years survival
Hypopharynx and cervical
9
40.4 (30.2–50.6)
Upper thoracic
16
48.1 (42.3–54.0)
Mid thoracic
20
44.5 (35.2–53.8)
Lower thoracic
16
46.8 (39.7–53.9)
Overall
61
45.6 (41.0–50.1)
5-years survival
Hypopharynx and cervical
3
10.7 (0.1–21.4)
Upper thoracic
11
32.6 (24.8–40.4)a
Mid thoracic
12
37.4 (24.9–49.9)a
Lower thoracic
12
39.6 (31.0–48.1)a
Overall
38
35.2 (28.8–41.5)a
SR, survival rate; CI, confidence interval; N, number of included original studies. Between-
group comparisons: aP < 0.05 compared with hypopharynx group. pooled survival of EAC might not be representative. Moreover,
TNM stage is also a crucial determinant for EC survival (26). Our findings showed a decreased trend of survival for patients
with T1, T2, T3, and T4 stage EC. The 5-years survival rate of
patients with stage T4 EC was nearly three times lower than
that of patients with T1 EC. About half of ECs locate in the
middle thoracic esophagus, followed by lower thoracic, higher
thoracic, and hypopharyngeal parts of the esophagus (27). Our TABLE 3 | Pooled survival and 95% CI of esophageal cancer of different
histologic types. Categories
Types
N
SR (%)
1-year survival
Combined
145
74.1 (72.1–76.0)
ESCC
80
75.3 (72.7–78.0)
SCC
5
55.6 (40.4–70.8)a
EAC
2
80.9 (62.3–99.5)
Overall
232
74.1 (72.6–75.7)
2-years survival
Combined
79
50.40 (44.5–56.2)
ESCC
41
48.70 (39.9–57.6)
SCC
4
24.40 (4.6–44.2)
EAC
1
–
Overall
125
49.00 (44.2–53.8)
3-years survival
Combined
127
47.8 (43.2–52.3)
ESCC
78
44.6 (39.4–49.7)
SCC
4
18.8 (2.6–35.0)a
EAC
2
45.7 (23.2–68.2)
Overall
210
46.0 (42.6–49.5)
5-years survival
Combined
37
41.30 (31.7–50.9)
ESCC
31
41.70 (32.4–51.0)
SCC
4
15.50 (12.4–18.6)a
EAC
1
–
Overall
72
40.10 (33.7–46.4)
SR, survival rate; CI, confidence interval; N, number of included studies; ESCC,
esophageal squamous cell carcinoma; SCC, esophageal small cell carcinoma; EAC,
esophageal adenocarcinoma; Combined, esophageal cancer patients not classified by
histology; N, number of included original studies. Between-group comparisons: aP < 0.05
compared with ESCC group. TABLE 4 | The pooled survival and 95% CI of esophageal cancer at different sites. Frontiers in Oncology | www.frontiersin.org June 2019 | Volume 9 | Article 548 DISCUSSION Our study examined the hospital-based survival across China of
patients with EC. Among the combined 79,777 patients from 331
hospital-based studies, the overall 5-years survival rate of EC was
40.1%. Tendency analyses show that survival rates of EC have
been increasing from 2000 to 2018. Subgroup analyses illustrate
that men with EC have poorer survival compared to women. Because China has the highest burden of EC worldwide,
our focus is to investigate the key measures of early detection
and appropriate treatment for EC patients, as well as the
strategies that can be taken to evaluate both the efficiency of
preventive policies and the effectiveness of healthcare services
across the country (28, 29). The national cancer registration
system initiated in 2002 has been reinforced since 2015 and
involved 416 population-based sites as of 2016 (30). Although
this registry provides information on nationwide epidemics and
burdens, it does not include all cancer patients in China. The
comparability and validity of the information might vary between
sites due to discrepancies in quality controls, as well as temporal
heterogeneities. Moreover, follow-up is not easy to implement in
the populations served by cancer registries. For instance, it has
been reported that the follow-up rate was only between 65 and
71% at some sites (31). p
p
In China, the regions with a high prevalence of EC are
located in Fujian, Guangdong, Henan, Jiangsu, Shandong,
Shanxi, Shaanxi, and Sichuan provinces (21–25). We found
that EC survival rates in high prevalence areas were similar
to those in other regions. It is notable that 90% of ECs in
the Chinese population are ESCCs, which is inconsistent with
other ethnicities. Our study found that survival of ESCC was
significantly higher than SSC in China. As a minor histologic
type of EC in China, EAC accounts for <1% of EC (19). Among
the hundreds of studies we included, only two reported an
independent result on EAC. Due to the lack of such studies, the June 2019 | Volume 9 | Article 548 June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 6 Hou et al. Survival of Esophageal Cancer in China FIGURE 5 | Funnel plots of publication bias analyses. FIGURE 5 | Funnel plots of publication bias analyses. Therefore, hospital-based studies are essential in order to
predict the prognosis of patients with EC. Frontiers in Oncology | www.frontiersin.org REFERENCES population-based cancer registries. Lancet Glob Health. (2018) 6:e555–67. doi: 10.1016/S2214-109X(18)30127-X population-based cancer registries. Lancet Glob Health. (2018) 6:e555–67. doi: 10.1016/S2214-109X(18)30127-X 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer
statistics. CA Cancer J Clin. (2011) 61:69–90. doi: 10.3322/caac.20107 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer
statistics. CA Cancer J Clin. (2011) 61:69–90. doi: 10.3322/caac.20107 13. Chen JG, Zhu J, Zhang YH, Zhang YX, Yao DF, Chen YS, et al. Cancer survival
in Qidong between 1972 and 2011: a population-based analysis. Mol Clin
Oncol. (2017) 6:944–54. doi: 10.3892/mco.2017.1234 2. Yu C, Tang H, Guo Y, Bian Z, Yang L, Chen Y, et al. Hot tea consumption
and its interactions with alcohol and tobacco use on the risk for esophageal
cancer: a population-based cohort study. Ann Intern Med. (2018) 168:489–97. doi: 10.7326/M17-2000 14. Brenner H, Hakulinen T. Implications of incomplete registration of deaths
on long-term survival estimates from population-based cancer registries. Int J
Cancer. (2009) 125:432–7. doi: 10.1002/ijc.24344 3. Wheeler JB, Reed CE. Epidemiology of esophageal cancer. Surg Clin North
Am. (2012) 92:1077–87. doi: 10.1016/j.suc.2012.07.008 15. Chen JG, Chen HZ, Zhu J, Yang YL, Zhang YH, Huang PX, et al. Cancer
survival in patients from a hospital-based cancer registry, China. J Cancer. (2018) 9:851–60. doi: 10.7150/jca.23039 4. Tang WR, Chen ZJ, Lin K, Su M, Au WW. Development of esophageal
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sleep apnea with hypertension: a systematic review and meta-analysis. J Glob
Health. (2018) 8:010405. doi: 10.7189/jogh.08.010405 5. Chen W, Zheng R, Zeng H, Zhang S. The incidence and mortality
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35:73. doi: 10.1186/s40880-016-0137-8 17. Guo L, Yang F, Yin Y, Liu S, Li P, Zhang X, et al. Prevalence
of human papillomavirus type-16 in head and neck cancer among
the Chinese population: a meta-analysis. Front Oncol. (2018) 8:619. doi: 10.3389/fonc.2018.00619 6. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics
in China, 2015. CA Cancer J Clin. (2016) 66:115–32. doi: 10.3322/caac.21338 18. Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are
C. Global trends in esophageal cancer. Surg Oncol. (2017) 115:564–79. DATA AVAILABILITY The Supplementary Material for this article can be found
online
at:
https://www.frontiersin.org/articles/10.3389/fonc. 2019.00548/full#supplementary-material All datasets generated for this study are included in the
manuscript and/or the Supplementary Files. FUNDING This
study
was
supported
by
the
Natural
Science
Foundation of Shandong Province, China (ZR2017MH100) This
study
was
supported
by
the
Natural
Science
Foundation of Shandong Province, China (ZR2017MH100)
and
National
Natural
Science
Foundation
of
China (81773527). In short, this systematic review and meta-analysis provides
hospital-based survival data for EC in China. Although this study
is subject to uncertain representability and obvious publication
bias, it offers insight into the prognosis of EC based on in-
hospital studies. and
National
Natural
Science
Foundation
of
China (81773527). AUTHOR CONTRIBUTIONS 12.14%, respectively (15), which is also significantly lower than
our results. YW
and
HH
designed
this
study. ZM,
XZ,
and
HH
contributed
to
the
literature
search,
review,
and
data
extraction. MS and GD conduced statistical analyses. HH,
ZM,
and
XZ
contributed
to
manuscript
drafting. WW
and
YW
contributed
to
manuscript
modification. All
authors have reviewed and approved the final version of
this manuscript. Limitations of our study are as follows: (1) Because the
survival information is from independent studies, our findings
are not representative of survival rates in China as a whole; (2)
republication of survival data cannot be eliminated entirely; (3)
most of the data in our study are from retrospective studies
and might bias the real survival level of EC. In addition,
significant publication bias was detected in both 1- and 2-years
survival analyses. Positive publication bias indicates incomplete
acquisition of original studies and might introduce potential
fallacy to our observations. DISCUSSION We conducted this
systematic review to combine the hospital-based survival data of
patients with EC that were collected in accordance with clinical
research criteria. We supposed that these results presented
survival information from the viewpoint of clinical oncologists. Our findings verified an increased tendency toward EC survival
from 2000 to 2018. The increase in EC survival has been
attributed to improved access to primary health care, greater
availability of diagnostic facilities, and improved effectiveness of
clinical treatment. The health insurance system of China has
been updated to cover all populations since 2003. Access to this
insurance support has improved the survival of patients with EC
across the country (11). population-based
study
estimated
a
decrease
in
survival
from 19.1 to 18.1% in urban China (11), in which EC was
the only cancer with a lower survival rate in urban compared
to rural areas. Such results might be due to observation bias,
which results from loss to follow-up of EC deaths in rural areas. In addition, it is known that in China, EC screening covered
more rural areas than urban area prior to 2012. This might lead
to the contrast fallacy between rural and urban populations. However, we did not analyze survival in urban or rural areas
due to the lack of original information in our study. Age is
also one of the important determinants closely related to the
survival of EC. Unfortunately, we did not compare the survival
between age classifications due to the lack of original data for
age-specific groups. In 2015, the third global surveillance of cancer survival
(CONCORD) program reported survival data from 2000 to 2014,
which included 734,428 adults with EC from 60 countries (32). During the 15-years period, 5-years age-standardized survival
rates ranged from 10 to 30% in most countries, which was
lower than what we observed. Data from a hospital-based cancer
registry between 2002 and 2014 found that the 1-, 3-, 5-, and
10-years survival rates of EC were 55.88, 26.24, 19.62, and A large-scale study involving 63,506 patients with EC from 17
population-based cancer registries reported increased survival
from 20.9 to 30.3% between 2003 and 2015 (12). However,
we found a higher survival rate among the hospital-based
population. This discrepancy is because population-based
data are collected from non-inclusive study participants, while
hospital-based data come from outpatients and inpatients
who
generally
receive
more
effective
therapy. DISCUSSION Another June 2019 | Volume 9 | Article 548 7 Survival of Esophageal Cancer in China Hou et al. REFERENCES doi: 10.1002/jso.24592 7. Lin Y, Totsuka Y, Shan B, Wang C, Wei W, Qiao Y, et al. Esophageal cancer
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risk score and postsurgical esophageal cancer-specific mortality: the Fujian
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10.21037/jtd.2017. 10.60 Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. 27. Yang D, Mao YS, He J, Gao SG, Sun KL, Mu JW, et al. Long-term survival of the
middle and lower thoracic esophageal cancer patients after surgical treatment
through left or right thoracic approach. J Thorac Dis. (2018) 10:2648–55. doi: 10.21037/jtd.2018.04.45 Copyright © 2019 Hou, Meng, Zhao, Ding, Sun, Wang and Wang. This is an open-
access article distributed under the terms of the Creative Commons Attribution
License (CC BY). June 2019 | Volume 9 | Article 548 REFERENCES The use, distribution or reproduction in other forums is permitted,
provided the original author(s) and the copyright owner(s) are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms. Copyright © 2019 Hou, Meng, Zhao, Ding, Sun, Wang and Wang. This is an open-
access article distributed under the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or reproduction in other forums is permitted,
provided the original author(s) and the copyright owner(s) are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms. Copyright © 2019 Hou, Meng, Zhao, Ding, Sun, Wang and Wang. This is an open-
access article distributed under the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or reproduction in other forums is permitted,
provided the original author(s) and the copyright owner(s) are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms. 28. Hur C, Choi SE, Kong CY, Wang GQ, Xu H, Polydorides AD, et al. High-resolution microendoscopy for esophageal cancer screening in China:
a cost-effectiveness analysis. World J Gastroenterol. (2015) 21:5513–23. doi: 10.3748/wjg.v21.i18.5513 29. Feng H, Song G, Yang J, Hao C, Wang M, Li B, et al. Cost-effectiveness
analysis of esophageal cancer once-in-a-lifetime endoscopic screening in June 2019 | Volume 9 | Article 548 Frontiers in Oncology | www.frontiersin.org 9
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English
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Effectiveness of a Problem-Solving Program in Improving Problem-Solving Ability and Glycemic Control for Diabetics with Hypoglycemia
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International journal of environmental research and public health/International journal of environmental research and public health
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cc-by
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Citation: Wu, F.-L.; Lin, C.-H.; Lin,
C.-L.; Juang, J.-H. Effectiveness of a
Problem-Solving Program in
Improving Problem-Solving Ability
and Glycemic Control for Diabetics
with Hypoglycemia. Int. J. Environ. Res. Public Health 2021, 18, 9559. https://doi.org/10.3390
/ijerph18189559 Keywords: diabetes; problem-solving; hypoglycemia; self-management; glycated hemoglobin Effectiveness of a Problem-Solving Program in Improving
Problem-Solving Ability and Glycemic Control for Diabetics
with Hypoglycemia Fei-Ling Wu 1,2, Chia-Hung Lin 2,3
, Chia-Ling Lin 1 and Jyuhn-Huarng Juang 2,4,* 1
Department of Nursing, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan;
flwu@mail.cgust.edu.tw (F.-L.W.); lcling@mail.cgust.edu.tw (C.-L.L.)
2
Division of Endocrinology and Metabolism, Department of Internal Medicine,
Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; adronlin@cgmh.org.tw
3
Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
4
Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
*
Correspondence: jjuang@cgmh.org.tw; Tel.: +886-3-3281200 (ext. 8821) Abstract: The purpose of this study was to evaluate the effects of a hypoglycemia problem-solving
program (HPSP) on problem-solving ability and glycemic control in diabetics with hypoglycemia. This was a prospective, quasi-experimental study with two groups, using a pre- and post-repeated
measures design. A total of 71 diabetic patients with hypoglycemia were purposively assigned to
an experimental group (n = 34) and a control group (n = 37). The experimental group participated
in an 8-week HPSP, and each weekly session lasted approximately 90 min, while the control group
received usual care. Participants were assessed at baseline, 1, 3, and 6 months after intervention care. In the experimental group, 6 months after the HPSP intervention, HbA1c was superior to that before
the intervention. In both groups, the score obtained using the hypoglycemia problem-solving scale
(HPSS) was low before the intervention. In the experimental group, HPSS tracking improved at all
stages after the intervention compared to before the intervention. In the control group, the HPSS
score improved slightly in the first month and sixth months after usual care. There were significant
differences between and within groups in HbA1c levels and HPSS score over time. The intervention
based on the HPSP effectively improves HbA1c level and hypoglycemia problem-solving ability in
patients with hypoglycemia. International Journal of
Environmental Research
and Public Health International Journal of
Environmental Research
and Public Health 1. Introduction In 2016, the World Health Organization issued a global call for action on dedicating
greater attention to diabetes and identifying relevant solutions [1]. Although diabetes-
related medical treatments and health care in Taiwan continue to improve, a survey on
type 2 diabetes in 2018 revealed that 2.2 million people in Taiwan had diabetes, with the
prevalence being 9.32%, and the number of new patients being nearly 160,000 annually. Because of the continual increase in the number of patients with diabetes, the pursuit of
optimal glycemic control and reduction of possible complications has long been a major
goal in diabetes care [2]. Therefore, patients with poor glycemic control should be encour-
aged to adopt insulin regimens as early as possible [3,4]. According to statistics from the
National Health Insurance (NHI) database in Taiwan, the use of insulin regimens increased
annually until 2014, with 4.67% of people with diabetes using insulin injections alone, and
8.01% using concomitant oral agents and insulin [5]. A global survey of patients receiving
insulin treatment indicated that the incidence of hypoglycemia is as high as 78.3% [6]. The
cost of achieving effective glycemic control may increase the incidence of hypoglycemia. As patients learn to adapt to having diabetes, they face a typical predicament: they are con-
cerned about experiencing hypoglycemia but are also aware that addressing the symptoms Publisher’s Note: MDPI stays neutral
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iations. Publisher’s Note: MDPI stays neutral
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iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
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under
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terms
and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/). Int. J. Environ. Res. Public Health 2021, 18, 9559. https://doi.org/10.3390/ijerph18189559 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2021, 18, 9559 2 of 10 of hypoglycemia may lead to high blood sugar [7]. Moreover, recurrent hypoglycemic
episodes tend to cause changes in nerve conduction between neuron synapses [8] as well
as reduced intelligence [9]. Therefore, hypoglycemia has become a principal limiting factor
in the management of patients with diabetes and may also lead to poor glycemic control in
such patients [10]. p
The most effective method for preventing hypoglycemia is to provide guidance to
patients with diabetes and their family and friends [11]. 1. Introduction The current diabetes health
education is based on a self-management model with the aim of maintaining optimal
health and quality of life. Patients must learn specific decision-making, adjustment, and
management methods according to their unique lifestyles, rather than allow the disease to
control their living habits. Problem-solving is a logical thinking process [12] and it is the
optimal approach for guiding patients to face care problems; moreover, an effective overall
care ability can be gradually achieved through experience and learning [13]. When solving
a problem, patients must use inductive reasoning and knowledge applications as they
attempt to develop possible solution strategies. This process requires the participation of
and flexible interactions between healthcare providers and patients [14]. Problem-solving
has been demonstrated to be a critical ability for patients with diabetes to successfully
master their self-management skills; however, it is also the most difficult skill for diabetes
health educators to teach to patients [13]. In addition, the problem-solving ability of
patients with hypoglycemia is positively correlated with their glycated hemoglobin (HbA1c)
control status [15]. Problem-solving is affected by a patient’s own perspectives, personal
factors, and external environmental factors. Thus, health educators must first understand a
patient’s solution and evaluate their disease problems before providing individual guidance
skills to help the patient effectively implement self-management [16]. Scholars point out that in the face of long-term and unchangeable health problems,
they may lack self-efficacy for problem solving, which often affects the application of
problem-solving skills [17]. According to research on diabetes care, problem-solving
interventions not only improve patients’ problem-solving ability but also have a positive
impact on the physical and psychological results of disease care [18,19]. Patients’ learning
of effective problem-solving methods and their use of blood glucose self-monitoring data
enable them to provide effective explanations, make informed decisions, accurately adjust
their insulin dosage, calculate the composition of their foods, and perceive the significance
of and risks indicated by the data [16]. Our goal is to coach the participants’ problem-
solving skills to enhance self-efficacy in identifying symptoms, analyzing the causes and
devising strategies to solve them, and effectively achieve glycemic control. Therefore, the
purpose of this study was to evaluate the effectiveness of a problem-solving intervention
program in the self-management of hypoglycemia in patients with diabetes. 2.1. Participants and Sample Size Purposive sampling was used to recruit patients with diabetes from the metabolic
outpatient clinics of two major medical centers and regional hospitals. Healthcare providers
referred outpatients who satisfied the inclusion criteria. These patients were then invited by
the researchers to participate in the study. The inclusion criteria were as follows: (1) being
≥20 years of age, (2) living with diagnosed type 2 diabetes for at least 1 year, (3) having
experienced at least one hypoglycemic episode in the previous 6 months (hypoglycemic
episode: blood glucose level <70 mg/dL or presenting hypoglycemic symptoms of shaking,
sweating, drowsiness, or behavioral changes), and (4) being treated with insulin. Patients
were excluded if they had renal failure, mental illness, blindness, severe physical handicap
or if they were pregnant. G-power version 3.1 was adopted to estimate the appropriate sample size, which was
64 participants; considering a 20% attrition rate, the required sample size was 76. The
corresponding statistical parameters were as follows: α = 0.05, power = 0.80, covariance
R2, and effect size = 0.40. This study was approved by the institutional review board of a Int. J. Environ. Res. Public Health 2021, 18, 9559 3 of 10 medical center in northern Taiwan (1040147B). All participants provided written informed
consent before data collection. medical center in northern Taiwan (1040147B). All participants provided written informed
consent before data collection. 2.2. Study Design This was a prospective, quasi-experimental study with two groups, and a pre- and
post-test repeated-measures design was employed. In order to avoid interventional con-
tamination, a draw was used to determine patients with single-month admissions as the
experimental group and patients with bimonthly admissions as the control group. Par-
ticipants in the experimental group participated in the hypoglycemic problem-solving
program (HPSP), whereas the control group received usual care. The main aim was to
compare the frequency of hypoglycemia, HbA1c level, and hypoglycemic problem-solving
abilities between the experimental and the control groups. 2.3. Interventions The HPSP was developed on the basis of the theory of social problem-solving. The
program consisted of two phases with a total duration of 8 weeks, and the weekly activity
time was approximately 90 min. The goal of the activities during the first stage was to learn
about problem-solving. The diabetes team (consisting of a physician, a health educator, and
a nutritionist) provided instruction on basic hypoglycemia care to improve the participants’
accuracy in solving hypoglycemia problems. Phase 2 focused on the application of problem-
solving skills. We used situational case introduction, group discussions, experience sharing,
and individual guidance to summarize the causes of hypoglycemia, develop feasible
goals and strategies, and perform self-analysis on the reasons for the difficulty or success
of the implemented strategy as a reference for the self-management of hypoglycemia. Table 1 provides a description summarizes the details of the program. Before each weekly
activity, the study team sent reminders to the participants by phone. The comparison group
received usual care only. Health education nurses provided instruction in the hypoglycemia
education leaflet (identification of hypoglycemia, management of hypoglycemia, and
prevention methods). Table 1. Course Schedule for the HPSP. Stage Number/Main Topic
Weekly
Course Content
Stage1
Recognition problem-solving
1–2 w
Learn the steps and skills of problem-solving
1. problem orientation responses
2. problem-solving perception
3. detection control
4. problem-solving skill
5. problem-solving principles
3–4 w
learned about hypoglycemia and self-care
1. blood glucose for self-monitoring
2. identify the symptoms and signs of hypoglycemia
3. hypoglycemia problem definition and formulation
4. analyze the causes of hypoglycemia
5. generation of alternative solutions
Stage2
Application of problem-solving
skills
5–6 w
clarify hypoglycemia-related problems
problem-solving health education manual, case studies
and discussions, situational case introduction, group
discussions, and experience sharing (diet, exercise,
medication, body weight control, disease stress
adjustment, and blood glucose self-monitoring)
7–8 w
implement and evaluate the solution strategies
1. coaching, modeling, shaping, rehearsal
2. solution implementation
3. verification Table 1. Course Schedule for the HPSP. Table 1. Course Schedule for the HPSP. Baseline data for all measures were obtained before intervention assignment. The
participants were assessed at four time points: the baseline assessment (T0) was conducted
before the HPSP, with follow-up assessments 1 (T1), 3 (T2), and 6 (T3) months after Int. J. Environ. Res. Public Health 2021, 18, 9559 4 of 10 participation in the HPSP. Outcome measures were HbA1c and Hypoglycemia Problem-
Solving Scale (HPSS) scores. 2.5. Statistical Analysis SPSS, version 23.0 for Windows (Armonk, NY, USA) was adopted to analyze the
data. Descriptive statistical analysis, including mean (SD), counts, and percentages, was
employed to describe the demographic data, disease characteristics, and hypoglycemia
problem-solving ability. Inferential statistical analysis was performed using a chi-square
distribution test, t test, and Fisher’s exact test. The effects of the HPSP on frequency of
hypoglycemic episodes, HbA1c levels, and hypoglycemic problem-solving ability were an-
alyzed using a repeated-measures analysis of variance (ANOVA), including the assessment
of changes over time and the time × group interaction effect. 2.4.1. Demographic and Disease Characteristics 2.4.1. Demographic and Disease Characteristics The demographic variables were sex, age, marital status, educational level, and
employment status. Disease characteristics were medication regimen, duration of insulin
treatment, and frequency of hypoglycemic episodes in the previous 6 months. HbA1c
was measured at the beginning of the study and at the 1-, 3-, and 6-month follow-ups. Demographic and disease-related characteristics were obtained from chart reviews and
self-monitored blood glucose records. 3. Results 3.1. Participant Characteristics by Group 2.4.2. HPSS The HPSS was used to measure the participants’ problem-solving ability in terms of
hypoglycemia [20]. The HPSS consists of 24 items scored on a 5-point Likert scale from
0 (not applicable) to 4 (always applicable), and higher scores indicate higher degrees of
problem-solving ability for hypoglycemia. The Cronbach’s alphas of the HPSS ranged from
0.83 to 0.90 in this study, indicating favorable to excellent internal consistency reliability. 2.4. Research Instruments 2.4. Research Instruments 2.3. Interventions participation in the HPSP. Outcome measures were HbA1c and Hypoglycemia Problem-
Solving Scale (HPSS) scores. 3.1. Participant Characteristics by Group A total of 76 eligible patients were invited to participate in this study. Five participants
withdrew during the intervention process because of limited time availability, unwilling-
ness to participate, and transportation problems. Therefore, the data of 71 participants were
analyzed; the experimental and control groups included 34 and 37 participants, respectively
(Figure 1). The intervention completion rate was 93.4%. To ensure the accuracy of the exper-
imental results, a chi-square test and an independent sample t test were employed to assess
the homogeneity of the two groups. No significant differences were observed between
the two groups (p > 0.05) regarding demographic or disease characteristics (Table 2). The
participants in the experimental and control groups had average ages of 53.71 (SD = 15.66)
and 54.87 (SD = 15.28) years, respectively. More than half of the participants were men,
married, and working, and the most common educational level was senior high school. In addition, 70.4% of the participants’ medication regimen was insulin injections alone. The mean duration of the insulin treatments was 7.19 (SD = 7.24) years. In the preceding
6 months, 69.01% of the participants had experienced ≥6 hypoglycemic episodes. 5 of 10 Int. J. Environ. Res. Public Health 2021, 18, 9559
y
p
cemic episod Figure 1. Recruitment for the Hypoglycemia Problem Solving Program. Figure 1. Recruitment for the Hypoglycemia Problem Solving Program. ure 1. Recruitment for the Hypoglycemia Problem Solving Program. Figure 1. Recruitment for the Hypoglycemia Problem Solving Program. ble 2. Homogeneity test of the demographic and disease characteristics of the two groups (N = 71). Table 2. Homogeneity test of the demographic and disease characteristics of the two groups (N = 71). Table 2. Homogeneity test of the demographic and disease characteristics of the two groups (N = 71). a Fisher’s exact test. 3 3 Effects of the
S
on
bA c
evels and
SS Scores
The results of the repeated-measures ANOVA for H
3.3. Effects of the HPSP on HbA1c Levels and HPSS Scores hypoglycemic episodes of the two groups at the four evaluation times are listed in Table
3. Regarding the HbA1c results, in the experimental group (HPSP), the average HbA1c
The results of the repeated-measures ANOVA for HbA1c levels, HPSS scores, and
hypoglycemic episodes of the two groups at the four evaluation times are listed in Table 3. Regarding the HbA1c results, in the experimental group (HPSP), the average HbA1c level
from T1 (1 month after intervention) to T3 (6 months after intervention) was significantly
lower than that at T0 (before intervention). The average HbA1c levels from T0 to T1 and
T2 to T3 decreased significantly, whereas that from T1 to T2 rose slightly; moreover, the
average HbA1c level at T3 was significantly lower than that at T0, and HbA1c reached a
statistically significant difference over time (F = 5.090, p < 0.01). The HbA1c levels of the
control group (usual care) did not change significantly from T0 to T3. HbA1c at T3 was
not significantly higher than that at T0. The average total HPSS score of the two groups
before the intervention was less than half of the total potential score (47.62 vs. 46.27 points). After the intervention, the HPSS scores of the experimental group from T1 to T3 were
significantly higher than that at T0, and the average problem-solving ability scores from T0
to T1 and T2 to T3 increased significantly, whereas that from T1 to T2 decreased slightly. In the control group, the average HPSS scores at T1 and T3 were higher than that at T0,
and the two groups differed significantly in HPSS scores. There was no significant change
in the frequency of hypoglycemia from T0 to T3 in the control and experimental groups. However, the frequency of hypoglycemia in the experimental group showed a decreasing
trend from T2 to T3. The two-way repeated-measures ANOVA revealed a significant interaction of time
and group for HbA1c level after the intervention (F = 5.816, p < 0.01). After 6 months,
the reduction of HbA1c in the experimental group was significantly greater than in the
control group. Notably, no significant difference was observed between the two groups of
patients with diabetes in terms of their ability to resolve hypoglycemia problems before
the start of the program. 3.2. Comparison of Group Outcomes at Baseline
3 2 Comparison of Group Outcomes at Baseline 3.2. Comparison of Group Outcomes at Baseline
3 2 Comparison of Group Outcomes at Baseline 3.2. Comparison of Group Outcomes at Baseline
3 2 Comparison of Group Outcomes at Baseline The HbA1c, HPSS, and hypoglycemic episodes results for the experimental and control
groups at baseline are presented in Figure 2. At baseline, no significant differences were
observed between the two groups in HbA1c level (Z = −0.053, p > 0.05), HPSS (Z = −0.948,
p > 0.05), and frequency of hypoglycemia (t = −0.913, p > 0.05). 3.2. Comparison of Group Outcomes at Baseline
The HbA1c, HPSS, and hypoglycemic episodes results for the experimental and con-
trol groups at baseline are presented in Figure 2. At baseline, no significant differences
were observed between the two groups in HbA1c level (Z = 0.053, p > 0.05), HPSS (Z =
0.948, p > 0.05), and frequency of hypoglycemia (t = 0.913, p > 0.05). The HbA1c, HPSS, and hypoglycemic episodes results for the experimental and control
groups at baseline are presented in Figure 2. At baseline, no significant differences were
observed between the two groups in HbA1c level (Z = −0.053, p > 0.05), HPSS (Z = −0.948,
p > 0.05), and frequency of hypoglycemia (t = −0.913, p > 0.05). 3.2. Comparison of Group Outcomes at Baseline
The HbA1c, HPSS, and hypoglycemic episodes results for the experimental and con-
trol groups at baseline are presented in Figure 2. At baseline, no significant differences
were observed between the two groups in HbA1c level (Z = 0.053, p > 0.05), HPSS (Z =
0.948, p > 0.05), and frequency of hypoglycemia (t = 0.913, p > 0.05). Figure 2. Comparison of group outcomes at baseline (N = 71): EG, experimental group (n = 34); CG, control group (n = 37);
HPSS, Hypoglycemia Problem-Solving Scale. Figure 2. Comparison of group outcomes at baseline (N = 71): EG, experimental group (n = 34); CG, control group (n = 37);
HPSS, Hypoglycemia Problem-Solving Scale. Figure 2. Comparison of group outcomes at baseline (N = 71): EG, experimental group (n = 34); CG, control group (n = 37);
HPSS, Hypoglycemia Problem-Solving Scale. Figure 2. Comparison of group outcomes at baseline (N = 71): EG, experimental group (n = 34); CG, control group (n = 37);
HPSS, Hypoglycemia Problem-Solving Scale. 3.1. Participant Characteristics by Group Variables
Total
(N = 71)
Experimental Group
(n = 34)
Control Group
(n = 37)
χ2/t
p
N%/M ± SD
n%/M ± SD
n%/M ± SD
Demographic data
Gender
0.104
0.814
Male
39
54.93
18
52.9
21
56.8
Female
32
45.07
16
47.1
16
43.2
Age (years)
53.10 15.98
53.71 15.66
54.87 15.28
0.158
0.692 a
40
18
25.4
7
20.6
11
29.7
41–50
13
18.3
9
26.5
4
10.8
51–60
12
16.9
3
8.8
9
24.3
61–70
16
22.5
9
26.5
7
18.9
>70
12
16.9
6
17.6
6
16.3
Marital status
0.592
0.502
Unmarried
24
33.8
11
32.3
13
35.1
Married
47
66.2
23
67.7
24
64.9
Education level
3.320
0.851 a
Variables
Total
(N = 71)
Experimental Group
(n = 34)
Control Group
(n = 37)
χ2/t
p
N%/M ± SD
n%/M ± SD
n%/M ± SD
Demographic data
Gender
0.104
0.814
Male
39
54.93
18
52.9
21
56.8
Female
32
45.07
16
47.1
16
43.2
Age (years)
53.10 ± 15.98
53.71 ± 15.66
54.87 ± 15.28
0.158
0.692 a
≤40
18
25.4
7
20.6
11
29.7
41–50
13
18.3
9
26.5
4
10.8
51–60
12
16.9
3
8.8
9
24.3
61–70
16
22.5
9
26.5
7
18.9
>70
12
16.9
6
17.6
6
16.3
Marital status
0.592
0.502
Unmarried
24
33.8
11
32.3
13
35.1
Married
47
66.2
23
67.7
24
64.9
Education level
3.320
0.851 a
Junior high school or below
16
22.5
7
20.6
9
24.3
Senior high school
31
43.7
16
47.1
15
40.6
University or above
24
33.8
11
32.3
13
35.1
Employment status
3.267
0.073
Unemployed
20
28.2
13
38.2
7
18.9
Working
51
71.8
21
61.8
30
81.1
Disease characteristics
0.012
0.963
Medication regimen
Insulin
50
70.4
24
70.6
26
70.3
Oral medication and Insulin
21
29.6
10
29.4
11
29.7
Duration of insulin treatment
(years)
7.19 ± 7.24
7.26 ± 7.45
7.11 ± 7.15
0.474
0.946
≤5
41
57.7
19
55.9
22
59.4
≥5.1
30
42.3
15
44.1
15
40.6
Frequency of hypoglycemia
(in the previous 6 months)
10.65 ± 8.38
9.56 ± 7.91
11.65 ± 8.78
0.913
0.343
<6
22
31.0
11
32.3
11
29.7
≥6
49
69.0
23
67.7
26
70.3
a Fisher’s exact test. 6 of 10 Int. J. Environ. Res. Public Health 2021, 18, 9559
(in the previous 6 months)
10.65
<6
22 4. Discussion Diabetes is a chronic disease that requires patients to implement self-management;
therefore, health education strategies are instrumental in disease treatment and blood
sugar control [21]. Although there is a rich body of research on the effects and man-
agement of diabetes, most studies focus on improving knowledge and behaviors in self-
management [22,23]. The literature is sparse in relation to the implementation of protocols
to manage hypoglycemia. Problem-solving skills are required for education and cumu-
lative experience training [13]. Our program facilitates healthcare providers’ work with
patients to develop care goals and plans and provides problem-solving skills using a va-
riety of strategies to address the realities of caring for people with hypoglycemia. The
training provided in the HPSP in this study focused on problem-solving guidance. The
HPSP intervention emphasizes that health-care personnel must guide patients with type 2
diabetes to clarify the cause of hypoglycemic events that they experience and must help
patients learn to self-monitor their blood glucose; self-monitoring helps patients detect the
factors of hypoglycemia and make timely corrections in their disease self-management
according to the monitored values. The healthcare personnel’s assistance with adjusting
patients’ daily treatment methods can reduce the patients’ sense of frustration during
problem-solving. Therefore, educational programs regarding hypoglycemia events should
focus on understanding the problems and analyzing the possible causes of hypoglycemia. g
p
y
g
p
yp g y
The HPSP intervention had a significant effect on HbA1c levels, with values from
T1 to T3 being lower than that at T0 (7.95%) before the intervention. Because a longer
period had elapsed after the intervention, the HbA1c level at T2 (7.63%) was higher than
that at T1 (7.41%). This project emphasized patient autonomy in disease care and focused
on the learning and application of problem-solving, including the numerous aspects that
must be considered in hypoglycemia self-management. After a period of dedication,
the participants’ perception of hypoglycemia might have been reduced. Similarly, their
ability to solve hypoglycemia problems at T2 (58.59 points) was slightly lower than that
at T1 (60.65 points). Thus, HbA1c control may have been affected by the participants’
problem-solving ability. Studies have suggested that training in problem-solving requires
patients and healthcare personnel to act as partners in a diabetes care team; this approach
helps cultivate patients’ problem-solving skills to manage diverse life situations [24,25]. 3 3 Effects of the
S
on
bA c
evels and
SS Scores
The results of the repeated-measures ANOVA for H
3.3. Effects of the HPSP on HbA1c Levels and HPSS Scores After 8 weeks of HPSP intervention and a 6-month interval, the
hypoglycemia problem-solving ability at T3 (6 months) in both groups was higher than
that at T0 (baseline). Although the problem-solving ability of the control group (usual
care) improved slightly, the effectiveness of this ability was significantly lower that of the
experimental group (F = 13.653, p < 0.001; Table 3). Int. J. Environ. Res. Public Health 2021, 18, 9559 7 of 10 Table 3. Repeated-measures analysis results for HbA1c level and HPSS scores by group (N = 71). Variables
Group
T0
Mean (SD)
T1
Mean (SD)
T2
Mean (SD)
T3
Mean (SD)
Time
F (p)
Time * Group
F (p)
HbA1c
EG
7.95 (1.20)
7.41 (0.98)
7.63 (0.84)
7.22 (0.61)
5.090
<0.01
5.816
<0.01
CG
8.16 (1.30)
8.20 (0.58)
8.13 (1.04)
8.30 (1.03)
2.487
0.080
HPSS
EG
47.62 (14.71)
60.65 (9.29)
58.59 (8.66)
64.53 (9.73)
19.476
<0.001
13.653
<0.001
CG
46.27 (12.52)
46.78 (11.81)
46.05 (11.80)
46.68 (11.67)
5.113
<0.05
FOH
EG
9.56 (7.91)
1.51 (1.08)
4.08 (1.78)
3.24 (0.75)
2.910
0.068
3.114
0.073
CG
11.65 (8.78)
1.96 (1.45)
5.34 (2.11)
6.63 (0.83)
0.872
0.640
EG, experimental group; CG, control group; FOH, frequency of hypoglycemia; HPSS, Hypoglycemia Problem-Solving Scale; T0, baseline;
T1, 1 month after HPSP or usual care; T2, 3 months after HPSP or usual care; T3, 6 months after HPSP or usual care. HPSP, Hypoglycemia
Problem-Solving Program. Time * Group, F value of the interaction of between groups and within pre- and post-test. Table 3. Repeated-measures analysis results for HbA1c level and HPSS scores by group (N = 71). EG, experimental group; CG, control group; FOH, frequency of hypoglycemia; HPSS, Hypoglycemia Problem-Solving Scale; T0, baseline;
T1, 1 month after HPSP or usual care; T2, 3 months after HPSP or usual care; T3, 6 months after HPSP or usual care. HPSP, Hypoglycemia
Problem-Solving Program. Time * Group, F value of the interaction of between groups and within pre- and post-test. 4. Discussion The results of the current 6-month short-term follow-up indicated that the participants
interacted with the care team through blood glucose monitoring and were taught how
to interpret their monitoring results and improve their blood glucose on the basis of the
measured values. Frequent discussions and reviews of the strategies not only improved the
participants’ ability to solve hypoglycemia problems but also supported their blood sugar
control, especially for participants with hypoglycemia who actively maintained optimal
blood sugar control. In addition, Schmitt et al. showed that better self-management was
associated with better control of HbA1c levels [26]. The mean HbA1c of the participants in
this study was 8.06%; although there was no significant difference between the samples Int. J. Environ. Res. Public Health 2021, 18, 9559 8 of 10 of the two groups before the intervention, their previous experience may have influenced
their self-management and compliance to control HbA1c levels. of the two groups before the intervention, their previous experience may have influenced
their self-management and compliance to control HbA1c levels. g
p
The HPSP intervention had a significant effect on HPSS scores. In this study, the
average HPSS score of the two groups before the intervention was less than half of the total
score (full score of 96) and lower than the average HPSS score (58.22) recorded in a study
investigating hypoglycemia in patients with type 1 and type 2 diabetes [15]. This result
indicates that the participants in the present study were generally deficient in their problem-
solving ability for hypoglycemia, which might be related to the long-term nature of higher
blood glucose in patients with type 2 diabetes; that is, these patients no longer regard
hypoglycemia events as a challenge requiring aggressive treatment. The HPSS score in the
experimental group (HPSP intervention) increased significantly by nearly 20 points from
T0 to T3. This result indicates that in the HPSP intervention, the healthcare team helped the
participants to develop problem-solving skills, which improved the participants’ positive
thinking and awareness of hypoglycemia, in addition to enhancing their willingness to
participate in problem-solving and their belief that hypoglycemia can be resolved. The control group received only conventional health education, and although their
scores after the intervention differed significantly from the baseline scores, the scores
for hypoglycemia problem-solving ability at T3 (46.68) remained in the middle or lower
level. 4. Discussion The results suggest that, although the provision of conventional health education
through medical and nursing personnel improved the participants’ problem-solving ability
or compliance with health education, addressing hypoglycemia-related problems requires
a clear goal that is developed according to patients’ daily information. This phenomenon
might also be related to the fact that the participants in this study were mainly middle-
aged and older patients with type 2 diabetes. Thus, patients in these age groups require
thorough educational interventions from health-care personnel, which should include
more interactive learning opportunities to compensate for the learning obstacles caused by
aging. Although the HPSP intervention had no significant effect on hypoglycemic episodes,
the frequency of hypoglycemia in the experimental group showed a decreasing trend at
T3 compared to T2. This is a limit of our study, related to the different collection times
between the T0 and the T3 stages, and the study design should be improved in the future. Patients with diabetes face diverse challenges that are affected by several personal
and environmental factors. Scholars have suggested that patients should learn to adjust
their lifestyles according to their particular situations. Moreover, problem-solving is a
critical element in self-management [27], and its effect on healthcare behaviors should not
be neglected. This study verified that a problem-solving intervention could significantly
improve the hypoglycemia care of patients with diabetes. Limitations and Suggestions Several limitations of our study should be considered. First, many relevant factors
were not included in the analysis, such as the evolution of the pharmacological ther-
apy, body mass index, physical exercise, meal times, consumption of snacks, and stress,
which may result in residual confounding. Second, time limitation affects the observation
effect. The intervention period of this study was six months. To understand whether
the participants could show the behavioral effect in the long term, it is suggested that a
longer intervention period should be observed in the future. Third, the management of
hypoglycemia is a core learning component of sick day management, and future research
suggests that it be included in the guidelines. 5. Conclusions Conflicts of Interest: The authors have no conflict of interest or competing interest to declare. J
g
J
y
13.
Schumann, K.P.; Sutherland, J.A.; Majid, H.M.; Hill-Briggs, F. Evidence—Based Behavioral Treatments for Diabetes: Problem-
Solving Therapy. Diabetes Spectr. 2011, 24, 64–69. [CrossRef] 5. Conclusions The current HPSP intervention effectively improved the problem-solving abilities
of the experimental group with hypoglycemia as measured by HbA1c level and HPSS
scores. Although conventional health education did not have a significant effect on the
HbA1c level of the control group, it had a small significant effect on problem-solving ability
for hypoglycemia at 6 months after the intervention compared to problem-solving ability Int. J. Environ. Res. Public Health 2021, 18, 9559 9 of 10 9 of 10 before the intervention. Problem-solving ability training involves the accumulation of
experiences and learning and emphasizes the importance of interactions between healthcare
providers and patients. For effective hypoglycemia-related problem-solving, patients must
apply their knowledge, analyze the causes of hypoglycemia, and attempt to develop their
own solution strategies, so to maintain an ideal blood sugar level and reduce the frequency
of hypoglycemia. The current results may serve as a reference for future hypoglycemia
care plans. Author Contributions: F.-L.W. and J.-H.J. conceived, designed the study and wrote the manuscript;
F.-L.W., C.-H.L. and J.-H.J. collected data; F.-L.W. and C.-L.L. performed analyses of the data. All
authors have read and agreed to the published version of the manuscript. Funding: This research was supported by Grant NSC 104-2314-B-255-002 -MY3 from the Ministry of
Science and Technology, Taiwan. Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Chang Gung Medical Foundation Institutional Review
Board (IRB No1040147B). Informed Consent Statement: Informed consent has been obtained from all participants involved in
the study and to publish this paper. Informed Consent Statement: Informed consent has been obtained from all participants involved in
the study and to publish this paper. Data Availability Statement: Data are from 71 participants of the metabolic outpatient clinics of two
major medical centers and regional hospitals. Due to legal restrictions imposed by the government of
Taiwan in relation to the “Personal Information Protection Act”, data cannot be made publicly shared. Acknowledgments: We acknowledge the support of experts in metabolism, nutrition, and healthcare
for their advice and assistance. We also thank the patients with diabetes who contributed to and
participated in this study. Acknowledgments: We acknowledge the support of experts in metabolism, nutrition, and healthcare
for their advice and assistance. We also thank the patients with diabetes who contributed to and
participated in this study. References 1. World Health Organization. Global Report on Diabetes. 2016. Available online: https://www.who.int/diabetes/global-report/
en/ (accessed on 21 March 2021). 2. Hsu, C.C.; Tu, S.T.; Sheu, W.H.H. 2019 Diabetes Atlas: Achievements and challenges in diabetes care in Taiwan. J. Formos. Med. Assoc. 2019, 118, S130–S134. [CrossRef] 3. Battelino, T.; Danne, T.; Bergenstal, R.M.; Amiel, S.A.; Beck, R.; Biester, T.; Bosi, E.; Buckingham, B.A.; Cefalu, W.T.; Close, K.L.;
et al. Clinical targets for continuous glucose monitoring data interpretation: Recommendations from the international consensus
on time in range. Diabetes Care 2019, 42, 1593–1603. [CrossRef] g
[
]
4. Reach, G.; Pechtner, V.; Gentilella, R.; Corcos, A.; Ceriello, A. Clinical inertia and its impact on treatment intensification in people
with type 2 diabetes mellitus. Diabetes Metab. 2017, 43, 501–511. [CrossRef] 5. Chu, C.H.; Hsu, C.C.; Lin, S.Y.; Chuang, L.M.; Liu, J.S.; Tu, S.T. Trends in antidiabetic medical treatment from 2005 to 2014 in
Taiwan. J. Formos. Med. Assoc. 2019, 118, S74–S82. [CrossRef] 6. Khunti, K.; Alsifri, S.; Aronson, R.; Berkovi´c, M.C.; Enters-Weijnen, C.; Forsén, T.; Galstyan, G.; Geelhoed-Duijvestijn, P.;
Goldfracht, M.C.; Gydesen, H.; et al. Impact of hypoglycaemia on patient-reported outcomes from a global, 24-country study of
27,585 people with type 1 and insulin-treated type 2 diabetes. Diabetes Res. Clin. Pract. 2017, 130, 121–129. [CrossRef] p
p
yp
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7. Wu, F.L.; Juang, J.H.; Yeh-Chang, M. The dilemma of diabetic patients living with hypoglycaemia. J. Clin. Nurs. 2011, 20,
2277–2285. [CrossRef] [PubMed] 8. McNay, E.C.; Cotero, V.E. Mini-review: Impact of recurrent hypoglycemia on cognitive and brain function. Physiol. Behav. 2010,
100, 234–238. [CrossRef] [PubMed] ron, F.J.; Northam, E.A.; Ryan, C.M. The effect of type 1 diabetes on the developing brain. Lancet Child. A
3, 427–436. 10. Yun, J.S.; Ko, S.H. Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes. Korean J. Intern. Med. 2015, 30,
6–16. [CrossRef] 11. Lo, F.S. Frequency, causes, risk factors and management of hypoglycemia in Type 1 diabetes. Formos. J. Med. 2020, 24, 280–288. 12. D’Zurilla, T.J.; Goldfried, M.R. Problem solving and behavior modification. J. Abnorm. Psychol. 1971, 78, 107–126. [CrossRef] 11. Lo, F.S. Frequency, causes, risk factors and management of hypoglycemia in Type 1 diabetes. Formos. J. Med. 2020, 24, 280–288. Lo, F.S. Frequency, causes, risk factors and managem J
g
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13. Schumann, K.P.; Sutherland, J.A.; Majid, H.M.; Hill-Briggs, F. Evidence—Based Behavioral Treatments for Diabetes: Problem-
Solving Therapy. Diabetes Spectr. 2011, 24, 64–69. [CrossRef] 13. 11.
Lo, F.S. Frequency, causes, risk factors and management of hypoglycemia in Type 1 diabetes. Formos. J. Med. 2020, 24, 280–288.
12.
D’Zurilla, T.J.; Goldfried, M.R. Problem solving and behavior modification. J. Abnorm. Psychol. 1971, 78, 107–126. [CrossRef] References Schumann, K.P.; Sutherland, J.A.; Majid, H.M.; Hill-Briggs, F. Evidence—Based Behavioral Treatments for Diabetes: Problem-
Solving Therapy. Diabetes Spectr. 2011, 24, 64–69. [CrossRef] 10 of 10 10 of 10 Int. J. Environ. Res. Public Health 2021, 18, 9559 14. Nieuwsma, J.A.; Wray, L.O.; Voils, C.I.; Gierisch, J.M.; Dundong, M.; Edelman, D. A problem-solving intervention for cardio-
vascular disease risk reduction in veterans: Protocol for a randomized controlled trial. Contemp. Clin. Trials 2017, 60, 42–50. [CrossRef] 15. Wu, F.L.; Wu, E.C.; Chang, Y.C.; Hu, W.Y.; Juang, J.H.; Yeh-Chang, M. Factors Affecting the Ability of
Avoid Hypoglycemia. J. Nurs. Res. 2018, 26, 44–51. [CrossRef] o
ypog yce
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[C oss e ]
16. Fitzpatrick, S.L.; Schumann, K.P.; Hill-Briggs, F. Problem solving interventions for diabetes self-management and control: A
systematic review of the literature. Diabetes Res. Clin. Pract. 2013, 100, 145–161. [CrossRef] [PubMed] yp g y
16. Fitzpatrick, S.L.; Schumann, K.P.; Hill-Briggs, F. Problem solving interventions for diabetes self-man
systematic review of the literature. Diabetes Res. Clin. Pract. 2013, 100, 145–161. [CrossRef] [PubMed] 17. D’Zurilla, T.J.; Maydeu-Olivares, A.; Kant, G.L. Age and gender differences in social problem-solving ability. Pers. Individ. Differ. 1998, 25, 241–252. [CrossRef] 18. Rees, G.; O’Hare, F.; Saeed, M.; Sudholz, B.; Sturrock, B.A.; Lamoureux, E.L. Problem-solving therapy for adults with diabetic
retinopathy and diabetes specific distress: A pilot randomized controlled trial. BMJ Open Diabetes Res. Care 2017, 5, e000307. [CrossRef] [PubMed] 19. Shin, N.; Hill-Briggs, F.; Langan, S.; Payne, J.; Lyketsos, C.; Hill, G.S. The association of minor and major depression with health
problem-solving and diabetes self-care activities in a clinic-based population of adults with type 2 diabetes mellitus. J. Diabetes
Complicat. 2017, 31, 880–885. [CrossRef] p
20. Wu, F.L.; Juang, J.H.; Lin, C.H. Development and validation of the hypoglycaemia problem-solving scale
mellitus. J. Int. Med. Res. 2016, 44, 592–604. [CrossRef] 21. American Diabetes Association. Facilitating behavior change and well-being to improve health outcomes: Standards of medical
care in diabetes 2020. Diabetes Care 2020, 43, S48–S65. [CrossRef] 22. Hill-Briggs, F.; Lazo, M.; Peyrot, M.; Doswell, A.; Chang, Y.T.; Hill, M.N.; Levine, D.; Wang, N.-Y.; Brancati, F.L. Effect of
problem-solving-based diabetes self-management training on diabetes control in a low income patient sample. J. Gen. Intern. Med. 2011, 26, 972–978. [CrossRef] 23. Huang, M.C.; Hung, C.H.; Yu, C.Y.; Diane, C.B.; Shin, S.J.; Hsu, Y.Y. The effectiveness of multimedia education for patients with
type 2 diabetes mellitus. J. Adv. Nurs. References 2017, 73, 943–954. [CrossRef] yp
24. American Diabetes Association. 4 Comprehensive medical evaluation and assessment of comorbidities: Standards of medical
care in diabetes-2019. Diabetes Care 2019, 42, S34–S45. [CrossRef] 25. A˘gce, Z.B.; Ekici, G.E. Person-centred, occupation-based intervention program supported with problem-solving therapy for type
2 diabetes: A randomized controlled trial. Health Qual. Life Outcomes 2020, 18, 265–279. [CrossRef] [PubMed] 25. A˘gce, Z.B.; Ekici, G.E. Person-centred, occupation-based intervention program supported with problem-solving therapy for type
2 diabetes: A randomized controlled trial. Health Qual. Life Outcomes 2020, 18, 265–279. [CrossRef] [PubMed] f
26. Schmitt, A.; Reimer, A.; Hermanns, N.; Huber, J.; Ehrmann, D.; Schall1, S.; Wang, X. Assessing diabetes self management with the
diabetes self management questionnaire (DSMQ) can help analyse behavioural problems related to reduced glycaemic control. PLoS ONE 2016, 11, e0150774. [CrossRef] [PubMed] f
26. Schmitt, A.; Reimer, A.; Hermanns, N.; Huber, J.; Ehrmann, D.; Schall1, S.; Wang, X. Assessing diabetes self management with the
diabetes self management questionnaire (DSMQ) can help analyse behavioural problems related to reduced glycaemic control. PLoS ONE 2016, 11, e0150774. [CrossRef] [PubMed] 27. Powers, M.A.; Bardsley, J.K.; Cypress, M.; Duker, P.; Funnell, M.M.; Uelmen, S. Diabetes self-management education and support
in adults with type 2 diabetes. Diabetes Educ. 2020, 46, 350–369. [CrossRef] [PubMed] 27. Powers, M.A.; Bardsley, J.K.; Cypress, M.; Duker, P.; Funnell, M.M.; Uelmen, S. Diabetes self-management education and support
in adults with type 2 diabetes. Diabetes Educ. 2020, 46, 350–369. [CrossRef] [PubMed]
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Editorial: Frontiers in oral health: Highlights in oral cancers 2021/2
|
Frontiers in oral health
| 2,022
|
cc-by
| 1,808
|
Front. Oral. Health 3:1083035.
doi: 10.3389/froh.2022.1083035 Oral cancer is a multi-step tumour associated with diverse presentations and unpredictable
outcomes. Regardless of advances in technology and research, the prognosis of oral cancer
has not improved over the last decades, which makes this condition a significant health
burden that warrants urgent attention in a multidisciplinary manner (1). COPYRIGHT
© 2022 Kujan and Coletta. This is an open-
access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms. © 2022 Kujan and Coletta. This is an open-
access article distributed under the terms of the
Creative Commons Attribution License (CC BY). This Frontiers Research Topic, Highlights in Oral Cancers 2021/2, aimed to shed light
on the latest evidence-based findings to answer historically debatable questions in this field. The use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms. This Research Topic starts with a review by Philips et al. titled Preoperative
immunotherapy in the multidisciplinary management of oral cavity cancer to provide
insights into current knowledge in the field of oral squamous cell carcinoma (OSCC)
immunotherapy. In this review, several hot topics were comprehensively discussed, like
immune
response,
the
rationale
for
preoperative
immunotherapy,
limitations
of
immunotherapy, and prospects. A table summarising the results of all relevant clinical
trials in the study area was presented to show the latest advances. In conclusion, the
authors proposed generating personalised, tumour-specific algorithms based on multiple
factors like pathology, response to preoperative immunotherapy, and immune profile to
assure optimum oncologic and functional outcomes. To highlight the inflammatory response’s critical role in explaining the defective
anti-tumour immunological responses in some OSCC patients, Laliberté et al. conducted a prospective, case-controlled pilot study to characterise OSCC-associated
inflammation titled Characterisation of oral squamous cell carcinoma associated
inflammation: a pilot study. In this study, inflammatory changes in the saliva of 37
OSCC patients were compared with changes in 32 healthy controls with and without
periodontitis. TYPE Editorial
PUBLISHED 08 December 2022
DOI 10.3389/froh.2022.1083035 EDITED AND REVIEWED BY
Arvind Babu Rajendra Santosh,
University of the West Indies, Jamaica
*CORRESPONDENCE
Omar Kujan
omar.kujan@gmail.com,
omar.kujan@uwa.edu.au
SPECIALTY SECTION
This article was submitted to Oral Cancers, a
section of the journal Frontiers in Oral Health
RECEIVED 28 October 2022
ACCEPTED 15 November 2022
PUBLISHED 08 December 2022
CITATION
Kujan O and Coletta RD (2022) Editorial:
Frontiers in oral health: Highlights in oral
cancers 2021/2. Front. Oral. Health 3:1083035. doi: 10.3389/froh.2022.1083035
COPYRIGHT
© 2022 Kujan and Coletta. This is an open-
access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not EDITED AND REVIEWED BY
Arvind Babu Rajendra Santosh,
University of the West Indies, Jamaica
*CORRESPONDENCE
Omar Kujan
omar.kujan@gmail.com,
omar.kujan@uwa.edu.au
SPECIALTY SECTION
This article was submitted to Oral Cancers, a
section of the journal Frontiers in Oral Health
RECEIVED 28 October 2022
ACCEPTED 15 November 2022
PUBLISHED 08 December 2022
CITATION
Kujan O and Coletta RD (2022) Editorial:
Frontiers in oral health: Highlights in oral
cancers 2021/2. Front Oral Health 3:1083035 EDITED AND REVIEWED BY
Arvind Babu Rajendra Santosh,
University of the West Indies, Jamaica
*CORRESPONDENCE
Omar Kujan
omar.kujan@gmail.com,
omar.kujan@uwa.edu.au
SPECIALTY SECTION
This article was submitted to Oral Cancers, a
section of the journal Frontiers in Oral Health
RECEIVED 28 October 2022
ACCEPTED 15 November 2022
PUBLISHED 08 December 2022
CITATION
Kujan O and Coletta RD (2022) Editorial:
Frontiers in oral health: Highlights in oral
cancers 2021/2. Front Oral Health 3:1083035 Omar Kujan
1* and Ricardo D. Coletta
2 1UWA Dental School, The University of Western Australia, Nedlands, WA, Australia, 2Department of
Oral Diagnosis and Graduate Program in Oral Biology, School of Dentistry of Piracicaba, Campinas
University, Piracicaba-São Paulo, Brazil Editorial on the Research Topic
Frontiers in oral health: Highlights in oral cancers 2021/2 Front. Oral. Health 3:1083035. doi: 10.3389/froh.2022.1083035 KEYWORDS oral cancer, head and neck cancer, special collection, recent advances, editorial Editorial on the Research Topic
Frontiers in oral health: Highlights in oral cancers 2021/2 Front. Oral. Health 3:1083035.
doi: 10.3389/froh.2022.1083035 Multi-channel flow cytometry with a panel of 12 antibodies was
employed to determine the inflammatory cell profile in saliva. Moreover, 30
cytokines/chemokines
were
evaluated
in
the
saliva
samples. Fluorescent
immunohistochemistry was undertaken to validate results using a cohort of cancer
specimens. This
paper
showed
an
increase
in
OSCC-associated
inflammation
characterised by specific cytokines (IL-6, IL-8, TNFa, and GMCSF). These findings
can be used to design clinical tests that may aid in treatment decision-making, like
identifying patients at higher risk of developing disease adverse events and recurrence. Frontiers in Oral Health frontiersin.org 01 Kujan and Coletta 10.3389/froh.2022.1083035 purpose
was
conducted. This
study,
Mesenchymal
gene
expression
subtyping
analysis
for
early-stage
human
papillomavirus-negative head and neck squamous cell carcinoma
reveals prognostic and predictive applications. For training, the
authors performed a retrospective genomic analysis of open-
source databases, including 418 patients. The classifier was then
validated
using
a
different
validation
cohort. This study
demonstrated that mesenchymal subtypes are associated with
poor survival rates even in early-stage, lymph node-negative
oral cancers. This finding was contrary to the favourable
outcomes of the mesenchymal subtype in non-oral cancer
cases. The study highlights the significance of gene expression
for the treatment decision-making of HNSCC. To report the incidence of malignant lymphoid neoplasms in
the
oral
and
maxillofacial
region,
Flores-Hidalgo
et
al. retrospectively reviewed records of patients diagnosed with
lymphoid neoplasms over ten years in two different institutions. This paper is titled Malignant lymphoproliferative disorders of
the oral and maxillofacial region: report of two institutions. Accordingly, a total of 318 records were retrieved and reassessed
according to an updated classification version, of which 138 met
the inclusion criteria. Most hematolymphoid malignancies are
associated
with
intra-bony
locations. Thus,
the
authors
highlighted the significance of microscopic examination of all
tissue samples, even if they present features of persistent
periapical lesions after failed root canal therapy. Further,
a
paper
titled
Preoperative
prediction
of
the
aggressiveness of oral tongue squamous cell carcinoma with
quantitative parameters from dual-energy computed tomography
was conducted by Yang et al. to propose a preoperative non-
surgical tool that helps clinicians and pathologists while diagnosing
tongue OSCC cases. Ninety-three out of 161 were included in this
study based on clearly specified inclusion criteria and underwent
preoperative dual-energy computed tomography (DECT). Specific
DECT
quantitative
parameters
were
compared
to
certain
pathological characteristics of tongue OSCC. Accordingly, the
inter-
and
intra-observer
agreements
in
evaluating
DECT
parameters were excellent. Front. Oral. Health 3:1083035.
doi: 10.3389/froh.2022.1083035 Among several DECT parameters, the
slope of the spectral Hounsfield unit curve in the venous phase was
associated with the highest accuracy (75.3%) in predicting the
overall pathological stage. Likewise, the accuracy of the normalised
iodine concentration in the venous phase in predicting the
histologic differentiation was 75.3%. In conclusion, DECT shows
the potential to be a valuable tool for the preoperative evaluation of
tongue OSCC aggressiveness. Interestingly, several studies assessed the prognosis of patients
with oral carcinoma using a mixed population of young and old
patients, which were associated with wide discrepancies and
heterogeneities, mainly because old patients usually suffered
poor systemic conditions. To reduce potential bias, Baba et al. conducted a study that classified patients into three groups
instead of two. This study is titled Comparison between three
age-stratified cohorts reveals poor prognosis of young patients
with tongue carcinoma. Two hundred fifty-seven eligible OSCC
patients were classified into three groups: young, middle-aged,
and
older. Accordingly,
multivariate
analyses
found
that
compared to young patients, there were no differences in overall
survival and disease-free survival rates for middle-aged or older
patients. However, middle patients were associated with a
significant low local recurrence rate. The authors emphasised the
importance
of
categorising
patients
into
various
groups
according to their age, specifically for patients older than 70
years, while this measure should also be applied to future
genomic research. To answer the controversial question about the concept of
resection margins in OSCC surgery, whether adequate or
inadequate, Pei et al. conducted a molecular study titled Risk
factors
of
microscopically
tumor-free
surgical
margins
for
recurrence and survival of oral squamous cell
carcinoma
patients. A total of 235 OSCC patients who underwent surgery
over ten years were retrospectively reviewed and included in
this study. Two epithelial-to-mesenchymal transition-associated
genes (Axin2 and Snail) were immunohistochemically assessed
using tissue specimens of surgical margins. The results were
validated by developing an in vitro model of a knocked-down
Axin2 cell line and injecting this cell line into mice. The
significant outcomes of this study found that molecular analysis
provides a more accurate and objective assessment of surgical
margins. In opposition to the histopathological assessment of
surgical margins, Axin2 and Snail expressions had independent
impacts on the overall survival and recurrence-free survival
rates of OSCC patients. Front. Oral. Health 3:1083035.
doi: 10.3389/froh.2022.1083035 The seven studies contained in this Research Topic described
many relevant aspects for development, progression and treatment
of oral cancers, especially highlighting possible therapeutic
developments and biomarkers to fight these very aggressive
cancers. Such studies are essential towards the development of
more effective and predictable therapeutic strategies. Author contributions All authors conceived the editorial and drafted and finalised
the manuscript. All authors contributed to the article and
approved the submitted version. Conflict of interest The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. Next, to predict the recurrence of early-stage, HPV-negative
head and neck squamous cell carcinoma (HNSCC), a study by
Mayhew et al. to identify a gene expression classifier for this Frontiers in Oral Health frontiersin.org 02 10.3389/froh.2022.1083035 10.3389/froh.2022.1083035 Kujan and Coletta Publisher’s note affiliated organizations, or those of the publisher, the editors
and the reviewers. Any product that may be evaluated in this
article, or claim that may be made by its manufacturer, is not
guaranteed or endorsed by the publisher. All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their Reference 1. Farah CS, Kujan O, Prime S, Zain R. “Oral mucosal malignancies”. In: Farah
C, Balasubramaniam R, McCullough M, editors. Contemporary Oral Medicine. Cham: Springer (2018). p. 1–188. doi: 10.1007/978-3-319-28100-1_21-1 03 Frontiers in Oral Health frontiersin.org 03
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Iranian Patients’ Experiences of the Internal Cardioverter Defibrillator Device Shocks: a Qualitative Study
|
Journal of caring sciences
| 2,015
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cc-by
| 6,391
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Journal of Caring Sciences, 2015, 4(4), 277-286
doi:10.15171/jcs.2015.028
http:// journals.tbzmed.ac.ir/ JCS Journal of Caring Sciences, 2015, 4(4), 277-286 ABSTRACT Data analysis was also performed simultaneously using
constant comparative analysis. p
y
Results: In this study, two main themes, namely “with a parachute for life” and “Faced
with nuisance”, were obtained representing the patients’ experiences regarding ICD
shock. With a parachute for life included subthemes, such as “Rebirth”, “Comforter
and healing”, and “Life assurance”. In addition, “Faced with nuisance” consisted of 2
subthemes of “Discomfort in moments of shock” and “Displeasure after shock”. Conclusion: This study provided a basis for evaluation of patients nursing after
discharge. By identification of the patients’ experiences regarding shock, the present
study can help the professional health staff to efficiently play their roles and provide
patients with holistic care. It can also be effective in designing behavioral and
cognitive interventional programs to change the patients’ attitude and promote their
adaptation with their conditions. p
y
Results: In this study, two main themes, namely “with a parachute for life” and “Faced
with nuisance”, were obtained representing the patients’ experiences regarding ICD
shock. With a parachute for life included subthemes, such as “Rebirth”, “Comforter
and healing”, and “Life assurance”. In addition, “Faced with nuisance” consisted of 2
subthemes of “Discomfort in moments of shock” and “Displeasure after shock”. Conclusion: This study provided a basis for evaluation of patients nursing after
discharge. By identification of the patients’ experiences regarding shock, the present
study can help the professional health staff to efficiently play their roles and provide
patients with holistic care. It can also be effective in designing behavioral and
cognitive interventional programs to change the patients’ attitude and promote their
adaptation with their conditions. Please cite this paper as: Pasyar N, Sharif F, Rakhshan M, Nikoo MH, Navab E. Iranian patients’ experiences of
defibrillator device shocks: a qualitative study. J Caring Sci 2015; 4 (4): 277-86. doi:10.15171/jcs.2015.028. deaths.2
Implantable
Cardioverter-
Defibrillator (ICD) is one of the rhythm
management devices utilized for prevention
of death in the patients survived after
cardiac arrest or life-threatening ventricular
arrhythmias.3 Implantation of ICD has
shown considerable improvements through ABSTRACT ARTICLE INFO
ABSTRACT
Article Type:
Original Article
Introduction: Implantable Cardioverter Defibrillator (ICD) is a valuable treatment for
the patients at risk of sudden cardiac death. In this method, after diagnosis of
pathological cardiac rhythms, shock is automatically applied to normalize the rhythms. Shock is discharged when the patients are conscious, but the patients’ experiences of
shock have remained unknown. Thus, this study aimed to identify and describe the
patients’ experiences of shocks received from ICD. Methods: The present qualitative study was conducted through thematic analysis and
semi-structured interviews on 9 patients mean age 41.55 (1.57) with ICD from
November 2013 to July 2014. Data analysis was also performed simultaneously using
constant comparative analysis. Results: In this study, two main themes, namely “with a parachute for life” and “Faced
with nuisance”, were obtained representing the patients’ experiences regarding ICD
shock. With a parachute for life included subthemes, such as “Rebirth”, “Comforter
and healing”, and “Life assurance”. In addition, “Faced with nuisance” consisted of 2
subthemes of “Discomfort in moments of shock” and “Displeasure after shock”. Conclusion: This study provided a basis for evaluation of patients nursing after
discharge. By identification of the patients’ experiences regarding shock, the present
study can help the professional health staff to efficiently play their roles and provide
patients with holistic care. It can also be effective in designing behavioral and
cognitive interventional programs to change the patients’ attitude and promote their
adaptation with their conditions. Article History:
Received: 17 Feb. 2015
Accepted: 25 Jun. 2015
ePublished: 1 Dec. 2015
Keywords:
Defibrillators, Implantable
Arrhythmias
Cardiac
Qualitative research
Please cite this paper as: Pasyar N, Sharif F, Rakhshan M, Nikoo MH, Navab E. Iranian patients’ experiences of the internal cardioverter
defibrillator device shocks: a qualitative study. J Caring Sci 2015; 4 (4): 277-86. doi:10.15171/jcs.2015.028. Introduction: Implantable Cardioverter Defibrillator (ICD) is a valuable treatment for
the patients at risk of sudden cardiac death. In this method, after diagnosis of
pathological cardiac rhythms, shock is automatically applied to normalize the rhythms. Shock is discharged when the patients are conscious, but the patients’ experiences of
shock have remained unknown. Thus, this study aimed to identify and describe the
patients’ experiences of shocks received from ICD. p
p
Methods: The present qualitative study was conducted through thematic analysis and
semi-structured interviews on 9 patients mean age 41.55 (1.57) with ICD from
November 2013 to July 2014. Nilofar Pasyar1, Farkhondeh Sharif2*, Mahnaz Rakhshan3, Mohammad Hussein Nikoo4, Elham
Navab5 1Department of Medical Surgical Nursing, Student Research Committee, School of Nursing and Midwifery , Shiraz University of
Medical Sciences, Shiraz, Iran 2Department of Psychiatric Nursing, Community Based Psychiatric Care Research Center, School of Nursing
Shiraz University of Medical Sciences, Shiraz, Iran Psychiatric Nursing, Community Based Psychiatric Care Research Center, School of Nursing and Midwifery,
of Medical Sciences, Shiraz, Iran y f
3Department of Medical Surgical Nursing, School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran
4Department of Cardiology, Cardiovascular Research Center, School of Medicine , Shiraz University of Medical Sciences, Shiraz,
Iran 3Department of Medical Surgical Nursing, School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran
4Department of Cardiology, Cardiovascular Research Center, School of Medicine , Shiraz University of Medical Sciences, Shiraz,
Iran 5Department of Critical Care Nursing and Management, School of Nursing and Midwifery, Tehran University of Medical
Sciences, Tehran, Iran 5Department of Critical Care Nursing and Management, School of Nursing and Midwifery, Tehran University of Medical
Sciences, Tehran, Iran 5Department of Critical Care Nursing and Management, School of Nursing and Midwifery, Tehran University of Medical
Sciences, Tehran, Iran © 2015 The Author(s). This work is published by Journal of Caring Sciences as an open access article distributed
under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/). Non-commercial
uses of the work are permitted, provided the original work is properly cited. *Corresponding Author: Farkhondeh Sharif (PhD), email: fsharif@sums.ac.ir. This project was approved and funded by the shiraz
University of Medical Sciences (Project number: 92-6757). Please cite this paper as: Pasyar N, Sharif F, Rakhshan M, Nikoo MH, Navab E. Iranian patients’ experiences of the internal cardioverter
defibrillator device shocks: a qualitative study. J Caring Sci 2015; 4 (4): 277-86. doi:10.15171/jcs.2015.028. the recent years.4 According to some studies, pacemaker
implantation is the first phase of lifetime
treatment
in
these
patients,5
because
insertion of a device into the heart is
accompanied by some alterations which
involve all but some unique characteristics
of the patients.6 Overall, we felt the need to raise
awareness about shock experiences of
patients with ICD. Despite some consistent
studies in other countries, multiple and
subjective
interpretations
of
reality
necessitate performance of this research. Thus, considering the effect of cultural and
religious contexts, the present qualitative
study was conducted on Iranian patients
with ICD in order to identify and describe
their experiences of the shocks they
received from the device. p
Determining the potentially dangerous
cardiac rhythms and discharging shock,
ICD
normalizes
cardiac
rhythm.7
Nevertheless, this treatment causes some
psychological distresses in this patients and
non-adaptation with ICD can affect the
patients’ quality of life.8 According to
research, almost half of the patients
experience shock within the first year after
implantation. Therefore,
these
patients
restrict
their
physical
daily
activities,
become depressed, and do not believe in
their adaptability.9 Determining the potentially dangerous
cardiac rhythms and discharging shock,
ICD
normalizes
cardiac
rhythm.7 Introduction deaths.2
Implantable
Cardioverter-
Defibrillator (ICD) is one of the rhythm
management devices utilized for prevention
of death in the patients survived after
cardiac arrest or life-threatening ventricular
arrhythmias.3 Implantation of ICD has
shown considerable improvements through Cardiovascular diseases are among the
major reasons of mortality and morbidity
worldwide.1 In spite of advances in
diagnosis and treatment, sudden cardiac
death is still considered as a global problem,
accounting for more than half of all cardiac Pasyar et al. included in designing healthcare services. This
can
increase
nurses’
ability
to
understand and interpret patients’ views,
improve the quality of patient care, create
positive outcomes, and enhance patients’
satisfaction. 278 | Journal of Caring Sciences, December 2015; 4 (4), 277-286 Materials and methods Considering the research question, this
qualitative study was conducted through
thematic analysis. Thematic analysis is
similar to content analysis, but requires
more attention to the qualitative aspects.33
This
method
is
appropriate
for
identification, analysis, and reporting of the
themes and reveals different dimensions of
the issues accurately.34 To date, the major part of our knowledge
is related to the technical function of the
device and the patients’ biophysical life. Yet, the negative psychosocial effects of
shock on the patients turn shock-related
experiences into a valuable source for
research.10 Up to now, only a limited
number of studies have been conducted on
the patients’ experiences of encounter with
ICD
shock
and
its
effects
on
their
adaptability,11 while more information is
required in this regard. Most previous
studies have investigated experiences of
living with ICD9,12-20 in female recipients,21
male recipients,22 old men,7,23 spouses of
patients with ICD,24,25 and these patients’
families.26 However, only few studies have
specifically focused on shock,27,28 mental
adaptability with shock,29 patients’ attitude
towards shock,30 and patients’ and their
families’ experiences regarding shock.31,32 The participants were selected through
purposive sampling based on a variety of
different characteristics, such as maximum
age range, gender differences, and different
cultural, economic, and social conditions. Considering patients’ follow-up at the clinic
for ICD analysis, the participants were
selected among the patients referred to the
cardiology clinics of two hospitals affiliated
to Shiraz University of Medical Sciences. The inclusion criteria of the study were
having lived with ICD for a year or more,
experience of shock from ICD, age above 18
years, understanding and speaking Persian,
being able to remember and express one’s
experiences related to the study objectives,
ability to take part in interviews for at least
20 minutes, being aware of time, place, and
person, and not suffering from cognitive Besides, most of these studies have been
carried out in other countries and no
reliable documents were found concerning
the experiences of patients with ICD in Iran. Knowing
the
lived
experiences
of
patients is important and should be 278 | Journal of Caring Sciences, December 2015; 4 (4), 277-286 Iranian patients’ experiences about ICD shocks disorders. After all, 9 patients with ICD
(7males and 2 females) were recruited into
the study. description of the concept of shock was
presented by considering all the categories’
meanings. Materials and methods g
In order to accelerate organization and
coding in this study, MAXQDA software
(version 2010) was used to seek for similar
themes and combine the categories. In
addition, various approaches were used to
ensure the trustworthiness of the data. The
researcher’s prolonged engagement and
insistent observation as well as considering
sufficient time for data collection and
patients’ follow-up at the clinic and at home
determined the credibility of the data. Also,
member checking was done by some
patients to compare the findings to their
expectations. This helped the researchers
better understand the study setting. It
should be noted that three relevant experts
directed data analysis and analytical field
note was used to accurately determine the
patients’ experiences of ICD shock. After selection of the participants based
on
the
inclusion
criteria,
the
study
objectives
were
explained
for
all
participants, and written informed consents
were
obtained. All
interviews
were
performed in a private room in the
cardiology clinics when the participants
were comfortable. Interview,
as
one
of
the
most
fundamental, certain, and flexible data
collection methods,35 allows entrance to
individuals’ lives and is consequently an
excellent source of data collection in
qualitative studies.36 In this study, the data
were gathered through semi-structured
interviews each lasting for 30-90 minutes
from November 2013 to July 2014. The
interviews were
started
by
an
open
question about the patients’ experiences of
shock while living with ICD, and the
patients could take a rest in case they got
tired during the interviews. Data collection
was continued until data saturation. Then,
the interviews were read word by word and
data
analysis
was
performed
simultaneously. In doing so, first the
participants’ descriptions were reviewed,
primary coding was performed, and themes
were determined. Afterwards, the codes
with specific meanings were located in the
same category with respect to context and
these subthemes were then placed in the
main categories based on content similarity. After that, the main themes were reviewed
again and appropriate abstract terms were
selected. All
the
research
processes
were
performed according to Declaration of
Helsinki. Besides, the study was approved
by
the
Ethics
Committee
of
Shiraz
University of Medical Sciences. When a
study is conducted on human subjects, their
rights should be taken into account. Therefore, the study participants were
provided with the necessary information
about the study objectives and procedures
and written informed consents for taking
part in the study were obtained from them. Materials and methods In
this
way,
the
participants
were
ascertained that they could withdraw from
the study at anytime. They were also
assured about the confidentiality of their
information and explained about voice
recording and how the recordings were
going to be used. Thus, the archives of
recordings,
notes,
and
participants’
information were kept completely secret. Data collection was stopped after nine
interviews and reaching the point of data
saturation when no new themes could be
found in the participants' statements. It
should be noted that the two final
interviews were performed so as to make
sure about data saturation. At the end, final
descriptions were selected based on the
research objectives and a comprehensive Results In the present study, 9 patients with the
mean age of 41.55 (1.57) years (range: 24-72
years) were selected through purposive Journal of Caring Sciences, December 2015; 4 (4), 277-286 |279 Pasyar et al. sampling based on the inclusion criteria of
the study. The participants’ characteristics
have been presented in Table 1. 1.2. Comforter and healing 1.2. Comforter and healing Concepts, such as convenience, healing,
relief of disease symptoms, and peace were
involved in emergence of this theme. Some
of
the
participants
referred
to
the
comforting and healing nature of the device
as follows: “After the device’s shock, my
heart was quiet. I mean I didn’t have
palpitation. My heart rate was regulated. Now
I’m
comfortable…somewhat
comfortable” (a 29-year-old man). A 47-
year-old man also mentioned: “A few
minutes later, you’re fit again; you’re on
your way and your heart rate will be
regular”. With regard to healing and peace,
a 45-year-old man stated: “Living with
shock
is
like
living
with
a
health
contributor. After the shock, the situation is
calming and healing…at least physically”. Concepts, such as convenience, healing,
relief of disease symptoms, and peace were
involved in emergence of this theme. Some
of
the
participants
referred
to
the
comforting and healing nature of the device
as follows: “After the device’s shock, my
heart was quiet. I mean I didn’t have
palpitation. My heart rate was regulated. Now
I’m
comfortable…somewhat
comfortable” (a 29-year-old man). A 47-
year-old man also mentioned: “A few
minutes later, you’re fit again; you’re on
your way and your heart rate will be
regular”. With regard to healing and peace,
a 45-year-old man stated: “Living with
shock
is
like
living
with
a
health
contributor. After the shock, the situation is
calming and healing…at least physically”. Investigating
the
participants’
descriptions in the interviews, 184 primary
codes were extracted according the research
objective. After review and summarization,
the codes were categorized based on their
similarity. Then, by further reviewing,
analyzing, and comparing the categories,
conceptual names were selected for their
meanings. Finally two main themes were
revealed as follows: “with a parachute for
life” and “Faced with nuisance”. These
themes were about the study objectives; i.e.,
identification
and
description
of
the
experiences of shock in the patients with
ICD. Now
I’m
comfortable…somewhat
comfortable” (a 29-year-old man). A 47-
year-old man also mentioned: “A few
minutes later, you’re fit again; you’re on
your way and your heart rate will be
regular”. With regard to healing and peace,
a 45-year-old man stated: “Living with
shock
is
like
living
with
a
health
contributor. After the shock, the situation is
calming and healing…at least physically”. 1. With a parachute for life Despite the discomforts of shock for the
patients, it was considered as a guarantee
for life, revealing the first theme; i.e., “with
a parachute for life”. Parachute for life
highlights the life-saving nature of the
device. “Rebirth”, “Comforter and healing”,
and “Life assurance” were the main axes of
this theme. 1.3. Life assurance In the patients’ descriptions of shock, life
assurance
was
of
great
importance. Accordingly, the device played the role of a
supporter for the patients. After ICD
implantation and shock delivery, the
patients experienced assuredness: “ICD is
like my second heart and shock is a body
protector. Well, I’m glad I had the device
implanted and I saved myself from worry
about cardiac arrest” (a 56-year-old man). One other patient also said: “I’m feeling
peace of mind that the device is implanted. I’m reassured, I have hope” (a 26-year-old
man). A 47-year-old man also stated:
“Finally, ICD has benefits…think…if you
fall somewhere, it gives you shock and you
can stand up again. I feel being supported”. Besides, a 56-year-old man explained:
“After receiving shock, I thought to
myself…don’t worry… you don’t have any
problems…if a problem arises, you won’t
need a doctor”. 2.2. Displeasure after shock By creating excitation in the patients, shock
led to dissatisfaction, inability to tolerate
shock, fear from shock, relating physical
problems to shock, anxiety after shock, and
worry about discharge of shock which
resulted from confusion, novelty of the
experience, permanent probability of shock
at any time and place, discharge of shock at
consciousness, and previous experience of
shock. The study participants stated that the
effects of shock were highly undesirable:
“It’s terrible; I’d rather die but not
experience shock again”. Fear from shock
was also experienced by most of the
patients and was expressed by “I was really
scared”, “I’ve become timid since then”,
and “I’m afraid of it”. In addition, some
patients indicated that confusion was
effective in their fear. For instance, a 49-year
old woman said: “Confusion adds to the
effect of anything. It was difficult that I was
confused”. On
the other
hand,
they
experienced
force
to
accept
shock,
preoccupation, mental evasion, irritation,
acceptance of the nature of shock, seeking a
way to remove shock from the device’s
program, and regret from implantation of
ICD. In this regard, a 72-year-old man said:
“I always have shock in mind, I never forget
it. I may forget eating, but I don’t forget the
shock. I always remember it”. Considering
acceptance of the nature of shock, a 45-year-
old-man stated with sadness: “Well, this is
what the device is good for, it is a part of it,
it discharges shock whenever needed”. However, some patients were desperately
seeking for a way to stop the shock. A 72-
year-old man mentioned: “I don’t know Shock was accompanied by a spiritual
experience in some patients. A 52-year-old
man said with worry: “At the moment of
shock, one recourses to God and holy
prophets until that moment is gone. One
still has the same feeling afterwards”. g
At the time of discharge, the patients
experienced physical problems, such as
pain, burning, being thrown, and reduction
of physical power, and then needed to
follow battery analysis. In spite of believing
in the life-saving role of shock, most
patients
considered
it
a
bitter
and
disappointing experience in life. A 45-year-
old man said: “When the device discharges
shock, it is a very bitter and disappointing
experience, a bitter experience”. Some
participants
stated
that
shock
was
accompanied by a pressure or strike on the
chest. 1.1. Rebirth According to some participants’ view
points, shock played the role of a survivor. These patients mainly focused on continue
living with the assistance of shock. A 52-
year-old
man
mentioned:
“See,
that
moment is a bad moment, but it is between
life and death. It means that if that moment
is not there, death will certainly happen,
cardiac arrest. Between life and death, all
choose life normally”. One of the participants pointed to rebirth
as follows: “I call it second life” (a 30-year-
old man). A 29-year-old man also said:
“When I experienced cardiac arrest and the
device gave me a shock, my life started
again”. Besides, a 56-year old woman with
grief stated: “Shock was a man of hope. If it
wasn’t there, I might have been dead. But I
gained a new life”. 2. Faced with nuisance 2. Faced with nuisance The other dimension of the patients’
experiences of shock was “faced with
nuisance”. Nuisance was experienced as a
whole and more detailed statements were 280 | Journal of Caring Sciences, December 2015; 4 (4), 277-286 Iranian patients’ experiences about ICD shocks expressed by the patients, which will be
discussed more extensively in this section. According to the study findings, nuisance
involved “discomfort in moments of shock”
and “displeasure after shock”. shock or I experienced an electric shock” (a
26-year-old man). Moreover, shock was
sometimes considered to be equal to death. In this regard, a 24-year-old woman said:
“Shock produces a sound inside you and
you think you are leaving here. You feel
you are leaving here and that’s too bad. Shock is a part of death”. 2.1. Discomfort in moments of shock 2.1. Discomfort in moments of shock In some patients, unpleasant alarming signs
of shock were expressed as an aura or a
relative awareness of the probability of
shock before shock discharge: “Shock is a
bad feeling. It is like you know something
bad is going to happen and you are aware
of it. One knows it is going to discharge
shock. It gives one a bad feeling” (a 52-year-
old man). In this regard, the patients stated
that they had a relative awareness of the
probability of shock before its discharge,
which was accompanied by apprehension
as well as physical signs, such as flushing
and dizziness. 2.2. Displeasure after shock 2.2. Displeasure after shock Discussion In line with the present study results,
some authors stated that shock resulted in
fear and anxiety and mentioned the effects
of shock as one of the themes of their
study.26 Some researchers also mentioned
fear from shock as one of the general
themes in ICD receptors.39 Moreover,
physical signs, such as dizziness, general
weakness, nausea, vomiting, palpitation,
chest pain, and chest soreness,31 and
psychological signs, such as fear, anxiety, Table 1. The characteristics of the participants Table 1. The characteristics of the participants
ID code
Age
Sex
Marital status
Education level
Employment status
1
72
Male
Married
Illiterate
Quit due to disability
2
24
Female
Single
Academic
Employee
3
45
Male
Married
Academic
Employee
4
52
Male
Married
Academic
Retired
5
30
Male
Married
High school
Quit due to disability
6
26
Male
Married
Primary school
Quit due to disability
7
49
Female
Married
High school
Housekeeper
8
29
Male
Married
High school
Quit due to disability
9
47
Male
Married
High school
Employee
secure 37
Also
the
patients
mentioned secure.37 Also, the patients mentioned
horrible feelings about shock along with
their appreciation of the device as their
survivor.38 expressed as a double-edged sword. In
spite of perceiving the worst conditions
after shock, from electric shock and
explosion in the chest to death, the patients
admitted the life-saving role of shock. They
had found out this role by experiencing
shock discharge. Shock with its special surviving function
has great effects on the patients’ lives. Recourse to God and holy prophets at the
moment of shock discharge represents the
spiritual effects of shock on the patients. Nonetheless, most studies have mainly
focused on the physical, mental, and
psychological effects of shock on the
patients. Shock was an unpleasant experience for
most of the patients and the alarming signs
of shock or aura are one of the special
findings of this study. 2.2. Displeasure after shock A 47-year-old man mentioned: “At
the moment of shock, you have just fallen
on the ground and something like a bomb is
exploding in your chest”. Also, some other participants considered
shock to be similar to electric shock and
stated that “It is like you have caught an
electric wire”, “Shock is itself an electric
flow”, and “I didn’t get whether it was Journal of Caring Sciences, December 2015; 4 (4), 277-286 |281 Pasyar et al. what to do. Please kindly do something that
it doesn’t give shock. I’m innocent”. Furthermore, some patients regretted ICD
implantation and expressed that “I don’t
want it anymore, I regret” (a 47-year-old
man). observed among the patients. For example,
a 72-year-old man said: “I don’t dare to go
anywhere. I’m afraid of shock. I’m very
scared. I don’t dare to go anywhere alone. Even when I want to go farming, I take one
of my children with me”. Shock led to some aggressive behaviors,
including
fighting
with
children
and
unwilling
to
watch
other
patients
experiencing shock. Shock also had various
effects on the patients’ social conditions. For
instance, restriction in daily activities and
dependence on others after shock were Discussion According to the findings of the present
study, shock has an important role in all
aspects of life of the patients with ICD. Table 1. The characteristics of the participants
ID code
Age
Sex
Marital status
Education level
Employment status
1
72
Male
Married
Illiterate
Quit due to disability
2
24
Female
Single
Academic
Employee
3
45
Male
Married
Academic
Employee
4
52
Male
Married
Academic
Retired
5
30
Male
Married
High school
Quit due to disability
6
26
Male
Married
Primary school
Quit due to disability
7
49
Female
Married
High school
Housekeeper
8
29
Male
Married
High school
Quit due to disability
9
47
Male
Married
High school
Employee
expressed as a double-edged sword. In
spite of perceiving the worst conditions
after shock, from electric shock and
explosion in the chest to death, the patients
admitted the life-saving role of shock. They
had found out this role by experiencing
shock discharge. Shock was an unpleasant experience for
most of the patients and the alarming signs
of shock or aura are one of the special
findings of this study. Some authors
reported the patients’ general experiences of
shock as "a blow to the body" or "a spasm
causing the entire body to jump".30 The
patients considered shock as a highly
frightening,
life-altering,
painful,
and
stressful experience and described it as an
explosion in the chest, explosion of mind,
and an impact of death.17Nevertheless, the
patients tolerated the shock because of its
life-saving role.30 In fact, although shock
reminded the patients of death, they
considered ICD as their survivor and felt
secure.37 Also, the patients mentioned
horrible feelings about shock along with
their appreciation of the device as their
survivor.38
Shock with its special surviving function
has great effects on the patients’ lives. Recourse to God and holy prophets at the
moment of shock discharge represents the
spiritual effects of shock on the patients. Nonetheless, most studies have mainly
focused on the physical, mental, and
psychological effects of shock on the
patients. Discussion Some authors
reported the patients’ general experiences of
shock as "a blow to the body" or "a spasm
causing the entire body to jump".30 The
patients considered shock as a highly
frightening,
life-altering,
painful,
and
stressful experience and described it as an
explosion in the chest, explosion of mind,
and an impact of death.17Nevertheless, the
patients tolerated the shock because of its
life-saving role.30 In fact, although shock
reminded the patients of death, they
considered ICD as their survivor and felt In line with the present study results,
some authors stated that shock resulted in
fear and anxiety and mentioned the effects
of shock as one of the themes of their
study.26 Some researchers also mentioned
fear from shock as one of the general
themes in ICD receptors.39 Moreover,
physical signs, such as dizziness, general
weakness, nausea, vomiting, palpitation,
chest pain, and chest soreness,31 and
psychological signs, such as fear, anxiety, 282 | Journal of Caring Sciences, December 2015; 4 (4), 277-286 Iranian patients’ experiences about ICD shocks depression, aggression, anger, and stress
levels, were higher among the patients who
had experienced shock compared to other
patients.37,40 the patients’ experiences of shock and the
effects of shock on various dimensions of
the patients’ lives can help healthcare
professionals to efficiently play their roles
and provide the patients with holistic care. p
Anxiety may result from unfamiliarity
with the experience of shock.9 Consistently,
some researchers believed that anxiety was
associated with shock due to unknown time
and place of shock discharge, experience of
shock, and recovery.14 Fear from shock
discharge is one of the factors affecting the
patients’ restriction of activities.22 Also, in
some previous qualitative studies, the
patients who had experienced shock within
the last year had restricted their daily
activities
due
to
physical
or
mental
problems.11 Similarly, some researchers
reported more limitations in patient’s
leisure activities,24 reduction of physical
activities for prevention of shock, fear from
loneliness and dependence on one’s partner
after
shock
among
their
study
participants.37 p
p
It is also of great help in designing
programs
for
strengthening
financial
resources, facilitating reduction of tensions,
and helping psychosocial adaptation in
these patients. Hence, healthcare staff can
change the patients’ views toward shock by
designing
behavioral
and
cognitive
interventions,
informing,
training,
supporting,
and
consultation,
which
eventually
accelerate
the
patients’
adaptability. Ethical issues None to be declared. Acknowledgments This study was carried out at Shiraz
University of Medical Sciences, Shiraz, Iran. The authors would like to thank the ICD
recipients who participated in the study. We
are
also
grateful
for
Ms. A. Keivanshekouh
at
the
Research
Improvement Center of Shiraz University
of Medical Sciences for improving the use
of English in the manuscript. Discussion Yet,
further
studies
are
required to be conducted on the issue to
open
new
horizons
regarding
this
phenomenon for directing holistic care for
such patients. One of the limitations of the
present study was that all the patients were
Muslim. Thus, the experiences of ICD
receptors with other religious backgrounds
should be investigated, as well. It should be noted that the previous
studies mainly focused on experience of
living with ICD, and shock was expressed
as one of the themes of the studies. Furthermore, experience of heartbreak,
uncertainty
about
future,14
uncertainty
about shock, tendency to remove ICD in
case of continuation of shock discharge,
breakability due to the probability of future
shocks, and regaining control through
acceptance of life changes have been
mentioned
in
various
studies. It
is
important to note that the patients finally
considered ICD as their survivor and
accepted the uncertainties.37 Conflict of interest The present study revealed the experiences
of the patients with ICD regarding shock
discharge referred to the cardiology clinics
of
two
hospitals
affiliated
to
Shiraz
University of Medical Sciences. According
to the main research question, the patients’
experiences of shock were classified into
two categories of “with a parachute for life”
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unpredictability:
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Evidence of general precursor events
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1.1
General precursor A general precursor is an individual of population whose current space/time is
generally entangled (correlated) with future space/time of general population. This correlation is aligned. Like any entanglement it is not absolutely lossless. Here, correlated phenom-
ena include physical and mental lifestyle, living conditions and, thus, experiences
that impact these conditions and states, but more specific details will not be
preserved - ie. reason for particular experience or condition will generally be
different. Due to difference in karma, not only reasons for change of states may be
different, but magnitude of impact. Current space/time of a general precursor is also correlated with current
space/time of general population, however, such correlation is generally anti-
aligned (ie. lifestyle of general population may be a complete opposite to lifestyle
of a general precursor). This will be changing with a pulse of strong evolution,
when evolution of general population accelerates while evolution of general pre-
cursor decelerates, leading to synchronization. Abstract Future can be predicted with great certainty when it has already hap-
pened elsewhere. In example, the events in embryonic development of
a human being can very accurately be predicted due to great relative
equality in development between individuals of species. y
Many (or all) cells and events in development (evolution) are preceded
by precursor cells and events. I have hypothesized elsewhere that evolution of complex life on the
surface of Earth during Phanerozoic is part of Earth’s neurogenesis and
that this process is qualitatively similar to neurogenesis of standard scale
complex life. Major extinction events here mark the events of cell/protein migration
to mantle layers. Since major extinction event is currently happening on
Earth, a lot of upcoming events can be predicted based on comparison
with past such events and standard scale neurogenesis. Predictable (expected) events should thus be asteroid bombardments,
earthquakes, volcanism, floods, etc. While all of these events should be
global (or have a global effect), each of these should be preceded by smaller
scale [precursor] events. If all these events are concentrated in specific space/time, then these
could be considered root events, a general precursor frame. Since cells
and proteins also exist as precursors, a general precursor frame should be
associated with a general precursor cell or a protein. This protein should be significantly more evolved (more neutral) than
other proteins at time of precursor events. In the context of Earth, pre-
cursor neuron proteins are human beings. Here, I hypothesize that I am
one of the general precursors and provide some evidence. 1 tion of] this knowledge. The more one is synchronized with its host or god (Earth, in this case), or,
the more evolved one is, the less one should be impacted by events of neuroge-
nesis. Such one is thus a good candidate for a general precursor, one who will
experience events in smaller scale. Due to low intensity and magnitude, these events may even be beneficial for
the habitat and life of such one rather than destructive. Based on my research and experience, due to determinism in physical laws
and synchronicity due to entanglement of past and future, even a thought of
a general precursor, regarding a specific upcoming event, can be strongly cor-
related to that event. Effectively, a wish of a general precursor will generally
become true, with confidence proportional to the proximity of the upcoming
event. This is natural and unsurprising, if one understands that mental pro-
cesses are physical on some scale. I am convinced that anyone who sincerely promotes truth and sincerely
lives in truth, one who is truly not anthropocentric and doesn’t support
the cancer of god is one of precursors whose wishes will eventually become
true. It’s logical - a cancer cannot be a precursor for something other than
death. This is natural and unsurprising, if one understands that mental pro-
cesses are physical on some scale. I am convinced that anyone who sincerely promotes truth and sincerely
lives in truth, one who is truly not anthropocentric and doesn’t support
the cancer of god is one of precursors whose wishes will eventually become
true. It’s logical - a cancer cannot be a precursor for something other than
death. 2
Intro I have previously hypothesized that I am a general precursor[1] and that many
events concentrated around me and in me, impacting my life, are precursors to
such events on global scale. Here I will present some evidence for that. A general precursor is likely to be experiencing synchronicity events on a
regular basis. A belief of a general precursor is generally a precursor to general knowl-
edge. A belief in general population is generally a postcursor of [corrup- 2 3
Seismic anomalies I have predicted that global earthquakes are common during events of neuro-
genesis and that these should be preceded by localized precursor earthquakes
which will then spread globally, increasing in magnitude. It is also possible that these precursor events are not only separated in
time from main events, but generally, in space too - the area of localized
precursor events will be less affected by global events they are a precursor
of. These precursor events should however be roughly localized to residence of
a general precursor. Perhaps there are more general precursors in this world, but evidence does
suggest that I am one. 3 Note that this does not imply a strong cause-effect relationship between
[the location of] a general precursor and precursor events, the correlation
is the effect of synchronicity. For the whole of my life I have lived in the country of Croatia, mostly in
Sibinj, but for significant part in Zagreb also. Exactly 1 year after I’ve left Zagreb and returned to Sibinj, a large earth-
quake hit Zagreb, in March, 2020. Soon, large earthquakes started happening
elsewhere in Croatia and the ground has been shaking ever since (although,
not much in Sibinj, suggesting that even if Croatia as a precursor won’t be so
strongly affected by earthquakes, there is a specific localized area within that
area which may be affected even less - the area where general precursor is located
or has been located for most of life). Last earthquake [that was felt by humans] in/around Sibinj occurred in
June, 2018, magnitude R4.0. Note that this earthquake was sychronized
with, and probably detected by one of my experiments[2]. I have also predicted increased frequency and magnitude of asteroids, so
something should land in Croatia as a precursor. I predicted a meteor will fall
north-east from my house precursor[3] and that this will be [at least roughly]
synchronized with an earthquake and creation of a spring of fresh water in that
area (possibly also hydrothermal). Well, this has now been confirmed to me, as I have noticed surface ruptures
started appearing exactly north-east of my house precursor. There were no
noticeable earthquakes here since 2018., but these ruptures clearly indicate the
presence of a fault below and recent strongly localized activity, boosting the
probability that a spring will indeed be created here. 3
Seismic anomalies Strongest ruptures are 5 cm wide and localized some 30-40 m north-east
of my house precursor. Ruptures continue up to ≈90 m south/south-
east and ≈60 m north/north-west from the hotspot but with much lower
intensity and magnitude. Outside of that area ruptures are scarce and
smaller. The affected north-east area seems somewhat elevated but no noticeable
changes in elevation have occurred in this event. While most and greatest
ruptures are concentrated along the north/north-west - south/south-east
line of a couple of meters in width, they are irregular and there seems to
be no preferred direction (ie. north-south) in ruptures themselves. (
)
All this suggests a strike-slip earthquake with an epicenter at the north- 4 east hotspot, but with a loose connection of top soil and the source,
possibly due to soil liquefaction along the fault. In any case, the epicenter is exactly where I predicted it (to be more
precise, in my prediction I did not specify where the epicenter of the
earthquake will be, only where the spring will be created with the earth-
quake, but it makes sense that the creation of a spring has the highest
probability at or near the epicenter). I guess it will take one or more earthquakes at the same location to
actually create the spring, but I’m not in a hurry. And, of course, it appears that I have noticed these ruptures on my
birthday, so it was another synchronicity event. east hotspot, but with a loose connection of top soil and the source,
possibly due to soil liquefaction along the fault. east hotspot, but with a loose connection of top soil and the source,
possibly due to soil liquefaction along the fault. In any case, the epicenter is exactly where I predicted it (to be more
precise, in my prediction I did not specify where the epicenter of the
earthquake will be, only where the spring will be created with the earth-
quake, but it makes sense that the creation of a spring has the highest
probability at or near the epicenter). )
I guess it will take one or more earthquakes at the same location to
actually create the spring, but I’m not in a hurry. And, of course, it appears that I have noticed these ruptures on my
birthday, so it was another synchronicity event. Ruptures are shown in Fig. 1. 3.1.1
2021.09.05 Another hotspot (2) appeared 40-50 m north from the original hotspot, with
similar configuration and maximum rupture width. 3
Seismic anomalies Red arrow on the left indicates the location
of my house precursor. Figure 1: left) Surface ruptures and house precursor, right) Closeup of ruptures Figure 1: left) Surface ruptures and house precursor, right) Closeup of ruptures Fig. 2 shows another view on the hotspot (1) ruptures. ( )
A land map with layout of hotspots is shown in Fig. 3. Green cross is my
house precursor, blue is the original hotspot, red are additional hotspots. 3.1.3
2021.09.15 The ground is still active. I’m noticing new ruptures on a daily basis. Interestingly, ruptures smaller in width seem to be connected by round holes. There are many holes not connected by ruptures, suggesting that these holes
precede ruptures. I wonder if these holes could be the smaller scale equivalent of holes appear-
ing recently in Siberia and Arctic permafrost. The ground is becoming increasingly bumpy at ruptures. The weather is
calm, sunny, and there is no precipitation. There were no changes in weather
since observations began. All of this suggests there is an ongoing vertical creation (or expansion) of
veins filled with a fluid mixture of gas and liquid (most likely water). Also, it
appears this is not a continuous process, rather pulsed phenomena, such as the
phenomena of geysers. While it is probably unlikely that water is coming out of ruptures period-
ically at this point, periodic degassing might be possible. I may increase the
periodicity of inspections to test this hypothesis. 3.1.2
2021.09.06 Another hotspot (3) appeared ≈40 m north-west from the original hotspot, with
similar configuration. Maximum rupture width here is 4 cm. 5 Figure 2: Surface ruptures Figure 2: Surface ruptures Figure 3: Land map, showing hotspots Figure 3: Land map, showing hotspots 6 Additional closer inspection of ruptures at original hotspot (1) has been
performed. A couple of ruptures were found with a noticeable difference in
elevation between sides. Some may be attributed to erosion, however, some are
more likely to have been caused by difference in pressure below. It is unknown
if this is a new feature or originally created. 3.1.5
2021.09.17 Some heavy rain today. I’ve learned from a separate experiment that, without
vegetation, most water simply goes down through the soil, taking soil with it if
that is possible. In this case, as the water goes down a hill it carries some mud with it. Once
it encounters the ruptures it goes down, eroding the northern side of ruptures
in the process and depositing all the mud inside. With rain, the southern side
of ruptures also gets eroded to some extent. But at some point, space becomes too tight and it becomes impossible for
soil to penetrate deeper with water, so it starts accumulating. Generally, this process is smoothing out the landscape - healing the ruptured
skin. Note that rain and wind are slowly eroding mountains and, generally over
millions of years, smoothing out the landscape globally. With no vege-
tation, tectonic processes and changes in pressure below - the smoother
the surface the older the body, as long as there is atmosphere. However,
this is all correlated. Energy cannot be destroyed. Thus, energy at the surface may only be lost
out to space or conserved deeper underground. It also has to oscillate,
but it will generally be getting lost outwards or lost inwards - if no
additional energy is acquired. Mars, for example, is not dead - it has
conserved this energy below the apparent surface, and it periodically
returns, when apparent surface becomes real (living) surface again. But what happens to water? The water goes down (more precisely, it follows
the gradient of gravitational potential) as long as it can. Once it encounters
denser rock, which it cannot penetrate, it starts accumulating and spreading
laterally. But if these ruptures were created with soil liquefaction, additional water
could create new ruptures. 3.1.4
2021.09.16 More holes observed, greatest concentration more south/south-east of main area. Typical holes 2 cm in width, shallow, different angles, some more horizontal than
vertical. 4 cm holes also common. Ruptures and holes typically appear in areas of low vegetation, as shown in
Fig. 4. Nice example of how plants protect the soil from erosion. Figure 4: Typical smaller ruptures Figure 4: Typical smaller ruptures 7 3.1.7
2021.09.19 I have previously considered my sinkholes to be small scale equivalent of Arctic
and Siberia sinkholes. However, even if they may be correlated, the mechanism
of creation must be different. More precisely, my sinkholes are the equivalent of sinkholes appearing with
some earthquakes, such as those that have appeared lately in Croatia[4]. Interestingly, these sinkholes started appearing in north/north-east Croatia,
while my sinkholes started appearing north/north-east of my house precursor
(interestingly, Arctic and Siberia are north/north-east of Croatia...). All this goes in favor of the general precursor hypothesis, and if these sink-
holes are precursor to ruptures, one can expect large scale ruptures there too. The question is how much time will pass before ruptures appear? To answer that question, I have already marked some sinkholes on 2021.09.15. At this point there are no significant changes. The other question is - is the scale difference in time proportional to scale
difference in space? Considering that the largest sinkhole was 25-30 m (25 m initially[5], grew
to 30 m), while my largest (pre-rain) sinkhole was 4-4.3 cm in width, that is a
spatial difference of ≈666 in magnitude. New large sinkholes were appearing on a weekly basis while my new sinkholes
were appearing daily - much lower difference in temporal magnitude (7). Large sinkholes are the aftermath of an M6.2 earthquake occurred on 2020.12.29
in Petrinja, Croatia[6]. These started appearing south of Petrinja (villages Boro-
jevići, Mečenčani). This area is some 120 km west (roughly at the same latitude) from my
sinkholes. It is thus entirely possible that these events are more correlated - in an
oscillatory fashion. Note that my faults and movements of rock seem to be a smaller scale copy
of faults and movements in Petrinja (shown in Fig. 5) - north-south horizontal
strike-slip block movement with a transverse component near the epicenter. In
that case, compared to Petrinja earthquake, if main ruptures appear at the
crossing of faults, the epicenter is near south-west, toward my precursor house. Assuming that my first sinkholes appeared on 2020.12.29, while ruptures
appeared 9 months later, large scale ruptures in Petrinja could follow approxi-
mately 63 (9*7) months after the sinkholes, 4-5 years from now. Due to accel-
erated evolution, this interval may be compressed. However, I find it likely that subsequent intervals between new ruptures will
be getting more and more compressed, this one may not. 3.1.6
2021.09.18 Some rupture healing has occurred, as expected. A lot of new holes have ap-
peared south/south-east of the main area. At least some should probably be
attributed to rainwater entering ruptures up north. It is unlikely, however, that main ruptures were created by the same process
(rain entering ground further up north), as there isn’t much ground up north [to
the top of the hill] and there was no rain before and during previous observations. The fact that, after heavy rain, only smaller holes appeared and mostly
concentrated south/south-east, goes in favor of the hypothesis. 8 8 3.1.7
2021.09.19 In that case, my next
ruptures should appear less than 9 months from now (perhaps in 3 months or
even less). Considering my largest ruptures are some 4 m in length and 5 cm in width,
large scale ruptures in Petrinja should be ≈2.66 km in length and ≈33 m in
width. 9 Figure 5: Earthquakes and faults in Petrinja, Markušić et al (2021) Figure 5: Earthquakes and faults in Petrinja, Markušić et al (2021)
Note that Petrinja was devastated in a war during 1990s so that war
could also be interpreted as a precursor to larger devastation. The war
is a product of human stupidity (humanity), but devastation is certainly
very relative in case of natural disasters. This is a reaction to human
stupidity, in order to restore the balance. Fig
e 5 Ea th
akes a d fa lts i
Pet i ja Ma k šić et al (2021) Figure 5: Earthquakes and faults in Petrinja, Markušić et al (2021) Note that Petrinja was devastated in a war during 1990s so that war
could also be interpreted as a precursor to larger devastation. The war
is a product of human stupidity (humanity), but devastation is certainly
very relative in case of natural disasters. This is a reaction to human
stupidity, in order to restore the balance. https://www.hgi-cgs.hr/urusavanje-tla-u-mecencanima-i-okolici-izazvano-
potresom-magnitude-6-2-kod-petrinje-te-prethodnim-i-naknadnim-
potresima/ [6] Destructive M6.2 Petrinja Earthquake (Croatia) in 2020—Preliminary Mul-
tidisciplinary Research (2021), S. Markušić et al
https://doi.org/10.3390/rs13061095 References [1] Amenoum (2020), Amenoum
https://amenoum.org/authors/Amenoum.html [1] Amenoum (2020), Amenoum
https://amenoum.org/authors/Amenoum.html [1] Amenoum (2020), Amenoum
https://amenoum.org/authors/Amenoum.html [2] Experiments on seismic activity (2021), Amenoum
https://amenoum.org/log/8_experiments_on_seismic_activity.html [3] Amenoum (2020), Amenoum
https://amenoum.org/authors/Amenoum.html [3] Amenoum (2020), Amenoum
https://amenoum.org/authors/Amenoum.html [4] The Croatian village where the land became ’Swiss cheese’ (2021), V. Simičević
https://www.bbc.com/future/article/20210702-how-an-earthquake-created-
a-village-full-of-sinkholes [4] The Croatian village where the land became ’Swiss cheese’ (2021), V. Simičević
https://www.bbc.com/future/article/20210702-how-an-earthquake-created-
a-village-full-of-sinkholes [5] Urušavanje tla u Mečenčanima i okolici izazvano potresom magnitude 6.2
kod Petrinje, te prethodnim i naknadnim potresima (2021), J. Terzić et al 10 https://www.hgi-cgs.hr/urusavanje-tla-u-mecencanima-i-okolici-izazvano-
potresom-magnitude-6-2-kod-petrinje-te-prethodnim-i-naknadnim-
potresima/
[6] Destructive M6.2 Petrinja Earthquake (Croatia) in 2020—Preliminary Mul-
tidisciplinary Research (2021), S. Markušić et al
https://doi.org/10.3390/rs13061095 11
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Clinical Assessment of Medical Students in the Emergency Department, a National Consensus Conference
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UC Irvine
Western Journal of Emergency Medicine: Integrating Emergen
Care with Population Health
Title
Clinical Assessment of Medical Students in the Emergency Department, a National
Consensus Conference
Permalink
https://escholarship.org/uc/item/4fb9g2kk
Journal
Western Journal of Emergency Medicine: Integrating Emergency Care with Population
Health, 18(1)
ISSN
1936-900X
Authors
Hiller, Katherine
Franzen, Douglas
Lawson, Luan
et al.
Publication Date
2017
DOI
10.5811/westjem.2016.11.32686
Supplemental Material
https://escholarship.org/uc/item/4fb9g2kk#supplemental
Copyright Information
Copyright 2017 by the author(s).This work is made available under the terms of a Creativ
Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/
Peer reviewed UC Irvine
Western Journal of Emergency Medicine: Integrating Emergen
Care with Population Health
Title
Clinical Assessment of Medical Students in the Emergency Department, a National
Consensus Conference
Permalink
https://escholarship.org/uc/item/4fb9g2kk
Journal
Western Journal of Emergency Medicine: Integrating Emergency Care with Population
Health, 18(1)
ISSN
1936-900X
Authors
Hiller, Katherine
Franzen, Douglas
Lawson, Luan
et al. Publication Date
2017
DOI
10.5811/westjem.2016.11.32686
Supplemental Material
https://escholarship.org/uc/item/4fb9g2kk#supplemental
Copyright Information
Copyright 2017 by the author(s).This work is made available under the terms of a Creativ
Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/
Peer reviewed UC Irvine
Western Journal of Emergency Medicine: Integrating Emergen
Care with Population Health
Title
Clinical Assessment of Medical Students in the Emergency Department, a National
Consensus Conference
Permalink
https://escholarship.org/uc/item/4fb9g2kk
Journal
Western Journal of Emergency Medicine: Integrating Emergency Care with Population
Health, 18(1)
ISSN
1936-900X
Authors
Hiller, Katherine
Franzen, Douglas
Lawson, Luan
et al. Publication Date
2017
DOI
10.5811/westjem.2016.11.32686
Supplemental Material
https://escholarship.org/uc/item/4fb9g2kk#supplemental
Copyright Information
Copyright 2017 by the author(s).This work is made available under the terms of a Creati
Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/
Peer reviewed Title Copyright Information
Copyright 2017 by the author(s).This work is made available under the terms of a Creative
Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/
Peer reviewed UC Irvine UC Irvine
Western Journal of Emergency Medicine: Integrating Emergency
Care with Population Health Powered by the California Digital Library
University of California eScholarship.org Brief Educational Advances Clinical Assessment of Medical Students in the Emergency
Department, a National Consensus Conference Hiller, MD, MPH*
Douglas Franzen, MD, MEd†
Luan Lawson, MD, MAEd‡
David Manthey, MD§
Jonathan Fisher, MD, MPH*
Marianne Haughey, MD¶
Matthew Tews, DO, MS||
Nicole Dubosh, MD#
Joseph House, MD**
Arleigh Trainor, MD††
David Wald, DO‡‡
Julianna Jung, MD§§ East Carolina University, Department of Emergency Medicine, Greenville, North
Carolina
‡ Wake Forest University, Department of Emergency Medicine, Winston-Salem,
North Carolina
§ St. Barnabas Medical Center, Department of Emergency Medicine, Bronx, New
York
¶ Medical College of Wisconsin, Department of Emergency Medicine, Milwaukee,
Wisconsin
H
d U i
it
D
t
t
f E
M di i
C
b id
||
# Harvard University, Department of Emergency Medicine, Cambridge,
Massachusetts
# University of Michigan, Department of Emergency Medicine, Ann Arbor, Michigan
University of South Dakota, Department of Emergency Medicine, Vermillion, South
Dakota
**
†† Section Editor: Andrew Phillips, MD
Submission history: Submitted September 28, 2016; Accepted November 1, 2016
Electronically published November 23, 2016
Full text available through open access at http://escholarship.org/uc/uciem_westjem
DOI: 10.5811/westjem.2016.11.32686
[West J Emerg Med. 2017;18(1)82-83.] BACKGROUND the executive committee and refined at a large-group planning
meeting at the 2015 CORD Academic Assembly (Table). i The clinical assessment of medical students in the
emergency department (ED) is a highly variable process in
which clerkship directors (CD) create and use institution-specific
tools, many with unproven reliability or validity, to assess
students of differing experience and from different institutions.1,2 In May 2015, theme leaders were identified and tasked
with recruiting relevant stakeholders to their respective small
groups, synthesizing the background literature and articulating
key issues surrounding their theme. Simultaneously, the
executive committee derived “building blocks” of assessment
from foundational source materials.1,3-9 Each contained the
following: name, background and definition, benefits/
drawbacks/alternatives to use in the clinical setting, areas of OBJECTIVES Standardization of assessment practices and tools of
assessment could enhance grading, improve the reliability and
validity of information on the standardized letter of evaluation
(SLOE) for program directors, and most importantly, provide
consistent, valid and reliable formative feedback for students. 2
Volume XVIII, no. 1: January 2017
Themes
Criterion vs norm-referenced assessment
Learners at different levels of learning
Translation of assessment data into other products
Utilization of clinical assessment tools
Ensuring post-implementation validation/research
CDEM, Clerkship Directors in Emergency Medicine. Table. Themes of assessment discussed at the CDEM national
end-of-shift consensus conference. 2
Volume XVIII, no. 1: January 2017
Themes
Criterion vs norm-referenced assessment
Learners at different levels of learning
Translation of assessment data into other products
Utilization of clinical assessment tools
Ensuring post-implementation validation/research
CDEM, Clerkship Directors in Emergency Medicine. Table. Themes of assessment discussed at the CDEM national
end-of-shift consensus conference. Table. Themes of assessment discussed at the CDEM national
end-of-shift consensus conference. Table. Themes of assessment discussed at the CDEM national
end-of-shift consensus conference. Clinical Assessment of Medical Students in the Emergency
Department, a National Consensus Conference p
,
Katherine M. Hiller, MD, MPH*
Douglas Franzen, MD, MEd†
Luan Lawson, MD, MAEd‡
David Manthey, MD§
Jonathan Fisher, MD, MPH*
Marianne Haughey, MD¶
Matthew Tews, DO, MS||
Nicole Dubosh, MD#
Joseph House, MD**
Arleigh Trainor, MD††
David Wald, DO‡‡
Julianna Jung, MD§§
Section Editor: Andrew Phillips, MD
Submission history: Submitted September 28, 2016; Accepted November 1, 2016
Electronically published November 23, 2016
Full text available through open access at http://escholarship.org/uc/uciem_westjem
DOI: 10.5811/westjem.2016.11.32686
[West J Emerg Med. 2017;18(1)82-83.]
University of Arizona, Department of Emergency Medicine, Tucson, Arizona
University of Washington, Department of Medicine, Division of Emergency
Medicine, Seattle, Washington
East Carolina University, Department of Emergency Medicine, Greenville, North
Carolina
Wake Forest University, Department of Emergency Medicine, Winston-Salem,
North Carolina
St. Barnabas Medical Center, Department of Emergency Medicine, Bronx, New
York
Medical College of Wisconsin, Department of Emergency Medicine, Milwaukee,
Wisconsin
Harvard University, Department of Emergency Medicine, Cambridge,
Massachusetts
University of Michigan, Department of Emergency Medicine, Ann Arbor, Michigan
University of South Dakota, Department of Emergency Medicine, Vermillion, South
Dakota
Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Johns Hopkins University, Department of Emergency Medicine, Baltimore, Maryland
*
†
‡
§
¶
||
#
**
††
‡‡
§§ University of Arizona, Department of Emergency Medicine, Tucson, Arizona
University of Washington, Department of Medicine, Division of Emergency
Medicine, Seattle, Washington
East Carolina University, Department of Emergency Medicine, Greenville, North
Carolina
Wake Forest University, Department of Emergency Medicine, Winston-Salem,
North Carolina
St. Barnabas Medical Center, Department of Emergency Medicine, Bronx, New
York
Medical College of Wisconsin, Department of Emergency Medicine, Milwaukee,
Wisconsin
Harvard University, Department of Emergency Medicine, Cambridge,
Massachusetts
University of Michigan, Department of Emergency Medicine, Ann Arbor, Michigan
University of South Dakota, Department of Emergency Medicine, Vermillion, South
Dakota
Lewis Katz School of Medicine, Philadelphia, Pennsylvania
Johns Hopkins University, Department of Emergency Medicine, Baltimore, Maryland
*
†
‡
§
¶
||
#
**
††
‡‡
§§ University of Arizona, Department of Emergency Medicine, Tucson, Arizona
University of Washington, Department of Medicine, Division of Emergency
Medicine, Seattle, Washington
*
† Katherine M. Western Journal of Emergency Medicine DESIGN A consensus conference on end-of-shift assessment of
medical students in the ED was held in the Clerkship Directors
in Emergency Medicine (CDEM) track of the Council of
Emergency Medicine Residency Directors (CORD) Academic
Assembly in Nashville, TN, in March 2016. Themes
surrounding the practice of end-of-shift assessment of medical
students were derived from small-group discussions among Volume XVIII, no. 1: January 2017 Western Journal of Emergency Medicine 82 Clinical Assessment of Medical Students in the ED Hiller et al. in our specialty. The creation of a reliable and valid assessment
tool will provide a critical method for measuring outcomes in
educational innovations and research in the future. overlap with other domains of assessment, examples of how
an assessment of this domain would appear on an assessment
form in three formats (narrative, dichotomous, and an
anchored ratings scale), and references. Please see Appendix for CDEM Consensus Conference on End-
of-shift Assessment of Medical Students: Executive Summary. On Day 1 of the conference, participants were divided into
small groups. Each theme leader met with each small group
providing background and guiding further discussion. Pre-
determined questions with discrete responses were asked within
each small group. During the second morning of the conference,
the “building blocks” were discussed. Participants voted using an
electronic audience response system (www.polleverywhere.com). Address for Correspondence: Katherine M. Hiller, MD, MPH,
University of Arizona, Department of Emergency Medicine, 1501
N Campbell Ave, Tucson, AZ 85724. Email: khiller@aemrc. arizona.edu. REFERENCES 1. Hiller K, Lawson L, Franzen D, et al. End-of-shift Emergency
Medicine Medical Student Clinical Evaluation Forms: A Taxonomy. Acad Emerg Med. 2015;22(S1):S196-7. 2. Lawson L, Jung J, Franzen D, et al. Clinical Assessment of Medical
Students in Emergency Medicine Clerkships: A Survey of Current
Practice. J Emerg Med. Sep 7 2016. Based on the variability of assessment forms currently in
use, we anticipated a large range of opinion on the topics
presented. Instead, we were surprised by the strength of
consensus on most topics. 3. Santen SA, Peterson WJ, Khandelwal S, et al. Medical student
milestones in emergency medicine. Acad Emerg Med. Aug
2014;21(8):905-11. 4. AAMC. Core Entrustable Professional Activities for Entering
Residency--Curriculum Developers Guide. Available at: https://
members.aamc.org/eweb/upload/core%20EPA%20Curriculum%20
Dev%20Guide.pdf. Accessed Feb 11, 2016. Limitations to this process include that only approximately
half of the CDEM Academy membership was present, despite
extensive advertisement about the conference. Additionally,
voting may have been affected by the order in which the building
blocks of assessment were presented. Participants may have been
more apt to comment later once they had a better understanding
and more familiarity with how the materials were presented and
referenced. We attempted to mitigate this effect by providing the
materials to participants beforehand and providing preparatory
background material in discussion groups. Finally, participants
were able to change their vote while group discussion occurred. Large-group discussion did sway votes; however, we feel this
culminated in a better representation of the group’s actual
opinions. Discussion helped guide the decision in real time, and
allowed minority opinions to be heard and considered.i 5. Tews MC, Ditz Wyte CM, Coltman M, et al. Implementing a Third-
Year Emergency Medicine Medical Student Curriculum. J Emerg
Med. Mar 27 2015. 6. Manthey DE, Ander DS, Gordon DC, et al. Emergency medicine
clerkship curriculum: an update and revision. Acad Emerg Med. 2010;17(6):638-43. 7. Englander R, Cameron T, Ballard AJ, et al. Toward a common
taxonomy of competency domains for the health professions and
competencies for physicians. Acad Med. Aug 2013;88(8):1088-94. 8. CORD. Standardized Letter of Evaluation in Emergency
Medicine. 2016. Available at: http://www.cordem.org/files/
DOCUMENTLIBRARY/SLOR/SLOE%20Standard%20Letter%20
of%20Evaluation%202015.pdf. Accessed May 25, 2016. This conference was a critical first step in the development
of national guidelines and a standardized clinical assessment
tool in EM. The education and discussion that the conference
provided elevated the level of conversation around assessment 9. Beeson MS, Carter WA, Christopher TA, et al. IMPACT/EFFECTIVENESS Conflicts of Interest: By the WestJEM article submission agreement,
all authors are required to disclose all affiliations, funding sources
and financial or management relationships that could be perceived
as potential sources of bias. The authors disclosed none. Sixty people participated on Day 1 and 70 participated on
Day 2 of the conference. Participants agreed on 63.4% of the
theme questions and 87.5% of the domains of assessment. The
group felt that both norm- and criterion-based assessment
should be incorporated, EM faculty and senior residents
should be allowed to complete the form, the unit of
observation should be a single shift, and that 6-10 shifts would
be adequate to accurately assess a student. Medical students
(MS3) and (MS4) should be assessed using the same tools, but
grading should differ. Learners with varying experience within
a year present a challenge; however, this is not prohibitive to
using a common form or grading rubric. Clinical assessment
data should be translated into a grade and onto the SLOE. Of
16 domains of assessment presented, nine were included, five
omitted, and two did not reach consensus. All domains should
be assessed via rating scale except professionalism, for which
a combined narrative/dichotomous approach was preferred. Copyright: © 2016 Hiller et al. This is an open access article
distributed in accordance with the terms of the Creative Commons
Attribution (CC BY 4.0) License. See: http://creativecommons.org/
licenses/by/4.0/ REFERENCES Emergency medicine
milestones. J Grad Med Educ. Mar 2013;5(1 Suppl 1):5-13. Volume XVIII, no. 1: January 2017 Western Journal of Emergency Medicine 83
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Oncogene-Expressing Senescent Melanocytes Up-Regulate MHC Class II, a Candidate Melanoma Suppressor Function
|
The journal of investigative dermatology/Journal of investigative dermatology
| 2,017
|
cc-by
| 10,116
|
Oncogene-Expressing Senescent
Melanocytes Up-Regulate MHC Class II,
a Candidate Melanoma Suppressor Function
John van Tuyn1, Farah Jaber-Hijazi1, Douglas MacKenzie1, John J. Cole1, Elizabeth Mann2,
Jeff S. Pawlikowski3, Taranjit Singh Rai4, David M. Nelson1, Tony McBryan1, Andre Ivanov5,
Karen Blyth6, Hong Wu7, Simon Milling2 and Peter D. Adams1,8 On acquisition of an oncogenic mutation, primary human and mouse cells can enter oncogene-induced
senescence (OIS). OIS is characterized by a stable proliferation arrest and secretion of proinflammatory
cytokines and chemokines, the senescence-associated secretory phenotype. Proliferation arrest and the
senescence-associated secretory phenotype collaborate to enact tumor suppression, the former by blocking
cell proliferation and the latter by recruiting immune cells to clear damaged cells. However, the interactions of
OIS cells with the immune system are still poorly defined. Here, we show that engagement of OIS in primary
human melanocytes, specifically by melanoma driver mutations NRASQ61K and BRAFV600E, causes expression
of the major histocompatibility class II antigen presentation apparatus, via secreted IL-1ß signaling and
expression of CIITA, a master regulator of major histocompatibility class II gene transcription. In vitro, OIS
melanocytes activate T-cell proliferation. In vivo, nonproliferating oncogene-expressing melanocytes localize
to skin-draining lymph nodes, where they induce T-cell proliferation and an antigen presentation gene
expression signature. In patients, expression of major histocompatibility class II in melanoma is linked to
favorable disease outcome. We propose that OIS in melanocytes is accompanied by an antigen presentation
phenotype, likely to promote tumor suppression via activation of the adaptive immune system. Journal of Investigative Dermatology (2017) 137, 2197e2207; doi:10.1016/j.jid.2017.05.030 1Institute of Cancer Sciences, University of Glasgow, Garscube Estate,
Switchback Road, Glasgow, UK; 2Institute for Infection, Immunity and
Inflammation, University of Glasgow, Glasgow, UK; 3Vanderbilt University
Medical Center, Nashville, Tennessee, USA; 4Institute of Biomedical and
Environmental Health Research, University of the West of Scotland, Paisley,
UK; 5Barts Cancer Institute. Queen Mary, University of London.
Charterhouse Square, London, UK; 6Beatson Institute for Cancer Research,
Garscube Estate. Switchback Road, Glasgow, UK; 7Fox Chase Cancer
Center, Philadelphia, Pennsylvania, USA; and 8Sanford Burnham Prebys
Medical Discovery Institute, San Diego, California, USA ORIGINAL ARTICLE ORIGINAL ARTICLE Oncogene-Expressing Senescent
Melanocytes Up-Regulate MHC Class II,
a Candidate Melanoma Suppressor Function
John van Tuyn1, Farah Jaber-Hijazi1, Douglas MacKenzie1, John J. Cole1, Elizabeth Mann2,
Jeff S. Pawlikowski3, Taranjit Singh Rai4, David M. Nelson1, Tony McBryan1, Andre Ivanov5,
Karen Blyth6, Hong Wu7, Simon Milling2 and Peter D. Adams1,8 Correspondence: Peter D. Adams, Sanford Burnham Prebys Medical
Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California
92037, USA. E-mail: padams@sbpdiscovery.org Abbreviations: MHC, major histocompatibility complex; NK, natural killer;
OIS, oncogene-induced senescence; RNA-seq, RNA sequencing; SA b-gal,
senescence-associated b-galactosidase ª 2017 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 12 May 2016; revised 26 April 2017; accepted 9 May 2017;
accepted manuscript published online 22 June 2017; corrected proof
published online 31 August 2017 Correspondence: Peter D. Adams, Sanford Burnham Prebys Medical
Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California
92037, USA. E-mail: padams@sbpdiscovery.org
Abbreviations: MHC, major histocompatibility complex; NK, natural killer;
OIS, oncogene-induced senescence; RNA-seq, RNA sequencing; SA b-gal,
senescence-associated b-galactosidase
Received 12 May 2016; revised 26 April 2017; accepted 9 May 2017;
accepted manuscript published online 22 June 2017; corrected proof
published online 31 August 2017 INTRODUCTION The time span of
oncogene activation was kept at 2
weeks for all OIS experiments
unless indicated otherwise. (b) Quantification of EdU
incorporation and SA ß-gal staining. Graph shows means standard
deviation, n ¼ 3. (c) Representative
RNA sequencing track showing HLA-
DRA sequence reads for control and
BRAFV600E-transduced melanocytes. Y-axis shows sequence tags per
million tags; x-axis shows position
along the HLA-DRA gene (spanning
5,178 base pairs), with boxed exons. (d) Detection of HLA-DRA transcript
levels by quantitative real-time reverse
transcriptaseePCR analysis. (e)
Representative immunofluorescent
image of HLA-DRA-GFP (left three
panels) and HLA-DRB-GFP (right
three panels) fusion protein-
transduced melanocytes. GFP staining
in green, staining for MHC class II in
red, and nuclei in blue. Scale bar ¼
200 mm. (f) Western blot showing
BRAF, beta-actin (ATCB), and MHC
class II (HLA-DR) expression. (g) Confocal immunofluorescent
image of melanocytes stained for
MHC class II (HLA-DR; red) and
nuclei (blue). Scale bar ¼ 10 mm. All
graphs show means standard
deviation, n ¼ 4. chr, chromosome;
MHC, major histocompatibility; OIS,
oncogene-induced senescence;
SA-Bgal, senescence-associated
b-galactosidase. Figure 1. Melanocytes express MHC
class II upon OIS. (a) Staining for SA
ß-gal activity (blue) on vector- or
BRAF600E-transduced melanocytes. Scale bar ¼ 100 mm. The time span of
oncogene activation was kept at 2
weeks for all OIS experiments
unless indicated otherwise. (b) Quantification of EdU
incorporation and SA ß-gal staining. Graph shows means standard
deviation, n ¼ 3. (c) Representative
RNA sequencing track showing HLA-
DRA sequence reads for control and
BRAFV600E-transduced melanocytes. Y-axis shows sequence tags per
million tags; x-axis shows position
along the HLA-DRA gene (spanning
5,178 base pairs), with boxed exons. (d) Detection of HLA-DRA transcript
levels by quantitative real-time reverse
transcriptaseePCR analysis. (e)
Representative immunofluorescent
image of HLA-DRA-GFP (left three
panels) and HLA-DRB-GFP (right
three panels) fusion protein-
transduced melanocytes. GFP staining
in green, staining for MHC class II in
red, and nuclei in blue. Scale bar ¼
200 mm. (f) Western blot showing
BRAF, beta-actin (ATCB), and MHC
class II (HLA-DR) expression. (g) Confocal immunofluorescent
image of melanocytes stained for
MHC class II (HLA-DR; red) and
nuclei (blue). Scale bar ¼ 10 mm. All
graphs show means standard
deviation, n ¼ 4. chr, chromosome;
MHC, major histocompatibility; OIS,
oncogene-induced senescence;
SA-Bgal, senescence-associated
b-galactosidase. stoco
pat b
ty; O S,
duced senescence;
escence-associated
se. INTRODUCTION oncogene-induced
senescence
(OIS)
(Munoz-Espin
and
Serrano, 2014). Nevus melanocytes express several molecu-
lar markers of senescence, including senescence-associated
ß-galactosidase (SA ß-gal) and tumor suppressor p16INK4a
(Gray-Schopfer et al., 2006; Michaloglou et al., 2005;
Pawlikowski et al., 2013; Suram et al., 2012). Aggregates of
apparently
nonmalignant,
nonproliferative,
p16INK4a-
expressing, melanocytic nevus-like cells, in the absence of
any concurrent or subsequent melanoma, have also been
well documented in the skin-draining lymph nodes of
humans (Mihic-Probst et al., 2003; Patterson, 2004). Melanoma is a frequently fatal cancer originating from
pigment-producing melanocytes of the skin (Lo and Fisher,
2014). The most common mutations found in melanoma
are those that activate the mitogen-activated protein kinase
signaling pathway, most notably in BRAF and NRAS (Lo and
Fisher, 2014). The same mutations are also commonly found
in benign nevi (or moles) (Omholt et al., 2002; Pollock et al.,
2003). However, benign nevi only rarely progress to cancer
because oncogene-expressing nevus melanocytes are ulti-
mately checked in a proliferation-arrested state called ,
;
,
OIS is also characterized by a secretory program, the
senescence-associated secretory phenotype (Acosta et al.,
2008; Krtolica et al., 2001; Kuilman et al., 2008). The
senescence-associated
secretory
phenotype
has
various
functions in OIS, including reinforcement and maintenance
of proliferation arrest (Acosta et al., 2008; Kuilman et al.,
2008) and recruitment of macrophages, neutrophils, and
natural killer (NK) cells of the innate immune system to clear
premalignant
oncogene-expressing
senescent
cells
(Xue
et al., 2007). NK cells also clear senescent cells in
response
to
other
cell-
and
tissue-damaging
stresses
(Krizhanovsky et al., 2008; Soriani et al., 2009). However,
clearance of mouse hepatocytes expressing an activated
NrasQ61K oncogene was also shown to depend on activa-
tion of adaptive immunity, specifically on CD4þ T cells
(Kang et al., 2011). Typically, CD4þ T cells are activated in
the secondary lymphoid tissues, such as lymph nodes and
spleen, by professional antigen-presenting cells such as Received 12 May 2016; revised 26 April 2017; accepted 9 May 2017;
accepted manuscript published online 22 June 2017; corrected proof
published online 31 August 2017 www.jidonline.org 2197 J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Figure 1. Melanocytes express MHC
class II upon OIS. (a) Staining for SA
ß-gal activity (blue) on vector- or
BRAF600E-transduced melanocytes. Scale bar ¼ 100 mm. INTRODUCTION nonproliferating melanocytes enact an antigen presentation
function to activate the adaptive immune system. nonproliferating melanocytes enact an antigen presentation
function to activate the adaptive immune system. dendritic cells (Trombetta and Mellman, 2005). Dendritic
cells endocytose and process antigens in peripheral tissues
and then migrate via the lymphatic vessels to the lymph
nodes, where they activate CD4þ T cells by major histo-
compatibility (MHC) class II-mediated antigen presentation
to naı¨ve T cells. RESULTS Melanocytes express MHC class II upon oncogene-induced
senescence initiated by melanoma driver mutations
As we and others previously showed (Michaloglou et al.,
2005; Pawlikowski et al., 2013), ectopic expression of
BRAFV600E in primary human melanocytes induces OIS. Indicative of senescence, BRAFV600E-expressing melano-
cytes up-regulated SA ß-gal (Figure 1a, 1b), arrested DNA
replication as determined by a lack of EdU incorporation
(Figure 1b) and showed senescence-associated heterochro-
matin foci in the nucleus (see Supplementary Figure S1
online). Melanocytes express MHC class II upon oncogene-induced
senescence initiated by melanoma driver mutations Melanocytes express MHC class II upon oncogene-induced
senescence initiated by melanoma driver mutations How senescent cells can activate the adaptive immune
systems has been a mystery. Here we show that OIS in me-
lanocytes caused by activation of the RAS/mitogen-activated
protein kinase pathway is accompanied by dramatic up-
regulation of the MHC class II antigen presentation com-
plex. Furthermore, melanocytes carrying either BrafV600E or
NrasQ61K mutations re-localize specifically to skin-draining
lymph nodes in mouse models. We also present functional
evidence
that
in
the
nodes,
oncogene-expressing Journal of Investigative Dermatology (2017), Volume 137
2198 2198 J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II We previously investigated the transcriptional changes of
melanocytes undergoing OIS by whole-genome microarray
analysis
and
RNA
sequencing
(RNA-seq)
analysis
(Pawlikowski
et
al.,
2013). Comparing
BRAFV600E-
expressing melanocytes against vector-transduced and unin-
fected melanocytes, we observed striking up-regulation of
MHC class II complex transcripts (Figure 1c, Supplementary
Table S1 online). The cell surface of MHC class II complex is
a heterodimer of a and ß polypeptides, for example HLA-
DRA and HLA-DRB1, respectively. Antigen presentation
also depends on expression of chaperones and accessory
factors, such as HLA-DM, HLA-D0, and CD74, which
facilitate antigen processing, loading, and presentation by
the MHC class II complex (Trombetta and Mellman, 2005). We observed HLA-DRA and HLA-DRB among the top
changes (see Supplementary Table S1). In addition, related
HLA-DQA, HLA-DQB, HLA-DPA, and HLA-DPB were also
up-regulated, together with important antigen processing and
presentation accessory molecules, such as HLA-DMA, HLA-
DMB,
and
invariant
chain
CD74
(see
Supplementary
Tables S2, S3 online). investigated replicative senescence melanocytes. Melano-
cytes were serially passaged until they ceased proliferation
and were confirmed to show replicative senescence by pos-
itive staining for SA ß-gal (Figure 2c, 2d) and lack of BrdU
incorporation
(Figure
2d). RESULTS In
contrast
to
BRAFV600E-
mediated OIS, replicative senescence did not induce robust
up-regulation of HLA-DRA or HLA-DRB, as detected by
quantitative real-time reverse transcriptaseePCR (Figure 2e). Finally, no MHC class II protein could be detected by
Western blotting (data not shown). These findings suggest that
MHC class II induction is specific to OIS in some cell types
and not replicative senescence. p
To establish whether MHC class II up-regulation in mela-
nocytes is specific to activated BRAFV600E or also triggered
by other perturbations of melanoma oncogenic and tumor
suppressor pathways, melanocytes were transduced with
activated oncogenes, HRASG12V and NRASQ61K, activated
MEK1Q56P (Emery et al., 2009), and activated myrAKT, as
well as two short hairpin RNAs to stably knock down PTEN
(Figure 2f). Ectopic expression of each of these oncogenes
and knockdown of PTEN resulted in senescence as deter-
mined by positive staining for SA ß-gal (Figure 2g, left, and
see Supplementary Figure S5 online) and lack of proliferation
indicated by the absence of EdU incorporation (Figure 2g,
right). Expression
of
NRASQ61K,
BRAFV600E,
and
MEK1Q56P resulted in robust up-regulation of both HLA-
DRA and HLA-DRB, whereas expression of HRASG12V
gave rise to a significantly weaker up-regulation of both. In
marked contrast, myrAKT expression and PTEN knockdown
did
not
result
in
detectable
HLA-DR
up-regulation
(Figure 2h). In contrast to results reported here, PTEN
knockdown has previously been reported to not cause in-
duction of senescence (Vredeveld et al., 2012). There could
be many reasons for this apparent discrepancy—genetic and/
or epigenetic differences in the melanocytes, cell culture
conditions, and others. Regardless, these results suggest that,
at least under conditions used here, MHC class II induction is
specific to aberrant mitogenic signaling through the RAS/
BRAF/ERK pathway but not the PTEN-Akt signaling pathway. Up-regulation of the major components of MHC class II
mRNAs
HLA-DRA
and
HLA-DRB
was
confirmed
by
quantitative
real-time
reverse
transcriptaseePCR
(Figure 1d). Expression of BRAFV600E also enhanced
expression of ectopic HLA-DRA and HLA-DRB GFP fusion
proteins (Figure 1e). Because this increase is independent
of
the
genes’
normal
transcription
control
elements,
this also suggests at least some level of posttranscriptional
regulation. Expression of endogenous HLA-DR protein
in melanocytes upon OIS was shown by Western blot
analysis (Figure 1f) and immunofluorescence (Figure 1g,
Supplementary Figure S2 online). RESULTS J
y
Oncogene-Carrying Melanocytes Activate MHC II Figure 2. Expression of MHC class II is specific to melanocytes and OIS. (a) Western blot of BRAFV600E expression in melanocytes, keratinocytes,
and fibroblasts transduced with a vector encoding BRAFV600E (B) or control vector (V). (b) HLA-DRA and HLA-DRB transcript levels detected by
quantitative real-time reverse transcriptaseePCR analysis, in melanocytes (mel), fibroblasts (fib), or keratinocytes (ker). ND indicates no signal detected. (c) Staining for SA ß-gal activity in melanocytes in exponential growth phase (PD 26) or at replicative senescence (PD 43). Scale bar ¼ 50 mm. (d) Quantification of SA ß-gale and BrdU-positive melanocytes. (e) HLA-DRA and HLA-DRB transcript levels in melanocytes detected by quantitative
real-time reverse transcriptaseePCR. (f) Western blots of HRASG12V, NRASQ61K, BRAFV600E, MEKQ56P, and myrAKT expression and knockdown
of PTEN. (g) Quantification of SA ß-gal staining (left) and EdU incorporation (right) of melanocytes transduced as indicated. (h) HLA-DRA and
HLA-DRB transcript levels detected by quantitative real-time reverse transcriptaseePCR of melanocytes transduced as indicated. (i) Western blot Figure 2. Expression of MHC class II is specific to melanocytes and OIS. (a) Western blot of BRAFV600E expression in melanocytes, keratinocytes,
and fibroblasts transduced with a vector encoding BRAFV600E (B) or control vector (V). (b) HLA-DRA and HLA-DRB transcript levels detected by
quantitative real-time reverse transcriptaseePCR analysis, in melanocytes (mel), fibroblasts (fib), or keratinocytes (ker). ND indicates no signal detected. (c) Staining for SA ß-gal activity in melanocytes in exponential growth phase (PD 26) or at replicative senescence (PD 43). Scale bar ¼ 50 mm. (d) Quantification of SA ß-gale and BrdU-positive melanocytes. (e) HLA-DRA and HLA-DRB transcript levels in melanocytes detected by quantitative
real-time reverse transcriptaseePCR. (f) Western blots of HRASG12V, NRASQ61K, BRAFV600E, MEKQ56P, and myrAKT expression and knockdown
of PTEN. (g) Quantification of SA ß-gal staining (left) and EdU incorporation (right) of melanocytes transduced as indicated. (h) HLA-DRA and
HLA DRB transcript levels detected by quantitative real time reverse transcriptaseePCR of melanocytes transduced as indicated (i) Western blot Figure 2. Expression of MHC class II is specific to melanocytes and OIS. (a) Western blot of BRAFV600E expr ass II is specific to melanocytes and OIS. (a) Western blot of BRAFV600E expression in melanocytes, keratinocytes, g
p
p
y
p
y
y
and fibroblasts transduced with a vector encoding BRAFV600E (B) or control vector (V). RESULTS A significant fraction of
HLA-DR was localized at the plasma membrane of se-
nescent cells (Figure 1g, Supplementary Figure S2b),
consistent with a role in antigen presentation. g
p
To establish whether BRAFV600E-associated MHC class
II expression is cell-type restricted, we transduced mela-
nocytes, primary human fibroblasts (IMR90), and primary
human epidermal keratinocytes with BRAFV600E or con-
trol vector (Figure 2Aa). In contrast to BRAFV600E-
transduced melanocytes, neither fibroblasts nor keratino-
cytes exhibited significant up-regulation of MHC class II
transcript levels (Figure 2b). Furthermore, gene expression
profiling
of
fibroblasts
transduced
with
BRAFV600E
showed
marked
down-regulation
of
proliferation-
promoting
genes
and
up-regulation
of
inflammatory/
senescence-associated secretory phenotype genes charac-
teristic of senescence (see Supplementary Figure S3 online)
and confirmed no significantly up-regulated MHC class II
genes
(see
Supplementary
Figure
S4
online). These results together suggest that MHC class II induction
is not a common feature of all primary cell types in
response to OIS (fibroblasts) and/or oncogene expression
(keratinocytes). Because MHC class II induction in BRAFV600E mutant
melanocytes occurs concomitantly with induction of senes-
cence, we wished to elucidate whether MHC class II in-
duction is dependent on known effectors of the senescence
program. In human cells, an intact p53 or pRB tumor sup-
pressor pathway is necessary for initiation and maintenance
of the senescence program (Salama et al., 2014), and aboli-
tion of p53/pRB signaling by ectopic expression of SV40
T-antigen disrupts most, if not all, hallmarks of senescence
(Shay et al., 1991). To test whether MHC class II induction is
abolished by ectopic expression of SV40 T antigen, we co-
expressed
BRAFV600E
together
with
SV40
T
antigen
(Figure 2i). As expected, T-antigen prevented the growth
arrest and SA ß-gal staining associated with senescence in
BRAF-expressing melanocytes (Figure 2j, Supplementary
Figure S6 online). Moreover, co-expression of SV40 T anti-
gen abolished virtually all of the MHC class II induction
(Figure 2k). This suggests that MHC class II induction is not
only initiated by expression of oncogenic BRAFV600E but
requires at least some elements of the p53/pRB-dependent
senescence effector pathways. In addition to activated oncogenes, other triggers also
initiate cell senescence. For example, so-called replicative
senescence, which results from excess rounds of cell division
(Salama et al., 2014). To test whether MHC class II up-
regulation is common to different modes of senescence, we www.jidonline.org 2199 J van Tuyn et al. J van Tuyn et al. RESULTS (b) HLA-DRA and HLA-DRB transcript levels detected by
quantitative real-time reverse transcriptaseePCR analysis, in melanocytes (mel), fibroblasts (fib), or keratinocytes (ker). ND indicates no signal detected. (c) Staining for SA ß-gal activity in melanocytes in exponential growth phase (PD 26) or at replicative senescence (PD 43). Scale bar ¼ 50 mm. (d) Quantification of SA ß-gale and BrdU-positive melanocytes. (e) HLA-DRA and HLA-DRB transcript levels in melanocytes detected by quantitative
real-time reverse transcriptaseePCR. (f) Western blots of HRASG12V, NRASQ61K, BRAFV600E, MEKQ56P, and myrAKT expression and knockdown
of PTEN. (g) Quantification of SA ß-gal staining (left) and EdU incorporation (right) of melanocytes transduced as indicated. (h) HLA-DRA and
HLA-DRB transcript levels detected by quantitative real-time reverse transcriptaseePCR of melanocytes transduced as indicated. (i) Western blot Journal of Investigative Dermatology (2017), Volume 137
2200 Journal of Investigative Dermatology (2017), Volume 137
2200 2200 J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Fi
re
m
ex
ce
Ca
RN
re
Co
tw
(n
an
bo
pa
(b
At
co
ve
ve
pa
of
ge
no
ex
an
lin
BR
m
ta
po
w
re
an
de
de
n
de
re
de
n
co
se Figure 3. CIITA is a candidate
regulator of MHC class II in OIS
melanocytes. (a) Whole transcriptome
expression correlation network
centered on CIITA generated from The
Cancer Genome Atlas melanoma
RNA sequencing data. Genes are
represented as nodes and a Pearson
Correlation Coefficient (PCC) between
two genes of at least 0.6 as an edge
(n ¼ 375). CIITA is shaded dark red,
and HLA genes are light red. The
boxed highlighted region in the left
panel is shown in the right panel. (b) Scatterplots of The Cancer Genome
Atlas melanoma RNA sequencing data
comparing the expression of CIITA
versus HLA-DRA (left) and CIITA
versus HLA-DRB1 (right) in 375
patients. (c) Representative University
of California Santa Cruz (UCSC)
genome browser tracks of library
normalized RNA sequencing
expression at HLA-DRA, HLA-DRB1,
and CIITA in seven melanoma cell
lines, melanocytes infected with
BRAFV600E, and uninfected
melanocytes. Y-axis shows sequence
tags per million tags; x-axis shows
position along the HLA-DRA gene,
with boxed exons. (d) Quantitative
real-time reverse transcriptaseePCR
analysis of CIITA transcript levels
detected in melanocytes. Graph
depicts means standard deviation,
n ¼ 4. (e) CIITA transcript levels
detected by quantitative real-time
reverse transcriptaseePCR. showing expression of BRAFV600E and SV40 T antigen. (j) Quantification of SA ß-gal staining and EdU incorporation of melanocytes transduced with
BRAFV600E and SV40 T-antigen. (k) All graphs show means standard deviation, n ¼ 4. MHC, major histocompatibility complex; SA ß-gal,
senescence-associated b-galactosidase; SA-Bgal, senescence-associated b-galactosidase.
= J van Tuyn et al. RNAs (Figure 4h) inhibited HLA-DRA and HLA-DRB
expression induced by recombinant IL-1ß (Figure 4k). Knockdown of CIITA with two different short hairpin RNAs
also tended to decrease BRAFV600E-induced expression of
HLA-DRA and HLA-DRB, and with the most effective short
hairpin RNA, the effect on HLA-DRB expression was sig-
nificant (P < 0.05) (Figure 4i). The reduced effectiveness of
CIITA knockdown in blocking the effects of activated BRAF
compared with IL-1ß suggests that BRAFV600E can act via
additional signaling effectors besides CIITA. Consistent
with an IL1ß-CIITA-MHC II pathway, ectopic expression of
CIITA was sufficient to induce expression of HLA-DRA and
HLA-DRB, but not IL-1ß, in melanocytes (Figure 4j). Together,
these
results
indicate
that
IL-1ßeinduced
expression of CIITA is a major pathway for expression of
MHC class II in OIS melanocytes. BRAFV600E-expressing
fibroblasts up-regulate IL-1ß but neither CIITA nor MHC
II (see Supplementary Figure S4). This suggests that func-
tional coupling between IL-1ß and CIITA occurs in OIS
melanocytes but not fibroblasts. RNAs (Figure 4h) inhibited HLA-DRA and HLA-DRB
expression induced by recombinant IL-1ß (Figure 4k). Knockdown of CIITA with two different short hairpin RNAs
also tended to decrease BRAFV600E-induced expression of
HLA-DRA and HLA-DRB, and with the most effective short
hairpin RNA, the effect on HLA-DRB expression was sig-
nificant (P < 0.05) (Figure 4i). The reduced effectiveness of
CIITA knockdown in blocking the effects of activated BRAF
compared with IL-1ß suggests that BRAFV600E can act via
additional signaling effectors besides CIITA. Consistent
with an IL1ß-CIITA-MHC II pathway, ectopic expression of
CIITA was sufficient to induce expression of HLA-DRA and
HLA-DRB, but not IL-1ß, in melanocytes (Figure 4j). Together,
these
results
indicate
that
IL-1ßeinduced
expression of CIITA is a major pathway for expression of
MHC class II in OIS melanocytes. BRAFV600E-expressing
fibroblasts up-regulate IL-1ß but neither CIITA nor MHC
II (see Supplementary Figure S4). This suggests that func-
tional coupling between IL-1ß and CIITA occurs in OIS
melanocytes but not fibroblasts. To confirm this correlation, we analyzed RNA-seq data from
seven different melanoma-derived cell lines (Pawlikowski
et al., 2013) and found that CIITA transcript levels corre-
lated strongly with HLA-DRA and HLA-DRB levels across this
panel of melanoma lines (Figure 3c). Moreover, we found
that
MHC
class
II
induction
in
melanocytes
upon
BRAFV600E-mediated OIS is also accompanied by increased
CIITA expression (Figure 3d). Like expression of MHC class II,
oncogene-induced expression of CIITA was abolished by
SV40 T-antigen (Figure 3e). J van Tuyn et al. Consistent with up-regulation of
MHC class II in OIS melanocytes, but not other modes
of senescence (Figure 2), we did not observe up-regulation of
CIITA in OIS fibroblasts (see Supplementary Figure S4). Together, these data from melanoma tumors, cell lines, and
primary human melanocytes indicate that CIITA is a likely
driver of HLA-DRA and HLA-DRB in OIS primary human
melanocytes. In cells known to conditionally express CIITA, expression is
frequently induced by extracellular ligands (Trombetta and
Mellman, 2005). Significantly, naı¨ve melanocytes exposed
to medium from OIS melanocytes up-regulated CIITA tran-
scripts (Figure 4a) in conjunction with MHC class II expres-
sion
(Figure
4a). To
identify
the
extracellular
factors
responsible for up-regulation of CIITA and MHC class II
expression, we probed conditioned medium with an anti-
body array. Medium from BRAFV600E OIS melanocytes
contained increased amounts of inflammatory cytokines
compared with conditioned medium from proliferating cells
(Figure 4b, Supplementary Table S4 online), including IL-1ß
(in the form of either uncleaved pro-IL1ß or cleaved mature
IL-1ß), CCL7, CXCL5, CXCL1, vascular endothelial growth
factor, and CCL5. The presence of one or more IL-1ß (180 9
pg/ml, n ¼ 4) isoforms in the extracellular medium of OIS
melanocytes was confirmed by ELISA (Figure 4c), and robust
up-regulation of IL-1ß mRNA transcripts was detected by
quantitative real-time reverse transcriptaseePCR (Figure 4d). When added as recombinant proteins to primary human
melanocytes, from a panel of secreted cytokines, only mature
IL-1ß was able to induce CIITA and MHC class II expression
(Figure 4e), but without accompanying activation of senes-
cence, as evidenced by lack of SA ß-gal staining and unim-
peded
DNA
synthesis
(Figure
4f). Conversely,
partial
knockdown of IL-1ß using three independent short hairpin
RNAs (Figure 4g) reduced MHC class II induction by
BRAFV600E (Figure 4g). Although we have not formally
confirmed secretion of cleaved mature IL-1ß in this study
(rather than uncleaved proeIL-1ß), previous studies have
shown that OIS cells do secrete processed mature IL-1ß
(Acosta et al., 2013), and IL-1a and IL-1ß are key upstream
regulators of the senescence-associated secretory phenotype
(Acosta et al., 2013; Orjalo et al., 2009). In sum, consistent
with these previous studies, our studies indicate a central role
for extracellular IL-1ß in induction of MHC class II. RESULTS Graph
depicts means standard deviation,
n ¼ 4. MHC, major histocompatibility
complex; OIS, oncogene-induced
senescence. MHC class II up-regulation is mediated by an IL-1ßeCIITA
signaling loop melanoma
gene
expression
datasets
from
the
Cancer
Genome Atlas (TCGA; http://cancergenome.nih.gov/). This
showed that, across all these datasets, expression of both
HLA-DRA and HLA-DRB correlated most strongly with other
HLA molecules (e.g., HLA-DQ and HLA-DP); other mole-
cules involved in antigen presentation (e.g., CD74); and
CIITA, a transcription factor already known to drive expres-
sion of HLA-DRA and HLA-DRB in dendritic cells (Figure 3a,
3b) (Muhlethaler-Mottet et al., 1997). Conversely, expression
of
CIITA
correlated
most
strongly
with
expression
of
MHC class II antigen presentation molecules (Figure 3a, 3b). g
g
p
Even though expression of SV40 T antigen suppressed in-
duction of HLA-DRA and HLA-DRB (Figure 2iek), it is well
documented that MHC class II expression is typically found
in 50e60% of freshly isolated melanomas (Taramelli et al.,
1986). We exploited this observation from the melanocytic
lineage to gain insight into candidate regulators of MHC class
II in primary human melanocytes. We assessed the correla-
tion between mRNA expression of HLA-DRA and HLA-DRB
and all other genes in the publicly available skin cutaneous Even though expression of SV40 T antigen suppressed in-
duction of HLA-DRA and HLA-DRB (Figure 2iek), it is well
documented that MHC class II expression is typically found
in 50e60% of freshly isolated melanomas (Taramelli et al.,
1986). We exploited this observation from the melanocytic
lineage to gain insight into candidate regulators of MHC class
II in primary human melanocytes. We assessed the correla-
tion between mRNA expression of HLA-DRA and HLA-DRB
and all other genes in the publicly available skin cutaneous www.jidonline.org 2201 J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Oncogene activation causes localization of melanocytes to
lymph nodes and T-cell activation y
p
Previously, a mouse model expressing activated NRASQ61K
in melanocytes under control of a tyrosinase promoter (Tyr-
NrasQ61K) was shown to be hyperpigmented because of an
excess of melanocytes in the skin but also to contain mela-
nocytes in the lymph nodes (Ackermann et al., 2005). Extending this observation in these mice, we showed that
infiltration of pigmented melanocytes occurs into skin-
draining (Figure 5a, inguinal and brachial) nodes but not
into noneskin-draining nodes (Figure 5a, mesenteric) and
spleen (Figure 5a, spleen). Although immunohistochemical
analysis showed melanotic material dispersed throughout the
skin-draining
lymph
nodes,
particularly
in
older
mice
(Figure 5a), immunofluorescence analysis in lymph nodes of
albino Tyr-NrasQ61K (but not wild-type) mice showed cells
expressing the melanocyte marker DCT and exhibiting den-
dritic features characteristic of melanocytes predominantly
localized adjacent to the subcapsular sinus of the lymph
node (Figure 5b, Supplementary Figure S8a online). There-
fore, to some extent, the melanotic material in the interior
cortex of the node might reflect residual cell debris, including
melanin
(oxidized
tyrosine
polymers),
after
phagocytic
digestion of melanocytes. To eliminate the possibility that
localization of melanocytes to lymph nodes is unique to Tyr-
NrasQ61K mice, we also confirmed in another mouse model
of inducible BRAFV600E in melanocytes (Tyr-Cre-Er:LSL-
BrafV600E) (Mercer et al., 2005) that 4 weeks after oncogene
activation, predominantly in the skin of young adult mice
(through topical application of tamoxifen), melanocytes also
accumulated in skin-draining brachial and inguinal lymph
nodes (see Supplementary Figure S8b). We next tested whether IL-1ßemediated up-regulation
of MHC class II also depends on CIITA. In support of this
idea, stimulation of melanocytes with IFN-g, a well-known
inducer of CIITA (Trombetta and Mellman, 2005), also up-
regulated expression of HLA-DRA and HLA-DRB (see
Supplementary Figure S7 online). More pointedly, partial
knockdown of CIITA using two different short hairpin As noted previously (Ackermann et al., 2005), compared
with wild-type mice, the lymph nodes of Tyr-NrasQ61K
mice were enlarged (Figure 5c, Supplementary Figure S8c),
and their size progressively increased over at least the first
several months after birth (Figure 5c). Moreover, the
Tyr-NrasQ61K mice exhibited more melanocytes in the
nodes than the Tyr-Cre-Er:LSL-BrafV600E mice (compare Journal of Investigative Dermatology (2017), Volume 137
202 2202 J van Tuyn et al. J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. Oncogene activation causes localization of melanocytes to
lymph nodes and T-cell activation (h) qRT-PCR analysis of CIITA,
HLA-DRA, and HLA-DRB transcripts in melanocytes induced with vehicle or recombinant IL-1ß and transduced with shRNAs against CIITA or nontargeting control (NTC). (i) qRT-PCR analysis of CIITA, HLA-DRA, and HLA-DRB transcripts in melanocytes transduced with vector or BRAFV600E and an shRNA against CIITA or nontargeting
control (NTC). Graphs depict means standard deviation, n ¼ 4. *P < 0.05. (j) qRT-PCR analysis of CIITA, HLA-DRA, HLA-DRB, and IL-1ß transcript levels in
melanocytes transduced with control vector (V), BRAFV600E (B), or CIITA (C) overexpression vectors. Graphs depict means standard deviation, n ¼ 4. MHC, major
histocompatibility complex; qRT-PCR, quantitative real-time reverse transcriptaseePCR; SA ß-gal, senescence-associated b-galactosidase; shRNA, short hairpin RNA. Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
conditioned medium for 14 days from mock, vector, and BRAFV600E-transduced melanocytes. Graphs depict means standard deviation, n ¼ 4. (b) Heat map of
cytokinesinconditionedculturemedium.SeeSupplementaryTableS4forfoldchangeandsignificanceincytokinelevels.(c)QuantificationbyELISAofIL-1ßinconditioned
culture medium. Graph shows mean standard deviation, n ¼ 4. *P < 0.0001. (d) qRT-PCR analysis of IL-1ß transcripts. Graphs depict means standard deviation,
n ¼ 4. (e) CIITA, HLA-DRA, and HLA-DRB transcripts detected by qRT-PCR of mock or cytokine-treated melanocytes. Cells were cultured for 6 days in culture medium
supplemented with 10 ng/ml of the indicated cytokine. Graph depicts means standard deviation, n ¼ 3. (f) Quantification of EdU incorporation and SA ß-gal staining of
melanocytes. Graphs are means standard deviation, n ¼ 4. (g) qRT-PCR analysis of IL-1ß and HLA-DRA transcripts in melanocytes transduced with vector (V) or
BRAFV600E (B) in combination with an shRNA to IL-1ß or nontargeting control (NTC). Graphs depict means standard deviation, n ¼ 4. (h) qRT-PCR analysis of CIITA,
HLA-DRA, and HLA-DRB transcripts in melanocytes induced with vehicle or recombinant IL-1ß and transduced with shRNAs against CIITA or nontargeting control (NTC). (i) qRT-PCR analysis of CIITA, HLA-DRA, and HLA-DRB transcripts in melanocytes transduced with vector or BRAFV600E and an shRNA against CIITA or nontargeting
control (NTC). Graphs depict means standard deviation, n ¼ 4. *P < 0.05. (j) qRT-PCR analysis of CIITA, HLA-DRA, HLA-DRB, and IL-1ß transcript levels in
melanocytes transduced with control vector (V), BRAFV600E (B), or CIITA (C) overexpression vectors. Graphs depict means standard deviation, n ¼ 4. Oncogene activation causes localization of melanocytes to
lymph nodes and T-cell activation (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
conditioned medium for 14 days from mock, vector, and BRAFV600E-transduced melanocytes. Graphs depict means standard deviation, n ¼ 4. (b) Heat map of
cytokinesinconditionedculturemedium.SeeSupplementaryTableS4forfoldchangeandsignificanceincytokinelevels.(c)QuantificationbyELISAofIL-1ßinconditioned
culture medium. Graph shows mean standard deviation, n ¼ 4. *P < 0.0001. (d) qRT-PCR analysis of IL-1ß transcripts. Graphs depict means standard deviation,
n ¼ 4. (e) CIITA, HLA-DRA, and HLA-DRB transcripts detected by qRT-PCR of mock or cytokine-treated melanocytes. Cells were cultured for 6 days in culture medium
supplemented with 10 ng/ml of the indicated cytokine. Graph depicts means standard deviation, n ¼ 3. (f) Quantification of EdU incorporation and SA ß-gal staining of
melanocytes. Graphs are means standard deviation, n ¼ 4. (g) qRT-PCR analysis of IL-1ß and HLA-DRA transcripts in melanocytes transduced with vector (V) or
BRAFV600E (B) in combination with an shRNA to IL-1ß or nontargeting control (NTC). Graphs depict means standard deviation, n ¼ 4. (h) qRT-PCR analysis of CIITA,
HLA-DRA, and HLA-DRB transcripts in melanocytes induced with vehicle or recombinant IL-1ß and transduced with shRNAs against CIITA or nontargeting control (NTC). (i) qRT-PCR analysis of CIITA, HLA-DRA, and HLA-DRB transcripts in melanocytes transduced with vector or BRAFV600E and an shRNA against CIITA or nontargeting
control (NTC) Graphs depict means standard deviation n ¼ 4 *P < 0 05 (j) qRT-PCR analysis of CIITA HLA-DRA HLA-DRB and IL-1ß transcript levels in
J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
conditioned medium for 14 days from mock, vector, and BRAFV600E-transduced melanocytes. Graphs depict means standard deviation, n ¼ 4. (b) Heat map of
cytokinesinconditionedculturemedium.SeeSupplementaryTableS4forfoldchangeandsignificanceincytokinelevels.(c)QuantificationbyELISAofIL-1ßinconditioned
culture medium. Graph shows mean standard deviation, n ¼ 4. *P < 0.0001. (d) qRT-PCR analysis of IL-1ß transcripts. Graphs depict means standard deviation,
n ¼ 4. (e) CIITA, HLA-DRA, and HLA-DRB transcripts detected by qRT-PCR of mock or cytokine-treated melanocytes. Cells were cultured for 6 days in culture medium
supplemented with 10 ng/ml of the indicated cytokine. Graph depicts means standard deviation, n ¼ 3. (f) Quantification of EdU incorporation and SA ß-gal staining of
melanocytes. Graphs are means standard deviation, n ¼ 4. Oncogene activation causes localization of melanocytes to
lymph nodes and T-cell activation (g) qRT-PCR analysis of IL-1ß and HLA-DRA transcripts in melanocytes transduced with vector (V) or
BRAFV600E (B) in combination with an shRNA to IL-1ß or nontargeting control (NTC). Graphs depict means standard deviation, n ¼ 4. (h) qRT-PCR analysis of CIITA, Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
diti
d
di
f
14 d
f
k
t
d BRAFV600E t
d
d
l
t
G
h d
i t
t
d d d
i ti
4 (b) H
t
f Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
conditioned medium for 14 days from mock, vector, and BRAFV600E-transduced melanocytes. Graphs depict means standard deviation, n ¼ 4. (b) Heat map of
cytokinesinconditionedculturemedium.SeeSupplementaryTableS4forfoldchangeandsignificanceincytokinelevels.(c)QuantificationbyELISAofIL-1ßinconditioned
culture medium. Graph shows mean standard deviation, n ¼ 4. *P < 0.0001. (d) qRT-PCR analysis of IL-1ß transcripts. Graphs depict means standard deviation,
n ¼ 4. (e) CIITA, HLA-DRA, and HLA-DRB transcripts detected by qRT-PCR of mock or cytokine-treated melanocytes. Cells were cultured for 6 days in culture medium Figure 4. Expression of MHC class II is controlled by an IL-1ßeCIITA loop. (a) qRT-PCR analysis of CIITA and HLA-DRA transcripts in melanocytes exposed to
conditioned medium for 14 days from mock, vector, and BRAFV600E-transduced melanocytes. Graphs depict means standard deviation, n ¼ 4. (b) Heat map of
cytokinesinconditionedculturemedium.SeeSupplementaryTableS4forfoldchangeandsignificanceincytokinelevels.(c)QuantificationbyELISAofIL-1ßinconditioned
culture medium. Graph shows mean standard deviation, n ¼ 4. *P < 0.0001. (d) qRT-PCR analysis of IL-1ß transcripts. Graphs depict means standard deviation,
n ¼ 4. (e) CIITA, HLA-DRA, and HLA-DRB transcripts detected by qRT-PCR of mock or cytokine-treated melanocytes. Cells were cultured for 6 days in culture medium
supplemented with 10 ng/ml of the indicated cytokine. Graph depicts means standard deviation, n ¼ 3. (f) Quantification of EdU incorporation and SA ß-gal staining of
melanocytes. Graphs are means standard deviation, n ¼ 4. (g) qRT-PCR analysis of IL-1ß and HLA-DRA transcripts in melanocytes transduced with vector (V) or
BRAFV600E (B) in combination with an shRNA to IL-1ß or nontargeting control (NTC). Graphs depict means standard deviation, n ¼ 4. J van Tuyn et al. Scale
( )
i
l l
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WT
NrasQ61K
a d
DCT
b
C
I
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0
50
100
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20
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NRASQ61K
wt
age (days)
Inguinal node size (mm3) b DCT c Ki67
CT
Merge d
DCT e
wt
NRASQ61K
0
2×10 06
4×10 06
6×10 06
8×10 06
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total cells
wt
NRASQ61K
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4×10 06
#
CD3+ lymphocytes DCT d e e NRAS
NRAS
g
CSFE
counts
CSFE
CSFE
CSFE
neg
LPS
vector
BRAFV600E
neg
LPS (pos) vector BRAFV600E
0
20
40
60
P < 0.0001
replicating CD3+ cells (%)
f g R
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GO:0050764
regulation of phagocytosis
6
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0.37%
GO:0045807
positive regulation of endocytosis
6
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1.62%
GO:0048002
antigen processing and presentation of peptide antigen
6
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GO:0030100
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GO:0060627
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h h j
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WT
NrasQ61K
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H2-AB1
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TGFB1
IGHG2C
2
-2
0
Figure 5. Oncogene-expressing melanocytes localize to skin-draining lymph nodes. (a) Hematoxylin and eosin-stained sections of lymph nodes and spleen of
WT and Tyr-NrasQ61K mice. Scale bar ¼ 100 mm. (b) DCT (green)-expressing cells in lymph node. DAPI, blue. C, cortex; Sub S, subcapsular sinus. Scale
bar ¼ 100 mm. (c) Inguinal lymph node size plotted against age of mouse. Each point is a single node (two nodes per mouse). (d) Melanocytes detected by DCT
(green) in lymph nodes of albino Tyr-NrasQ61K transgenic mice and cycling cells detected by Ki67 (red). Scale bar ¼ 100 mm. (e) Quantification of total j
i
WT
NrasQ61K
WT
NrasQ61K
STON2
VAMP2
PTX3
SLC11A1
CD63
SIRPA
H2-Q10
H2-Q6
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H2-AB1
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2
-2
0 j
i
WT
NrasQ61K
STON2
VAMP2
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H2-Q6
TAPBP
H2-AB1
CTSE
TGFB1
IGHG2C
2
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0 j
WT
NrasQ61K i Figure 5. Oncogene-expressing melanocytes localize to skin-draining lymph nodes. J van Tuyn et al. J van Tuyn et al. J
y
Oncogene-Carrying Melanocytes Activate MHC II brachial lymph node
Inguinal lymph node
mesenteric lymph node
spleen
WT
NrasQ61K
a
c
e
d
Ki67
DCT
b
C
Sub S
C
0
50
100
150
200
250
0
10
20
30
40
50
NRASQ61K
wt
age (days)
Inguinal node size (mm3)
wt
NRASQ61K
0
2×10 06
4×10 06
6×10 06
8×10 06
1×10 07
*
total cells
wt
NRASQ61K
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#
CD3+ lymphocytes
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CSFE
counts
CSFE
CSFE
CSFE
neg
LPS
vector
BRAFV600E
neg
LPS (pos) vector BRAFV600E
0
20
40
60
P < 0.0001
replicating CD3+ cells (%)
R
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GO:0050764
regulation of phagocytosis
6
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GO:0045807
positive regulation of endocytosis
6
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1.62%
GO:0048002
antigen processing and presentation of peptide antigen
6
7.49
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GO:0030100
regulation of endocytosis
8
6.72
0.28%
GO:0060627
regulation of vesicle-mediated transport
9
4.74
1.00%
h
j
i
WT
NrasQ61K
WT
NrasQ61K
STON2
VAMP2
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TGFB1
IGHG2C
2
-2
0
f
e 5. Oncogene-expressing melanocytes localize to skin-draining lymph nodes. (a) Hematoxylin and eosin-stained sections of lymph nodes and splee
nd Tyr-NrasQ61K mice. Scale bar ¼ 100 mm. (b) DCT (green)-expressing cells in lymph node. DAPI, blue. C, cortex; Sub S, subcapsular sinus. Oncogene activation causes localization of melanocytes to
lymph nodes and T-cell activation MHC, major
histocompatibility complex; qRT-PCR, quantitative real-time reverse transcriptaseePCR; SA ß-gal, senescence-associated b-galactosidase; shRNA, short hairpin RNA. www.jidonline.org 2203 J van Tuyn et al. (a) Hematoxylin and eosin-stained sections of lymph nodes and spleen of
WT and Tyr-NrasQ61K mice. Scale bar ¼ 100 mm. (b) DCT (green)-expressing cells in lymph node. DAPI, blue. C, cortex; Sub S, subcapsular sinus. Scale
bar ¼ 100 mm. (c) Inguinal lymph node size plotted against age of mouse. Each point is a single node (two nodes per mouse). (d) Melanocytes detected by DCT
(green) in lymph nodes of albino Tyr-NrasQ61K transgenic mice and cycling cells detected by Ki67 (red). Scale bar ¼ 100 mm. (e) Quantification of total Figure 5. Oncogene-expressing melanocytes localize to skin-draining lymph nodes. (a) Hematoxylin and eosin-stained sections of lymph nodes and spleen of
WT and Tyr-NrasQ61K mice. Scale bar ¼ 100 mm. (b) DCT (green)-expressing cells in lymph node. DAPI, blue. C, cortex; Sub S, subcapsular sinus. Scale
bar ¼ 100 mm. (c) Inguinal lymph node size plotted against age of mouse. Each point is a single node (two nodes per mouse). (d) Melanocytes detected by DCT
(green) in lymph nodes of albino Tyr-NrasQ61K transgenic mice and cycling cells detected by Ki67 (red). Scale bar ¼ 100 mm. (e) Quantification of total Journal of Investigative Dermatology (2017), Volume 137
2204 Journal of Investigative Dermatology (2017), Volume 137
2204 2204 J van Tuyn et al. Oncogene-Carrying Melanocytes Activate MHC II Tyr-NrasQ61K mice could be associated with immune acti-
vation or induction of immune tolerance, the latter by acti-
vation of regulatory T cells (Delacher et al., 2014). To
distinguish between these possibilities, we stained lymph
nodes
for
expression
of
FoxP3,
a
transcription
factor
expressed by regulatory T cells (Delacher et al., 2014). This
did not show an increase in the frequency of regulatory T
cells in lymph nodes from Tyr-NrasQ61K mice (Figure 5j). We conclude that oncogene-expressing, nonproliferating
primary melanocytes, directly or indirectly, facilitate an an-
tigen presentation function and potential immune activation
function in the lymph nodes. Figure 5a and Supplementary Figure S8b, NrasQ61K and
BrafV600E), paralleling the relative numbers of melano-
cytes in the skin of each model (Ackermann et al., 2005;
Dhomen et al., 2009). Figure 5a and Supplementary Figure S8b, NrasQ61K and
BrafV600E), paralleling the relative numbers of melano-
cytes in the skin of each model (Ackermann et al., 2005;
Dhomen et al., 2009). J van Tuyn et al. To determine the proliferative status of the melanocytes in
the lymph nodes, we used two-color immunofluorescence to
stain melanocyte-containing lymph nodes of wild-type and
Tyr-NRasQ61K albino mice for Ki67, a marker of cycling
cells, and DCT, a marker of melanocytes. DCT-positive me-
lanocytes in lymph nodes were invariably Ki67 negative,
whereas large numbers of surrounding lymphocytes stained
positive for Ki67 (Figure 5d). In fact, quantification of the cell
fractions from the nodes, showed a massive expansion of
nonmelanocyte (nonemelanin-containing) cells (Figure 5e,
left) and of CD3þ T cells in particular (Figure 5e, right),
suggesting that the melanocytes present in the lymph nodes,
directly or indirectly, induce a marked activation and
expansion of T cells in these nodes. In sum, the increase in
lymph node size appears to result primarily from expansion
of T-cell populations in melanocyte-containing nodes. y
p
To assess the significance of MHC class II expression in
human melanocytic neoplasia, we mined human melanoma
Cancer Genome Atlas data comparing expression of CIITA,
HLA-DRA, and HLA-DRB with patient survival. Remarkably,
high expression of each of these genes predicted improved
patient survival (see Supplementary Figure S10 online). Moreover, HLA-DRA and HLA-DRB are both components of
the recently defined “immune infiltration” gene expression
signature that is associated with good prognosis in this dis-
ease (The Cancer Genome Atlas Network, 2015; data not
shown). Of course, at least part of the CIITA, HLA-DRA, and
HLA-DRB could be expressed by infiltrating immune cells
themselves. However,
previous
studies
have
reported
expression of HLA-DR on melanoma cells (Barbieri et al.,
2011; Colloby et al., 1992; Pollack et al., 1981), and we
also confirmed expression of HLA-DRA, HLA-DRB, and
CIITA in a number of melanoma cell lines (Figure 3c). This
underscores the importance of MHC class II expression in
melanoma and is consistent with a tumor suppressor role for
MHC class II. p p
y
g
T-cell activation and proliferation can be stimulated by
MHC class II-mediated antigen presentation (Trombetta and
Mellman,
2005). To
investigate
whether
MHC
class
II-expressing melanocytes acquire the ability to activate T
cells, we performed the mixed leukocyte reaction in which
antigen-presenting cells stimulate proliferation of T cells. Indeed, BRAFV600E-expressing OIS melanocytes induced
cell division in Carboxyfluorescein diacetate succinimidyl
esterelabeled CD3þ cells in vitro, much more efficiently than
control melanocytes (2.3-fold, P < 0.0001) (Figure 5f, 5g). nonmelanocyte (nonpigmented, left) and CD3þ fraction (right) from pooled inguinal, brachial, and axillary lymph nodes per mouse. Graph plots means standard
deviation, n ¼ 3 per group. *7.2-fold difference, P ¼ 0.0049. #5.3-fold difference, P ¼ 0.0007. (f) FACS analysis of CSFE levels in CD3þ cells after co-culture
with WBCs (neg, solid line), WBCs incubated with LPS (LPS), and melanocytes transduced with vector or BRAFV600E. The plot with the negative sample result also
shows unstained WBCs (neg, dotted line). (g) Percentage of replicating CD3þ cells after induction with WBCs (neg), WBCs incubated with LPS (LPS), and vector or
BRAFV600E-transduced melanocytes. Bars represent means standard deviation, n ¼ 4. (h) Table of the five most enriched gene ontologies (FDR 5%) for
genes that are up-regulated by RNA sequencing (FDR 5%) in Tyr-NrasQ61K over WT lymph nodes. (i) Column clustered heat map of all genes in the ontologies
given in h for WT and Tyr-NrasQ61K lymph nodes. Genes are given by column and samples by row. The color intensity represents column z-score, where red
indicates more highly expressed and blue indicates more lowly expressed genes. (j) Representative Foxp3 staining (brown) of albino WTand Tyr-NrasQ61K mice.
Nuclei are counterstained with hematoxylin (blue). Scale bar ¼ 50 mm. Quantification of the number of positive cells in two NRAS61K mice and two WT littermates,
by calculating the average number positive cells from two slides per lymph node and counting three lymph nodes (two inguinal, one brachial) per mouse,
showed no significant difference between the nodes (160.8 21.1 vs. 174.3 27.6, n ¼ 2, P ¼ 0.83). CSFE, Carboxyfluorescein diacetate succinimidyl ester; FDR,
false discovery rate; ID, identification; LPS, lipopolysaccharide; neg, negative; WBC, white blood cell; WT, wild type.
= J van Tuyn et al. Although this assay using unpurified T cells does not allow us
to attribute T-cell activation to a direct physical interaction
between T cells and MHC II on melanocytes, it does show
that BRAFV600E mutant melanocytes are more able, either
directly by physical interaction or indirectly via other cell
types or secreted factors, to stimulate T cells than are control
melanocytes. ACKNOWLEDGMENTS We thank Neil Robertson and Billy Clark for RNA-seq analysis; Colin Nixon
for immunohistochemistry; Richard Marais, Catrin Pritchard, Friedrich Beer-
mann, Lynda Chin, and Marcus Bosenberg for mouse gene alleles; Daniel
Peeper for the BRAFV600E oncogene; and the Scottish National Blood
Transfusion Service (SNBTS) for excess human donor buffy coats. Work in the
laboratory of PDA was funded by CRUK program C10652/A16566 and
A17196, AI by Kay Kendall Leukemia Fund KKL1101, and EM by the Medical
Research Council grants MR/K021095/1 and MR/N023625/1. Thanks to all
members of the Adams laboratory for critical discussions. Cell culture Lightly pigmented neonatal human epidermal melanocytes, human
neonatal epidermal keratinocytes (both from Gibco, Waltham, MA)
IMR90 fibroblasts (ATCC, Manassas, VA) were cultured according to
supplier instructions. Infections with lentiviral vectors were per-
formed as described (Pawlikowski et al., 2013). In all experiments,
oncogene and control vector transduced cells were kept in culture
under selection for 2 weeks before being assayed for senescence and
gene expression. Alternatively, melanocytes were cultured in me-
dium supplemented with 10 ng/ml recombinant growth factor listed
in Figure 4e (all from Gibco, Waltham, MA) for 6 days. MATERIALS AND METHODS MATERIALS AND METHODS antigen-presenting dendritic cells, not nonspecifically via the
blood. Second, these cells do not appear to be malignant, as
judged by the absence of proliferation and their routine
occurrence in mice lacking any detectable melanoma. Both
the NRas and Braf models exhibit a long latency in progres-
sion to melanoma, of several months to more than a year
(Ackermann et al., 2005; Dhomen et al., 2009). In both
models, melanocytes were detected in nodes months before
any melanoma was detected and is expected (e.g., at 39 days
old). As noted previously, aggregates of apparently nonma-
lignant, nonproliferative, p16INK4a-expressing, melanocytic
nevus-like cells, in the absence of any concurrent or subse-
quent melanoma, have also been reported in the skin-
draining lymph nodes of humans (Mihic-Probst et al., 2003;
Patterson, 2004) (albeit not as frequently or markedly as
observed
in
the
Tyr-NrasQ61K
mouse
model). Third,
oncogene-expressing primary melanocytes appear to pro-
mote activation of the immune system. Oncogene-expressing
senescent melanocytes stimulated T-cell proliferation in vitro
in the mixed leukocyte reaction assay, and localization of
melanocytes to the nodes was accompanied by a large in-
crease in node-resident CD3þ T cells. RNA-seq analysis of
lymph nodes also showed gene expression signatures char-
acteristic
of
increased
antigen
presentation
in
the
melanocyte-containing lymph nodes of Tyr-NrasQ61K mice. The increase in T cells was not accounted for by an overt
increase in FoxP3-expressing tolerance-inducing regulatory T
cells. In sum, although we cannot, of course, formally rule
out the possibility that the node melanocytes are very early
and/or failed micrometastases, the collective data from mice
and humans at least suggest the possibility that oncogene-
expressing
premalignant
melanocytes
might
be
pro-
grammed to activate the adaptive immune system. Details
of
materials
and
methods
are
available
in
the
Supplementary
Materials
and
Methods
online
(see
also
Supplementary Tables S5, S6). Details
of
materials
and
methods
are
available
in
the
Supplementary
Materials
and
Methods
online
(see
also
Supplementary Tables S5, S6). Details
of
materials
and
methods
are
available
in
the
Supplementary
Materials
and
Methods
online
(see
also
Supplementary Tables S5, S6). Genetically modified mouse strains Mice carrying a tyrosinase promoter driven NrasQ61K gene
(Tyr-NrasQ61K) have been described (Ackermann et al., 2005). Mice conditionally expressing the mutant BrafV600E gene under
control of tyrosinase driven CRE-ER (Delmas et al., 2003) (Tyr-CRE-
ER:LSL-BrafV600E) have also been described (Dhomen et al., 2009). Albino mice carrying the Tyr-NrasQ61K allele were generated by
cross-breeding with the albino FVB/NJ (Taketo et al., 1991) strain. Control wild-type mice were littermate albino mice lacking the
Tyr-NRasQ61K transgene. All experiments were carried out in
compliance with UK Home Office guidelines at the Beatson Institute
for Cancer Research (Home Office PCD 60/2607) under project
license 60/4079. Microarray, RNA-seq, and The Cancer Genome Atlas data
Microarray and RNA-seq analysis of melanocytes transduced with
BRAF600E expression or control vectors has been described
(Pawlikowski et al., 2013); sequences are available from www.ncbi. nlm.nih.gov/geo (accession nos. GSE46818, GSE99397). g
p
y
Other caveats should also be considered. In general,
benign human nevi do not express MHC II, nor are they
associated with immune infiltration (Campoli et al., 2012;
Lyle et al., 2000). By IHC, we also found that nevi only
very rarely (<10%) express detectable MHC II. Conceivably,
benign human nevi represent a subset of OIS melanocytes
that have been selected for down-regulation of MHC II via
evasion of MHC II-mediated immune- editing. In apparent
contrast
to
the
data
presented
here,
vemurafenib,
a
BRAFV600E inhibitor, was previously found to up-regulate
IFN-mediated MHC II expression in A375 melanoma cells
(Sapkota et al., 2013). A wider comparison of the functional
relationship between BRAFV600E and expression of MHC II
in transformed melanoma cells, compared with primary OIS
melanocytes studied here, is justified. CONFLICT OF INTEREST The authors state no conflict of interest. SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at www. jidonline.org, and at http://dx.doi.org/10.1016/j.jid.2017.05.030. Notwithstanding these caveats and the overall complexity of
immune responses, composed of intricate temporally and
spatially controlled antagonistic and synergistic interactions
between many cell types, these data suggest a model whereby
oncogene-expressing
primary
melanocytes
up-regulate
expression of MHC class II via an IL-1ß/CIITA autocrine
loop. These melanocytes re-localize to the skin-draining
lymph nodes, where they appear able to directly or indi-
rectly stimulate proliferation of T cells. We propose that
the ability of oncogene-expressing primary melanocytes to
engage the adaptive immune system may facilitate tumor
suppression. DISCUSSION
h Here we show that oncogene activation in primary human
melanocytes is accompanied by up-regulation of MHC class
II antigen presentation molecules, and phenotypes and
functions suggestive of an antigen presentation role in vivo. Up-regulation of MHC class II molecules in OIS melanocytes
is triggered by senescence-associated secretory phenotype
factor IL-1ß, followed by IL-1ßemediated up-regulation of
CIITA, a master regulator of MHC class II expression
(Trombetta and Mellman, 2005). y
To
investigate
whether
melanocyte-containing
lymph
nodes of Tyr-NRasQ61K mice exhibited features of increased
antigen presentation, we harvested RNA from lymph nodes
and performed RNA-seq. This showed up- and down-
regulation of approximately 577 and 423 genes, respec-
tively (see Supplementary Figure S9 online). Remarkably, the
top five gene ontologies represented in the up-regulated
genes of Tyr-NRasQ61K nodes reflected increased antigen
presentation and associated processes, such as endocytosis
and vesicle-mediated transport (Figure 5h, 5i). In principle,
T-cell expansion and antigen presentation in lymph nodes of Several observations suggest that MHC class II expression
in
oncogene-expressing
melanocytes
has
a
dedicated
function. First, melanocytes are restricted to the skin-
draining nodes, suggesting that they reach the nodes specif-
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The pathogenicity of novel GUCY2D mutations in Leber congenital amaurosis 1 assessed by HPLC-MS/MS
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Abstract Citation: Feng X, Wei T, Sun J, Luo Y, Huo Y, Yu P,
et al. (2020) The pathogenicity of novel GUCY2D
mutations in Leber congenital amaurosis 1
assessed by HPLC-MS/MS. PLoS ONE 15(4):
e0231115. https://doi.org/10.1371/journal. pone.0231115 Leber congenital amaurosis (LCA) is a group of severe congenital retinal diseases. Variants
in the guanylate cyclase 2D gene (GUCY2D), which encodes guanylate cyclase 1 (ROS-
GC1), are associated with LCA1 and account for 6%–21% of all LCA cases. In this study, one
family with LCA1 was recruited from China. A combination of next generation sequencing and
Sanger sequencing was used to screen for disease-causing mutations. We found three novel
mutations (c.139delC, p.Ala49Profs*36; c.835G>A, p.Asp279Asn and c.2783G>A, p.Gly928-
Glu) in the GUCY2D gene. Proband III-2 carries mutations c.139delC and c.2783G>A, which
are inherited from the heterozygous mutation carriers, II-2 (c.139delC) and II-3 (c.2783G>A)
that possess c.139delC and c.2783G>A. Additionally, II-8 carries heterozygous mutation
c.835G>A. Sanger sequencing was used to confirm the presence of the three novel mutations
in other family members. Mutation c.139delC results in a truncated protein. Mutations
c.835G>A and c.2783G>A significantly reduce the catalytic activity of ROS-GC1. Our findings
highlight the gene variants range of LCA. Moreover, HPLC-coupled tandem mass spectrome-
try (HPLC-MS/MS) was used to analyze the concentration of 3’,5’-cyclic guanosine mono-
phosphate (cGMP), suggesting that HPLC-MS/MS is an effective alternative method to
evaluate the catalytic activity of wild-type and mutant ROS-GC1. Editor: Karl-Wilhelm Koch, Carl von Ossietzky
Universitat Oldenburg, GERMANY
Received: November 11, 2019
Accepted: March 16, 2020
Published: April 7, 2020
Copyright: © 2020 Feng et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Editor: Karl-Wilhelm Koch, Carl von Ossietzky
Universitat Oldenburg, GERMANY
Received: November 11, 2019
Accepted: March 16, 2020
Published: April 7, 2020 Copyright: © 2020 Feng et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files. PLOS ONE RESEARCH ARTICLE Abstract Funding: The study was supported by grants from
National Key R&D Program of China
(2018YFC1004900), the National Natural Science
Foundation of China (31371271, 81200662) and
the Natural Science Foundation of Zhejiang
Province (LZ14C060001, LY12H12010). In this
research, the funding organization exerted no role
in the design or conduct. BGI-Wuhan provided Xue Feng1☯, Tianying Wei1☯, Junhui Sun1, Yuqin Luo2, Yanan Huo3, Ping Yu1, Jiao Chen1,
Xiaoming Wei4, Ming Qi1*‡, Yinghui YeID5*‡ 1 Department of Cell Biology and Medical Genetics, School of Medicine Zhejiang University, Hangzhou,
Zhejiang, China, 2 Department of Reproductive Genetics, Women’s Hospital, School of Medicine Zhejiang
University, Hangzhou, Zhejiang, China, 3 Department of Eye Center, The Second Affiliated Hospital of
School of Medicine Zhejiang University, Hangzhou, Zhejiang, China, 4 BGI-Wuhan, Wuhan, China,
5 Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics, Ministry of
Education, and Women’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital School of
Medicine Zhejiang University, Hangzhou, Zhejiang, China a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 ☯These authors contributed equally to this work. ‡ MQ and YY also contributed equally to this work
* yeyh1999@zju.edu.cn (YY); mingqi@zju.edu.cn (MQ) PLOS ONE PLOS ONE The pathogenicity of novel GUCY2D mutations
in Leber congenital amaurosis 1 assessed by
HPLC-MS/MS Xue Feng1☯, Tianying Wei1☯, Junhui Sun1, Yuqin Luo2, Yanan Huo3, Ping Yu1, Jiao Chen1,
Xiaoming Wei4, Ming Qi1*‡, Yinghui YeID5*‡ Introduction Leber congenital amaurosis (LCA), accounts for at least 5% of all inherited retinal dystro-
phies, and is the earliest and most severe form of all inherited retinal dystrophies [1]. LCA is
generally inherited in an autosomal recessive manner [2–4] and characterized by genetic
and phenotypic heterogeneity. Currently, mutations in 20 genes are associated with LCA
[5]. The distribution of pathogenic genes vary considerably among different populations; 1 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 however, guanylate cyclase 2D (GUCY2D) is a prevalent LCA gene because mutations to
GUCY2D account for 6%-12% of all LCA (LCA1) cases [4, 5]. support in the form of salaries for authors
[Xiaoming Wei], but did not have any additional
role in the study design, data collection and
analysis, decision to publish, or preparation of the
manuscript. The specific roles of this author are
articulated in the ‘author contributions’ section. Guanylate cyclase 1 (ROS-GC1), encoded by GUCY2D, is expressed in rod and cone cells of
vertebrae retina and catalyzes the synthesis of 3’,5’-cyclic guanosine monophosphate (cGMP). ROS-GC1 is negatively controlled by a Ca2+ feedback loop because a reduction in Ca2+ con-
centration causes an increase in ROS-GC1 activity. However, the effects of the Ca2+ concentra-
tion on ROS-GC1 activity are indirect because this feedback loop is regulated by small Ca2
+-binding guanylate cyclase-activating proteins (GCAPs), which interact with overlapping
binding sites within the juxtamembrane domain (JMD), kinase homology domain (KHD) and
dimerization domain (DD) of ROS-GC1. In addition to these latter domains, ROS-GC1 also
possesses a leader sequence (LS), an extracellular domain (ECD), a transmembrane domain
(TM) and a cyclase catalytic domain (CCD) [6]. Currently, 127 GUCY2D point mutations in
different domains of ROS-GC1 cause protein dysfunction and subsequently result in LCA1
[5]. Competing interests: The authors report no
conflict of interests. BGI-Wuhan provided support
in the form of salaries for authors [Xiaoming Wei],
but this does not alter our adherence to PLOS ONE
policies on sharing data and materials. Abbreviations: CCD, cyclase catalytic domain; DD,
dimerization domain; ECD, extracellular domain;
GCAPs, guanylate cyclase-activating proteins;
GUCY2D, guanylate cyclase 2D; HPLC-MS/MS,
HPLC-coupled tandem mass-spectrometry; JMD,
juxtamembrane domain; KHD, kinase homology
domain; LCA, Leber congenital amaurosis; LS,
leader sequence; NGS, next-generation
sequencing; ROS-GC1, guanylate cyclase protein 1;
TM, transmembrane domain; wt, wild type. LCA patients A family with a 5-year-old proband (III-2) and two suspected patients (III-1 and III-3) was
recruited for this study. The proband was diagnosed with LCA at Guangdong Zhongshan Hos-
pital, Shanghai General Hospital and the Second Affiliated Hospital of the School of Medicine,
Zhejiang University. The pedigree was constructed for the proband based on information pro-
vided by the guardians. Ethics approval and consent to participate All procedures performed were in accordance with the Declaration of Helsinki and approved
by the ethical standards of the Institutional Review Board, Zhejiang University. Written
informed consent was obtained from all individuals who participated in this study and the
parent of children under 16. Introduction In the present study, targeted-next generation sequencing (NGS) was performed to screen
222 genes that are responsible for 24 kinds of ophthalmic genetic diseases in the proband. After confirming the results by Sanger sequencing, the identity of three novel variants of the
GUCY2D gene were found, c.139delC (p.Ala49Profs36), c.835G>A (p.Asp279Asn) and
c.2783G>A (p.Gly928Glu). Mutations c.139delC and c.2783G>A were carried by proband
III-2, and heterozygous mutation c.835G>A was carried by II-2. This study probes the patho-
genesis of LCA1 and addresses the effects of mutations on ROS-GC1 activity. The three novel
mutations may be suitable for LCA1 screening, and HPLC-MS/MS represents a convenient
and effective method for cGMP quantification. DNA isolation and qualification Total genomic DNA was extracted using the Relax Gene Blood DNA System (Tiangen, Beijing,
China) following the manufacturer’s instructions. All DNA was dissolved in sterilized double-
distilled water and kept at –20 ˚C until assayed. One percent agarose gels were used to monitor DNA degradation and contamination. All
DNA samples were examined for protein contamination (as indicated by the A260/A280 ratio)
and reagent contamination (indicated by the A260/A230 ratio) with a NanoDrop ND 1000 spec-
trophotometer (NanoDrop, Wilmington, DE, USA). 2 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 Targeted-next generation sequencing (NGS) DNA samples obtained from the proband were sequenced using microarray-based targeted-
NGS. A customized Agilent SureSelect All Exome Kit (Agilent Technologies, CA, USA) was
designed to capture 3093 exons (including 100 bp regions that flanked the exons) from 222
genes known to be associated with common genetic diseases, including retinitis pigmentosa,
Waardenburg syndrome, X-linked juvenile retinoschisis, crystalline retinitis pigmentosa, albi-
nism, LCA, Bardet Biedl syndrome and cone-rod dystrophy (Additional Table 1). The procedure
for the preparation of the libraries was consistent with standard protocols published previously
[7]. The data of targeted-NGS assay was analyzed by Illumina basecalling Software 1.7. Mutation validation by Sanger sequencing Sanger sequencing was used to validate candidate variants identified by NGS. Primers of the
GUCY2D gene (NG_009092.1) used in Sanger sequencing were designed by Primer-BLAST
(http://www.ncbi.nlm.nih.gov/tools/primer-blast/) and synthesized by Sangon Biotech (Shang-
hai, China) (Table 1). All amplifications were examined by electrophoresis using 2% agarose
gels and sequenced by BioSune Biotechnology Co., Ltd. (Shanghai, China). The sequencing
results were further compared and analyzed by Mutation Surveyor [8]. Construction of wild-type (wt) and mutant human ROS-GC1 recombinant
plasmids The cDNA of human ROS-GC1 was obtained from Gene Copoeia (EX-Z0715-M98). Primers
F and R containing XhoI and AgeI restriction sites were used to amplify ROS-GC1 (Table 2). The pEGFP-N1 vector was digested with XhoI and AgeI restriction enzymes. PCR amplifica-
tion product was sub-cloned into pEGFP-N1 using ClonExpress (Vazyme, Nanjing, China) to
give the recombinant plasmid pEGFP-GC1. Site-directed mutagenesis PCR was used to construct the ROS-GC1 mutants. Primers used
in site-directed mutagenesis PCR are shown in Table 2. Each mutant was achieved by two-step
PCRs using pEGFP-GC1 as the template. For c.835G>A (p.Asp279Asn) two pairs of primers,
F and r-835 and R-BamHI and f-835, were used in the first PCR step. Primers F and R-BamHI
were used in the second step. For c.2783G>A (p.Gly928Glu), primers F-BamHI and r-2783
and R and f-2783 were used in the first PCR step. Primers F-BamHI and R were used in the
second step. For each mutation, amplification products in the first step were cleaned (Axygen,
CA, USA), mixed and used as the template in the second PCR reaction. All final PCR amplifi-
cations were ligated into the digested pEGFP-N1 vector using ClonExpress. g
g
g
Recombinant plasmids pEGFP-GC1, pEGFP-Asp279Asn and pEGFP-Gly928Glu were
transformed into Escherichia coli DH5α cells. DNA was prepared by using a plasmid DNA
purification kit from Macherey-Nagel following the manufacturer’s instructions. Sanger
sequencing was used to verify sequences. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 PLOS ONE Table 1. Primers for mutation screening. Name
Sequence
Length (bp)
GUCY2D-exon1-F
GAAGCCAGGACAGATCCCAC
322
GUCY2D-exon1-R
GGAGGCGTCAGGGGTCA
GUCY2D-exon2-1-F
GCCCCAGTTAGTCTTCCCAG
550
GUCY2D-exon2-1-R
AGGGTTCACCGGACCCAC
GUCY2D-exon2-2-F
TGCTGCCCGAGCCTTG
549
GUCY2D-exon2-2-R
TCCTCGCCACCCAGCA
GUCY2D-exon3-F
CAGGTAGGCTCCCTTGCAG
496
GUCY2D-exon3-R
AGAGCTGCCAGTGGTTCTTT
GUCY2D-exon4-F
AACAGTGGATACCCTGGGC
550
GUCY2D-exon4-R
GGGCATCGAAGACGGATTAC
GUCY2D-exon5-F
ATTCCCAGCCTCTCCCCTTT
387
GUCY2D-exon5-R
ACTCTACCAGCCCACCAGAA
GUCY2D-exon6-F
TTCTGGTGGGCTGGTAGAGT
464
GUCY2D-exon6-R
CCCGCCAGGAAAGTAGTCAG
GUCY2D-exon7-F
CCTGACTACTTTCCTGGCGG
477
GUCY2D-exon7-R
TCCCTAGATCCTGTCTGGGC
GUCY2D-exon8-F
ATGGCTGTGAAGTGGATGGG
423
GUCY2D-exon8-R
ATCCTCCCTCACATCTGCCT
GUCY2D-exon9-F
GAGAGCCCCCGTACATACCT
487
GUCY2D-exon9-R
CGCCTCGATGGTGCAGATAC
GUCY2D-exon10-F
ATCAAGGTGTGTGTCTGGGG
476
GUCY2D-exon10-R
CAGCTCAGGTACAAGTCCCG
GUCY2D-exon11-F
GGCCTATTTGCCAGGCTTTC
476
GUCY2D-exon11-R
ACCTGCAGATGCCAGCTTT
GUCY2D-exon12-F
CTAGCAACCCCCTTCCACAC
402
GUCY2D-exon12-R
AGCTGTCTCAGGTTGCTGAC
GUCY2D-exon13-F
ACGTGCCTCCTAATCGTGTC
505
GUCY2D-exon13-R
GCTCAAAGTACTCGGGCTCC
GUCY2D-exon14-F
GCTGCTTACACAGATGCTGC
440
GUCY2D-exon14-R
TAAGGGACAGGAGGTCTGGG
GUCY2D-exon15-F
CAGCTCAGTCCTTCCACTAGC
468
GUCY2D-exon15-R
CGCACCCATTATCTCCACCA
GUCY2D-exon16-17-F
AGAGGATGCACTTAACAAGGCT
538
GUCY2D-exon16-17-R
ATCTCGAGTCTGCGTGGAAC
GUCY2D-exon18-F
CCCTGTCCTGAGGCACC
365
GUCY2D-exon18-R
CTCAGGGAAGGGGAATGGG
GUCY2D-exon19-F
CGAGGGACCCCTGCCT
393
GUCY2D-exon19-R
ATTCCTGCAATGGCTGCTTC
GUCY2D-exon20-F
TAGCTGGCAGAGCAGTGATG
487
GUCY2D-exon20-R
ACTTCCCCTCTTCAGGCCAT
https://doi.org/10.1371/journal.pone.0231115.t001 Cellular localization of wt and mutant ROS-GC1 recombinant plasmids pEGFP-N1, pEGFP-GC1, pEGFP-Asp279Asn and pEGFP-Gly928Glu were transfected into
HeLa cells using the PolyJet Reagent (SigmaGen, MD, USA). After 36 h, cells were washed and
fixed in 4% paraformaldehyde. The antibody anti-Na+/K+-ATPase (1:100, HuaAn Biotechnol-
ogy Co., Ltd., Hangzhou, China) was used to identify the plasma membrane of HeLa cells. Details about the process have been described previously [9]. In HeLa cells, the localization of
pEGFP-N1, pEGFP-GC1, pEGFP-Asp279Asn and pEGFP-Gly928Glu was acquired by observ-
ing EGFP at 488nm excitation wavelength using a Nikon A1R. 3 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Validation of cGMP quantitation by HPLC-MS/MS HeLa cells were transfected with pEGFP-N1, pEGFP-GC1, pEGFP-Asp279Asn and pEGFP--
Gly928Glu. After 36 h, cells were collected from 100 mm plates and washed three times with
PBS. The supernatant was removed carefully and 300 μL of ice-cold extraction medium (aceto-
nitrile/methanol/water, 2/2/1 v/v/v) was added to each tube. Twenty-five ng/mL Tenofovir
(TNF) was added as the internal standard. After dissolving, the sample was frozen immediately
in liquid nitrogen for 30 s to terminate cGMP metabolism, and this was followed by incubation
in a 37 ˚C water bath for 60 s. After repeating 6 times, samples were heated at 98 ˚C for 20
min. Samples were cooled on ice and centrifuged at 20,000 × g at 4 ˚C for 10 min. The superna-
tant was transferred into a new tube and the non-dissolved residue was extracted two more
times with 400-μL extraction medium. After evaporation, residues were collected and dis-
solved in water for further analysis. The cGMP concentrations were analyzed via HPLC-MS/MS. The samples were applied to
an HPLC utilizing an ACQUITY CSH-C18 column (1.7 μm, 2.1 × 100 mm column, Waters,
Ireland). The binary pump system supplied two eluents for chromatographic analysis, eluent A
(10 mM formic acid) and eluent B (acetonitrile). The flow rate was 0.3 mL/min. Analyte detec-
tion was conducted on a sensitive triple quadrupole mass spectrometer (Waters TQ-XS, USA). Nitrogen was used as the collision gas. One-hundred ng/mL cGMP (G7504, Sigma, Germany)
was used as the standard. All processes were referenced to the method described previously
[10]. cGMP concentrations presented as means ± SEM are based on three repeated measure-
ments. P-values were calculated by means of the independent sample T-test. PLOS ONE PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 Table 2. Primers for construction of recombination plasmids. Primer
Sequence
Restriction Enzyme
F
TCCGCTAGCGCTACCGGACTCAGATctcgagATGACCGCCTGCGCCCGCCGAGCGGGTGGGCTT
XhoI
R
CTCGCCCTTGCTCACCATGGTGGCGaccggtGGTGAAGAGAACTGGCCCGGCCGCGCC
AgeI
f-835
GGCTCCCTGGTCTTCCTGCCCTTCaACACGATCCACTACGCCTTGTCCCCA
r-835
TGGGGACAAGGCGTAGTGGATCGTGTtGAAGGGCAGGAAGACCAGGGAGCC
R-BamHI
GGCGGAGAGGAAGGAGCCCCGGGCAggatccAGCATGTATGTGGCAAAAAGCCGGT
BamHI
F-BamHI
ACCGGCTTTTTGCCACATACATGCTggatccTGCCCGGGGCTCCTTCCTCTCCGCC
BamHI
f-2783
CTACAAGGTGGAGACAATAGaGGACGCCTATATGGTGGCC
r-2783
GGCCACCATATAGGCGTCCtCTATTGTCTCCACCTTGTAG Table 2. Primers for construction of recombination plasmids. washed with PBS and incubated with fluorescent secondary antibodies (1:1000, Abbkine,
Wuhan, China) for 2 h at room temperature. The protein bands were visualized using an
Odyssey Imager (Li-Cor Biosciences, NE, USA). GAPDH was used as the standard. Western blotting Proteins from transfected HeLa cells were electrophoresed on a 12% sodium dodecyl sulfate-
polyacrylamide gel (SDS-PAGE) and transferred to polyvinylidene fluoride (PVDF) mem-
branes (Millipore, MA, USA), and then incubated with the primary antibodies, anti-GFP
(1:1000, Proteintech, Wuhan, China) or anti-glyceraldehyde 3 phosphate dehydrogenase
(GAPDH) (1:5000, Abcam, Cambridge, UK) overnight at 4 ˚C. The PVDF membranes were PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 4 / 12 Clinical description of the proband The proband (III-2) was a five-year-old girl who showed the disorder visually but could per-
ceive light in a dark room. The proband displayed the classic signs of oculo-digital symptoms. Ophthalmological examination revealed pendular nystagmus, roving eye movements, macular
“colobomas” and optic disc abnormalities. Additionally, dim retina and salt-and-pepper pig-
mentation were found in the fundus. The results of flash visual evoked potential (VEP) showed
that the latent period of binocular P-waves was severely prolonged and the amplitudes were
severely reduced. The electroretinogram (ERG) results showed that the latent period and the
amplitude of binocular scotopia rod response b-wave, mixed response a-wave and mixed
response b-wave were flat. With an attenuated photopic 30-Hz flicker, the full-field ERG
(ffERG) showed a worsening delay of the cone-dependent response. The latent period and
amplitude of the binocular photopic cone response a-wave and b-wave were flat. Clinical
examination of the parents confirmed that neither was affected. Bioinformatics analysis All sequences were analyzed by Mutation Surveyor software and aligned to the NCBI nucleo-
tide sequence of GUCY2D (NG_009092.1). The pathogenicity of mutations was evaluated
using the in silico predictors SIFT (http://sift.jcvi.org/), PolyPhen-2 (http://genetics.bwh. harvard.edu/pph2/) and Mutation Taster (http://www.mutationtaster.org/). Computational
modeling of the mutant ROS-GC1 by Chimera (PDB ID: 1AWL) was carried out to study the
effect of the p.Gly928Glu mutation on the three-dimensional (3D) structure of ROS-GC1. 5 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 GUCY2D mutation analysis In order to discover the pathogenesis of the proband, targeted-NGS was performed using
Agilent SureSelect All Exome Kit with Hiseq2000 sequencer. After analyzing the sequencing
results of targeted-NGS, two novel mutations, c.139delC and c.2783G>A, in the GUCY2D
gene were identified in the proband (III-2). Sanger sequencing confirmed the presence of
c.139delC and c.2783G>A in other family members. The sequencing results showed that II-2
and II-3 are heterozygous mutation carriers that possess c.139delC and c.2783G>A, respec-
tively (Fig 1B1 and 1B2). Fig 1. Brief introduction to the GUCY2D mutations in the LCA1 family. (A) Pedigree of the LCA1 family. %
represents the proband, □represents the normal male, represents the normal female and crosses represent the
deceased subject. ●and ■denote patients, whereas the half-shaded icons denote the mutation carriers as ⚅=
c.139delC (p.Ala49Profs36), ▨= c.2783G>A (p.Gly928Glu) and ▤= c.835G>A (p.Asp279Asn). (B) 1: The
sequencing results of the family show the mutation c.139delC, indicated by the arrows. 2: The sequencing results of the
family show the mutation c.2783G>A, indicated by the arrows. 3: The sequencing result of the family member II-8
with mutation c.835G>A; forward sequencing result (top) and reverse sequencing result (bottom). https://doi.org/10.1371/journal.pone.0231115.g001 Fig 1. Brief introduction to the GUCY2D mutations in the LCA1 family. (A) Pedigree of the LCA1 family. %
represents the proband, □represents the normal male, represents the normal female and crosses represent the
deceased subject. ●and ■denote patients, whereas the half-shaded icons denote the mutation carriers as ⚅=
c.139delC (p.Ala49Profs36), ▨= c.2783G>A (p.Gly928Glu) and ▤= c.835G>A (p.Asp279Asn). (B) 1: The
sequencing results of the family show the mutation c.139delC, indicated by the arrows. 2: The sequencing results of the
family show the mutation c.2783G>A, indicated by the arrows. 3: The sequencing result of the family member II-8
with mutation c.835G>A; forward sequencing result (top) and reverse sequencing result (bottom). https://doi.org/10.1371/journal.pone.0231115.g001 6 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 III-3 was described as an LCA1 patient (Fig 1A). Sanger sequencing was used to determine
the GUCY2D gene sequences of the suspected sibling of the patient (III-4) and parents (II-7
and II-8). The results showed that II-7 is a c.2783G>A mutation carrier, and II-8 possesses
another novel mutation c.835G>A (Fig 1B3). The sibling (III-4) possessed no GUCY2D muta-
tion. In addition, all heterozygous mutation carriers showed no clinical symptoms. Prediction of the pathogenic effect of ROS-GC1 mutations p.Ala49Profs36, p.Asp279Asn and p.Gly928Glu are located in the LS, ECD and CCD of
ROS-GC1, respectively (Fig 2C). After analyzing the three mutations by SIFT, PolyPhen-2 and
Mutation Taster, we propose that c.835G>A (SIFT: damaging, score: 0.01; PloyPhen-2: proba-
bly damaging, score: 1.00; Mutation Taster: disease-causing), c.2783G>A (SIFT: damaging,
score: 0.00; PloyPhen-2: probably damaging, score: 1.00; Mutation Taster: disease causing) and
c.139delC (Mutation Taster: disease-causing) are disease-causing mutations. Additionally,
multiple sequence alignments showed that aspartic acid and glycine at positions 279 and 928
are highly conserved across species (S1 Fig), indicating that p.Asp279 and p.Gly928 play
important roles in ROS-GC1 and that mutations to these two residues are likely to cause
ROS-GC1 dysfunction. The high-resolution 3D structure of full-length ROS-GC1 remains unsolved. The theoreti-
cal model (PDB ID: 1AWL), which contains 158 amino acids from 871 to 1028 was used to
study the impact of c.2783G>A (p.Gly928Glu) on the 3D structure of ROS-GC1. 3D modeling
analysis showed that Glu928 directly interacts with GTP (Fig 2) and this change may reduce
the size of the catalytic core, leading to a change in the relative position of GTP and the cata-
lytic core. Furthermore, this mutation likely hampers ligand binding and reduces the catalytic
activity of ROS-GC1. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Localization of wt and mutant ROS-GC1 ROS-GC1 is a member of the membrane guanylyl cyclase family, the correct localization of
ROS-GC1 is critical for the synthesis of cGMP. In this study, immunofluorescence was used to
confirm the localization of wt and mutant ROS-GC1. pEGFP-N1, pEGFP-GC1, Fig 2. Protein domains and modeling analysis of the p.Gly928Glu mutation. (A) 3D-modeling analysis of Gly928. (B) 3D-modeling analysis of
Glu928. The green line indicates the ROS-GC1 residue. (C) ROS-GC1 domains and location of p.Ala49Profs36, p.Asp279Asn and p.Gly928Glu. LS:
leader sequence; ECD: extracellular domain; TM: transmembrane domain; JMD: juxtamembrane domain; KHD: kinase homology domain; DD:
dimerization domain; and CCD: cyclase catalytic domain. https://doi org/10 1371/journal pone 0231115 g002 Fig 2. Protein domains and modeling analysis of the p.Gly928Glu mutation. (A) 3D-modeling analysis of Gly928. (B) 3D-modeling analysis of
Glu928. The green line indicates the ROS-GC1 residue. (C) ROS-GC1 domains and location of p.Ala49Profs36, p.Asp279Asn and p.Gly928Glu. LS:
leader sequence; ECD: extracellular domain; TM: transmembrane domain; JMD: juxtamembrane domain; KHD: kinase homology domain; DD:
dimerization domain; and CCD: cyclase catalytic domain. https://doi.org/10.1371/journal.pone.0231115.g002 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 7 / 12 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 pEGFP-Asp279Asn and pEGFP-Gly928Glu were transfected into HeLa cells after verification
by Sanger sequencing (S2 Fig) and the localization was acquired by observing EGFP under the
488nm excitation. The localization of p.Asp279Asn and p.Gly928Glu was similar to the locali-
zation of the wt ROS-GC1. (Fig 3, top panels). The anti-Na+/K+-ATPase antibody was used as
a specific marker of the plasma membrane (Fig 3, second panels). Catalytic features of wt and mutant ROS-GC1 HPLC-MS/MS was used to analyze cGMP concentrations in HeLa cells. The cGMP concentra-
tion in cells transfected with pEGFP-N1 was undetectable. In contrast, the cGMP concentration
in cells transfected with pEGFP-GC1 was about 3.631 pmol/mL. Compared with wt, cells trans-
fected with pEGFP-Asp279Asn or pEGFP-Gly928Glu showed significantly lower concentrations
of cGMP (Fig 4A), implying that p.Asp279Asn and p.Gly928Glu significantly reduced the cata-
lytic activity of ROS-GC1. In addition, p.Gly928Glu disrupted the catalytic activity of ROS-GC1
more severely than the other mutants, which is consistent with the bioinformatics analysis. Moreover, all missense mutations did not affect the expression level of ROS-GC1 (Fig 4B). PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Discussion Twenty known genes associated with LCA have been identified. The large number of genes
and exons and the lack of mutational hot spots make individual screening for disease-causing
mutations by Sanger sequencing difficult and expensive. However, NGS technologies provide
more convenient and effective strategies to screen for pathogenic mutations in genes [11–13]. Fig 3. Cellular localization of wt and mutant ROS-GC1 in HeLa cells. Localization of ROS-GC1 wt and mutants
were acquired by observing EGFP. Immunostaining from top to bottom: EGFP with 488nm excitation (top panels),
anti-Na+/K+-ATPase (second panels) as the cell membrane marker, DAPI (third panels) as the nucleus marker, and
overlay images (bottom panels). The scale bar is 10 μm. https://doi.org/10.1371/journal.pone.0231115.g003 Fig 3. Cellular localization of wt and mutant ROS-GC1 in HeLa cells. Localization of ROS-GC1 wt and mutants
were acquired by observing EGFP. Immunostaining from top to bottom: EGFP with 488nm excitation (top panels),
anti-Na+/K+-ATPase (second panels) as the cell membrane marker, DAPI (third panels) as the nucleus marker, and
overlay images (bottom panels). The scale bar is 10 μm. https://doi.org/10.1371/journal.pone.0231115.g003 8 / 12 PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 Fig 4. cGMP concentrations and ROS-GC1 expression levels in HeLa cells. (A) Transfected HeLa cells with pEGFP-N1, pEGFP-GC1,
pEGFP-Asp279Asn and pEGFP-Gly928Glu. Cells were collected and used to estimate cGMP concentrations. P-values were calculated by means of an
independent sample T-test. : p 0.001. (B) Western blot of HeLa cells expressing human EGFP, wt and mutant ROS-GC1. https://doi.org/10.1371/journal.pone.0231115.g004 Fig 4. cGMP concentrations and ROS-GC1 expression levels in HeLa cells. (A) Transfected HeLa cells with pEGFP-N1, pEGFP-GC1,
pEGFP-Asp279Asn and pEGFP-Gly928Glu. Cells were collected and used to estimate cGMP concentrations. P-values were calculated by means of an
independent sample T-test. : p 0.001. (B) Western blot of HeLa cells expressing human EGFP, wt and mutant ROS-GC1. https://doi.org/10.1371/journal.pone.0231115.g004 https://doi.org/10.1371/journal.pone.0231115.g004 In this study, a family with one LCA proband was analyzed. Targeted-NGS and Sanger
sequencing were combined to identify three mutations (c.139delC, c.2783G>A and
c.835G>A) in the GUCY2D gene in this pedigree, and all the mutations have yet to be docu-
mented by the 1000 Genomes Project. According to the description, there are two suspected
patients in this pedigree, III-1 and III-3. However, both of them died at a very young age,
thereby we only verified the GUCY2D gene mutation in II-7 and II-8. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Discussion Additionally, in this
pedigree all the heterozygous mutation carriers showed no clinical symptoms. The novel disease-causing mutation c.139delC (p.Ala49Profs36) carried by II-1 and puta-
tively by II-2 and III-3 generates a truncated protein (83 amino acids), containing only a part of
the LS (Fig 2C). As all the domains of ROS-GC1 are presumably absent, there is no enzymatic
activity for this ROS-GC1 mutant and thus no cGMP production. Thus, the absence of suffi-
cient levels of cGMP results in photoreceptor cell polarization, which finally leads to vision loss. Multiple sequence alignments indicated that aspartic acid and glycine at positions 279 and
928 are highly conserved across species, indicating that these residues are important for pro-
tein function. This is consistent with previous observations that mutations located in the ECD
decrease cGMP production and result in LCA1 [14]. The p.Asp279Asn mutation of this
reported family decreased ROS-GC1 catalytic activity significantly; however, this mutation
does not alter the cellular localization and the expression level of ROS-GC1. Mutant
c.2783G>A (p.Gly928Glu) is located in the pocket like catalytic domain of ROS-GC1 [15]. Bioinformatics analysis was used to estimate the effects of p.Gly928Glu on the catalytic activity
of ROS-GC1. In contrast to Gly928, Glu928 directly interacts with the substrate GTP. Alter-
ation of the catalytic core pocket by the p.Gly928Glu mutation perturbs the catalytic activity of
ROS-GC1. HPLC-MS/MS was used to further characterize the effect of the missense mutations
on ROS-GC1 activity, and therefore provide additional experimental evidence of the effects of
the mutations on ROS-GC1 activity. Results from HPLC-MS/MS showed that mutations p. Asp279Asn and p.Gly928Glu decreased ROS-GC1 activity significantly, especially p.Gly928-
Glu, consistent with the 3D-modeling and bioinformatics analysis by SIFT, PolyPhen-2 and
Mutation Taster. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 9 / 12 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 In this study, the endogenous concentration of cGMP in HeLa cells, which were transfected
with pEGFP-N1, is too low to be measured. This phenomenon can be observed in other studies
of GUCY2D mutations, such as HEK293 cells expressed mutant ROS-GC1 (A710V and P873R)
showed undetectable cGMP concentrations, indicating that endogenous cGMP concentration
exerted no contribution to cGMP levels. Although GUCY2D gene encodes a retina-specific
protein, use other cell lines to investigate the localization and enzymatic activity of ROS-GC1
is feasible, for example, HEK293 cells were widely used to study the cellular localization of
ROS-GC1 [9,10, 16,17,18]. Conclusions In this study, we found three novel mutations (c.139delC, c.2783G>A and c.835G>A) in the
GUCY2D gene. Mutation c.139delC results in a truncated protein that lacks all functional
domains of ROS-GC1. Although mutations c.835G>A and c.2783G>A showed normal pro-
tein expression levels and subcellular localization, both mutations significantly reduced the
catalytic activity of ROS-GC1. As an alternative to radioisotope labeling assays, HPLC-MS/
MS was used herein to analyze cGMP concentrations. Compared with traditional methods,
HPLC-MS/MS is more convenient and is an effective alternative to evaluate the cGMP con-
centration in cells. Discussion It has been reported that ROS-GC1 was present in cell membranes
and mainly co-localized with the endoplasmic reticulum in HEK293 cells [9,16]. However, in
our study, ROS-GC1 exhibited endoplasmic reticulum localization, without obvious co-locali-
zation with plasma membrane marker in HeLa cells. The discrepancy may be explained by the
different cells type and the different method used to detect the localization of ROS-GC1. It has
been found that ROS-GC1 trafficking from reticulum to the plasma membrane was facilitated
by co-expression of retinal degeneration 3 (RD3) protein [19]. Thus, impaired interaction
between ROS-GC1 and RD3 cannot be ruled out. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Acknowledgments We thank the patient and his family for their cooperation and participation in the study. Addi-
tionally, we thank Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text
of a draft of this manuscript. Supporting information S1 Fig. Multiple sequence alignment of ROS-GC1 from different species. Results from mul-
tiple sequence alignment reveal that codon 279 and 928 where the mutations Asp279Asn and
Gly928Glu occurred are located within a highly conserved region. (TIF) (TIF)
S2 Fig. Sequencing results of wt and mutant GUCY2D. Sanger sequencing was used to verify
the sequences of the recombinant plasmids pEGFP-GC1, pEGFP-Ala49Profs36, pEGFP-As-
p279Asn and pEGFP-Gly928Glu. (TIF)
S1 Table. Screening scope of the targeted-NGS in eye diseases. (DOCX)
S1 File. (RAR)
S2 File. (RAR)
S3 File. (RAR)
S4 File. (RAR) S2 Fig. Sequencing results of wt and mutant GUCY2D. Sanger sequencing was used to verify
the sequences of the recombinant plasmids pEGFP-GC1, pEGFP-Ala49Profs36, pEGFP-As-
p279Asn and pEGFP-Gly928Glu. S2 Fig. Sequencing results of wt and mutant GUCY2D. Sanger sequencing was used to verify
the sequences of the recombinant plasmids pEGFP-GC1, pEGFP-Ala49Profs36, pEGFP-As-
p279Asn and pEGFP-Gly928Glu. (TIF) PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 10 / 12 PLOS ONE GUCY2D gene mutations cause Leber congenital amaurosis 1 S5 File. (RAR)
S6 File. (RAR)
S7 File. (RAR)
S8 File. (RAR)
S9 File. (RAR)
S10 File. (RAR)
S11 File. (RAR) Data curation: Xiaoming Wei. Funding acquisition: Ming Qi, Yinghui Ye. Funding acquisition: Ming Qi, Yinghui Ye. Investigation: Tianying Wei, Yanan Huo. Investigation: Tianying Wei, Yanan Huo. Methodology: Xue Feng, Tianying Wei, Junhui Sun, Yuqin Luo, Ping Yu, Jiao Chen, Xiaom-
ing Wei. Resources: Yuqin Luo, Yanan Huo. Writing – original draft: Xue Feng. Writing – original draft: Xue Feng. Writing – review & editing: Ping Yu, Ming Qi, Yinghui Ye. Writing – review & editing: Ping Yu, Ming Qi, Yinghui Ye. PLOS ONE | https://doi.org/10.1371/journal.pone.0231115
April 7, 2020 Author Contributions Data curation: Xiaoming Wei. References References
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Relationship between Selenium and Hematological Markers in Young Adults with Normal Weight or Overweight/Obesity
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Antioxidants
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cc-by
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Received: 22 September 2019; Accepted: 5 October 2019; Published: 8 October 2019 Abstract: Selenium deficiency has been linked to anemia of inflammation, which is mediated
by hepcidin. However, there are few studies providing evidence of the role of hepcidin in this
relationship. In this study, we investigated the interrelationships among selenium biomarkers,
hepcidin concentration, and iron status among individuals with overweight/obesity compared to
their normal weight counterparts, since obesity is associated with chronic inflammation. A total of 59
college students were recruited for this study. Fasting blood samples were collected for the analysis
of iron status, plasma selenoproteins (glutathione peroxidase (GPX) activity and selenoprotein P
(SEPP1)), and plasma hepcidin. Subjects completed three-day dietary records to determine average
daily nutrient intakes. SEPP1 concentration, GPX activity, and iron status biomarkers (serum
iron, transferrin saturation, and hemoglobin concentration) were lower among individuals with
overweight/obesity compared with individuals with normal weight, but these differences were not
significant (p > 0.05). Regression analysis showed that GPX activity (β = −0.018, p = 0.008) and SEPP1
concentration (β = −1.24, p = 0.03) were inversely associated with hepcidin concentration. The inverse
association between selenoproteins and hepcidin concentration supports a potential role of hepcidin
as a mediator between selenium and iron status and warrants further studies to better understand
this relationship. Keywords: anemia of inflammation; hepcidin; iron status; selenoprotein P; glutathione peroxidase;
inflammation Relationship between Selenium and Hematological
Markers in Young Adults with Normal Weight or
Overweight/Obesity Doreen Yvonne Larvie 1
, Jeanne Lynn Doherty 1, George L. Donati 2
and
Seth Mensah Armah 1,* 1
Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA;
dylarvie@uncg.edu (D.Y.L.); jldohert@uncg.edu (J.L.D.)
2
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA; donatigl@wfu.edu
*
Correspondence: s_armah@uncg.edu; Tel.: +1-336-256-0324
antioxidants antioxidants antioxidants Antioxidants 2019, 8, 463; doi:10.3390/antiox8100463 www.mdpi.com/journal/antioxidants 1. Introduction Anemia affects a third of the world’s population [1]. In the US, the prevalence increased by
3% from years 2003 to 2012 [2]. Anemia results from a homeostatic iron imbalance with increased
destruction and/or impaired synthesis of erythrocytes [1]. Iron deficiency is the most common cause of
anemia accounting for about half of all cases, followed by inflammation [3,4]. Inflammation refers to a biological response of the immune system to infection and is a secondary
component of chronic diseases [5,6]. Inflammation accounts for about a fifth of anemia cases in older
adults in the US and, among individuals with obesity, the observed chronic low-grade inflammation
is implicated to result in hypoferremia [1,3,4,7]. Anemia caused by inflammation is associated with
alterations in iron metabolism, erythrocyte life span and production, lowered transferrin saturation and
serum iron, and increased ferritin concentrations [8]. The link between inflammation and anemia has
been explained by the iron regulatory protein, hepcidin. Hepcidin is a 25-amino-acid (disulfide-rich)
peptide that plays a critical role in iron metabolism by acting as a signaling molecule, and in immunity Antioxidants 2019, 8, 463; doi:10.3390/antiox8100463 www.mdpi.com/journal/antioxidants 2 of 10 Antioxidants 2019, 8, 463 due to its antimicrobial properties [9,10]. Hepcidin acts by binding to the iron transporter (ferroportin)
resulting in its degradation [11]. Hepcidin concentration increases in response to high iron stores and
inflammation and decreases with anemia and hypoxia [12]. In obesity, macrophages and immune
system cells invade the adipose tissue in response to fat accumulation leading to the production
of proinflammatory cytokines including interleukin 6 (IL-6) [13]. With the increased production of
IL-6, hepcidin is upregulated leading to a reduction in circulating iron, an increase in iron storage in
macrophages and hepatocytes, and a consequent mild iron deficiency [14,15]. Due to oxidative stress and inflammation in obesity, there is increased need for antioxidant
nutrients such as selenium [16,17]. Selenium is incorporated as part of selenocysteine at the active site
of selenoproteins (glutathione peroxidase (GPX), selenoprotein P (SEPP1), and thioredoxin reductase). GPX refers to a family of antioxidant enzymes that protects cells against oxidative stress while SEPP1,
an extracellular protein, functions in selenium distribution [18,19]. Studies show that selenoproteins
may play a critical role in reducing inflammation in adipose tissue [16,20]. Poor selenium status also
impairs functional iron status as it contributes to the formation of methemoglobin, which contains ferric
iron (Fe3+) and is unable to carry oxygen to tissues [21,22]. 1. Introduction Studies also suggest that selenium is linked
to anemia through the modulation of inflammation via the IL-6 pathway, the increased expression of
heme-oxygenase 1 and oxidative stress [17,23–25]. Other researchers cite serum zinc as a potential
mediator in this relationship [26]. Despite the increasing knowledge about the role of selenium in addressing inflammation, no
study has investigated how selenium influences the chronic inflammation found in obesity and its
relationship with hepcidin and iron status. The aim of this study was to compare selenium status,
hepcidin concentration, and iron status biomarkers between individuals with normal weight and those
with overweight/obesity, and to determine the associations among these biomarkers. We hypothesized
that selenium status will be negatively correlated with hepcidin concentration and positively correlated
with iron status biomarkers among study participants. 2.1. Study Participants and Recruitment Students and staffof the University of North Carolina, Greensboro (UNCG), USA, were recruited
via mass emails in the summer of 2018. Out of a total of 129 subjects who responded to the mass
emailing, 66 came for screening at the Cemala Foundation Human Nutrition Research Laboratories of
the Nutrition Department (Figure 1). At the screening visit, potential subjects were provided with
a copy of the informed consent form to read and sign if they agreed to participate in the study. The
informed consent contained information on the study, as well as benefits and risks of participating. After the subjects had provided consent, they filled out the screening form with information on
demographics, use of vitamin and mineral supplements, medical history, and any current medication. As part of the screening procedure, duplicates of their height and weight were also measured to
estimate their body mass index (BMI) to assess their eligibility for the study. Subjects were eligible
for the study if they were 18 to 49 years of age, with a BMI of 18.5 kg/m2 or over, with no history of
inflammation-associated chronic diseases such as chronic kidney disease, cancer, heart disease, diabetes
mellitus, and severe/mild hypertension. In addition, they were eligible if they were non-smokers,
non-pregnant, non-lactating, and not taking any mineral/vitamin supplements or medicines that could
interfere with iron and selenium status or inflammatory markers. Additionally, individuals who had
donated blood within two months to the start of the study were excluded. We estimated that 58 subjects were needed to determine a significant association between selenium
biomarkers and hepcidin concentration in a regression model assuming an R-squared of 0.5 (with a
partial R-squared of 15% from selenium biomarkers) for a regression model with up to nine predictors
at an alpha level of 0.05 and with a statistical power of 0.8. To meet this sample size, we recruited a total
of 66 subjects with equal numbers of subjects having either normal weight or overweight/obesity. Out 3 of 10 Antioxidants 2019, 8, 463 of this number, 2 subjects opted out for personal reasons, 3 of them did not come in for blood draw, 1
had a BMI < 18.5 kg/m2 at the screening visit, and 1 was excluded from the analysis because the required
volume of blood could not be drawn at the study visit. Thus, 59 subjects were used in the final data
analysis. 2.2. Study Design
2.2. Study Design The study was a cross-sectional study in which anthropometry, dietary intake data, and blood
samples were obtained from subjects. Subjects who qualified based on the inclusion/exclusion criteria
were provided with three-day dietary record forms and weighing scales to weigh and record foods
eaten. They were to be completed and returned at the study visit. Instructions for completing the
dietary record were provided by trained research assistants. The study was a cross-sectional study in which anthropometry, dietary intake data, and blood
samples were obtained from subjects. Subjects who qualified based on the inclusion/exclusion criteria
were provided with three-day dietary record forms and weighing scales to weigh and record foods
eaten. They were to be completed and returned at the study visit. Instructions for completing the
dietary record were provided by trained research assistants. y
p
y
For the study visit, the participants were required to do a 10 h overnight fast. Dietary records
were collected and height, weight, and other anthropometric measurements were taken. Approximately 30 mL of venous blood was collected to measure the concentrations of selenium
biomarkers, C-reactive protein (CRP), and hematological parameters. For the study visit, the participants were required to do a 10 h overnight fast. Dietary records were
collected and height, weight, and other anthropometric measurements were taken. Approximately
30 mL of venous blood was collected to measure the concentrations of selenium biomarkers, C-reactive
protein (CRP), and hematological parameters. 2.1. Study Participants and Recruitment The study was conducted in accordance with the Declaration of Helsinki, and the protocol
was approved by the Ethics Committee of University of North Carolina at Greensboro (18-0173). Antioxidants 2019, 8, x FOR PEER REVIEW
3 of 11
were used in the final data analysis. The study was conducted in accordance with the Declaration of
Helsinki, and the protocol was approved by the Ethics Committee of University of North Carolina at
Greensboro (18-0173). Figure 1. Subject recruitment. Figure 1. Subject recruitment. Figure 1. Subject recruitment. Figure 1. Subject recruitment. 2.5. Sample Analyses Fasting blood samples collected at the study visit were processed into serum, plasma, or whole
blood for the measurement of selenium, iron status, and inflammatory markers as well as plasma
hepcidin. Iron status biomarkers (ferritin, hemoglobin, total iron-binding capacity (TIBC), transferrin
saturation, and serum iron) and CRP concentration were measured from serum or whole blood (in the
case of hemoglobin) by LabCorp Laboratories (Burlington, NC, USA). With the exception of the serum
and whole blood samples that were sent to LabCorp, all other samples were stored at the Department
of Nutrition of UNCG at −80 ◦C and analyzed upon study completion. To measure plasma selenium concentration, plasma samples were digested with trace metal grade
HNO3 overnight in a sand bath at 65 ◦C. The samples were then diluted to a final concentration
of 2% v/v HNO3 using deionized water. The digested plasma samples were analyzed for plasma
selenium concentration using an Agilent 8800 ICP-MS/MS from Agilent Technologies (Santa Clara,
CA, USA) at the Department of Chemistry, Wake Forest University (Winston-Salem, NC, USA). Plasma concentrations of hepcidin, SEPP1, and GPX activity were measured using Enzyme Linked
Immunosorbent Assay (ELISA) kits. Erythrocyte GPX activity was measured from red blood cell
lysate obtained after the plasma was collected and the remaining red blood cells lysed. The GPX
activity ELISA kit was obtained from Cayman Chemical (Ann Arbor, MI, USA), whereas the SEPP1
and hepcidin kits were obtained from MyBioSource (San Diego, CA, USA) and Peninsula Laboratories
International (San Carlos, CA, USA) respectively. 2.4. Dietary and Nutrient Intake To assess dietary intake using the three-day weighed dietary record, subjects were required
to keep a log of all foods consumed on 3 non-consecutive days (2 weekdays and 1 weekend day)
between the screening and study visits as previously described [28]. Dietary records were analyzed
into nutrients and food groups using the Nutrition Data System for Research (NDSR software, version
2016, University of Minnesota, Minneapolis, MN, USA). To ensure reliability and accuracy of dietary
records, a trained research assistant reviewed the dietary information with participants on the study
visit and data were reviewed by another research assistant during data entry into NDSR. 2.3. Anthropometry
2.3. Anthropometry A Seca 213 stadiometer (Seca, Hammer Steindamm, HH, Germany) was used to measure the
standing height of the study participants following standard procedure, and weight in kilograms was
measured using a Tanita BWB-800 weighing scale (Tanita Corporation of America, Inc., Arlington
Heights, IL, USA) with subjects in light clothing [27]. A Seca 213 stadiometer (Seca, Hammer Steindamm, HH, Germany) was used to measure the
standing height of the study participants following standard procedure, and weight in kilograms was
measured using a Tanita BWB-800 weighing scale (Tanita Corporation of America, Inc., Arlington
Heights, IL, USA) with subjects in light clothing [27]. 4 of 10 Antioxidants 2019, 8, 463 2.6. Statistical Analysis Data were stratified according to subject BMI category (normal or overweight/obese). The primary
outcome variables were the hematological parameters, whereas the independent variables were GPX
activity and SEPP1. Means and standard deviations were reported for continuous variables with
normal distributions. Median and interquartile ranges were reported for nutrient intakes. Percentages
were reported for categorical variables. Ferritin, TIBC, SEPP1, plasma selenium, CRP, and hepcidin
concentrations were log transformed to approximate normality. Student’s t-test was used to compare
continuous variables between the two groups. The Wilcoxon rank-sum test was used to determine
significant differences in nutrient intakes between the two subject groups. Linear regression analysis
was used to determine the associations among selenium biomarkers, iron status, and hepcidin
concentration adjusting for the potential confounders. Variables adjusted for in the regression analysis
were age, gender, BMI category, ethnicity, and dietary selenium. Statistical significance was set at
p ≤0.05. The R-software (Rx64 3.5.0.ink, R Foundation for Statistical Computing, Vienna, Austria) was
used for data analysis. 3. Results Out of the 59 participants included in the final analysis, a majority (71%; n = 42) were female, and
42% (n = 25) were Non-Hispanic Blacks. There were 46% (n = 27) of study participants with normal
weight and 54% (n = 32) with overweight/obesity. About 19% (n = 11) of the participants had high
C-reactive protein (CRP ≥3 mg/L). 5 of 10 Antioxidants 2019, 8, 463 Table 1 shows the nutrient intake of participants. The median caloric intake was not significantly
different between subjects with normal weight and those with overweight/obesity. Among the
nutrients, vitamin C intake was lower in individuals with overweight/obesity (43.37 mg/day) compared
to individuals with normal weight (88 mg/day), p = 0.028. All other nutrient intakes were not
significantly different between the two groups (p > 0.05). Table 1. Daily nutrient intakes among young adults with normal weight or overweight/obesity 1. Nutrient/Calories
Normal (n = 27)
Overweight/Obese (n = 32)
Total
p-Value 2
Caloric intake, kcal
1844 (1423, 2611)
1878 (1347, 2234)
1875 (1357, 2304)
0.667
Total fat, g
66.28 (56, 107)
80.67 (53, 98)
72.01 (54, 104)
0.982
Protein, g
70.52 (50, 97)
73.1 (52, 96)
73.16 (51, 97)
0.994
Selenium, mcg
99.42 (70, 151)
102 (83, 153)
101.82 (79, 152)
0.645
Iron, mg
17.24 (10, 20)
12.41 (10, 16)
13.33 (10, 19)
0.272
Zinc, mg
8.97 (6, 16)
9.28 (7, 12)
9.19 (6, 14)
0.886
Vitamin A, mcg
352.51 (214, 442)
318.71 (180, 427)
352.51 (190, 430)
0.667
Vitamin C, mg
88 (52, 124)
43.37 (19, 95)
57.44 (34, 103)
0.028 *
Vitamin E, mg
11.22 (7, 21)
9.39 (7, 12)
10.53 (7, 13)
0.19
* p < 0.05; 1 Values are median (25th, 75th percentile); 2 p-values are based on the Wilcoxon rank-sum test. Table 1. Daily nutrient intakes among young adults with normal weight or overweight/obesity 1. Table 1. Daily nutrient intakes among young adults with normal weight or As expected, the mean BMI was significantly lower among individuals with normal weight
compared with individuals with overweight/obesity, p < 0.001 (Table 2). The results showed a trend
of high hepcidin and ferritin, and low selenium biomarkers, transferrin saturation, serum iron, and
hemoglobin concentrations in the overweight/obese group although the differences were not statistically
significant (p > 0.05). Table 2. BMI and biochemical markers among young adults with normal weight or overweight/obesity 1. 3. Results BMI/Biochemical Markers
Normal (n = 27)
Overweight/Obese
(n = 32)
Total
p-Value 2
Mean
Mean
Mean
BMI, kg/m2
22.43 ± 0.34
29.28 ± 0.74
26.15 ± 0.62
<0.001 ***
Erythrocyte GPX activity,
nmol/min/mL
1001 ± 76
1077 ± 75
1042 ± 523
0.766
Plasma GPX activity,
nmol/min/mL
84.29 ± 3.59
79.48 ± 3.31
81.75 ± 2.41
0.169
Hemoglobin 3, g/dL
13.48 ± 0.30
13.25 ± 0.35
13.35 ± 0.23
0.616
Transferrin saturation, %
29.33 ± 2.98
26.59 ± 2.21
27.85 ± 1.79
0.456
Serum iron, µg/dL
98.37 ± 8.96
91.06 ± 7.55
94.41 ± 5.71
0.528
Ferritin 4, ng/mL
36.2 (13, 101)
41.07 (13,136)
38.76 (13, 118)
0.677
TIBC 4, µg/dL
350.37 (284, 432)
347.56 (296, 407)
348.84 (287, 420)
0.874
Plasma selenium 4, ng/mL
114.38 (90, 145)
112.06 (92, 137)
113.1 (91, 141)
0.363
SEPP1 4, ng/mL
360.77 (290, 450)
352.13 (276, 446)
356.05 (284, 450)
0.347
Hepcidin 4, ng/mL
9.95 (3, 29)
15.09 (3, 67)
12.47 (3, 47)
0.218
BMI, Body mass index; TIBC, Total iron-binding capacity; SEPP1, selenoprotein P. *** p < 0.001; 1 Values are mean ±
SD; 2 Missing data (n = 1); 3 p-values are based on independent t-test; 4 Values are geometric means (± 1SD). Table 2. BMI and biochemical markers among young adults with normal weight or overweight/obesity 1. In multiple linear regression analysis, hepcidin concentration was significantly predicted by
plasma GPX activity (β = −0.02, p < 0.01), SEPP1 concentration (β = −1.23, p = 0.028), and ferritin
concentration (β = 1.01, p < 0.001), as shown in Table 3. Serum iron was predicted by ferritin
concentration (β = 13.26, p = 0.035). Transferrin saturation was predicted by ferritin concentration
(p < 0.001). Hemoglobin concentration was significantly predicted by ferritin concentration (p < 0.01). All the regression models were adjusted for age, gender, BMI category, and ethnicity. 6 of 10 Antioxidants 2019, 8, 463 Table 3. Association between iron status biomarkers and selenoproteins in young adults with normal weight or overweight/obesity. 4. Discussion In spite of the recognized association between selenium status and anemia, to our knowledge, no
study has investigated the role of hepcidin in this relationship. The aim of this study was to investigate
the associations among selenium status, hepcidin concentration, and iron status biomarkers among
young adults with normal weight or overweight/obesity. Although a few studies have reported significantly higher concentrations of serum iron, transferrin
saturation, and hemoglobin in obese adolescents compared to their non-obese counterparts (20,21),
most studies have demonstrated that obesity is associated with iron deficiency, hypoferremia, and
hyperferritinemia [29,30]. This is due to low-grade chronic inflammation which results in increased
hepcidin concentration and concomitant iron sequestration [31,32]. There is supporting evidence that
invading macrophages in obese adipose tissue sequester iron, resulting in iron overload [33]. While
the results of this study showed the expected trends in serum iron, hemoglobin, transferrin saturation
and ferritin, it is likely that the differences were not significant because there were no individuals with
morbid obesity in the overweight/obese group, with most of them having overweight status. Studies
comparing subjects with extreme obesity to those with normal weight may show statistically significant
relationships among these variables. In addition, while higher hepcidin concentration is expected in
obesity due to increased inflammation [34] and IL-6 concentration [35], the observed difference in this
study between the normal weight and overweight/obese groups was not statically significant. Selenium is incorporated as selenocysteine into selenoproteins which exert immune and
anti-inflammatory effects. Total plasma selenium is measured by the concentrations of the two
predominant selenoproteins (GPX and SEPP1) in the body [36]. Low levels of selenium biomarkers are
seen in obesity [37,38]. For example, there was a reduction in local SEPP1 expression in obese mice,
and this is possibly because these selenoproteins, which regulate oxidative stress, are depleted due to
the increased inflammation in obesity [39]. While some studies have reported a significant negative
correlation between selenoproteins and BMI [23], our observed differences in plasma SEPP1 and GPX
concentrations between the BMI categories were not significant, which may be because almost all
subjects in our study were selenium replete. The daily median selenium intake for subjects in this
study was 100.5 mcg compared to the recommended intake of 55 mcg for adults in the US [40]. Mean
plasma selenium concentration of subjects was 113.1 ng/mL, also well above the reference level of
70 ng/mL [41]. 3. Results Demographic and Biochemical
Indicators
Hepcidin ng/mL (n = 55) 1
Serum Iron, ug/dL (n = 55)
Transferrin Saturation, %
(n = 55)
Hemoglobin, g/dL (n = 54)
Predictors
β ± SE
p
β ± SE
p
β ± SE
p
β ± SE
p
Plasma GPX activity, nmol/min/mL
−0.02 ± 0.01
0.009
−0.24 ± 0.33
0.474
−0.03 ± 0.09
0.705
−0.01 ± 0.01
0.208
Ferritin, ng/mL 1
1.01 ± 0.12
<0.001
13.26 ± 6.07
0.035
6.58 ± 1.59
<0.001
0.51 ± 0.16
0.002
C-reactive protein, mg/L 1
0.02 ± 0.09
0.849
−6.47 ± 4.53
0.161
−2.23 ± 1.18
0.067
−0.08 ± 0.12
0.483
Erythrocyte GPX activity, nmol/min/mL
−0.00 ± 0.00
0.776
−0.00 ± 0.01
1.000
0.00 ± 0.00
0.839
0.00 ± 0.00
0.808
Selenoprotein P, ng/mL 1
−1.23 ± 0.54
0.028
−26.15 ± 26.74
0.334
−4.26 ± 6.99
0.545
−0.93 ± 0.70
0.192
Gender
Male
−0.38 ± 0.32
0.245
20.92 ± 15.80
0.193
6.07 ± 4.13
0.149
1.94 ± 0.41
<0.001
Age, years
0.01 ± 0.04
0.887
1.65 ± 1.85
0.376
0.37 ± 0.48
0.454
0.05 ± 0.05
0.343
Weight status, kg/m 2
Overweight/obese
0.23 ± 0.26
0.386
0.14 ± 12.77
0.991
−0.07 ± 3.34
0.984
0.30 ± 0.34
0.383
Ethnicity
Black
−0.12 ± 0.31
0.699
−10.00 ± 15.17
0.513
−3.92 ± 3.96
0.328
−1.27 ± 0.41
0.003
Hispanic
−0.46 ± 0.40
0.262
−25.83 ± 19.88
0.201
−9.34 ± 5.19
0.079
−0.73 ± 0.53
0.173
Other Race 2
0.33 ± 0.37
0.376
−4.22 ± 18.22
0.818
−4.93 ± 4.76
0.307
−0.54 ± 0.49
0.273
1 Variables were log transformed before analysis; 2 Other Race are Asians, Arabs, Multiracial, and Persians. Table 3. Association between iron status biomarkers and selenoproteins in young adults with normal weight or overweight/obesity. Table 3. Association between iron status biomarkers and selenoproteins in young adults with norm n iron status biomarkers and selenoproteins in young adults with normal weight or overweight/obesity. Antioxidants 2019, 8, 463 7 of 10 7 of 10 5. Limitations Causal inference cannot be drawn from this study because it is a cross-sectional study. Additionally,
other parameters that can influence the antioxidant and hepcidin levels of subjects were not measured
in this study. Most of our participants were selenium sufficient and none had anemia of inflammation,
hence the inability to observe obvious trends in selenium and iron status markers as statistically
significant. In this study, GPX activity in erythrocytes was measured to determine intracellular GPX
pools and long-term selenium status. However, erythrocytes are collected with blood and, if not treated
properly, may be less advantageous over plasma as a specimen for assessing selenium status. Also of
note is the likely interaction of glutathione with heme iron impacting the results [41]. To mitigate this
shortcoming, GPX activity in plasma was also measured. 4. Discussion Both plasma selenium concentration and dietary selenium intakes were not significantly
different between the subjects with normal weight and those with overweight/obesity. Our key finding in this study was that hepcidin concentration was predicted by SEPP1 and plasma
GPX activity in a regression model adjusted for potential confounders. The results from the model
indicate that lower SEPP1 and plasma GPX activity were associated with higher hepcidin concentration. This observation supports one of the proposed mechanisms through which selenium deficiency
increases anemia risk. This inverse relationship may be due to the fact that lower concentrations of
selenoproteins are associated with increased oxidative stress, leading to inflammation. In inflammation,
there is increased production of IL-6, which induces hepcidin production that leads to hypoferremia
as described earlier, eventually resulting in anemia. Petrova et al. espoused this relationship and
reported higher hepcidin and lower GPX concentrations in chronic kidney patients with ischemic
stroke compared with healthy adults [42]. In these patients and among Alzheimer’s disease patients,
hepcidin concentration was negatively correlated with superoxide dismutase and GPX [42,43]. To the
best of our knowledge, this study is the first to discover this relationship among healthy individuals
with normal weight or overweight/obesity. Other mechanisms by which selenium deficiency increases
risk of anemia include increases in heme oxygenase 1, oxidative stress, and possibly through the effect
of serum zinc as suggested by Houghton et al. [26]. It is interesting that, despite observing this relationship between selenoprotein concentrations and
hepcidin, we did not find a significant association between selenoproteins and iron status biomarkers,
as shown by other studies [22,23]. Since this relationship is well documented, our lack of significant
observations may be because the study was not powered to determine those associations as significant. 8 of 10 Antioxidants 2019, 8, 463 The sample size was calculated to determine a 15% variability in hepcidin concentration attributed to
selenoproteins which is close to what we observed (16%). Other possible reasons for the non-significant
association between circulating iron and selenium biomarkers may be because few subjects (17%; n = 10)
in this study had anemia, with 7 of these subjects in the overweight/obese category. Moreover, none of
these anemia cases were due to inflammation. Studies show that pathological conditions of induced
anemia in mice is linked to reduced glutathione peroxidase and selenoprotein W concentrations,
suggesting that these associations may be more evident in anemia [24]. 6. Conclusions This study is novel in showing an inverse association between hepcidin and selenium status among
healthy subjects with normal weight or overweight/obesity. Additional studies on this relationship,
including individuals with morbid obesity (who due to adipose tissue inflammation are prone to
selenium deficiency and impaired iron status), are needed. Furthermore, using animal models of
obesity will be helpful in investigating mechanistic relationships among selenium status, hepcidin,
and iron status. Studies are also needed to investigate whether improving selenium status among
individuals with selenium deficiency will improve iron status via hepcidin. Author Contributions: Conceptualization, D.Y.L., J.L.D., and S.M.A.; Methodology, D.Y.L., J.L.D., and S.M.A.;
Formal Analysis, D.Y.L., J.L.D., S.M.A., and G.L.D.; Investigation, D.Y.L., J.L.D., and S.M.A.; Resources, D.Y.L.,
J.L.D., S.M.A., and G.L.D.; Data Curation, D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Original Draft Preparation,
D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Review and Editing, D.Y.L., J.L.D., S.M.A., and G.L.D. Author Contributions: Conceptualization, D.Y.L., J.L.D., and S.M.A.; Methodology, D.Y.L., J.L.D., and S.M.A.;
Formal Analysis, D.Y.L., J.L.D., S.M.A., and G.L.D.; Investigation, D.Y.L., J.L.D., and S.M.A.; Resources, D.Y.L.,
J.L.D., S.M.A., and G.L.D.; Data Curation, D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Original Draft Preparation,
D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Review and Editing, D.Y.L., J.L.D., S.M.A., and G.L.D. Author Contributions: Conceptualization, D.Y.L., J.L.D., and S.M.A.; Methodology, D.Y.L., J.L.D., and S.M.A.;
Formal Analysis, D.Y.L., J.L.D., S.M.A., and G.L.D.; Investigation, D.Y.L., J.L.D., and S.M.A.; Resources, D.Y.L.,
J.L.D., S.M.A., and G.L.D.; Data Curation, D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Original Draft Preparation,
D.Y.L., J.L.D., S.M.A., and G.L.D.; Writing—Review and Editing, D.Y.L., J.L.D., S.M.A., and G.L.D. Funding:
This research was supported in part by the National Science Foundation’s Major Research
Instrumentation Program (NSF MRI, grant CHE-1531698). Funding:
This research was supported in part by the National Science Foundation’s Major Research
Instrumentation Program (NSF MRI, grant CHE-1531698). Funding:
This research was supported in part by the National Science Foundation’s Major Rese
nstrumentation Program (NSF MRI, grant CHE-1531698). Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References The elemental role of iron in DNA synthesis
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and hypoferraemia in adults: A systematic review. Obes. Rev. 2012, 13, 150–161. [CrossRef] [PubMed] 30. Hamza, R.T.; Hamed, A.I.; Kharshoum, R.R. Iron homeostasis and serum hepcidin-25 levels in obese children
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41. Combs, G.F. Biomarkers of selenium status. Nutrients 2015, 7, 2209–2236. [CrossRef] 42. Petrova, J.; Manolov, V.; Hadjidekova, S.; Yonova, D.; Bogov, B.; Vasilev, V.; Tzatchev, K.; Petrova, M.;
Vazelov, E.; Georgieva, I. Quantification of hepcidin, Se, Zn, SOD and GPX in chronic kidney disease patients
with ischemic stroke. Austin J. Cardiovasc. Dis. Atheroscler. 2017, 4, 1032. 43. Manolov, V.; Hadjidekova, S.; Petrova, J.; Vasilev, V.; Petrova, M.; Traykov, L.; Tzatchev, K.; Borislav, M.;
Grozdanova, R.E.; Bogov, I. The role of iron homeostasis in alzheimer’s disease. J. Alzheimers Neurodegener. Dis. 2017, 3, 1–4. [CrossRef] © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/). © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita Javid Nama Tanaka Manalu
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Gondang
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cc-by
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Abstrak Music kontemporer muncul sebagai sebuah perkembangan kekinian pada proses perjalanan seni music. Kontemporer dianggap
sebagai sebuah cara untuk menanggapi yang kekinian, atau pola penggarapan mutakhir ataupun juga salah satu sikap menggarap
keseni yang digeluti. Walaupun kemudian, perkembangan musik kontemporer justru banyak memunculkan pertanyaan akan
keberadaan musik kontemporer di Indonesia. Music kontemporer semakin mewabah dan menyebar dengan tidak terbendung
diantara bergamnya definisi kontemporer itu sendiri. Dalam sebuah hajatan yang dipergelarkan oleh anak-anak muda Medan,
dengan menyajikan karya music sesuai dengan cara pandang mereka. Nampak jelas bahwa kesimpang siuran istilah kontemporer
tidak bisa membendung hasrat berkarya generasi muda, yang menampilkan sisi yang masih berkaitan dengan budaya dalam negeri
sendiri dan tetap menggambarkan ciri khas budaya Indonesia. Kata Kunci: Keunikan Musik Kontemporer Keunikan Empat Karya Musik Kontemporer pada Gelaran
Seremonialita Javid Nama Tanaka Manalu Wiflihani* Jurusan Sendratasik, Fakultas Bahasa dan Seni, Universitas Negeri Medan Jurusan Sendratasik, Fakultas Bahasa dan Seni, Universitas Negeri Medan Gondang: Jurnal Seni dan Budaya , 1 (1) (2017): 1-5 Gondang: Jurnal Seni dan Budaya , 1 (1) (2017): 1-5 E-mail: wiflihani@unimed.ac.id *Corresponding author: PENDAHULUAN tetapi juga menggunakan sarana yang non alat
musik. Misalnya saja seperti batu, alat dapur,
meja, kursi maupun kaleng juga bisa menjadi
sarana untuk mengekspresikannya. Hal ini yang
menyebabkan terkadang aransemen dalam
music kontemporer menjadi aneh dan sulit
dicerna oleh semua penonton dalam sebuah
pertunjukan. Ungkapan bahwa seni sedemikian terkait
dengan ekspresi jiwa manusia, sehingga dengan
kesadarannya
sendiri,
terciptalah
bentuk-
bentuk seni dengan berbagai media ungkapnya. Musik kontemporer, menjadi salah satu bentuk
seni dari ekspresi seniman secara individual
untuk mengungkapkan subjektifitasnya dalam
bentuk objektifitas. Hasil dari pengendapan
pengalaman
secara
individual
(subjektif),
digelar dan dipertontonkan (objektif) untuk
didinikmati oleh audience. Salah satu format
penggarapan yang bisa mewadahinya adalah
kontemporer. Wajar apabila hal ini menimbulkan
berbagai pendapatpun di masyarakat tentang
music kontemporer, baik itu positif maupun
negative. Pendapat negative yang sering muncul
adalah karena karya musik kontemporer susah
untuk
dipahami
oleh
penonton
yang
menganggap susah untuk dimengerti. Penonton
pada umumnya lebih gampang untuk menikmati
musik pop atau tradisi dalam kesehariannya
music tradisi lebih sering didengar, sehingga
tidak asing lagi bagi telinga setiap orang. Musik kontemporer menurut kajian Prof
Dieter Mack seorang komposer,pianis dan
pakar tentang budaya musik Indonesia dari
Universitas Freiburg Jerman, keberadaan musik
kontemporer di Indonesia dapat dibagi menjadi
3, yaitu : (1) Musik kontemporer dalam idiom
tradisi barat yang materi garapannya berupa
musik tradisional, namun teknik garapannya
memakai prinsip-prinsip yang lazim dikenal
pada musik barat. (2) Musik kontemporer yang
bersumber
dari
unsure
etnik
yang
bisa
dikatakan sebuah revitalisasi musik tradisi.cara
menabuh dengan teknik baru. Misalnya dengan
sendok makan, gesekan kuku jari, ataupun
adanya solis pada tiap instrument di gamelan
jawa. (3) Musik baru yang berlatar budaya
Indonesia dan budaya barat teknik garapan
gendhing gamelan. Walaupun tidak semuanya bisa ditandai
di semua musik kontemporer, biasanya judul
karyanya menggunakan judul yang aneh dan
bahkan asing. Tema yang diangkat dalam karya
musik kontemporer sedemikian yang lazim
dikenal seperti musik biasa , yaitu berkisar pada
cinta, duka, gembira. Yang membedakannya
adalah mengusung tema yang seringkali bisa
dibilang unik, dan penuh dengan kebaruan. Instrumentasi
dalam
musik
kontemporer,
karena
menggunakan
sarana
non
musik,
sehingga terdengar berbeda dengan yang lain. Keunikan
yang
lain
adalah
dalam
menggunakan partitura, yaitu tidak cukup
dengan notasi balok dan/atau angka, akan tetapi
seringkali disertai petunjuk yang detail tentang
gambaran bunyi dan cara memproduksi bunyi
tersebut. Teknik garapan musik kontemporer
membuat sendiri tata gramatika, idiom musik,
susunan dan struktur harmoni yang baru. Ide
garapan dapat saja menggunakan idiom dan tata
gtramatik musik tradisi. PENDAHULUAN Pada gelaran Seremonialita Javid Nama
Tanaka Manalu yang diselenggarakan di akhir
bulan Juni tahun 2014 lalu, terlihat beberapa
penggarapan
musik
kontemporer
yang
dipertunjukkan. Karya-karya tersebut berasal
dari Hendrik Perangin-angin, Tanaka Manalu,
Brehme Adyatmo Purba (Medan) dan Antonio
Montoya (Yogyakarta). Hendrik Perangin-angin adalah sosok
yang tidak kenal lelah dalam menggarap musik
baru maupun aransemen yang berlatar musik
tradisi. Terutama musik tradisi dari etnis Karo
yang khusus digarapnya untuk pertunjukan
malam itu. Alat musik tradisi etnis Karo, yaitu
kulcapi
menjadi
inspirasinya
dengan Abstract Contemporary music emerges as a contemporary development in the journey of the art of music. Contemporary is regarded as a way
to respond to the present, or the latest cultivation pattern or also one of the working attitude of art that is involved. Although later,
the development of contemporary music that many raises questions about the existence of contemporary music in Indonesia. Contemporary music is increasingly pervasive and spreads unstoppable among the contemporary definition of bergamnya itself. In a
celebration performed by young people of Medan, by presenting the work of music in accordance with their perspective. It seems clear
that contemporary terminology is not able to stem the desire to work of the young generation, which shows a side that is still related
to the culture of the country itself and still describes the characteristics of Indonesian culture. Keywords: Uniqueness, Contemporary Music. How to Cite: Wiflihani, (2017). Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita
Javid Nama Tanaka Manalu. Gondang: Jurnal Seni dan Budaya, 1 (1): 1-5 p-ISSN 2599 - 0594
e-ISSN 2599 - 0543 E-mail: wiflihani@unimed.ac.id 1 1 Wiflihani, Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita Javid Wiflihani, Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita Javid HASIL DAN PEMBAHASAN Ekspresi yang ditujukkan oleh seniman
dalam musik kontemporer, karena keunikan dan
kebebasannya,
terkadang
terlihat
aneh,
membosankan atau sulit dicerna oleh penonton. Penyajian musik kontemporer, memang tidak
semata-mata terpaku pada alat musik saja, akan 2 2 Gondang: Jurnal Seni dan Budaya, 1 (1) (2017): 1-5 menghadirkan 6 pemusik untuk memainkannya. “Resah”, terdiri dari untaian bunyi yang berasal
dari 6 kulcapi, terangkai dalam aransemen
berbeda dengan karakter dan warna khas bunyi
musik tradisi. musik modern yang mengkolaborasikan idiom-
idiom musik, seni tari, kontemporer dan
kendang sebagai instrumen tradisi jawa untuk
mempertegas ritme. Reportoar komposisi ini
dimainkan oleh empat orang. Dua diantaranya
sebagai penari, dan musisi lainya memainkan
piano dan kendang. Di
tangannya. musik
tradisi
yang
sepertinya biasa-biasa saja saat didengar oleh
peminatnya, menjadi satu olahan unik dan
tertata
serta
menjadi
menarik
penonton. Rangkaian ke 6 bunyi kulcapi itu saling
membunyikannya
secara
bergantian,
serta
dimainkan dengan cara yang berbeda. Teknik
saling mengisi (invention) bunyi petikannya satu
dengan
yang
lain
sedemikian
harmonis,
demikian juga permainan teknik interlocking
yang tingkah meningkah menjadi sedemikian
menarik. Kolaborasi antara permainan piano dan
penari dilakukan dengan teknik inversi (saling
mengisi),
antara
gerak
dan
bunyi
yang
dihadirkan. Bisa diartikan bahwa peran musisi
(bunyi)
dan
penari
(gerak)
tidak
bisa
dihilangkan, dikarenakan satu sama lain saling
berkaitan. Antonio
Montoya
hanya
mereproduksi bentuk dan gaya penari pada
kesenian ronggeng dalam karya ini, oleh karena
hanya menggunakan instrumen diatonis yaitu
piano
dan
kendang
(etnis
jawa),
bukan
menggunakan instrumen tradisi asli pengiring
ronggeng. Dinamika penyajiannya juga runut untuk
diikuti, padahal tanpa ada partitur untuk
memainkannya. Satu dengan yang lain, seperti
secara otomatis bisa memainkan repertoar
“Risau” terlihat menyatu dan berjalan apa
adanya. Ada kesepakatan-kesepakatan yang
hanya dimengerti diantara mereka, terutama
Hendrik
Perangin-angin
sebagai
leader. Penonton seolah-olah dibawa ke suasana yang
terkadang tidak terlihat ketradisiannya, dengan
hadirnya alat musik kulcapi lewat harmonisasi
irama yang tersaji. Antonio Montoya, sebagai salah satu
pemusik yang khusus didatangkan ke Medan di
acara tersebut, menjadi salah satu tamu yang
membawa sesuatu yang bisa dikatakan berbeda. Gerak tari tradisi tidak lagi identik dengan
iringan tradisi, akan tetapi instrumen diatonis
juga bisa menjadi pengiringnya. Bisa menjadi
sesuatu yang indah jika dapat dikemas dalam
suatu ide dan teknik tertentu, yang dapat
menghasilkan suatu karya baru. Sebuah penggarapan musik kontemporer
yang bersumber dari unsure etnik dengan cara
memetik kulcapi, dengan teknik baru seperti
sebuah perkusi. Bisa dibilang punya kesulitan
tersendiri, karena tidak mudah mengumpulkan
pemain dan tidak mudah pula menggarapnya. HASIL DAN PEMBAHASAN Namun, pada malam itu, sudah terealisasi untuk
menjadi sebuah karya yang menarik, khususnya
bagi pecinta musik. Itulah yang menjadi
insprirasi Hendrik Peranginangin menggarap
musik tradisi dalam aransemen kontemporer
bersama grupnya Incidental Music. Antonio Montoya mulai mengenal musik
secara formal pada waktu bersekolah di Sekolah
Menengah Musik Yogyakarta (SMM)d engan
mengambil instrumen mayor oboe. Kemudian
melanjutkan Sarjana S1 Musik pendidikan dan
komposisi, S2 minat utama penciptaan Musik
Barat (komposisi) dan mengajar instrument
mayor oboe dan ansambel tiup kayu di Institut
Seni Indonesia (ISI) Yogyakarta. Melihat latar
belakang pendidikan, dia sedemikian lekat
dengan musik barat, akan tetapi tidak menutup
kemungkinan untuk mengambil ide dasar karya
tradisi. Penggarapan Hendrik Perangin-angin,
bisa dibilang hampir sama dengan pola garap
Antonio Montoya (Yogyakarta) yang sama-sama
mengangkat tradisi. Hendrik dengan alat musik
tradisi, sedangkan Antonio Montoya mengambil
tema tradisi yaitu “Ronggeng”. Komposisi
“Ronggeng” adalah sebuah karya komposisi Karya lain dari Tanaka Manalu selain Javid
Nama (Ziarah Abadi) adalah Lake, Still, dan
Invetion. Masih dalam penggarapan orchestra
musik barat, Lake, merupakan komposisi
ansambel musik programa dari 20 gitar akustik. 3 3 Wiflihani, Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita Javid Wiflihani, Keunikan Empat Karya Musik Kontemporer pada Gelaran Seremonialita Javid (cello) menggambarkan sosok seorang laki-laki
yang sudah menjadi seorang ayah. Sosok
perempuan (piano) yang selalu mengisi dan
pada perjalanannya menjadi seorang ibu dari
anak-anaknya. Mereka dipandang sebagai dua
sisi yang berbeda, tetapi menjalin sebuah
keharmonisan, damai dan sejahtera serta
dipersatukan untuk saling mendukung dan
melengkapi. Dalam beberapa bagian musik
terdapat
gambaran
cerita
bukan
hanya
kebahagiaan namun ada suatu kontra dan
kejanggalan, yang diakhiri dengan keterikatan
yang menjadi satu kesatuan. Mengambarkan
suasana
keindahan
danau
dalam nuansa ketenangan yang lebih mendekati
ke-Jawa-an berbentuk suita. Memang secara
abriter karya ini menggambarkan sebuah
kekaguman
tentang
sebuah
ruang
yang
mempunyai nilai, sedikit menggunakan idiom-
idiom yang menyerupai medium di dalam ruang
tersebut. Semuanya diwakili oleh dentingan 20
gitar akustik yang apik dan rapi. Masih dalam instrument gitar, Still
merupakan karya komposisi trio bass ini
mengusung gaya modern. Masih menggunakan
unsur atau gaya yang umum pada permainan
gitar bass di komposisi ini, akan tetapi berbeda
dengan
karya
Giovanni Bottesini yang
terkenal dengan trio double bass. Jika Giovani
Botessini (1821 - 1889) hidup di zaman
romantic dengan double bass dalam orchestra
musik barat, maka Tanaka Manalu trio bass
gitar,
sehingga
sedikit
berbeda
melalui
perkembangan instrumen. HASIL DAN PEMBAHASAN Sedikit berbeda dengan “Mutual Support”,
karya
“Kebersamaan”
merupakan
yang
dijadikan musik untuk sebuah kegiatan dimana
mengangkat konteks tema sebuah Perhelatan
Ziarah Abadi. Karena setiap yang dilakukan
dalam hal apapun selalu bersama, hingga
nantinya pada saat terselenggaranya ada sebuah
Kebersamaan dalam menyaksikan sajian musik,
dihadiri penyaji dan yang disaji, berbeda-beda
namun saat itu ada bersama. Ada berbagai
macam kemampuan dan potensi yang dimiliki
seseorang dalam suatu tim, namun sulit untuk
maksimal jikalau tidak dipersatukan dalam
kepentingan suatu proses. Dalam musiknya
dibawakan dalam empat instrumen gesek
dengan unsur musik minor mayor, direlasikan
dalam
suatu
kesedihan
dan
diakhiri
kegembiraan
menggambaran
cerita
itulah
bagian proses yang dialami suatu tim. Invetion adalah Karya Tanaka manalu
berupa solo piano dengan menggunakan teknik-
teknik dua suara yaitu polifoni dengan arah
menuju fuga, yang dimainkan oleh Jovita. Dia
mencoba kembali ke masa 300 tahun yang lalu,
yaitu berasal dari karya JS Bach “Invention” . Invention ditulis untuk mengajarkan kebenaran
dalam bermain dan membantu murid untuk
dapat menghasilkan nada yang bernyanyi
(singing
out). Tanaka
Manalu
menerjemahkannya, tidak sekedar gerakan
sinkronisasi jari tangan kiri kanan, akan tetapi
kepada
produksi
bunyi
dan
nada
yang
semanusiawi mungkin. SIMPULAN Sebagai sebuah wadah ekspresi secara
individual, format karya music kontemporer
kian
berkembang,
walaupun
masih
dipertanyakan, apakah akan mendominasi cara
berkarya music. Musik kontemporer sedemikian
cepat
menyebar
menjangkiti
beberapa
composer
muda,
diiringi
dengan
mendominasinya Institusi pendidikan music
setara master yang menjadi penyebar ‘virus’
kontempporer. Beberapa anak muda yang
kemudian pulang ke asalnya, menjadi salah satu
actor yang berperan. Di sisi lain, aktivitas yang
berbasis tradisional akan terus dipelihara oleh
institusi
tersebut
sebagai
salah
satu Komposer yang terakhir adalah dua karya
dari Brehme Adyatmo Purba yaitu Mutual
Support dan Kebersamaan. Admo, demikian
panggilan kesehariannya mendapatkan gelar
sarjana seni dari Fakultas Bahasa & Seni
Universitas
HKBP
Nommensen
dengan
mendalami
Jurusan
komposisi. Pemuda
kelahiran Tarutung 07 Juli 1990 ini dalam
penggarapannya komposisi musiknya, masih
menggunakan idiom musik barat dengan
instrumentnya
gesek
dan
piano. Mutual
Support adalah karya duet cello dan piano yang
merupakan
gambaran
kehidupan
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Microplate Reader
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Diagnostic TCD for intracranial stenosis in acute stroke patients: experience from a tertiary care stroke center in Karachi, Pakistan
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Kamal et al. BMC Res Notes (2015) 8:341
DOI 10.1186/s13104-015-1289-3
RESEARCH ARTICLE
Diagnostic TCD for intracranial stenosis
in acute stroke patients: experience from a
tertiary care stroke center in Karachi, Pakistan
Ayeesha Kamran Kamal1*, Hasan Rehman2, Nasir Mustafa2, Bilal Ahmed3, Mohammad Jan4, Faisal Wadivalla2
and Syed Kamran2
Open Access Kamal et al. BMC Res Notes (2015) 8:341
DOI 10.1186/s13104-015-1289-3
RESEARCH ARTICLE
Diagnostic TCD for intracranial stenosis
in acute stroke patients: experience from a
tertiary care stroke center in Karachi, Pakistan
Ayeesha Kamran Kamal1*, Hasan Rehman2, Nasir Mustafa2, Bilal Ahmed3, Mohammad Jan4, Faisal Wadivalla2
and Syed Kamran2
Open Access Kamal et al. BMC Res Notes (2015) 8:341
DOI 10.1186/s13104-015-1289-3 © 2015 Kamal et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abstract Conclusions: This study indicates the poor sensitivity of TCD to be a reliable screening tool for the presence of ICAD
in the South Asian population in a real life clinical setting. Keywords: Transcranial Doppler, Intracranial stenosis, Magnetic resonance angiography, Cerebral infarction
prevention, Cerebrovascular accident Keywords: Transcranial Doppler, Intracranial stenosis, Magnetic resonance angiography, Cerebral infarction
prevention, Cerebrovascular accident disease (ICAD) is believed to have a higher frequency
among the South Asians [2–7] with one study [8] report-
ing it to be responsible for at least 30–50% strokes among
the Asian population. Abstract Background: Stroke is a common cause of morbidity and mortality around the world. Intracranial large artery
atherosclerosis (ICAD) is a frequent etiology of stroke in the South Asian population. There is a need for widely avail-
able screening tools to identify patients that are at high risk of stroke due to ICAD for aggressive risk management. This study describes the experience of using the transcranial Doppler (TCD) as a screening tool for this purpose at a
tertiary care hospital in a developing country. Methods: 86 Patients admitted with stroke due to ICAD underwent TCD for six arteries (Right and left middle cer-
ebral arteries, right and left anterior cerebral arteries, right and left posterior cerebral arteries) in addition to the mag-
netic resonance angiography (MRA) that is done routinely at the stroke center. Arteries were labeled with either <50
or >50% stenosis by TCD using two separate criteria. These findings were compared with those from the MRA which
was used as the gold standard. The proportion of patients that had complete exams (all six arteries insonated by TCD)
was reported. The success rate of each TCD criteria in detecting arteries with >50% stenosis was also calculated. Results: There was an attempt to visualize 516 arteries (86 patients with 6 arteries each) of which 375 (72.7%) were
successfully insonated. 38 of the 86 (55.8%) patients had complete examinations. MRA reported 43 (8.3%) arteries as
stenosed >50%. The TCD did not categorize any artery as stenosed using either criterion and hence failed to classify
any stenosed artery correctly. The positive predictive and sensitivity was 0 for this study and the negative predictive
value was 93.3%. Results: There was an attempt to visualize 516 arteries (86 patients with 6 arteries each) of which 375 (72.7%) were
successfully insonated. 38 of the 86 (55.8%) patients had complete examinations. MRA reported 43 (8.3%) arteries as
stenosed >50%. The TCD did not categorize any artery as stenosed using either criterion and hence failed to classify
any stenosed artery correctly. The positive predictive and sensitivity was 0 for this study and the negative predictive
value was 93.3%. Conclusions: This study indicates the poor sensitivity of TCD to be a reliable screening tool for the presence of ICAD
in the South Asian population in a real life clinical setting. Diagnostic TCD for intracranial stenosis
in acute stroke patients: experience from a
tertiary care stroke center in Karachi, Pakistan Ayeesha Kamran Kamal1*, Hasan Rehman2, Nasir Mustafa2, Bilal Ahmed3, Mohammad Jan4, Faisal Wadivalla2
and Syed Kamran2 *Correspondence: ayeesha.kamal@aku.edu
1 Stroke Service, Stroke Fellowship Program, International Cerebrovascular
Translational Clinical Research Training Program, Fogarty International
Center and The National Institute of Neurologic Disorders and Stroke,
Section of Neurology, Department of Medicine, Aga Khan University,
Stadium Road, Karachi 74800, Pakistan
Full list of author information is available at the end of the article © 2015 Kamal et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Background Stroke is a leading cause of morbidity and mortality
worldwide resulting in an estimated 4.4 million deaths
each year [1]. Large vessel intracranial atherosclerotic The pathophysiology of ischemic stroke revolves
around atherosclerotic plaque formation over a number
of years in the arteries of the Circle of Willis before the
final cerebrovascular event. This event is presumably
caused by a rupture of that plaque or progressive hemo-
dynamic stenosis leading to decompensated low flow
state with failure of the collaterals [9, 10]. Kamal et al. BMC Res Notes (2015) 8:341 Page 2 of 6 Data collection instruments Regardless of the mechanism of stroke, prevention is
the key to reduce mortality [11]. Studies such as WASID
study [12] have identified medications that are beneficial
in high risk patients. However, to identify intracranial
stenosis there need to be screening tools that are not only
effective but also widely available at an affordable cost to
make them relevant to low income countries where this
condition is prevalent. Relevant demographic data including, age and gender
was extracted from the medical records available.h The subtype of stroke was determined using the causa-
tive classification system for ischemic stroke (CCS) [22].h i
The MRA was interpreted on digital images and the
degree of stenosis was calculated using the following
equation [13]: The gold standard to detect large artery intracranial
stenosis is conventional cerebral angiography [13] but
the cost, unavailability and risk of stroke [14–17] make
it impractical for screening purposes. Similarly magnetic
resonance angiography (MRA) is not considered a viable
option due to its high cost and availability issues [18]. Due to its wide availability, significantly less cost and
non-invasiveness, the transcranial Doppler sonography
(TCD) is considered a potentially valuable screening tool
[19]. Previous studies that have looked at this diagnostic
modality have shown encouraging results by reporting
negative predictive values and sensitivities comparable to
that of the MRA [20]. % stenosis = [1 −(Dstenosis/Dnormal)] × 100 Using the degree of stenosis, the artery was then clas-
sified as normal or with mild atherosclerotic changes,
moderately stenosed and severely stenosed or occluded. A normal artery had <30% stenosis, a moderately sten-
osed artery had 30–50% stenosis and a severely sten-
osed artery was defined as an artery with >50% stenosis. Study settingh This study was conducted in a tertiary care hospital in
Karachi, a metropolitan city located in the south of Paki-
stan with a multiethnic population of more than 13 mil-
lion persons [21]. The hospital has its own stroke team
and is equipped with MRA and TCD facilities along with
on call radiologists round the clock. Using the TCD, intracranial stenosis was categorized as
>50 or <50%. There were two criteria that were used for
this purpose. The first criterion used the mean velocity
(MV) while the second criterion used the peak velocity
(PV). Both criteria were used independently and results
using each criterion are reported. Background The severely stenosed artery was used as the outcome of
interest since the WASID study [12] had defined this as
the critical value beyond which there is proven benefit
of antiplatelet therapy. The MRA was used as the gold
standard since catheter angiography was considered too
invasive for the purpose of this study. However, the majority of these studies have been per-
formed on the Western population. Hence, this study
aims to explore the viability of the TCD in this region
as a screening tool to detect intracranial atherosclerotic
disease in a real life low middle income country clinical
setting. All the TCDs were performed and reported by the
same sonographer who had received training in this field. He was blinded to the MRA findings and was required
to report the peak velocity (PV) and the time averaged
mean of the maximum velocity (MV) for the following
arteries: the right middle cerebral artery (RMCA), the
left middle cerebral artery (LMCA), the right anterior
cerebral artery (RACA), the left anterior cerebral artery
(LACA), the right posterior cerebral artery (RPCA) and
the left posterior cerebral artery (LPCA). The vertebral
and the basilar arteries were excluded. Statistical considerationshi The findings of the MRA were compared to those from
the TCD to calculate the sensitivity, the positive predic-
tive value and the negative predictive value of the TCD. Sensitivity = true positive/(true positive + false nega-
tive) [25]. Negative predictive value = true negative/(true nega-
tive + false negative) [25]. All data was entered and analyzed via SPSS v19. Statis-
tical analysis were reviewed by a biostatistician. Selection of participants The arteries most
successfully insonated were the MCAs (91.7% RMCAs
and 89.5% LMCAs) followed by the ACAs (65.1% LACAs
and 68.6% RACAs) while the PCAs were insonated least
successfully (61.6% in right 60.5% in left). Insonation suc-
cess rate for each artery is given in Table 2.hi The highest proportion of severely stenosed arteries was
in the RMCA (17.4%, n = 15) followed by the LMCA
(9.3%). Detailed findings of the MRA are given in Table 1. (9.3%). Detailed findings of the MRA are given in Table 1. Of the 86 patients, 38 (44.2%) had complete exami-
nations where all 6 arteries of interest (LACA, RACA,
LMCA, RMCA, LPCA, RPCA) were seen, 45 had incom-
plete assessments where at least one but not all arteries
were visualized and there were 3 patients, all women, in
whom not a single artery was visualized. Overall, there
was an attempt to visualize a total of 516 arteries in 86
patients (6 arteries in each patient) through the TCD but
they were successful in insonating only 375 (72.7%) arter-
ies. The insonation failure in men was 19.6% (n = 53)
while it was 35.7% (n = 88) in women. The arteries most
successfully insonated were the MCAs (91.7% RMCAs
and 89.5% LMCAs) followed by the ACAs (65.1% LACAs
and 68.6% RACAs) while the PCAs were insonated least
successfully (61.6% in right 60.5% in left). Insonation suc-
cess rate for each artery is given in Table 2.hi Ethical considerations Prior to obtaining data, the study protocol was approved
by the Ethical Review Committee of the Aga Khan Uni-
versity Hospital. No financial incentives were provided
to any study participant. Written informed consent and
verbal assent was given by all participants or their legal
surrogate respondents prior to the investigation. The findings of the sonography were categorized both
via the peak velocity as well as the mean velocity to cat-
egorize the degree of stenosis as assessed by the TCD. Regardless of the criteria used, no artery was labeled as
having >50% stenosis by the TCD. This essentially gives
us sensitivity and positive predictive values of 0% for
all arteries using either criterion. Similarly both criteria Selection of participants All patients admitted to this center after being diagnosed
with stroke between January 2012 and January 2013 were
eligible for this study. Participants were men and women
aged >18 years who presented to the Emergency Depart-
ment and were subsequently diagnosed with stroke due
to atherosclerotic disease via CT scan or MRI. Partici-
pants had to consent to TCD in addition to routine MRA
which is done as part of standard of care of every patient
admitted with stroke at this center. Using the MV, any artery with a time averaged mean
of the maximum velocity of >100 m/s was considered to
have >50% stenosis. This value was chosen taking into
consideration the findings of the SONIA trial [20]. i
Using the peak velocity to determine the degree of ste-
nosis, the criterion verified by Baumgartner et al. [23]
was used which was slightly more complex. The cut offs
for the peak velocity for >50% stenosis were as follows:
for the MCAs >220 cm/s; for the PCAs >145 cm/s; For
the ACAs >155 cm/s. Patients were excluded from participation if they had
concomitant acute coronary syndrome or any extracra-
nial vascular disease. Any patient who refused consent
was also excluded. As in the SONIA trial [20], the standards set by the
Intersocietal Commission for the Accreditation of Page 3 of 6 Page 3 of 6 Kamal et al. BMC Res Notes (2015) 8:341 Vascular Laboratories (ICAVL) [24] were followed for the
TCD. Details of these standards are given in Additional
file 1: Appendix 1. The highest proportion of severely stenosed arteries was
in the RMCA (17.4%, n = 15) followed by the LMCA
(9.3%). Detailed findings of the MRA are given in Table 1. Of the 86 patients, 38 (44.2%) had complete exami-
nations where all 6 arteries of interest (LACA, RACA,
LMCA, RMCA, LPCA, RPCA) were seen, 45 had incom-
plete assessments where at least one but not all arteries
were visualized and there were 3 patients, all women, in
whom not a single artery was visualized. Overall, there
was an attempt to visualize a total of 516 arteries in 86
patients (6 arteries in each patient) through the TCD but
they were successful in insonating only 375 (72.7%) arter-
ies. The insonation failure in men was 19.6% (n = 53)
while it was 35.7% (n = 88) in women. Resultsh There were a total of 86 patients who were enrolled in the
study. 45 (52%) were male while 41 (48%) were female. The mean age for male patients was 57 (SD: 16) while
the mean age for female patients was 60 (SD: 14). 97.7%
patients (n = 84) had suffered from an ischemic stroke
while only 2.3% (n = 2) had a hemorrhagic stroke. Table 2 The proportion of successful and unsuccessful
insonations in each artery
Successful
Unsuccessful
Right middle cerebral artery
78 (91.7%)
8 (9.3%)
Left middle cerebral artery
77 (89.5%)
9 (10.5%)
Right anterior cerebral artery
59 (68.6%)
27 (31.4%)
Left anterior cerebral artery
56 (65.1%)
30 (34.9%)
Right posterior cerebral artery
53 (61.6%)
33 (38.4%)
Left posterior cerebral artery
52 (60.5%)
34 (39.5%)
Total
375 (73.7%)
141 (27.3) Table 2 The proportion of successful and unsuccessful
insonations in each artery Among the 86 patients enrolled in the study, all 6 arter-
ies (LACA, RACA, LMCA, RMCA, LPCA, RPCA) were
found normal in 55 (63.9%) of the patients as detected by
the MRA while the remaining 31 patients had at least one
diseased artery. In all, 516 arteries (86 patients with 6 arteries each)
were looked at and the MRA reported 407 (78.9%) of
the arteries to be either normal or with mild atheroscle-
rotic irregularity, 66 (12.8%) had moderate stenosis and
43 (8.3%) were severely stenosed or completely occluded. Table 1 Magnetic resonance angiography findings
Normal/mild atherosclerotic
changes (<30% stenosis)
Moderately stenosed
(30–50% stenosis)
Severely stenosed
(>50% stenosis)
Right middle cerebral artery
60 (69.8%)
11 (12.8%)
15 (17.4%)
Left middle cerebral artery
67 (77.9%)
11 (12.8%)
8 (9.3%)
Right anterior cerebral artery
71 (82.6%)
10 (11.6%)
5 (5.8%)
Left anterior cerebral artery
70 (81.4%)
11 (12.8%)
5 (5.8%)
Right posterior cerebral artery
70 (81.4%)
12 (14.0%)
4 (4.7%)
Left posterior cerebral artery
69 (80.2%)
11 (12.8%)
6 (7.0%)
Overall
407 (78.9%)
66 (12.8%)
43 (8.3%) Table 1 Magnetic resonance angiography findings Kamal et al. BMC Res Notes (2015) 8:341 Page 4 of 6 also had an identical negative predictive value (93.3%). A
brief comparison on MRA and TCD findings is given in
Table 3. when it used multivariate analysis. Discussion With the abundant data available on the prevalence and
the magnitude of ICAD [6, 26–29] it is important to look
at screening and diagnostic modalities that can be effec-
tive in reducing morbidity and mortality. This is one of
the earlier studies to explore the use of intracranial Dop-
pler among the South Asian population. Previous stud-
ies [20, 30–33] in other parts of the world regarding the
TCD have had promising results. Although the sensitivity
has been reported to be as low as 65% in some cases [20],
a negative predictive value of over 90% would suggest
that the Doppler can be used to screen out patients who
would benefit from aggressive risk management [34]. Unfortunately, this study suggests the Doppler ultra-
sound is an ineffective tool for this purpose in the South
Asian setting when done in a pragmatic fashion in real
life patients admitted for stroke. The rate of insonation failures was higher in women
as compared to men. Although this finding has not been
encountered commonly, there has been at least one pre-
vious study [40] that reported a higher insonation fail-
ure rate in women compared to men. On the other hand,
Hashimoto et al. [37] reported a much higher (84 vs. 52%)
rate of successful insonations in men compared to women. The most significant result pertaining to the outcome
of the ultrasound was the inability of the TCD to cor-
rectly detect any vessel as stenosed or occluded. This
would rule out the TCD as a screening tool since it fails
to identify high risk patients that need to be managed. The two criteria that were used to classify stenosis TCD
findings, the PV and MV, both reported negative predic-
tive values of 93.3%. This would seem to be in line with
previous studies [20] but it is in fact a reflection of the
proportion of normal vessels and their of correct classifi-
cation Hence, this does not have any importance in rela-
tion to identifying diseased vessels. This study therefore
cannot be used to establish the superiority of one cri-
terion over another nor does this have any importance
when assessing the TCD as a screening tool. Since only 38 of the 86 patients had complete exami-
nations, TCD appears to be an unreliable screening
tool since most patients will then have to undergo fur-
ther evaluation based on inconclusive results. Resultsh This would support
the belief that difficulties that have been documented
[19] using TCD, such as difficulty in visualizing temporal
windows and fixating probe positions, are more applica-
ble to certain populations compared to others and more
specifically Asians and African Americans as compared
to Caucasians. The proportion of stenosed vessels among arteries
that were not successfully insonated was 12.7% which is
higher than the proportion of stenosed or occluded ves-
sels (8.3%) among the visualized arteries. What is also of note however, is that most studies [20,
33, 41–44] that have studied the TCD have primarily
looked at the MCAs while only some have studied the ver-
tebrobasilar arteries [32], the PCAs [32, 45, 46] or all the
arteries that were included in this study [35, 47]. When we
look at the failure rate of MCAs in our study (<10%), it
does become comparable to the other studies mentioned
earlier. And so perhaps the only artery that had any results
was the MCA but even this does not seem feasible.h Discussion Although
previous studies [35, 36] have reported insonation fail-
ures, these failures are estimated to be between 10 and
30%. Hashimoto et al. [37] reported a failure to visualize
temporal windows in 29% of the subjects when he stud-
ied the Japanese population while another study, also in
Japan, by Itoh [38] had a failure rate of around 22.8%. Similarly, when Seidel used the color coded doppler in
the German population, he failed to visualize the intrac-
ranial arteries in 20% of cases [39]. One study in 2011
[40] in the United States reported an insonation failure
of around 22.2% in 99 patients Interestingly, the study
mentioned above quoted higher insonation failure rates
for African Americans (47%) compared to whites (15%) This study is one of the first to look at the TCD in the
South Asian population. However, it is a limited observa-
tion in a single center with a trained operator who had
standardized training and audit. The strokes were classi-
fied with rigor and the images reviewed with MRA and
radiology. Under these settings and clinical conditions it
appears that the TCD is not a useful tool at all. Whether
broad based population studies on community based
patients would be different is an area of further investi-
gation and these finding are limited to an inpatient type
setting. Table 3 Comparison of transcranial Doppler and magnetic
resonance angiography findings
TCD
MRA
>50% stenosis
<50% stenosis
>50% stenosed
0
0
<50% stenosed
25
350
Failed to insonate
18
123
Total
43
473 Table 3 Comparison of transcranial Doppler and magnetic
resonance angiography findings Acknowledgements 12. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S
et al (1995) The warfarin-aspirin symptomatic intracranial sisease study. Neurology 45(8):1488–1493 This work was facilitated by the following: The Karachi Intracranial Stenosis
Study was funded by a grant awarded to Ayeesha Kamran Kamal and Philippe
M Frossard (formerly Dept. of Biologic and Biomedical Sciences, Aga Khan
University) by the Higher Education Commission, Government of Pakistan,
and No. 20-941/R&D/07. Ayeesha Kamran Kamal was also the recipient of a
seed money Grant from the University Research Council, Aga Khan University
Hospital to initiate exploratory work that led to the elaborated study. Dr. Faisal
Wadiwalla trained as neurovascular research fellow whose training was cur-
rently funded by Award Number D43TW008660 from the Fogarty Interna-
tional Center and the National Institute of Neurologic Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision
to publish, or preparation of the manuscript. The content is solely the respon-
sibility of the authors and does not necessarily represent the official views of
the Fogarty International Center, National Institute of Neurologic Disorders
and Stroke or the National Institute of Health or the Higher Education Com-
mission, Government of Pakistan. 13. Samuels OB, Joseph GJ, Lynn MJ, Smith HA, Chimowitz MI (2000) A stand-
ardized method for measuring intracranial arterial stenosis. AJNR Am J
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(1995) Endarterectomy for asymptomatic carotid artery stenosis. JAMA
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lowing neuroangiography: a prospective study. Stroke 18(6):997–1004 17. Hobson RW, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB et al
(1993) Efficacy of carotid endarterectomy for asymptomatic carotid
stenosis. N Engl J Med 328(4):221–227 18. Feldmann E (2009) Diagnosis and quantitation of intracranial stenosis. J
Neuroimaging 19(Suppl 1):22S–24S The authors would like to acknowledge the patience, kindness, time and
cooperation of all patients and their families who contributed to this study. We would also like to take this opportunity to acknowledge, Hina Tejani for
their excellent secretarial support. In addition the stroke team would like to
acknowledge the support of the Section of Neurology at AKUH who always
facilitate logistically all research endeavors. 19. Received: 3 March 2014 Accepted: 22 July 2015 Received: 3 March 2014 Accepted: 22 July 2015 Received: 3 March 2014 Accepted: 22 July 2015 Additional file 1: Appendix 1. Reference standards for TCD
performance. Additional file 1: Appendix 1. Reference standards for TCD
performance. Competing interests p
g
The authors declare that they have no competing interests. Abbreviations ICAD: large artery intracranial atherosclerosis; TCD: transcranial Doppler;
MRA: magnetic resonance angiography; WASID: warfarin aspirin sympto-
matic intracranial disease; SONIA: the stroke outcomes and neuroimaging of
intracranial atherosclerosis; CCS: causative classification system for ischemic
stroke; PV: peak velocity; MV: time averaged mean of the maximum velocity;
PCA: posterior cerebral artery; MCA: middle cerebral artery; ACA: anterior
cerebral artery; LPCA: left posterior cerebral artery; LMCA: left middle cerebral
artery; LACA: left anterior cerebral artery; RPCA: right posterior cerebral artery;
RMCA: right middle cerebral artery; RACA: right anterior cerebral artery; ICAVL:
Intersocietal Commission for the Accreditation of Vascular Laboratories. 2. De Silva DA, Woon FP, Lee MP, Chen CP, Chang HM, Wong MC (2007)
South Asian patients with ischemic stroke: intracranial large arteries are
the predominant site of disease. Stroke 38(9):2592–2594 3. Feldmann E, Daneault N, Kwan E, Ho KJ, Pessin MS, Langenberg P et al
(1990) Chinese-white differences in the distribution of occlusive cerebro-
vascular disease. Neurology 40(10):1541–1545 y
4. Kieffer SA, Takeya Y, Resch JA, Amplatz K (1967) Racial differences in cer-
ebrovascular disease. Angiographic evaluation of Japanese and American
populations. Am J Roentgenol Radium Ther Nucl Med 101(1):94–99 5. Nishimaru K, McHenry LC Jr, Toole JF (1984) Cerebral angiographic and
clinical differences in carotid system transient ischemic attacks between
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Cerebrovasc Dis Stroke 5(2):93–105 Authors’ contributions AKK conceptualized the study and organized it, reviewed this manuscript
and wrote the first outline; HR, wrote the second draft, edited the paper and
helped analyze the results; NM reviewed the paper and performed ultrasound
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matic intracranial stenosis: a university hospital-based ultrasound study. Perspect Med 1(1–12):211–213 Compliance with ethical guidelines that can identify high risk patients so that strokes may be
prevented. This study evaluated the TCD as a potential
screening tool for this purpose in a hospital setting. Conclusions With the rapidly growing morbidity and mortality rates of
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VS et al (2006) Predictors of ischemic stroke in the territory of a sympto-
matic intracranial arterial stenosis. Circulation 113(4):555–563 44. Telman G, Namestnikov O, Kouperberg E, Sprecher E, Yarnitsky D (2008)
Ischemic middle cerebral artery stroke missing the tissue plasminogen
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(2000) Evaluation of posterior cerebral artery blood flow with transcranial
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31. Cher LM, Chambers BR, Smidt V (1992) Comparison of transcranial Dop-
pler with DSA in vertebrobasilar ischaemia. Clin Exp Neurol 29:143–148 46. Tian JW, Sun LT, Zhao ZW, Gao J (2006) Transcranial color Doppler flow
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25(10):1931–1934 47. Wong KS, Li H, Chan YL, Ahuja A, Lam WWM, Wong A et al (2000) Use
of transcranial Doppler ultrasound to predict outcome in patients with
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(2002) Feasibility and validity of transcranial duplex sonography in
patients with acute stroke. J Neurol Neurosurg Psychiatry 73(1):17–20 34. Nahab F, Kingston C, Frankel MR, Dion JE, Cawley CM, Mitchell B et al
(2013) Early aggressive medical management for patients with sympto-
matic intracranial stenosis. J Stroke Cerebrovasc Dis 22(1):87–91 35. Acknowledgements Alexandrov AV, Babikian VL, Adams RJ, Tegeler CH, Caplan LR, Spencer MP
(1998) The evolving role of transcranial doppler in stroke prevention and
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J et al (2007) The Stroke Outcomes and Neuroimaging of Intracranial
Atherosclerosis (SONIA) trial. Neurology 68(24):2099–2106 37. Hashimoto H, Etani H, Naka M, Kinoshita N, Nukada T (1992) Assessment
of the rate of successful transcranial Doppler recording through the
temporal windows in Japanese with special reference to aging and sex. Nihon Ronen Igakkai Zasshi 29(2):119–122 21. GeoHive (2014) Cities: largest (without surrounding suburban areas). http://www.geohive.com/earth/cy_notagg.aspx. Cited 16 Jan 2014 38. Itoh T, Matsumoto M, Handa N, Maeda H, Hougaku H, Hashimoto H
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color-coded sonography in stroke patients. Stroke 26(11):2061–2066 40. Suri MF, Georgiadis AL, Tariq N, Vazquez G, Qureshi N, Qureshi AI (2011)
Estimated prevalence of acoustic cranial windows and intracranial
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Alvarez-Sabin J (2001) Progression and clinical recurrence of symptomatic
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42. Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I, Grotta JC et al
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42(1 Suppl):S20–S23 27. Acknowledgements Felberg RA, Christou I, Demchuk AM, Malkoff M, Alexandrov AV (2002)
Screening for intracranial stenosis with transcranial Doppler: the accuracy
of mean flow velocity thresholds. J Neuroimaging 12(1):9–14 36. Saqqur M, Shuaib A, Alexandrov AV, Hill MD, Calleja S, Tomsick T et al
(2005) Derivation of transcranial Doppler criteria for rescue intra-arterial
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(2005) Derivation of transcranial Doppler criteria for rescue intra-arterial
thrombolysis: multicenter experience from the interventional manage-
ment of stroke study. Stroke 36(4):865–868 Submit your next manuscript to BioMed Central
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https://openalex.org/W3159476791
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https://www.frontiersin.org/articles/10.3389/fphar.2021.633505/pdf
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English
| null |
Analysis of Pharmacokinetics in the Cochlea of the Inner Ear
|
Frontiers in pharmacology
| 2,021
|
cc-by
| 12,555
|
Edited by:
Tod Edward Kippin,
University of California, United States Edited by:
Tod Edward Kippin,
University of California, United States REVIEW published: 03 May 2021
doi: 10.3389/fphar.2021.633505 †ORCID: Seishiro Sawamura
orcid.org/0000-0002-3713-303X
Genki Ogata
orcid.org/0000-0003-1753-428X
Kai Asai
orcid.org/0000-0002-2885-7116
Sasya Madhurantakam
orcid.org/0000-0001-5605-9448
Daisuke Ino
orcid.org/0000-0002-8112-0746
Sho Kanzaki
orcid.org/0000-0001-9056-0850
Masato Moriyama
orcid.org/0000-0002-8773-8686
Yasuo Saijo
orcid.org/0000-0003-4721-1270
Arata Horii
orcid.org/0000-0002-6036-0492
Yasuaki Einaga
orcid.org/0000-0001-7057-4358
Hiroshi Hibino
orcid.org/0000-0003-0688-1489 Hearing loss affects >5% of the global population and therefore, has a great social and
clinical impact. Sensorineural hearing loss, which can be caused by different factors, such
as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily
from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against
sensorineural hearing loss are available. To develop effective treatments for this disease, it
is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the
microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have
addressed this issue by different methodologies. However, there is much less information
on pharmacokinetics in the cochlea than that in other organs; the delay in ontological
pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ
that is encased with a bony wall and has a fine and complicated internal structure. In this
review, we not only summarize the observations and insights obtained in classic and recent
studies on pharmacokinetics in the cochlea but also describe relevant analytical
techniques, with their strengths, limitations, and prospects. Keywords: sensorineural hearing loss, pharmacokinetics, ototoxic drug, therapeutic reagent, cochlea, real-time
measurement Specialty section:
This article was submitted to
Neuropharmacology,
a section of the journal
Frontiers in Pharmacology Specialty section:
This article was submitted to
Neuropharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 25 November 2020
Accepted: 16 April 2021
Published: 03 May 2021 *Correspondence:
Hiroshi Hibino
hibino@pharma2.med.osaka-
u.ac.jp *Correspondence:
Hiroshi Hibino
hibino@pharma2.med.osaka-
u.ac.jp INTRODUCTION Audition is an essential sensation for animals. Humans can hear sounds at diverse frequencies ranging
from 20 to 20,000 Hz and perceive a millionfold difference in sound pressure level (Hudspeth, 2014). These characteristics stem primarily from the specialized function of the cochlea in the inner ear
(Dallos, 1981; Hudspeth, 1989). In mammals, the cochlea has snail-like structure. The interior of this
organ is separated by membranous partitions into three chambers: the scala media, scala tympani, and
scala vestibuli (Figure 1). The scala media contains a K+-rich extracellular solution, endolymph,
whereas the scala tympani and scala vestibuli are filled with perilymph, which has ionic composition
similar to that of a regular extracellular fluid. Between the scala media and scala tympani lies the
“cochlear partition,” which consists of sensory hair cells, supporting cells, and the basilar membrane. Mechanical stimuli of a sound elicit oscillatory waves that travel apically along the cochlear partition. The width of the partition increases, and its thickness and stiffness decrease longitudinally toward the
apex from the base (Wever, 1971; Webster and Webster, 1980; Naidu and Mountain, 2007; Ekdale, Received: 25 November 2020
Accepted: 16 April 2021
Published: 03 May 2021 Keywords: sensorineural hearing loss, pharmacokinetics, ototoxic drug, therapeutic reagent, cochlea, real-time
measurement Analysis of Pharmacokinetics in the
Cochlea of the Inner Ear Reviewed by:
Philip A. Vieira,
California State University,
United States
Philippe Dauphin Ducharme,
Université de Sherbrooke, Canada
Netz Arroyo,
Johns Hopkins University,
United States Seishiro Sawamura 1†, Genki Ogata 1†, Kai Asai 2†, Olga Razvina 3,4, Takeru Ota 1, Qi Zhang 1,3,5,
Sasya Madhurantakam 1†, Koei Akiyama 3, Daisuke Ino 1†, Sho Kanzaki 6†, Takuro Saiki 7,
Yoshifumi Matsumoto 7, Masato Moriyama 7†, Yasuo Saijo 7†, Arata Horii 5†, Yasuaki Einaga 2†
and Hiroshi Hibino 1,8*† Seishiro Sawamura 1†, Genki Ogata 1†, Kai Asai 2†, Olga Razvina 3,4, Takeru Ota 1, Qi Zhang 1,3,5,
Sasya Madhurantakam 1†, Koei Akiyama 3, Daisuke Ino 1†, Sho Kanzaki 6†, Takuro Saiki 7,
Yoshifumi Matsumoto 7, Masato Moriyama 7†, Yasuo Saijo 7†, Arata Horii 5†, Yasuaki Einaga 2†
and Hiroshi Hibino 1,8*† 1Division of Glocal Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan,
2Department of Chemistry, Keio University, Yokohama, Japan, 3Department of Molecular Physiology, Niigata University School of
Medicine, Niigata, Japan, 4G-MedEx Office, Niigata University School of Medicine, Niigata, Japan, 5Department of
Otolaryngology, Head and Neck Surgery Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan,
6Department of Otolaryngology, School of Medicine, Keio University, Tokyo, Japan, 7Department of Medical Oncology, Niigata
University Graduate School of Medical and Dental Sciences, Niigata, Japan, 8AMED-CREST, AMED, Osaka, Japan *Correspondence:
Hiroshi Hibino
hibino@pharma2.med.osaka-
u.ac.jp Citation: Sawamura S, Ogata G, Asai K, Razvina O,
Ota T, Zhang Q, Madhurantakam S,
Akiyama K, Ino D, Kanzaki S, Saiki T,
Matsumoto Y, Moriyama M, Saijo Y,
Horii A, Einaga Y and Hibino H (2021)
Analysis of Pharmacokinetics in the
Cochlea of the Inner Ear. Front. Pharmacol. 12:633505. doi: 10.3389/fphar.2021.633505 May 2021 | Volume 12 | Article 633505 1 Frontiers in Pharmacology | www.frontiersin.org Pharmacokinetics in the Cochlea Sawamura et al. FIGURE 1 | Structure of the cochlea in the inner ear. Schematic images of a human ear and a cross-section of the cochlea are depicted in the upper left and right
panels, respectively. The lower panel illustrates the tissue and cellular architecture of the cochlea. Perilymph has ionic composition similar to that of an ordinary
extracellular liquid. On the other hand, endolymph maintains 150 mM K+ and a highly positive endocochlear potential (EP) relative to perilymph. Cellular composition of
the cochlear partition is shown as well. Inner and outer hair cells are surrounded by various types of supporting cells. These cells are mounted on the basilar
membrane. Adapted from Nin et al. (2008) with permission. Copyright (2008) National Academy of Sciences. FIGURE 1 | Structure of the cochlea in the inner ear. Schematic images of a human ear and a cross-section of the cochlea are depicted in the upper left and right
panels, respectively. The lower panel illustrates the tissue and cellular architecture of the cochlea. Perilymph has ionic composition similar to that of an ordinary
extracellular liquid. On the other hand, endolymph maintains 150 mM K+ and a highly positive endocochlear potential (EP) relative to perilymph. Cellular composition of
the cochlear partition is shown as well. Inner and outer hair cells are surrounded by various types of supporting cells. These cells are mounted on the basilar
membrane. Adapted from Nin et al. (2008) with permission. Copyright (2008) National Academy of Sciences. 2016). This physical property allows a traveling wave to peak in a
specific region in accordance with the stimulus frequency; high-
pitch sounds induce a motion at the base, whereas low-frequency
sounds excite the apex (Békésy and Wever, 1960; Zhang et al.,
2007). Vibrations of the cochlear partition next stimulate hair cells,
which are classified into inner- and outer hair cells. Both types of
cells have their cell bodies immersed in perilymph, whereas their
apical surfaces are exposed to endolymph. Frontiers in Pharmacology | www.frontiersin.org Citation: Method
categories
Method
names
Sensitivity
Selectivity
Spatial
resolution
Temporal
resolution
Live
monitoring
Invasiveness
Detection
of
metabolites
Spatial
dimensionality
In vitro chemical
analysis
HPLC
++
++
+
+
±a
+++
++
1 dimension
LC-MS
+++
+++
+
+
±a
+++
+++
1 dimension
Immunoassay
+
+
+
+
±b
+++
—
1 dimension
Imaging
Fluorescence
microscopy
+
+ to ++
+++
+
±b
++
+
2 dimensions
Imaging MS
+++
+++
++
+
–
++
+++
2 dimensions
MRI
+
+
+
++
+
+
—
3 dimensions
μCT
+
+
++
++
+
+
—
3 dimensions
In vivo
electrochemistry
+ to +++c
++
++
+++
+
++
– to ++c
1 dimension
aP
ibl
i h
i
di l
i
li TABLE 1 | Comparison of profiles of different drug detection methods. FIGURE 2 | In vitro chemical analyses of the perilymph and endolymph. High-performance liquid chromatography (HPLC, top panel) can quickly separate a mixture
of molecules from a sample according to their chemical properties such as size and hydrophobicity. Each reagent is sequentially detected as a peak and quantified by
calculating the peak area. Liquid chromatography coupled with mass spectrometry (LC-MS, middle panel) is a highly sensitive and selective analytical method for
molecular identification and quantification. First, mixtures of multiple compounds are separated by liquid chromatography (LC). Thereafter, the target drug(s) can be
extracted and quantified via mass spectrometry (MS). An immunoassay can analyze target molecules using a specific antibody conjugated with a fluorescent dye
(bottom panel). This method is characterized by relatively high quantitativity, easy handling, and time- and cost-savings. FIGURE 2 | In vitro chemical analyses of the perilymph and endolymph. High-performance liquid chromatography (HPLC, top panel) can quickly separate a mixture
of molecules from a sample according to their chemical properties such as size and hydrophobicity. Each reagent is sequentially detected as a peak and quantified by
calculating the peak area. Liquid chromatography coupled with mass spectrometry (LC-MS, middle panel) is a highly sensitive and selective analytical method for
molecular identification and quantification. First, mixtures of multiple compounds are separated by liquid chromatography (LC). Thereafter, the target drug(s) can be
extracted and quantified via mass spectrometry (MS). An immunoassay can analyze target molecules using a specific antibody conjugated with a fluorescent dye
(bottom panel). This method is characterized by relatively high quantitativity, easy handling, and time- and cost-savings. Citation: irreversible due to extensive destruction of cochlear cells,
including hair cells. More than 150 drugs have ototoxic effects
(Cianfrone et al., 2011; Lanvers-Kaminsky et al., 2017). The
measurement
of
drug
pharmacokinetics
in
the
cochlear
compartment
of
live
animals would
vastly improve
our
understanding of molecular permeability across the cochlear
membranes, and could further aid in improving drug design
during lead compound development. It is likely to be difficult to
access and accurately analyze the cochlea in vivo because this
organ is deeply buried in the temporal bone and is composed of
fragile membranous and cellular structures. Therefore, relevant
pharmacological information is scarce. This problem is also the
case for common prescription drugs for the treatment of SNHL;
they include corticosteroids, vasodilators, antioxidants, and
vitamin preparations. It is noteworthy that although these
agents are used empirically for the disease worldwide, their pharmacological
targets
and
clinical
significance
remain
controversial
(Rauch,
2008;
Agarwal
and
Pothier,
2009;
Schreiber et al., 2010; Wei et al., 2013; Crowson et al., 2017). Accordingly, the pharmacokinetics of ototoxic and therapeutic
reagents in the cochlea of the inner ear need to be clarified and
have been recently examined by chemical analysis, imaging, and
electrochemical procedures. Each of these approaches has its own
merits and limitations (Table 1). In the following sections, we
describe cochlear pharmacokinetics of different drugs and
characteristics of the methodologies used. Citation: The mechanical
vibrations deflect the hair bundle projecting from the apical
surfaces; this event results in the opening of mechanoelectrical
transduction channels at the tip of the bundle and permits K+ to
enter hair cells from endolymph (Oghalai, 2004; Hibino and
Kurachi,
2006;
Reichenbach
and
Hudspeth,
2014). Depolarization of inner hair cells induces a neurotransmitter
release on the basolateral surface. On the other hand, excitation
of outer hair cells changes the length of the cell bodies. This somatic
motility can mechanically amplify oscillations of the cochlear
partition (Ashmore, 2008; Fettiplace, 2020). The high sensitivity
of hearing depends not only on the properties of outer hair cells but
also on a highly positive potential of +70 to +90 mV observed in K+-enriched endolymph (Békésy, 1952; Dallos, 1996; Hibino et al.,
2010; Hudspeth, 2014; Nin et al., 2016). This endocochlear
potential
(EP)
accelerates
sound-induced
K+
entry
from
endolymph
into
hair
cells:
the
process
that
triggers
neurotransmission in inner hair cells and somatic motility in
outer hair cells. Several studies have shown that the EP is likely
to be maintained by ion transport mechanisms in the lateral
cochlear wall, which is made up of the stria vascularis and
spiral ligament (Wangemann, 2006; Hibino et al., 2010; Nin
et al., 2016). Sensorineural hearing loss (SNHL) is caused by noise
exposure, aging, a viral or bacterial infection, or ototoxic drugs
(Cunningham and Tucci, 2017). The main organ affected by this
disease is the cochlea. In particular, the hearing loss induced by
such drugs as loop diuretics, anticancer agents, and antibiotics is a
global problem because this adverse effect limits the treatment
options and directly worsens the patients’ quality of life during
and/or after therapies (Lanvers-Kaminsky et al., 2017). The
hearing impairment is reversed by discontinuation of drug
administration
in
many
cases
but
sometimes
becomes May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 2 Pharmacokinetics in the Cochlea Sawamura et al. i
ibl
d
i
d
i
f
hl
ll
h
l
i
l
d
li i
l
i
ifi
i
TABLE 1 | Comparison of profiles of different drug detection methods. Frontiers in Pharmacology | www.frontiersin.org Citation: Method
categories
Method
names
Sensitivity
Selectivity
Spatial
resolution
Temporal
resolution
Live
monitoring
Invasiveness
Detection
of
metabolites
Spatial
dimensionality
In vitro chemical
analysis
HPLC
++
++
+
+
±a
+++
++
1 dimension
LC-MS
+++
+++
+
+
±a
+++
+++
1 dimension
Immunoassay
+
+
+
+
±b
+++
—
1 dimension
Imaging
Fluorescence
microscopy
+
+ to ++
+++
+
±b
++
+
2 dimensions
Imaging MS
+++
+++
++
+
–
++
+++
2 dimensions
MRI
+
+
+
++
+
+
—
3 dimensions
μCT
+
+
++
++
+
+
—
3 dimensions
In vivo
electrochemistry
+ to +++c
++
++
+++
+
++
– to ++c
1 dimension
aPossible with microdialysis sampling. bPossible by means of two-photon laser microscopy. cThese properties vary among different drugs. FIGURE 2 | In vitro chemical analyses of the perilymph and endolymph. High-performance liquid chromatography (HPLC, top panel) can quickly separate a mixture
of molecules from a sample according to their chemical properties such as size and hydrophobicity. Each reagent is sequentially detected as a peak and quantified by
calculating the peak area. Liquid chromatography coupled with mass spectrometry (LC-MS, middle panel) is a highly sensitive and selective analytical method for
molecular identification and quantification. First, mixtures of multiple compounds are separated by liquid chromatography (LC). Thereafter, the target drug(s) can be
extracted and quantified via mass spectrometry (MS). An immunoassay can analyze target molecules using a specific antibody conjugated with a fluorescent dye
(bottom panel). This method is characterized by relatively high quantitativity, easy handling, and time- and cost-savings. TABLE 1 | Comparison of profiles of different drug detection methods. IN VITRO CHEMICAL ANALYSIS Their assay detected a low concentration and slow time
course (Cmax: 1.61 μg/ml, Tmax: 60 min) as compared to the
profile
in
perilymph
(Cmax:
4.9 μg/ml,
Tmax:
15 min). Pretreatment with probenecid, an inhibitor of the anion
transporters
mediating
active
transport
of
furosemide,
drastically delayed the delivery of the drug into perilymph,
whereas this arrangement had a negligible effect on the
pharmacokinetics
in
endolymph
and
serum. This
result
suggests that furosemide is passively imported into endolymph
through a blood vessel with relatively low permeability. Liquid chromatography coupled with mass spectrometry (LC-
MS) has the advantage of highly sensitive detection of drugs as
ll
t
ti
f
d
ith i
il
t
t Immunoassays for drug quantification are currently employed
not only for basic research but also for clinical tests (Figure 2). In
general, the advantages are relatively high quantitativity, easy
handling, and time- and cost savings (Stead, 2000; Taylor et al.,
2015). Nevertheless, sensitivity and selectivity of these methods
are lower than those of HPLC and MS. Moreover, their
applications are limited to the drugs against which antibodies
have been developed. Specific antibodies are available against
several
antibiotics
including
vancomycin,
amikacin,
and
gentamicin. As for the cochlea of guinea pigs and chinchillas,
a fluorescence polarization immunoassay clarified the kinetics
and longitudinal gradient of ototoxic gentamicin in perilymph
(Hoffer et al., 2001). In chinchillas, a continuous release of the
drug
toward
the
round
window
membrane
through
a
microcatheter controlled by an osmotic pump resulted in
lower Cmax and longer retention time than did intratympanic
administration (Hoffer et al., 2001). A peak concentration of
913 mg/ml was registered 24 h after transient injection of 3.75 mg
gentamicin sulfate, and then the drug was quickly eliminated,
within 48 h. On the other hand, sustained delivery of a 10 mg/ml
drug solution at a rate of 1 μl/h led to nearly identical
concentrations at 24, 48, and 72 h, with a peak of 322 mg/ml
(72 h). In a guinea pig cochlea into which gentamicin was
administered from the round window membrane, a large
concentration gradient along the longitudinal axis was found;
the concentration was >4000-fold higher at the base than at the
apex (Plontke et al., 2007). Conversely, after systemic application
of intravenous and subcutaneous dosing, the perilymphatic drug
level was highest at the apex and gradually decreased as the
analyzed point was moved toward the basal region (Hahn et al.,
2013). IN VITRO CHEMICAL ANALYSIS To determine drug behavior in the cochlea, in many cases,
perilymph and/or endolymph are collected from inner ears of May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 3 Pharmacokinetics in the Cochlea Sawamura et al. multiple live animals, and the samples are chemically analyzed
in vitro. High-performance liquid chromatography (HPLC) is a
commonly used technique for the quantification of different
classes of drugs in the cochlea (Figure 2). The analytes are
ototoxic drugs, such as loop diuretics and platinum anticancer
drugs, as well as therapeutic agents for deafness, including
corticosteroids (Green et al., 1981; Rybak et al., 1984; Laurell
et al., 1995; Hahn et al., 2012; Liu et al., 2015). In guinea pigs and
chinchillas, drug behavior in cochlear fluids is characterized by a
slow time course of the distribution and elimination of the drugs,
as compared to the kinetic profiles of plasma and cerebrospinal
fluid (Hara et al., 1993; Laurell et al., 1995; Parnes et al., 1999;
Hellberg et al., 2009). The relevance of different administration
routes to the pharmacokinetics has also been reported; the level of
corticosteroids in perilymph after intratympanic administration
is significantly higher than that after administration via systemic
routes, e.g., intravenous injection or oral gavage (Parnes et al.,
1999). Regarding
hydrocortisone,
maximum
concentration
(Cmax) and the time to achieve Cmax (i.e., Tmax) for different
administration routes are as follows: 72.42 ± 23.31 mg/L and 1 h
for intratympanic injection, 2.03 ± 0.22 mg/L and 1 h for
intravenous injection, and 0.86 ± 0.22 at 4 h for oral gavage. In guinea pigs treated with dexamethasone or cisplatin, a small
aliquot of cochlear perilymph is aspirated gradually and
sequentially via a narrow glass capillary inserted into the apex
to determine the longitudinal gradient of the drug concentrations
along the cochlea axis. The dexamethasone level in the basal
region (136 ± 185 μg/ml) exceeds that in the apical region (∼1 μg/
ml) for 2–3 h after intratympanic injection (Plontke et al., 2008). As for cisplatin, its perilymphatic concentration is 4-fold higher
in the base than in the apex 10 min after intravenous
administration (Hellberg et al., 2013). Notably, this gradient
disappears in 30 min. The endolymph in the scala media is
more difficult to access and has much smaller volume (∼2 µl)
than does the perilymph in the scala tympani and scala vestibuli
(∼10 µl) (Shinomori et al., 2001). IN VITRO CHEMICAL ANALYSIS Nevertheless, this K+-enriched
fluid has been analyzed in a few studies. Some researchers
approached
the
guinea
pig
cochlea
and
quantified
corticosteroids in endolymph (Parnes et al., 1999). They
demonstrated
that
a
few
hours
after
intratympanic
administration, hydrocortisone concentration in endolymph
substantially
exceeds
that
in
perilymph. Other
authors
examined the pharmacokinetics of an ototoxic loop diuretic,
furosemide, in the endolymph of guinea pigs (Hara et al.,
1993). Their assay detected a low concentration and slow time
course (Cmax: 1.61 μg/ml, Tmax: 60 min) as compared to the
profile
in
perilymph
(Cmax:
4.9 μg/ml,
Tmax:
15 min). Pretreatment with probenecid, an inhibitor of the anion
transporters
mediating
active
transport
of
furosemide,
drastically delayed the delivery of the drug into perilymph,
whereas this arrangement had a negligible effect on the
pharmacokinetics
in
endolymph
and
serum. This
result
suggests that furosemide is passively imported into endolymph
through a blood vessel with relatively low permeability e.g., metabolites (Figure 2). With this method, perilymph in
guinea pigs was analyzed to clarify the pharmacokinetics of
dexamethasone
administered
via
three
different
routes:
intraperitoneal, intratympanic, and postaural injection (Wang
et al., 2018). The intratympanic administration yielded a higher
maximum drug concentration within a shorter period (Cmax:
25,343.38 ± 2641.17 ng/ml, Tmax: 1 h) than did the other two
routes (Cmax: 532.56 ± 145.66 ng/ml, Tmax: 4 h for postaural
injection;
Cmax:
100.87
±
48.05 ng/ml,
Tmax:
2 h
for
intraperitoneal injection). Some investigators addressed how a
difference in the dosing route can affect drug pharmacokinetics in
the rat cochlea, as follows (Grondin et al., 2013): They
administered
antioxidant
D-methionine
to
animals
intratracheally, intranasally, orally, or intravenously; sampled a
cochlear fluid containing both perilymph and endolymph; and
examined the compounds’ behavior by LC-MS. The pulmonary
delivery induced the highest concentrations of methionine (Cmax:
110.3 ± 27.6 µM) and its metabolite acetyl-L-carnitine (Cmax:
12.9 ± 12.5 µM), whereas the intranasal route was the least
effective: Cmax of 12.0 ± 7.4 µM for methionine and 2.9 ±
0.3 µM for the metabolite. multiple live animals, and the samples are chemically analyzed
in vitro. High-performance liquid chromatography (HPLC) is a
commonly used technique for the quantification of different
classes of drugs in the cochlea (Figure 2). IN VITRO CHEMICAL ANALYSIS The analytes are
ototoxic drugs, such as loop diuretics and platinum anticancer
drugs, as well as therapeutic agents for deafness, including
corticosteroids (Green et al., 1981; Rybak et al., 1984; Laurell
et al., 1995; Hahn et al., 2012; Liu et al., 2015). In guinea pigs and
chinchillas, drug behavior in cochlear fluids is characterized by a
slow time course of the distribution and elimination of the drugs,
as compared to the kinetic profiles of plasma and cerebrospinal
fluid (Hara et al., 1993; Laurell et al., 1995; Parnes et al., 1999;
Hellberg et al., 2009). The relevance of different administration
routes to the pharmacokinetics has also been reported; the level of
corticosteroids in perilymph after intratympanic administration
is significantly higher than that after administration via systemic
routes, e.g., intravenous injection or oral gavage (Parnes et al.,
1999). Regarding
hydrocortisone,
maximum
concentration
(Cmax) and the time to achieve Cmax (i.e., Tmax) for different
administration routes are as follows: 72.42 ± 23.31 mg/L and 1 h
for intratympanic injection, 2.03 ± 0.22 mg/L and 1 h for
intravenous injection, and 0.86 ± 0.22 at 4 h for oral gavage. In guinea pigs treated with dexamethasone or cisplatin, a small
aliquot of cochlear perilymph is aspirated gradually and
sequentially via a narrow glass capillary inserted into the apex
to determine the longitudinal gradient of the drug concentrations
along the cochlea axis. The dexamethasone level in the basal
region (136 ± 185 μg/ml) exceeds that in the apical region (∼1 μg/
ml) for 2–3 h after intratympanic injection (Plontke et al., 2008). As for cisplatin, its perilymphatic concentration is 4-fold higher
in the base than in the apex 10 min after intravenous
administration (Hellberg et al., 2013). Notably, this gradient
disappears in 30 min. The endolymph in the scala media is
more difficult to access and has much smaller volume (∼2 µl)
than does the perilymph in the scala tympani and scala vestibuli
(∼10 µl) (Shinomori et al., 2001). Nevertheless, this K+-enriched
fluid has been analyzed in a few studies. Some researchers
approached
the
guinea
pig
cochlea
and
quantified
corticosteroids in endolymph (Parnes et al., 1999). They
demonstrated
that
a
few
hours
after
intratympanic
administration, hydrocortisone concentration in endolymph
substantially
exceeds
that
in
perilymph. Other
authors
examined the pharmacokinetics of an ototoxic loop diuretic,
furosemide, in the endolymph of guinea pigs (Hara et al.,
1993). Frontiers in Pharmacology | www.frontiersin.org IN VIVO IMAGING TECHNIQUES Molecular imaging is widely utilized to analyze biological
phenomena and is applied in pharmacological research. Recent
progress in optics and data-processing techniques offers a variety
of options. Fluorescence imaging using confocal microscopy is a
common method. This approach is characterized by the high
spatial resolution of several hundred nanometers and can
determine the cellular distribution or subcellular localization of
drugs in biological samples. In the cochlea, the distribution of
dexamethasone was visualized as follows: mice were treated with
dexamethasone via hypodermic or intratympanic routes, and the
distribution and pharmacokinetics in cochlear slice sections were
examined
(Grewal
et
al.,
2013). The
drug
was
immunohistochemically detected with a specific antibody and
a secondary antibody conjugated with a fluorescent molecule. Fluorescence was well pronounced in inner hair cells, and this
cellular signal gradually decreased from the base toward the apex
along the cochlear axis. In addition, dexamethasone injected via
the transtympanic route was retained in the hair cells for the long
period of 12 h, whereas the systemically administered drug was
rapidly eliminated from the cells, with weak staining at 6 h and
almost no signal after 12 h. In rats, an intracochlear distribution
of dexamethasone was determined (Lee et al., 2018); in that study,
the
compound
was
directly
labeled
with
fluorescein
isothiocyanate. Obvious signals were noted in the spiral
ganglion, organ of Corti, and lateral cochlear wall 6 h and
3 days
after
intraperitoneal
or
intratympanic
injection. Furthermore, in these tissue components, the drug was likely
to be retained for 7 days after intratympanic administration,
whereas at that time point, only a small proportion remained
there in the case of systemic application. Distribution and
pharmacokinetics of gentamicin and cisplatin are examined by
fluorescence imaging as well. One research group assayed
gentamicin
in
the
inner
ear
of
chinchillas
by
an
immunolabeling approach and analyzed the difference in the
effect on the drug behavior between intratympanic injection and a
sustained release from an osmotic pump (Roehm et al., 2007). Cochlear samples were evaluated at 4 and 8 h. With either
administration route, the fluorescent signal was concentrated
on the spiral ganglion, lateral wall, and organ of Corti. A
minimal
concentration
gradient
was
observed
along
the
longitudinal axis of the cochlea. In another work, fluorescent-
dye–conjugated cisplatin was used to determine the cellular
distribution in the mouse cochlea (Figure 3A) (Breglio et al.,
2017). IN VIVO IMAGING TECHNIQUES The procedure for preparation of the cisplatin ototoxicity Molecular imaging is widely utilized to analyze biological
phenomena and is applied in pharmacological research. Recent
progress in optics and data-processing techniques offers a variety
of options. Fluorescence imaging using confocal microscopy is a
common method. This approach is characterized by the high
spatial resolution of several hundred nanometers and can
determine the cellular distribution or subcellular localization of
drugs in biological samples. In the cochlea, the distribution of
dexamethasone was visualized as follows: mice were treated with
dexamethasone via hypodermic or intratympanic routes, and the
distribution and pharmacokinetics in cochlear slice sections were
examined
(Grewal
et
al.,
2013). The
drug
was
immunohistochemically detected with a specific antibody and
a secondary antibody conjugated with a fluorescent molecule. Fluorescence was well pronounced in inner hair cells, and this
cellular signal gradually decreased from the base toward the apex
along the cochlear axis. In addition, dexamethasone injected via
the transtympanic route was retained in the hair cells for the long
period of 12 h, whereas the systemically administered drug was
rapidly eliminated from the cells, with weak staining at 6 h and
almost no signal after 12 h. In rats, an intracochlear distribution
of dexamethasone was determined (Lee et al., 2018); in that study,
the
compound
was
directly
labeled
with
fluorescein
isothiocyanate. Obvious signals were noted in the spiral
ganglion, organ of Corti, and lateral cochlear wall 6 h and
3 days
after
intraperitoneal
or
intratympanic
injection. Furthermore, in these tissue components, the drug was likely
to be retained for 7 days after intratympanic administration,
whereas at that time point, only a small proportion remained
there in the case of systemic application. Distribution and
pharmacokinetics of gentamicin and cisplatin are examined by
fluorescence imaging as well. One research group assayed
gentamicin
in
the
inner
ear
of
chinchillas
by
an
immunolabeling approach and analyzed the difference in the
effect on the drug behavior between intratympanic injection and a
sustained release from an osmotic pump (Roehm et al., 2007). Cochlear samples were evaluated at 4 and 8 h. With either
administration route, the fluorescent signal was concentrated
on the spiral ganglion, lateral wall, and organ of Corti. A
minimal
concentration
gradient
was
observed
along
the
longitudinal axis of the cochlea. In another work, fluorescent-
dye–conjugated cisplatin was used to determine the cellular
distribution in the mouse cochlea (Figure 3A) (Breglio et al.,
2017). IN VITRO CHEMICAL ANALYSIS Nevertheless, the method remains invasive because it should be
accompanied by insertion of a sampling probe with a diameter of
>200 µm into the cochlea; this technique may damage tissue
structure and affect fluid flow (Khan and Michael, 2003). In
addition, considerable prolonged sample collection is likely
necessary to ensure the quantitativity of drug concentration. IN VITRO CHEMICAL ANALYSIS All the analytical methods described above require a few
invasive procedures for animal preparation. First, because the
cochlea is deeply buried in the temporal bone, a surgical
procedure to approach this organ is mandatory. Further, it is
necessary to make a fenestra on the cochlear bony wall to sample Liquid chromatography coupled with mass spectrometry (LC-
MS) has the advantage of highly sensitive detection of drugs as
well as accurate separation of compounds with similar structure, May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 4 Pharmacokinetics in the Cochlea Sawamura et al. cochlear fluids. Additionally, the sampling requires insertion and
indwelling of pipettes or tubes. Another problem is that excess
collection of perilymph or endolymph is likely to impair
physiological function of the cochlea and to contaminate such
fluids with neighboring blood and cerebrospinal fluid. Owing to
this issue as well as the extremely small total volume of perilymph
(∼10 μl) and endolymph (∼2 μl; guinea pig), only a limited
amount of cochlear fluids can be obtained. In this context,
highly
sophisticated
and
expert
skills
are
necessary
to
implement
stable
and
reproducible
experiments. Most
investigators validate the purity of a sample and/or intactness
of cochlear function during fluid aspiration by measuring
perilymphatic and/or endolymphatic physiological parameters
such as ion concentrations and a potential (Green et al., 1981;
Rybak et al., 1984; Hara et al., 1993; Parnes et al., 1999). On the
basis of such observations, it seems probable that cochleostomy
and contamination with cerebrospinal fluid during sample
collection considerably affect drug kinetics (Salt and Plontke,
2005). An additional concern is relatively low spatial resolution. The conventional methods require certain amounts of samples
and therefore necessitate the collection of perilymph or
endolymph compartments that may originate from a wide
range of cochlear chambers. As described above, a few research
groups have examined the longitudinal gradient of drug
distribution in the guinea pig cochlea (Plontke et al., 2008;
Hellberg et al., 2013; Salt et al., 2016). In these cases,
perilymph was sequentially sampled from a hole made in the
cochlear apex such that the fluid was sorted into 10 or fewer
segments along the longitudinal axis. Spatial resolution of this
procedure may be worse than 1 mm because the total longitudinal
length is approximately 18 mm (Shinomori et al., 2001). IN VITRO CHEMICAL ANALYSIS It is also
crucial that the number of samplings of cochlear fluids be
practically restricted to once or twice in an individual animal. Therefore, a large number of animals should be examined to
determine the kinetics of a drug over time. In this regard,
significant differences in the data are observed among different
animals, and this interanimal variation can interfere with accurate
determination of pharmacokinetics (Hahn et al., 2006). This
disadvantage further worsens time resolution of the kinetic
data. The Tmax values of the majority of drugs are in the scale
of dozens of minutes to several hours when administrated to living
animals systemically (Rowland and Tozer, 2005; Brunton et al.,
2018). Therefore, ideally, the drug concentration should be
measured every 2–10 min for a few hours or even for a few
days to accurately understand the kinetics. Nonetheless, to achieve
this resolution with the conventional methods, a large number of
experimental animals is required. Accordingly, in most studies,
the data are collected at an interval of dozens of minutes or hours. These problems may be at least in part overcome by a
microdialysis technique that can continuously obtain biological
samples from an individual animal (Chaurasia et al., 2007). Nevertheless, the method remains invasive because it should be
accompanied by insertion of a sampling probe with a diameter of
>200 µm into the cochlea; this technique may damage tissue In summary, HPLC, LC-MS, and an immunoassay with
sampled
perilymph
and
endolymph
are
the
methods
frequently used for quantifying drug concentrations in these
cochlear
fluids
over
time. Although
such
conventional
methods have provided key insights into the pharmacokinetics
of a few ototoxic and therapeutic reagents, the shortcomings to be
addressed are the invasiveness associated with the sampling, low
spatiotemporal resolution, and necessity of a large number of
animals for the determination of longitudinal drug behavior. cochlear fluids. Additionally, the sampling requires insertion and
indwelling of pipettes or tubes. Another problem is that excess
collection of perilymph or endolymph is likely to impair
physiological function of the cochlea and to contaminate such
fluids with neighboring blood and cerebrospinal fluid. Owing to
this issue as well as the extremely small total volume of perilymph
(∼10 μl) and endolymph (∼2 μl; guinea pig), only a limited
amount of cochlear fluids can be obtained. In this context,
highly
sophisticated
and
expert
skills
are
necessary
to
implement
stable
and
reproducible
experiments. IN VITRO CHEMICAL ANALYSIS Most
investigators validate the purity of a sample and/or intactness
of cochlear function during fluid aspiration by measuring
perilymphatic and/or endolymphatic physiological parameters
such as ion concentrations and a potential (Green et al., 1981;
Rybak et al., 1984; Hara et al., 1993; Parnes et al., 1999). On the
basis of such observations, it seems probable that cochleostomy
and contamination with cerebrospinal fluid during sample
collection considerably affect drug kinetics (Salt and Plontke,
2005). An additional concern is relatively low spatial resolution. The conventional methods require certain amounts of samples
and therefore necessitate the collection of perilymph or
endolymph compartments that may originate from a wide
range of cochlear chambers. As described above, a few research
groups have examined the longitudinal gradient of drug
distribution in the guinea pig cochlea (Plontke et al., 2008;
Hellberg et al., 2013; Salt et al., 2016). In these cases,
perilymph was sequentially sampled from a hole made in the
cochlear apex such that the fluid was sorted into 10 or fewer
segments along the longitudinal axis. Spatial resolution of this
procedure may be worse than 1 mm because the total longitudinal
length is approximately 18 mm (Shinomori et al., 2001). It is also
crucial that the number of samplings of cochlear fluids be
practically restricted to once or twice in an individual animal. Therefore, a large number of animals should be examined to
determine the kinetics of a drug over time. In this regard,
significant differences in the data are observed among different
animals, and this interanimal variation can interfere with accurate
determination of pharmacokinetics (Hahn et al., 2006). This
disadvantage further worsens time resolution of the kinetic
data. The Tmax values of the majority of drugs are in the scale
of dozens of minutes to several hours when administrated to living
animals systemically (Rowland and Tozer, 2005; Brunton et al.,
2018). Therefore, ideally, the drug concentration should be
measured every 2–10 min for a few hours or even for a few
days to accurately understand the kinetics. Nonetheless, to achieve
this resolution with the conventional methods, a large number of
experimental animals is required. Accordingly, in most studies,
the data are collected at an interval of dozens of minutes or hours. These problems may be at least in part overcome by a
microdialysis technique that can continuously obtain biological
samples from an individual animal (Chaurasia et al., 2007). IN VIVO IMAGING TECHNIQUES After the
completion of the regimen, a fluorescent signal was well
pronounced in the stria vascularis and moderately strong in
the spiral ganglion, organ of Corti, and interscalar septum, a
bony plate that separates adjoining cochlear turns. HPLC and MS. In addition, it cannot be ruled out that
labeling a drug with fluorescent molecules can affect its
properties related to pharmacokinetics and tissue distribution. HPLC and MS. In addition, it cannot be ruled out that
labeling a drug with fluorescent molecules can affect its
properties related to pharmacokinetics and tissue distribution. Imaging mass spectrometry is an advanced technique that
extends mass spectrometry to two-dimensional mapping of
substances
in
biological
samples. This
approach
can
quantitatively determine a spatial distribution of a broad array
of molecules, such as drugs, proteins, and their metabolites, at
high resolution (McDonnell and Heeren, 2007). A practical
example is a cisplatin distribution in a cochlear slice section in
mice (Breglio et al., 2017). Although imaging mass spectrometry
requires no labeling procedure for the compounds, the samples
need to be prepared from the cochleae extracted from euthanized
animals. Therefore, pharmacokinetics cannot be assessed over
time in a live animal. Imaging mass spectrometry is an advanced technique that
extends mass spectrometry to two-dimensional mapping of
substances
in
biological
samples. This
approach
can
quantitatively determine a spatial distribution of a broad array
of molecules, such as drugs, proteins, and their metabolites, at
high resolution (McDonnell and Heeren, 2007). A practical
example is a cisplatin distribution in a cochlear slice section in
mice (Breglio et al., 2017). Although imaging mass spectrometry
requires no labeling procedure for the compounds, the samples
need to be prepared from the cochleae extracted from euthanized
animals. Therefore, pharmacokinetics cannot be assessed over
time in a live animal. The imaging approaches mentioned above provide crucial
insights
into
drug
distribution,
which
is
valuable
for
understanding the mechanisms underlying desired and adverse
therapeutic effects. Nevertheless, some disadvantages should be
considered. In general, this method is applied to slice sections of
cochlear tissues dissected from euthanized animals. Therefore,
only single-timepoint data can be obtained from an individual
animal. Furthermore, in many cases, the cochlea is perfused with
phosphate buffers and/or fixation agents before sectioning. This
pretreatment washes out the drugs from the scala tympani, scala
vestibuli, and/or scala media to some extent. IN VIVO IMAGING TECHNIQUES The procedure for preparation of the cisplatin ototoxicity May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org Frontiers in Pharmacology | www.frontiersin.org 5 Pharmacokinetics in the Cochlea Sawamura et al. FIGURE 3 | In vivo imaging analyses of the cochlea. (A) Confocal image of a slice from cochlear cryosections of mice systemically administered cisplatin conjugated
with a green fluorescent dye, BODIPY FL. The green signal indicates cisplatin accumulation. SG: spiral ganglion, OC: organ of Corti, SV: stria vascularis, IS: interscalar
septum. Adapted from Breglio et al. (2017) with permission from Springer Nature. Copyright (2017) Nature Communications. (B,C) Three-dimensional magnetic
resonance images taken 1 day after intratympanic injection of gadolinium in a patient with Meniere’s disease. (B) Gadolinium signals are observed in the
perilymphatic area of the basal and second turns of the cochlea, as well as in the vestibule and semicircular canals. Large black areas in the vestibule represent vestibular
endolymphatic hydrops (arrow). (C) The same image scanned at a different cross-section. The scala tympani of the three turns of the cochlea are clearly visualized by
gadolinium. Adapted from Nakashima et al. (2007) with permission from John Wiley and Sons. Copyright (2007) The Laryngoscope. FIGURE 3 | In vivo imaging analyses of the cochlea. (A) Confocal image of a slice from cochlear cryosections of mice systemically administered cisplatin conjugated
with a green fluorescent dye, BODIPY FL. The green signal indicates cisplatin accumulation. SG: spiral ganglion, OC: organ of Corti, SV: stria vascularis, IS: interscalar
septum. Adapted from Breglio et al. (2017) with permission from Springer Nature. Copyright (2017) Nature Communications. (B,C) Three-dimensional magnetic
resonance images taken 1 day after intratympanic injection of gadolinium in a patient with Meniere’s disease. (B) Gadolinium signals are observed in the
perilymphatic area of the basal and second turns of the cochlea, as well as in the vestibule and semicircular canals. Large black areas in the vestibule represent vestibular
endolymphatic hydrops (arrow). (C) The same image scanned at a different cross-section. The scala tympani of the three turns of the cochlea are clearly visualized by
gadolinium. Adapted from Nakashima et al. (2007) with permission from John Wiley and Sons. Copyright (2007) The Laryngoscope. model was as follows: The mice underwent three cycles of
cisplatin treatment; each cycle consisted of intraperitoneal
drug administration at 3.5 mg/kg per day for four consecutive
days, followed by a recovery period of 10 days. Frontiers in Pharmacology | www.frontiersin.org IN VIVO ELECTROCHEMISTRY Electrochemistry with the help of small and sharp electrodes is a
powerful analytical method for detecting substances in vivo. In
this procedure, the electrode is directly exposed to a solution
containing
chemical
compound(s);
application
of
suitable
potentials to this sensor causes a redox reaction of the
compound. The reaction is accompanied by a transfer of
electron(s), whose number depends on the concentration of
the
reactant. Therefore,
the
detected
current
density
is
commensurate
with
the
concentration
of
the
compound
(Bagotsky, 2005). The conventional materials utilized for
constructing the electrodes are gold, platinum, and some
carbon types including glassy carbon. A major application of
this technique is the monitoring of neurotransmitters in the brain
(Venton and Wightman, 2003; Jackowska and Krysinski, 2013); a
limited number of investigators have examined the cochlea. An
example is real-time measurement of ascorbate concentration in
the perilymph of guinea pigs by means of carbon fiber
microelectrodes modified with multiwalled carbon nanotubes
(Liu et al., 2012). This experiment showed that when ototoxic
salicylate was injected into perilymph through a microinfusion
system, ascorbate concentration sharply decreased to 28 ± 10%
(45.0 ± 5.1 μM) of its baseline level in 2.5 min. The other
approach is a microsensing system that we recently developed
(Ogata et al., 2017). The sensor here is a needle-type electrode
composed of boron-doped diamond (BDD), which is an
advanced material for electrochemistry (Figure 4A), and this
sensor was employed for in vivo real-time detection of a drug. BDD has several prominent advantages (Einaga et al., 2001;
Fujishima
et
al.,
2005). First,
this
material
offers
high
physicochemical stability and response speed and thus enables
prolonged recording with high temporal resolution. Additionally,
a BDD electrode can detect a broad array of compounds due to
the wider potential window of water stability as compared with
that of classic materials such as carbon, platinum, and gold. Moreover, the background noise induced by the reaction on the
BDD electrode is low. These characteristics depend primarily on
the properties of the electrode’s surface, which is composed
predominantly
of
sp3
carbon;
this
material
reduces
the
adsorption of reactants to the electrode (Fujishima et al.,
2005). In our microsensing system, the needle-type BDD
microelectrode was combined with a glass microelectrode,
which can monitor cellular electrical activity in a small area
(Ogata et al., 2017). Drug behavior can be determined every 5 s,
thereby providing high temporal resolution for pharmacokinetic
studies. IN VIVO IMAGING TECHNIQUES Note that in >50% of the tested cochleae,
a significant inflammatory response was found in the scala
tympani with either contrast agent. CT can yield tomographic
images of an object via multiangle X-ray scanning. Combining
the multiple images results in the reconstruction of three-
dimensional structure of the object. μCT is a specialized
technique that is characterized by high spatial resolution and
is applicable to tiny biological samples. A few researchers have
taken the challenge of μCT imaging of cochlear fluids in live
animals. For instance, in mice, artificial perilymph containing an
iodine-based contrast agent, ioversol, was continuously perfused
into the cochleae from the scala tympani at the basal turn, while
μCT imaging was performed on the organ (Haghpanahi et al.,
2013). A series of scans took 13.2 min, which visualized the
anatomy of the whole cochlea (voxel size: 15 × 15 × 15 μm). From signal intensities in each pixel of the image, the distribution
and kinetics of the agent were determined over ∼90 min within
scala tympani and scala vestibuli. As expected, the compound’s
concentration was the highest at the base of the cochlea. In
addition, the longitudinal gradient of the concentration stabilized
55 min after the infusion. Another research group performed
μCT imaging to examine the kinetic profile of iopamidole in the
mouse cochlea (Moudgalya et al., 2019). This contrast agent was
infused from the scala tympani at the cochlear basal end. In each
experiment, the imaging was started after ∼30 min of iopamidole
infusion. Five contrast scanning images were continuously
acquired during 20 min. The temporal distribution of the
agent along the longitudinal axis was quantified in the scala
tympani, scala media, and scala vestibuli by using reconstructed
three-dimensional images. By means of this spatiotemporal
profile, diffusion and transport parameters of the agent were
estimated to be: the diffusion coefficient at zero concentration
(D0) 6.226 × 10–4 mm2/s and transport coefficients between the
scala tympani and scala media (KST-SM) 1.01 × 10–3 mm/s,
between the scala media and scala vestibuli (KSM-SV) 0.38 ×
10–3 mm/s,
and
between
scala
media
and
a
clearance
compartment
(KSM-clearance)
0.035
×
10–3 mm/s. This
information
was
used
to
develop
a
cochlear
pharmacokinetic model. IN VIVO IMAGING TECHNIQUES A series of scans took 13.2 min, which visualized the
anatomy of the whole cochlea (voxel size: 15 × 15 × 15 μm). From signal intensities in each pixel of the image, the distribution
and kinetics of the agent were determined over ∼90 min within
scala tympani and scala vestibuli. As expected, the compound’s
concentration was the highest at the base of the cochlea. In
addition, the longitudinal gradient of the concentration stabilized
55 min after the infusion. Another research group performed
μCT imaging to examine the kinetic profile of iopamidole in the
mouse cochlea (Moudgalya et al., 2019). This contrast agent was
infused from the scala tympani at the cochlear basal end. In each
experiment, the imaging was started after ∼30 min of iopamidole
infusion. Five contrast scanning images were continuously
acquired during 20 min. The temporal distribution of the
agent along the longitudinal axis was quantified in the scala
tympani, scala media, and scala vestibuli by using reconstructed
three-dimensional images. By means of this spatiotemporal
profile, diffusion and transport parameters of the agent were
estimated to be: the diffusion coefficient at zero concentration
(D0) 6.226 × 10–4 mm2/s and transport coefficients between the
scala tympani and scala media (KST-SM) 1.01 × 10–3 mm/s,
between the scala media and scala vestibuli (KSM-SV) 0.38 ×
10–3 mm/s,
and
between
scala
media
and
a
clearance
compartment
(KSM-clearance)
0.035
×
10–3 mm/s. This
information
was
used
to
develop
a
cochlear
pharmacokinetic model. So far the application of the three dimensional live imaging the drugs; this modification may alter the kinetics, distribution,
and pharmacological effects in some cases. Besides, it is difficult
for this methodology to separate the signals of parent drugs from
the signals of their metabolites. (Figure 3B). The behavior of the injected contrast agent was
analyzed too; gadolinium first went into the basal turn of the scala
tympani and then spread to almost all parts of perilymphatic
space 1 day after the injection (Figure 3C). In rats, the
perilymphatic
space
was
visualized
through
9.4 T
µMRI
imaging. The cochlea was scanned every 30 min from the
timepoint of 1–4 h after intratympanic injection of either
gadoterate meglumine or gadodiamide (Park et al., 2016). The
perilymphatic space, but not endolymphatic space, was clearly
analyzed in live animals. IN VIVO IMAGING TECHNIQUES These shortcomings
can be addressed by two-photon excitation microscopy, which
employs highly tissue-penetrating long-wavelength types of light
and thus enables live and deep-tissue imaging. Nevertheless,
readers should keep in mind that exposure to high-power laser
pulses for a long period can have deleterious effects, including
photobleaching and heating (Huisken and Stainier, 2009). The
other problem for fluorescence imaging is relatively low
quantitativity as compared to in vitro techniques such as Noninvasive three-dimensional imaging technologies such as
magnetic
resonance
imaging (MRI)
and
micro–computed
tomography
(μCT)
are
available
for
physiological
and
pharmacological studies. MRI can acquire information on
tissue structures and functions by measuring the signals
generated by magnetic resonance of certain atomic nuclei. A
contrast
agent,
gadolinium
hydrate,
was
injected
intratympanically into patients with an inner ear disorder,
Meniere’s disease, and the distribution was monitored over
time to track the sizes of the cochlear chambers, scala
tympani, and scala vestibuli (Nakashima et al., 2007). With
this technique, endolymphatic hydrops was detected clearly May 2021 | Volume 12 | Article 633505 6 Pharmacokinetics in the Cochlea Sawamura et al. (Figure 3B). The behavior of the injected contrast agent was
analyzed too; gadolinium first went into the basal turn of the scala
tympani and then spread to almost all parts of perilymphatic
space 1 day after the injection (Figure 3C). In rats, the
perilymphatic
space
was
visualized
through
9.4 T
µMRI
imaging. The cochlea was scanned every 30 min from the
timepoint of 1–4 h after intratympanic injection of either
gadoterate meglumine or gadodiamide (Park et al., 2016). The
perilymphatic space, but not endolymphatic space, was clearly
analyzed in live animals. Note that in >50% of the tested cochleae,
a significant inflammatory response was found in the scala
tympani with either contrast agent. CT can yield tomographic
images of an object via multiangle X-ray scanning. Combining
the multiple images results in the reconstruction of three-
dimensional structure of the object. μCT is a specialized
technique that is characterized by high spatial resolution and
is applicable to tiny biological samples. A few researchers have
taken the challenge of μCT imaging of cochlear fluids in live
animals. For instance, in mice, artificial perilymph containing an
iodine-based contrast agent, ioversol, was continuously perfused
into the cochleae from the scala tympani at the basal turn, while
μCT imaging was performed on the organ (Haghpanahi et al.,
2013). Frontiers in Pharmacology | www.frontiersin.org IN VIVO ELECTROCHEMISTRY As a test analyte, we selected the ototoxic reagent
bumetanide;
this
loop
diuretic
can
reduce
the
EP
in
endolymph and thus induce hearing loss (Figure 4B). The
BDD microelectrode, when placed in perilymph, detected a
clear-cut and rapid response with Tmax of ∼1.5 min and Cmax So far, the application of the three-dimensional live imaging
mentioned above has been restricted to the quantitation of
contrast agents per se. This approach may be applied to
different ototoxic or therapeutic drugs from the standpoint of
minimally invasive pharmacokinetic studies in live animals. Nonetheless, there are a few limitations to this method. Firstly,
temporal resolution is still insufficient because multiple scanning
for
three-dimensional
reconstruction
of
the
object
takes
10–30 min. Furthermore, these techniques require labeling of May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 7 Pharmacokinetics in the Cochlea Sawamura et al. FIGURE 4 | In vivo electrochemical drug monitoring with a boron-doped diamond (BDD) electrode. (A) A needle-type BDD microelectrode. As shown in the left
panel, the BDD needle was encased with a glass capillary tube. The needle tip, which has a diameter of ∼40 μm, was pulled out of the capillary. The right panel displays a
magnified image of the tip obtained by means of a scanning electron microscope. (B) The experimental setup for in vivo detection of bumetanide in a cochlea. A BDD
microelectrode was inserted into the perilymph of the scala tympani (ST), whereas a glass microelectrode for recording of the endocochlear potential (EP) was
placed in the endolymph of the scala media (SM). SV: scala vestibuli. (C) In vivo recording of bumetanide levels in the cochlea. Bumetanide was injected into the external
jugular vein 30 min (arrowhead) after the onset of the measurement. The green line denotes the current detected by the BDD microelectrode, whereas the EP measured
with the glass microelectrode is displayed by the red line. The concentration scale on the vertical axis was calculated on the basis of in vitro calibration of the BDD
electrode (for details, see Ogata et al., 2017). The brown line means the in vivo limit of detection for the microelectrode. Adapted from Ogata et al. (2017) with permission
from Springer Nature. Copyright (2017) Nature Biomedical Engineering. (D) Schematic illustration of the in vivo experimental setup for methylcobalamin detection in a
guinea pig. IN VIVO ELECTROCHEMISTRY The system contains two different BDD microsensors: one was inserted into cochlear perilymph, and the other was placed in the extracellular space of the
gracilis muscle of the right hind leg. (E,F) In vivo recording of methylcobalamin concentrations. The currents in perilymph (blue) and in the muscle (red) were
simultaneously measured with two BDD microelectrodes. The concentration scales on the vertical axis are derived from in vitro calibration for each electrode (for details,
see Hanawa et al., 2020). Methylcobalamin (10 mg/kg) was injected into the left external jugular vein at 30 min (filled arrowhead) after the onset of the recording. Then,
doxorubicin (5 mg/kg) was injected via the same route (open arrowhead). The trace in the boxed region in (E) is enlarged in panel (F). The limit of detection (LOD) for each
microsensor is indicated as a blue (muscle) or red (cochlea) dotted line. Adapted from Hanawa et al. (2020) with permission. Copyright (2020) American Chemical
Society. FIGURE 4 | In vivo electrochemical drug monitoring with a boron-doped diamond (BDD) electrode. (A) A needle-type BDD microelectrode. As shown in the left
panel, the BDD needle was encased with a glass capillary tube. The needle tip, which has a diameter of ∼40 μm, was pulled out of the capillary. The right panel displays a
magnified image of the tip obtained by means of a scanning electron microscope. (B) The experimental setup for in vivo detection of bumetanide in a cochlea. A BDD
microelectrode was inserted into the perilymph of the scala tympani (ST), whereas a glass microelectrode for recording of the endocochlear potential (EP) was
placed in the endolymph of the scala media (SM). SV: scala vestibuli. (C) In vivo recording of bumetanide levels in the cochlea. Bumetanide was injected into the external
jugular vein 30 min (arrowhead) after the onset of the measurement. The green line denotes the current detected by the BDD microelectrode, whereas the EP measured
with the glass microelectrode is displayed by the red line. The concentration scale on the vertical axis was calculated on the basis of in vitro calibration of the BDD
electrode (for details, see Ogata et al., 2017). The brown line means the in vivo limit of detection for the microelectrode. Adapted from Ogata et al. (2017) with permission
from Springer Nature. Copyright (2017) Nature Biomedical Engineering. (D) Schematic illustration of the in vivo experimental setup for methylcobalamin detection in a
guinea pig. IN VIVO ELECTROCHEMISTRY The system contains two different BDD microsensors: one was inserted into cochlear perilymph, and the other was placed in the extracellular space of the
gracilis muscle of the right hind leg. (E,F) In vivo recording of methylcobalamin concentrations. The currents in perilymph (blue) and in the muscle (red) were
simultaneously measured with two BDD microelectrodes. The concentration scales on the vertical axis are derived from in vitro calibration for each electrode (for details,
see Hanawa et al., 2020). Methylcobalamin (10 mg/kg) was injected into the left external jugular vein at 30 min (filled arrowhead) after the onset of the recording. Then,
doxorubicin (5 mg/kg) was injected via the same route (open arrowhead). The trace in the boxed region in (E) is enlarged in panel (F). The limit of detection (LOD) for each
microsensor is indicated as a blue (muscle) or red (cochlea) dotted line. Adapted from Hanawa et al. (2020) with permission. Copyright (2020) American Chemical
Society. space
of
a
leg
muscle
(Figure
4D). Then,
a
solution
containing 10 mg/kg methylcobalamin was injected into the
left external jugular vein. Figure 4E shows a representative
recording. Over a period of 120 min, little change in the current
was observed in perilymph. By contrast, a clear response was
detectable in the leg muscle; current amplitude markedly
increased immediately after the injection and reached a peak
of 0.4 μM in 45 min. As a control experiment, 5 mg/kg
doxorubicin, which can react on a BDD microelectrode
(Ogata et al., 2017), was additionally injected at a time point
of 150 min (Figures 4E,F). As expected, a rapid response was
detectable in both perilymph and the leg muscle. Although the
amount
of
the
systemically
injected
methylcobalamin
(10 mg/kg) greatly exceeded the clinical dose (10 μg/kg)
(Yamane et al., 1995), a current exceeding the detection limit
was not detectable in cochlear perilymph. These findings
suggest that methylcobalamin possibly reaches compartments
other than perilymph and exerts a pharmacological effect. of 5.3 µM in an experiment shown in Figure 4C. On the other
hand, the EP measured by the glass microelectrode inserted into
endolymph began to decrease when bumetanide concentration
was maximized. Finally, the EP reached a negative value of
–30 mV, which mirrors severe hearing impairment, although
the signal detected by the BDD electrode returned to baseline. It
is noteworthy that the drug kinetics were clearly different from
the EP kinetics, which correlate with the hearing threshold. IN VIVO ELECTROCHEMISTRY These results indicate that our microsensing system can
simultaneously
monitor
pharmacokinetics
and
pharmacodynamics
in
a
live
cochlea. Additionally,
we
constructed a different
system, composed of two
BDD
microelectrodes,
and
examined
methylcobalamin
concentration in separate targets (Hanawa et al., 2020). This
cobalamin derivative is often administered to patients with
SNHL (Wang et al., 2013). In an anesthetized guinea pig, one
microsensor was inserted into cochlear perilymph in scala
tympani, whereas the other was placed in the extracellular of 5.3 µM in an experiment shown in Figure 4C. On the other
hand, the EP measured by the glass microelectrode inserted into
endolymph began to decrease when bumetanide concentration
was maximized. Finally, the EP reached a negative value of
–30 mV, which mirrors severe hearing impairment, although
the signal detected by the BDD electrode returned to baseline. It
is noteworthy that the drug kinetics were clearly different from
the EP kinetics, which correlate with the hearing threshold. These results indicate that our microsensing system can
simultaneously
monitor
pharmacokinetics
and
pharmacodynamics
in
a
live
cochlea. Additionally,
we
constructed a different
system, composed of two
BDD
microelectrodes,
and
examined
methylcobalamin
concentration in separate targets (Hanawa et al., 2020). This
cobalamin derivative is often administered to patients with
SNHL (Wang et al., 2013). In an anesthetized guinea pig, one
microsensor was inserted into cochlear perilymph in scala
tympani, whereas the other was placed in the extracellular May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 8 Pharmacokinetics in the Cochlea Sawamura et al. fluids is correlated with its distribution within the cellular and
tissue components of the cochlear partition and lateral wall. The
analytical procedures described in this review have various
advantages
and
disadvantages. In
addition
to
technical
improvements, the combination of multiple methods will help
to clarify unexpected drug behavior in the “labyrinth.” As described above, the electrochemical approach can help to
monitor
concentrations
of substances
in vivo
with high
sensitivity. This method can target a small region—even inside
cochlear chambers—with a sharp sensor so that it can minimize
contamination with off-target body fluids and cells. Nevertheless,
the surgical procedures for exposure of the cochlea and for
making a hole for electrode insertion on the cochlear bony
wall are invasive for animals to some extent and may
modestly but significantly affect hearing. Another limitation is
that certain types of chemical compounds are electrochemically
inactive. REFERENCES Crowson, M. G., Hertzano, R., and Tucci, D. L. (2017). Emerging Therapies for
Sensorineural Hearing Loss. Otol. Neurol. 38, 792–803. doi:10.1097/MAO. 0000000000001427 Agarwal, L., and Pothier, D. D. (2009). Vasodilators and Vasoactive Substances for
Idiopathic Sudden Sensorineural Hearing Loss. Cochrane Database Syst. Rev. 2009, CD003422. doi:10.1002/14651858.CD003422.pub4 Cunningham, L. L., and Tucci, D. L. (2017). Hearing Loss in Adults. N. Engl. J. Med. 377, 2465–2473. doi:10.1056/NEJMra1616601 Dallos, P. (1981). Cochlear Physiology. Annu. Rev. Psychol. 32, 153–190. doi:10. 1146/annurev.ps.32.020181.001101 Ashmore, J. (2008). Cochlear Outer Hair Cell Motility. Physiol. Rev. 88, 173–210. doi:10.1152/physrev.00044.2006 Dallos, P. (1996). “Overview: Cochlear Neurobiology,” in The Cochlea. Editors
P. Dallos, A. N. Popper, and R. R. Fay (New York, NY: Springer), 1–43. doi:10. 1007/978-1-4612-0757-3_1 Bagotsky, V. S. (2005). Fundamentals of Electrochemistry. New York, NY: John
Wiley & Sons. doi:10.1002/047174199X Békésy, G. V., and Wever, E. G. (1960). Experiments in Hearing. 195, New York,
NY: McGraw-Hill. Einaga, Y., Kim, G-S., Park, S-G., and Fujishima, A. (2001). A Study of the
Crystalline Growth of Highly Boron-Doped CVD Diamond: Preparation of
Graded-Morphology Diamond Thin Films. Diam. Relat. Mater. 10 (3–7),
306–311. doi:10.1016/S0925-9635(01)00375-2 Békésy, G. V. (1952). DC Resting Potentials Inside the Cochlear Partition. J. Acoust. Soc. Am. 24, 72–76. doi:10.1121/1.1906851 Ekdale, E. G. (2016). Form and Function of the Mammalian Inner Ear. J. Anat. 228,
324–337. doi:10.1111/joa.12308 Breglio, A. M., Rusheen, A. E., Shide, E. D., Fernandez, K. A., Spielbauer, K. K.,
McLachlin, K. M., et al. (2017). Cisplatin Is Retained in the Cochlea Indefinitely
Following Chemotherapy. Nat. Commun. 8, 1654. doi:10.1038/s41467-017-
01837-1 Fettiplace, R. (2020). Diverse Mechanisms of Sound Frequency Discrimination in the
Vertebrate Cochlea. Trends Neurosci. 43, 88–102. doi:10.1016/j.tins.2019.12.003 Brunton, L. L., Hilal-Dandan, R., and Knollmann, B. C. (2018). Goodman &
Gilman’s The Pharmacological Basis of Therapeutics. New York, NY:
McGraw-Hill Education. Fujishima, A., Einaga, Y., Rao, T. N., and Tryk, D. A. (2005). Diamond
Electrochemistry. Amsterdam: Elsevier Science. Green, T. P., Rybak, L. P., Mirkin, B. L., Juhn, S., and Morizono, T. (1981). Pharmacologic Determinants of Ototoxicity of Furosemide in the chinchilla. J. Pharmacol. Exp. Ther. 216, 537–542. Chaurasia, C. S., Müller, M., Bashaw, E. D., Benfeldt, E., Bolinder, J., Bullock, R.,
et al. (2007). AAPS-FDA Workshop White Paper: Microdialysis Principles,
Application and Regulatory Perspectives. Pharm. Res. 24, 1014–1025. doi:10. 1007/s11095-006-9206-z Grewal, A. S., Nedzelski, J. M., Chen, J. M., and Lin, V. Y. (2013). Dexamethasone
Uptake in the Murine Organ of Corti with Transtympanic versus Systemic
Administration. IN VIVO ELECTROCHEMISTRY Moreover, with a needle-type microelectrode, two-
dimensional mapping of drug distribution is impossible. AUTHOR CONTRIBUTIONS SS, GO, YE, and HH conceptualized the review. SS, KAs, OR, QZ,
and HH wrote the first draft. SS, SM, KAk, DI, SK, TS, YM, MM,
YS, AH, and HH revised and corrected the manuscript. SS, OR,
TO, SM, and MM prepared or modified the figures. All the
authors contributed to the manuscript and approved the
submitted version. SS, GO, YE, and HH conceptualized the review. SS, KAs, OR, QZ,
and HH wrote the first draft. SS, SM, KAk, DI, SK, TS, YM, MM,
YS, AH, and HH revised and corrected the manuscript. SS, OR,
TO, SM, and MM prepared or modified the figures. All the
authors contributed to the manuscript and approved the
submitted version. DISCUSSION The
determination
of
pharmacokinetics
of
ototoxic
and
therapeutic drugs in the cochlea should provide key insights
into the mechanisms underlying drug-induced hearing loss and
may facilitate the development of effective therapies for SNHL. Nonetheless, this task is still challenging due to technical hurdles. As
the
cochlea
has
a
complicated
structure
and
a
“blood–labyrinth barrier” that interferes with drug permeation,
it is difficult to predict the pharmacokinetics in a target small area
inside the organ. The majority of pharmacokinetic studies in the
cochlea have analyzed the perilymph. In this regard, these
observations provide valuable insights into the permeability of
a few drug molecules across the vessels and cellular membranes to
the perilymph. Nevertheless, little is known about the transport of
compounds into the endolymph. Furthermore, it remains largely
unclear whether and how the behavior of a drug in these cochlear FUNDING This work is supported by the following research grants and
funds: AMED-CREST JP20gm0810004 (to HH) from AMED,
Grant-in-Aid for Young Scientists 20K16005 (to SS), Grant-
in-Aid for Scientific Research B 18H03513 (to GO), Grant-
in-Aid for Young Scientists 19K16442 (to RO), Grant-in-Aid
for Young Scientists 19K16826 (to YM), Grant-in-Aid for
Scientific Research C 20K07842 (to MM), Grant-in-Aid for
Scientific Research A 18H04062 (to HH), and Grant-in-Aid
for Challenging Exploratory Research 20K21883 (to HH) from
the Ministry of Education,
Culture, Sports, Science
and
Technology of Japan. REFERENCES Visualization of Endolymphatic Hydrops in Patients with Meniere’s
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Endocochlear Potential Depends on Two K+ Diffusion Potentials and an
Electrical Barrier in the Stria Vascularis of the Inner Ear. Proc. Natl. Acad. Sci. U. S. A. 105, 1751–1756. doi:10.1073/pnas.0711463105 Hanawa, A., Ogata, G., Sawamura, S., Asai, K., Kanzaki, S., Hibino, H., et al. (2020). In vivo real-time Simultaneous Examination of Drug Kinetics at Two Separate
Locations Using Boron-Doped Diamond Microelectrodes. Anal. Chem. 92,
13742–13749. doi:10.1021/acs.analchem.0c01707 Nin, F., Yoshida, T., Sawamura, S., Ogata, G., Ota, T., Higuchi, T., et al. (2016). The
Unique Electrical Properties in an Extracellular Fluid of the Mammalian
Cochlea; Their Functional Roles, Homeostatic Processes, and Pathological
Significance. Pflugers Arch. 468, 1637–1649. doi:10.1007/s00424-016-1871-0 Hara, A., Machiki, K., Senarita, M., Komeno, M., and Kusakari, J. (1993). Pharmacokinetics of Furosemide in Endolymph. Auris Nasus Larynx 20,
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et al. (2009). Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear
Kinetics as a Determinant for Ototoxicity. J. Natl. Cancer Inst. 101, 37–47. doi:10.1093/jnci/djn418 Ogata, G., Ishii, Y., Asai, K., Sano, Y., Nin, F., Yoshida, T., et al. (2017). A
Microsensing System for the in vivo Real-Time Detection of Local Drug
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within the Inner Ear. Curr. Opin. Otolaryngol. Head Neck Surg. 12, 431–438. doi:10.1097/01.moo.0000134449.05454.82 Hellberg, V., Wallin, I., Ehrsson, H., and Laurell, G. (2013). Cochlear
Pharmacokinetics of Cisplatin: an in vivo Study in the Guinea Pig. Laryngoscope 123, 3172–3177. doi:10.1002/lary.24235 Park, M., Lee, H. S., Kim, H., Oh, S. H., Lee, J. H., and Suh, M-W. (2016). Differences in Perilymphatic Space Enhancement and Adverse Inflammatory
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s12070-012-0604-8 Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest. Wang, Y., Han, L., Diao, T., Jing, Y., Wang, L., Zheng, H., et al. (2018). A
Comparison of Systemic and Local Dexamethasone Administration: From
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1–10. doi:10.1016/j.heares.2018.09.002 Copyright © 2021 Sawamura, Ogata, Asai, Razvina, Ota, Zhang, Madhurantakam,
Akiyama, Ino, Kanzaki, Saiki, Matsumoto, Moriyama, Saijo, Horii, Einaga and
Hibino. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction in
other forums is permitted, provided the original author(s) and the copyright owner(s)
are credited and that the original publication in this journal is cited, in accordance
with accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms. Wangemann, P. (2006). Supporting Sensory Transduction: Cochlear Fluid
Homeostasis and the Endocochlear Potential. J. Physiol. 576 (Pt 1), 11–21. doi:10.1113/jphysiol.2006.112888 Webster, D. B., and Webster, M. (1980). Mouse Brainstem Auditory Nuclei
Development. Ann. Otol. Rhinol. Laryngol. Suppl. 89 (3 Pt 2), 254–256. doi:10.1177/00034894800890s359 May 2021 | Volume 12 | Article 633505 Frontiers in Pharmacology | www.frontiersin.org 11
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In vivo Expansion of Naïve CD4+CD25high FOXP3+ Regulatory T Cells in Patients with Colorectal Carcinoma after IL-2 Administration
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Abstract Competing Interests: The authors have read the journal’s policy and have the following conflicts: This study was supported through a research grant from
Becton Dickinson to JLS and MB. There are no patents or products in development and this does not alter the authors9 adherence to all the PLoS ONE policies on
sharing data and materials. * E-mail: marc.beyer@uni-bonn.de (MB); j.schultze@uni-bonn.de (JLS) Treg cells seem to be a hallmark of tumor progression and
metastasis
[10,11]. Moreover,
efficient
anti-tumor
immune
responses are induced by deletion of these cells resulting in
complete tumor regression [12,13]. In humans, we and others
have demonstrated that CD4+CD25highFOXP3+ Treg cells are also
expanded
in
patients
with
solid
tumors
and
hematologic
malignancies and contribute to the overall immunosuppression
in these patients [14,15]. Numerous animal models over the last
years could demonstrate that increased numbers of Treg cells are
beneficial for tumor growth while depletion of Treg cells can lead
to tumor regression [16]. In humans, administration of an IL-2
immunotoxin to tumor patients results in decreased numbers of
Treg cells and higher responses against simultaneously adminis-
tered tumor peptides [17,18]. Several studies over the last years
have addressed the question of Treg-cell frequencies in colorectal
cancer patients [19,20,21]. These reports could demonstrate
increased number of FOXP3+ Treg cells in the peripheral blood,
tumor-draining lymph nodes and in close tumor proximity
[19,20,21]. Still, the question why Treg cells are expanded in
human tumors remains elusive. Abstract Regulatory T cells (Treg cells) are increased in context of malignancies and their expansion can be correlated with higher
disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical
vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of
Treg cells was established. In IL-2 treated cancer patients a further Treg-cell expansion was described, yet, the mechanism of
expansion is still elusive. Here we report that functional Treg cells of a naı¨ve phenotype - as determined by CCR7 and
CD45RA expression - are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal
cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naı¨ve Treg-cell pool. Higher frequencies of T-cell receptor excision circles in naı¨ve Treg cells indicate IL-2 dependent thymic generation of naı¨ve
Treg cells as a mechanism leading to increased frequencies of Treg cells post IL-2 treatment in cancer patients. This finding
could be confirmed in naı¨ve murine Treg cells after IL-2 administration. These results point to a more complex regulation of
Treg cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel
strategies to circumvent expansion and differentiation of naı¨ve Treg cells. Citation: Beyer M, Schumak B, Weihrauch MR, Andres B, Giese T, et al. (2012) In vivo Expansion of Naı¨ve CD4+CD25high FOXP3+ Regulatory T Cells in Patients with
Colorectal Carcinoma after IL-2 Administration. PLoS ONE 7(1): e30422. doi:10.1371/journal.pone.0030422 Editor: Hossam M. Ashour, Wayne State University, United States of America Editor: Hossam M. Ashour, Wayne State University, United States of America Received June 6, 2011; Accepted December 15, 2011; Published January 20, 2012 Copyright: 2012 Beyer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Sofja Kovalevskaja Award of the Alexander von Humboldt-Foundation (JLS), the Wilhelm-Sander Stiftung (JLS and MB),
the Deutsche-Jose-Carreras-Leuka¨mie-Striftung (JLS and MB), and the German Research Foundation (SFB 704, SFB 832, INST 217/576-1, INST 217/577-1). JLS and
MB have received support through a research grant from Becton Dickinson. The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript. In vivo Expansion of Naı¨ve CD4+CD25high FOXP3+
Regulatory T Cells in Patients with Colorectal Carcinoma
after IL-2 Administration Marc Beyer1*, Beatrix Schumak2, Martin R. Weihrauch3, Bettina Andres3, Thomas Giese4, Elmar Endl5,
Percy A. Knolle5, Sabine Classen1, Andreas Limmer5, Joachim L. Schultze1* 1 Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, Bonn, Germany, 2 Institute of Medical Microbiology, Immunology and
Parasitology (IMMIP), University of Bonn, Bonn, Germany, 3 Clinic I for Internal Medicine, University of Cologne, Cologne, Germany, 4 Institute of Immunology, University
of Heidelberg, Heidelberg, Germany, 5 Institute for Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany Expansion of CD4+CD25highFOXP3+ Treg cells after
chemoimmunotherapy including low-dose IL-2
administration Next, we investigated changes in frequency of Treg cells in
respect to IL-2 administration (Fig. 2). From the 15 patients
included in the trial, 12 successfully completed the whole protocol,
while 3 patients were rapidly progressing under therapy and
deceased shortly thereafter. Blood samples from the 12 patients
(P1–12) who completed the whole treatment were taken after
completion of IL-2 treatment following vaccination. For the 3
rapidly progressing patients (P13–15) who were taken off study,
Treg-cell frequencies were assessed at the last time point were
material was available. As depicted for patient P11 in Figure 2A
we observed an expansion of CD4+CD25highFOXP3+ Treg cells in
the majority of patients. When assessing all patients, 11 colorectal
cancer patients had higher frequencies post therapy while 2 (P3,
P15) had lower frequencies at the second time point of analysis and
two other patients (P4, P5) showed similar frequencies at both time
points (Fig. 2B). No feature (laboratory test, treatment or clinical
parameter) we have assessed so far showed an association with
changes in Treg-cell frequency in these patients (data not shown). In addition, we did not observe any cytopenia greater grade 2
during therapy. Overall, in the majority of patients the frequency
of Treg cells after combined chemoimmunotherapy was increased
compared to the initial frequencies before treatment (5.8%61.7%
vs. 4.7%61.2%, p,0.05) (Fig. 2C) as well as in comparison to
healthy donors (5.8%61.7% vs. 2.9%61.2%, p,0.001). When
assessing the absolute numbers of Treg cells we observed the same
trend; total numbers of Treg cells were increased after chemoim-
munotherapy (after: 29.26106/l620.56106/l vs. before: 21.36
106/l617.16106/l, p,0.005) and only one of the rapidly
progressing patients showed reduced numbers of Treg cells
(Fig. 2D). On the one hand, IL-2 is both important for the development
and expansion of effector T cells and also critical in the context of
immune
tolerance
[32]. On
the
other
hand,
experiments
performed in murine models established that IL-2 and its
downstream effector molecules are essential for the generation,
maintenance, and function of Treg cells [33,34,35,36]. Several
studies have addressed the role of IL-2 administration on the
frequency and function of human Treg cells in cancer patients and
demonstrated that treatment with recombinant IL-2 induces an
expansion of Treg cells in peripheral blood, thereby interfering
with efficient anti-tumor immune responses [37,38,39,40,41,
42,43]. These studies pointed to a peripheral expansion of Treg
cells post IL-2 therapy [41]. Expansion of CD4+CD25highFOXP3+ Treg cells after
chemoimmunotherapy including low-dose IL-2
administration It was further suggested that altered
migratory behavior due to increased expression of CCR4 and
CXCR4 on Treg cells might be associated with peripheral
expansion and increased migration to the tumor site [41]. In
two recent studies however, Correale et al. demonstrated that the
combination of chemotherapy with GM-CSF and IL-2 adminis-
tration leads to reduced Treg-cell numbers [44,45]. These findings
suggested a more complex regulation of Treg-cell frequency,
distribution and function than previously thought. Moreover, it
remains unclear whether different mechanisms might be respon-
sible for frequency changes of Treg cells in these different patient
populations treated with IL-2. In the current study, we investigated the impact of IL-2
administration on the frequency and function of CD4+CD25high-
FOXP3+ Treg cells. We provide clear evidence for an increased
expansion of naı¨ve Treg cells particularly post IL-2 therapy as a
major mechanism of overall Treg-cell expansion in these cancer
patients. Our data clearly suggest an increase of newly generated
Treg cells in cancer patients. These novel findings are of particular
interest for strategies targeting Treg cells in cancer patients. Among the 15 colorectal cancer patients, 4 patients had
progressive disease at the time of analysis while 11 showed a
response or stable disease. Comparing these two patient cohorts
revealed no significant difference in the proportion of Treg cells,
whereas both patient cohorts showed higher frequencies of Treg
cells compared to healthy controls (data not shown). Next, we
assessed if Treg-cell frequencies were indicative of longer freedom
from treatment failure or overall survival or if these 2 parameters
were linked to the expansion of Treg cells, yet no statistically
significant correlation was detected (data not shown). Our data
indicate that an expansion of CD4+CD25highFOXP3+ Treg cells
occurred in the majority of colorectal cancer patients after IL-2
administration as part of combined chemoimmunotherapy. IL-2 Induced Naı¨ve Treg Cell Expansion in CRC CD45RO expression has been primarily linked to Treg cells,
which led to the assumption that Treg cells belong to the memory
T-cell compartment [4,22]. Recently, a Treg-cell population with a
naı¨ve phenotype (CCR7+CD45RA+) was identified in healthy
individuals [23,24]. These naı¨ve Treg cells proliferated vigorously
in response to auto-antigens suggesting that particularly this
subpopulation was specific for self rather than foreign antigens
[23]. Persistence of naı¨ve Treg cells has been described throughout
adult life [25,26], although it must be pointed out that this pool of
naı¨ve Treg cells is relatively small in peripheral blood of healthy
individuals [27]. In patients with multiple myeloma (MM),
however, we could demonstrate an expansion of naı¨ve Treg cells
[28]. We could validate this finding for a number of hematologic
malignancies and patients with solid tumors and even show strong
suppressive function for the naı¨ve Treg-cell population [29]. Comparison of levels of T-cell receptor excision circles (TREC)
in Treg cells of healthy individuals addressed the diversity and
developmental stage of thymic emigrants as well as peripheral
blood Treg cells [30,31]. As expected, TREC numbers were
significantly higher in thymic emigrants compared to peripheral
blood derived Treg cells, which supports thymic development of
human CD4+CD25high Treg cells [31]. healthy controls (Fig. 1A). The frequency of Treg cells in healthy
donors (n = 22, 2.9%61.2%) was comparable to previously
published results (Fig. 1B) [46,47]. In contrast, individuals with
colorectal cancer assessed before initiation of treatment (n = 15,
4.7%61.2%, p,0.001) showed significantly increased frequencies
of Treg cells compared to healthy individuals (Fig. 1A and 1B). We
also assessed previously described surface receptors associated with
Treg cells including CTLA4 and GITR on CD4+CD25high-
FOXP3+ T cells in colorectal cancer patients as well as healthy
individuals. As depicted in Figure 1C, we observed comparable
expression of both molecules on Treg cells from healthy donors and
colorectal cancer patients while percentages of CD4+CD25high-
FOXP3+ Treg cells expressing either molecule were significantly
increased in colorectal cancer patients (CTLA4: 3.7%61.2% vs. 1.5%60.6%, p,0.001; GITR: 1.7%60.8% vs. 0.5%60.2%,
p,0.001) (Fig. 1D). Expansion of CD4+CD25highFOXP3+ Treg cells after
chemoimmunotherapy including low-dose IL-2
administration PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 Introduction Human regulatory T cells (Treg cells) have been characterized as
CD4+CD25high T cells with inhibitory function [1]. They are
crucial for the preservation of T-cell homeostasis and self-tolerance
and regulate the immune responses to alloantigens, pathogens and
tumors [2]. Both in humans and animal models activation of Treg
cells results in exertion of their full suppressive function [3,4]. Natural Treg cells are generated in the thymus as a distinct lineage
of anergic CD4+ T cells bearing self-reactive T-cell receptors,
although cells with similar characteristics can also be generated in
the periphery under appropriate conditions [5]. Typically, Treg
cells express cytotoxic T-lymphocyte–associated-antigen 4 (CTLA-
4) and glucocorticoid-induced tumor-necrosis-factor receptor-
related protein (GITR), although both molecules can also be
expressed by activated T cells [6,7]. The transcription factor
forkhead box P3 (FOXP3) has been demonstrated to be expressed
exclusively on Treg cells in the mouse [2], while data concerning its
expression in humans are not as clear-cut [8,9]. In numerous
murine tumor models increased frequencies of CD4+CD25high January 2012 | Volume 7 | Issue 1 | e30422 1 PLoS ONE | www.plosone.org IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Increased frequencies of CD4+CD25highFOXP3+ Treg cells
in peripheral blood of patients with metastatic colorectal
cancer Shown here are
median, 25th and 75th percentile (box), 10th and 90th percentile (whiskers) and outliers (dots), (*, p,0.05, Student’s t test). doi:10.1371/journal.pone.0030422.g001 Inhibitory function of CD4+CD25high Treg cells from
colorectal cancer patients Increased frequencies of CD4+CD25highFOXP3+ Treg cells
in peripheral blood of patients with metastatic colorectal
cancer Within a clinical phase I/II combined chemoimmunotherapy
trial of patients with metastatic colorectal cancer we assessed
frequencies of FOXP3-expressing CD4+CD25high Treg cells in
peripheral blood before initiation of therapy in comparison to PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 January 2012 | Volume 7 | Issue 1 | e30422 2 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Figure 1. Frequency of CD4+CD25highFOXP3+ Treg cells. (A) Flow cytometric analysis of CD25 and FOXP3 on peripheral blood derived CD4+ T
cells from a representative healthy individual (left panel) and a representative colorectal cancer patient before treatment (right panel). Number
represent percentage of events within the gate. (B) Frequency of CD4+CD25highFOXP3+ Treg cells in 22 healthy donors and 15 colorectal cance
patients (CRC) before treatment. Each dot represents a single individual assessed in the respective group; mean expression (line) of all samples in
each group is also shown (*, p,0.05, Student’s t test). (C) CTLA4 (top) and GITR expression (bottom) in CD4+CD25highFOXP3+ Treg cells of health
donors (left, grey fill) and colorectal cancer patients (right, grey fill). Isotype control (black line). (D) Frequency of CTLA4 (left) and GITR (right
expressing CD4+CD25highFOXP3+ Treg cells in healthy donors (white) and colorectal cancer patients (grey, CRC) before treatment. Shown here ar
median, 25th and 75th percentile (box), 10th and 90th percentile (whiskers) and outliers (dots), (*, p,0.05, Student’s t test). doi:10.1371/journal.pone.0030422.g001
IL-2 Induced Naıve Treg Cell Expansion in CRC Figure 1. Frequency of CD4+CD25highFOXP3+ Treg cells. (A) Flow cytometric analysis of CD25 and FOXP3 on peripheral blood derived CD4+ T
cells from a representative healthy individual (left panel) and a representative colorectal cancer patient before treatment (right panel). Numbers
represent percentage of events within the gate. (B) Frequency of CD4+CD25highFOXP3+ Treg cells in 22 healthy donors and 15 colorectal cancer
patients (CRC) before treatment. Each dot represents a single individual assessed in the respective group; mean expression (line) of all samples in
each group is also shown (*, p,0.05, Student’s t test). (C) CTLA4 (top) and GITR expression (bottom) in CD4+CD25highFOXP3+ Treg cells of healthy
donors (left, grey fill) and colorectal cancer patients (right, grey fill). Isotype control (black line). (D) Frequency of CTLA4 (left) and GITR (right)
expressing CD4+CD25highFOXP3+ Treg cells in healthy donors (white) and colorectal cancer patients (grey, CRC) before treatment. Inhibitory function of CD4+CD25high Treg cells from
colorectal cancer patients basis highly purified CD4+CD25high Treg cells from colorectal
cancer patients (before initiation of therapy) showed an equally
strong inhibitory function on conventional CD4+CD252 T-cell
proliferation
(dark
grey
bar,
Fig. 3C,
p,0.001). Titration
experiments demonstrated that the inhibitory function of Treg cells
from healthy individuals and colorectal cancer patients was
comparable also at lower Treg:Tconv ratios (data not shown). Moreover, after IL-2 treatment of colorectal cancer patients (after
treatment), Treg cells had equal suppressive function on conven-
tional CD4+CD252 T-cell proliferation when compared to Treg
cells isolated before start of therapy (light grey bar, Fig. 3C,
p,0.001). Taken together, these data suggest, that Treg cells from
colorectal cancer patients have normal suppressive function. In 4 colorectal cancer patients sufficient numbers of highly
purified CD4+CD25high Treg cells (Fig. 3A and B) were isolated from
peripheral blood by flow cytometric cell sorting before and after
vaccination to analyze their inhibitory function in comparison to
Treg cells from healthy controls (n = 4). Proliferation of allogeneic
conventional CD4+CD252 T cells stimulated by beads coated with
CD3 and CD28 mAbs was used as the read out to assess inhibitory
function of CD4+CD25high Treg cells [28]. Proliferation of allogeneic
conventional CD4+CD252 T cells was significantly inhibited when
highly purified CD4+CD25high T cells from healthy donors were
added at a 1:1 ratio (white bar, Fig. 3C, p,0.001). On a cell-to-cell PLoS ONE | www.ploson January 2012 | Volume 7 | Issue 1 | e30422 PLoS ONE | www.plosone.org 3 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Figure 2. Analysis of frequencies of CD4+CD25highFOXP3+ Treg cells after chemoimmunotherapy. (A) Flow cytometric analysis of CD25
and FOXP3 on peripheral blood derived CD4+ T cells from a representative colorectal cancer patient before (left panel) and after
chemoimmunotherapy (right panel). Numbers represent percentage of events within the gate. (B) Serial analysis of frequencies of
CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients before and after chemoimmunotherapy. (C) Frequency of CD4+CD25highFOXP3+ Treg
cells in 15 colorectal cancer patients before (light grey box) and after (dark grey box) chemoimmunotherapy. Shown here are median, 25th and 75th
percentile (box), 10th and 90th percentile (whiskers) and outliers (dots), (*, p,0.05, Student’s t test). (D) Serial analysis of total numbers of
CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients before and after chemoimmunotherapy. doi:10.1371/journal.pone.0030422.g002 Figure 2. Analysis of frequencies of CD4+CD25highFOXP3+ Treg cells after chemoimmunotherapy. Administration of IL-2 leads to an expansion of a
population of murine ‘‘naı¨ve’’ CD4+ CD25highFOXP3+ Treg
cells Administration of IL-2 leads to an expansion of a
population of murine ‘‘naı¨ve’’ CD4+ CD25highFOXP3+ Treg
cells To demonstrate that IL-2 administration indeed leads to an
increase of naı¨ve Treg cells, we administered IL-2 or PBS i.p. in
C57BL/6 mice for 10 days and assessed the frequency of
CD4+CD25highFOXP3+ Treg cells in these animals after the
treatment period. In comparison to PBS-treated animals a
significant expansion of CD4+CD25highFOXP3+ Treg cells oc-
curred after IL-2 administration in spleen, peripheral as well as
mesenteric lymph nodes, peripheral blood, thymus, and liver
(Fig. 6A). Of particular interest was the increase of Treg cells in the
thymus, which could be indicative of an increased thymic output. As a first approximation for vicinity of T cells to thymic output
expression of CD45RB on CD4+CD25highFOXP3+ Treg cells was
assessed since up to now no true marker for murine naı¨ve Treg cells
has been established. We observed a significant increase of
CD45RBhigh CD4+CD25highFOXP3+ Treg cells in spleen, periph-
eral as well as mesenteric lymph nodes, peripheral blood, thymus,
and liver of IL-2 treated mice (Fig. 6B) clearly indicating that an
increase of naı¨ve Treg cells contributed to the overall expansion of
Treg cells after IL-2 administration and that the overall Treg-cell
expansion was related to elevated frequencies of naı¨ve Treg cells in
the thymus. Next, we assessed the suppressive function of naı¨ve versus
memory Treg-cell populations before and after therapy (Fig. 4E). We observed a clear inhibition of conventional CD4+CD252 T-
cell proliferation induced by stimulation with CD3/CD28-coated
beads by adding sorted Treg cells to the culture irrespective of the
subtype (naı¨ve vs. memory) used or the status of therapy (no
therapy vs. chemoimmunotherapy) demonstrating that the differ-
ent subtypes of Treg cells have full suppressive activity independent
of IL-2 therapy. Taken together, these data demonstrate a
significant expansion of naı¨ve Treg cells post IL-2 treatment. Furthermore, these cells are similarly effective in suppressing
conventional T-cell activation when analyzed on a cell-to-cell
basis, suggesting an overall higher suppressive effect of these cells
in colorectal cancer patients. To further delineate if IL-2 treatment induces generation of
naı¨ve
Treg
cells
in
the
thymus
we
sorted
CD45RB+
CD44lowCD62L+ naı¨ve Tconv and Treg cells from IL-2 as well as
PBS treated animals (Fig. 6C) and assessed TREC levels in the
naı¨ve Tconv and Treg-cell population. We observed significantly
higher levels of TREC in Tconv and Treg-cell populations after IL-2
administration (Fig. Administration of IL-2 leads to an expansion of a
population of murine ‘‘naı¨ve’’ CD4+ CD25highFOXP3+ Treg
cells 6C) suggesting that IL-2 treatment indeed
results in a higher thymic output of naı¨ve Treg cells as observed in
IL-2 treated human colorectal cancer patients. Thymic expansion of naı¨ve CD4+CD25highFOXP3+ Treg
cells in patients with colorectal cancer after IL-2
administration As Treg cells with a naı¨ve phenotype were increased in patients
with colorectal cancer, particularly post IL-2 treatment, we were
interested to assess whether the increase of Treg cells resulted from
peripheral
expansion
or
possibly
thymic
generation
of
CD4+CD25highFOXP3+ Treg cells. We previously reported that
the level of TREC can be used as a marker to estimate the
developmental vicinity of Treg cells to the thymus and their IL-2 Induced Naı¨ve Treg Cell Expansion in CRC division history [28] and therefore applied TREC analysis to
address this issue in relation to IL-2 treatment. PB derived CD4+
T cells from two colorectal cancer patients and two age-matched
healthy individuals were sorted according to their CD25, CCR7
and CD45RA expression into the appropriate CD4+CD25high
Treg-cell subsets, namely Tnaı¨ve, TCM, and TEM (Fig. 5A and B). TREC values for the highly purified Treg-cell subsets were assayed
by real-time PCR. As described before, CD4+CD25high Treg cells
showed relatively low TREC contents in the naı¨ve T-cell
population and TREC levels were below detection threshold in
the TCM and TEM subsets (Fig. 5C) [28]. These observations are in
line with the concept of antigen-driven peripheral expansion of
Treg cells in healthy individuals rather than recent thymic
emigration. In contrast, the TREC content on the single cell level
in naı¨ve CD4+CD25high Treg cells in colorectal cancer patients was
more than two-fold higher in average compared to healthy
individuals before initiation of chemoimmunotherapy and even
more increased after administration of IL-2 (.4–fold in average,
Fig. 5C). These results strongly suggest that the expansion of Treg
cells in colorectal cancer patients was nurtured by the generation
of new Treg cells in the thymus and the further increase of Treg-cell
frequencies post IL-2 administration was strongly associated with
an increase of thymic emigrants of naı¨ve Treg cells. Inhibitory function of CD4+CD25high Treg cells from
colorectal cancer patients (A) Flow cytometric analysis of CD25
and FOXP3 on peripheral blood derived CD4+ T cells from a representative colorectal cancer patient before (left panel) and after
chemoimmunotherapy (right panel). Numbers represent percentage of events within the gate. (B) Serial analysis of frequencies of
CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients before and after chemoimmunotherapy. (C) Frequency of CD4+CD25highFOXP3+ Treg
cells in 15 colorectal cancer patients before (light grey box) and after (dark grey box) chemoimmunotherapy. Shown here are median, 25th and 75th
percentile (box), 10th and 90th percentile (whiskers) and outliers (dots), (*, p,0.05, Student’s t test). (D) Serial analysis of total numbers of
CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients before and after chemoimmunotherapy. doi:10.1371/journal.pone.0030422.g002 Figure 3. Functional analysis of CD4+CD25highFOXP+ Treg cells. (A) CD4+ cells were separated by flow cytometric cell sorting into
conventional CD4+CD252 and regulatory CD4+CD25high T cells as defined by their expression of CD25. (B) Re-analysis of FOXP3 expression in
CD4+CD252 Tconv (left, grey fill) and CD4+CD25high Treg cells (right, grey fill) post cell sorting. Isotype control (black line). (C) Reduction of proliferation
of CD4+CD252 Tconv cells stimulated with beads coated with CD3 and CD28 mAbs (black bar) by highly purified CD4+CD25highFOXP3+ Treg cells from
healthy donors (white bar) or colorectal cancer patients before (dark grey bar) and after therapy (light grey bar). doi:10.1371/journal.pone.0030422.g003 Figure 3. Functional analysis of CD4+CD25highFOXP+ Treg cells. (A) CD4+ cells were separated by flow cytometric cell sorting into
conventional CD4+CD252 and regulatory CD4+CD25high T cells as defined by their expression of CD25. (B) Re-analysis of FOXP3 expression in
CD4+CD252 Tconv (left, grey fill) and CD4+CD25high Treg cells (right, grey fill) post cell sorting. Isotype control (black line). (C) Reduction of proliferation
of CD4+CD252 Tconv cells stimulated with beads coated with CD3 and CD28 mAbs (black bar) by highly purified CD4+CD25highFOXP3+ Treg cells from
healthy donors (white bar) or colorectal cancer patients before (dark grey bar) and after therapy (light grey bar). doi:10.1371/journal.pone.0030422.g003 January 2012 | Volume 7 | Issue 1 | e30422 PLoS ONE | www.plosone.org 4 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Expansion of fully functional naı¨ve Treg cells in colorectal
cancer patients after chemoimmunotherapy Expansion of fully functional naı¨ve Treg cells in colorectal
cancer patients after chemoimmunotherapy y
It has been previously reported by us and others that differential
expression of the cell surface receptors CD45RA and CCR7 can
be used to differentiate between naı¨ve, central and effector
memory Treg cells (Fig. 4A) [23,28,48]. This approach can be used
to address the question, if naı¨ve, central or effector memory Treg
cells contribute to the overall expansion of Treg cells in patients
with solid tumors and how treatment, particularly administration
of IL-2 influences the frequency and function of naı¨ve versus
memory CD4+CD25highFOXP3+ Treg cells. In healthy individuals,
naı¨ve CCR7+CD45RA+ Treg cells were hardly detectable (Fig. 4B). Treg cells were almost exclusively of a memory phenotype (Fig. 4C
and D) with a higher frequency of TEM cells (Fig. 4D). In contrast,
in colorectal cancer patients we observed a significantly higher
number of Treg cells with a CCR7+CD45RA+ naı¨ve phenotype
(Fig. 4B). This was further accompanied by an increase of Treg
cells with a central memory phenotype in colorectal cancer
patients prior to therapy (Fig. 4C) while effector memory Treg cell
levels were comparable in colorectal cancer patients (prior to
therapy) and healthy donors (Fig. 4D). However, most surprising,
after IL-2 treatment, expansion of Treg cells almost exclusively
occurred within the naı¨ve Treg-cell population (Fig. 4B) while
frequencies of central and effector memory Treg cells remained
unchanged (Fig. 4C and D). To further characterize the increased
subset of naı¨ve CD4+CD25highFOXP3+ Treg cells, we assessed the
expression of intracellular CTLA4 or GITR expression. Compa-
rable to the data obtained for the total Treg-cell population both
molecules were expressed at similar levels on a per cell basis on
naı¨ve Treg-cells from healthy individuals and cancer patients
irrespective of IL-2 treatment (data not shown) while percentages
of CD4+CD25highFOXP3+ Treg cells expressing either molecule
were significantly increased in colorectal cancer patients (CTLA4:
0.31%60.23% vs. 0.05%60.01%, p,0.05; GITR: 0.10%6
0.07% vs. 0.02%60.01%, p,0.05) with a further increase after
IL-2 administration (CTLA4: 0.78%60.56% vs. 0.31%60.23%,
p,0.001; GITR: 0.24%60.19% vs. 0.10%60.07%, p,0.05)
(Fig. S1). IL-2 Induced Naı¨ve Treg Cell Expansion in CRC IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Figure 4. Increase of naı¨ve CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients after chemoimmunotherapy. (A) Strategy of
flow cytometric analysis of CCR7 and CD45RA expression on the surface of CD4+CD25highFOXP3+ Treg cells as exemplified for a representative healthy
donor (left) and a representative colorectal cancer patient (right). Frequencies of (B) CCR7+CD45RA+ naı¨ve Treg cells (Tnaive), (C) CCR7+CD45RA2
central memory Treg cells (TCM), and (D) CCR72CD45RA2 effector memory Treg cells (TEM) were assessed in peripheral blood of colorectal cancer
patients (n = 15) before (light grey bars) and after therapy (dark grey bars) as well as healthy individuals (white bars, n = 22). Significant differences
(p,0.05, Student’s t test) between healthy donors and colorectal cancer patients before and after chemoimmunotherapy are marked by an asterisk
(*). Error bars represent SD. (E) Assessment of regulatory function of naı¨ve and memory CD4+CD25high Treg cells sorted according to their CD45RA
expression from colorectal cancer patients. Reduction of proliferation of CD4+CD252 Tconv cells stimulated with beads coated with CD3 and CD28
mAbs by highly purified naı¨ve and memory CD4+CD25high Treg cells from colorectal cancer patients before and after therapy. doi:10 1371/journal pone 0030422 g004 Figure 4. Increase of naı¨ve CD4+CD25highFOXP3+ Treg cells in colorectal cancer patients after chemoimmunotherapy. (A) Strategy of
flow cytometric analysis of CCR7 and CD45RA expression on the surface of CD4+CD25highFOXP3+ Treg cells as exemplified for a representative healthy
donor (left) and a representative colorectal cancer patient (right). Frequencies of (B) CCR7+CD45RA+ naı¨ve Treg cells (Tnaive), (C) CCR7+CD45RA2
central memory Treg cells (TCM), and (D) CCR72CD45RA2 effector memory Treg cells (TEM) were assessed in peripheral blood of colorectal cancer
patients (n = 15) before (light grey bars) and after therapy (dark grey bars) as well as healthy individuals (white bars, n = 22). Significant differences
(p,0.05, Student’s t test) between healthy donors and colorectal cancer patients before and after chemoimmunotherapy are marked by an asterisk
(*). Error bars represent SD. (E) Assessment of regulatory function of naı¨ve and memory CD4+CD25high Treg cells sorted according to their CD45RA
expression from colorectal cancer patients. Reduction of proliferation of CD4+CD252 Tconv cells stimulated with beads coated with CD3 and CD28
mAbs by highly purified naı¨ve and memory CD4+CD25high Treg cells from colorectal cancer patients before and after therapy. doi:10.1371/journal.pone.0030422.g004 there was no difference in Treg cells with an effector memory
phenotype. PLoS ONE | www.plosone.org Discussion In the current study we addressed the question whether IL-2
treatment leads to an expansion of fully functional Treg cells in
colorectal cancer patients and whether an increase of Treg cells in
colorectal cancer patients
is due to peripheral
or thymic PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 January 2012 | Volume 7 | Issue 1 | e30422 5 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Most surprising, expansion of Treg cells post IL-2
treatment was almost exclusively due to an increase of naı¨ve Treg
cells. Expansion of naı¨ve Treg cells was further supported by the
increase of TREC numbers that were significantly higher in naı¨ve
Treg
cells
from
untreated
colorectal
cancer
patients
when
compared to healthy controls and further increased post IL-2
treatment. To demonstrate that the observed results in humans are
dependent on the IL-2 administration, we treated mice with IL-2
and could detect increased levels of Treg cells in these animals. In
line with our results in humans, we observed thymic generation of
naı¨ve Treg cells after IL-2 treatment as shown by high TREC levels
in the naı¨ve Treg-cell population. These findings strongly suggest
that Treg-cell expansion in colorectal cancer patients is due to
higher thymic output which is further increased by IL-2 treatment. expansion. Using phenotypic, functional and molecular approach-
es we demonstrate an increase of CD4+CD25highFOXP3+ Treg
cells in colorectal cancer patients already before initiation of an IL-
2 containing chemoimmunotherapy regimen. The increase of Treg
cells in these patients was further augmented after completion of
treatment, clearly demonstrating that IL-2 treatment is associated
with an increase in Treg-cell numbers an alarming effect which
could potentially influence and dampen the immune response in
an immunotherapy protocol. Treg cells expressed phenotypic
markers associated with Treg cells (e.g. CTLA-4 and GITR) and
suppressed the proliferation of CD4+CD252 Tconv cells. Further-
more, we can clearly show that Treg cells in colorectal cancer
patients have normal suppressive function. In addition, we demonstrate that the expansion of Treg cells in
colorectal cancer patients was particularly prominent within the
naı¨ve CCR7+CD45RA+ CD4+CD25highFOXP3+ Treg cell popu-
lation and to a lesser extent in central memory Treg cells, while Over the last years several murine studies showed the
importance of IL-2 for Treg cells. IL-2 is a critical growth factor PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 6 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Figure 5. Replicative history of CD4+CD25highFOXP3+ Treg cell populations defined by the expression of CD45RA and CCR7. CD4+CD25high Treg cells were isolated by flow cytometric cell sorting according to their expression of CD25 as well as CD45RA and CCR7 in three Treg-
cell subsets, namely Tnaı¨ve (CD45RA+CCR7+), TCM (CD45RA2CCR7+), and TEM cells (CD45RA2CCR72). IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Indeed, a recent study in
patients with renal cell carcinoma or malignant melanoma
suggested an enormously high proportion of naı¨ve Treg cells
[39]. However, the number of naı¨ve Treg cells in the healthy
control group was also reported to exceed 50% of all Treg cells, a
frequency that could never be confirmed by us and others [24,27]. Irrespective of these experimental differences in earlier studies,
we clearly unraveled the expansion of naı¨ve Treg cells to be one of
the mechanisms leading to an overall expansion of fully functional
Treg cells in colorectal cancer patients which was further
augmented by IL-2 therapy. Over the last years differentiation
of Treg cells into naı¨ve, central and effector memory Treg cells
according to their expression of CCR7 and CD45RA has been
established for healthy individuals [23,24,25,31,53]. We have
incorporated this strategy for the analysis of Treg cells in cancer
patients and demonstrated an expansion of naı¨ve Treg cells in
human multiple myeloma patients and B-CLL patients [28]. Remarkably, in B cell malignancies, increase of Treg cells was
associated with peripheral expansion of naı¨ve Treg cells while in
patients with colorectal cancer the expansion seems to be thymus These rather opposite results might be explained by the
differences in the vaccination and chemotherapy protocols, e.g. high-dose vs. low-dose 5-FU, irinotecan vs. oxaliplatin, forgoing of
gemcitabine, dosage and schedule of GM-CSF administration, or
addition of CAP-1-peptide, in the time course of administration, in
the patient cohort under study (metastatic colorectal cancer vs. unselected colorectal cancer), number of patients analyzed, and
additional, yet unknown, confounding factors. Further conflicting
might be technical issues as it has been previously stated by
Baecher-Allan et al. that the assessment of human Treg cells is still
difficult and the use of different assays sometimes makes it difficult
to compare different studies [47]. Indeed, a recent study in
patients with renal cell carcinoma or malignant melanoma
suggested an enormously high proportion of naı¨ve Treg cells
[39]. However, the number of naı¨ve Treg cells in the healthy
control group was also reported to exceed 50% of all Treg cells, a
frequency that could never be confirmed by us and others [24,27]. for murine Treg cells, it is responsible for maintenance and
regulation of Treg cells in the periphery [33,34,35]. IL-2 Induced Naı¨ve Treg Cell Expansion in CRC IL-2 seems to
be involved in the generation of Treg cells during antigen-specific
immune responses [49] and has been suggested to be involved in
the suppressive function of Treg cells [50,51]. In human Treg-cell
biology, IL-2 is supposed to induce a peripheral expansion of
CD4+CD25highFOXP3+ Treg cells as suggested by Wei et al. [41]
while it has no effect on FOXP3 expression in conventional T
cells. This has been further confirmed in a second study which
reported that IL-2 induced STAT-dependent mechanisms are
responsible for the selective expression of FOXP3 in Treg cells and
in vivo expansion following IL-2 administration indicating a unique
programming of CD4+CD25high Treg cells within the IL-2
signaling pathway [52]. hi h for murine Treg cells, it is responsible for maintenance and
regulation of Treg cells in the periphery [33,34,35]. IL-2 seems to
be involved in the generation of Treg cells during antigen-specific
immune responses [49] and has been suggested to be involved in
the suppressive function of Treg cells [50,51]. In human Treg-cell
biology, IL-2 is supposed to induce a peripheral expansion of
CD4+CD25highFOXP3+ Treg cells as suggested by Wei et al. [41]
while it has no effect on FOXP3 expression in conventional T
cells. This has been further confirmed in a second study which
reported that IL-2 induced STAT-dependent mechanisms are
responsible for the selective expression of FOXP3 in Treg cells and
in vivo expansion following IL-2 administration indicating a unique
programming of CD4+CD25high Treg cells within the IL-2
signaling pathway [52]. Most recently increased frequencies of CD4+CD25highFOXP3+ Treg
cells were reported for patients with renal cell carcinoma, malignant
melanoma or ovarian cancer patients after IL-2 monotherapy
[37,39,40,41] and administration of IL-2 during immune reconstitu-
tion after chemotherapy in pediatric sarcomas led to a preferential
expansion of Treg cells after cytoreductive chemptherapy [38]. In
contrast, patients with metastatic colorectal cancer treated with a
combined chemoimmunotherapy containing gemcitabine and FOL-
FOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy
followed by the subcutaneous administration of GM-CSF and low-
dose IL-2 showed clinical objective responses in the majority of patients
associated with a significant reduction in CD4+CD25highFOXP3+ Treg
cells as reported by Correale et al. [44,45]. IL-2 Induced Naı¨ve Treg Cell Expansion in CRC (A) Strategy of flow cytometric analysis of CD4
and CD25 expression on the surface of CD4+ T cells as exemplified for a colorectal cancer patient. (B) Re-analysis of FOXP3 and CD25 expression (left)
as well as CCR7 and CD45RA expression (right) in CD4+CD25high Treg cells. (C) Naı¨ve, central and effector memory CD4+CD25high Treg cells from healthy
donors and colorectal cancer patients before and after chemoimmunotherapy were assessed for TREC (T-cell receptor excision circle) content. Genomic DNA of sorted subsets was isolated, and the number of TREC was determined by quantitative real-time PCR. Data are shown as the mean
values obtained for 2 independent healthy donors and 2 colorectal cancer patients. Error bars represent SD. doi:10.1371/journal.pone.0030422.g005 Figure 5. Replicative history of CD4+CD25highFOXP3+ Treg cell populations defined by the expression of CD45RA and CCR7. CD4+CD25high Treg cells were isolated by flow cytometric cell sorting according to their expression of CD25 as well as CD45RA and CCR7 in three Treg-
cell subsets, namely Tnaı¨ve (CD45RA+CCR7+), TCM (CD45RA2CCR7+), and TEM cells (CD45RA2CCR72). (A) Strategy of flow cytometric analysis of CD4
and CD25 expression on the surface of CD4+ T cells as exemplified for a colorectal cancer patient. (B) Re-analysis of FOXP3 and CD25 expression (left)
as well as CCR7 and CD45RA expression (right) in CD4+CD25high Treg cells. (C) Naı¨ve, central and effector memory CD4+CD25high Treg cells from healthy
donors and colorectal cancer patients before and after chemoimmunotherapy were assessed for TREC (T-cell receptor excision circle) content. Genomic DNA of sorted subsets was isolated, and the number of TREC was determined by quantitative real-time PCR. Data are shown as the mean
values obtained for 2 independent healthy donors and 2 colorectal cancer patients. Error bars represent SD. doi:10.1371/journal.pone.0030422.g005 These rather opposite results might be explained by the
differences in the vaccination and chemotherapy protocols, e.g. high-dose vs. low-dose 5-FU, irinotecan vs. oxaliplatin, forgoing of
gemcitabine, dosage and schedule of GM-CSF administration, or
addition of CAP-1-peptide, in the time course of administration, in
the patient cohort under study (metastatic colorectal cancer vs. unselected colorectal cancer), number of patients analyzed, and
additional, yet unknown, confounding factors. Further conflicting
might be technical issues as it has been previously stated by
Baecher-Allan et al. that the assessment of human Treg cells is still
difficult and the use of different assays sometimes makes it difficult
to compare different studies [47]. January 2012 | Volume 7 | Issue 1 | e30422 PLoS ONE | www.plosone.org IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Irrespective of these experimental differences in earlier studies,
we clearly unraveled the expansion of naı¨ve Treg cells to be one of
the mechanisms leading to an overall expansion of fully functional
Treg cells in colorectal cancer patients which was further
augmented by IL-2 therapy. Over the last years differentiation
of Treg cells into naı¨ve, central and effector memory Treg cells
according to their expression of CCR7 and CD45RA has been
established for healthy individuals [23,24,25,31,53]. We have
incorporated this strategy for the analysis of Treg cells in cancer
patients and demonstrated an expansion of naı¨ve Treg cells in
human multiple myeloma patients and B-CLL patients [28]. Remarkably, in B cell malignancies, increase of Treg cells was
associated with peripheral expansion of naı¨ve Treg cells while in
patients with colorectal cancer the expansion seems to be thymus Our data however support an alternative outcome of combined
chemoimmunotherapy as low-dose IL-2 in combination with a
peptide-vaccination
resulted
in
increased
frequencies
of
CD4+CD25highFOXP3+ Treg cells, particularly naı¨ve Treg cells. PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 7 January 2012 | Volume 7 | Issue 1 | e30422 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC PLoS ONE | www.plosone.org IL-2 Induced Naı¨ve Treg Cell Expansion in CRC All
patients received low-dose IL-2 (16106 IU) post vaccination. For
vaccination, several approaches were compared in this study,
namely a vaccine containing only the CAP-1-peptide, or the CAP-
1-peptide together with 50 mg GM-CSF (Novartis) or the CAP-1-
peptide together with an oligonucleotide adjuvant (dSLIM,
Mologen); as a fourth option, patients obtained autologous CAP-
1-pulsed dendritic cells as a cellular vaccine. For the analysis of
Treg-cell
frequency
and
function
post
IL-2
treatment,
no
statistically significant influence of the different types of vaccina-
tions could be established (data not shown). Two cycles of
vaccination and IL-2 treatment were given 2 and 1 week before
the first cycle of chemotherapy consisting of 80 mg/m2 irinotecan,
2,000 mg/m2 high-dose 5-FU, and 500 mg/m2 leucovorin (six
weekly administrations). Alternating, two cycles of IL-2 and
vaccination were combined with one cycle of chemotherapy and
repeated three times. After the third cycle, patients were treated
with IL-2 and CAP-1-peptide vaccination on a weekly schedule
until progressive disease. At baseline and after three cycles of
chemoimmunotherapy, patients underwent a leukapheresis to
obtain PBMC for diagnostic and therapeutic purposes. PBMC
were isolated using Ficoll/Hypaque (Amersham, Uppsala, Swe-
den) density centrifugation. Staging was performed according to
the UICC classification for colorectal cancer. All patients were
UICC stage IV. The treatment schedule is provided as Figure S2. Characteristics of the patients studied are summarized in Table 1. The assessment of the source of expanded Treg cells in cancer
patients is of particular importance as the mechanism of
expansion, an augmented production of Treg cells in the thymus,
expansion of Treg cells in the periphery, preferential migration of
Treg cells to the tumor site, increased conversion of conventional T
cells into Treg cells as well as diminished apoptosis and cell death of
peripheral Treg cells, might influence the strategy to therapeuti-
cally target Treg cells to increase anti-tumor immunity. E.g. peripherally expanded Treg cells might be deleted by short-term
use of cytotoxic agents such as denileukin diftitox while continuing
thymic expansion would require either long-term treatment or
deletion of the cause of thymic expansion of these inhibitory cells
to induce a long-lasting reduction of Treg cells. IL-2 Induced Naı¨ve Treg Cell Expansion in CRC dependent as determined by analysis of TREC as an approxima-
tion of adjacency of Treg cells to the thymus. Moreover,
administration of IL-2 further augmented this increase. Two
recent publications underlined the importance of IL-2 for the
development of Treg cells in the thymus [54,55], while other results
support a more restricted role for IL-2 of regulating Treg cells in
the periphery without alteration of the thymic output [34]. The
latter proposition has been further strengthened by data obtained
by Wei et al. who could demonstrate expansion of memory Treg
cells in vitro by IL-2 treatment [41]. To address whether effects
induced by IL-2 were limited to peripheral expansion of mainly
memory Treg cells, we treated C57BL/6 mice with IL-2 and
assessed the frequencies of Treg cells with a special focus on naı¨ve
Treg cells in the periphery and in the thymus. We observed an
overall expansion of Treg cells in these animals and detected a
particular enrichment of naı¨ve Treg cells in the thymus and
peripheral lymph nodes. By assessment of TREC in the naı¨ve Treg-
cell population we could demonstrate thymic generation of naı¨ve
Treg cells as a result of IL-2 adminstration, clearly suggesting that
increased thymic output is an important mechanism leading to
increased frequencies of naı¨ve Treg cells post IL-2 treatment and
these cells subsequently can differentiate into peripheral Treg cells
with a memory phenotype. Whether peripheral expansion might
also occur under these conditions might be further studied by
administration of IL-2 to thymectomized animals. with a HLA-A2 peptide derived from the carcinoembryonic
antigen CEA (CAP-1) and irinotecan, 5-fluorouracil, and leucov-
orin after approval by the institutional review committee at the
University of Cologne and the German Drug Administration [56]. All patients signed informed consent. Mean age was 56.2613.1
years; 8 were male and 7 were female; 12 had colon while 3 had
rectal cancer. Mean age for the corresponding healthy controls
was 49.569.3 years with no significant differences in gender and
age. Inclusion criteria required an age of between 18 and 75 years,
positive HLA-A2 status, elevated serum CEA (.5 mg/l) and/or
CEA-positive tumor, untreated metastatic disease, chemotherapy-
free interval after adjuvant treatment of at least 6 months,
Karnofsky index .70%, life expectancy of at least 3 months,
sufficient bone marrow and liver function, HIV and hepatitis B
and C negativity, absence of central nervous system metastases, no
immunosuppressant medication, and negative pregnancy test. Isolation of CD4+CD25high and CD4+CD252 T cells
hi h For functional analysis, CD4+CD25high T cells were purified
from PBMC. Briefly, CD4 MACS Beads (Miltenyi Biotec) were
used for isolation of CD4+ T cells [28,46]. After staining with
CD25-PE, and CD4-APC (BDPharMingen) according to the
manufacturer’s recommendations, CD4+CD25high T cells were
purified using a FACSDiVa Cell Sorter (BDBiosciences) and used IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Other mechanisms
such as conversion of differentiated conventional T cells into Treg
cells might also contribute to the overall expansion of Treg cells in
cancer patients as well the preferential egress of activated Treg cell
from the tumor microenvironment into the peripheral blood and
will have to be addressed when targeting Treg cells [5]. IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Figure 6. IL-2 administration leads to an expansion of ‘‘naı¨ve’’ CD4+CD25highFOXP3+ Treg cells in C57BL/6 mice. (A) Flow cytometric
analysis of CD4 and FOXP3 expression in CD4+ T cells from untreated as well as IL-2-treated animals in spleen, peripheral and mesenteric lymph
nodes, peripheral blood, thymus, and liver. Significant differences (p,0.05, Student’s t test) between untreated and IL-2 treated animals are marked
by an asterisk (*). (B) Analysis of ‘‘naı¨ve’’ CD45RBhigh CD4+CD25highFOXP3+ Treg cells in spleen, peripheral and mesenteric lymph nodes, peripheral
blood, thymus, and liver. Significant differences (p,0.05, Student’s t test) between untreated and IL-2 treated animals are marked by an asterisk (*). Similar results were obtained in two independent experiments. (C) CD45RB+CD44lowCD62L+ naı¨ve CD4+CD252 Tconv and CD4+CD25high Treg cells were
isolated by flow cytometric cell sorting and assessed for TREC content. Genomic DNA of sorted subsets was isolated, and the number of TREC was
determined by quantitative real-time PCR (n = 3, p,0.05, Student’s t test). Error bars represent SD. Similar results were obtained in three independent
experiments. doi:10.1371/journal.pone.0030422.g006 Figure 6. IL-2 administration leads to an expansion of ‘‘naı¨ve’’ CD4+CD25highFOXP3+ Treg cells in C57BL/6 mice. (A) Flow cytometric
analysis of CD4 and FOXP3 expression in CD4+ T cells from untreated as well as IL-2-treated animals in spleen, peripheral and mesenteric lymph
nodes, peripheral blood, thymus, and liver. Significant differences (p,0.05, Student’s t test) between untreated and IL-2 treated animals are marked
by an asterisk (*). (B) Analysis of ‘‘naı¨ve’’ CD45RBhigh CD4+CD25highFOXP3+ Treg cells in spleen, peripheral and mesenteric lymph nodes, peripheral
blood, thymus, and liver. Significant differences (p,0.05, Student’s t test) between untreated and IL-2 treated animals are marked by an asterisk (*). Similar results were obtained in two independent experiments. (C) CD45RB+CD44lowCD62L+ naı¨ve CD4+CD252 Tconv and CD4+CD25high Treg cells were
isolated by flow cytometric cell sorting and assessed for TREC content. Genomic DNA of sorted subsets was isolated, and the number of TREC was
determined by quantitative real-time PCR (n = 3, p,0.05, Student’s t test). Error bars represent SD. Similar results were obtained in three independent
experiments. doi:10.1371/journal.pone.0030422.g006 January 2012 | Volume 7 | Issue 1 | e30422 PLoS ONE | www.plosone.org 8 Antibodies and FACS analysis Phenotype of T cells was defined by flow cytometry using the
following antibodies: CD4-FITC, CD45RA-PE-Cy-5, CD4-APC,
CD4-APC-Cy-7 (all from Becton Dickinson PharMingen), CD25-
PE-Cy7 (BDBiosciences), CCR7-FITC (R&D Systems) as well as
the corresponding isotype control antibodies (BDPharMingen). Intracellular staining was performed with the following antibodies:
FOXP3-PE or APC (eBioscience), GITR-FITC (R&D Systems),
CTLA4-PE or with the appropriate isotype controls (BDPharMin-
gen) [28,46]. Cells were stained according to the manufacturer’s
recommendations. g
Taken together, we demonstrate an in vivo expansion of fully
functional CD4+CD25highFOXP3+ Treg cells in colorectal cancer
patients due to an increase in naı¨ve Treg cells with an increased
TREC content. Moreover, naı¨ve Treg cells with a further increase of
TREC are expanded post IL-2 treatment clearly pointing to an
increased thymic output of naı¨ve Treg cells after IL-2 therapy, a
mechanism also observed in mice in vivo post IL-2 treatment. This
expansion of Treg cells post administration of IL-2 can potentially
hinder an immune response towards co-administered anti-tumor
reagents and should therefore be avoided when planning new
cancer immunotherapy protocols. The existence of different
mechanisms of expansion of Treg cells (thymic vs. peripheral
expansion and conversion) highlights the complexity of regulation of
these cells and cautions the use of simple strategies targeting these
highly regulated cells in future cancer immunotherapy approaches. Samples were acquired on a FACSCanto and analyzed with
FlowJo software (TreeStar Inc.). Frequencies of CD4+CD25high-
FOXP3+ T cells are shown as percent values of CD4+ T cells. Isolation of CD4+CD25high and CD4+CD252 T cells
For functional analysis, CD4+CD25high T cells were purified
from PBMC. Briefly, CD4 MACS Beads (Miltenyi Biotec) were
used for isolation of CD4+ T cells [28,46]. After staining with
CD25-PE, and CD4-APC (BDPharMingen) according to the
manufacturer’s recommendations, CD4+CD25high T cells were
purified using a FACSDiVa Cell Sorter (BDBiosciences) and used Materials and Methods Patients and clinical parameters 15 HLA-A2+ patients with primary metastatic colorectal cancer
were enrolled in this Phase I/II combined chemoimmunotherapy PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 9 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Table 1. patient characteristics. Patient ID
Sex
Age(y)
Primary
tumor
Sites of
metastases
Primary vaccine
Boost
time point of
2nd analysis
Clinical
response
FFTF
(mo)
Survival
(mo)
P01
M
66
Colon
Liver
CAP-1+GM-CSF+IL-2
CAP-1+IL-2
after 3 cycles
PR
15
34
P02
F
44
Colon
Liver
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
SD
5
21
P03
F
70
Colon
Liver
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
SD
12
32
P04
F
32
Colon
Liver, spleen,
ovaries, pelvis,
peritoneum
DC-CAP-1+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
CR
12
26
P05
F
60
Colon
Liver
CAP-1+IL-2
CAP-1+IL-2
after 3 cycles
SD
11
15
P06
M
57
Rectum
Lung
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
SD
7
17
P07
M
44
Rectum
Liver
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
CR
12
28
P08
M
64
Colon
Liver, lung
DC-CAP-1+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
SD
10
28
P09
F
43
Rectum
Liver, bone,
pararectal,
paraaortal
lymphnodes
CAP-1+GM-CSF+IL-2
CAP-1+GM-CSF+IL-2
after 3 cycles
PD
6
13
P10
M
61
Colon
Liver
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
CR
9
11
P11
M
62
Colon
Peritoneum
CAP-1+IL-2
CAP-1+IL-2
after 3 cycles
CR
13
21
P12
M
55
Colon
Liver (primary
resection)
CAP-1+dSLIM+IL-2
CAP-1+dSLIM+IL-2
after 3 cycles
CR
24
24
P13
F
38
Colon
Liver
DC-CAP-1+IL-2
CAP-1+dSLIM+IL-2
after 1 cycle
PD
3
10
P14
F
72
Colon
Liver, spleen,
lung,
mediastinum
CAP-1+IL-2
CAP-1+IL-2
after 0.5 cycle
PD
2
2
P15
M
75
Colon
Liver
CAP-1+IL-2
CAP-1+IL-2
after 0.5 cycle
PD
1
6
doi:10.1371/journal.pone.0030422.t001 using a FACSDiVa Cell Sorter and used for either functional
characterization or assessment of TREC levels. for functional characterization. The CD4+CD252 T cells isolated
from healthy individuals were used as effectors to assess Treg cell
function independently of potential defects of conventional CD4+
T cells from colorectal cancer patients [28,46]. The cells were re-
analyzed for FOXP3 expression after sorting and routinely showed
.95% purity. DNA was isolated from purified CD4+CD252, CD4+CD25low
and CD4+CD25high Tnaı¨ve, TCM, and TEM cells respectively using
a DNA Isolation Kit (Roche Diagnostics) following the manufac-
turer’s instructions. Relative TREC levels were determined using real-time PCR with
a LightCycler (Roche Diagnostics) based on specific primers and
general fluorescence detection with SYBR Green. Analysis of IL-2 effects on murine Treg cells Analysis of IL 2 effects on murine Treg cells
Female C57BL/6 mice of 7 weeks were obtained from Elevage
Janvier (France) and maintained in our animal facility. In vivo
experiments were approved by the Animal Care Commission of
Nord-Rhein-Westfalia, Germany (TVZ 9.93.2.10.31.07.089). Af-
ter either treatment with human IL-2 (16105 IU/mouse/day,
Proleukin) i.p. or PBS as control for 10 days [57], mice were
sacrificed and their spleens, thymi, liver, and LN removed. Single-
cell suspensions were prepared and stained for flow cytometric
analysis. Antibodies used for staining were CD4-PE-Cy7, CD8a-
Pacific Blue, CD45RB-APC-Cy7, CD25-Alexa 647, and FOXP3-
Alexa 488 as well as appropriate isotype controls (all from
BDBiosciences or BioLegend). Samples were acquired on a
FACSCantoII and analyzed with FlowJo software. Frequencies
of CD4+CD25highFOXP3+ Treg cells are shown as percent values
of CD4+ T cells. Materials and Methods All PCR were
performed using LightCycler-FastStart DNA Master SYBR Green I
kit (Roche Diagnostics). All samples were studied in duplicate
reactions using the human TREC primer kit (Search-LC). The
number of TREC molecules in the sample was calculated as
number of copies per 104 cells (detection limit $10 molecules). Assessment of inhibitory function To assess the suppressive activity of Treg cells, 5,6-Carboxy-
fluorescin-Diacetat-Succinimidyl-Ester
(CFSE,
Sigma-Aldrich)
stained CD4+CD252 T cells (56104/well) were stimulated with
magnetic beads (Dynal Biotech) coated with 5% anti-CD3
(OKT3), 14% anti-CD28 (9.3) and 81% anti-MHC class I (W6/
32) at a ratio of 3:1 (cells:beads) in X-VIVO 15 supplemented with
10% fetal calf serum, 100 U/ml penicillin/streptomycin and
2 mM glutamine (all from Invitrogen). PKH-26 (Sigma-Aldrich)-
labelled allogeneic CD4+CD25high T cells or naive or memory
CD4+CD25high T cells activated for 20 hours with 10 U/ml IL-2
(ProleukinH, Chiron) and 0.5 mg/ml anti-CD3 mAb in X-VIVO
15 (BioWhittakker) were added at a 1:1 ratio to the culture and
proliferation of CD4+CD252 T cells was determined by assessing
CFSE dilution after four days of culture [28]. References 10. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, et al. (2011) Tumour-
infiltrating regulatory T cells stimulate mammary cancer metastasis through
RANKL-RANK signalling. Nature 470: 548–553. g
y
(
)
g
y
T cells in the human immune system. Nature reviews Immunology 10: 490–500. 2. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory
T cells in immunological tolerance to self and non-self. Nat Immunol 6:
345–352. 2. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory
T cells in immunological tolerance to self and non-self. Nat Immunol 6:
345–352. 11. Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, et al. (2009) Regulation of
the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer cell 15: 114–123. 3. Shevach EM (2001) Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 193: F41–46. 12. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, et al. (2004)
CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to
cyclophosphamide which allows immunotherapy of established tumors to be
curative. Eur J Immunol 34: 336–344. 4. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, et al. (2001) Human
anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and
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removing CD25+CD4+ T cells: a common basis between tumor immunity and
autoimmunity. J Immunol 163: 5211–5218. 5. Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, et al. (2006) Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid
turnover of memory populations in vivo. J Clin Invest 116: 2423–2433. 14. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108: 804–811. 14. Beyer M, Schultze JL (2006) Regulatory T cells 6. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, et al. (2000)
Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells
constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp
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target in malignancy. Curr Oncol Rep 10: 130–136. 16. Beyer M, Schultze JL (2009) Regulatory T cells: major players in the tumor
microenvironment. Current pharmaceutical design 15: 1879–1892. 7. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, et al. )
(TIF) Figure S2
Therapy schedule. Patients were first randomized
to receive CAP-1 and IL-2 with different adjuvants (dSLIM, GM-
CSF, or none). Subsequently, they were randomized to receive
their first vaccination with or without pulsed autologous dendritic
cells. Vaccinations (V) and chemotherapy (Chemo) were given in
an alternating schedule, starting with two vaccinations. (TIF) Figure S2
Therapy schedule. Patients were first randomized
to receive CAP-1 and IL-2 with different adjuvants (dSLIM, GM-
CSF, or none). Subsequently, they were randomized to receive
their first vaccination with or without pulsed autologous dendritic
cells. Vaccinations (V) and chemotherapy (Chemo) were given in
an alternating schedule, starting with two vaccinations. (TIF) Acknowledgments We are indebted to our patients for their commitment to this study. We
thank I. Bu¨chmann, A. Dolf, and P. Wurst for excellent technical
assistance, and J. Oldenburg and the Division of Transfusion Medicine for
providing us with blood samples from healthy individuals. We thank Dr. Yu-Waye Chu (National Institutes of Health) for providing the TREC
protocol and standards for murine TRECs and CD8b. Author Contributions Conceived and designed the experiments: MB JLS. Performed the
experiments: MB BS MRW BA TG EE SC AL JLS. Analyzed the data:
MB JLS. Contributed reagents/materials/analysis tools: EE PAK. Wrote
the paper: MB BS MRW BA TG SC AL JLS EE PAK. Statistical analysis Comparison between paired or unpaired groups was performed
using the appropriate Student’s t-test. A p-value,0.05 was defined
as statistically significant. All statistical analyses were performed
using the SPSS statistical software package (SPSS 19, SPSS Inc.). Figures were created using SigmaPlot 12.0 (Systat Software Inc). Briefly, CD4 MACS Beads were used for isolation of murine
CD4+ T cells from the spleen after treatment with IL-2 as
described above [46]. After staining with CD44-FITC, CD62L-
PE, CD25-Alexa 647, CD45RB-APC-Cy-7, CD8a-PE-Cy-7, and
CD4-Alexa 405, naı¨ve CD45RB+CD44lowCD62L+ conventional
CD4+CD252 T cells as well as naı¨ve CD4+CD25+ Treg cells were
purified using a FACSDiVa Cell Sorter and used for assessment of
TREC levels. Supporting Information Figure S1
CTLA4 and GITR expression in naı¨ve Treg
cells. Frequency of CTLA4 (left) and GITR (right) expressing
naı¨ve CCR7+CD45RA+ CD4+CD25highFOXP3+ Treg cells in
healthy donors (white) and colorectal cancer patients before (light
grey) and after IL-2 administration (dark grey) before treatment. Shown here are median, 25th and 75th percentile (box), 10th and
90th percentile (whiskers) and outliers (dots), (*, p,0.05, Student’s t
test). (TIF) Murine dRec-yJa TRECs were determined using real-time
quantitative polymerase chain reaction (PCR) as described before
[58]. Briefly, cells were centrifuged and the pellet frozen at 280uC
until analysis. DNA was isolated from purified naı¨ve CD4+CD252
Tconv and naı¨ve CD4+CD25high Treg cells using a DNA Isolation
Kit (Roche Diagnostics) following the manufacturer’s instructions. Relative TREC levels were determined using real-time PCR
containing mdRec primer (59-GGGCACACAGCAGCTGTG),
yJa
primer
(59-GCAGGTTTTTGTAAAGGTGCTCA),
and
mdRec-yJa
fluorescent
probe
(59-FAM-CACAAGCACCTG-
CACCCTGTGCA-TAMRA-39). Lysates were separately subject-
ed to amplification of the single-copy CD8b chain gene using a
CD8b forward primer (59-CAGGACCCCAAGGACAAGTACT-
39), CD8b reverse primer (59-CACTTTCACCATACAAAA-
CTCCTTTG-39), and CD8b probe (59-FAMTGAGTTCCT-
GGCCTCCTGGAGTTCTTC-TAMRA-39). Reactions
con-
tained 0.5 mM of each primer, 0.3 mM fluorescent probe, and
Platinum Quantitative PCR Supermix-UDG (Invitrogen) Ampli-
fications were performed in triplicate on an LightCycler 480 II
(Roche Diagnostics). Amplification conditions were 50uC for
2 minutes, 95uC for 5 minutes, then 40 cycles of 95uC for
15 seconds, and 60uC for 1 minute. Standards for murine TRECs
(mdREC-yJa) and CD8b were provided by Dr. Y.-W. Chu
(Center for Cancer Research, National Institutes of Health). Standard curves were generated as described before [58]. TREC
frequency (TREC molecules per 10 000 cells) was determined by
normalizing the number of TRECs amplified in the real-time PCR
reaction to the number of amplified CD8b molecules. y
gy
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T cells in immunological tolerance to self and non-self. Nat Immunol 6:
345–352. Isolation of CD4+CD25high T-cell subpopulations for
assessment of T-cell receptor excision circles and
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cells [46]. After staining with CCR7-FITC, CD25-PE, CD45RA-
PE-Cy-5, and CD4-APC, CD4+CD25high T cells and the
respective T cell subsets, CCR7+CD45RA+ Tnaı¨ve, CCR7+
CD45RA2 TCM, and CCR72CD45RA2 TEM cells were purified PLoS ONE | www.plosone.org January 2012 | Volume 7 | Issue 1 | e30422 10 IL-2 Induced Naı¨ve Treg Cell Expansion in CRC IL-2 Induced Naı¨ve Treg Cell Expansion in CRC Isolation of CD4+CD45RB+CD44lowCD62L+ naı¨ve murine
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Stevens and Golebiowska Asian Journal of Gambling Issues and Public Health 2013, 3:1
http://www.ajgiph.com/content/3/1/1
RESEARCH ARTICLE
Open Access
Gambling problems amongst the CALD
population of Australia: hidden, visible or not a
problem?
Matthew Stevens1,2* and Kate Golebiowska1
* Correspondence: matthew.
stevens@menzies.edu.au
1
Charles Darwin University, The
Northern Institute, Darwin, Australia
2
Charles Darwin University, Menzies
School of Health Research, Darwin,
Australia
Abstract
There have been mixed research results when studying gambling problems in
Culturally and Linguistically Diverse (CALD) communities in Australia and
internationally. This study tests the feasibility of using nationally representative
General Social Surveys for examining trends and patterns in gambling problems and
other life stressors amongst the Australian CALD population. Two surveys were
analysed to determine whether the CALD population experienced gambling
problems and other life stressors at different levels to the non-CALD population, and
to identify, using multivariable models, whether CALD related variables showed
evidence of an association with reported gambling problems after adjustment for
other covariates. There was no evidence that 2002 estimates of gambling problems
were different in CALD and non-CALD populations. In 2006, there was evidence that
gambling problems were lower in the CALD population compared with the nonCALD population (1.3% cf. 3.5%). In 2002 multivariable models there was no evidence
of an association between CALD status or related variables with gambling problems,
after adjustment for other variables. In 2006 multivariable models, there was
evidence of an association between being the CALD population (protective), and
being born in Oceania or New Zealand (risk) with gambling problems, after
adjustment for other variables.
Keywords: Culturally and linguistically diverse, Gambling, Population surveys,
Ethnicity
Background
Australia has an ethnically diverse population, with nearly 25% of the population being
born overseas (Department of Immigration and Citizenship 2009). Within this group,
the term ‘Culturally and Linguistically Diverse’ (CALD), has been used to describe
people born overseas who do not speak English at home. The make-up of this group
within Australia has changed markedly since early immigration waves post World War
II, with early waves of immigrants predominantly coming from the United Kingdom
and European countries and an increase in intake from Asian countries from the
1980’s onwards (Australian Bureau of Statistics 2008; Stevens et al. 2010).
Grants of permanent residence visas in Australia are made in three categories: skill
(comprises business), family and humanitarian. Skilled and business migrants have
been sought by successive Australian Governments predominantly since the 1980s to
© 2013 Stevens and Golebiowska; licensee Springer. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Stevens and Golebiowska Asian Journal of Gambling Issues and Public Health 2013, 3:1
http://www.ajgiph.com/content/3/1/1
contribute to the economic growth and development of the country. Their proportionate share has been increasing and in 2007–08 it represented nearly 70% of the annual
migration program in Australia. The Australian Government periodically adjusts skilled
entry criteria to select higher calibre migrants and match economic conditions. For example, in 2007 and 2010, it tightened entry requirements for skilled visas with regards
to the types of skills, level of education and proficiency in English language (Minister
for Immigration and Citizenship 2007, 2010), leading to more educated immigrants
compared with past decades (Department of Immigration and Citizenship 2009). The
policy changes and economic conditions between 1999–2000 and 2008–09, led to a
more than doubling in the number of skilled and business visas from 38,000 to
134,000, respectively (Markus et al. 2009). The family stream group of migrants are not
subject to skilled entry criteria and many of these visa holders are women from various
Asian countries and the proportionate share of this stream has fallen from 42% (2000–
01) to 30% (2008–09) as the skilled and business stream increased its share (Department of Immigration and Citizenship 2009).
Australia has a long history of re-settling refugees. This is the smallest migration
stream, which over the decade of 1999–2000 and 2008–09 has fluctuated between
10,000 and 14,000 annually. Around half of these places go to refugees selected from
refugee camps (Markus, et al. 2009). Currently, humanitarian entrants largely come
from the African, Asian and Middle East countries. Their human capital varies greatly
from no schooling at all to trades and professional qualifications but no recognition of
qualifications and common English language difficulties mean it is some time before
this group can become financially self-sufficient. Humanitarian and family entrants are
entitled to free English language tuition upon arrival to enable them to quickly participate in economic and social life of Australia. All in all, the composition of the Australian immigration intake is socio-economically and culturally very diverse, includes
native and non-native English speakers as well as those who will learn it only in
Australia.
Research on problem gambling with CALD populations has tended to focus on specific ethnic communities (Loo et al. 2008), or on particular geographic locations
(Brozovic-Basic 2005; Cultural Partners Australia 2000; The Ethnic Communities'
Council of New South Wales 1999) or both (Chui and O'Connor 2006). The research
in Australia and from other English speaking countries has found that non-Caucasian
ethnicity is a risk factor for gambling related harm (Clarke et al. 2007; Gibbs Van
Brunschot 2000; Raylu and Oei 2004). Factors found to be conducive to gambling may
be a) uniquely related to the minority status experience and b) to more universal
circumstances (e.g. low income status) relevant to gambling among ethnic groups and
the general community alike. Three cultural variables, which have been considered in
the uptake and maintenance of gambling, are: a) adherence to cultural values; b) acculturation, and c) culturally-determined help seeking behaviours (Oei and Raylu 2009;
Raylu and Oei 2004). These three factors have also been found to be important in the
initiation of mental health and drug and alcohol-related issues (De La Rosa et al. 2000;
Escobar et al. 2000; Loue 1998; Westermeyer 1999).
Cultural norms, practices and beliefs related to gambling can be passed to an individual in different ways. The social learning perspective, which proposes that such norms
and beliefs are socially transmitted is often invoked (Bandura 1986). For example, the
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transfer can occur via the behaviour of the immediate family members and/or other
respected community members who are perceived as role models. It can also occur if
role models show their approval of gambling, or share an oral or written history which
accepts it (Raylu and Oei 2004). Studies of the role of familial influence on gambling
focus upon parental/caregiver gambling and they have found correlations between
problem and/or pathological gambling of the offspring and parents’ gambling
(Ladouceur and Mireault 1988; Lesieur et al. 1991; Lesieur and Heineman 1988; Oei
and Raylu 2009; Teo et al. 2007; Toneatto and Brennan 2002).
So, while there have been numerous small-scale, geographically-contained studies
across Australia, there is a lack of data that are comparable through time that allow for
identification of gambling problems at the national level for the CALD population. The
Australia Bureau of Statistics (ABS) conducts the General Social Survey (GSS) 4-yearly,
which collects a broad range of information from demographic, social, cultural, economic and emotional and social well-being (ESWB) domains including information on
gambling problems. However, the feasibility of using this data set to measure gambling
problems for Australia’s CALD population has not been tested. The advantage of being
able to use information collected from national surveys comes from the use of a consistent methodology to measure gambling problems geographically and over time.
To test the feasibility of using the routinely collected nationally representative surveys
for measuring gambling problems amongst the CALD population, data access was
obtained to analyse the 2002 and 2006 GSS’s. This allowed for a range of important
demographic, socioeconomic, and social connectedness variables to be included in the
analyses of reported gambling problems amongst the CALD population. Specifically the
research addresses the following questions:
(1) Does the CALD population experience life stressors, including gambling
problems, at different levels to the non-CALD population in Australia?
(2) Are CALD status and related variables associated with reported gambling
problems after adjustment for other variables in multivariable models?
(3) Is the GSS a suitable data set to measure gambling problems amongst the CALD
population?
Methods
Data sources and survey design
Full details of sample design, collection methods, and data quality for the General Social Surveys (GSSs) have been reported elsewhere (Australian Bureau of Statistics 2003,
2007) and a summary is therefore provided here. The GSS is a general population survey conducted every four years and forms part of the ABS social survey program. The
2002 and 2006 GSSs employed a stratified multistage area sample, with a scope that
included all people aged 15 years and over in non-remote areas of Australia, with all
data collected in face-to-face interviews. The map in Figure 1 provides the boundaries
of the remoteness structure used in Australian Bureau of Statistics (ABS) surveys in
Australia. Non-remote areas include major cities and inner and outer regional areas,
and cover over 98% of Australia’s total population. The survey goes through a process
of testing questions, before completing a full dress-rehearsal of all survey processes.
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Figure 1 ABS Australian Standard Geographical Classification remoteness structure.
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Accessibility
CALD, demographic, SES
Social networks
Gambling
problems
Acculturation
Norms & beliefs: luck, control
Availability
Figure 2 Framework conceptualising pathways to gambling related problems.
For the current analyses, only data from people aged 18 years and over were used because respondents under the age of 18 years were not administered the module
containing the question on gambling problems. Confidentialised Unit Record Files
(CURFs) or data files for the GSSs were accessed via the ABS Remote Access Data
Laboratory or RADL (Australian Bureau of Statistics 2006). This is a web-based interface that allows the user to enter code, which is then processed on site at the ABS, to
ensure confidentiality restrictions associated with the 1905 Census and Statistics Act
for Australia are adhered to. All ABS survey data is de-identified and ethics approval
was not required as the analyses constitute secondary use of data.
Socio-environmental pathways model to gambling problems
Figure 2 shows a conceptual framework representing pathways to gambling problems
(from the outside square through to the middle square). Starting from the outside moving in, if gambling opportunities through accessibility or availability are not there then
it is not possible to develop problems with gambling (Nerilee Hing and Haw 2009;
Moore and Ohtsuka 1997). If gambling is accessible and available then factors relating
to being a member of the CALD population along with other socio-demographic and
socioeconomic factors may indicate higher (or lower) risk associated with developing
gambling related problems (Stevens et al. 2010; Teo, et al. 2007; Volberg 1994). For example, young men, low or high income, and labour force status have all been shown to
be associated with increased levels of problem gambling (Young and Stevens 2009).
Also in this square are social norms and personal beliefs (e.g. luck and control over
outcomes) which have been shown to have bearing on the risk of problem gambling
(Chantal and Vallerand 1996; Nerilee Hing and Breen 2001; Tanasornnarong et al.
2004; Wohl and Enzle 2002; Wohl et al. 2005). For example, research suggests that
gamblers who learnt to play from their parents are at higher risk due to the normalisation of gambling as an activity (even when it is problematic) (Breen et al. 2010). The
box surrounding ‘gambling problems’ contains factors associated with social networks
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and acculturation. These factors can be either protective (Beattie et al. 1999; Stanton
2004) or risk factors (Kidman 2004) in the development of gambling problems.
Measurement of gambling problems and the Negative Life Events Scale (NLES)
The NLES is a regular survey module used by the ABS in social and health surveys,
and is designed to measure individuals’ emotional and social wellbeing (ESWB) by
identifying life stressors that individuals are exposed to. The NLES module was
developed for use with the Aboriginal and Torres Strait Islander populations, with the
specific purpose of comparing ESWB between the Indigenous and non-Indigenous
populations of Australia (Australian Bureau of Statistics 2004). The NLES asks
respondents have any of these things [list of ‘stressors’ or ‘negative life events’] been a
problem for you or your family or friends during the last year? Respondents then answer ‘yes’ or ‘no’ to a list of 12 ‘stressors’ or ‘negative life events’, which are: gambling
problem; divorce or separation; death of family member or close friend; serious illness
or disability; serious accident; alcohol or drug related problems; not able to get a job;
lost job, made redundant, sacked; witness to violence; victim of abuse or violent crime;
trouble with the police; and mental illness.
It is clear from the wording of the NLES question that the instrument does not measure problem gambling prevalence or prevalence for any of the items. It asks
respondents if gambling has . . .been a problem for you, your family or close friends during the last year. Therefore, the NLES gambling problem item measures the reach or
extent of gambling problems throughout peoples’ social and family networks and is not
an individual measure of problem gambling. This broader conceptualisation of
gambling-related harm is consistent with the Australian definition of problem gambling
which states that “problem gambling is characterised by difficulties in limiting money
and/or time spent on gambling which leads to adverse consequences for the gambler,
others, or for the communities” (Neal et al. 2005, p 126).
Explanatory variables
There is no single variable contained in the GSS indicating a respondents’ CALD status
and therefore it had to be derived from related variables. Two variables, region of birth
and main language spoken at home were used to generate a CALD status variable that
indicated whether the respondent was both born overseas and did not speak English at
home. Other variables related to CALD status were main language spoken at home,
level in spoken English, region of birth, and year of arrival in Australia. The GSS also
contains a large number of variables from demographic (age sex, location, marital status, crowding, household and family type), socioeconomic status (tenure type, income,
education), financial stress (ran out of money, raise money in emergency), social connectedness (participation in a range of social and sporting activities and events) and
health (self-reported health) related domains that are used in the analyses.
Statistical analysis
The distribution of CALD related social connectedness variables, and estimates of NLES
items are given for the 2002 and 2006 surveys. Statistical differences were determined by
dividing the absolute difference between the estimates by the standard error of the
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pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
difference ( SE1 2 þ SE2 2 ), where SE1 and SE2 are the standard errors of the estimates
being compared respectively, to obtain a test statistic for comparison with Student’s
t-distribution. Statistical differences were determined for CALD related variables between
the 2002 and 2006 CALD populations; for social connectedness variables between the
2006 CALD and non-CALD populations; and for NLES items between 2002 and 2006
CALD populations, and between CALD and non-CALD populations for 2002 and 2006.
The outcome variable, reported gambling problem is dichotomous and therefore well
suited to logistic regression modelling. Separate models for the CALD and non-CALD
populations were unable to be generated due to the small percentage of the CALD
population reporting gambling problems and the relatively small size of this subpopulation group. Therefore models for the total population were first generated and
then CALD related variables were substituted into final models to assess if the CALD
status or any related variables showed an independent association with reported gambling problems after controlling for other variables.
First, unadjusted associations between reported gambling problem and all explanatory
variables, including those relating to CALD status (region of birth, year of arrival, language region, proficiency in English and the CALD status variable) were assessed.
Explanatory variables (but not CALD related variables) showing a significant (p ≤ 0.05)
association with gambling problems were then assessed for collinearity to ensure the
assumptions associated with logistic regression modelling were adhered to. Where two
or more explanatory variables were significantly correlated, these were first entered into
a separate model and variable(s) remaining significant were retained for the next stage.
Next, significant explanatory variables were entered simultaneously into a multivariable
logistic regression model and backward elimination carried out with removal of
variables set at p > 0.05. Lastly, CALD-related variables were added to models to determine if any had an adjustyed association with reported gambling problems.
All analyses were carried out using Stata v9.2 accessed via the ABS Remote Access
Data Laboratory or RADL (Australian Bureau of Statistics 2006) using the expanded
confidentialised unit record files (CURF) for the 2002 and 2006 GSS’s. Data was
weighted to the Estimated Resident Population for non-remote Australia at the time of
the survey, and survey replicate method (SVR) set of commands was used to analyse
data (Winter 2008). All confidence intervals were calculated using the Jack Knife (jk1)
method and adjusted for the survey design.
Results
Table 1 shows the distribution of CALD related variables for 2002 and 2006.
Statistically significant differences were present for main language spoken at home
(South European, East European, East Asian) and region of birth (Europe, North/
South/East Asia) and year of arrival (Recent, Long term). In 2002, 13% of Australia’s
adult population were defined as CALD, increasing to 13.3% in 2006.
Table 2 reports estimates for variables related to social connectedness for the 2006
CALD and non-CALD populations, and the 2002 CALD population. All measures of
social connectedness, except participation in church or religious activities, indicated
lower levels of participation for the CALD population in 2006. Social support amongst
the CALD population was also significantly lower than in the non-CALD population.
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Table 1 Distribution of CALD status for the total Australian population and the
distribution of CALD-related variables for the CALD population, 2002 and 2006
Culture and language variables
2002
2006
% (SE)
% (SE)
t-value
p-value
69.4 (0.5)
68.7 (0.7)
0.81
0.416
3.0 (0.2)
3.1 (0.3)
0.28
0.782
14.6 (0.4)
14.8 (0.3)
0.40
0.689
13.0 (0.4)
13.3 (0.5)
0.47
0.639
Non-CALD population
87.0 (0.4)
86.7 (0.5)
0.47
0.639
CALD population
13.0 (0.4)
13.3 (0.5)
0.47
0.639
100.0
100.0
-
-
14,548,869
15,307,066
-
-
North European
4.8 (0.7)
6.3 (0.7)
1.52
0.130
South European
25.6 (1.6)
19.3 (1.6)
2.78
0.005
East European
15.9 (1.0)
11.0 (1.4)
2.85
0.004
SW Asian central
9.4 (1.0)
10.3 (1.4)
0.52
0.601
South Asian
9.2 (0.9)
9.9 (1.0)
0.52
0.603
Total Australian population
CALD: Birthplace and language groups
Non-CALD population
Australia & English at home
Australia & not English at home
Overseas & English at home
CALD population
Overseas & not English at home
CALD status
Total Australian population
N (weighted population)
Total CALD population
Main language spoken at home
SE Asian
11.9 (1.2)
14.9 (1.8)
1.39
0.166
East Asian
18.5 (1.3)
23.3 (1.8)
2.16
0.031
4.6 (0.7)
4.9 (0.9)
0.26
0.792
Other language
Level in spoken English
Very well
35.9 (1.6)
38.4 (2.0)
0.98
0.329
Well
38.7 (1.5)
38.0 (2.1)
0.27
0.786
Not well
23.0 (1.7)
20.8 (1.3)
1.03
0.304
2.4 (0.5)
2.8 (0.6)
0.51
0.609
None
Region of birth
Europe
40.8 (1.8)
32.4 (2.3)
2.88
0.004
Africa/Middle East
11.5 (0.9)
14.1 (1.5)
1.49
0.137
North/South/East Asia
30.9 (1.5)
38.1 (2.1)
2.79
0.005
7.8 (0.9)
8.7 (1.1)
0.63
0.527
India/Central Asia
New Zealand/Oceania
4.5 (0.8)
3.7 (0.8)
0.71
0.480
Americas and not stated
4.6 (0.7)
2.9 (0.7)
1.72
0.086
5.1 (0.8)
16.9 (1.6)
6.60
0.000
1991-2000 (medium)
26.8 (1.8)
23.0 (1.7)
1.53
0.125
Before 1991 (long term)
68.1 (1.9)
60.2 (1.8)
3.02
0.003
100.0
100.0
-
-
1,891,353
2,034,595
-
-
Year of arrival
2001-2006 / 2002 (recent)1
Total CALD population
N (weighted population)
NOTES: Percentages may not add to 100% due to rounding.
Totals for 18 years and over.
1 Recent = 2001–2002 in the 2002 GSS and Recent = 2001–2006 in the 2006 GSS.
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Table 2 Distribution of social connectedness variables by CALD status: 2006 GSS
Social connectedness and
support variables
2006
2006
CALD
Non-CALD
t-value
p-value
CALD
2002
% (SE)
% (SE)
% (SE)
None
42.5 (1.6)
32.0 (0.6)
6.14
0.000
nc
Participated in
57.5 (1.6)
68.0 (0.6)
6.14
0.000
nc
None
69.2 (1.7)
82.0 (0.5)
7.22
0.000
60.4 (1.5)
Participated in religion
30.8 (1.7)
18.0 (0.5)
7.22
0.000
39.6 (1.5)
None
88.3 (1.4)
78.7 (0.5)
6.46
0.000
nc
Attended
11.7 (1.4)
21.3 (0.5)
6.46
0.000
nc
None
81.3 (1.7)
63.4 (0.6)
9.93
0.000
67.4 (1.9)
Participate/attended/watched
18.7 (1.7)
36.6 (0.6)
9.93
0.000
32.6 (1.9)
Social activities last 12 months
Adult education/special interest group
Church or religious
Restaurant/cafe/bar/social club
Sports/physical activity
Arts/craft group
None
93.4 (0.9)
83.7 (0.4)
9.85
0.000
nc
Visited
6.6 (0.9)
16.3 (0.4)
9.85
0.000
nc
None
18.7 (1.3)
10.3 (0.3)
6.30
0.000
20.2 (1.2)
Attended
81.3 (1.3)
89.7 (0.3)
6.30
0.000
79.8 (1.2)
None
73.3 (2.1)
44.0 (0.6)
13.42
0.000
74.3 (1.5)
Attended
26.7 (2.1)
56.0 (0.6)
13.42
0.000
25.7 (1.5)
None
48.6 (2.3)
36.1 (0.8)
5.13
0.000
51.7 (1.5)
Participated
51.4 (2.3)
63.9 (0.8)
5.13
0.000
48.3 (1.5)
Leisure/culture/recreation
Sport/physical activity attendance
Sport/physical activity participation
Support if needed help in last 12 months
No support
13.5 (0.8)
5.6 (0.3)
9.25
0.000
12.1 (1.0)
Support
86.5 (0.8)
94.4 (0.3)
9.25
0.000
87.9 (1.0)
Total
100.0
100.0
100.0
N (weighted population)
2,034,595
13,272,471
1,891,353
Australia
13.3 (0.5)
86.7 (0.5)
13.0 (0.4)
NOTES: Percentages may not add to 100% due to rounding.
nc = Non-comparable due to different wording in questions between 2002 and 2006 surveys.
Figures 3 and 4 present estimates for NLES items by CALD status for the 2002 and
2006 populations’ respectively. In 2002, there was no evidence of a difference between
a report of ‘gambling problem’ in the CALD and non-CALD populations respectively
(3.3% and 3.5%). In 2002, estimates for all NLES items were statistically lower in the
CALD population compared with the non-CALD population, except for ‘gambling
problem’, ‘not able to get a job (no job)’, ‘death of a family member’, and ‘other stressor’.
The most commonly reported stressor for the CALD population was ‘death of family
member’ (17.5%), while for the non-CALD population it was having or living with
someone with a ‘chronic illness’ (24.5%).
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Death family member
Chronic illness
No job
Divorce
Serious accident
Lost job
Gambling problem
Mental illness
Alcohol and/or drugs
Abuse or violent crime
Police trouble
2002 CALD
Witness to violence
2002 non-CALD
Other stressor
0
2
4
6
8
10
12
14
16
18
20
22
24
26
%
Figure 3 NLES item estimates (standard errors) by CALD status for 2002.
Estimates of NLES items in 2006 were all statistically lower for the CALD population
except for ‘not able to get a job’ and ‘other stressor’. Estimates for reported ‘gambling
problem’ were 1.3% and 3.5% for the CALD and non-CALD 2006 populations respectively. Living with someone or having a ‘chronic illness’ was reported most frequently
for the CALD (20.3%) and non-CALD (20.7%) 2006 populations. Comparing the 2002
and 2006 CALD populations, only one NLES item, ‘gambling problem’ showed evidence
of a difference (3.3% to 1.3%).
Table 3 presents unadjusted associations between CALD status and related variables
and reported gambling problems. None of the CALD related variables had a significant
unadjusted association with reported gambling problems in the 2002 survey. When the
variables country of birth and main language spoken at home were combined, the category of being born overseas and speaking English at home, was marginally nonsignificant (p = 0.080) and associated with reduced levels of reported gambling
problems (Odds Ratio (OR) 0.69, 95% confidence interval (CI) 0.51 to 0.93).
In 2006, the CALD status variable and a number of other CALD related variables
showed a significant association with reported gambling problems. Being a member of
the CALD population was significantly associated with reduced levels of reporting gambling problems (OR 0.38, CI 0.21 to 0.68). The variable combining country of birth and
main language spoken at home was also significantly associated with reported gambling
problems, with people not born in Australia and not speaking English at home (equivalent to the CALD population) being associated with reduced reporting of gambling
problems, while people born in Australia and not speaking English at home had marginally non-significant association with increased reporting of gambling problems (OR
2.14, CI 0.95 to 4.85). People who spoke either a southern, south-eastern or eastern
Asian language reported fewer gambling problems (OR 0.14, CI 0.04 to 0.54), though
this was marginally non-significant (p = 0.067), while people not speaking English very
well, also reported significantly (p = 0.015) fewer gambling problems (OR 0.30, CI 0.14
to 0.65). People whose region of birth was from New Zealand or Oceania reported significantly higher levels of gambling problems (OR 2.16, CI 1.04 to 4.49).
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Chronic illness
Death family member
No job
Divorce
Mental illness
Serious accident
Alcohol and/or drugs
Lost job
Police trouble
Gambling problem
Witness to violence
2006 CALD
Abuse or violent crime
2006 non-CALD
Other stressor
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
%
Figure 4 NLES item estimates (standard errors) by CALD status for 2006.
No models are presented for the 2002 survey as no CALD related variables showed a
significant association with reported gambling problems, and multivariable adjusted
models for reported gambling problems have been reported in previous work (Stevens
and Young 2009; Stevens et al. 2010). Table 4 presents multivariable adjusted models
for reported gambling problems from the 2006 survey. Two models are presented that
contain variables related to CALD status which remained significant after adjusting for
all other significant correlates of reported gambling problems. Model 1 includes the
combination variable, country of birth and main language spoken at home, with people
born overseas and not speaking English at home having reduced odds of reporting a
gambling problem (OR 0.53, CI 0.30 to 0.95), after adjustment for state/territory, age,
cash flow problems, social participation, victim of physical or threatened violence and
self-assessed health.
In Model 2, the CALD status variable and the region of birth variable remained significant after adjustment for all other significant correlates of reported gambling
problems (Table 2: Model 2). Being a member of the CALD population was associated
with reduced odds of reporting a gambling problem (OR 0.47, CI 0.26 to 0.85), while
being born in either New Zealand or Oceania was associated with increased odds (OR
2.13, CI 1.00 to 4.52). All other variables reported for Model 1 remained significant in
this model with minimal change in reported odds ratios.
Discussion
Using population surveys to measure gambling problems in the CALD population
This paper presented an analysis of gambling problems in the CALD population using
nationally representative ABS population surveys. The analyses, while providing an
overall picture of reported gambling problems amongst individuals, their family and
close friends for the CALD population of Australia, also raised a number of issues and
questions regarding the utility of current ABS general social survey for this purpose.
While gambling problem estimates for the total CALD population were able to be
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Table 3 Unadjusted associations between reported gambling problems and CALDrelated variables
2002
OR (95% CI)
2006
Reported gambling
problems% (SE)
OR (95% CI)
Reported gambling
problems% (SE)
CALD status
Non-CALD
(p = 0.758) 1.00
3.5 (0.2)
(p = 0.002) 1.00
3.5 (0.3)
CALD
0.94 (0.64-1.39)
3.3 (0.6) 0.38 (0.21-0.68)
1.3 (0.4)
Country of birth and language
Australia and English
at home
(p = 0.080) 1.00
3.6 (0.2)
(p = 0.017) 1.00
3.3 (0.2)
Australia and not
English at home
1.74 (0.85-3.59)
6.1 (1.7)
2.14 (0.95-4.85)
6.7 (2.4)
0.69 (0.51-0.93)
2.5 (0.4)
1.13 (0.71-1.80)
3.7 (0.7)
3.3 (0.6) 0.40 (0.23-0.72)
1.3 (0.4)
Overseas & English
at home
Overseas & not
English at home1
0.92 (0.61-1.38)
Language region2
Australia
(p = 0.252) 1.00
3.4 (0.2)
(p = 0.067) 1.00
3.3 (0.2)
North European
0.52 (0.01-41.2)
1.8 (1.6)
1.72 (0.37-7.97)
5.6 (3.2)
South/East European
South-west Asian
1.39 (0.73-2.64)
4.6 (1.2)
0.94 (0.44-1.97)
3.1 (1.0)
2.41 (1.10-5.27)
7.8 (2.6)
0.65 (0.17-2.45)
2.2 (1.2)
0.5 (0.2)
South/South-east/
East Asian
0.45 (0.19-1.09)
1.6 (0.6) 0.14 (0.04-0.54)
Other language
region
1.70 (0.51-5.71)
5.6 (2.8)
2.87 (0.79-10.4)
9.0 (4.5)
(p = 0.334) 1.00
3.4 (0.2)
(p = 0.015) 1.00
3.3 (0.2)
Proficiency in English
Speaks English at
home
Very well
1.38 (0.84-2.26)
4.6 (0.9)
1.15 (0.64-2.07)
3.8 (1.0)
Well/not well/none
0.92 (0.58-1.46)
3.1 (0.7) 0.30 (0.14-0.65)
1.0 (0.4)
(p = 0.531) 1.00
3.7 (0.2)
Region of birth2
Australia
1.34 (0.91-1.97)
3.4 (0.3)
Europe
0.73 (0.45-1.18)
2.7 (0.6)
0.71 (0.48-1.04)
2.4 (0.4)
Africa/Middle East
0.95 (0.44-2.07)
3.5 (1.3)
0.84 (0.36-1.99)
2.7 (1.1)
North/South/East
Asia
0.53 (0.22-1.28)
2.0 (0.8)
0.61 (0.23-1.60)
2.0 (0.8)
India/North/West
Asia
0.49 (0.04-5.69)
1.9 (1.4)
ne
0.4 (0.4)
New Zealand/
Oceania
1.35 (0.73-2.50)
4.9 (1.3) 2.16 (1.04-4.49)
6.4 (2.0)
Americas/not stated
0.85 (0.18-3.98)
3.2 (1.9)
0.29 (0.02-4.15)
1.0 (0.7)
Born in Australia
(p = 0.354) 1.00
3.7 (0.2)
(p = 0.266) 1.00
3.4 (0.3)
Recent
(2001-2002/2006)
0.64 (0.10-3.95)
2.4 (1.6)
0.66 (0.22-2.02)
2.3 (1.1)
Time in Australia
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Table 3 Unadjusted associations between reported gambling problems and CALDrelated variables (Continued)
Medium
(1991–2000)
0.61 (0.29-1.27)
2.3 (0.7)
1.22 (0.67-2.22)
4.1 (1.1)
Long-term
(before 1991)
0.82 (0.58-1.16)
3.0 (0.5)
0.65 (0.41-1.03)
2.2 (0.4)
NOTES: Bold font indicates statistically significant difference (p ≤ 0.05).
1 This category is the same as the CALD group in the CALD status variable.
2 For 2006 data, the small sample size restricted the bivariate analysis, so odds ratios for Region of Birth are calculated
for individual regions, with the reference category being all other regions including Australia.
ne = Not estimable due to small sample size for this group.
produced, estimates for states and territories could not be produced with adequate accuracy. Further, the GSS is a population level survey, and CALD sub-populations may
not be randomly sampled within the overall sample, due to the patchy nature of their
distribution across Australia (Markus, et al. 2009). The small sample sizes associated
with sub-populations within the CALD population also gave rise to unacceptably high
standard errors associated with estimates of reported gambling problems for CALD
sub-populations. This also limited the power of the statistical models to detect evidence
that gambling problems were occurring at significantly higher (or lower) levels than in
the non-CALD population.
In addition to these survey and statistical problems, the composition of CALD population is not stable over time due to the changing circumstances in which people immigrate to Australia. There are three primary reasons for this:
1) Australia has substantially increased its skilled immigrant intake to lessen the
effects of the skills shortage in the job market;
2) the stability of various countries around the world from which migrants move to
Australia is more often than not in a state of flux, changes substantially over time and is
dependent on circumstances outside of the control of Australian immigration policy; and
3) the heterogeneity within the CALD population, which includes a diverse range of
different cultural attributes (e.g. collectivist cf. individualistic cultures).
Related to this third point, the definition used to identify the CALD population
excludes approximately 18% of the adult population that could also be considered part
of the CALD population (see ‘country of birth’ and ‘language spoken at home’ variable
in Table 1). For example, 3% of the adult population were born in Australia and do not
speak English at home – these people were not included in the CALD population
derived from the survey data used in the analyses. Furthermore, some 13% of adults
were born overseas and spoke English at home, of which an unknown percentage
would be multi-lingual and would very likely exhibit characteristics of the CALD population as defined for the analyses.
The CALD population is not a homogenous population group either, so from a statistical viewpoint it is not a clearly identifiable population. Within the CALD population
there will be people of different religions, from different countries and from differing
circumstances (e.g. skilled migrants, refugees from war torn countries). These factors
lead to the CALD population, as a grouped entity being heterogeneous, which means
that issues that may be occurring for various segments within this population may remain obscured.
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Table 4 Multivariable models for 2006 reported gambling problems
Explanatory variables
Model 1
Model 2
OR (95% CI)
OR (95% CI)
Reported
gambling
problems
% (SE)
Non-CALD
na
(p = 0.015) 1.00
3.5 (0.3)
CALD
na
0.47 (0.26-0.85)
1.3 (0.4)
Australia and English at home
(p = 0.064) 1.00
na
3.3 (0.2)
Australia and not English at home
1.58 (0.64-3.87)
na
6.7 (2.4)
CALD status
Country of birth and language
Overseas and English at home
1.48 (0.92-2.37)
na
3.7 (0.7)
0.53 (0.30-0.95)
na
1.3 (0.4)
Any other country (incl. Australia)
na
(p = 0.049) 1.00
3.1 (0.2)
New Zealand/Oceania
na
2.13 (1.00-4.52)
6.4 (2.0)
Speaks at home
dropped
3.3 (0.2)
Very well
dropped
3.8 (1.0)
Well/not well/none
dropped
1.0 (0.4)
Overseas and not English at home
Region of birth
Proficiency in English language
State/Territory
WA
NSW
1.00
1.00
1.5 (0.4)
2.58 (1.35-4.92)
2.39 (1.27-4.51)
3.3 (0.5)
VIC
2.60 (1.44-4.69)
2.45 (1.34-4.47)
3.2 (0.5)
QLD
2.45 (1.41-4.23)
2.31 (1.32-4.02)
3.6 (0.5)
SA
2.70 (1.54-4.73)
2.66 (1.52-4.67)
3.6 (0.5)
NT
2.65 (1.61-4.36)
2.57 (1.57-4.22)
4.5 (0.6)
ACT
3.26 (1.79-5.92)
3.14 (1.73-5.69)
4.3 (0.5)
TAS
1.93 (1.01-3.71)
1.87 (0.96-3.67)
2.4 (0.4)
1.90 (1.12-3.21)
1.84 (1.12-3.05)
4.0 (0.9)
Age (years)
18-24
25-34
2.83 (1.68-4.75)
2.71 (1.66-4.45)
4.3 (0.6)
35-44
2.70 (1.61-4.53)
2.64 (1.62-4.30)
4.0 (0.4)
45-54
2.59 (1.41-4.73)
2.54 (1.40-4.63)
3.7 (0.7)
1.00
1.00
1.3 (0.2)
1.00
1.00
2.3 (0.2)
55 or more
Cash flow problems
No cash flow problems
One problem
Two or more problems
1.62 (0.97-2.70)
1.63 (0.98-2.72)
4.8 (1.0)
2.39 (1.61-3.55)
2.40 (1.61-3.59)
8.6 (1.0)
1.36 (1.05-1.76)
1.40 (1.08-1.80)
4.0 (0.4)
1.00
1.00
2.7 (0.2)
1.53 (1.03-2.27)
1.55 (1.04-2.31)
4.5 (0.7)
1.00
1.00
2.9 (0.3)
2.94 (2.16-4.01)
2.99 (2.18-4.10)
9.8 (1.0)
Social participation last 12 months
Sport and recreation
No sport and recreation
Social participation last 12 months
Arts and crafts
No arts and crafts
Physical or threatened violence
Victim
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Table 4 Multivariable models for 2006 reported gambling problems (Continued)
Not a victim
1.00
1.00
2.4 (0.2)
Self assessed health
Excellent
Very good
Good
1.00
1.00
2.5 (0.5)
1.13 (0.68-1.88)
1.11 (0.67-1.84)
2.7 (0.3)
1.66 (1.04-2.63)
1.62 (1.02-2.58)
4.0 (0.5)
Fair
1.75 (0.90-3.40)
1.71 (0.89-3.29)
3.5 (0.8)
Poor
1.96 (0.93-4.15)
1.92 (0.92-4.02)
4.1 (1.1)
NOTE: Bold font indicates statistically significant difference (p ≤ 0.05).
In terms of data quality and quantity, the GSSs have limited information on gambling
and associated concepts (e.g. belief in luck, frequency of gambling, game preferences,
and time and money spent gambling). Therefore, the analyses could not relate the
measurement of gambling problems to the gambling habits and potential problems
associated with gambling by members of the CALD population (or the non-CALD
population). However, the strong associations with social connectedness variables did
suggest that the CALD population, as a whole, were less socially connected and
experienced fewer life stressors, including gambling problems, than the non-CALD
population.
The subjective nature of the module that captured information on gambling
problems could also be influencing findings for the CALD population, as this group
may be less reluctant to report problems, even if they do exist (Cultural Perspectives
Pty Ltd 2005). There is no way of testing this possibility, though the ABS goes through
extensive testing for all survey questions used in the General Social Survey (Australian
Bureau of Statistics 2003, 2007). The following section now discusses what could be
ascertained from the analyses of gambling problems amongst the CALD population.
However, the previously noted caveats should be considered in the following
interpretations.
The relationship between CALD status and reported gambling problems
In the analysis of the 2002 survey, there was no evidence of an association between
gambling problems and being a member of the CALD population (or related variables).
However, the 2006 analysis revealed that being a member of the CALD population was
protective of gambling problems and this association remained after controlling for
other variables that showed evidence of an association with reported gambling
problems (State/Territory, age, financial stress, social connectedness, being a victim of
physical or threatened violence, and self-assessed health).
Social connectedness has been shown to be protective against developing problems
associated with gambling in some studies (Escobar, et al. 2000; Tanasornnarong, et al.
2004). However, the 2006 multivariable model for the total population showed that
people who were more likely to be socially connected were more likely to report a gambling problem for themselves or someone in the family and social networks. Importantly, social connectedness variables were lower amongst the CALD population (except
for attending religious activities), as were most estimates of stressors collected as part
Stevens and Golebiowska Asian Journal of Gambling Issues and Public Health 2013, 3:1
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of the NLES. These two findings alone support the notion that the CALD population
as a whole, experience fewer gambling-related problems.
Problems with acculturation for immigrants have also been shown to be associated
with problem gambling in CALD communities (Brozovic-Basic 2005; Scull and
Woolcock 2005), though in the current analysis there was no evidence of an association
between year of arrival and reported gambling problems. The lack of an association between this year of arrival and reported gambling problems is most likely attributable to
heterogeneity within the CALD population and the smaller sample size when crosstabulating variables.
Another possibility explaining the lower levels of gambling problems observed for the
CALD population may relate to actually not being able to speak English and therefore
not attending places where gambling facilities are available. In all variables relating to
social connectedness except for attending church or religious activities (which is protective of problem gambling), the CALD population had lower participation. So, if the
CALD population does not socialise in places where commercial gambling is available,
then language is acting as a barrier to access, therefore limiting their interaction with
gambling activities such as electronic gambling machines (EGMs or ‘pokies’). This may
be important, as EGMs are the most common form of gambling available in places
where people socialise in Australia, and is also the most risky form of gambling, in
terms of developing gambling-related problems (Productivity Commission 2010).
Given the change in migrant intake over the last decade or two, the lower levels of
gambling problems and social connectedness, may be a result of migrants not having
had time to be cultured into EGM gambling and various Australian social activities.
Additionally, many recent immigrants have been encouraged to live in regional
locations (Department of Immigration and Citizenship 2009), and it may be that accessibility to gambling opportunities is limited (physically and socially), leading to lower
levels of participation in gambling. Furthermore, many skilled immigrants come from
middle-eastern countries where Islam is the predominant religion and gambling is specifically forbidden in the Koran (Binde 2005). Overall, this could translate into a lower
percentage of this group developing problems associated with gambling, and lower participation in gambling leads to lower average time and money spent gambling, which in
turn leads to lower levels of problem gambling. This is known as the consumption
model, where the average amount consumed of a product increases with the percentage
of the population that use the product and has been found to hold with alcohol and
gambling (Lund 2006).
The literature reviewed indicates that some CALD sub-populations may have significant problems with gambling, but they are likely to be in the minority in their respective communities (Clarke et al. 2006; Cultural Partners Australia 2000; Loo, et al. 2008).
Additionally, gambling participation rates have also been found to be lower amongst
some CALD sub-populations compared with the general community (Cultural Partners
Australia 2000). Only one sub-population of immigrants to Australia showed a significant association with reported gambling problem, those originating from New Zealand
or Oceania. This finding is consistent with research in New Zealand, where Pacific
Islanders and Maori populations have been found to have levels of problem gambling
up to four times higher than the general New Zealand population after accounting for
age differences (Abbott et al. 2004; Clarke, et al. 2006; Ministry of Health 2009). This
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finding may indicate the need to develop programs and improve services targeting this
population group.
In the current study, the CALD population were more likely to be unemployed and
have lower incomes, which are both risk factors associated with problem gambling
(Hraba and Lee 1995; Shepherd et al. 1998; Young et al. 2008). However, the better
levels of education observed for the CALD population would likely act as a protective
factor with regards to developing gambling problems (Productivity Commission 1999,
2010), and are a by-product of Australia’s recent migration policies that select for
skilled immigrants (Department of Immigration and Citizenship 2009).
An important point is that the definition of the CALD population used for the
current analyses excluded people born in Australia, who did not speak English at home.
There was some evidence to suggest that this group experienced higher levels of gambling problems for themselves, family or friends. The combination variable of birth
country and language spoken at home showed this group to have higher levels of
reported gambling problems in both 2002 (6.1%) and 2006 (6.7%) than the non-CALD
population (3.5% and 3.5% respectively), though these elevated levels were marginally
non-significant. This group represents a small percentage of the Australian adult population, which would partly contribute to the non-significance of the association between
reported gambling problems and being a member of the CALD population. However,
this highlights the subjective nature of ‘CALD’ as a label for use in research and policy.
For example, if this group of non-English speaking Australians were included in the
CALD population used in this analysis, it is possible that the finding that being in the
CALD population is protective may not have been observed. More nuanced studies of
ethnic groups within the CALD population are required to gain a better understanding
of which groups are more at risk of developing gambling problems.
Conclusions
The analysis of gambling problems amongst the CALD population did not support the
notion that gambling problems are occurring at higher levels amongst this group (as a
whole) compared with the non-CALD population in Australia. Consistent with less
reporting of gambling problems, the CALD population had lower reports of other life
stressors measured in the NLES. There was also no evidence to suggest that
immigrants who had settled in Australia at different times were more likely to report
gambling problems. Consistent with the conceptual framework presented earlier,
variables relating to a person’s age, socioeconomic status, and social connectedness
were all related to reports of gambling problems.
Future studies on Australia’s CALD populations will require more targeted
approaches. Perhaps a more effective future strategy is to carefully measure the
characteristics of different immigration waves and/or populations to help identify their
relationships to different forms of gambling behaviour. These characteristics may include, for example, not just ‘country of origin’ and ‘language spoken at home’, but exposure to violence and trauma, social position in their country of origin, English
proficiency and skills/qualifications, refugee status, forms of economic participation in
Australia and level of social integration as well as the usual battery of demographics
measures. First, the specificity of these and other measures are more likely to help
Page 17 of 20
Stevens and Golebiowska Asian Journal of Gambling Issues and Public Health 2013, 3:1
http://www.ajgiph.com/content/3/1/1
identify both risk and protective factors for gambling-related harm and the various
ways that such groups gamble. Second, they may indicate where, when, to what purpose and for what motivation these groups gamble. What is required is more targeted
research identifying which CALD populations are more vulnerable to problem gambling and more generally, identify the risk factors that may predispose people regardless
of their cultural background. Another avenue may involve identifying people (and
CALD sub-populations) within venues, rather than using population based surveys to
monitor trends at a coarse level for CALD population.
Key messages
The 2006 CALD population, as whole, experienced fewer gambling problems than
the non-CALD population of Australia.
The CALD population is a diverse population group that includes people who differ
across important, demographic, socioeconomic, cultural and historical factors.
National social surveys were limited in their usefulness for monitoring trends in
gambling amongst the CALD population and sub-populations in Australia.
More nuanced and targeted research designs are required to identify how gambling
affects different CALD sub-populations.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KG carried out the literature review that informed the introduction and discussion, and was partially responsible for
drafting the introduction. MS carried out all statistical analyses and was responsible for the overall drafting of the
manuscript, including introduction, methods, results and discussion. Both authors read and approved the final
manuscript.
Acknowledgements
We would like to acknowledge two anonymous reviewers for comments on an earlier draft of this paper. We would
also like to thank the Australian Bureau of Statistics for making their survey data available and the respondents who
participated in the surveys.
Funding
Research grant CD/09/148478 from Gambling Research Australia made on behalf of the Ministerial Council on
Gambling
Received: 2 February 2013 Accepted: 2 February 2013
Published: 20 February 2013
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Exploring the interconnectedness of fatigue, depression, anxiety and potential risk and protective factors in cancer patients: a network approach
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Exploring the interconnectedness of fatigue, depression, anxiety and potential risk and
protective factors in cancer patients
Schellekens, Melanie; Wolvers, Marije; Schroevers, Maya; Bootsma, Tom I; Cramer,
Angélique; van der Lee, Marije Citation for published version (APA):
Schellekens, M., Wolvers, M., Schroevers, M., Bootsma, T. I., Cramer, A., & van der Lee, M. (2020). Exploring
the interconnectedness of fatigue, depression, anxiety and potential risk and protective factors in cancer
patients: A network approach. Journal of Behavioral Medicine, 43(4), 553-563. https://doi.org/10.1007/s10865-
019-00084-7 General rights
Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners
and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Tilburg University Tilburg University General rights
Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners
and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Citation for published version (APA):
Schellekens, M., Wolvers, M., Schroevers, M., Bootsma, T. I., Cramer, A., & van der Lee, M. (2020). Exploring
the interconnectedness of fatigue, depression, anxiety and potential risk and protective factors in cancer
patients: A network approach. Journal of Behavioral Medicine, 43(4), 553-563. https://doi.org/10.1007/s10865-
019-00084-7 • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.
• You may not further distribute the material or use it for any profit-making activity or commercial gain Melanie P. J. Schellekens1,2
• Marije D. J. Wolvers1 • Maya J. Schroevers3 • Tom I. Bootsma1,4 •
Ange´lique O. J. Cramer2 • Marije L. van der Lee1 Melanie P. J. Schellekens1,2
• Marije D. J. Wolvers1 • Maya J. Schroevers3 • Tom I. Bootsma1,4 •
Ange´lique O. J. Cramer2 • Marije L. van der Lee1 Received: February 4, 2019 / Accepted: July 17, 2019 / Published online: August 22, 2019
The Author(s) 2019 and stability of the network were explored. Among risk
factors, the relationship of helplessness and physical
symptoms with fatigue stood out as they were stronger than
most other connections in the network. Among protective
factors, illness acceptance was most centrally embedded
within the network, indicating it had more and stronger
connections than most other variables in the network. The
network identified key connections with risk factors
(helplessness, physical symptoms) and a key protective
factor (acceptance) at the group level. Longitudinal studies
should explore these risk and protective factors in indi-
vidual dynamic networks to further investigate their causal
role and the extent to which such networks can inform us
on what treatment would be most suitable for the individual
cancer patient. Abstract Researchers have extensively studied fatigue,
depression and anxiety in cancer patients. Several risk and
protective factors have been identified for these symptoms. As most studies address these constructs, independently
from other symptoms and potential risk and protective
factors, more insight into the complex relationships among
these constructs is needed. This study used the multivariate
network approach to gain a better understanding of how
patients’ symptoms and risk and protective factors (i.e. physical symptoms, social withdrawal, illness cognitions,
goal adjustment and partner support) are interconnected. We used cross-sectional data from a sample of cancer
patients seeking psychological care (n = 342). Using net-
work modelling, the relationships among symptoms of
fatigue, depression and anxiety, and potential risk and
protective factors were explored. Additionally, centrality
(i.e. the number and strength of connections of a construct) Abstract Researchers have extensively studied fatigue,
depression and anxiety in cancer patients. Several risk and
protective factors have been identified for these symptoms. Keywords Cancer Cancer-related fatigue Anxiety
Depression Acceptance Helplessness Coping Network
analysis Keywords Cancer Cancer-related fatigue Anxiety
Depression Acceptance Helplessness Coping Network
analysis Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10865-019-00084-7) contains sup-
plementary material, which is available to authorized users. Receiving a cancer diagnosis has a major impact on
patients’ lives. General rights
C
i h
d • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. f
h
di
ib
h
i l
i f
fi
ki
i i
i l
i • You may not further distribute the material or use it for any profit-making activity or
• You may freely distribute the URL identifying the publication in the public portal Take down policy
f you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately down policy
believe that this document breaches copyright please contact us providing details, and we will remove access to the wo
vestigate your claim. y
this document breaches copyright please contact us providing details, and we will remove access to the work immediate
ur claim Download date: 24. Oct. 2024 J Behav Med (2020) 43:553–563
https://doi.org/10.1007/s10865-019-00084-7 & Melanie P. J. Schellekens
mschellekens@hdi.nl Melanie P. J. Schellekens1,2
• Marije D. J. Wolvers1 • Maya J. Schroevers3 • Tom I. Bootsma1,4 •
Ange´lique O. J. Cramer2 • Marije L. van der Lee1 One of the most prevalent long-term side-
effects of cancer and its treatment is fatigue. Patients who
suffer from severe fatigue also often suffer from symptoms
of depression and/or anxiety (Donovan et al., 2013; Hof-
man et al., 2007; Zhu et al., 2017). In addition, depression
and anxiety often co-occur in cancer patients (Mitchell
et al., 2011). Multiple studies have demonstrated high
correlations among these three problem areas in cancer
patients (Brown & Kroenke, 2009). Agasi-Idenburg et al. (2017) demonstrated that fatigue, depression and anxiety
form a symptom cluster: a set of multiple co-occurring
symptoms that are strongly interrelated (Miaskowski et al.,
2017). Compared with a single symptom, the occurrence of & Melanie P. J. Schellekens
mschellekens@hdi.nl 1
Scientific Research Department, Centre for Psycho-
Oncology, Helen Dowling Institute, Professor Bronkhorstlaan
20, Postbus 80, 3720 AB Bilthoven, The Netherlands 2
Department of Methodology and Statistics, School of Social
and Behavioral Sciences, Tilburg University, Tilburg, The
Netherlands 3
Department of Health Psychology, University Medical Centre
Groningen, University of Groningen, Groningen, The
Netherlands 4
Department of Cultural Studies, School of Humanities and
Digital Sciences, Tilburg University, Tilburg, The
Netherlands 12 3 554 J Behav Med (2020) 43:553–563 symptom clusters appears to worsen patient outcomes as
symptoms interact with one another. Longitudinal studies
provide additional support for this clustering, such that
when patients improve on either fatigue, depression or
anxiety, they are likely to improve on the other problem
areas as well (Zhu et al., 2017). These strong relationships
between fatigue, depressive and anxiety symptoms is not
surprising, given that ‘‘fatigue or loss of energy’’ is one of
the three overlapping criteria (i.e. in addition to concen-
tration problems and sleep problems) between major
depression disorder (MDD) and generalized anxiety dis-
order (GAD), according to the Diagnostic Statistical
Manual version 5 (DSM-5) (APA, 2013). In order to pro-
vide patients with the best possible care, we need a better
understanding of how these symptoms are interconnected
and what kind of risk and protective factors are related to
these symptoms. tions (such as structural equation modeling), most studies
address these constructs, independently from other symp-
toms and potential risk and protective factors. This most
likely is not a reflection of reality. The notion that these
symptoms are likely interrelated in more complex ways
(e.g. fatigue ? concentration problems ? social with-
drawal ? worthlessness ? depressed mood) and can have
a reciprocal relationship (e.g. Melanie P. J. Schellekens1,2
• Marije D. J. Wolvers1 • Maya J. Schroevers3 • Tom I. Bootsma1,4 •
Ange´lique O. J. Cramer2 • Marije L. van der Lee1 fatigue ? depressed mood;
depressed mood ? fatigue) is ignored. To gain a more
comprehensive understanding of the complex nature of
how these symptoms and risk and protective factors are
interconnected, it might be more suitable to take a network
approach. The network approach is a relatively new research area
in clinical psychology and psychiatry, in which a mental
disorder such as MDD is theorized to be the result of the
causal interplay between symptoms in a network structure
(Borsboom, 2017; Borsboom & Cramer, 2013; Cramer
et al., 2010, 2016). A network structure consists of ‘‘nodes’’
representing the selected variables and ‘‘edges’’ repre-
senting the links that connect two nodes (e.g. regularized
partial correlation coefficients). Thus, rather than viewing
symptoms as manifestations of a common cause (i.e. you
feel depressed because you have MDD), symptoms are
conceptualized as elements of a complex dynamical sys-
tem, in which symptoms are mutually interacting with one
another (Borsboom & Cramer, 2013). That is, a certain
symptom can activate other symptoms in the network (e.g. sleep problems can trigger fatigue and worthlessness,
which in turn can trigger depressed mood and loss of
enjoyment) and, in line with what has long been common
knowledge among clinicians, symptoms can reinforce one
another leading to symptom cycles. Consequently, such a
network of strongly interconnected symptoms can fulfil the
criteria of MDD (Borsboom, 2017). To date, the network
approach has contributed to several advancements in psy-
chopathology research [for a review of hallmark empirical
insights, see Fried et al., 2017]. y p
A
relevant
and
well-known
theory
to
understand
patients’ adaptation to cancer and their functioning is the
stress-coping model. The model predicts that a diagnosis of
cancer can lead to symptoms of fatigue, depression, and/or
anxiety, due to the appraisal of and patients’ coping with
cancer and related stressful events (Maes et al., 1996). In
line with the stress-coping model, several studies have
successfully identified factors that put patients at risk or
protect them from the development and persistence of
fatigue, depression and anxiety. For example, several
studies found evidence that indeed, patients’ appraisals or
illness cognitions such as acceptance, helplessness and
perceived benefits, are significantly related to patients’
reports of distress and fatigue (Evers et al., 2001; Hudson
et al., 2018; Richardson et al., 2017; Westbrook et al.,
2016). Symptom measures Symptom measures For an overview of the used questionnaires and selected
nodes, see Online Supplementary Table 1. Symptoms were
selected based on clinical relevance, assuring that the items
did not overlap in content. That is, we selected eight
symptom measures from the available dataset that matched
a subset of the DSM-5 criteria of MDD and GAD (APA,
2013): fatigue (FATIG), depressed mood (DEPRE), loss of
enjoyment (ENJOY), anxiety (ANXIE), sleep problems
(SLEEP), concentration problems (CONCE), worthlessness
(WORTH) and appetite loss (APPET). If there were more
items representing a DSM criterion we averaged those
items into one score. The following criteria of MDD or
GAD were not assessed in the available dataset: suicidality,
difficulty controlling anxiety, restlessness, irritability and
muscle tension. Note that in the selection of symptoms and
risk and protective factors we were limited by the size of
the available sample. We ensured that at least the number
of estimated parameters in the network did not exceed the
number of cases (Epskamp et al., 2017). In order to study which symptoms activate or trigger one
another, dynamic networks are needed, which requires
intensive longitudinal study designs. However, network
modeling can also be employed in cross-sectional designs
to study the co-occurrence of certain concepts, offering
insight into patterns of symptoms, risk and protective
factors across individuals. Moreover, cross-sectional net-
works provide a valuable first step in designing longitudi-
nal studies as they can offer insight into what concepts and
what connections are of importance at the group level. The
aim of the present study is to contribute to revealing the
complex nature of the cross-sectional relationships among
patients’ symptoms (i.e. fatigue, depression and anxiety)
and potential risk and protective factors (i.e. physical
symptoms, social withdrawal, illness cognitions, goal
adjustment and partner support), by analysing the multi-
variate network structure of these symptoms and factors at
the group level. To assess the MDD/GAD criteria of Fatigue, we used all
of the 8-item Fatigue Severity subscale of the Dutch
Checklist Individual Strength (CIS-FS) (Vercoulen et al.,
1994). A sample item is ‘‘I feel tired’’. For each item,
participants indicated the extent to which it was true during
the past 2 weeks. Response categories ranged from 1 (yes,
that is true) to 7 (no, that is not true). Symptom measures The CIS has been
validated and showed good psychometric properties in
chronic fatigue syndrome patients and the general popu-
lation (Vercoulen et al., 1994; Worm-Smeitink et al.,
2017). Internal consistency was good in the present sample
(a = .92). Participants and procedure We analysed data from an observational cohort study
(Garssen et al., 2016), which evaluated psychological care
for cancer patients. Patients who applied for psychological
care at one of the seven mental health care institutes spe-
cialised in psycho-oncology care (IPSO) in the Netherlands
were consecutively sampled. The full sample consisted of
patients with cancer (n = 384) and their partners (n = 99). In the present study, we used baseline data from the patient
sample only. Inclusion criteria were: (1) diagnosed with
cancer and seeking psychological help at one of the seven
IPSO, (2) C 18 years of age and (3) sufficient under-
standing of Dutch language. Patients who agreed to par-
ticipate signed the informed consent form and were
assessed before initiating psychological care. The study
was approved by the Ethical Board of the Helen Dowling
Institute. More detailed information on the study is
described elsewhere (Garssen et al., 2016; Zhu et al.,
2017). Depressive and anxiety symptoms were measured with 8
items of the 16-item version of the Center for Epidemio-
logic Studies Depression Scale (CES-D). The Dutch ver-
sion of the CES-D has been validated in cancer patients and
healthy controls and shows good psychometric properties
(Schroevers et al., 2000). To assess Depressed Mood the
following items were averaged: ‘‘I felt I could not shake of
the blues’’, ‘‘I felt depressed’’ and ‘‘I felt sad’’ (a = .85 in
the present sample). Note that the CES-D does not use as
skip structure when the basic criteria of MDD (depressed
mood and loss of enjoyment) are not met. To measure
Sleep Problems the item ‘‘My sleep was restless’’ was used. To measure Concentration Problems the item ‘‘I had
trouble keeping my mind on what I was doing’’ was used. To assess feelings of Worthlessness the item ‘‘I thought my
life had been a failure’’ was used. To measure Appetite
Loss the item ‘‘I did not feel like eating; my appetite was
poor’’ was used. One item of the CES-D was used to
measure Anxiety: ‘‘I felt fearful’’. We choose an item of the
CES-D rather than the total scale of the 6-item State Melanie P. J. Schellekens1,2
• Marije D. J. Wolvers1 • Maya J. Schroevers3 • Tom I. Bootsma1,4 •
Ange´lique O. J. Cramer2 • Marije L. van der Lee1 Moreover, the stress-coping model poses that the
extent to which cancer patients are able to flexibly manage
the goals that have become unattainable is a key factor in
adaptively coping with cancer and related symptoms. Previous research in cancer patients has shown that being
better able in such goal adjustment is related to less
depressive and anxiety symptoms (Schroevers et al., 2011;
Zhu et al., 2015). Finally, the stress-coping model states
that additional stressful events in terms of somatic
comorbidity as well as (a lack of) social support from the
environment may impact adaptation. In cancer patients, it
has been found that an overall poorer health and comor-
bidity are related to higher levels of fatigue, depression and
anxiety (Husson et al., 2015; Zhu et al., 2017) and that
social support (e.g. from the partner) is related to less
psychological distress (Kamen et al., 2015; Kuijer et al.,
2000). Recently, researchers have suggested to move beyond
symptom measures and also include theoretically relevant
nodes within the network to gain more insight into the
nature of the relationships and core mechanisms involved
in psychopathology (Borsboom, 2017; Fried & Cramer,
2017). By including other factors in addition to symptoms
of psychopathology in the multivariate model, the network
model provides a more integrative approach, making it
ideally suited to study constructs that operate at the
crossroads between psychology and health (Van der Lee &
Schellekens, 2019). For example, it provides the opportu-
nity to examine how bodily symptoms related to cancer are
associated
with
symptoms
of
psychopathology. Also
potential risk or protective factors related to appraisals of
cancer (e.g. feeling helpless, acceptance of illness) and While these studies have provided valuable insights into
the risk and protective factors for the development and
persistence of fatigue, depression and anxiety, current
research findings are limited. With some notable excep- 123 123 555 J Behav Med (2020) 43:553–563 social support, can be added to the network model,
allowing us to explore patients’ adjustment to cancer in its
full complexity. Measures Socio-demographic (age, gender, relationship status, chil-
dren at home, educational level, job status) and clinical
characteristics (time since diagnosis, cancer type, metas-
tasis, medical treatment and current treatment) were
obtained through a self-report questionnaire. 12 3 3 J Behav Med (2020) 43:553–563 556 Anxiety Inventory (SAI) (Korfage et al., 2006) because the
SAI refers to anxious feelings from a different timeframe
than the other symptom measures (i.e. the present moment
rather than the past week/weeks). Participants scored how
often they experienced a symptom in the past week,
ranging from 0 (rarely or none of the time) to 3 (most or all
of the time). der Lubbe, 2001; Van der Lubbe, 1995). A sample item is
‘‘I contacted my friends and close acquaintances less than
usual’’. Participants indicated to what extent they agreed
with the statement in the past 4 weeks, ranging from 1
(strongly disagree) to 5 (strongly agree). The GSBQ has
been validated in psychiatric patients, showing good psy-
chometric properties (De Jong & Van der Lubbe, 2001;
Van der Lubbe 1995). In the present study internal con-
sistency was good (a = .91). To assess the MDD criteria Loss of Enjoyment (De
Bruin et al., 1996) we used the Wellbeing subscale of the
Dutch Health and Disease Inventory (HDI). The HDI has
shown good psychometric properties (De Bruin et al.,
1996). We selected four (out of 13) items that focus on
enjoyment: ‘‘I have lots of plans’’, ‘‘I enjoy the things I
do’’, ‘‘I have pleasant things to look forward to’’, ‘‘I enjoy
my life’’ (a = .82 in present sample). Scores were recoded
such that a higher score portrayed less enjoyment. Each
item was rated to how often it was true in the past four
weeks, ranging from 1 (never) to 6 (always). The illness cognitions Helplessness, Acceptance of Ill-
ness, and Perceived Benefits of Illness were assessed with
all items of the corresponding subscales of the 18-item -
Dutch Illness Cognitions Questionnaire (ICQ). Helpless-
ness is considered a way of emphasizing the negative
meaning of the disease, Acceptance as a way to diminish
the aversive meaning, and Perceived Benefits as a way of
adding positive meaning to the disease. A sample item of
each subscale is ‘‘My illness makes me feel useless at
times’’, ‘‘I have learned to live with my illness’’, ‘‘Dealing
with my illness has made me a stronger person’’, respec-
tively. Measures Each item is answered to the extent to which one
agrees with the item, ranging from 1 (not at all) to 4
(completely). The ICQ was validated in a sample of
patients with rheumatoid arthritis and multiple sclerosis
and showed to be valid and reliable. In the present study
the subscales Helplessness (a = .84), Acceptance (a = .89)
and Perceived Benefits (a = .86) showed good internal
consistency. Measures of risk and protective factors Based on the stress-coping model and previous findings
(e.g. Evers et al., 2001; Kamen et al., 2015; Zhu et al.,
2015, 2017), risk and protective factors were chosen from
the dataset. This led to the following selection of risk
factors (physical symptoms (PHYSI), social withdrawal
(SOCIAL), and helplessness (HELPL)) and protective
factors (acceptance of illness (ACCEPT), perceived bene-
fits of illness (BENEF), disengagement of unattainable
goals
(DISENG)
and
reengagement
of
new
goals
(REENG)) for the network analysis. Additional analyses
also included three partner support factors: active engage-
ment (P-ACTI), protective buffering (P-BUFF) and over-
protection (P-OVER). Goal Disengagement and Goal Reengagement were
assessed with all items of the corresponding subscales of
the 10-item Goal Adjustment Scale (GAS) (Wrosch et al.,
2003). The 4-item subscale Goal Disengagement measures
the ease with which participants can give up efforts and
commitment towards unattainable goals. A sample item is
‘When I could no longer pursue this goal, it was easy for
me to reduce effort towards the goal’. The 6-item subscale
Goal Reengagement measures the extent to which patients
reengage into new attainable goals when confronting
unattainable goals. A sample item is ‘When I could no
longer pursue this goal, I put effort towards other mean-
ingful goals’. Participants rated to what extent they agreed
with each item, ranging from 1 (strongly disagree) to 5
(strongly agree). The GAS has been validated in the gen-
eral population as well as in cancer patients, showing good
psychometric properties (Schroevers et al., 2011; Wrosch
et al., 2003). Internal consistency of the subscales Goal
Disengagement
(a = .82)
and
Goal
Reengagement
(a = .87) was good in the present study. Physical Symptoms were measured with the Rotterdam
Symptom Checklist (RSCL) (de Haes et al., 1990). Previ-
ous validation studies in cancer patients showed good
psychometric properties (de Haes et al., 1990). We selected
the following nine (out of twelve) items: ‘‘nausea’’,
‘‘headache’’, ‘‘stomach ache’’, ‘‘shivering’’, ‘‘tingling’’,
‘‘shortness
of
breath’’,
‘‘dizziness’’,
‘‘diarrhoea’’
and
‘‘constipation’’ (a = .74 in the present sample). Because of
the limited number of variables that can be included in the
network, we averaged these symptoms into one variable. Three items were not selected because the symptoms (i.e. appetite loss, insomnia, concentration problems) were
already covered by the CES-D. Patients indicated to what
extent they were bothered by the symptom in the past week
from 0 (not at all) to 4 (very much). Measures of risk and protective factors The 6-item Overprotection subscale mea-
sures an underestimation of the patients’ capabilities,
resulting in unnecessary help or attempts to restrict activ-
ities. Sample item of the subscales are ‘‘My partner asks
me how I feel’’, ‘‘My partner tries to hide his or her worries
about me’’, ‘‘When it comes down to it, my partner seems
to think that I don’t know what’s right for me’’, respec-
tively. Patients were asked to rate to what extent their
partner adopted these ways of giving support, ranging from
1 (never) to 5 (very often). Psychometric properties of the
WGS seem adequate (Buunk et al., 1996; Kuijer et al.,
2000). Internal
consistency
of
the
subscales
Active
Engagement (a = .73), Protective Buffering (a = .58) and
Overprotection (a = .72) were adequate to good in the
present sample. The R package bootnet (Epskamp et al., 2017) was used
to explore the stability of the network parameters. To
estimate the accuracy of edge weights, bootnet estimates
95% bootstrapped confidence intervals around each edge in
the network. The package also provides significance tests
to examine whether certain edges are stronger than other
edges, based on the bootstrapping results. Only the edges
that prove to be significantly stronger than most other
edges will be interpreted as such. Statistical analysis The data analysis plan was pre-registered online at Open
Science Framework, before we commenced data analysis
(https://osf.io/5r3pn/). We estimated two network models:
(1) a network with symptoms, risk and protective factors,
based on complete cases (i.e. main sample) and (2) a net-
work with partner support in addition to the symptoms and
factors explored in the first network, based on complete
cases from patients with a partner (i.e. relationship sample). As the data were not multivariate normally distributed, a
nonparanormal transformation was applied to relax the
normality assumption prior to estimating the networks (Liu
et al., 2009). Node centrality To examine the importance of each node in the network we
estimated three indices of node centrality (Opsahl et al.,
2010): node strength, betweenness and closeness. In a
weighted network, node strength refers to the number and
strength of the direct connections of a node. Betweenness is
a measure of how often a node lies on the shortest path
between every combination of two other nodes, indicating
to what extent the node facilitates the flow of information
through the network. Closeness measures the average dis-
tance from a node to all other nodes in the network, rep-
resenting how fast a node can be reached from the other
nodes in the network. To estimate the stability of node
centrality, the R package bootnet provides the central sta-
bility coefficient (CS-coefficient), which is estimated based
on a subsetting bootstrapping procedure. The CS-coeffi-
cient represents the proportion of participants that can be
dropped from the analysis, such that the correlation
between the original centrality indices and the subset
centrality indices is at least 0.7 with 95% probability
(Costenbader & Valente, 2003). Only the centrality mea-
sures with a CS-coefficient C 0.25 will be interpreted. Measures of risk and protective factors Partner support in terms of Active Engagement, Pro-
tective Buffering and Overprotection was assessed with all
items of the corresponding subscales of the 19-item Ways
of Giving Support (WGS) questionnaire (Buunk et al.,
1996). The 5-item Active Engagement subscale assesses Social Withdrawal was assessed with all items of the
8-item subscale Social Roles of the Dutch Groningen
Social Behaviour Questionnaire (GSBQ) (De Jong & Van 123 123 557 J Behav Med (2020) 43:553–563 To control for spurious connections that may result from
sampling error (Costantini et al., 2015), we applied the
least absolute shrinkage and selection operator (LASSO)
(Tibshirani, 1996). The LASSO is a regularization method,
leading (small) edge estimates to shrink to exactly zero. Consequently, the LASSO returns a sparse and more
interpretable network model. To control the degree to
which regularization is applied the LASSO utilizes a tuning
parameter, which can be selected by minimizing the
Extended Bayesian Information Criteria (EBIC). The
qgraph package in R (Epskamp et al., 2012) combines the
graphical LASSO (glasso, a well-established and fast
algorithm for estimating LASSO regularization) (Friedman
et al., 2008) with EBIC model selection (using the default
value of hyperparameter c = 0.5) to estimate a regularized
partial correlation network. constructive problem-solving methods of giving support,
such as involving the patient in discussions. The 8-item
Protective Buffering subscale measures behaviour like
hiding concerns and yielding to the patient in order to avoid
disagreements. The 6-item Overprotection subscale mea-
sures an underestimation of the patients’ capabilities,
resulting in unnecessary help or attempts to restrict activ-
ities. Sample item of the subscales are ‘‘My partner asks
me how I feel’’, ‘‘My partner tries to hide his or her worries
about me’’, ‘‘When it comes down to it, my partner seems
to think that I don’t know what’s right for me’’, respec-
tively. Patients were asked to rate to what extent their
partner adopted these ways of giving support, ranging from
1 (never) to 5 (very often). Psychometric properties of the
WGS seem adequate (Buunk et al., 1996; Kuijer et al.,
2000). Internal
consistency
of
the
subscales
Active
Engagement (a = .73), Protective Buffering (a = .58) and
Overprotection (a = .72) were adequate to good in the
present sample. constructive problem-solving methods of giving support,
such as involving the patient in discussions. The 8-item
Protective Buffering subscale measures behaviour like
hiding concerns and yielding to the patient in order to avoid
disagreements. Network estimation Of all patients, 58.5% was considered severely
fatigued (CIS-SF C 35), 68.1% was depressed (total CES-
D C 10) and 56.1% was anxious (SAI C 14) (Korfage
et al., 2006). See Table 1 for baseline characteristics. Table 1 Demographic and clinical characteristics of 342 cancer
patients
n (%)
Age [M (SD)]
51.35 (10.62)
Female gender
264 (77.2)
In a relationshipa
271 (79.2)
Educational levelbc
Low
38 (11.1)
Intermediate
129 (37.7)
High
173 (50.6)
Paid job
203 (59.4)
Absenteeism due to cancer past montha
164/203 (80.8)
Months since diagnosis [M (SD)]d
37.46 (64.30)
Cancer typee
Breast
156 (45.6)
Digestive system
37 (10.8)
Lung
22 (6.4)
Hematologic
44 (12.9)
Head and neck
26 (7.6)
Gynaecological
31 (9.1)
Other types
62 (18.2)
Cancer recurrence
53 (15.5)
Cancer metastasesb
126 (36.8)
Medical treatmentfg
Surgery
255 (74.6)
Chemotherapy
207 (60.5)
Radiotherapy
166 (48.5)
Hormone treatment
89 (26.0)
Immunotherapy
16 (4.7)
Bone marrow transplant
8 (2.3)
Other treatment
52 (15.2)
Current treatmenth
159 (46.5)
a1 missing
b
Table 2 Labels and mean scores of the selected nodes
Node (range)
M (SD)
Fatigue (7–56)
36.76 (12.25)
Depressed mood (0–9)
3.15 (2.43)
Loss of enjoyment (4–24)
12.93 (4.14)
Anxiety (0–3)
1.03 (0.94)
Sleep problems (0–3)
1.44 (1.00)
Concentration problems (0–3)
1.41 (0.90)
Worthlessness (0–3)
0.58 (0.86)
Appetite loss (0–3)
0.42 (0.73)
Physical symptoms (0–36)
14.08 (4.06)
Social withdrawal (8–40)
20.37 (7.48)
Helplessness (6–24)
12.92 (3.95)
Acceptance of illness (6–24)
12.80 (3.72)
Perceived benefits of illness (6–24)
13.96 (4.27)
Disengagement of unattainable goals (4–20)
10.84 (3.05)
Reengagement of new goals (6–30)
20.56 (3.85) cases did not differ from the patients with missing data
regarding sociodemographic, clinical and psychological
characteristics (p [ .05), except for hormone treatment. Patients included in the analysis were more often treated
with hormone treatment than excluded patients (respec-
tively 26.2% vs. 9.5%, p = .018). Patients in the main
sample, of whom 77.2% were female, had a mean age of
51.35 years (SD = 10.62). Patients were mainly diagnosed
with breast cancer (45.6%). In 36.8% of cases the cancer
had metastasized and 46.5% received current treatment for
their cancer. Of all patients, 58.5% was considered severely
fatigued (CIS-SF C 35), 68.1% was depressed (total CES-
D C 10) and 56.1% was anxious (SAI C 14) (Korfage
et al., 2006). See Table 1 for baseline characteristics. Table 2 presents the mean scores of the nodes used in the
networks. Network estimation The regularized partial correlation coefficients networks
were estimated using the R package qgraph (Epskamp
et al., 2012; Epskamp & Fried, 2016; R Core Team, 2016). In the network, ‘‘nodes’’ represent the selected variables
while ‘‘edges’’ (links connecting two nodes) represent the
regularized partial correlation coefficients. In regularized
partial correlation networks the association between two
nodes is estimated while controlling for all other nodes. As
such, edges in these networks can be interpreted as con-
ditional (in)dependence relations: if an edge is absent
between two nodes, this means that these two nodes are
conditionally independent given all other nodes. If an edge
is present between two nodes, this means that these two
nodes are conditionally dependent given all other nodes in
the network. 123 12 J Behav Med (2020) 43:553–563 558 Results
Table 1 Demographic and clinical characteristics of 342 cancer
patients
n (%)
Age [M (SD)]
51.35 (10.62)
Female gender
264 (77.2)
In a relationshipa
271 (79.2)
Educational levelbc
Low
38 (11.1)
Intermediate
129 (37.7)
High
173 (50.6)
Paid job
203 (59.4)
Absenteeism due to cancer past montha
164/203 (80.8)
Months since diagnosis [M (SD)]d
37.46 (64.30)
Cancer typee
Breast
156 (45.6)
Digestive system
37 (10.8)
Lung
22 (6.4)
Hematologic
44 (12.9)
Head and neck
26 (7.6)
Gynaecological
31 (9.1)
Other types
62 (18.2)
Cancer recurrence
53 (15.5)
Cancer metastasesb
126 (36.8)
Medical treatmentfg
Surgery
255 (74.6)
Chemotherapy
207 (60.5)
Radiotherapy
166 (48.5)
Hormone treatment
89 (26.0)
Immunotherapy
16 (4.7)
Bone marrow transplant
8 (2.3)
Other treatment
52 (15.2)
Current treatmenth
159 (46.5)
a1 missing
b2 missing
cLow = primary and lower secondary education, intermediate = up-
per secondary education, high = higher vocational training/university
d100 missing
ePercentages do not add up to 100 because 33 patients had multiple
types of cancer
f4 missing
gPercentages do not add up to 100 because patients followed multiple
treatments
h34 missing cases did not differ from the patients with missing data
regarding sociodemographic, clinical and psychological
characteristics (p [ .05), except for hormone treatment. Patients included in the analysis were more often treated
with hormone treatment than excluded patients (respec-
tively 26.2% vs. 9.5%, p = .018). Patients in the main
sample, of whom 77.2% were female, had a mean age of
51.35 years (SD = 10.62). Patients were mainly diagnosed
with breast cancer (45.6%). In 36.8% of cases the cancer
had metastasized and 46.5% received current treatment for
their cancer. Network estimation Of the 342 complete cases in the first network, 71 were
dropped because they had no partner and 3 were dropped
because they had missing data on the partner support
variables, leaving 268 (72%) complete cases to be included
in the relationship sample. Patients included in the rela-
tionship sample did not differ from those excluded from the
relationship sample (p [ .05), except for having a job. Included patients more often had a paid job than excluded
patients (respectively 62.3% vs. 48.6%, p = .034). gPercentages do not add up to 100 because patients followed multiple
treatments h34 missing Network centrality The CS-coefficients for strength, closeness, and between-
ness were 0.59, 0.44 and 0.21, respectively (Online Sup-
plementary Figure 4), indicating that strength was the most
reliable centrality index (see Fig. 2, for the other centrality
indices see Online Supplementary Figure 5). Significance
tests of differences in strength (Online Supplementary
Figure 6) indicated that Depressed Mood, Worthlessness,
Loss of Enjoyment and Acceptance were more central than
most other nodes, that is these nodes had more and stronger
connections with both symptoms and risk and protective
factors than most other nodes in the network. Sleep prob-
lems, Goal Reengagement, Goal Disengagement and Social
Withdrawal were the least central nodes in the network. Fig. 2 Strength centrality of each node in the network. Node strength
refers to the number and strength of the direct connections of a node Figure 2). Significance tests of edge weight differences
(Online Supplementary Figure 3) indicated that the seven
thickest and most saturated edges were significantly
stronger than most other edges (i.e. 33–51) in the network:
Depressed Mood—Worthlessness, Depressed Mood—Loss
of Enjoyment, Acceptance—Perceived Benefits, Accep-
tance—Helplessness,
Fatigue—Helplessness,
Fatigue—
Physical Symptoms, Appetite loss—Physical Symptoms. Many of the remaining edges were not reliably different
from other edges, that is ten edges were significantly factors Of the 384 patients who filled out the baseline question-
naire, 342 (89%) were complete cases and were therefore
included in the analysis of the main sample. The complete The regularized partial correlation network is presented in
Fig. 1. Based on the 95% bootstrapped CI, the edge
weights appeared rather stable (Online Supplementary 123 J Behav Med (2020) 43:553–563 559 Fig. 1 The network structure of symptoms and risk and protective
factors of 342 cancer patients. The stronger a connection between two
nodes, the thicker and more saturated the edge. Positive and negative
connections are denoted by blue and red edges, respectively. FATIG = fatigue,
DEPRE = depressed
mood,
ENJOY = loss
of
enjoyment,
ANXIE = anxiety;
SLEEP = sleep
problems,
CONCE = concentration
problems,
WORTH = worthlessness,
APPET = appetite loss, PHYSI = physical symptoms, SOCIAL = so-
cial withdrawal, HELPL = helplessness, ACCEPT = acceptance of
illness, BENEF = perceived benefits of illness; DISENG = disen-
gagement of unattainable goals; REENG = reengagement of new
goals CONCE = concentration
problems,
WORTH = worthlessness,
APPET = appetite loss, PHYSI = physical symptoms, SOCIAL = so-
cial withdrawal, HELPL = helplessness, ACCEPT = acceptance of
illness, BENEF = perceived benefits of illness; DISENG = disen-
gagement of unattainable goals; REENG = reengagement of new
goals CONCE = concentration
problems,
WORTH = worthlessness,
APPET = appetite loss, PHYSI = physical symptoms, SOCIAL = so-
cial withdrawal, HELPL = helplessness, ACCEPT = acceptance of
illness, BENEF = perceived benefits of illness; DISENG = disen-
gagement of unattainable goals; REENG = reengagement of new
goals Fig. 1 The network structure of symptoms and risk and protective
factors of 342 cancer patients. The stronger a connection between two
nodes, the thicker and more saturated the edge. Positive and negative
connections are denoted by blue and red edges, respectively. FATIG = fatigue,
DEPRE = depressed
mood,
ENJOY = loss
of
enjoyment,
ANXIE = anxiety;
SLEEP = sleep
problems, Fig. 2 Strength centrality of each node in the network. Node strength
refers to the number and strength of the direct connections of a node stronger than a few other edges (i.e. 1–23) and 39 edges
were not stronger than any other edge. Discussion A possible
explanation could be that all other nodes in the network
reflect patients’ thoughts, feelings and behaviour while
partner support reflects patients’ perception of their part-
ners’ behaviour. Future studies could further explore the
role of the partner by studying other aspects of the rela-
tionship (e.g. relationship satisfaction, intimacy, commu-
nication) in a network perspective on cancer patients’
functioning. The present finding that depressed mood and loss of
enjoyment are centrally embedded in the network corre-
spond with the diagnostic criteria of MDD, which require
that either depressed mood or loss of interest/pleasure are
present. In other studies depressed mood and loss of
interest/pleasure have also shown high centrality in both
healthy controls as well as psychiatric patients (Boschloo
et al., 2016; Fried et al., 2016). Regarding the connection
between depressed mood, anxiety and fatigue, we found
that anxiety and depressed mood are strongly related to one
another but not to fatigue. This is in line with a recent study
in a mixed sample of psychiatric patients and healthy
controls, who also found that anxiety and depressed mood
are mainly connected to fatigue via loss of enjoyment
(Bekhuis et al., 2016). Other studies with samples of
depressed patients, however, found different patterns
regarding the connection between fatigue and depression
(Beard et al., 2016; McWilliams et al., 2017). Overall, the symptoms of fatigue, anxiety and depres-
sion appear to be strongly interconnected. Past research
efforts may have overlooked the implications of concep-
tualizing psychiatric disorders as mutually interacting
symptoms in cancer patients. While the literature has
concluded that patients with cancer are vulnerable to
develop psychiatric disorders (Mitchell et al., 2011), such
as MDD, the network perspective might offer us an
understanding into why these patients are vulnerable:
cancer might lead to certain symptoms of MDD, which, in
turn, can trigger other symptoms and eventually develop A key hypothesis of the network approach is that by
identifying and subsequently intervening on key nodes or
connections in the network it should be possible to modify
the behaviour of the network. That is, intervening on cer-
tain aspects of a network structure may serve to make the
system, or network, return to a healthier state (e.g. no case
of CRF or MDD). It would seem likely that for treatment to
be successful, therapists could target (central) nodes in the
network or specific relationships between nodes. Discussion The present study applied a network approach to examine
the interconnectedness among risk and protective factors
on the one hand and symptoms of fatigue, depression and
anxiety on the other hand, in cancer patients seeking psy-
chological care. The network revealed that the symptoms
depressed mood, loss of enjoyment and worthlessness were
central nodes in the network, meaning that these symptoms
had more and stronger connections than most other nodes
in the network. Regarding risk factors, the relationships of
helplessness and physical symptoms with fatigue were
among the strongest connections in the network. The node
physical symptoms was also strongly associated with
appetite loss. Among the protective factors, acceptance of
illness was centrally embedded in the network. Thus, while
taking into account several risk and protective factors,
acceptance of illness was most strongly connected to both
symptoms as well as other risk and protective factors. The
symptom sleep problems and the factors related to goal
adjustment, social withdrawal and partner support appeared
peripheral in the network and were less strongly associated
with other nodes. Among the risk factors, the relationship between help-
lessness and fatigue stood out. This is in line with previous
qualitative research showing how cancer related fatigue
(CRF) is often experienced as uncontrollable, unpre-
dictable and unchangeable, making patients feel helpless
and distressed (Hofman et al., 2007; Scott et al., 2011). Among protective factors, acceptance of illness was cen-
trally embedded in the network. This confirms previous
bivariate research showing that coming to terms with one’s
illness and its consequences is associated with a variety of
physical and psychological health indicators, such as
decreased anxiety and depression, adjustment to disease,
and improved quality of life (Chabowski et al., 2017; Evers
et al., 2001; Li & Moore, 1998; Peters et al., 2014). Fur-
thermore, interventions targeting acceptance, such as
Mindfulness-Based Cognitive Therapy, are effective in
reducing fatigue, depression and anxiety (Bruggeman-
Everts et al., 2017; Compen et al., 2018; Piet et al., 2012;
Schellekens et al., 2017). Contrary to our expectations, the
partner support factors were not strongly connected to
symptoms and appeared peripheral in the network. This
indicates that partner support is associated with patients’
symptoms and functioning but does not seem to play a
central role in fatigue, depression and anxiety. Relationship among symptoms, risk and protective
factors, including partner support The regularized partial correlation network of the rela-
tionship sample was similar to the network of the main
sample. The nodes on partner support (Active Engagement,
Protective Buffering, Overprotection) were peripheral in
the network. See Online Supplementary Material 7 for the
results. 12 3 J Behav Med (2020) 43:553–563 560 into a network of symptoms that correspond with the
diagnostic criteria of MDD (Guloksuz et al., 2017; Van der
Lee & Schellekens, 2019). This hypothesis is reflected in
the present findings, showing that physical symptoms are
strongly connected with fatigue and appetite problems,
which in turn are related to other depressive symptoms. Note, however, that the cross-sectional design prevents us
from drawing conclusions on any potential causal nature of
these relationships. Discussion However,
note that in order to make statements regarding the suit-
ability of treatment we need to study the dynamic networks
of individual patients rather than group-level networks 123 123 J Behav Med (2020) 43:553–563 561 (Borsboom, 2017; Borsboom & Cramer, 2013). Future
studies exploring individual dynamic networks can provide
information on which symptoms and which risk and pro-
tective factors play a key role in the network for a specific
individual, informing us which nodes and connections
could and should be intervened upon, and consequently,
what kind of treatment would be best suited for him or her. Given the present findings, acceptance and helplessness
would be prime candidates to explore in these future
studies. embedded in the network. Longitudinal studies should
explore these constructs in individual dynamic networks to
further investigate their causal role and the extent to which
such networks can inform us on what treatment would be
most suitable for the individual cancer patient. Funding The study was financially supported by the Ingeborg
Douwes Stichting and the Dutch Pink Ribbon Foundation. This report
was supported by a Grant from the Dutch Cancer Society (10761)
awarded to Dr. M.L. van der Lee and Dr. A.O.J. Cramer. The present study is the first to provide a network per-
spective on how risk and protective factors are related to
key symptoms in cancer patients seeking psychological
care. Moreover, the used questionnaires were selected
based on their importance in clinical practice. We were
able to analyse the stability of the estimated networks and
identify differences between how central and how strongly
connected certain symptoms and risk and protective factors
were (Epskamp et al., 2017). Besides these strengths, some
limitations should be taken into account. The study sample
consisted of distressed cancer patients seeking psycholog-
ical care. Consequently, findings cannot be generalized to
distressed patients who are not seeking help. In addition,
while the network models estimate how symptoms and
factors are interrelated at a certain moment in time, the
associations between such variables may be different when
observed over multiple time points. Importantly, the cross-
sectional between-subjects design allows for estimating
conditional dependence relations, which are consistent with
causal hypotheses about these relations but not sufficient to
base causality on. In addition, as is the case for any cross-
sectional model—whether it be networks or, say, factor
models—cross-sectional results do not readily generalize
to individuals (Bos & Wanders, 2016). Compliance with ethical standards Conflict
of
interest Melanie
P. J. Schellekens,
Marije
(M. D. J.) Wolvers, Maya J. Schroevers, Tom I. Bootsma, Ange´lique O. J. Cramer, and Marije L. van der Lee declare that they have no
conflict of interest. Human and animal rights and Informed consent All procedures
followed were in accordance with ethical standards of the responsible
committee on human experimentation (institutional and national) and
with the Helsinki Declaration of 1975, as revised in 2000. Informed
consent was obtained from all individual participants included in the
study. Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards. Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
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Springer Nature remains neutral with regard to
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Tumeur desmoïde géante de la paroi abdominale: à propos d’un cas
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The Pan African medical journal
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Issam Loukil, Amine Zouari Corresponding
author:
Issam
Loukil,
Service
de
Chirurgie
Générale
Tataouine,
Tataouine,
Tunisie. issamloukilyoussef@gmail.com Received: 20 Jan 2021 - Accepted: 05 Jul 2021 - Published: 23 Jul 2021 Keywords: Tumeur desmoïde, géante, chirurgie, à propos d’un cas Copyright: Issam Loukil et al. Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed
under
the
terms
of
the
Creative
Commons
Attribution
International
4.0
License
(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited. Cite this article: Issam Loukil et al. Tumeur desmoïde géante de la paroi abdominale: à propos d’un cas. Pan African
Medical Journal. 2021;39(211). 10.11604/pamj.2021.39.211.27965 Available online at: https://www.panafrican-med-journal.com//content/article/39/211/full Article Case report Case report Résumé La tumeur desmoïde de taille géante rarement
rapportée à travers la littérature et qui implique un
défi dans sa prise en charge thérapeutique. Pour
notre cas la tumeur exerce un effet de masse
abdominal, ce qui la rend douloureuse, et un
problème esthétique majeur. Le bilan d'extension
radiologique a permis de délimiter son extension en
profondeur et ses limites d'exérèses. La tumeur
desmoïde de la paroi abdominale a été évoquée et
réséquée
chirurgicalement
avec
des
suites
opératoires simples. Ce cas illustre les difficultés de
prise en charge de cette entité vu sa grande taille. Giant abdominal wall desmoid tumor: a case report 1Service
de
Chirurgie
Générale
Tataouine,
Tataouine, Tunisie, 2Service de Chirurgie Générale
Sfax, Sfax, Tunisie English abstract magnétique (IRM) abdominale en juillet 2020 a
montré une volumineuse masse tissulaire aux
dépens du muscle droit de l´abdomen gauche
grossièrement ovalaire de contours lobulés
mesurant 190x188x160 mm faiblement hypo-
dense qui prend le contraste après injection de
gadolinium (Figure 2). Devant ce tableau une
tumeur fibromateuse type desmoïde a été évoquée
et une colonoscopie a été demandée à la recherche
de polypes coliques associés, revenue sans
anomalies. Giant desmoid tumor has been rarely reported in
the literature but it is a therapeutic challenge. We
here report a case of tumor manifesting as painful
abdominal mass causing a major esthetic problem. Radiological assessment allowed to determine its
depth extension and limits of resection. Desmoid
tumor of the abdominal wall was evoked and
surgically resected, with simple outcome. This study
highlights challenges in the management of this
entity,due to its large size. Intervention thérapeutique: la patiente a été
opérée par laparotomie médiane. L´exploration
peropératoire montre une masse polylobée aux
dépends des différentes tuniques adjacentes de la
paroi abdominale gauche sans extension ni
localisations secondaires intra-péritonéale. Une
résection en monobloc de cette masse a été faite
emportant le plan cutané, sous cutané, la partie
musculaire envahie ainsi que ses aponévroses et le
plan
péritonéal
adjacent
avec
une
marge
chirurgicale macroscopique de sécurité minimale
de 1 cm en latéral et en profondeur (Figure 3). La
fermeture pariétale a nécessité un geste de
reconstruction par une prothèse synthétique biface
(Figure 4). Key words: Desmoid tumor, giant, surgery, case
report Introduction Les tumeurs desmoïdes sont extrêmement rares. Elles représentent 3% des tumeurs des tissus mous
et son incidence est estimée de 2 à 4 cas/millions
de population [1]. La taille géante de cette tumeur
est rarement rapportée dans la littérature. Le
diagnostic positif est difficile et la prise en charge
thérapeutique est très complexe nécessitant une
approche multidisciplinaire impliquant chirurgien,
radiologue et carcinologue, en raison de l´évolution
imprévisible et des conséquences fonctionnelles de
la maladie [2]. Suivi
et
résultats
des
interventions
thérapeutiques: l´étude histologique de la pièce
opératoire a confirmé le diagnostic d´une
fibromatose agressive en montrant un agencement
cellulaire en longs faisceaux divergents dissociant le
muscle
strié
avec
marge
de
résection
microscopique saine (Figure 5). Le dossier a été
présenté
en
réunion
de
concertation
pluridisciplinaire
et
un
traitement
adjuvant
postopératoire n´a pas été indiqué. Un contrôle à 6
mois clinique et scannographique n´a pas montré
de signes de récidive locale. Patient et observation Article English abstract &Auteur correspondant Issam Loukil, Service de Chirurgie Générale
Tataouine, Tataouine, Tunisie Issam Loukil, Service de Chirurgie Générale
Tataouine, Tataouine, Tunisie Article Discussion Le point fort de cette publication est qu´il rapporte
un cas très rare de tumeur desmoïde de grande
taille. Notre approche s´est basée sur l´étude des
cas rapportés, bien que limités à travers la
littérature et notre discussion du consensus de
prise en charge. La tumeur desmoïde est définie par
l´Organisation Mondiale de la Santé en tant qu´une
prolifération fibroblastique clonale qui survient
dans les tissus mous profonds et se caractérise par
une incapacité à métastaser même si elle peut être
multifocale dans le même membre ou partie du
corps [3]. Elle touche plus fréquemment les
femmes entre 15 et 60 ans avec un pic entre 30 et
40 ans [4,5]. Deux grandes catégories de tumeurs desmoïdes
sont
reconnues:
les
tumeurs
sporadiques
majoritaires de 85 à 90 % des cas associée à une
mutation dans la voie codante pour la béta-
caténine CTNNB1, et les tumeurs associées à la
mutation
du
gène
APC
de
la
polypose
adénomateuse
familiale
(PAF)
touchant
principalement l´abdomen [4,6]. Le tableau clinique
peut
présenter
plusieurs
aspects
selon
la
localisation et peuvent être très agressives avec
une croissance accrue et effet de masse comme
pour le cas de notre patiente [7]. L´IRM est
l´examen de référence pour le diagnostic, la
stadification et le suivi. Elle permet d´étudier
l´extension tumorale et de déterminer le plan de
résection chirurgicale à atteindre. Sur les images
pondérées en T1, la tumeur apparait hypo ou iso-
intense par rapport au muscle et apparait hyper-
intense en T2 avec un renforcement après injection
de gadolinium et persistance de bondes hypo-
intenses [3,4]. Le diagnostic de certitude est
histologique sur une biopsie percutanée ou de la
pièce opératoire en montrant une prolifération de
cellules fusiformes uniformes ressemblant à des
myofibroblastes, dans un stroma de collagène
abondant et de réseau vasculaire. Les recommandations du consensus de Milan 2018
ont défini un algorithme de prise en charge
(Figure 6) et adopte la stratégie initiale de
surveillance active pour les patients qui présentent
des tumeurs desmoïdes pour une période de 1 à 2
ans par examen clinique et IRM mensuel durant les
premiers mois puis à un intervalle de 3 à 6 mois, à
la
recherche
de
progression
tumorale
ou
augmentation des symptômes qui va justifier un
traitement actif [4,9]. Certaines situations rendent
la chirurgie inévitable telle que les complications
(occlusions, perforation, hémorragie) ou des
problèmes esthétiques majeurs, tel est le cas de
notre patiente. Patient et observation Informations sur le patient: nous rapportons le cas
d´une patiente âgée de 46 ans, sans antécédents
pathologiques notables, qui a consulté en juin 2020
pour une volumineuse masse abdominale évoluant
depuis plus d´un an. Résultats cliniques: l´examen a montré une masse
de 20 cm de grand axe para-ombilicale gauche, non
douloureuse et mobile par rapport au plan profond
(Figure 1). La patiente n´a pas rapporté de signes
digestifs associés. Perspectives du patient: la patiente a déclaré être
satisfaite de la qualité de la prise en charge et des
soins fournis. Démarche diagnostique: pour mieux spécifier cette
tumeur et étudier ses rapports, un complément
d´exploration
par
imagerie
par
résonance Consentement éclairé: la patiente a fourni son
consentement. 2 2 Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Article pour les chirurgiens surtout pour les tumeurs
géantes. En raison du schéma de croissance
infiltrant, la portée de la résection nécessaire pour
obtenir des marges négatives pourrait souvent
entrainer
des
altérations
fonctionnelles
importantes et des altérations esthétiques [5]. Cette résection confère un bon taux de contrôle
local à environ 80% à 5 ans [3]. Aucun consensus
concernant la technique chirurgicale de fermeture
des défects abdominaux n´a été établit. Le
chirurgien aura le choix entre l´utilisation des
prothèses pariétales synthétiques ou l´utilisation
de lambeaux libres musculo-cutanés et les
procédés de rapprochement aponévrotiques [1]. La
chimiothérapie reste une option dans les cas des
maladies symptomatiques non résécables ou
avancées [4-6]. Les thérapies ciblés (Imatinib)
confère un taux élevé de stabilisation de la maladie
de 60 à 80% des cas [5], l´hormonothérapie
(Tamoxifène) par son action anti-oestrogéniques
est associée à un bénéfice clinique dans environ
30% des cas [6] et les anti-inflammatoire non
stéroïdien (AINS) par leur capacité de réguler la voie
de la ß-caténine par l´inhibition de la cyclo-
oxygénase-2 ou des prostaglandines [5]. Le
traitement locorégional par radiothérapie ou de
cryothérapie peut réduire le risque de récidive
après résection chirurgicale incomplète [3,4,6,8]. Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Conflits d’intérêts Les auteurs ne déclarent aucun conflit d´intérêts. PubMed| Google Scholar 3. Kasper B, Baumgarten C, Garcia J, Bonvalot S,
Haas R, Haller F et al. An update on the
management
of
sporadic
desmoid-type
fibromatosis: a European Consensus Initiative
between Sarcoma PAtients EuroNet (SPAEN)
and European Organization for Research and
Treatment of Cancer (EORTC)/Soft Tissue and
Bone Sarcoma Group (STBSG). Annals of
Oncology. 2017;28(10): 2399-2408. PubMed|
Google Scholar Article et qui prend le contraste après injection de
gadolinium
Figure 3: aspect macroscopique de la masse
abdominale réséquée
Figure 4: réfection du défect pariétal par une
prothèse synthétique biface
Figure 5: aspect histologique
Figure 6: algorithme de prise en charge tumeurs de grandes tailles sont plus susceptibles de
récidiver. En conclusion, il s´agit bien d´une tumeur
rare dont la taille géante rend sa prise en charge
plus délicate. L´approche thérapeutique actuelle
opte pour la stratégie de surveillance active. Le cas
de notre patiente présente des arguments
d´atteinte esthétique et de douleur abdominale,
indiquant une résection chirurgicale d´emblée. La
résection de cette masse implique un deuxième
geste
de
réfection
pariétale
par
plaque
synthétique. Références 1. Couto Netto SD, Teixeira F, Menegozzo CAM,
Albertini
A,
Akaishi
EH,
Utiyama
EM. Abdominal wall reconstruction after desmoid
type fibromatosis radical resection: case series
from a single institution and review of the
literature. International Journal of Surgery
Case Reports. 2017;33: 167-172. PubMed|
Google Scholar Google Scholar 4. Master SR, Mangla A, Shah C. Desmoid Tumor. In: StatPearls. 2020. PubMed 4. Master SR, Mangla A, Shah C. Desmoid Tumor. In: StatPearls. 2020. PubMed Discussion La surveillance après résection
chirurgicale, est essentiellement clinique et
radiologique par une IRM ou tomodensitométrie
(TDM) [10]. Les taux de récidive locale dépendent
essentiellement des marges de résection. Les La prise en charge thérapeutique comporte
plusieurs
volets:
chirurgical,
systémique
et
locorégional. Le traitement chirurgical reste un défi Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. 3 3 Article Conclusion Les
tumeurs
desmoïdes
géantes
sont
des
fibromatoses agressives du fait de leur caractère
infiltrant avec un haut potentiel de récidive. Le
diagnostic doit être évoqué devant toute masse
tissulaire pariétale abdominale. L´IRM permet de
poser le diagnostic, de guider la prise en charge
thérapeutique et de suivre l´évolution. La
confirmation du diagnostic est histologique. Le
traitement repose actuellement sur une stratégie
de surveillance active initiale en quête de signes de
complications ou de progression. 2. Penel N, Coindre J-M, Bonvalot S, Italiano A,
Neuville A, Le Cesne A et al. Management of
desmoid tumours: a nationwide survey of
labelled reference centre networks in France. European Journal of Cancer. 2016;58: 90-96. PubMed| Google Scholar 2. Penel N, Coindre J-M, Bonvalot S, Italiano A,
Neuville A, Le Cesne A et al. Management of
desmoid tumours: a nationwide survey of
labelled reference centre networks in France. European Journal of Cancer. 2016;58: 90-96. PubMed| Google Scholar Contributions des auteurs Tous les auteurs ont participé à la mise en œuvre et
la rédaction de ce manuscrit. Ils déclarent
également avoir lu et approuvé la version finale du
manuscrit. Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Figures 5. Martínez Trufero J, Pajares Bernad I, Torres
Ramón I, Hernando Cubero J, Pazo Cid R. Desmoid-Type Fibromatosis: Who, When, and
How to Treat. Curr Treat Options in Oncol. 2017;18(5): 29. PubMed| Google Scholar Figure
1:
masse
abdominale
géante,
vue
préopératoire
Figure 2: IRM abdominale, masse tissulaire aux
dépens du muscle droit de l´abdomen gauche
grossièrement ovalaire de contours lobulés
mesurant 190x188x160 mm faiblement hypo dense Figure
1:
masse
abdominale
géante,
vue
préopératoire Figure
1:
masse
abdominale
géante,
vue
préopératoire Figure 2: IRM abdominale, masse tissulaire aux
dépens du muscle droit de l´abdomen gauche
grossièrement ovalaire de contours lobulés
mesurant 190x188x160 mm faiblement hypo dense 6. Napolitano A, Mazzocca A, Spalato Ceruso M,
Minelli A, Baldo F, Badalamenti G et al. Recent
advances in desmoid tumor therapy. Cancers. 2020;12(8): 2135. PubMed| Google Scholar Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. 4 Article Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. Article 9. Alman B, Attia S, Baumgarten C, Benson C, Blay
J-Y, Bonvalot S et al. The management of
desmoid tumours: a joint global consensus-
based guideline approach for adult and
paediatric patients. European Journal of
Cancer. 2020; 127: 96-107. PubMed| Google
Scholar 7. Zenzri Y, Yahyaoui Y, Charfi L, Ghodhbani Z,
Letaief F, Ayadi M et al. The Management of
desmoid tumors: a retrospective study of 30
cases. International
Journal
of
Surgical
Oncology. 2020
Jul
18;2020:
9197216. PubMed| Google Scholar 8. Kurtz J-E, Gantzer J, Garnon J, Gangi A. Traitements
loco-régionaux
des
tumeurs
desmoides? quelles perspectives?. Bulletin du
Cancer. 2020; 107(3): 371-374. PubMed|
Google Scholar 8. Kurtz J-E, Gantzer J, Garnon J, Gangi A. Traitements
loco-régionaux
des
tumeurs
desmoides? quelles perspectives?. Bulletin du
Cancer. 2020; 107(3): 371-374. PubMed|
Google Scholar 10. Kasper B, Raut CP, Gronchi A. Desmoid tumors:
to treat or not to treat, that is the question. Cancer. 2020; 126(24): 5213-5221. PubMed|
Google Scholar Figure 1: masse abdominale géante, vue préopératoire Figure 1: masse abdominale géante, vue préopératoire 5 Article Figure 2: IRM abdominale, masse tissulaire aux dépens du muscle droit de l´abdomen gauche grossièrement
ovalaire de contours lobulés mesurant 190x188x160 mm faiblement hypo dense et qui prend le contraste
après injection de gadolinium Figure 2: IRM abdominale, masse tissulaire aux dépens du muscle droit de l´abdomen gauche grossièrement
ovalaire de contours lobulés mesurant 190x188x160 mm faiblement hypo dense et qui prend le contraste
après injection de gadolinium Figure 3: aspect macroscopique de la masse abdominale réséquée Figure 3: aspect macroscopique de la masse abdominale réséquée Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. 6 Article Figure 4: réfection du défect pariétal par une prothèse synthétique
biface Figure 4: réfection du défect pariétal par une prothèse synthétique
biface Figure 5: aspect histologique Figure 5: aspect histologique 7 Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes. 7 Article Figure 6: algorithme de prise en charge Figure 6: algorithme de prise en charge Issam Loukil et al. PAMJ - 39(211). 23 Jul 2021. - Page numbers not for citation purposes 8
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https://openalex.org/W2090948760
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Educação em saúde para a prevenção do câncer cérvico-uterino
|
Revista Brasileira de Educação Médica
| 2,012
|
cc-by
| 4,585
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RESUMO Este estudo se trata do relato de uma experiência vivenciada por graduandos de Medicina e Enfer-
magem participantes do PET-Saúde da Universidade de Brasília, cujo objetivo foi realizar atividades
de educação em saúde dentro do tema prevenção de câncer cérvico-uterino nos municípios de Ceres
e Santa Isabel, Goiás. Para tanto, foram feitas diferentes ações comunicativas, tais como: confecção e
distribuição de cartazes/panfletos; produção de um programa de rádio; e promoção de rodas de conver-
sa na sala de espera das unidades básicas de saúde. Essa atividade se mostrou como uma oportunidade
de compartilhar experiências e sentimentos, bem como discutir ideias e conceitos visando a construir
um novo conhecimento, com contribuições do saber teórico dos acadêmicos e do saber prático das
usuárias. As dúvidas e questionamentos das usuárias estavam de acordo com os apontados trazidos
pela literatura, e as atividades mostraram-se uma boa forma de esclarecer as dúvidas das usuárias e
aproximar sistema de saúde e população, bem como de promover a educação em saúde, especialmente
no âmbito da autovalorização, da prevenção e da promoção da saúde. Educação em Saúde para a Prevenção do
Câncer Cérvico-uterino
Health Education for Cervical Cancer
Prevention Bruna Côrtes RodriguesI
Ana Catarine Melo de Oliveira CarneiroI
Tábata Longo da SilvaI
Ana Cláudia Nunes SoláI
Natália de Melo ManziI
Noel Peixoto SchechtmanI
Hugo Leonardo Gonçalves de Oliveira MagalhãesI
Jane Lynn Garrison Dytz I Bruna Côrtes RodriguesI
Ana Catarine Melo de Oliveira CarneiroI
Tábata Longo da SilvaI
Ana Cláudia Nunes SoláI
Natália de Melo ManziI
Noel Peixoto SchechtmanI
Hugo Leonardo Gonçalves de Oliveira MagalhãesI
Jane Lynn Garrison Dytz I PALAVRAS-CHAVE: – Serviços Preventivos de Saúde
– Educação em Saúde
– Neoplasias do Colo do Útero
– Saúde Pública. – Serviços Preventivos de Saúde
– Educação em Saúde
– Neoplasias do Colo do Útero
– Saúde Pública. – Serviços Preventivos de Saúde – Educação em Saúde – Neoplasias do Colo do Útero – Saúde Pública. I Universidade de Brasília, Brasília, DF, Brasil. ABSTRACT This case report describes the experience of undergraduate medical and nursing students participa-
ting in the Educational Program for Health Work (PET-Saúde) at the University of Brasília, the ob-
jective of which was to conduct health education activities in cervical cancer prevention in Ceres and
Santa Isabel, Goiás State. The following communications activities were used: preparation and dis-
tribution of posters and leaflets; production of a radio program; and conversation groups held in the
waiting rooms of primary healthcare units. This activity provided an opportunity to share experiences
and feelings, as well as discussing ideas and concepts aimed at building new knowledge, with con-
tributions from the students’ academic training and the users’ practical knowhow. The users’ doubts
and questions were consistent with those found in the literature, and the activities proved to be a good
way for clearing up users’ doubts and drawing the health system and the population closer, as well as
promoting health education, especially in the areas of self-esteem, prevention, and health promotion. INTRODUÇÃO Alguns motivos identificados para não realização do exa-
me são: crença de ser saudável por não apresentar queixas
ginecológicas; medo em relação ao câncer e ao próprio proce-
dimento; sentimentos de embaraço ou vergonha; desconfor-
to físico; desconhecimento da importância e da finalidade do
exame; dificuldades em marcá-lo e em ter acesso ao local, entre
outros.6 Percebe-se que, em muitos casos, a falha no diagnósti-
co precoce encontra explicação no conhecimento inadequado
da população sobre a doença e sua condição assintomática,
bem como sobre a importância do exame e possibilidade de
tratamento precoce. O câncer de colo do útero é o segundo tipo de câncer mais
frequente entre as mulheres, apresentando aproximadamente
500 mil casos novos por ano no mundo, sendo responsável
pelo óbito de 230 mil mulheres por ano. No Brasil, para 2010,
eram esperados 18.430 novos casos, com um risco estimado de
18 casos para cada 100 mil mulheres.1 Sabe-se da existência de fatores de risco para o desenvolvi-
mento desse tumor. Os principais são: infecção pelo papiloma
vírus humano (HPV); tabagismo; multiplicidade de parceiros
sexuais; uso de contraceptivos orais; multiparidade; baixa in-
gestão de vitaminas; iniciação sexual precoce; e coinfecção por
agentes infecciosos, como o vírus da imunodeficiência huma-
na (HIV) e o Chlamydia trachomatis. A educação em saúde representa uma estratégia muito
importante na formação de comportamentos que promovam
ou mantenham uma boa saúde.7 Ela é uma prática social que
contribui para a formação da consciência crítica das pessoas
a respeito de seus problemas de saúde, levando em conta a
sua realidade. Estimula também a busca de soluções e a orga-
nização de ações individuais e coletivas.8 É considerada um
recurso por meio do qual o conhecimento científico na área
de saúde atinge a vida cotidiana das pessoas, uma vez que
a compreensão dos condicionantes do processo saúde-doença
oferece subsídios para a adoção de novos hábitos e condutas
de saúde.9 O tratamento do câncer de colo de útero é mais efetivo
quando a doença é diagnosticada na fase inicial, antes do apa-
recimento dos sintomas clínicos. Esse fato justifica a importân-
cia de estratégias para a detecção precoce desse tipo de câncer
e de suas lesões precursoras. Dentre os métodos de diagnós-
tico, destaca-se o exame citopatológico cérvico-vaginal (Papa-
nicolau), que consiste em uma tecnologia simples, eficaz e de
baixo custo para o sistema de saúde. INTRODUÇÃO De acordo com a OMS,
quando o rastreamento apresenta boa cobertura – 80% – e é
realizado dentro dos padrões de qualidade, modifica efetiva-
mente as taxas de incidência e mortalidade por esse tipo de
câncer.2 Posto isso, verifica-se que a educação em saúde é forte
aliada no objetivo de despertar mudanças de comportamento. Por intermédio dela, as usuárias do sistema de saúde podem
adquirir informação, refletir sobre suas práticas, bem como
sobre a importância do exame ginecológico e da autovaloriza-
ção. O desafio está em buscar um momento e um espaço para
educar. Diante disso, a sala de espera se mostra como um local
propício para passar informações relevantes à paciente, antes
da consulta, e para compartilhar informações com pessoas que
possuam uma necessidade de saúde em comum.10 Porém, essa
prática deve ser aliada a outras estratégias que visem a pro-
mover e a facilitar a disseminação das informações de forma
criativa e atraente ao maior número de pessoas possível. Apesar da possibilidade de tratamento precoce, essa do-
ença ainda é um problema de saúde pública em países em
desenvolvimento, pois apresenta altas taxas de prevalência
e morbi-mortalidade em mulheres de nível socioeconômico
baixo e na fase produtiva de suas vidas.3 Há um prejuízo
financeiro e social considerável, já que essas mulheres, uma
vez doentes, podem ocupar leitos hospitalares, ficar afas-
tadas do mercado de trabalho e ser privadas do convívio
familiar. Diante dos índices elevados de morbi-mortalidade por
câncer de colo uterino, o governo brasileiro, por meio do Inca/
Ministério da Saúde, desenvolveu, em 1997, um Programa Na-
cional de Rastreamento do Câncer do Colo Uterino, chamado
Programa Viva Mulher. A abordagem adotada pelo programa
é o oferecimento do exame citopatológico e do tratamento ou
acompanhamento das lesões detectadas.4 Assim, o objetivo deste estudo é relatar uma experiência
prática em educação em saúde acerca do tema prevenção do
câncer cérvico-uterino que foi realizada em Ceres e Santa Isa-
bel, GO, tendo como público-alvo usuárias da rede pública
de saúde desses municípios. A temática foi definida a par-
tir da demanda apresentada pelos profissionais de saúde de
ambos os municípios, em razão da baixa adesão ao exame
colpocitológico. KEYWORDS: KEYWORDS:
– Preventive Health Services
– Health Education
– Uterine Cervical Neoplasms
– Public Health. Recebido em: 01/04/2010
Reencaminhado em: 20/08/2010
Aprovado em: 18/09/2010
REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1, Supl. 1) : 149-154; 2012
149 – Preventive Health Services – Health Education – Uterine Cervical Neoplasms – Public Health. Recebido em: 01/04/2010
Reencaminhado em: 20/08/2010
Aprovado em: 18/09/2010
REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1, Supl. 1) : 149-154; 2012
149 149 Bruna Côrtes Rodrigues et al. Educação para Prevenir CA Colo Uterino REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
150 RESULTADOS E DISCUSSÃO Os resultados do período de integração entre acadêmicos e
comunidade são apresentados a seguir. Embora de curta du-
ração, essa vivência foi muito gratificante para os participan-
tes e terá inegável repercussão em suas práticas profissionais
futuras. Como o objetivo era alcançar o maior número de pessoas
possível, optou-se por realizar diferentes ações comunicativas,
tais como: 1. Confecção e distribuição de cartazes e panfletos;
2. Apresentação de um programa de rádio; 3. Realização de
rodas de conversa na sala de espera com as usuárias nas Uni-
dades Básicas de Saúde (UBS). Os panfletos confeccionados, além de serem distribuídos
às usuárias, também foram fornecidos aos agentes comu-
nitários de saúde para serem entregues à comunidade, pois
foi percebido que, dessa forma, esse meio de comunicação
poderia ser mais bem propagado entre a população. Na sala
de espera, os acadêmicos também utilizaram o folheto como
guia para as respostas, auxiliando na compreensão deste pelas
usuárias. O material impresso permite ao usuário uma leitu-
ra posterior, reforçando as informações orais e servindo como
guia de orientação.12 O panfleto continha informações em forma de perguntas e
respostas sobre exame citopatólogico e câncer do colo do úte-
ro. Procurou-se utilizar linguagem coerente com o público-al-
vo e elaborar explicações e orientações de uma forma didática,
auxiliadas por figuras simples e coloridas. Foram feitos dois
modelos de cartazes, ambos bem coloridos e atrativos, com
mensagens e figuras de incentivo à realização desse exame. A preparação e a apresentação de um programa de rádio
foram feitas de forma a abordar o tema de maneira clara e
didática, incluindo-o em situações cotidianas da vida da po-
pulação. O programa foi transmitido ao vivo pela Rádio Al-
vorada de Rialma – GO, na frequência de 810 kHz (AM), no
dia 4/2/2010 às 20h, com duração de 30 minutos. Foi disponi-
bilizado o número do telefone da rádio para que os ouvintes
pudessem expor dúvidas sobre o assunto. Os dois modelos de cartazes foram afixados em todas
as UBSs, mas verificou-se que, em uma das unidades, o car-
taz com a silhueta de mulher nua havia sido retirado um dia
após a colagem. A justificativa dada para esse ato foi a de
que a imagem poderia escandalizar a população. INTRODUÇÃO Apesar dessa iniciativa, os resultados não têm sido satis-
fatórios, pois as taxas de mortalidade por esse tipo de câncer
continuam moderadamente altas no País e, do ponto de vista
temporal, vem-se mantendo estáveis.5 Uma explicação para
esse resultado pode ser a não adesão das mulheres ao exame
preventivo. Tal atividade faz parte do Programa de Educação pelo
Trabalho para a Saúde (PET-Saúde), instituído pelo Ministé-
rio da Saúde em parceria com o Ministério da Educação, para
viabilizar programas de iniciação ao trabalho, estágios e vi- REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
150 Educação para Prevenir CA Colo Uterino Bruna Côrtes Rodrigues et al. vências dirigidos aos estudantes da área da saúde e pesquisas
voltadas para melhoria da qualidade dos serviços de saúde. por figuras, espéculo e molde do aparelho reprodutor femini-
no. As questões foram estruturadas com o intuito de estimular
reflexão e debate sobre o assunto. Além disso, as mulheres fo-
ram instigadas a discutir e partilhar tanto seus conhecimentos
prévios a respeito do tema, quanto suas experiências pessoais. Após cada conversa, os educadores/coordenadores se reu-
niam para discutir as vivências e registrar suas observações e
percepções, bem como as manifestações dos grupos. METODOLOGIA O trabalho se trata de um relato descritivo sobre uma ativida-
de de educação em saúde desenvolvida por nove acadêmicos
de Medicina e Enfermagem da Universidade de Brasília – UnB
acerca do tema prevenção do câncer de colo cérvico-uterino,
nos municípios de Ceres e Santa Isabel, Goiás, no período de 2
a 7 de fevereiro de 2010. RESULTADOS E DISCUSSÃO Essa atitu-
de evidencia a dificuldade que existe em lidar com o corpo e
corrobora o fato de a vergonha e o desconforto serem moti-
vos para as mulheres não realizarem o exame citopatológico
cérvico-vaginal.6 Esses sentimentos são comuns na realização
de exames íntimos, mas devem ser confrontados quando im-
pedem a realização de um procedimento que, feito dentro dos
padrões de qualidade, modifica efetivamente as taxas de inci-
dência e mortalidade pelo câncer do colo de útero.2 Por isso,
foi escolhida a figura de uma silhueta de mulher nua para
fazer parte dos cartazes. Tomados os devidos cuidados para
que a imagem não fosse agressiva ou vulgar, ela represen-
tava a mulher em contato com seu corpo e sem conflito. No
entanto, o estigma existente sobre a relação da mulher com
o próprio corpo, no qual se compreende o seu contato como
algo inapropriado, ainda é muito forte, inclusive entre alguns
profissionais da saúde que desconhecem a interferência desse
estigma na adesão ao exame. Por prever esse tipo de reação
e ter como objetivo principal a divulgação de informações, Veríssimo e Valle11 referem que o grupo de sala de espera é
caracterizado como uma forma produtiva de ocupar um tem-
po ocioso nas instituições, com a transformação do período
de espera pelas consultas médicas em momento de trabalho. Com o intuito de preencher esse espaço em potencial, foram
realizadas rodas de conversas na sala de espera em três Unida-
des Básicas de Saúde, com duração média de 30 minutos cada
uma delas. O grupo era disposto em círculo em local reserva-
do, e a temática era desenvolvida em duas etapas distintas:
dinâmica corporal e conversa estruturada por perguntas. Na primeira etapa, a proposta era realizar uma atividade
de alongamento e contato corporal individual, acompanhada
de música relaxante. Na segunda etapa, cada mulher selecio-
nava um número correspondente a uma pergunta previamen-
te elaborada pelos acadêmicos. Em seguida, cada participante
respondia à pergunta selecionada e, caso necessário, os acadê-
micos explicavam e/ou sanavam dúvidas, sendo auxiliados REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
151 Bruna Côrtes Rodrigues et al. Educação para Prevenir CA Colo Uterino Na primeira unidade, oito mulheres participaram ativa-
mente tanto da dinâmica quanto da discussão e criaram um
ambiente de descontração e cumplicidade. RESULTADOS E DISCUSSÃO Foi observado que
elas já conversavam descontraídas antes da atividade, inclusi-
ve sobre o exame colpocitológico. Já na segunda UBS, o gru-
po de oito usuárias aguardava a consulta antes da atividade
sem muito entrosamento, mostrando-se bem inibido e pouco
participativo na etapa inicial, o que revelou dde sua parte di-
ficuldade em tocar o próprio corpo. Na discussão do tema, as
mulheres expressaram-se pouco, respondendo com escassez
de palavras aos questionamentos feitos pelos acadêmicos. No
entanto, após a chegada de uma usuária que fazia diversas
perguntas, elas se sentiram mais à vontade para participar da
atividade, expor dúvidas e compartilhar histórias. Na terceira
unidade, apenas quatro mulheres participaram, o que, con-
tudo, não tornou a conversa menos proveitosa. As usuárias
pareciam tranquilas, esclareceram dúvidas e uma participante
que não fazia o exame há 10 anos decidiu marcar uma consul-
ta logo após a conversa. também foram confeccionados cartazes com gravura menos
impactante. Optou-se pela realização de programa de rádio por ser,
segundo Nascimento,13 “um poderoso instrumento de comu-
nicação e um espaço de interação entre a lógica de pensar das
camadas populares e a lógica do conhecimento técnico-cientí-
fico representado principalmente pelos profissionais da saú-
de”. Também por ser um dos meios de comunicação de massa
mais acessíveis para a população rural,14 como era o caso dos
municípios envolvidos, o rádio torna-se um importante canal
para realização de iniciativas que aproximam diferentes reali-
dades, visando a um crescimento cultural e educacional. Nessa experiência, buscou-se inserir as situações viven-
ciadas pela comunidade e a linguagem utilizada pela popu-
lação ao tratar do tema prevenção do câncer cérvico-uterino. O programa de rádio contou com a participação de duas en-
fermeiras e, no seu decorrer, três usuárias ligaram para sanar
dúvidas quanto ao exame colpocitológico. De acordo com
Freire,15 “a educação é comunicação, é diálogo, na medida em
que não é a transferência de saber, mas um encontro de sujei-
tos interlocutores que buscam a significação dos significados”. Portanto, quanto maior a participação do receptor no processo
de educação, mais efetivo este é. As questões levantadas por
ouvintes durante o programa de rádio demonstraram que eles
se apropriaram do tema abordado e o transferiram para suas
próprias realidades. RESULTADOS E DISCUSSÃO Os questionamentos foram: se o exame é
recomendado para mulheres que realizaram histerectomia; se
quem ainda não teve relação sexual pode realizá-lo; e o que
fazer se não for possível realizar o exame nos dias da semana
determinados pela UBS. Além de as dúvidas terem sido es-
clarecidas durante o programa de rádio, elas também foram
abordadas pelos acadêmicos durante as conversas nas salas de
espera. Isso demonstra que o conteúdo tratado nas atividades
estava de acordo com a necessidade da comunidade. A priori, os clientes que estão na sala de espera não cons-
tituem um grupo propriamente dito, mas um agrupamento. Geralmente as pessoas que se encontram nesse espaço não
se conhecem nem mantêm um vínculo estável,17 entretanto,
como expressam Rodrigues et al.,18 a sala de espera permite o
“reconhecimento da realidade sociocultural, bem como cren-
ças e a expressão dos sentimentos dos participantes”. Para
isso, quanto mais confortáveis as usuárias estiverem para ex-
por suas ideias e anseios, mais fáceis serão as trocas entre as
participantes da conversa. Foi observado que a interação das
usuárias com a atividade esteve relacionada ao entrosamento
delas entre si, o que justifica a diferença de reação entre a pri-
meira e a segunda UBS. Na terceira, as usuárias também não
estavam interagindo antes da atividade, mas o fato de haver
poucas pessoas no grupo possivelmente permitiu que elas se
sentissem mais à vontade para expor opiniões e dúvidas sobre
o tema. Abrir espaços de produção de diálogo, reflexão e pro-
blematização junto à comunidade possibilita a construção
de uma relação de corresponsabilidade, favorecendo formas
mais humanas e efetivas do processo de trabalho em saúde.16
Com esse intuito, a atividade de sala de espera tem-se mostra-
do interessante meio de estreitamento da relação entre serviço
de saúde e usuários e, por isso, foi utilizada como estratégia
nessa vivência. A etapa das perguntas previamente elaboradas estimulou
a reflexão e a discussão sobre o assunto. Durante a atividade,
outras questões foram discutidas pelo grupo, seja por dúvidas
e comentários expostos pelas usuárias, seja por novos questio-
namentos trazidos pelos acadêmicos. A pergunta sobre o conceito de câncer foi a que mais gerou
dúvidas ou respostas gerais, como: “é uma doença que mata”. REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
152 RESULTADOS E DISCUSSÃO Aparentemente, esse assunto é transmitido para a população
como algo assustador, uma doença cruel que deve ser evitada
por intermédio da realização do exame, porém, geralmente,
outras informações relevantes não costumam ser comunica-
das. Apesar de, aparentemente, ser a maneira mais eficaz de As rodas de conversas realizadas nas UBSs foram condu-
zidas por uma dupla fixa de acadêmicos, seguindo um roteiro
pré-estruturado. Contudo, verificou-se que cada grupo reagiu
de forma diferente a essa dinâmica. Tal fato era esperado uma
vez que a sala de espera é um local onde as pluralidades emer-
gem por meio do processo interativo.17 REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
152 Educação para Prevenir CA Colo Uterino Bruna Côrtes Rodrigues et al. e a prevenção de doenças. Além disso, mostrou ser uma ótima
oportunidade no sentido de estreitar a relação entre ensino,
serviço e comunidade, a partir da qual todos saem beneficia-
dos. Durante as conversas, foi possível aferir que a carência
de informação da população foi abrangida e foi permitido
um processo de trocas de experiências entre pessoas distintas
e intercâmbios de saberes. Aos acadêmicos foi permitido de-
senvolver a capacidade reflexiva diante dos diversos cenários
encontrados e expandir seus conhecimentos acerca do tema
prevenção do câncer cérvico-uterino. Além disso, possibilitou-
-se a interação interdisciplinar entre acadêmicos de Medicina
e Enfermagem. Se as atividades repercutirão em maior adesão
das usuárias à prevenção do câncer do colo do útero, ainda é
cedo para afirmar. No entanto, os autores do presente trabalho
acreditam que a educação em saúde é um ponto fundamental
na edificação de um sistema de saúde mais eficaz e, portanto,
mais experiências devem ser relatadas a fim de que se expan-
da tal prática. conseguir a adesão das usuárias de saúde, essa prática parece
ser pouco efetiva, pois várias usuárias demonstraram o medo
de desenvolver o câncer, mas, contraditoriamente, não reali-
zam o exame colpocitológico com justificativas diversas, tais
como: “não sinto nada”, “só tive um homem”, “eu esqueço”,
“dá muita vergonha fazer esse exame”, entre outras. A interpretação equivocada de que a usuária é desprovida
de autocuidado por enumerar tais justificativas não deve ser
prática na rotina da assistência. Deve-se ter em mente que o
cuidado que a paciente tem consigo mesma adentra a esfera
relacional, ou seja, compreende a relação estabelecida entre
ela, o serviço e os profissionais da saúde. REFERÊNCIAS 1. Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Estimativa 2010: incidência de câncer no Brasil. Rio de Ja-
neiro: INCA; 2009. 1. Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Estimativa 2010: incidência de câncer no Brasil. Rio de Ja-
neiro: INCA; 2009. 2. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Controle dos cânceres
do colo do útero e da mama. Brasília: Ministério da Saúde;
2006. 3. Brenna SMF. Conhecimento, atitude e prática do exame
de Papanicolau em mulheres com câncer de colo uteri-
no. Caderno de Saúde Pública. Jul-ago de 2001; 17(4):909-
914. 4. Pinho VFS, Coutinho ESF. Variáveis associadas ao câncer
de mama em usuárias de unidades básicas de saúde. Ca-
derno de Saúde Pública. 2007; 23(5):1061-1069. 5. Martins LFL, Thuler LCS, Valente JG. Cobertura do exa-
me de Papanicolau no Brasil e seus fatores determinantes:
uma revisão sistemática da literatura. Rev. bras. ginecol. obstet. Ago de 2005; 27(8):485-492. RESULTADOS E DISCUSSÃO Tal relação engloba
acesso, acolhimento, vínculo construído, compartilhamento
de queixas e angústias e elaboração de condutas adequadas
ao contexto.16 A visão do autocuidado por essa óptica é impor-
tante no sentido de questionar a abordagem que está sendo
oferecida às pacientes e de incentivar a corresponsabilização
pela adesão a tratamentos e medidas preventivas. Apoio: Projeto financiado pelo Fundo Nacional de Saúde. Especificamente relacionada ao tema desenvolvido neste
trabalho está a importância de os profissionais se esforçarem
em dissociar a visão funesta do câncer e despertar ânimo ao
lidar com um paciente que tenha recebido tal diagnóstico. Quando informadas de como o câncer surge, os fatores de ris-
co associados, por que o exame previne e por que é realizado
daquela maneira, há uma emancipação das usuárias, que por
meio do conhecimento deixam de ter uma atuação passiva e
passam a ser sujeitos na promoção de sua própria saúde.9 Por-
tanto, o empoderamento da usuária dentro do seu processo
de autocuidado perpassa o conhecimento. Nesse contexto, é
necessária a construção de espaços de diálogo com a comu-
nidade.16 Tendo em vista essa proposta, as rodas de conversa
em sala de espera mostraram-se uma ferramenta útil para a
discussão sobre o câncer de colo uterino e sua prevenção, ca-
racterizando-se como uma oportunidade de troca de saberes e
aprendizagem. CONTRIBUIÇÃO DOS AUTORES CONTRIBUIÇÃO DOS AUTORES 9. Candeias NMF. Conceitos de educação e de promoção em
saúde: mudanças individuais e mudanças organizacionais. Rev. Saúde Pública [Internet]. 1997; 31(2):209-213. Disponí-
vel em: http://www.scielo.br/pdf/rsp/v31n2/2249.pdf. Todos os autores auxiliaram na concepção e planejamento do
projeto e desenho do estudo, análise e interpretação dos da-
dos e revisão crítica do artigo. Bruna C. Rodrigues também
auxiliou na redação resumo, introdução, metodologia e resul-
tados/discussão. Ana Catarine M de Oliveira Carneiro e Ana
Cláudia N. Solá, auxiliaram na obtenção de dados, na redação
resumo, introdução, metodologia e resultados/discussão e
considerações finais. Tábata L. da Silva auxiliou na redação
da introdução, resultados/discussão e metodologia. Natália
de Melo Manzi auxiliou na, obtenção de dados, na redação
da metodologia e resultados/discussão. Noel P. Schechtman
auxiliou na redação do abstract e resultados/discussão. Hugo
Leonardo G. de Oliveira Magalhães auxiliou na obtenção dos
dados, redação do abstract e resultados/discussão. Jane L. G. Dytz auxiliou na concepção e desenho do estudo e ajuda na
redação da metodologia. 10. Moraes MLC, Costa PB, Aquino OS, Pinheiro AKB. Edu-
cação em saúde com prostitutas de Fortaleza: relato de
experiência. Rev. Eletr. Enf. [Internet]. 2008;10(4):1144-51. Disponível em: http://www.fen.ufg.br/revista/v10/n4/
v10n4a27.htm. 11. Veríssimo DS, Valle ERM. A experiência vivida por pessoas
com tumor cerebral e por seus familiares. Psicol. Argum. Abr-jun de 2006; 24(45):45-57. 12. Torres HC, Candido NA, Alexandre LR, Pereira FL. O pro-
cesso de elaboração de cartilhas para orientação do auto-
cuidado no programa educativo em Diabetes. Rev. bras. enferm. Mar-abr de 2009; 62(2):312-316. 13. Nascimenro JA, Dias CV, Rodrigues HC, Passos MRS,
Faustino RV. Educação popular na prática do PSF: expe-
riência em rádio comunitária. Rev. Sobralense de Políticas
Públicas. 1999; 1(1):32-37. CONSIDERAÇÕES FINAIS A partir dessa vivência, compreendeu-se a experiência como
algo de grande valia, apesar de não ter sido possível a men-
suração de quanto a população assimilou e quanto a informa-
ção foi disseminada. A utilização da mídia impressa e verbal
visou a atingir o maior número de usuárias, porém o alcance
de tal estratégia é de difícil delimitação. Em contrapartida, as
conversas na sala de espera, considerando-se o número de
pessoas abordadas, foi o de menor impacto quantitativo, mas
foi a estratégia que permitiu a maior interação entre os aca-
dêmicos e as usuárias. Tal atividade demonstrou ser uma boa
alternativa para promover o processo de educação em saúde 6. Pinho AA. Cobertura e motivos para a realização ou não
do teste de Papanicolau no Município de São Paulo. Cad. Saúde Pública. 2003; 19(2):303-313. 7. Campos JADB, Zuanon ACC, Guimarães MS. Educação
em saúde na adolescência. Ciên. odontol. bras. Out-dez de
2003; 6(4):48-53. 8. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Especializada. Manual de Edu-
cação em Saúde. Brasília: Ministério da Saúde; 2008. REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
153 Bruna Côrtes Rodrigues et al. Educação para Prevenir CA Colo Uterino REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
154 CONFLITO DE INTERESSES
Declarou não haver. Declarou não haver. 14. Oliveira KF. O potencial educativo do rádio e da comuni-
cação popular. Cad. Cult. Ciênc. 2008; 2(1):22-35. ENDEREÇO PARA CORRESPONDÊNCIA ENDEREÇO PARA CORRESPONDÊNCIA
Bruna Côrtes Rodrigues
SGAS 606, conj A, apto 15
Asa Sul – Brasília
CEP. 70200-660 DF
E-mail: brunacr.med@gmail.com ENDEREÇO PARA CORRESPONDÊNCI
Bruna Côrtes Rodrigues
SGAS 606, conj A, apto 15
Asa Sul – Brasília
CEP. 70200-660 DF
E-mail: brunacr.med@gmail.com 15. Freire P. Pedagogia da Esperança. 8ª ed. Rio de Janeiro: Paz
e Terra; 2001. 16. Camargo-Borges C, Japur M. Sobre a (não) adesão ao trata-
mento: ampliando sentidos do autocuidado. Texto e Con-
texto Enferm. Jan-Mar de 2008; 17(1):64-71. 17. Teixeira ER, Veloso RC. O grupo em sala de espera: territó-
rio de práticas e representações em saúde. Texto e Contex-
to Enferm. Abr-Jun de 2006; 15(2):320-325. 18. Rodrigues AD, Dallanora CR, Rosa J. Sala de espera: um
ambiente para efetivar a educação em saúde. Vivências. Mai de 2009; 5(7):101-106. REVISTA BRASILEIRA DE EDUCAÇÃO MÉDICA
36 (1 Supl. 1) : 149 – 154 ; 2012
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BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young
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© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
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https://doi.org/10.1186/s40478-020-01023-3 Tateishi et al. acta neuropathol commun (2020) 8:139
https://doi.org/10.1186/s40478-020-01023-3 Open Access BRAF V600E mutation mediates
FDG‑methionine uptake mismatch
in polymorphous low‑grade neuroepithelial
tumor of the young Kensuke Tateishi1* , Naoki Ikegaya1, Naoko Udaka2, Jo Sasame1, Takahiro Hayashi1, Yohei Miyake1,
Tetsuhiko Okabe3, Ryogo Minamimoto4, Hidetoshi Murata1, Daisuke Utsunomiya3, Shoji Yamanaka2
and Tetsuya Yamamoto1 Abstract We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography
imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous
low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor
as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-
methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major
transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also
found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and
c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF
V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in
PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc
induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease. Keywords: PLNTY, BRAF V600E mutation, Methionine PET, LAT1 are commonly driven by genomic alterations in the Ras/
mitogen-activated protein kinase (MAPK) pathway,
such as mutations in BRAF and NF-1 [23, 29]. Recent
large-scale genomic studies and genome-wide meth-
ylation analyses allowed a thorough characterization of
P-LGNTs [24], and cIMPACT-NOW (the Consortium
to Inform Molecular and Practical Approaches to CNS
Tumor Taxonomy) currently classifies P–LGNTs as dis-
tinct disease entities [4, 17]. In 2017, Huse et al. described
ten cases of polymorphous low-grade neuroepithelial
tumor of the young (PLNTY), which were histologically
characterized by oligodendroglioma-like cellular compo-
nents with intense CD34 immunopositivity. According
to previous publications, PLNTYs are indolent tumors Introduction Pediatric low-grade neuroepithelial tumors (P-LGNTs)
encompass a group of central nervous system neoplasms
that includes long-term epilepsy-associated tumors
(LEATs), such as ganglioglioma and dysembryoplastic
neuroepithelial tumor (DNT). P-LGNTs have differ-
ent characteristics than their adult counterparts, and *Correspondence: ktate12@yokohama‑cu.ac.jp
1 Department of Neurosurgery, Graduate School of Medicine, Yokohama
City University, 3‑9 Fukuura, Kanazawa, Yokohama 2360004, Japan
Full list of author information is available at the end of the article *Correspondence: ktate12@yokohama‑cu.ac.jp
1 Department of Neurosurgery, Graduate School of Medicine, Yokohama
City University, 3‑9 Fukuura, Kanazawa, Yokohama 2360004, Japan
Full list of author information is available at the end of the article Western blotting
ll
l
d Cells were lysed in RIPA buffer (Sigma-Aldrich) with a
cOmplete™, Mini, EDTA-free Protease Inhibitor Cocktail
(Roche). Fifty micrograms of protein was separated by
10% SDS-PAGE gel and transferred to polyvinylidene dif-
luoride membranes (Millipore) by electroblotting. After
blocking with 1% or 5% nonfat dry milk in TBST (25 mM
Tris [pH, 7.4], 137 mM NaCl, 0.5% Tween20), mem-
branes were incubated at 4 °C overnight with primary
antibodies. After washing and incubation with horserad-
ish peroxidase-conjugated secondary antibodies (Cell
Signaling Technology), blots were washed, and signals
were visualized with chemiluminescent HRP substrate
(Millipore). Primary antibodies against BRAF (Gene
Tex), c-Myc (Cell Signaling Technology), GAPDH (Gene
Tex), LAT1 (Cell Signaling Technology), phospho-MEK
(Cell Signaling Technology), phospho-ERK (Bethyl Labo-
ratories), and Vinculin (Novus Biologicals) were used for
western blotting. Tateishi et al. acta neuropathol commun (2020) 8:139 Tateishi et al. acta neuropathol commun (2020) 8:139 Page 2 of 8 that generally exhibit a benign clinical course and har-
bor either a BRAF V600E mutation or FGFR2/FGFR3
fusion [9]. Based on its histological and genomic profiles,
cIMPACT-NOW Update 6 recommends PLNTY as a
possible future classification for pediatric-type glial/gli-
oneuronal tumors. However, because of their rare etiol-
ogy, only a few PLNTYs have been described to date [3, 5,
9, 10, 16, 21, 27, 28], and it is unclear how genomic alter-
ations promote the pathogenesis of the disease. Herein,
we present a case of PLNTY with unique metabolic imag-
ing features. Using positron emission tomography (PET),
we found regions of heterogeneous high 11C-methionine
uptake and homogenous low 18F-fluorodeoxyglucose
(FDG) uptake within the tumor. Activation of the MAPK
pathway, c-Myc, and expression of L-type amino acid
transporter 1 (LAT1) were increased in the high-methio-
nine-uptake area compared with the surrounding cortex
(low-methionine-uptake). Glycolytic metabolites were
expressed only weakly in tumor cells. Pharmacological
and genetic inhibition of the MAPK pathway suppressed
c-Myc and LAT1 and inhibited tumor cell viability, sug-
gesting that MAPK signaling and downstream c-Myc
activates methionine metabolism and inhibition of this
pathway induces therapeutic vulnerability in PLNTY. non-silencing lentiviral shRNA Control (RHS4348, Hori-
zon Discovery) was used as a non-silencing (NS) control. Materials and methods
Cell viability analysis y
y
AM-38 and normal human astrocytes was purchased
from JCRB Cell Bank and ScienCell Research Labora-
tories, respectively. Tumorsphere lines were cultured
in serum-free neural stem cell medium, as previously
described [31]. Normal human astrocytes were cultured
with astrocyte medium (ScienCell). To assess cell viabil-
ity, primary cultured cells were dissociated into single
cells and seeded into 96-well plates at a density of 3000
cells/well. After 12 h, dabrafenib (Selleck) and trametinib
(Selleck) were serially diluted and added to the wells. Cell
viability was measured using the CellTiter-Glo (Promega)
assay at day 3, and the results were indicated as % viabil-
ity of the DMSO control. Immunohistochemistry Tumor tissue specimens were fixed in 10% neutral buff-
ered formalin and embedded in paraffin. Hematoxylin
and eosin staining was performed using standard pro-
cedures. For immunohistochemical analysis, 5-µm-thick
sections were deparaffinized, treated with 0.5% H2O2 in
methanol, rehydrated, and heated for 20 min for antigen
retrieval. After blocking with serum, tissue sections were
incubated with primary antibodies against CD34 (Novus
Biologicals), LAT1 (Cell Signaling Technology), phospho-
MEK (Cell Signaling Technology), phospho-ERK (Bethyl
Laboratories), and c-Myc (Cell Signaling Technology) at
4 °C overnight. The next day, sections were washed with
PBS, incubated with biotinylated secondary antibody for
30 min at room temperature, and then incubated with
ABC solution (PK-6101, PK-6102; Vector laboratories)
for 30 min at room temperature. Finally, the sections
were incubated with DAB (Dako) and counter-stained
with hematoxylin. Case presentationh To knockdown BRAF, 293T cells were transfected with
lentiviral vector packaging plasmid DNA containing
6 μg of Human BRAF shRNA (#1, TRCN0000381693;
#2, TRCN0000196844; Sigma Aldrich), 3.5 μg of pHIV-
GP, and 3.5 μg of pVSVg-Rev with Lipofectamine™ 3000
(Thermo Fisher Scientific). YMG62 and AM-38 cells were
infected with lentivirus in polybrene (8 μg/mL) for 12 h. Two days later, the cells were selected with puromycin
(0.6 μg/mL) for 2 days, and used for experiments. GIPZ This study was performed in accordance with decla-
ration of Helsinki and was approved by the Institu-
tional Review Board (Yokohama City University [YCU,
Yokohama, Japan], IRB numbers: A1711300006 and
B190600002). Written informed consent was obtained
from the patient and parents. A 14-year old boy pre-
sented with chronic medial temporal lobe epilepsy for
a year. Magnetic resonance imaging (MRI) indicated Page 3 of 8
Tateishi et al. acta neuropathol commun (2020) 8:139
Fig. 1 Characteristics of a patient with PLNTY. a T2-weighted (left), T1-weighted (middle), and contrast-enhanced (right) MR images. b Computed
tomography (CT, left), 18F-fluorodeoxyglucose-PET/CT (middle), and 11C-methionine-PET/CT (right) images. c Video electroencephalography
indicating ictal onset in the left temporal lobe, with spread to the contralateral temporal lobe. d PET/CT and MRI merged intraoperative navigation
image (left) and surgical image (right) showing the high-methionine-uptake region (#1) and surrounding abnormal lesion (#2) on MRI
(See figure on next page.) Tateishi et al. acta neuropathol commun (2020) 8:139 Page 3 of 8 Fig. 1 Characteristics of a patient with PLNTY. a T2-weighted (left), T1-weighted (middle), and contrast-enhanced (right) MR images. b Computed
tomography (CT, left), 18F-fluorodeoxyglucose-PET/CT (middle), and 11C-methionine-PET/CT (right) images. c Video electroencephalography
indicating ictal onset in the left temporal lobe, with spread to the contralateral temporal lobe. d PET/CT and MRI merged intraoperative navigation
image (left) and surgical image (right) showing the high-methionine-uptake region (#1) and surrounding abnormal lesion (#2) on MRI
(See figure on next page.) Fig. 1 Characteristics of a patient with PLNTY. a T2-weighted (left), T1-weighted (middle), and contrast-enhanced (right) MR images. b Computed
tomography (CT, left), 18F-fluorodeoxyglucose-PET/CT (middle), and 11C-methionine-PET/CT (right) images. c Video electroencephalography
indicating ictal onset in the left temporal lobe, with spread to the contralateral temporal lobe. Case presentationh d PET/CT and MRI merged intraoperative navigation
image (left) and surgical image (right) showing the high-methionine-uptake region (#1) and surrounding abnormal lesion (#2) on MRI
(See figure on next page.) hypointensity on T2-weighted images and hyperinten-
sity on T1-weighted images, with a cystic component in
the left temporal lobe. Contrast-enhanced MRI showed
no significant enhancement in the lesion (Fig. 1a) while
computed tomography revealed heavy calcification. FDG-PET showed lower FDG uptake in the tumor, while
11C-methionine-PET demonstrated increased methio-
nine uptake in the same lesion (SUVmax = 3.9, tumor/
normal tissue ratio = 2.9; Fig. 1b). Video-electroenceph-
alographic (EEG) monitoring indicated ictal onset in the
left temporal lobe with subsequent spread to the con-
tralateral temporal lobe (Fig. 1c). We speculated that this
abnormal lesion was a LEAT. Since we considered this
tumor to be completely resectable, the patient underwent
craniotomy and resection of the neoplasm, including the
high-methionine-uptake region (Fig. 1d). To achieve epi-
leptic control, electrocorticography was performed intra-
operatively. After removal of the high-methionine-uptake
and T2 hyperintense lesions, the surrounding tissue was
resected until interictal epileptiform discharge could no
longer be detected by electrocorticography. The patient
became epilepsy-free after lesion removal, and MRI indi-
cated complete remission 16 months after the surgery. transporter, was more highly expressed in #1 than in #2
(Fig. 3a). In contrast, GLUT-1 and HK-2, which is cor-
related with FDG uptake, and lactate dehydrogenase A
(LDHA) expression were weak in either region (Addi-
tional file 1: Fig. S1). LAT1 expression is mediated by
c-Myc activation and BRAF V600E mutation activates
the MAPK pathway and downstream c-Myc [8, 32, 33]. Therefore, we hypothesized that BRAF V600E mutation
promotes LAT1 expression through MAPK signaling
and consequent c-Myc activation in PLNTY. Levels of
phospho-MEK, phospho-ERK, and c-Myc were higher
in tissue region #1 than in #2 (Fig. 3a), suggesting activa-
tion of the MAPK pathway and c-Myc within the high-
methionine-uptake lesion. To verify whether the BRAF
V600E mutation can induce the expression of LAT1,
we exposed primary cultured YMG83 PLNTY cells to a
BRAF inhibitor (dabrafenib). As expected, the expression
of phospho-MEK, phospho-ERK, c-Myc, and LAT1 was
suppressed after dabrafenib treatment in YMG83 cells
(Fig. 3b). Notably, BRAF inhibitor (dabrafenib)-treated
YMG83 cells had lower cell viability compared to normal
human astrocytes (Fig. 3c). Case presentationh To confirm the reproducibil-
ity of these molecular features, we used patient-derived
YMG62 cells (epithelioid glioblastoma with the BRAF
V600E mutation), which exhibited high 11C-methionine
uptake by PET imaging (Additional file 1: Fig. S2), and
AM-38 glioblastoma cells (BRAF V600E mutant). We
found that dabrafenib and a MEK inhibitor (trametinib)
inhibited the expression of proteins in the MAPK path-
way as well as c-Myc and LAT1 (Fig. 3d and 3e). Similarly,
BRAF knockdown suppressed the expression of pro-
teins in the MAPK pathway as well as c-Myc and LAT1
(Fig. 3f). Collectively, these findings indicated that acti-
vation of the MAPK pathway by the BRAF V600E muta-
tion deregulates c-Myc and promotes LAT1 expression. This oncogenic signaling pathway increases methionine
metabolism and tumor maintenance in PLNTY. Tissue samples of the high-methionine-uptake region
(#1) and surrounding cortex (low methionine uptake, #2)
were collected. Hematoxylin and eosin staining indicated
diffusely infiltrating growth patterns and presence of
oligodendroglia-like cellular components (Fig. 2a). Astro-
cytic and high-grade features were absent, with a Ki-67
index of less than 2%. Chicken wire-like branching capil-
laries and microcalcification were also found in region #1. Despite lower cellularity, oligodendroglia-like cells were
present in the surrounding tissue. Immunohistochemis-
try revealed extensive CD34 expression and peripherally
associated ramified neural elements in the tumor cells
(Fig. 2a). Targeted DNA sequencing identified a BRAF
V600E mutation in the tumor, without recurrent muta-
tions in IDH1, IDH2, TERT promoter, FGFR1, H3F3A, or
HIST3H1B (Fig. 2b). Chromosome 1p/19q co-deletion
was absent (Fig. 2c). The above histological and genetic
features fulfilled the diagnostic criteria for PLNTY. Discussionh Thirty cases of PLNTY have been described to date, with
the first ten reported by Huse et al. in 2017 [3, 5, 9, 10,
16, 21, 27, 28]; BRAF V600E mutation was seen in 14 of
the patients and BRAF fusion in 1 patient. These BRAF
alterations were mutually exclusive with other genomic
events, including FGFR3-TACC3 fusion, FGFR3 ampli-
fication, FGFR2-CTNNA3 fusion, FGFR2-INA fusion, i
To assess the mechanisms underlying the methionine-
FDG uptake mismatch indicated by PET, we compared
the expression of LAT1, glucose transporter 1 (GLUT-
1), and hexokinase-2 (HK-2) between tissue regions #1
and #2. Notably, LAT1, which is a major methionine Tateishi et al. acta neuropathol commun (2020) 8:139 Page 4 of 8 Tateishi et al. acta neuropathol commun (2020) 8:139 Page 5 of 8 Fig. 2 Histopathologic and genomic features of a patient with PLNTY. a Hematoxylin and eosin (H&E) staining (top) and CD34
immunohistochemistry (bottom) in the high-methionine-uptake (#1) and low-methionine-uptake (#2) region within tumor tissue. Bars, 50 μm. b Sanger sequencing for detection of BRAF V600E (arrow, left) and IDH1 R132H (arrow, right) mutations. c Fluorescence in situ hybridization for
detection of 1p31/1q25 (left) and 19q13/19p13 (right) chromosomal deletions Fig. 2 Histopathologic and genomic features of a patient with PLNTY. a Hematoxylin and eosin (H&E) staining (top) and CD34
immunohistochemistry (bottom) in the high-methionine-uptake (#1) and low-methionine-uptake (#2) region within tumor tissue. Bars, 50 μm. b Sanger sequencing for detection of BRAF V600E (arrow, left) and IDH1 R132H (arrow, right) mutations. c Fluorescence in situ hybridization for
detection of 1p31/1q25 (left) and 19q13/19p13 (right) chromosomal deletions Fig. 2 Histopathologic and genomic features of a patient with PLNTY. a Hematoxylin and eosin (H&E) staining (top) and CD34
immunohistochemistry (bottom) in the high-methionine-uptake (#1) and low-methionine-uptake (#2) region within tumor tissue. Bars, 50 μm. b Sanger sequencing for detection of BRAF V600E (arrow, left) and IDH1 R132H (arrow, right) mutations. c Fluorescence in situ hybridization for
detection of 1p31/1q25 (left) and 19q13/19p13 (right) chromosomal deletions Fig. 2 Histopathologic and genomic features of a patient with PLNTY. a Hematoxylin and eosin (H&E) staining (top) and CD34
immunohistochemistry (bottom) in the high-methionine-uptake (#1) and low-methionine-uptake (#2) region within tumor tissue. Bars, 50 μm. b Sanger sequencing for detection of BRAF V600E (arrow, left) and IDH1 R132H (arrow, right) mutations. Discussionh c Fluorescence in situ hybridization for
detection of 1p31/1q25 (left) and 19q13/19p13 (right) chromosomal deletions FGFR2- KIAA1598 fusion, FGFR2 rearrangement, and
NTRK2 disruption, suggesting that the vast majority of
PLNTYs are induced by BRAF mutation or FGFR fusion
and subsequent MAPK activation. Therefore, target-
ing MAPK signaling may become a potential therapeu-
tic strategy in PLNTY. Indeed, BRAF V600E-mutated
PLNTY cells were relatively vulnerable to dabrafenib and
trametinib in the present study. Thus, targeted molecular
therapy for the MAPK pathway may be particularly use-
ful in PLNTY located in surgically unresectable regions. In addition, Koh et al. reported that the BRAF V600E mutation contributes to the intrinsic epileptogenicity
in pediatric brain tumors, and that inhibition of BRAF
suppressed epileptic seizures [14]. Thus, BRAF/MEK
inhibitors could exert anti-epileptic as well as anti-tumor
effects in PLNTY. f
PET imaging revealed a region with increased
methionine uptake and low FDG uptake within tumor
tissue in our patient. Consistent with this finding, pre-
vious case reports demonstrated increased methio-
nine uptake but only mild FDG uptake in patients with
BRAF V600E-mutated PLNTY [5, 16]. Thus, excessive Tateishi et al. acta neuropathol commun (2020) 8:139 Page 6 of 8 Fig. 3 Activating the MAPK pathway induces LAT1 expression in a patient with PLNTY. a Immunohistochemistry of indicated proteins in the
high-methionine-uptake (#1) and low-methionine-uptake (#2) regions within tumor tissue. Bars, 50 μm. b Western blot analysis of phospho-MEK,
phospho-ERK, c-Myc, and LAT1 proteins in YMG83 (PLNTY, left) cells treated with DMSO and 10 μM BRAF inhibitor (BRAFi, dabrafenib) for 12 h. GAPDH, loading control. c Relative cell viability of dabrafenib-treated (left) and trametinib-treated (right) YMG83 cells and immortalized normal
human astrocytes (NHA). *P < 0.05, DMSO versus dabrafenib (left) and trametinib (right). d Western blot analysis for indicated proteins in YMG62
(epithelioid glioblastoma, left) and AM-38 (glioblastoma, right) cells treated with DMSO, 10 μM BRAF inhibitor (BRAFi, dabrafenib), and 10 μM MEK
inhibitor (MEKi, trametinib) for 24 h. GAPDH, loading control. e Western blot analysis of BRAF, phospho-MEK, phospho-ERK, c-Myc, and LAT1 proteins
in YMG62 (left) and AM-38 (right) cells treated with DMSO and dabrafenib at indicated concentrations. Vinculin, loading control. f Western blot
analysis for indicated proteins in non-silencing- (NS) and BRAF- (#1 and #2) transduced YMG62 and AM38 cells. GAPDH, loading control Fig. 3 Activating the MAPK pathway induces LAT1 expression in a patient with PLNTY. Supplementary information accompanies this paper at https://doi.
org/10.1186/s40478-020-01023-3. Supplementary information accompanies this paper at https://doi. org/10.1186/s40478-020-01023-3. Previous studies have reported that methionine
uptake was correlated with LAT1 in gliomas [13, 18]. LAT1 plays a major role in the transport of neutral
essential amino acids, including methionine, and is
driven by several cancer-related genes such as MYC
[25]. It has been demonstrated that c-Myc, which
is partly mediated by the MAPK pathway, regulates
LAT1 expression and MEK inhibitor suppresses LAT1
(SLC7A5) transcription [6, 8], thereby indicating a role
of the MAPK pathway and c-Myc in the regulation of
LAT1. Since RAS/MAPK pathway-associated genomic
alterations are common in LEATs [24] and that the
BRAF V600E mutation has been identified in 20–60%
and 30% of gangliogliomas and DNTs, respectively [2,
26], there is a possibility that the BRAF V600E mutation
and MAPK pathway-related genomic alterations may
activate methionine metabolism in LEATs. To investi-
gate this hypothesis, we evaluated the protein expres-
sion of LAT1 and the molecules that are involved in the
MAPK pathway. As expected, levels of phospho-MEK,
phospho-ERK, c-Myc, and LAT1 were higher in the
high-methionine-uptake area than in the low-methio-
nine-uptake area. We also found that genetic and/or
pharmacological BRAF inhibition suppressed MAPK
pathway activation and attenuated LAT1 expression in
BRAF V600E-mutated-PLNTY cells and -glioblastoma
cell lines. These findings support the hypothesis that
the BRAF V600E mutation may upregulate LAT1 and
methionine metabolism through c-Myc activation for
cell survival. In addition to LAT1, methionine uptake
was correlated with microvascular density (MVD) in
gliomas [15]. PLNTYs are considered benign brain neo-
plasms (proposed as WHO grade I); however, in the
present case, a chicken wire-like MVD, which is one
of the histopathological characteristics of oligoden-
droglioma, was also observed in the high-methionine-
uptake tissue region. Intriguingly, methionine uptake
has been reported to be relatively higher in oligoden-
drogliomas than in astrocytomas [11]. Thus, PLNTY,
which has an oligodendroglioma-like microvascular
structure, might show unique metabolic imaging fea-
tures. Further studies are warranted to validate this
hypothesis. Nonetheless, our data indicated that the
BRAF V600E mutation induced MAPK pathway activa-
tion and downstream c-Myc promoted LAT1 expres-
sion and methionine metabolism with little effect
on glycolytic pathway activation. These findings may Additional file 1: Figure S1. Low glycolysis activation in a patient with
PLNTY. Immunohistochemistry for glucose transporter 1, hexokinase 2,
and lactate dehydrogenase A in the high-methionine-uptake (#1, upper)
and low-methionine-uptake (#2, lower) region within tumor tissue. A. explain the unique metabolic imaging features of FDG-
methionine mismatch in PLNTY. high-grade adult gliomas than in lower-grade gliomas
[7, 30]. In epileptogenic brain tumors, however, all gan-
gliogliomas and 37–57% of DNT had increased methio-
nine uptake, although these tumors are classified as
WHO grade I [20, 22], implying that methionine uptake
may be irrespective of tumor grade in LEATs. Authors’ contributions KT led the study, collected samples, designed experiments, performed experi-
ments, interpreted data, and wrote the manuscript. JS, TH, and YM performed
experiments. NI, HM provided tumor samples and associated clinical details. TO, RM, and DU interrupted PET and MRI studies. NU, and SY performed the
histological classification of tumor samples. TY designed experiments and
interpreted data. All authors read and approved the final manuscript. Received: 26 June 2020 Accepted: 12 August 2020 Received: 26 June 2020 Accepted: 12 August 2020 Received: 26 June 2020 Accepted: 12 August 2020 Supplementary information accompanies this paper at https://doi.
org/10.1186/s40478-020-01023-3. Bars, 50 μm. Figure S2. Images of the patient’s glioblastoma with the
BRAF V600E mutation. Contrast-enhanced magnetic resonance (left) and
11C-methionine positron emission tomography (right) images of the
YMG62 patient. Funding This work was supported by Grant-Aid for Scientific Research (19K09488),
Princess Takamatsu Cancer Research Fund, Takeda Science Foundation, SGH
Cancer foundation, Yokohama Foundation for Advancement of Medical Sci-
ence, and Bristol-Myers Squibb Foundation. Acknowledgements We thank Mrs. Emi Hirata and Yasuko Tanaka (YCU) for technical and adminis-
trative assistance. We also would like to thank Editage (www.editage.com) for
English language editing. The authors declare that they have no competing interests. The authors declare that they have no competing interests. Competing interests p
g
The authors declare that they have no competing interests. Author details 1 Department of Neurosurgery, Graduate School of Medicine, Yokohama City
University, 3‑9 Fukuura, Kanazawa, Yokohama 2360004, Japan. 2 Department
of Pathology, Yokohama City University Hospital, Yokohama, Japan. 3 Depart-
ment of Radiology, Graduate School of Medicine, Yokohama City University,
Yokohama, Japan. 4 Departmento of Radiology, Division of Nuclear Medicine,
National Center for Global Health and Medicine, Tokyo, Japan. Discussionh a Immunohistochemistry of indicated proteins in the
high-methionine-uptake (#1) and low-methionine-uptake (#2) regions within tumor tissue. Bars, 50 μm. b Western blot analysis of phospho-MEK,
phospho-ERK, c-Myc, and LAT1 proteins in YMG83 (PLNTY, left) cells treated with DMSO and 10 μM BRAF inhibitor (BRAFi, dabrafenib) for 12 h. GAPDH, loading control. c Relative cell viability of dabrafenib-treated (left) and trametinib-treated (right) YMG83 cells and immortalized normal
human astrocytes (NHA). *P < 0.05, DMSO versus dabrafenib (left) and trametinib (right). d Western blot analysis for indicated proteins in YMG62
(epithelioid glioblastoma, left) and AM-38 (glioblastoma, right) cells treated with DMSO, 10 μM BRAF inhibitor (BRAFi, dabrafenib), and 10 μM MEK
inhibitor (MEKi, trametinib) for 24 h. GAPDH, loading control. e Western blot analysis of BRAF, phospho-MEK, phospho-ERK, c-Myc, and LAT1 proteins
in YMG62 (left) and AM-38 (right) cells treated with DMSO and dabrafenib at indicated concentrations. Vinculin, loading control. f Western blot
analysis for indicated proteins in non-silencing- (NS) and BRAF- (#1 and #2) transduced YMG62 and AM38 cells. GAPDH, loading control methionine uptake and low FDG uptake may be imag-
ing features specific to PLNTY. A preclinical study has
demonstrated that high uptake of 18F-FDG was cor-
related with increased Glut-1 and HK-2 expression in
human cancers [19]. Although the diagnostic accuracy
is insufficient, FDG-PET imaging is useful to differ-
entiate high-grade from low-grade gliomas [1]. In the present case, low FDG uptake and weak expression of
Glut-1, HK-2, and LDHA were observed in tumor tis-
sue, suggesting low glycolytic activity in PLNTY. On
the other hand, due to a high signal-to-noise ratio,
11C-methionine PET imaging is practical for brain
tumors [12, 34]. Several PET imaging studies have
demonstrated that methionine uptake was higher in Tateishi et al. acta neuropathol commun (2020) 8:139 Page 7 of 8 explain the unique metabolic imaging features of FDG-
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Bars D, Hammers A, Ryvlin P (2014) Accuracy of distinguishing between 20. Rheims S, Rubi S, Bouvard S, Bernard E, Streichenberger N, Guenot M, Le
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Educación y trabajo juvenil en el Perú urbano
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Economía Vol. XXXVIII, N° 76, semestre julio-diciembre 2015, pp. 117-148 / ISSN 0254-4415
Educación y trabajo juvenil en el Perú urbano*
Cecilia Garavito**
RESUMEN
El objetivo de este artículo es analizar qué determina que los jóvenes que aún viven en la casa
de sus padres se encuentren estudiando, trabajando, combinado ambas actividades, o fuera del
sistema educativo y de la fuerza laboral. Nos interesa determinar qué mantiene a los jóvenes en
el sistema educativo, aun si están trabajando, y si existen diferencias por género. Partimos de
un modelo de negociación cooperativa eficiente entre los padres y el joven, y estimamos una
regresión Logit Multinomial con datos del Perú Urbano para el año 2014. Encontramos que los
jóvenes se mantendrán en el sistema educativo aun si están trabajando, mientras mayor sea su
poder de negociación en el hogar, menor su costo de oportunidad, y más años de estudios tengan
sus padres.
Palabras clave: empleo juvenil, educación, mercado de trabajo
Códigos JEL: D1, I24, J16, J22, D21
Education and Youth Employment in Urban Peru
ABSTRACT
The objective of this paper is to analyze which variables determine that young people who still
live with their parents study, work, combine both activities or stay away from them. We are
interested in what is it that keeps young people in the educative system, even if they are working,
and if there are differences related to gender roles. We work with a model of efficient cooperative negotiation between parents and the son or daughter, and estimate a Multinomial Logit
regression with data for urban Peru in the year 2014. We find that young people will stay in the
educative system, even if they are working, when their negotiation power at home is high, when
their opportunity cost is low, and when their parents have a higher level of education.
Keywords: Youth employment, Education, Labor market.
JEL Codes: D1, I24, J16, J22, D21
* Agradezco los comentarios de un árbitro anónimo sobre esta versión del artículo, y de colegas del Departamento de Economía de la PUCP sobre versiones anteriores. Como siempre, los errores que subsistan son
de mi responsabilidad.
** Profesora principal del Departamento de Economía de la Pontificia Universidad Católica del Perú.
118 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
1. INTRODUCCIÓN
Uno de los problemas más importantes que enfrentan los miembros jóvenes de una
familia es la disyuntiva entre trabajo y educación. Si bien parte de este grupo demográfico es aún menor de edad y no se puede asumir que la decisión de continuar estudiando
o no sea independiente de lo que desean sus progenitores, aquellos jóvenes mayores de
18 años de edad son adultos que ya toman algunas decisiones propias, aun si todavía
forman parte del hogar de sus padres. La transición del estudio al trabajo, parte normal de su desarrollo se ve alterada en algunos casos y el joven abandona los estudios
prematuramente para insertarse en la fuerza laboral, o bien permanece en el hogar sin
participar en la actividad económica ni estudiar, todo lo cual determina un deterioro del
capital humano adquirido previamente, y un perfil de ingresos bajos a lo largo de su vida
laboral. En esta etapa de transición en la vida del joven es importante determinar qué
factores lo retienen en el sistema educativo y cuáles lo llevan a retirarse de él.
El objetivo de este artículo es analizar qué determina que los jóvenes adultos que aún
viven con sus padres se encuentren estudiando, trabajando, combinado ambas actividades o no llevando a cabo ninguna. Trabajaremos el tema por medio de un modelo de
negociación entre los miembros de la familia, lo cual nos permitirá tomar en cuenta las
diferencias en el comportamiento laboral de los jóvenes por sexo. Nos parece importante
estudiar a los jóvenes que aún viven en casa de sus padres dado que si bien contarían con
facilidades para continuar invirtiendo en su capital humano, no siempre lo hacen debido
tanto a variables individuales como su poder de negociación, su nivel de educación y su
estado marital, como a variables relacionadas con la estructura del hogar, así como los
ingresos y nivel de educación de sus padres. Al ser este un estudio de corte transversal no
es posible incluir el efecto de la variación de la actividad económica sobre las decisiones
de los jóvenes, análisis que podría hacerse con datos de panel.
Los primeros modelos sobre el tema de la utilización del tiempo de la familia sobre
la base de una negociación entre sus miembros (Manser y Brown, 1980; MacElroy y
Horney, 1981, 1990; Browning y Chiappori, 1998; y Chen y Woolley, 2001) analizan
la negociación entre esposos, sin incluir a los hijos, lo cual implica un cambio en la naturaleza de dicha negociación. Chiappori y Donni (2009) nos dan algunos alcances sobre
lo que significa negociar entre más de dos miembros en el hogar, si bien no mencionan
el efecto que una relación jerárquica entre padres e hijos tendría sobre esta negociación.
Esto es especialmente importante en el caso de los jóvenes que aún viven en la casa de
sus padres. Mientras la madre y el padre son adultos en una relación libremente acordada, las decisiones de los hijos también adultos no son del todo independientes de las
decisiones de los padres mientras viven en el hogar común1. En este caso, tomamos en
1
Aun si se tratara de un hogar monoparental, las decisiones de los hijos no son independientes de las
decisiones del único padre presente en el hogar.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
119
cuenta las características de los padres como determinantes adicionales de las decisiones
de los jóvenes en un modelo de negociación cooperativa eficiente.
El análisis se hará a nivel nacional urbano, dado que en las ciudades hay un mayor
desarrollo del mercado de trabajo; asimismo, la distancia a los centros educativos no es
muy grande, todo lo cual nos permite analizar la decisión familiar en un contexto de
bajos costos de transacción y mercados completos. Desde el punto de vista de la relevancia empírica de este trabajo, el 76,7% de la población peruana2, y el 80,5% de la
Población en Edad de Trabajar (PET) se encuentra en las ciudades. Asimismo, la población juvenil urbana de 18 a 24 años constituye el 17,2% de la PET urbana total, y
un 74,9% de este grupo aún vive con sus padres3. Vamos a emplear los datos para el
Perú Urbano de la Encuesta Nacional de Hogares (ENAHO) del Instituto Nacional de
Estadística e Informática (INEI) para el año 2014.
En la sección 2 discutimos la literatura sobre el tema. En la sección 3 presentamos
un análisis descriptivo de los datos, el cual nos permite establecer ciertas regularidades
empíricas para el caso del Perú Urbano. En la sección 4 presentamos el modelo que
vamos a emplear así como las hipótesis de nuestro trabajo. En la sección 5 llevamos a
cabo el análisis empírico y por medio de una regresión Logit Multinomial estimamos
los efectos de variables individuales y familiares sobre la probabilidad de que el joven se
encuentre estudiando, trabajando, combinando ambas actividades, o fuera de la fuerza
laboral y del sistema educativo. Finalmente, en la sección 6 presentamos las conclusiones
y recomendaciones de política.
2. NEGOCIACIÓN EN EL HOGAR Y ACTIVIDADES DE LOS JOVENES
Los trabajos de Becker (1965, 1993) y Gronau (1977) ponen las bases para el análisis
de los determinantes de la asignación del tiempo de la familia entre el trabajo doméstico, el trabajo en el mercado y el ocio. Los problemas de consistencia de la función de
utilidad familiar, ya señalados por Arrow (1966) y discutidos por Samuelson (1956)
llevan al desarrollo del modelo del jefe de hogar altruista y el teorema del rotten kid
(Becker, 1974,1976), así como a modelos de negociación en el hogar, tanto cooperativos, como no cooperativos (Leuthold, 1968; Chen y Woolley, 2001). Entre los modelos
de negociación cooperativa tenemos los de Manser y Brown (1980) y McElroy y Horney
(1981, 1990), quienes analizan la negociación en el hogar entre esposos como un juego
cooperativo eficiente, donde la amenaza es el divorcio; mientras que Lundberg y Pollak
(1993) modelan la amenaza como un comportamiento no cooperativo. Por otro lado,
Browning y Chiappori (1998) y Chiappori y Donni (2009) trabajan con una función
2
Instituto Nacional de Estadística e Informática, porcentaje a junio del año 2015.
No tomamos en cuenta a los nietos de dicho rango de edad (5,9%), ya que aun cuando en teoría también
viven con sus padres, estos no son jefes de hogar y lo que queremos es establecer la relación de un hijo adulto
con el jefe de hogar.
3
120 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
de preferencias colectiva, donde los pesos de las funciones individuales son los poderes
de negociación de cada esposo al interior del hogar. Con datos para Canadá los autores
muestran que los ingresos de los esposos no se agrupan como predice el modelo unitario,
y que el modelo colectivo que postulan es plausible. Para el caso del Perú, Monge (2004)
encuentra evidencia empírica que permite rechazar el modelo unitario para el caso de
los gastos en comida, en educación y en salud de los miembros del hogar; mientras que
la evidencia con respecto a los gastos relacionados a la vivienda es consistente con el
modelo unitario; asimismo, encuentra evidencia estadística que le permite afirmar que
la negociación entre los miembros de la familia es eficiente. Finalmente, con datos para
Perú, Vera Tudela (2009) encuentra que la mayor parte de las decisiones en el hogar son
tomadas por la mujer, o de manera conjunta con su compañero.
Si aceptamos que el modelo unitario no es adecuado, y adoptamos el modelo de
negociación, un punto importante a discutir es la diferencia en el poder de negociación
de mujeres y varones en el hogar, la cual afectaría las decisiones de los miembros del
hogar. En este punto hay dos elementos a tomar en cuenta: la medida del poder de
negociación en el hogar, y los resultados de un aumento de dicho poder de negociación
(Doss, 2013). Así, por ejemplo, con datos para Tailandia, Schultz (1990) encuentra que
un aumento del poder de negociación de la madre, entendido como un mayor ingreso no
laboral, aumenta su propio consumo y tiempo libre4. Sobre el mismo tema, Datta Gupta
y Straton (2008) encuentran que el tiempo libre (ocio) está positivamente asociado al
poder de negociación en el hogar en el caso de los Estados Unidos de Norteamérica,
donde los beneficios sociales van a personas de bajos ingresos, mientras que no ocurre
así en Dinamarca, donde los beneficios sociales son universales. Song (2008) encuentra
para el sector rural de China que el poder de negociación de las mujeres aumenta con
su nivel de educación.
En cuanto a los efectos del poder de negociación de la madre sobre el bienestar de
los hijos, tenemos el estudio de Thomas (1990) para las familias brasileñas. Tomando el
ingreso no laboral de que dispone cada miembro de la pareja como indicador del poder
de negociación al interior del hogar, el autor encuentra evidencia de que el aumento
del poder de negociación de la madre tiene mayor efecto sobre el bienestar de los hijos
que el aumento del ingreso no laboral del padre. En relación con este tema, Song
(2008) encuentra que un aumento del poder de negociación de la madre en el hogar
aumenta los gastos en la salud de sus hijos, pero que aun en este caso se da una diferencia a favor de los niños varones debido a que en el sector rural son ellos quienes se
hacen cargo de los padres ancianos; esto nos permite decir que las instituciones sociales
deben ser tomadas en cuenta en el análisis. En el caso del Perú, Riesco y Alburqueque
(2007) encuentran que mientras el ingreso de los varones alivia la percepción subjetiva
4
También aumenta el número de hijos, lo cual el autor atribuye a que es tradición que los hijos se ocupen
de la madre anciana cuando esta ya no puede valerse por sí misma.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
121
de estrechez económica5, el ingreso de la mujer asegura estabilidad en los ingresos familiares y suficientes comidas al día. Como vemos, el ingreso de la madre, así como su poder
de negociación en el hogar, son determinantes importantes del bienestar de los hijos.
Con relación al problema que nos ocupa, la relación entre trabajo juvenil y educación,
es necesario discutir la asignación del tiempo de los jóvenes en el hogar. En general, el
tiempo de un individuo se puede asignar al trabajo en el mercado, al trabajo doméstico,
a la educación y a otras actividades heterogéneas que llamaremos “tiempo libre”. Dado
que el trabajo del joven en el mercado contribuye a los ingresos familiares, el costo alternativo de cualquier otra actividad es el ingreso dejado de ganar6; mientras que en el caso
específico de la educación es necesario tomar en cuenta el costo directo de esta. Entonces, ¿qué determina que una parte del tiempo de los jóvenes sea asignada a la educación?
A partir de los modelos de acumulación de capital humano al interior del hogar de
Ben Porath (1967) y Becker (1993) se deriva la literatura sobre demanda de educación
para los hijos, la cual busca determinar las causas de las diferencias en la inversión en su
capital humano por parte de los padres. Becker y Tomes (1979) demuestran que bajo
ciertos supuestos los padres invertirán más en el capital humano de los hijos más hábiles, compensando a los menos hábiles por medio de la inversión en capital no humano.
Lundberg y Pollak (2007) señalan que la inversión inadecuada en el capital humano
de los hijos puede deberse a dos razones: las externalidades positivas de esta inversión
hacen que parte de los beneficios no sean capturados privadamente, sino que pasen a
la sociedad; y la limitada capacidad de los padres para diseñar contratos que obliguen a
los hijos a repagarles por la inversión. Para el caso de América Latina, Dahan y Gaviria
(2000) encuentran que la desigualdad en la inversión en el capital humano entre hermanos es mayor entre las familias moderadamente pobres y de clase media, y que los padres
tienden a invertir más en los hijos más hábiles. Asimismo, Gaviria (2001) encuentra que
los hogares responden a los shocks de ingresos, trabajando más, reduciendo la inversión
en capital humano, y vendiendo activos, siendo los que los hogares de menores ingresos
los que tienen una mayor probabilidad de sufrir estos shocks. Finalmente, con datos
para el Perú, Castro y asociados (2008) encuentran que las restricciones crediticias que
enfrentan las familias ubicadas en los quintiles más bajos de ingresos afectan su demanda
por educación superior, aun en periodos de crecimiento de la economía. Es decir, los
hogares con menores ingresos invertirán menos y desigualmente en el capital humano
de sus hijos. Dos determinantes importantes de la inversión en la educación de los
hijos son el nivel de educación de la madre y el sexo de los hijos. En la India rural,
Rosenzweig y Evenson (1977) encuentran que un mayor nivel de educación de la madre
lleva a un incremento en la escolaridad de las hijas. Gertler y Glewwe (1992) encuentran,
5
Los autores emplean las siguientes preguntas de la encuesta de hogares: ¿con sus ingresos viven bien? ¿sus
ingresos le permiten garantizar el número de comidas al día? ¿sus ingresos son estables?
6
Incluso en el caso del trabajo doméstico de los jóvenes, que permite la liberación del tiempo de los padres
para el trabajo en el mercado, el costo sigue siendo el ingreso dejado de ganar en el mercado.
122 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
para el sector rural del Perú, que los padres prefieren enviar a los hijos que a las hijas al
colegio, si bien existe una demanda de educación para ellas. Gaviria (2001) y Dahan y
Gaviria (2000) señalan que la preferencia de los padres por invertir más en la educación
de los hijos varones afecta el ingreso relativo por sexo, y por lo tanto, su bienestar. Estas
diferencias por sexo también se dan en la distribución de las tareas domésticas al interior
del hogar. Así, la literatura empírica confirma que la mayor carga de las tareas domésticas
recae sobre la mujer (Coltrane, 2000; Dagsvik y Aaberge, 1991; y Garavito, 2001); y
que el ciclo de vida solamente influye en la dedicación a las tareas domésticas de estas
(Programa de Estadísticas Laborales, 2009a, 2009b). La literatura también nos muestra
que la contribución del varón a las tareas domésticas es mayor cuando la mujer trabaja,
mayor es su nivel de educación, y/o más alto su salario (Bloemen, Pasqua y Stancanelli,
1998; Newman, 2002; García, 2007). Asimismo señala que este patrón de distribución
de tareas domésticas en el hogar alcanza también a los hijos e hijas, por lo cual estas
últimas dedicarán más tiempo a las tareas del hogar.
Se podría concluir que una parte importante de los trabajos empíricos presentan
evidencias de que el modelo unitario de la familia no es consistente con la realidad.
Deaton (1988), Folbre (1984), Bhalotra y Attfield (1998), y Monge (2004) encuentran
evidencia empírica de una distribución desigual de los frutos del trabajo al interior del
hogar. Asimismo, Song (2008), Thomas (1990), y Schultz (1990) encuentran evidencia
de diferencias en el comportamiento y en el poder de negociación de mujeres y varones
al interior del hogar, resultados que nos alejan del enfoque de los modelos unitarios de
la economía de la familia. Finalmente, Browning y Chiappori (1998) aplican a sus datos
pruebas estadísticas que permiten rechazar el modelo unitario y establecer el modelo de
negociación familiar que proponen como plausible.
3. HECHOS ESTILIZADOS PARA EL PERU URBANO
Vamos a emplear los datos de la Encuesta Nacional de Hogares (ENAHO) del Instituto
Nacional de Estadística e Informática (INEI)7 para el año 2014. Trabajaremos solamente con el Perú urbano, ya que consideramos que los determinantes de la asignación
del tiempo de los jóvenes entre las actividades mencionadas son cualitativamente distintos en la ciudad y en el campo. Asimismo, nuestra muestra incluye solamente a los
jóvenes adultos que aún viven en casa de sus padres que constituyen más del 70% del
total de jóvenes entre 18 y 24 años de edad.
7
Esta encuesta es de cobertura nacional, y tiene como población objetivo al conjunto de viviendas y sus
ocupantes, tanto para el área urbana como rural del país El tipo de muestreo es probabilístico, estratificado,
multietápico y de áreas, y el marco muestral para el diseño de ambas encuestas es la información estadística
del Censo Nacional 2005.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
123
Un punto importante a tomar en cuenta es que no existe una diferencia significativa
entre la proporción de jóvenes varones y mujeres que aún viven con sus padres —los
porcentajes son de 49,7% y 50,3%, respectivamente8—. Si vemos los mismos datos de
acuerdo al sexo del jefe de hogar, los porcentajes serán de 50,5% y 49,4% en los hogares
donde el jefe de hogar es varón, y de 47,5% y 52,5% en los hogares donde el jefe de
hogar es mujer9.
En el Cuadro 1 presentamos los datos de las cuatro actividades a las que los jóvenes
mayores de edad que aún viven con sus padres dedican su tiempo. Vemos en primer
lugar que la mayoría de los jóvenes “solamente trabaja”, siendo los porcentajes mayores
para los varones, lo cual es consistente con el papel tradicional de “proveedor” que se
espera de estos. En segundo lugar vemos que la siguiente actividad en importancia es
“estudia y trabaja”, siendo el porcentaje mayor en el caso de las mujeres. En cuanto a la
categoría “no estudia ni trabaja” esta es la última actividad en importancia; sin embargo,
las mujeres se encuentran en mayor porcentaje en esta situación.
Cuadro 1. Perú urbano. Actividades de los jóvenes (18 – 24 años)
Actividad
2014
Mujer
Varón
Total
Solo estudia
Estudia y trabaja *
Solo trabaja *
No estudia ni trabaja
19,5%
22,5%
40,3%
17,7%
17,5%
20,6%
49,0%
12,9%
18,5%
21,6%
44,6%
15,3%
Total
100,0%
100,0%
100,0%
Población a/
1 635 648
1 617 100
3 252 748
4899
4904
9803
Muestra
Fuente: ENAHO - INEI
Elaboración propia
a / Valores expandidos
* Incluye a TFNR que trabajan menos de 15 horas a la semana
En el Anexo 1 podemos ver el mismo cuadro para la población en edad activa total,
y si bien la actividad más importante sigue siendo “solo trabaja”, el porcentaje de varones que “solamente estudia” es similar al de mujeres en la misma actividad. En el caso
de “estudia y trabaja” los varones lo hacen en un porcentaje mayor que las mujeres, al
contrario que entre los jóvenes que viven en la casa de sus padres. Es posible que el estar
en el hogar paterno les de cierta ventaja a las jóvenes, la cual pierden al independizarse.
8
Ver el Anexo 1 para los porcentajes de varones y mujeres a nivel nacional, urbano y rural, y jóvenes
urbanos menores y mayores de edad.
9
En el caso del Perú, en el año 2014, el 78,6%de los hogares con jefe de hogar mujer son monoparentales;
en el caso de los jóvenes adultos que aún viven en casa de sus padres, el porcentaje es de 80,1%.
124 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
Sin embargo, la diferencia más importante se da en el caso de las mujeres que “no estudian ni trabajan”, las cuales superan en 14,6 puntos porcentuales a los varones, mientras
que en el caso de los jóvenes que viven en casa de sus padres, la diferencia es solamente
de 4,8 puntos porcentuales. Esto nos estaría mostrando la importancia de la educación
de las mujeres jóvenes ya que la situación será desventajosa para ellas a mayor edad.
Una pregunta que surge en este punto es si los datos simplemente reflejan la evolución “normal” de los jóvenes hacia la adultez, donde el paso de estudiar a combinar los
estudios con el trabajo, y finalmente a solamente trabajar es la vía usual de desarrollo10.
Este proceso es ciertamente parte de lo que sucede, pero los datos de las actividades por
edades en el Gráfico 1 nos muestran que si bien el porcentaje de los jóvenes que solamente estudian va disminuyendo al aumentar la edad, a la vez que aumenta el porcentaje
que solamente trabaja, los porcentajes de jóvenes que “estudian y trabajan” y sobre todo
de quienes “no estudian ni trabajan” no tienen un patrón claro de acuerdo a la edad
del joven, lo cual nos hace presumir que hay otras causas que explican esta situación.
Un examen de los Gráficos 2 y 3 nos muestra la las diferencias por sexo; así vemos que
el porcentaje de jóvenes varones que solamente trabaja es mayor que el porcentaje respectivo de jóvenes mujeres, a todas las edades, y llegar a su pico más rápido. Asimismo,
podemos ver que el porcentaje de jóvenes mujeres que solamente estudian es mayor que
el porcentaje de varones, en todos los casos.
Gráfico 1. Perú urbano: actividades de los jóvenes por edades
70.0
60.0
50.0
18
19
20
21
22
23
24
40.0
30.0
20.0
10.0
0.0
Sólo Estudia
Estudia y Trabaja *
Fuente: ENAHO INEI. Elaboración propia
10
Sobre esto ver J. Chacaltana y C. Ruiz (2012).
Sólo Trabaja *
No Estudia Ni Trabaja
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
Gráfico 2. Perú urbano: Actividades de los jóvenes (varones) por edades
80.0
70.0
60.0
50.0
18
19
20
21
22
23
24
40.0
30.0
20.0
10.0
0.0
Sólo Estudia
Estudia y Trabaja *
Sólo Trabaja *
No Estudia Ni Trabaja
Gráfico 3. Perú urbano: Actividades de los jóvenes (mujeres) por edades
70.0
60.0
50.0
18
19
20
21
22
23
24
40.0
30.0
20.0
10.0
0.0
Sólo Estudia
Estudia y Trabaja *
Fuente: ENAHO INEI. Elaboración propia
Sólo Trabaja *
No Estudia Ni Trabaja
125
126 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
El patrón no es claro para quienes estudian y trabajan o solamente estudian, por lo
cual de nuevo podemos decir que habría otras razones además de la edad y el sexo del
joven para estas diferencias. Es importante asimismo analizar las razones por las cuales
los jóvenes que aún viven en el hogar de sus padres no estudian ni trabajan. Si bien el
vivir con sus padres implica que su salario de reserva es más alto que si hubieran dejado
el hogar, están en una edad de formación, por lo cual sería de esperar que si no están
trabajando estuvieran estudiando.
En el Cuadro 2 podemos ver las razones que los jóvenes señalan como causas de su
inactividad. Aun si solamente el 11,1% de los jóvenes que no estudian ni trabajan responden a esta pregunta en la encuesta, es un indicador grueso de la tendencia. Vemos en
primer lugar que en general las razones principales son: “no hay trabajo” y “quehaceres
del hogar”, siendo la primera razón la más importante para los varones y la segunda para
las mujeres. Si bien es cierto que la falta de trabajo explica en gran medida la inactividad de los jóvenes, el hecho de vivir con sus padres permite que continúen inactivos, o
es quizá una solución al problema. Por otro lado, los quehaceres del hogar pesan más
sobre las mujeres. En cuanto a los (21) jóvenes que aducen estudios como razón para su
inactividad, estos no están matriculados ni asisten a un centro de estudios de acuerdo a
lo visto cruzando preguntas de la encuesta.
Vemos así que si bien en la mayoría de los casos la razón más importante está relacionada con la falta de trabajo (28,5% de la muestra en el agregado), en el caso de las
mujeres la razón más importante son los quehaceres del hogar (43,2%). Así, podemos
ver que alrededor de un tercio de los jóvenes no son activos porque no encuentran trabajo o han dejado de buscarlo. Aun cuando puede argumentarse una falta de demanda,
si tomamos en cuenta que todos los jóvenes enfrentan el mismo contexto macroeconómico y que todos viven con sus padres, es necesario considerar el hecho que si los jóvenes
no contaran con el ingreso de sus padres no podrían permanecer inactivos.
Cuadro 2. Razones de inactividad de los jóvenes por sexo (18 – 24 años)
Actividad
Mujer
Varón
Total
No hay trabajo
Se canso de buscar
Falta de experiencia
Estudios
Quehaceres del hogar
Razones de salud
Otro
15,6
9,6
7,4
14,7
43,2
3,9
5,6
43,0
3,3
23,8
7,3
1,1
3,1
18,3
28,5
6,7
15,1
11,2
23,4
3,6
11,6
Total
100,0
100,0
100,0
Muestra
98
71
169
Fuente: ENAHO - INEI. Elaboración propia
* Incluye a TFNR que trabajan menos de 15 horas a la semana
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
127
En los Cuadros 3a y 3b presentamos las características del joven y de su hogar, de
acuerdo al sexo, para las distintas actividades que realizan. Vemos así que la mayoría de los
jóvenes urbanos se reconocen como mestizos o blancos y que las diferencias por actividad
no son destacables a este nivel de desagregación. Por otro lado, si bien las mujeres tienen
una edad promedio mayor que los varones en todos los casos, las diferencias no son estadísticamente significativas. Asimismo, en la mayoría de los casos las jóvenes mujeres tienen en
promedio más años de educación que los varones, sin embargo, el coeficiente de variación
que hemos calculado es también mayor. En el caso del ingreso no laboral propio del joven11,
este es mayor para aquellos que solamente estudian y los que no estudian ni trabajan, lo
cual es consistente con un mayor salario de reserva y por lo tanto, un mayor su poder de
negociación al interior del hogar. En el caso de las mujeres, en cambio, sus ingresos no
laborales propios son mayores para aquellas que solamente trabajan, y para aquellas que
no estudian ni trabajan, siendo el primer resultado no esperado y el segundo consistente
con un mayor salario de reserva y poder de negociación dentro del hogar. Es decir que un
mayor ingreso no laboral propio permite a los jóvenes disponer de más tiempo fuera del
mercado de trabajo, pero que los efectos por sexo no son los mismos. En el caso del estado
marital, vemos que el porcentaje de varones casados o convivientes es mayor para quienes
solamente trabajan, mientras que en el caso de las mujeres el mayor porcentaje de casadas
y convivientes se encuentra entre quienes no estudian ni trabajan. De nuevo tenemos un
efecto distinto de una variable sobre las actividades de los jóvenes, donde la inactividad de
la mujer estaría asociada en muchos casos a su decisión de vivir en pareja.
En cuanto a las características del hogar, vemos que los jóvenes sin hermanos tienen
más probabilidades de no estudiar ni trabajar, mientras que en segundo lugar los jóvenes
varones solamente estudian mientras que las jóvenes mujeres estudian y trabajan. Esto
estaría relacionado con una salida más temprana de las jóvenes al mercado laboral con
relación a los varones, aun si no abandonan sus estudios. En un trabajo anterior encontramos que las mujeres se concentran en una mayor proporción en las carreras cortas
(estudios superiores no universitarios) para salir antes al mercado (Garavito, 2005).
Vemos, asimismo, que en los hogares donde la jefa de hogar es mujer, es más probable que los jóvenes trabajen, lo cual estaría relacionado a los menores ingresos de
la familia. En cuanto a los años de educación de ambos padres, vemos que mayor será la
probabilidad de que los hijos de ambos sexos solamente estudien; sin embargo, también
hay un efecto positivo sobre la probabilidad de las jóvenes mujeres trabajen y continúen
estudiando. Observamos asimismo un efecto positivo similar en el caso de los ingresos
laborales de la madre y del padre, los cuales estarían relacionados con mayores niveles de
estudios de ambos. Sin embargo, dado que el nivel de educación también mide la actitud hacia la educación de los hijos por parte de los padres, incluiremos ambas variables
en el análisis empírico.
11
Ingreso no laboral total = suma de ingresos por transferencias + rentas + otros ingresos extra + ingresos
extraordinarios.
128 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
Cuadro 3a. Varones de 18 – 24 años por variables principales - 2014
Solo estudia
Estudia y trabaja Solo trabaja No est. ni trab.
Características del joven
% de jóvenes blancos y mestizos
Edad promedio del joven
Años de estudios promedio
% de jóvenes casados / convivientes
Ingreso no laboral del joven
72,3%
20,2
12,5
0,1%
647,9
68,4%
20,3
12,2
1,3
442,3
68,5%
20,9
10,9
6,0%
413,9
69,4%
19,9
11,1
0,8%
692,3
% hogares con jefe de hogar mujer
% de jóvenes sin hermanos
21,1%
35,9%
22,2%
33,9%
25,4%
28,8%
27,1%
37,8%
Nivel educativo de la madre*
Ingreso laboral de la madre
Ingreso no laboral de la madre
6,2
14 245,6
1774,8
5,5
10 396,0
1412,6
4,7
8456,6
1378,5
5,8
11 382,8
2053,1
Nivel educativo del padre*
Ingreso laboral del padre
Ingreso no laboral del padre
6,9
25 895,5
4909,4
6,3
20 493,9
2195,9
5,4
15 901,8
1479,9
6,4
22 643,5
3144,6
Características del hogar
Fuente: ENAHO - INEI. Elaboración propia
Las cifras entre paréntesis son las desviaciones estándar
* Un nivel educativo de 5 es equivalente a estudios secundarios completos
Cuadro 3b. Mujeres de 18 – 24 años por variables principales - 2014
Solo estudia
Estudia y trabaja Solo trabaja No est. ni trab.
Características de la joven
% de jóvenes blancos y mestizos
Edad promedio de la joven
Años de estudios promedio
% de jóvenes casados / convivientes
Ingreso no laboral del joven
73,9%
20,2
12,7
2,2%
652,7
62,9%
20,4
12,6
1,4%
615,4
67,6%
21,2
11,7
7,4%
746,4
74,5%
20,5
11,0
10,0%
745,9
% hogares con jefe de hogar mujer
% de jóvenes sin hermanos
19,0%
30,3%
29,9%
31,9%
28,9%
26,5%
25,5%
33,1%
Nivel educativo de la madre*
Ingreso laboral de la madre
Ingreso no laboral de la madre
6,5
15 154,8
2848,4
5,6
11 713,3
1834,1
4,9
9294,6
1095,9
5,2
11 016,8
1397,4
Nivel educativo del padre*
Ingreso laboral del padre
Ingreso no laboral del padre
6,9
24 056,5
4118,6
6,4
21 097,1
2696,2
5,6
17 333,6
1680,3
6,0
19 465,1
2824,8
Características del hogar
Fuente: ENAHO - INEI. Elaboración propia
Las cifras entre paréntesis son las desviaciones estándar
* Un nivel educativo de 5 es equivalente a estudios secundarios completos
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
129
Finalmente, los ingresos no laborales de la madre y del padre, al no estar relacionados con su nivel de educación o con sus horas de trabajo, son proxies de su poder de
negociación en el hogar y como tal podrían ser otro indicador de sus preferencias con
respecto a las actividades de sus hijos. Así vemos que mayores ingresos no laborales de
ambos padres están en general relacionados a una mayor probabilidad de que los jóvenes
solamente estudien, o de que no estudien ni trabajen, si bien en el caso de las jóvenes
mujeres un mayor ingreso no laboral de la madre lleva a una mayor probabilidad de que
estudien y trabajen en segundo lugar. Vemos que en general, los ingresos de los padres
permiten que los jóvenes se mantengan en el sistema educativo. En el caso de los jóvenes
que no estudian ni trabajan, los ingresos de los padres les permiten quedarse en casa,
lo cual estaría relacionado ya sea a los roles de género como a las dificultades de encontrar trabajo12. En la siguiente sección presentamos un modelo de negociación entre los
padres y el (la) hijo(a) que busca tomar en cuenta las regularidades encontradas en esta
sección.
4. MODELO DE NEGOCIACIÓN
El modelo a desarrollar en esta sección toma como base el trabajo de Browning y Chiappori (1998) y Chiappori y Donni (2009), presentando una negociación de ambos padres
con el hijo. Asumimos que los padres tienen una función de utilidad que incluye las
horas de educación del hijo por motivos altruistas13; en el caso de tratarse de un hogar
monoparental, la función de utilidad del padre presente será individual. Si asumimos
que los padres no consumen ocio y trabajan en el mercado todas sus horas disponibles,
su función agregada de utilidad14 tendrá como argumentos la canasta de bienes que
consumen (C )15, y las horas de estudios del hijo (E ):
U = U[C, E(g )]
Uj > 0; Uij > 0; Ujj < 0 ∀iu, j = C, E
(1)
12
En el año 2014 el producto interno bruto creció a una tasa menor que en el año anterior, mientras que el
producto per cápita disminuyo. Podemos asumir que la dificultad para encontrar trabajo fue mayor en este
año, en relación con los años anteriores. Sin embargo, debemos recordar que al ser este un análisis de corte
transversal todos los jóvenes enfrentan la misma situación.
13
La educación como un bien negociable entre los padres es consistente con lo hallado por Monge (2004)
para el caso del Perú.
14
La función de utilidad es estrictamente cuasi-cóncava, con derivadas de primer y segundo orden continuas. Si solamente está presente un progenitor, esta será su función de utilidad individual.
15
C es un bien hicksiano, es decir, una canasta de bienes en la cual los precios relativos de sus componentes
no varían.
130 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
Donde el parámetro g representa las diferencias en las preferencias del padre y de la
madre con respecto a la educación de los hijos de acuerdo a su sexo (Iversen y R
osenbluth,
2006); Gertler y Glewwe, 1992). En cuanto al hijo, este consume una canasta de bienes
(Ch ), horas de educación (E ) y horas libres (H ). Por lo tanto, su función de utilidad será16:
V = V(Ch, E, H )
Vj > 0; Vij > 0 ∀i, j = Ch, E, H
(2)
Planteamos entonces un modelo de negociación eficiente en el sentido de Pareto17
donde la función de utilidad colectiva es la suma ponderada de las funciones de utilidad
de los padres y del hijo. Por lo tanto la función a maximizar será la siguiente:
Ω = (1 - m)U[C, E(g )] + mV(Ch, E, H)
(3)
Donde 0 < m < 1 es el poder de negociación del hijo frente a los padres. En cuanto
a los determinantes del poder de negociación en el hogar son varios los indicadores
posibles, como hemos visto en la literatura revisada. Destacan el nivel de educación, que
está asociado a la capacidad potencial de generación de ingresos y por lo tanto, a la posibilidad de tomar decisiones; y los ingresos no laborales que cada individuo pueda tener,
los cuales aumentarían no solamente su salario de reserva en el mercado sino también su
capacidad de negociación en el hogar. En el caso de los jóvenes el número de hermanos
también influye —negativamente en este caso— en su capacidad de negociación en el
hogar, ya que los recursos generados deben repartirse entre más personas.
Dado que asumimos que ambos padres trabajan todas sus horas disponibles, ya
sea como asalariados o en un negocio propio, sus ingresos (Ii, ∀i = P.M ) serán fijos e
independientes de las horas de trabajo del hijo. Entonces, la restricción de presupuesto
familiar será la siguiente:
wT + IP + IM = PC + PhCh + (Pe + w)E + wH
(4)
Donde T es la dotación de tiempo del hijo, P y Ph los precios de las canastas de consumo de los padres y del hijo, Pe el precio por hora de la educación, y w la tasa salarial
del hijo. Dado que la dotación de tiempo es fija, una vez que se determinan el tiempo
que el hijo dedica a la educación y al ocio, sus horas de trabajo quedarán también determinadas. Si L son las horas de trabajo del hijo, su restricción de tiempo será:
16
T=H+E+L
(5)
La función de utilidad del hijo es estrictamente cuasi-cóncava, y sus derivadas de primer y segundo orden
son continuas.
17
Este supuesto tiene sentido dado que los miembros de una familia están inmersos en una relación de
largo plazo y por lo tanto tienen un conocimiento bastante cercano de las preferencias de cada miembro de
la familia.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
131
El problema económico que la familia debe resolver por medio de una negociación
cooperativa eficiente será entonces:
Max Ω = (1 - m)U[C, E(g )] + mV(Ch, E, H )
s.a.
wT + Ip + IM = PC + PhCh + (Pe + w)E + wH
L=T-E-H
0<m<1
A partir de la ecuación de Lagrange obtenemos las condiciones de primer orden:
(1 - m)UC - lP = 0
(6)
(1 - m)UE(g ) + mVE - l(Pe + w) = 0
(7)
mVCh - lPh = 0
(8)
mVH - lw = 0
(9)
wT + IP + IM - PC - PhCh - (Pe + w)E - wH = 0
(10)
De las cuales obtenemos las curvas de demanda de educación y de horas libres del hijo:
E = E(P, Pe, w, IP, IM; g, m)
(11)
H = H(P, Pe, w, IP, IM; g, m)
(12)
Finalmente, a partir de la expresión (5), obtenemos la curva de oferta de trabajo del
hijo18:
L = L(P, Pe, w, IP, IM; g, m)
(13)
La condición de equilibrio de la solución interior será la siguiente:
λ1 =
(1 − µ )U C (1 − µ )U E (γ ) µU Ch µU H
=
=
=
P
Pe + wh
Ph
wh
(14)
18
Debido a limitaciones de los datos, esta es la única ecuación que podría estimarse, ya que no tenemos los
datos de las horas que los jóvenes dedican a los estudios o al ocio.
132 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
En el Anexo 2 se encuentra la presentación matricial del sistema de ecuaciones, que
nos permitirá evaluar los efectos sobre las actividades del joven de su costo de oportunidad, de su ingreso no laboral, del número de hermanos que tiene, así como de los
ingresos y preferencias de sus padres19.
En primer lugar esperamos que un aumento del costo de oportunidad del tiempo de
los hijos en el mercado llevará, por efecto sustitución, a una menor demanda de horas
de estudios y de horas libres. Sin embargo, si bien el efecto ingreso ordinario también
llevará a un menor consumo de ambos bienes al caer el ingreso real, el efecto ingreso
dotación llevaría a un mayor consumo de ambos bienes debido al mayor valor de la
dotación. El efecto final dependerá de las magnitudes de los efectos parciales20.
En segundo lugar, esperamos que un mayor ingreso no laboral y un menor número
de hermanos aumenten el poder de negociación de los hijos en el hogar, aumentando
sus horas de estudios y de tiempo libre. Esto reduciría sus horas de trabajo. En este caso,
dado que los padres también desean que los jóvenes estudien y asumimos que su poder
de negociación es mayor esperaríamos que el balance entre las horas de estudio y de
tiempo libre se de en favor de la primera actividad. En todo caso, más horas de tiempo
libre a mayor ingreso no laboral del joven, proxy de su poder de negociación en el hogar,
serían un resultado consistente con lo esperado.
En tercer lugar, esperamos que un mayor ingreso de ambos padres aumente el consumo de horas de educación y de horas libres de educación de los jóvenes de ambos
sexos. Sin embargo, es necesario tomar en cuenta las diferencias en las actitudes de los
padres de cada sexo con respecto a las actividades de los hijos de acuerdo a su sexo. Por
lo tanto, si los padres prefirieran educar a los hijos varones, un aumento en sus ingresos
reduciría las horas de trabajo de los hijos en mayor medida que en el caso de las hijas.
Sin embargo, en ambos casos mayores ingresos de los padres llevarían a menos horas de
trabajo de los jóvenes en el mercado.
Finalmente, mayores niveles de estudios de los padres debería llevar a mayores niveles de educación y de horas libres de los hijos. Aun si un mayor nivel de educación está
correlacionado con los ingresos, en el caso de las mueres esta correlación podría ser más
débil. En todo caso, hay efectos positivos del capital humano de los padres sobre la
adquisición de capital humano de los hijos.
19
En Garavito (2011) se presenta una estimación algebraica de los efectos esperados de las variables que
nos interesan sobre la demanda de horas de estudio y la demanda de horas de trabajo. En dicho modelo, el
poder de negociación de los padres es cercano a 1, lo cual nos permite tomar en cuenta el hecho de que si
bien el poder de negociación en el hogar del joven adulto aumenta con su edad, sus ingresos no laborales y
su nivel de educación, persiste una jerarquía en las decisiones ya que aún vive en la casa de sus padres.
20
Si el hijo no trabaja, o trabaja pocas horas (T - E - H ≈ 0), el efecto precio total será negativo.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
133
Soluciones de Esquina:
Los jóvenes se encontrarán estudiando siempre que el precio pagado por hora de la
educación sea menor o igual al precio de reserva de la educación (Pe* ), el cual dependerá
de los precios de los bienes de consumo, de la tasa salarial del hijo, del ingreso de los
padres, de sus preferencias con respecto a la educación del hijo, y del poder de negociación de este:
Pe* = Pe*(P, Ph, w, IP, IM; g, m)
(15)
Por otro lado, los jóvenes entrarán a trabajar si el ingreso por hora obtenido en el
mercado es mayor que el valor de su tiempo o salario de reserva (w* ), el cual dependerá
de los precios de los bienes de consumo, del precio de la educación superior, del ingreso
de los padres y de sus preferencias con respecto a la educación de los hijos, así como del
poder de negociación del hijo en el hogar:
w* = w*(P, Ph, Pe, IP, IM; g, m)
(16)
Por lo tanto, tenemos las siguientes posibles situaciones:
Si Pe < Pe* y w ≤ w* ⇒ E > 0 & L = 0, el joven solo estudia
Si Pe < Pe* y w > w* ⇒ E > 0 & L > 0, el joven estudia y trabaja
Si Pe ≥ Pe* y w > w* ⇒ E = 0 & L > 0, el joven solo trabaja
Si Pe ≥ Pe* y w ≤ w* ⇒ E = 0 & L = 0, el joven no estudia ni trabaja
A partir de estos resultados podemos plantear nuestras hipótesis. En primer lugar
deberíamos esperar que un mayor poder de negociación del hijo en el hogar lleve a un
aumento en la probabilidad de que dedique su tiempo al estudio o al tiempo libre, lo
cual reducirá la probabilidad de que esté trabajando. En segundo lugar, un mayor costo
de oportunidad del tiempo del joven reducirá la probabilidad de que solamente estudie
o que dedique horas a trabajar o al tiempo libre, y por lo tanto mayor será la probabilidad de que se encuentre trabajando, aun si está estudiando. En tercer lugar, un mayor
ingreso de los padres elevará tanto el salario de reserva de los hijos como el precio de
reserva de la educación, lo cual aumentará la probabilidad de que el joven se encuentre
estudiando o dedicando horas al tiempo libre, reduciendo la probabilidad de que esté
trabajando; este efecto sería mayor para los varones que para las mujeres, debido al
mayor precio de reserva de la educación de estos. Finalmente, dado que las preferencias
del padre y de la madre influyen en la demanda de educación para sus hijos, esperamos
que un mayor nivel de educación de los padres reduzca la probabilidad de que los hijos
dejen de estudiar, ya que padres más educados tienen una valoración positiva (preferencias) de la educación de sus hijos. Asimismo, un mayor nivel de educación de la madre
134 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
equilibraría la demanda diferencial por educación, aumentando la probabilidad de que
las hijas se mantengan en el sistema educativo.
En la siguiente sub-sección llevamos a cabo el análisis econométrico de los determinantes de la asignación del tiempo de los jóvenes al estudio, al trabajo, a la combinación
de ambas actividades, y a actividades no económicas.
5. EVALUACION EMPIRICA
En esta sección vamos a realizar regresiones para estudiar las asociaciones entre las
variables con el fin de ver si tales asociaciones son consistentes con las predicciones del
modelo teórico. Dado que nuestro objetivo es analizar la probabilidad de que los jóvenes hayan asignado su tiempo a cuatro actividades (solamente trabaja, estudia y trabaja,
solamente trabaja, no estudia ni trabaja), vamos a emplear el modelo Logit Multinomial
(Cameron y Trivedi, 2005). Tomaremos como base a la categoría “solo trabaja”, donde
se encuentran la mayoría de los jóvenes. Entonces, si yj es la variable endógena:
yj = 0 Solo trabaja (Pe > Pe*, w > w*) (base)
yj = 1 Solo estudia (Pe < Pe*, w < w*)
yj = 2 Estudia y trabaja (Pe < Pe*, w > w*)
yj = 3 No estudia ni trabaja (Pe > Pe*, w < w*)
Las variables explicativas (xi) serán las siguientes:
– Sexo: variable dicotómica que se tomará en cuenta separando la muestra en jóvenes varones y mujeres.
– Jefev: Variable dicotómica que indica si el jefe de hogar es varón o no, y se tomará
en cuenta separando las submuestras por sexo en aquellos jóvenes que viven en
hogares donde el jefe es varón y aquellos que lo hacen en hogares donde el jefe
es mujer.
– Logaritmo natural del costo de oportunidad del tiempo del hijo (COTH): variable
numérica medida en nuevos soles por hora, y que representa el costo de oportunidad de las horas que el hijo dedica a estudiar o a actividades no económicas. Dado
que no todos los jóvenes trabajan, y que parte de los que trabajan no reciben una
remuneración (TFNR) estimaremos esta variable para aquellos que no tienen
ingresos por medio de la ecuación de Mincer, corrigiendo el sesgo de selección
por medio de Heckman (1974, 1979)21. Un mayor costo de oportunidad debería
llevar a una mayor probabilidad de que los jóvenes estén trabajando.
21
Ver el Anexo 3 para la estimación del ingreso esperado de los jóvenes que solamente estudian o que no
trabajan ni estudian.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
135
– Indicadores del poder de negociación del hijo (IPNH ): variable multidimensional
no observable para la cual emplearemos dos variables proxy: los ingresos no laborales del hijo22, que aumentarían su poder de negociación en el hogar ya que son
ingresos propios e independientes de su trabajo; y el número de hermanos, que
lo disminuirían al tener que repartirse los ingresos familiares entre más personas.
Esperamos que a mayor poder de negociación del hijo, mayor sea la probabilidad
de que esté estudiando, aun si trabaja.
– Estado marital: variable dicotómica que toma el valor de 1 si el joven está casado
o es conviviente y el valor de cero en caso contrario. Se espera que los varones
casados o convivientes estén trabajando y estudiando o solamente trabajando,
mientras que en el caso de las mujeres no es claro el resultado debido a que
podrían estar fuera de la fuerza laboral y del sistema educativo si es que tienen
hijos, o estar trabajando ya que aún viven en el hogar de sus padres.
– Logaritmos naturales de los ingresos laborales de la madre (ILM) y del padre
(ILP): variables numéricas, medidas en nuevos soles. Un mayor ingreso de los
padres llevaría a una menor probabilidad de que los jóvenes estén trabajando.
– Logaritmos naturales de los ingresos no laborales de la madre (INLM) y del padre
(INLP): variables numéricas, medidas en nuevos soles. Un mayor ingreso no
laboral de los padres también llevaría a una menor probabilidad de que los jóvenes estén trabajando. Por otro lado, los ingresos no laborales de los padres son
indicadores de su poder de negociación en el hogar.
– Nivel de educación de la madre (NEM) y del padre (NEP), variables numéricas
que empleamos como proxi de sus preferencias. Un resultado empírico establecido en otros trabajos es que a mayor nivel de educación de la madre, mayor es la
probabilidad que los hijos estudien, aun si la madre no trabaja, razón por la cual
examinamos aquí el efecto del nivel de educación de cada padre por separado.
En los Cuadro 4a-4d presentamos las estimaciones de la ecuación de Logit Multinomial para jóvenes varones que viven en un hogar donde el jefe es varón, para los que
viven en un hogar donde la jefa es mujer, para jóvenes mujeres que viven en un hogar
donde el jefe de hogar es varón y para aquellas que viven en un hogar donde la jefa es
mujer23. Presentamos asimismo los respectivos efectos marginales. Vemos que en todos
los casos el test F es significativo al 1%, lo cual nos permite decir que las variables explicativas en conjunto son estimadores adecuados de la variable estudiada.
22
Es importante señalar que un 31,0% de la muestra reporta tener ingresos no laborales propios.
Si bien existe un porcentaje pequeño de hogares donde la jefa de hogar es mujer y el padre está presente
hemos estimado estas ecuaciones sin los datos del padre. Los resultados incluyéndolos no varían sustantivamente de los resultados presentados aquí.
23
136 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
En cuanto a las variables personales, podemos ver que el mayor costo de oportunidad
de los jóvenes lleva a una menor probabilidad de solamente estudiar o de no estudia ni
trabajar, con respecto a solamente trabajar, independientemente de su sexo, lo cual que
es un resultado esperado. Además, las probabilidades de solamente estudiar, estudiar y
trabajar y no estudiar ni trabajar, con respecto a solamente trabajar, se reducen con la
edad. Esto se corrobora en los efectos marginales, donde un año más aumenta la probabilidad de solamente trabajar. En cuanto a los ingresos no laborales de los jóvenes, la
primera de nuestras variables proxy de su poder de negociación en el hogar, podemos
ver similitudes y diferencias tanto por sexo del joven como por el sexo del jefe de hogar.
En todos los casos, un mayor ingreso no laboral del joven lleva a una menor probabilidad
de solamente estudiar, lo cual es un resultado no esperado ya que asumimos que el joven
desea estudiar. Dado que los padres del joven también desean que estudie, un resultado
que nos permitiría decir que el ingreso no laboral del joven es adecuado para representar
su poder de negociación en el hogar sería un aumento en la probabilidad de no estudiar
ni trabajar, con relación a solamente trabajar, a mayor ingreso no laboral. Esto solamente
se cumple para los jóvenes varones en hogares con jefe mujer y las jóvenes mujeres es
hogares con jefe varón; sin embargo, los signos no son significativos. Es posible que otros
elementos expliquen este resultado, como problemas de medición, o el hecho que solamente un porcentaje reducido de la PEA consigna ingresos no laborales en la encuesta.
En el caso del estado marital existen diferencias importantes por sexo. Encontramos que
la probabilidad de que los varones solamente estudien, estudien y trabajen, y no estudien
ni trabajen, en relación con solamente trabajar es menor si están casados o conviven,
independientemente del sexo del jefe del hogar. En el caso de las jóvenes mujeres, esta
probabilidad es positiva —si bien no significativa— si el jefe de hogar es varón, y en
general negativa si el jefe de hogar es mujer. En el caso de esta muestra particular no se
puede explicar el resultado positivo para las jóvenes en hogares donde el jefe es varón por
una diferencia de ingresos promedio o mediana de ingresos entre ambos tipos de hogares. Estas diferencias son similares a las halladas para el número de hermanos, nuestra
segunda variable proxy de poder de negociación en el hogar. Así vemos que un mayor
número de hermanos reduce la probabilidad de solamente estudiar, estudiar y trabajar
y no estudiar ni trabajar, con respecto a solamente trabajar, en todos los casos, salvo
cuando el jefe de hogar es mujer, donde la probabilidad de no estudiar ni trabajar con
respectoa solamente trabajar, es mayor para los jóvenes de ambos sexos. En cuanto a los
efectos marginales, la reducción en la probabilidad de solamente estudiar y el aumento
en la probabilidad de solamente trabajar, a mayor número de hermanos, es mayor para
los varones que para las mujeres.
Costo de oportunidad del joven
Edad del joven
Ingreso no laboral del joven
Casado o conviviente
Número de hermanos
Ingreso laboral de la madre
Ingreso no laboral de la madre
Nivel educativo promedio de la madre
Constante
F
Tamaño de la población
Número de observaciones
Efectos marginales
-0.4973**
-0.2243***
-0.0869**
-3.1187**
-0.3534***
0.0819
-0.0369
0.0899**
0.0042
0.2756***
0.1773**
1.9306
316.74***
623288
1921
0.1264
-0.0684
0.0521
-0.6669
-0.2672**
8.74E-02
4.46E-02
3.02E-02
-2.81E-02
0.0010
0.1027
-0.6859
-0.5242**
-0.2578***
-0.0754
-22.0607***
-0.2425
7.88E-02
0.0253
0.0006
-0.0639*
0.1312*
0.1122
3.5100**
0.0591
0.0041
0.0156**
-0.0119
-0.0269
0.0104
0.0991
0.0014
-0.0038
-0.0058
0.0079
*** significativo al 1%
** significativo al 5%
*significativo al 10%
-0.0726**
-0.0265**
-0.0144**
-0.1725***
-0.0375**
7.00E-03
-7.80E-03
0.0125**
3.20E-03
0.0400***
0.0205**
0.0544
0.0397***
0.0054
0.3542***
0.0729***
-0.0209
-3.20E-03
-0.0114
5.80E-03
-0.0308**
-0.0326**
Efectos marginales
-0.6152**
-0.02047
-0.3660**
-19.9873***
0.4436
1.77E-01
-0.0646
0.4958***
-2.5571
56.01***
188242
573
-0.1532
-0.2854***
1.39E-02
-2.4133**
-9.04E-02
2.02E-01
1.57E-02
0.0553
3.0479
-0.5126**
-0.4328**
0.0006
-19.8698***
0.1139
0.3836
0.1131
0.3561**
0.1249
-0.0035**
-0.0009
-0.0022**
-0.0174**
0.0028
8.00E-04
-4.00E-04
0.0029**
*** significativo al 1%
** significativo al 5%
*significativo al 10%
-0.0234
-0.0454***
0.0027
-0.0153
-0.0153
0.0319
0.0025
0.0079
0.0296
0.0484***
-0.0005
0.2282***
0.0118
-3.47E-02
-2.70E-03
-0.0127
-0.0027*
-0.0021**
3.54E-06
5.57e-08
0.0007
0.0019
6.00E-04
0.0019
solo estudia estudia y trabaja no estudia ni trabaja solo e studia estudia y trabaja solo trabaja no estudia ni trabaja
Estimaciones
-0.0409**
-0.0173**
-0.0064
-0.1699***
-0.0086
3.40E-03
0.0018
-0.0024
-0.0052
0.0065
0.0042
solo estudia estudia y trabaja no estudia ni trabaja solo estudia estudia y trabaja solo trabaja no estudia ni trabaja
Estimaciones
Cuadro 4b. Logit Multinomial y efectos marginales jóvenes varones, jefe de hogar mujer – 2014
Regresión Logit Multinomial
Base=Solo trabaja
F
Tamaño de la población
Número de observaciones
Costo de oportunidad del joven
Edad del joven
Ingreso no laboral del joven
Casado o conviviente
Número de hermanos
Ingreso laboral del padre
Ingreso laboral de la madre
Ingreso no laboral del padre
Ingreso no laboral de la madre
Nivel educativo promedio del padre
Nivel educativo promedio de la madre
Constante
Regresión Logit Multinomial
Base=Solo trabaja
Cuadro 4a. Logit Multinomial y efectos marginales jóvenes varones, jefe de hogar varón – 2014
F
Tamaño de la población
Número de observaciones
Costo de oportunidad de la joven
Edad de la joven
Ingreso no laboral de la joven
Casada o conviviente
Número de hermanos
Ingreso laboral del padre
Ingreso laboral de la madre
Ingreso no laboral del padre
Ingreso no laboral de la madre
Nivel educativo promedio del padre
Nivel educativo promedio de la madre
Constante
Regresión Logit Multinomial
Base=Solo trabaja
Efectos marginales
-0.8458***
-0.1469**
-0.0575
0.5313
-0.0919
0.0391
-0.0319
0.0318
0.0589*
0.0797
0.3405***
1.1287
4.61***
555764
1771
0.1375
-0.1562**
0.0508
0.8446
-0.1106
6.45E-02
-2.09E-02
2.34E-02
2.86E-02
0.1906**
0.0197
0.8123
-0.0756***
-0.2019**
0.0174
0.6679
-0.0774
5.24E-02
0.0209
0.0561
-0.0091
0.0109
0.1741**
2.6512
0.0961**
-0.0089
0.0103*
-0.1326**
-0.0095
0.0060
-0.0024
-0.0002
0.0017
0.0252**
-0.0216**
*** significativo al 1%
** significativo al 5%
*significativo al 10%
-0.1326***
-0.0099
-0.0149*
0.0942
-0.0082
1.50E-03
-6.40E-03
2.00E-03
0.0106*
0.0051
0.0569***
0.0197**
0.0370**
0.0008
-0.0689
0.0207
-0.0113
-1.47E-06
2.90E-03
-8.20E-03
-0.0234*
-0.0439**
-0.0832***
-0.0182
0.0039
0.1073
-0.0031
3.80E-03
0.0059
0.0063
-0.0057
-0.0099
0.0086
solo estudia estudia y trabaja no estudia ni trabaja solo estudia estudia y trabaja solo trabaja no estudia ni trabaja
Estimaciones
Cuadro 4c. Logit Multinomial y efectos marginales jóvenes mujeres, jefe de hogar varón – 2014
Efectos marginales
-1.5355**
-0.1688
-7.8261***
1.2314
0.2824
-0.2117
-0.2667**
0.4644**
2.0618
170.95*** 201703 541
0.3841*
-0.1208
-5.22E-02
-2.3031**
-0.2388
8.37E-02
0.0007
0.0634
1.2257
-0.0013
-0.00009
-0.0008
-0.0044
0.00005
6.00E-04
-5.38E-06
0.0002
*** significativo al 1%
** significativo al 5%
*significativo al 10%
0.0915*
-0.0286
-0.0121
-0.3521***
-0.0566
0.0196
0.0002
0.0149
-0.0902*
0.0287
0.0129
0.3565***
0.0565
-2.02E-02
-2.00E-04
-0.0151
-4.27E-12
-3.10e-13
-1.98e-11
1.00e-11
9.50e-13
-6.21e-13
-6.77E-13
1.12E-12
Los efectos marginales para “no estudia ni trabaja” no pudieron ser calculados adecuadamente debido a problemas con la variable edad. Se trató de cambiar la
escala de dicha variable, pero aun así el paquete estadístico no pudo encontrar la derivada.
24
F
Tamaño de la población
Número de observaciones
Estimaciones
solo estudia estudia y trabaja no estudia ni trabaja solo estudia estudia y trabaja solo trabaja no estudia ni trabaja
Costo de oportunidad de la joven
-1.2470**
Edad de la joven
-0.1474
Ingreso no laboral de la joven
-0.9214**
Casada o conviviente
-25.5112***
Número de hermanos
-0.0332
Ingreso laboral de la madre
0.6351**
Ingreso no laboral de la madre
-0.0056
Nivel educativo promedio de la madre
0.1980
Constante
-4.0181
Regresion Logit Multinomial
Base=Solo trabaja
Cuadro 4d. Logit Multinomial y efectos marginales jóvenes mujeres, jefe de hogar mujer – 201424
140 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
En cuanto a las variables familiares, los coeficentes de los ingresos laborales de los
padres no son significativos, si bien podemos decir que en general aumentan la probabilidad de solamente estudiar, estudiar y trabajar y no estudiar ni trabajar, con relación a
solamente trabajar. Los ingresos no laborales, en cambio, tienen efectos distintos según
sexo. Un mayor ingreso no laboral del padre aumenta la probabilidad de solamente
estudiar, estudiar y trabajar y no estudiar ni trabajar, en relación solamente trabajar. El
ingreso no laboral de la madre aumenta las dos primeras probabilidades pero reduce la
probabilidad de no estudiar ni trabajar para los jóvenes de ambos sexos. Estimaciones
sumando los ingresos laborales y no laborales de cada padre no mejoran el ajuste. Estos
resultados coinciden con lo obtenido por Garavito (2011) para los años 2008 y 2009,
y estimaciones no publicadas hechas para los años 2011 y 2013. En general, un mayor
nivel de ingresos de los padres reduce la probabilidad de solamente trabajar, y un mayor
ingreso laboral de la madre aumenta la probabilidad de que los jóvenes de ambos sexos
no abandonen el sistema educativo.
Finalmente, a más años de estudios del padre y de la madre, mayor es la probabilidad
de que los jóvenes de ambos sexos solamente estudien, estudien y trabajen, y no estudien ni trabajen con relación a solamente trabajar. El efecto de los años de educación
del padre sobre la probabilidad de que los jóvenes solamente estudien con relación a
solamente trabajar es mayor para los hijos que para las hijas, mientras que en el caso de
los años de educación de la madre se da lo contrario. En general, asimismo, vemos en los
efectos marginales que más años de estudios de ambos padres reducen la probabilidad
de que los jóvenes de ambos sexos solamente trabajen, siendo este último efecto siempre
mayor en el caso de la madre.
6. CONCLUSIONES Y RECOMENDACIONES DE POLITICA
Las estimaciones llevadas a cabo nos permiten establecer que nuestras hipótesis son en
su mayor parte consistentes con la realidad. Una primera interrogante es qué determina
que aumente la probabilidad de que los jóvenes estudien, aun si también trabajan. Sobre
este punto podemos decir que un mayor ingreso no laboral del joven, un mayor ingreso
de sus padres y más años de educación de estos aumentan la probabilidad de que los
jóvenes se mantengan en el sistema educativo aun si también trabajan. En el caso de los
años de educación de los padres existe un sesgo a favor de los varones en el caso del padre
y a favor de las mujeres en el caso de la madre. En el caso de la presencia de hermanos,
esta reduce la probabilidad de solamente estudiar de los jóvenes, independientemente
de su sexo, salvo para el caso de varones en hogares donde la jefa de hogar es mujer.
Esto ya un indicio de una actitud diferente ante la educación de los varones en hogares
monoparentales.
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
141
Como era de esperarse, la probabilidad de que los jóvenes de ambos sexos solamente trabajen aumenta con su costo de oportunidad, con su edad, y con el número de
hermanos. Sin embargo, las jóvenes mujeres casadas o convivientes tienen una menor
probabilidad de solamente trabajar cuando el jefe del hogar donde viven es varón, lo
cual es otro indicio de diferencias en los roles por género de los jóvenes. Por otro lado,
el efecto de más años de educación de la madre sobre la reducción de la probabilidad de
que los jóvenes solamente trabajen es mayor para las hijas que para los hijos; el efecto de
más años de educación del padre es el contrario, es decir, mayor para los hijos que para
las hijas.
Finalmente, a más años de estudios del padre y de la madre, mayor es la probabilidad
de que los jóvenes de ambos sexos solamente estudien, estudien y trabajen, y no estudien ni trabajen con relación a solamente trabajar. El efecto de los años de educación
del padre sobre la probabilidad de que los jóvenes solamente estudien con relación a
solamente trabajar es mayor para los hijos que para las hijas, mientras que en el caso de
los años de educación de la madre se da lo contrario.
En cuanto a la probabilidad de que el joven no estudie ni trabaje esta aumenta con
los ingresos no laborales de los jóvenes, y con los años de educación de la madre, y se
reduce con su costo de oportunidad y con el número de hermanos. Sin embargo, los
efectos de los ingresos de los padres no son concluyentes. Aquí es necesario recordar la
heterogeneidad de las razones por las cuales los jóvenes de ambos sexos no estudian ni
trabajan, por lo cual sería necesario un estudio en profundidad sobre estos jóvenes que
no están ni en el mercado laboral ni en el sistema educativo.
Es posible plantear algunas recomendaciones a partir de nuestros resultados. En primer lugar, si bien el efecto de los ingresos no laborales sobre la probabilidad de que el
joven siga estudiando no es concluyente, su efecto es positivo por lo cual transferencias
o préstamos condicionados a llevar a cabo estudios superiores con cierto éxito y regularidad los mantendrían en el sistema educativo.
En segundo lugar, vemos que en general mayores ingresos de los padres llevan a una
mayor probabilidad de que los jóvenes estudien, aunque también trabajen. Una manera
de aumentar estas probabilidades es tomar medidas para aumentar los ingresos de los
padres en situación de vulnerabilidad, con programas de empleo y de capacitación.
Finalmente vemos que un mayor nivel de educación de ambos padres aumenta la
probabilidad de que los jóvenes de ambos sexos continúen estudiando, si bien el efecto
marginal es distinto de acuerdo al sexo de los padres y del hijo. En general la madre
tiene una influencia muy importante en la asignación de parte del tiempo del joven a los
estudios, por lo cual los programas de apoyo a familias en situación de vulnerabilidad
mencionados arriba deberán dirigirse en especial a las madres.
142 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
ANEXO 1. Estructura de la muestra total por género
Perú urbano: nuestra por sexo - 2014
Mujeres
Varones
Total
Muestra
Perú total
54,6
45,4
100,0
124 054
Perú urbano
Perú rural
54,9
53,4
45,1
46,6
100,0
100,0
82 913
41 141
Jóvenes
51,2
48,8
100,0
39 858
14 - 17 años
18 - 24 años
48,8
53,3
51,2
46,7
100,0
100,0
19 626
20 232
Jóvenes urbanos
51,7
48,3
100,0
25 070
Jóvenes urbanos 18 - 24 años
53,5
46,5
100,0
14127
Jóvenes urbanos hijos
50,3
49,7
100,0
9803
Fuente: ENAHO 2014. Elaboración propia.
Perú urbano: población en edad de trabajar - 2014
2014
Actividad
Mujer
Varón
Total
8,0%
9,1%
58,7%
24,2%
8,7%
11,9%
69,8%
9,6%
8,3%
10,4%
63,8%
17,5%
100,0%
100,0%
100,0%
Solo estudia
Estudia y trabaja *
Solo trabaja *
No estudia ni trabaja
Total
Población a/
Muestra
17 874 030 14 870 055 32 744 085
67 721
56 316
124 037
Fuente: ENAHO - INEI. Elaboración propia
a/ Valores expandidos
* Incluye a TFNR que trabajan menos de 15 horas a la semana
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
143
ANEXO 2. Presentación matricial de la solución interior
(1 − µ )U CE
0
0
− P dC
(1 − µ )U CC
(1 − µ )U
(1 − µ )U EE + µVEE µVECh µVEH −( Pe + w) dE
EC
µVCh E
µVChCh µVCh H
− Ph dCh =
0
0
µVHE
µVHCh µVHH
− w dH
dλ
0
−P
−( Pe + wh )
− Ph
−w
A
λ
0
0
0
C
0
0
λ
0
λ
0
0
0
λ
0
λ
E −(T − E − H ) Ch
0
dP
0
UC
dP
0 (U E − VE ) e
dw
0
−VCh
dPh
0
−VH
dI i
0
−1
d µ
∀i = P, M
El determinante de la matriz A es positivo:
det( A) = µ 2 P(VChCh VHH − VC2h H ){(1 − µ )( Pe + w)U CE − [(1 − µ )U EE + VEE ]} > 0
ANEXO 3. Estimación del ingreso laboral esperado del joven
La estimación del ingreso laboral por hora del joven se hace sobre la base de una ecuación
de ingresos de Mincer, y corrigiendo el sesgo de selección por el método de Heckman
(1974, 1979). Para ello planteamos una ecuación de ingresos y una ecuación de participación en la fuerza laboral. La ecuación de ingresos es muy simple para no perder
información, dado el rango de edad con el cual trabajamos:
ln( w) = β 0 + β1Sexo + β 2 Blanco _ mestizo + β 3 Lengua _ nativa + β 4 AEH
+ β 5 EXPLAB + β 6 LM + β 7 λM + ε 1
Donde w es el ingreso laboral por hora del hijo, medido en nuevos soles. Asimismo,
la ecuación de participación será la siguiente:
PL = γ 0 + γ 1Sexo + γ 2 Edad + γ 3 Ln( Ingnolab) + γ 4 Ln( Inglabpadre)
+γ 5 Ln(IInglabmadre) + γ 6 Ln( Ingnolabpadre) + γ 7 Ln( Ingnolabmadre) + ε 2
144 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
Donde PL es una variable dicotómica, cuyos valores son 1 si el joven participa en la
fuerza laboral, y 0 si no participa. Las variables explicativas serán las siguientes:
– Sexo: variable dicotómica cuyo valor es 1 si el joven es varón, y es 0 en caso contrario. En la ecuación de ingresos se busca capturar diferencias en los ingresos
asociados a los efectos de los roles de género en la sociedad. En la ecuación de
participación se busca capturar las diferencias en la participación laboral de varones y mujeres.
– Blanco_mestizo: variable dicotómica que busca capturar el “premio” a los ingresos que reciben los trabajadores blancos y mestizos, ampliamente documentado
en estudios sobre el tema.
– Lengua_nativa: variable dicotómica que busca capturar el “castigo” en los ingresos que reciben los trabajadores cuya lengua materna es nativa, documentado en
estudios sobre el tema.
– Años de educación del Hijo (AEH ): variable numérica que mide el efecto de más
años de educación sobre el ingreso laboral. Esperamos que el signo de esta variable sea positivo.
– Experiencia laboral potencial (EXPLAB = Edad - AEH - 6): variable numérica
que mide la experiencia potencial de los jóvenes, tomando en cuenta que los estudios primarios empiezan a los 6 años de edad. Se espera un efecto positivo de esta
variable sobre los ingresos laborales.
– LM: Variable dicotómica que toma el valor de 1 si el joven vive en Lima Metropolitana, y de = en caso contrario. Esta variable intenta capturar las diferencias en
los niveles de desarrollo económico de la capital y el resto de la zona urbana.
– Lambda de Mills (lM): La inversa del Ratio de Mills que mide la probabilidad
estimada de trabajar.
– Edad: variable numérica medida en años. Se espera un efecto positivo sobre la
probabilidad de participación del joven en la fuerza laboral.
– Logaritmos de los ingresos laborales y no laborales del padre y de la madre:
variables numéricas medida en nuevos soles anuales, que incluye la suma de los
ingresos laborales y no laborales de cada progenitor. Se espera que a mayor ingreso
de sus padres, el joven tenga una menor probabilidad de formar parte de la fuerza
laboral.
Como se ve en el cuadro siguiente, los signos de las variables son los esperados y en
su mayoría significativos al 99%. En cuanto a la inversa del ratio de Mills, el coeficiente
es positivo y significativo, por lo cual existe un sesgo de selección en la participación de
los jóvenes en el mercado de trabajo. Finalmente, el Test de Wald es significativo al 1%,
Cecilia Garavito
Educación y trabajo juvenil en el Perú urbano
145
lo cual indica que las variables independientes explican la participación y los ingresos
en forma conjunta. A partir de los coeficientes obtenidos en cada regresión de ingresos
estimamos el costo de oportunidad del tiempo de los jóvenes sin ingresos.
Modelo de Selección de Heckman en dos etapas
Número de obs = 4957
(modelo de regresión con sesgo de selección)
Obs Truncadas =
2678
Obs No Truncadas = 2279
Test de Wald chi2(6) = 140,21
Prob > chi2 = 0,0000
Coef,
Std, Err,
z
P>|z|
[95% Conf, Interval]
Sexo
0,3394
0,0530
6,40
0,000
0,2355
0,4433
Blanco o mestizo
0,1402
0,0493
2,84
0,004
0,0435
0,2369
Lengua nativa
-0,0391
0,0933
-0,42
0,675
-0,2220
0,1438
Años de estudios
0,1728
0,0182
9,51
0,000
0,1372
0,2084
Ln(Ingreso por Hora)
Experiencia potencial
0,1403
0,0179
7,82
0,000
0,1051
0,1755
Lima Metropolitana
0,2559
0,0603
4,24
0,000
0,1378
0,3742
Constante
-1,7893
0,3783
-4,73
0,000
-2,5308
-1,0478
Select
Sexo
0,2860
0,0367
7,79
0,000
0,2141
0,3579
Edad
0,1241
0,0095
13,01
0,000
0,1054
0,1428
Ln(ingreso no laboral)
0,0639
0,0064
10,01
0,000
0,0514
0,0764
Ln(ingreso laboral del padre)
-0,0369
0,0103
-3,59
0,000
-0,0571
-0,0168
Ln(ingreso laboral de la madre)
-0,0014
0,0059
-0,24
0,810
-0,0131
0,0102
Ln(ingreso no laboral del padre)
-0,0278
0,0051
-5,48
0,000
-0,0378
-0,0179
Ln(ingreso no laboral de la madre)
-0,0173
0,0054
-3,19
0,001
-0,0279
-0,0067
Constante
-2,4294
0,2333
-10,88
0,000
-2,8672
-1,9917
0,1574
2,9
0,004
0,1473
0,7646
Lambda de Mills
0,4559
rho
0,4060
sigma
1,1229
146 Economía Vol. XXXVIII, N° 76, 2015 / ISSN 0254-4415
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Documento recibido el 20 de agosto de 2015
y aprobado el 5 de noviembre de 2015
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Photocatalytic properties of persistent luminescent rare earth doped SrAl2O4 phosphor under solar radiation
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1.
Introduction Today, environmental pollution is major concern, especially resulting from volatile organic compounds like ben-
zene or textile dyes, like Methylene blue, Congo red, etc.; these volatile organic compounds are known to be toxic
and carcinogenic. It is required to develop photo-catalysts for the degradation of these toxic materials to reduce air
pollution and to develop better wastewater cleaning process. Advanced oxidation is a process which produces reactive
oxygen groups to react with different chemicals which in turn help in degradation of these chemicals. Photocatalysis
is also a kind of advanced oxidation process to remove organic pollutants from water [1,2]. When photocatalysts are
dispersed in water, they absorb UV or sun light to produce electron-hole pairs which in turn generate free radicals
(e.g. hydroxyl radicals OH−and O2−) that take part in secondary reactions which removes organic pollutants from
water [3]. Photocatalysts are semiconductors or insulators such as Al2O3 [4], ZnO [5], Fe2O3 [6]. TiO2 has been
widely used for decolorizing of organic contaminants, dyes and phenols. The problem with TiO2 is that it is toxic for
living organisms [7,8] like fish and other aquatic animals, as it can penetrate their skin to produce oxidative stress and
impaired liver function. Hence, the search for new environmentally friendly photocatalysts is required that could be
easily removed from water. It has been found that long-lasting phosphors show photocatalytic properties [9]. Rare
earth doped alkaline earth aluminates are a very important class of luminescent materials due to their higher quan-
tum efficiency and persistent luminescence [10]. They are good host materials and have wide band gaps, thus, they
have been suggested for possibile application such as development of white LED’S, gamma ray dosimeter, pressure
sensor, stress sensor, environmental radiation dosimetry, luminescent paint, emergency exit lamps, radiation detec-
tion [11,12] etc. There are few papers which report persistent luminescent phosphors prepared by combustion method
as photocatalytic materials. In this paper, we have reported the synthesis of SrAl2O4 doped with Eu/Dy/Ho by combustion method and their
photocatalytic properties. NANOSYSTEMS: PHYSICS, CHEMISTRY, MATHEMATICS, 2020, 11 (5), P. 590–594 NANOSYSTEMS: PHYSICS, CHEMISTRY, MATHEMATICS, 2020, 11 (5), P. 590–594 PACS 52.70.Kz, 81.16.Hc, 87.15.Mi This paper aims to study the photocatalytic properties of strontium aluminate phosphors. The rare earth doped strontium aluminate was synthesized
by combustion method. The photocatalytic property was studied by absorption of methyle orange in aqueous solution under solar radiation. Eu:Dy
codoped SrAl2O4 shows better photocatalytic properties than Eu or Dy doped or Eu, Dy, Ho codoped SrAl2O4. Structural and morphological
characterization was done by X-ray diffraction, SEM, EDX techniques. Keywords: photocatalysis, strontium aluminate, combustion method, persistence luminescence. Received: 10 May 2020
Revised: 26 August 2020
Final revision: 16 September 2020 Received: 10 May 2020 Final revision: 16 September 2020 Final revision: 16 September 2020 Photocatalytic properties of persistent luminescent rare earth doped SrAl2O4 phosphor
under solar radiation Deepika Pal1, Anil Kumar Choubey2 1Department of Nanotechnology, Christian College of Engineering & Technology,
Kailash Nagar Bhilai, Chhattisgarh, India
2Department of Physics, M. J. College, Junwani-Kohka Road, Bhilai, Chhattisgarh, India 1Department of Nanotechnology, Christian College of Engineering & Technology,
Kailash Nagar Bhilai, Chhattisgarh, India
2Department of Physics, M. J. College, Junwani-Kohka Road, Bhilai, Chhattisgarh, India deepikapal664@gmail.com, anil.choubey@hotmail.com deepikapal664@gmail.com, anil.choubey@hotmail.com DOI 10.17586/2220-8054-2020-11-5-590-594 PACS 52.70.Kz, 81.16.Hc, 87.15.Mi 2.
Experimental The combustion method involves a highly exothermic reaction between an organic fuel and metal nitrates. The
reaction is initiated at low temperatures (around 610 ◦C) and proceeds to completion in a few minutes. The exothermic
chemical reaction between the metal nitrates and fuel provides the required heat for synthesis of nano-phosphor. Research grade strontium nitrate Sr(NO3)2, aluminum nitrate Al(NO3)3 · 9H2O, europium oxide Eu2O3, dysprosium
oxide Dy2O3, holmiun oxide Ho2O3 were used as the staring materials and urea CO(NH2)2 was used as a fuel. The
Stoichiometric composition to prepare Sr1−xAl2O4:Eux phosphor, the chemical reaction used for the combustion
reaction is as follows: 591 Photocatalytic properties of persistent luminescent rare earth doped SrAl2O4 phosphor ... (1 −x) Sr (NO3)2 + x1
2Eu2O3 + 2Al (NO3)3 · 9H2O = Sr1−xAl2O4 : Eux + 4N2 + 18H2O + 10O2,
2CO (NH2)2 + 3O2 = 2CO2 + 2N2 + 4H2O. 2CO (NH2)2 + 3O2 = 2CO2 + 2N2 + 4H2O. The stoichiometric composition of the metal nitrates (oxidizers) and urea (fuel) were calculated using the total
oxidizing and reducing valences of the components, which serve as the numerical coefficients so that the equivalence
ratio is unity and the heat liberated during combustion is at a maximum. For the calculation of oxidizer to fuel ratio,
the elements were assigned formal valences as follows: Sr = +2, Al = +3, Eu/Dy/Ho = +3, C = +4, N = 0, O = −2
and H= +1. Nitrogen had a valence of zero because N2 was assumed to be liberated during the combustion process. The rare earth oxides were dissolved in minimum amount of HNO3. The stoichiometric quantities of metal nitrate
and urea were mixed for crushing in a mortar; then the nitrates of rare earth were mixed. The composition was stirred
for 1 hour at 80 ◦C to form a thick paste. The paste was transferred to a crucible and put into a vertical cylindrical
muffle furnace maintained at 610 ◦C. The mixture went decomposition with the evolution of large amount of gases
(oxides of carbon, nitrogen and ammonia). The exothermic reaction continues and the spontaneous ignition occurs. The solution underwent smoldering combustion with enormous swelling, producing white foamy and voluminous
ash. The whole process completed in ∼30 seconds. The foamy product was milled to obtain the precursor powder. Sample annealing was done at 1050 ◦C for 3 hours in reducing atmosphere. 2.
Experimental The structural characterization XRD was
done with a PANalytical 3kW X’pert powder- Multifunctional X-ray diffractometer available at NIT, Raipur in the
range 10◦< 2θ < 80◦with a step of 0.02◦. The morphology of the sample powders was done with ZEISS EVO 18
Scanning Electron Microscope (SEM), 30 kV of acceleration voltage with Quorum SC7620 sputter gold coater. The
Energy Dispersive X-ray (EDX) of the phosphor was done with INCA 250 EDS with X-MAX 20 nm detector at NIT,
Raipur. The absorbance spectra of powders were taken using ELICO-SL210 UV Spectrometer in 200 – 700 nm range. Photocatalytic properties were studied after dissolving 0.1 gm of photocatalysts powder in the solution of methylene
orange. The mixture was stirred in the dark for 30 minutes and then placed in direct sunlight for different intervals and
absorbance studies were performed subsequently. 3.1.
Structural and morphological characterization Figure 1 shows the XRD patterns of the SrAl2O4 powders doped and codoped with Eu/Dy/Ho which matchs well
with the monoclinic phase of SrAl2O4, JCPDS card number 34-0379. The main peak corresponds to 220, 031, −211,
211 planes. The doping of rare earth ions does not affect the crystal structure due similar ionic radii of Sr2+ (0.114 nm),
Eu2+ (0.112 nm), Dy3+ (0.117 nm), Ho3+ (0.115 nm). The average crystallite sizes calculated by Scherrer method
for Eu, Dy, EuDy, EuDyHo doped samples were found to be 17.12, 20.54, 17.78 and 18.34 nm respectively. The SEM micrograph of Eu, Dy, Eu:Ho, Eu:Dy:Ho doped SrAl2O4 is shown in Fig. 2(A), 2(B), 2(C) and 2(D)
respectively. Each sample were coated with gold by gold sputter before SEM. The samples show flower like structure
with flakes randomly oriented. The EDX spectral studies provide the elemental contents qualitatively and quantitatively. The EDX studies of Eu,
Dy, Eu:Ho, Eu:Dy:Ho doped SrAl2O4 is shown in Fig. 3(A), 3(B), 3(C) and 3(D) respectively. Clearly the spectra
show sharp peaks corresponding to Sr, Al, O and Eu/Dy/Ho elements respectively and show no other impurities
presence of the samples. The elemental contents are shown in Table 1. 3.2.
Photocatalytic activity under solar irradiation It has been reported earlier [13] that Eu:Dy codoped SrAl2O4 was known to be more
persistent luminescent material than that of the doped alone, though its luminescence intensity decreased. Since the
photocatalytic activity depends upon the generation of free carriers, the long persistent luminescent materials allow
more time for the free carriers for catalytic action, in comparison to the high luminescent but less persistent materials. With codoping of Ho and Dy in SrAl2O4:Eu,Dy, the luminescence intensity increases but the persistence time is
decreased [14] which results in less photocatalytic activity in Ho:Dy codoped phosphor. 3.2.
Photocatalytic activity under solar irradiation Photocatalytic activity was observed by the percentage degradation of methylene orange (MO) in aqueous so-
lution. MO shows an absorbance band at 465 nm and absorption intensity of this peak as a function of time was
observed. Decrease in absorbance intensity indicate the decrement of MO concentration. The percentage degradation
was calculated as: Degradation (%) = It −I0
I0
× 100 %,
(1) (1) where I0 – absorbance before solar radiation, It – absorbance after time t of solar radiation. ance before solar radiation, It – absorbance after time t of solar radiation. where I0 – absorbance before solar radiation, It – absorbance after time t of solar radiation. Aqueous solutions of Methylene Orange (0.0025 gm /100 mL) were prepared in a beaker subsequently, 0.1 gm
of photocatalysts powder were added to 100 ml aliquots of these solutions. The mixture was stirred in the dark for
half hour. Later, the solutions of dye photocatalyst were directly exposed to sunlight for regular intervals. Fig. 4
shows the percentage degradation of MO as a function of time. The percentage degradation of undoped samples were 592 592 Deepika Pal, Anil Kumar Choubey 592
Deepika Pal, Anil Kumar Choubey
FIG. 1. The XRD image of rare earth doped and codoped SrAl2O4
(A)
(B)
(C)
(D)
FIG. 2. SEM micrograph of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01 FIG. 1. The XRD image of rare earth doped and codoped SrAl2O4
(A)
(B)
(C)
(D)
FIG. 2. SEM micrograph of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01 FIG. 1. The XRD image of rare earth doped and codoped SrAl2O4 FIG. 1. The XRD image of rare earth doped and codoped SrAl2O4 arth doped and codoped SrAl2O4
(B) (A) (B)
(D) (A) (B) (A)
(C) (D) (C) FIG. 2. SEM micrograph of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01 Photocatalytic properties of persistent luminescent rare earth doped SrAl2O4 phosphor ... 593 (A)
(B)
(C)
(D)
FIG. 3. EDX spectra of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01
TABLE 1. Element contents of SrAl2O4 (B) (A) (A) (B) (C) (D) (C) (D) FIG. 3. EDX spectra of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01
TABLE 1. Element contents of SrAl2O4 FIG. 3. EDX spectra of SrAl2O4 doped with A) Eu0.05; B) Dy0.1; C) Eu0.05Ho0.01; D) Eu0.05Dy0.1Ho0.01 TABLE 1. 3.2.
Photocatalytic activity under solar irradiation Element contents of SrAl2O4 Elements
SrAl2O4:Eu0.05 %
SrAl2O4:Dy0.1 %
SrAl2O4:Eu0.05Ho0.1 %
SrAl2O4:
Eu0.05Dy0.1Ho0.01 %
weight %
Atomic %
weight %
Atomic %
weight %
Atomic %
weight %
Atomic %
Sr
36.11
10.73
34.66
10.19
34.96
10.48
35.93
10.73
Al
20.95
20.21
22.05
21.06
23.71
23.08
21.39
20.73
O
42.4
68.97
42.61
68.64
40.37
66.28
41.84
68.4
Eu
0.54
0.09
–
–
0.41
0.07
0.21
0.04
Dy
–
–
0.68
0.11
–
–
0.46
0.07
Ho
–
–
–
–
0.57
0.09
0.17
0.03
Total
100
100
100
100
100
100
100
100 negligible and not reported here. The percentage degradation of Eu, Dy, Eu:Dy, and Eu:Dy:Ho doped samples after
240 minutes were 20.8%, 15.7%, 22.8%, and 13.2% respectively. The highest percentage degradation was obtained
for Eu:Dy codoped SrAl2O4. It has been reported earlier [13] that Eu:Dy codoped SrAl2O4 was known to be more
persistent luminescent material than that of the doped alone, though its luminescence intensity decreased. Since the
photocatalytic activity depends upon the generation of free carriers, the long persistent luminescent materials allow
more time for the free carriers for catalytic action, in comparison to the high luminescent but less persistent materials. With codoping of Ho and Dy in SrAl2O4:Eu,Dy, the luminescence intensity increases but the persistence time is
decreased [14] which results in less photocatalytic activity in Ho:Dy codoped phosphor. negligible and not reported here. The percentage degradation of Eu, Dy, Eu:Dy, and Eu:Dy:Ho doped samples after
240 minutes were 20.8%, 15.7%, 22.8%, and 13.2% respectively. The highest percentage degradation was obtained
for Eu:Dy codoped SrAl2O4. It has been reported earlier [13] that Eu:Dy codoped SrAl2O4 was known to be more
persistent luminescent material than that of the doped alone, though its luminescence intensity decreased. Since the
photocatalytic activity depends upon the generation of free carriers, the long persistent luminescent materials allow
more time for the free carriers for catalytic action, in comparison to the high luminescent but less persistent materials. With codoping of Ho and Dy in SrAl2O4:Eu,Dy, the luminescence intensity increases but the persistence time is
decreased [14] which results in less photocatalytic activity in Ho:Dy codoped phosphor. negligible and not reported here. The percentage degradation of Eu, Dy, Eu:Dy, and Eu:Dy:Ho doped samples after
240 minutes were 20.8%, 15.7%, 22.8%, and 13.2% respectively. The highest percentage degradation was obtained
for Eu:Dy codoped SrAl2O4. 4.
Conclusions SrAl2O4 doped and codoped with Eu, Dy and Ho were synthesized by combustion method. The XRD analysis
shows monoclinic structure of SrAl2O4 without any considerable effect on structure due to doping. The photocatalytic
properties under solar radiation were observed. The undoped samples showed negligible photocatalytic effect with
respect to the doped samples. The Eu:Dy codoped samples showed better photocatalytic properties than Eu/Dy doped
or Eu:Dy:Ho codoped samples. The photocatalytic response of strontium aluminate phosphors were less than TiO2
but they are more environmental friendly as they are activated by solar radiation and they can be removed from water
by simple precipitation method. 594 Deepika Pal, Anil Kumar Choubey
FIG. 4. The percentage degradation of MO under solar radiation as a function of time Deepika Pal, Anil Kumar Choubey Deepika Pal, Anil Kumar Choubey
FIG. 4. The percentage degradation of MO under solar radiation as a function of time FIG. 4. The percentage degradation of MO under solar radiation as a function of time References [1] Berlanga A., Garcia-Diaz R., et al. Photocatalytic Activity of SrAl2O4:αCu powders under Solar Irradiation. Nano Hybrid and Composites,
2017 16 P 63 66 [2] Sang Y., Liu H., Umar A. Photocatalysis from UV/Vis to near-infrared light: Towards full solar-light spectrum activity. Chem. Cat. Che
2015, 7, P. 559–573. [3] Ibhadon A., Fitzpatrick P. Heterogeneous Photocatalysis: Recent Advances and Applications. Catalysts, 2013, 3, P. 189–218. [4] Tzompantzi F., Pi˜na Y., et al. Hydroxylated sol-gel Al2O3 as photocatalyst for the degradation of phenolic compounds in presence of UV
light. Catalysis Today, 2014, 220–222, P. 49–55. dy M.A., Modirshahla N., Hamzavi R. Kinetic study on photocatalytic degradation of C.I. Acid Yellow 23 by ZnO photocatalyst
of Hazardous Materials,2006, 133 (1–3), P. 226–232. [6] Karunakaran C., Senthilvelan S. Fe2O3-photocatalysis with sunlight and UV light: Oxidation of aniline. Electrochemistry Communications,
2006, 8 (1), P. 95–101. [7] Wu J., Liu W., et al. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after sub chronic dermal exposure. Toxicology Letters, 2009, 191, P. 1–8. , Zeng G., et al. An overview on limitations of TiO2-based particles for photocatalytic degradation of organic pollutants and the
nding countermeasures. Water Research, 2015, 79, P. 128–146. p
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[9] Zhong J.B., Ma D., et al. Sol-gel preparation and photocatalytic performance of TiO2/SrAl2O4: Eu2+, Dy3+ toward the oxidation of gaseous
benzene. Journal of Sol-Gel Science and Technology, 2009, 52 (1), P. 140–145. f
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[10] Liu B., Gu M., et al. Theoretical Study of Structural, Electronic, lattice dynamical and dielectric properties of SrAl2O4. Journals of Alloys
and Compounds, 2011, 509, P. 4300–4303. [11] Choubey A.K., Brahme N., et al. Thermoluminescence characterization of γ-ray irradiated Dy3+ activated SrAl4O7 nanophosphor. Advanced
Materials Letters, 2014, 5 (7), P. 396–399. hou S., Pan T., Zhang S. Band structure calculations on the monoclinic bulk and nano- SrAl2O4 crystals. Journals of Solid state
ry, 2005, 178, P. 230–233. [13] L¨u X., Shu W.et al. Roles of Doping Ions in Persistent Luminescence of SrAl2O4: Eu2+, RE3+ Phosphors. Glass Physics and Chemistry,
2007, 33 (1), P. 62–67. [14] Gy¨ori Z., Havasi V., et al. Luminescence properties of Ho3+ co-doped SrAl2O4: Eu2+, Dy3+ long-persistent phosphors synthesized with a
solid-state method. Journal of Molecular Structure, 2013, 1044, P. 87–93.
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Work honored by Nobel prizes clusters heavily in a few scientific fields
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PLOS ONE RESEARCH ARTICLE a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 OPEN ACCESS OPEN ACCESS
Citation: Ioannidis JPA, Cristea I-A, Boyack KW
(2020) Work honored by Nobel prizes clusters
heavily in a few scientific fields. PLoS ONE 15(7):
e0234612. https://doi.org/10.1371/journal. pone.0234612
Editor: Sergi Lozano, Universitat de Barcelona,
SPAIN
Received: October 8, 2019
Accepted: May 29, 2020
Published: July 29, 2020
Copyright: © 2020 Ioannidis et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Citation: Ioannidis JPA, Cristea I-A, Boyack KW
(2020) Work honored by Nobel prizes clusters
heavily in a few scientific fields. PLoS ONE 15(7):
e0234612. https://doi.org/10.1371/journal. pone.0234612 Citation: Ioannidis JPA, Cristea I-A, Boyack KW
(2020) Work honored by Nobel prizes clusters
heavily in a few scientific fields. PLoS ONE 15(7):
e0234612. https://doi.org/10.1371/journal. pone.0234612 Editor: Sergi Lozano, Universitat de Barcelona,
SPAIN Copyright: © 2020 Ioannidis et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Abstract We aimed to assess whether Nobel prizes (widely considered the most prestigious award in
science) are clustering in work done in a few specific disciplines. We mapped the key Nobel
prize-related publication of each laureate awarded the Nobel Prize in Medicine, Physics,
and Chemistry (1995–2017). These key papers mapped in only narrow sub-regions of a
91,726-cluster map of science created from 63 million Scopus-indexed published items. For
each key Nobel paper, a median of 435 (range 0 to 88383) other Scopus-indexed items
were published within one year and were more heavily cited than the Nobel paper. Of the
114 high-level domains that science can be divided into, only 36 have had a Nobel prize. Five of the 114 domains (particle physics [14%], cell biology [12.1%], atomic physics
[10.9%], neuroscience [10.1%], molecular chemistry [5.3%]) have the lion’s share, account-
ing in total for 52.4% of the Nobel prizes. Using a more granular classification with 849 sub-
domains shows that only 71 of these sub-domains (8.3%) have at least one Nobel-related
paper. Similar clustering was seen when we mapped all the 40,819 Scopus-indexed publi-
cations representing the career-long output of all the Nobel laureates. In conclusion, work
resulting in Nobel prizes is concentrated in a small minority of scientific disciplines. Work honored by Nobel prizes clusters
heavily in a few scientific fields John P. A. IoannidisID1,2*, Ioana-Alina CristeaID1,3, Kevin W. BoyackID4 1 The Meta-Research Innovation Center at Stanford (METRICS), Stanford, CA, United States of America,
2 The Meta-Research Innovation Center Berlin (METRIC-B), Berlin, Germany, 3 Department of Brain and
Behavioral Science, University of Pavia, Pavia, Italy, 4 SciTech Strategies, Inc., Albuquerque, NM, United
States of America 1 The Meta-Research Innovation Center at Stanford (METRICS), Stanford, CA, United States of America,
2 The Meta-Research Innovation Center Berlin (METRIC-B), Berlin, Germany, 3 Department of Brain and
Behavioral Science, University of Pavia, Pavia, Italy, 4 SciTech Strategies, Inc., Albuquerque, NM, United
States of America * jioannid@stanford.edu * jioannid@stanford.edu a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 PLOS ONE PLOS ONE Results The map of science that we used (Fig 1) includes data from a total of 63 million published
items, and it is divided into 12 major disciplines and a total of 91,726 clusters. The full list of the key papers related to the Nobel work (with one paper selected per Nobel
laureate) along with relevant data appear in the Supporting Information (S1 Table). Fig 1B
shows where the key papers of the laureates are placed within the map of science: they tend to
be localized to a small number of neighboring areas. Conversely, the vast majority of clusters
in the science map contain no key Nobel papers in themselves or in their vicinity. Fig 1C shows the localization in the science map of the papers that have cited the key Nobel
papers as of May 2017. We examined the location of the papers that have cited the key Nobel
papers, since an even spread of such papers across the science map could signal a wide interest
of the research rewarded with the Nobel prize, while a more circumscribed and limited spread
would suggest more topical interest. The vast majority of these citing papers are also in the
same disciplinary areas as the key Nobel index papers. There is some modest spill over in some
other, mostly neighboring, disciplines, but very few citing papers are in areas that are not in
the immediate vicinity of the Nobel key papers, if not in the same exact sub-discipline. Fig 1D shows the location of papers that have been more-cited than the respective Nobel
key paper even though they were published within one calendar year of the Nobel key paper. Their distribution is very wide, and it covers almost all major fields of science. The distribution
is almost as variegated as the distribution of all papers in Fig 1A. For each key Nobel paper, a
median of 435 (range 0 to 88383) other Scopus-indexed items were published within one year
and were more heavily cited than the Nobel paper as of May 2017. If one adds published items
that are not indexed in Scopus but can still be cited by Scopus-indexed items (mostly these
would be books), a median of 915 items (range 0 to 128049) published within one year of the
respective key Nobel papers were more heavily cited than the Nobel paper as of May 2017. Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Information files. This does not alter our adherence to
PLOS ONE policies on sharing data and materials. While it is difficult, if not impossible, to answer reliably whether any clustering is deserved
or undeserved for this top recognition, at a minimum it would help to understand whether
this clustering of favored scientific disciplines does exist and, if so, how strong it is. If it does
exist, what fields are mostly preferred and how strong is the selection? How many major fields
have never been honored by Nobel prizes? Here we aimed to address these issues systemati-
cally by mapping Nobel prize work in Physics, Chemistry, and Medicine/Physiology as well as
the spread of the subsequent scientific publications that cited this work within a comprehen-
sive map of science [15]. Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Information files. Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Information files. The Nobel prize is undoubtedly the most visible, influential, and coveted award across science. Nobel laureates represent a readily demarcated and most illustrious cohort of exceptional sci-
entists, and data on their work have been repeatedly used [1–14] to assess aspects of citation
impact, perception of rewards, credit allocation, paradigm shifts, and networking in science. Much can be learned by studying this influential cohort. A fundamental question is what disci-
plines of science are really covered by these top awards. Funding: JPAI is one of the two directors of the
Meta-Research Innovation Center at Stanford
(METRICS), which is supported by a grant from the
Laura and John Arnold Foundation. JPAI is also a
visiting Einstein fellow and director of METRIC B
and the Einstein fellowship is supported by the
Foundation Charite´ and the Einstein Foundation. The work of JPAI is also supported by an
unrestricted gift from Sue and Bob O’Donnell. Not all fields of scholarship are thematically covered by the Nobel prizes, but the three
prizes that focus on the natural and biomedical sciences (Chemistry, Physics, and Physiology/
Medicine) have very wide coverage. In theory, almost any work within the broad range of nat-
ural sciences or biomedicine would be potentially eligible for this honor, if it has tremendous 1 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields impact. However, a different viewpoint may be that these awards should be sharply focused in
specific disciplines. Particular areas or sub-disciplines may attract far more Nobel honors than
others and some investigators have suggested that a select scientific elite is more deserving and
legitimately attract more honors, prizes; according to this view, a relatively constrained num-
ber of ideas and scholars push the boundaries of science [11]. Conversely, clustering in a few
fields may herald bias and undeserved neglect of many/most scientific disciplines from these
utmost rewards. Additional funding was provided by SciTech
Strategies Inc in the form of salary for KWB. The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript. The specific roles of these authors
is articulated in the ‘author contributions’ section. Competing interests: KWB is an employee of
SciTech, Inc. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 Results (D) The location of papers that have been more-cited than the respective Nobel key paper even though they were published within one calendar year
of the Nobel key paper. Color legend as in panel A. (E) the location of the entire career-long publication record (40,819 papers) published by scientists awarded Nobel
prizes in Physics, Chemistry, and Physiology/Medicine 1995–2017. Color legend as in panel A. In order to map the location of the key Nobel papers in specific domains that are more
granular than the 12 large disciplines of science, but more concentrative than the 91,726 finely
delineated clusters, we used the DC2 classification system which has been previously described
[17] and which breaks science into 114 domains, aggregated from the 91,726 clusters. Table 1
shows that of the 114 domains, only 36 have been touched at all by Nobel prizes and have at
least 0.333 points (i.e. representing one of three laureates awarded a prize in a single year); of
those 36 domains only 20 have at least 1 full point. Five domains (particle physics [14%], cell
biology [12.1%], atomic physics [10.9%], neuroscience [10.1%], molecular chemistry [5.3%])
have the lion’s share, accounting in total for 52.4% of the 69 Nobel prizes that we mapped,
even though these 5 domains publish only 10.2% of all the Scopus-indexed papers. Using the
DC3 classification [17], an intermediate level of aggregation that breaks science into 849 sub-
domains, only 71 of these sub-domains (8.3%) are touched by at least one Nobel-related paper. Of the 114 DC2 domains, only 20,10, and 15 domains are ever represented in Chemistry,
Physics, and Medicine/Physiology Nobel prizes, respectively. Of note, Chemistry Nobel prizes
are more scattered across more domains, many of which may not be seen as typical core chem-
istry areas (Table 1). The 76 domains that have not been touched by any Nobel prizes in In order to map the location of the key Nobel papers in specific domains that are more
granular than the 12 large disciplines of science, but more concentrative than the 91,726 finely
delineated clusters, we used the DC2 classification system which has been previously described
[17] and which breaks science into 114 domains, aggregated from the 91,726 clusters. Table 1
shows that of the 114 domains, only 36 have been touched at all by Nobel prizes and have at
least 0.333 points (i.e. Results In
fact, there is only one case where the key Nobel paper has been the most-cited than anything
else published within one year across science (the paper in Science on graphene [16]). A large
share of the items that are more heavily cited than the respective key Nobel paper belong actu-
ally in the same field as the Nobel paper. Some caution is needed because these are crude cita-
tion counts and different fields and subfields have different citation densities. However, most
Nobel papers come from fields with quite high citation densities. The full distribution of the
more highly-cited per field is shown in the Supporting Information (S2 Table). PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 2 / 11 PLOS ONE Clustering of Nobel prizes to few fields Fig 1. Location of papers in a map of science. (A) Map of science 91,726 clusters and associated large disciplines. The color legend is derived from the original
construction of that map of science [15]). (B) The location of the key papers for Nobel prizes in Physics (purple), Chemistry (blue), and Physiology/Medicine (red) in
1995–2017. (C) The location of papers citing the key papers for Nobel prizes. Color legend as in panel B; grey color is used for areas that cite papers from two or more of
three Nobel types. (D) The location of papers that have been more-cited than the respective Nobel key paper even though they were published within one calendar year
of the Nobel key paper. Color legend as in panel A. (E) the location of the entire career-long publication record (40,819 papers) published by scientists awarded Nobel
prizes in Physics, Chemistry, and Physiology/Medicine 1995–2017. Color legend as in panel A. https://doi.org/10.1371/journal.pone.0234612.g001 Fig 1. Location of papers in a map of science. (A) Map of science 91,726 clusters and associated large disciplines. The color legend is derived from the original
construction of that map of science [15]). (B) The location of the key papers for Nobel prizes in Physics (purple), Chemistry (blue), and Physiology/Medicine (red) in
1995–2017. (C) The location of papers citing the key papers for Nobel prizes. Color legend as in panel B; grey color is used for areas that cite papers from two or more of
three Nobel types. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 The following 76 fields did not have any key paper of any Nobel prize in Medicine/Physiology, Chemistry, or Physics in 1995–2017: Lithography, Offshore Mechanics,
Tobacco, Acoustic Engineering, Electronic Packaging, Mycology, Petroleum Engineering, Brazil & Latin America, Information Science, Blood Disorders, Forestry, Law,
Tuberculosis, Alcohol, Machining & Tribology, Philosophy, Plasma Physics, Energy Usage, Veterinary Sciences, Music & Sound, Mining Chemistry, Transportation,
Bone Research, Energy Production, Separation Science, Nuclear Science, Cryptography, Metabolism Science, Environmental Engineering, Virology, Anesthesiology,
Neurology & Neurosurgery, Endocrinology, Toxicology, Statistics, Emergency Medicine, Dermatology, Human Computing, Optical Materials, Archaeology, Pregnancy
& Childbirth, Agricultural Policy, Urology, Composites, Nuclear Medicine, Ophthalmology, Planetary Science, Respiratory Diseases, Geological Engineering,
Environmental Chemistry, Hematology, Civil Engineering, Liver Diseases, Operations Research, Dentistry, Power & Electricity, Microbiology, Brain/Vision & Hearing,
Medicinal Chemistry, Oncology, Industrial Engineering, Fluid Mechanics, Animal Science, Networks, Cardiology, Orthopedics, Medieval Studies, Patient Care &
Health Practitioners, Learning, Economics & Finance, Management, Computer Vision & Imaging
Computing, Marine Science, Geoscience, Plant Science, Psychiatry & Psychology, Governance
https //doi org/10 1371/jo rnal pone 0234612 t001 Results representing one of three laureates awarded a prize in a single year); of
those 36 domains only 20 have at least 1 full point. Five domains (particle physics [14%], cell
biology [12.1%], atomic physics [10.9%], neuroscience [10.1%], molecular chemistry [5.3%])
have the lion’s share, accounting in total for 52.4% of the 69 Nobel prizes that we mapped,
even though these 5 domains publish only 10.2% of all the Scopus-indexed papers. Using the
DC3 classification [17], an intermediate level of aggregation that breaks science into 849 sub-
domains, only 71 of these sub-domains (8.3%) are touched by at least one Nobel-related paper. Of the 114 DC2 domains, only 20,10, and 15 domains are ever represented in Chemistry,
Physics, and Medicine/Physiology Nobel prizes, respectively. Of note, Chemistry Nobel prizes
are more scattered across more domains, many of which may not be seen as typical core chem-
istry areas (Table 1). The 76 domains that have not been touched by any Nobel prizes in 3 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields Table 1. The 36 domains that have been touched by at least 1 key paper from a Nobel prize. DC2
Domain
Major field
Papers in Scopus
Nobel points
Chemistry
Physics
Medicine
32
Particle Physics
6—Basic Physics
478415
9.667
9.667
7
Cell Biology
5—Biochemistry
1085864
8.333
2.000
6.333
25
Atomic Physics
8—Appl Physics
576205
7.500
2.500
5.000
8
Neuroscience
2—Medicine
952232
7.000
1.333
5.667
1
Molecular Chemistry
5—Biochemistry
1159261
3.667
3.667
19
Molecular Biochemistry
5—Biochemistry
743948
2.667
1.333
1.333
15
Semiconductor Physics
8—Appl Physics
789874
2.667
2.667
28
Magnetics
8—Appl Physics
573316
2.333
2.333
38
Optoelectronics & Photonics
8—Appl Physics
546614
2.333
2.000
0.333
64
Carbon Science
8—Appl Physics
293274
2.167
1.167
1.000
106
Medical Imaging
2—Medicine
90218
1.833
0.833
1.000
70
Reproductive Medicine
2—Medicine
240215
1.667
1.667
37
Gastrointestinal Science
2—Medicine
495843
1.333
0.333
1.000
79
Receptor & Channel Science
5—Biochemistry
227776
1.333
1.333
41
Nanochemistry
8—Appl Physics
454873
1.333
1.333
11
Immunology
2—Medicine
921957
1.333
1.333
102
Nonlinear Dynamics
7—Artif Intell
110760
1.000
1.000
10
Materials
9—Engineering
770157
1.000
1.000
80
Sleep
2—Medicine
230643
1.000
1.000
48
Astronomy & Astrophysics
6—Basic Physics
253024
0.833
0.833
23
Electrochemistry & Energy
8—Appl Physics
658303
0.833
0.833
20
Mathematics
7—Artif Intell
560776
0.833
0.500
0.333
110
Gasotransmitters
5—Biochemistry
64778
0.667
0.667
42
Tropical Disease & Parasites
3—Inf Disease
378898
0.667
0.667
31
Entomology
4—Sustainability
363741
0.667
0.667
63
AIDS
3—Inf Disease
284973
0.500
0.500
54
Climate Science
4—Sustainability
269801
0.500
0.500
49
Cancer in Women
2—Medicine
349174
0.500
0.500
21
Ecology
4—Sustainability
447972
0.500
0.500
91
Reconstructive Surgery
2—Medicine
156004
0.333
0.333
77
Analytical Chemistry
5—Biochemistry
217249
0.333
0.333
68
Pharmacology
5—Biochemistry
259001
0.333
0.333
52
Telecommunications
7—Artif Intell
348515
0.333
0.333
30
Wildlife Science
4—Sustainability
384807
0.333
0.333
18
Diabetes & Lifestyle/Prevention
2—Medicine
790664
0.333
0.333
16
Polymers
8—Appl Physics
657627
0.333
0.333 Table 1. The 36 domains that have been touched by at least 1 key paper from a Nobel prize. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 4 / 11 PLOS ONE Clustering of Nobel prizes to few fields Chemistry, Physics or Medicine/Physiology appear in the footnote of Table 1 and data on their
numbering/classification in DC2 and the number of papers in each appear in the Supporting
Information (S3 Table). PLOS ONE One of the 76 is Economics and Finance, and certainly Nobel prizes in
Economics (which we did not consider here) are likely to cluster in that domain. Some key
papers of the same Nobel prize may also spill over in some additional fields. However, the
majority of scientific fields seem to have been excluded by Nobel honors, even though in the-
ory work done in these areas would be eligible for one or more of the three types of Nobel
prizes that we analyzed. One may argue that a single paper may not suffice to represent the work underlying a
Nobel prize and a different rule may have selected different papers as being the most important
hallmark of some Nobel-honored work. However, typically all the major papers underlying
the same work tend to locate very close to each other in the map of science. A different empiri-
cal study [12] that tried to evaluate which authors are considered the ones deserving more
credit in papers that led to Nobel recognitions selected papers with a different approach. Another group of scientists [13,14] used their own rules to arrive at a set of Nobel-related
papers. These different selections largely pertain to the same domains as those papers that we
selected. For example, 97 of the 144 papers that we selected overlap with the Li et al. selection
[13,14] and the others are mostly in similar domains as those selected by Li et al. To take this a
step further, we also identified all the 40,819 Scopus-indexed publications representing the
career-long output of all the scientists awarded a Nobel prize in Physics, Chemistry, or Medi-
cine/Physiology in 1995–2017. These 40,819 papers are mapped in Fig 1E and they still show
strong clustering into the same, few scientific fields. Discussion This may reinforce a circle where
privileged fields become even more privileged and achieve even more power and funds, rela-
tive to other scientific fields that remain more neglected. A similar circle may be reinforced at
the level of what work will get recognized by Nobel awards in the following years. One limitation of the present study is that it is sometimes difficult to identify a single paper
that is clearly the epitome of the Nobel work. Other investigators [10] have used the same
source of information as we did (information deposited in the Nobel official website) and tried
to identify the most relevant papers for each laureate qualitatively by reading several papers
that would have been candidates for selection. We preferred to use more objective bibliometric
criteria of impact to select one paper for each laureate when there were several contesters, so as
to avoid potential subjectivity. Regardless, the papers that we selected match substantially the
corpus of papers selected by other authors [13,14]. Moreover, we also performed analyses
focusing on the entire publication corpus of each laureate and this evaluation gave a similar
overall picture, since most laureates (like most other scientists) largely focus their work in a
particular single discipline. Moreover, we should acknowledge that some disciplines may indeed not be very relevant
for the three Nobel awards that we examined. For example, most work in law, philosophy, and
medieval studies may be far too remote from medicine, chemistry, or physics. For several
other disciplines, their exact level of relevance to the three Nobel awards may also be contested. Therefore, we do not argue that papers across all disciplines should be equally represented in
Nobel awards. Moreover, we avoid testing the observed distribution of the past awards across
disciplines versus some preconceived “gold standard” of what that distribution should ideally
look like. Nevertheless, a perusal of the list of disciplines that have no Nobel award shows
many disciplines that clearly would be relevant to the three Nobel award areas. Even taking for granted that different disciplines unavoidably have different levels of rele-
vance for Medicine/Physiology, Chemistry and Physics, the lack of representation of many
fields in Nobel awards means that these fields never enjoy the prestige stemming from this
most illustrious recognition. This may have implications for scientists and scientific communi-
ties, creating perceptions of second-class citizenship. Discussion The present study shows that there is strong clustering of the work leading to Nobel awards in
Medicine, Chemistry, and Physics. Five out of 114 fields of science (particle physics, atomic
physics, cell biology, neuroscience, molecular chemistry) account for more than half of the
awards. The majority of scientific fields were never honored with a Nobel prize in the exam-
ined period (1995–2017). This observation remains true regardless of the level of granularity
in defining scientific fields and disciplines. The current analysis also shows that almost always when a Nobel prize is awarded there are
many other works that were published at the same time as the Nobel-honored work and that
have been cited more extensively than the honored work. We should acknowledge, however,
that citations do not cover the entire picture of potential impact. E.g., some work may lead to
major advances but stop being cited because it helped the field move very far ahead. Con-
versely, a field where little progress is made may continue citing the same reference papers, e.g. nutritional epidemiology receives very high numbers of citations despite having made very lit-
tle uncontested progress. Moreover, highly cited papers may differ substantially in ingenuity,
innovation and translational potential [18]. Of course, not all highly-cited papers have identi-
cal value. Some types of articles and some books may attract a lot of citations, but there is no
gold standard on measuring impact in ways that would be applicable to all science and would
have high consensus across scientists doing different types of work (e.g. methods, discovery,
applications, implementation). E.g. scientists may sometimes think more highly of the type of
work that they do than other types of work. Previous work [19] suggests that the most influential papers are extremely concentrated in
few journals, especially in fields with high citation density. Nobel prizes also tend to come
from fields with quite high citation densities. Thus clustering operates at multiple levels,
including discipline, journal, as well as institutions [10]. Moreover, Nobel-awarded work may 5 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields also influence future research, including allocation of funds and preferences of the most influ-
ential multidisciplinary journals regarding what to publish. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 Discussion Uneven prestige may affect institutional
decisions in universities and research institutes on what work to cherish and support. Funders
may also be influenced in their decisions on what to include or prioritize in their funding
agenda. Even the perceptions of lay people on what fields of science are valuable (or even on
what science is really dealing with) may be grossly distorted. One solution to achieve more
evenness might be to create additional awards that are equally prestigious and that cover other
fields besides those already primarily honored. For example, the addition of the Nobel Memo-
rial Prize in Economic Sciences represents such an expansion of field coverage. It needs to be
better appreciated that the chances of a scientist getting a Nobel prize are markedly different
depending on what field he/she works in, regardless of the excellence, rigor or quality of his/
her work. For example, 108,277 scientists have published at least 5 papers and focus primarily
in Economics- and Business-related disciplines (Scopus data until end of 2017) [20], and there
are 84 Nobel laureates in economics to-date. Thus, the odds of getting a Nobel prize is about 1
in 1,300 among economists. Conversely, there are over 3 million scientists working in medi-
cine and life sciences and who have published at least 5 papers [20]. The average odds of get-
ting a Nobel prize for them is miniscule compared with economists. Moreover, the odds of
such a top recognition varies a lot for people working in different subdisciplines within bio-
medicine. In some subdisciplines, the odds of a scientist getting a Nobel prize may be better
than 1:1,000, while in other subdisciplines no scientist may ever be honored, even though
many tens of thousands of scientists work diligently in that subdiscipline. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 6 / 11 PLOS ONE Clustering of Nobel prizes to few fields It is unknown whether the clustering is driven by the nomination of candidates or by the
selection of the winners among those who have been nominated, or both. One would need to
assess whether strong clustering is already present among the group of nominees. Information
on nominees is released however with a 50 years’ lag and thus the work of released nominees is
largely outside the remit of the Scopus data. Discussion Acknowledging these caveats, the clustering of Nobel-honored work in a few, restricted
parts of the map of science seems highly prominent. The phenomenon may have different
explanations, and different investigators may disagree on whether this intense clustering is
desirable or not. Scientists working in the privileged domains may consider this inequality-in-
honors highly appropriate, while other “excluded” scientists may consider it grossly unfair. There is a risk that this inequality creates a culture of exclusivity with some scientists consid-
ered second-class citizens simply because of the field in which they work or the type of
research that they do. The clustering may reflect how different fields are perceived in general
and/or by those scientists who nominate and award these prestigious prizes. A Matthew effect
[21] may operate where the rich fields become richer, e.g. if the opinion of past awardees mat-
ters a lot either directly through their recommendations or by creating a frame upon which the
next years’ prizes will be placed in context. This Matthew effect of reinforced field-specificity
may apply also to any prestigious award, besides the Nobel prize. Some critics even claim [22]
that the notion of trying to identify and single out one to three people goes against the commu-
nal spirit of science; for most major advances currently, there are important and distributed
contributions across hundreds and thousands of researchers [23]. Fields that use more team
science may thus be at a disadvantage and those where solitary investigators thrive may be at
an advantage for a Nobel prize. Other investigators still propose that small teams are better
suited for disruptive discoveries [24]. The large inequality in Nobel prize allocation across different domains of science may also
resonate the debate about whether the relative extent to which scientific progress depends on
bench science and reductionist discoveries, or more applied work, e.g. clinical or population
research in the case of medicine [25,26]. Obviously, the Nobel prizes have focused to-date
more on the former, with few prizes given for the latter (e.g. the work on H. pylori and peptic
ulcer) [27]. Some may argue that we need to strengthen more bench discovery and this may
create even greater concentration of honors to very few fields that are already privileged. Oth-
ers may argue that we need to shift more attention to team work, since team work has become
dominant in science [23]. Discussion Or to interdisciplinary work, data sciences, social determinants,
applied clinical research, and other domains that may have even more translational value, but
which have remained largely outside the remit of Nobel prizes [28,29]. We offer the data in
this analysis as a stimulus for scientists in all fields, privileged or not, to ponder on these issues. Selection of key papers for Nobel laureates We focus on Nobel prizes starting in 1995, since earlier prizes are more likely to recognize
work done a long time ago and very old papers may not be contained in the Scopus database
or may be less relevant to place in the map of science that we used based on Scopus data. We
refer to the Nobel website (https://www.nobelprize.org/) for more details on the process of
receiving nominations for the Nobel prize and choosing laureates. We mapped the key Nobel prize-related publication of each laureate awarded the Nobel
Prize between 1995 and 2017. We picked only a single paper per laureate, to avoid giving more
weight to the work of some laureates over the others. Key papers (one per laureate) were iden-
tified from the Advanced Background Material/Advanced Information section for each Nobel
Prize, as listed the official website (https://www.nobelprize.org/). As a general rule, both cita-
tion count and main authorship were considered in choosing a key paper for each author. Main authorship was defined as being listed as 1st or last author. Specifically, for each Nobel
laureate, we selected the most highly cited paper listed in the advanced information and where
the laureate was a main author. Citation searches in Google Scholar were conducted between
May 25th and July 18th, 2018. If a laureate also appeared on papers co-authored with other lau-
reates, main authorship was prioritized (i.e., the paper where the 1st laureate was 1st or last was
retained) unless the other paper (i.e., where the 1st laureate was a not main author) had at least
3 times more citations. A few special cases occurred. For a few laureates, no papers including them as main authors
were present in the Advanced Information. In these cases, we selected the most highly cited
paper that was present in the Advanced Information and had the laureate in any authorship
position (i.e., even if not main). Precedence was given to papers listed in the Advanced Infor-
mation, so as to minimize the need to have to decide whether other, not listed, papers, were
relevant to the Nobel prize. In two cases, authorship on the most highly cited paper in the
Advanced Information was determined alphabetically; the papers in question was included
even if the laureates were not main authors, as the practice appeared to be the custom of the
research group laureates belonged to. Map of science based on Scopus data We used a previously developed comprehensive map of science which is based on the Scopus
database [15]. The map consists of approximately 63 million documents through 2016 and was
created in a multi-step process. The original map was created using 48 million documents
through 2012 of which roughly half were Scopus indexed source documents from 1996–2012
and the other half were documents not indexed in Scopus but that were cited at least twice. 582 million direct citation links between the documents were used as the clustering input, and
clustering was done using the smart local moving (SLM) modularity-based algorithm [30]. Clustering resulted in a four-level hierarchical solution with 91,726 clusters each containing at
least 50 articles at the most granular (DC5, roughly 105 clusters) level, 10,058 clusters at the 7 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields DC4 (~104 clusters) level, 849 sub-disciplines at the DC3 (~103 clusters) level and 114 disci-
plines at the DC2 (~102 clusters) level [17]. An additional 15 million papers through 2016 were
later added to the existing clusters; each paper was added to the cluster to which it had the
most reference links. Each paper resides in a cluster with other papers that either cite or are
cited by them. y
A visual map of the DC5 clusters (Fig 1A) was created using the following process: 1) simi-
larity between pairs of clusters was calculated from the titles and abstracts of the documents in
each topic using the BM25 text similarity measure [31], 2) the resulting similarity list was fil-
tered to keep only the top-n (between 5 and 15) similarities per cluster, and 3) a layout of the
clusters was generated using the DrL/OpenOrd algorithm [32], which gives each an x,y posi-
tion based on the similarity graph. The DrL/OpenOrd algorithm is available at https://www. sandia.gov/smartin/software.html and is also available at https://www.cs.otago.ac.nz/
homepages/smartin/software.php. Clusters with similar content are adjacent in the map. Each
cluster has been designated as belonging primarily to one of twelve high-level fields and is col-
ored accordingly. Color designations were made by assigning papers to fields using the UCSD
journal-to-field assignments [33]. Map of science based on Scopus data A visual map of the DC5 clusters (Fig 1A) was created using the following process: 1) simi-
larity between pairs of clusters was calculated from the titles and abstracts of the documents in
each topic using the BM25 text similarity measure [31], 2) the resulting similarity list was fil-
tered to keep only the top-n (between 5 and 15) similarities per cluster, and 3) a layout of the
clusters was generated using the DrL/OpenOrd algorithm [32], which gives each an x,y posi-
tion based on the similarity graph. The DrL/OpenOrd algorithm is available at https://www. sandia.gov/smartin/software.html and is also available at https://www.cs.otago.ac.nz/ homepages/smartin/software.php. Clusters with similar content are adjacent in the map. Each
cluster has been designated as belonging primarily to one of twelve high-level fields and is col-
ored accordingly. Color designations were made by assigning papers to fields using the UCSD
journal-to-field assignments [33]. PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 Sensitivity analyses We performed similar analyses to understand the potential clustering, using the database of
Nobel-related papers constructed by other authors [13,14]. We also mapped all 40,819 papers
published by the Nobel laureates examined in this project. Selection of key papers for Nobel laureates Conversely, if papers present in the Advanced Informa-
tion section including the laureate as main author had low citation counts compared to others
in the section that did not list the laureate as main author, citation counts were prioritized over
main authorship if the difference was large (i.e., three-fold or more). For the years where there 8 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields were very few papers listed in the Advanced Information section, where all had low citation
counts or in which no Advanced Information document accompanied the Nobel Prize, prece-
dence was given to the most highly-cited paper that seemed relevant for the prize. For the analyses pertaining to the DC2 and DC3 aggregations, we allocated 1 point to each
Nobel prize each year, which means for example that if there were three laureates with three
different papers, each paper gets 0.333 points. With 23 years and three prizes for each, a total
of 69 points could be allocated. The analysis of citing papers considers all papers that cited the key Nobel papers and that
had been indexed in Scopus as of May 2017. The same time stamp was used to search for
papers and other published items (e.g. books) that had received more citations than each key
Nobel paper even though they were published within one year of the respective key Nobel
paper. Of course, competition for Nobel awards is not limited to single years (or three year
windows), but the number of highly cited papers that are temporally congruent with each
paper that led to an award places the citation impact of the honored work in better context, by
adjusting for time since publication which is a key factor affecting citation counts. Supporting information Supporting information
S1 Table. Selected key papers for Nobel prizes in Physics, Chemistry, and Medicine/Physi-
ology, 1995–2017. (DOCX)
S2 Table. Number of papers in different fields published within one year of each Nobel
paper that are more cited than the Nobel paper. (XLSX)
S3 Table. 76 scientific domains that have had no key papers for the three types of Nobel
prizes. (DOCX)
Acknowledgments
We thank Albert-Laszlo Baraba´si for insightful comments. Author Contributions
Conceptualization: John P. A. Ioannidis, Kevin W. Boyack. Data curation: Ioana-Alina Cristea, Kevin W. Boyack. Formal analysis: Kevin W. Boyack. Funding acquisition: Kevin W. Boyack. Investigation: John P. A. Ioannidis. Methodology: John P. A. Ioannidis, Ioana-Alina Cristea, Kevin W. Boyack. Project administration: John P. A. Ioannidis. S1 Table. Selected key papers for Nobel prizes in Physics, Chemistry, and Medicine/Physi-
ology, 1995–2017. (DOCX) S1 Table. Selected key papers for Nobel prizes in Physics, Chemistry, and Medicine/Physi-
ology, 1995–2017. (DOCX)
S2 Table. Number of papers in different fields published within one year of each Nobel
paper that are more cited than the Nobel paper. (XLSX)
S3 Table. 76 scientific domains that have had no key papers for the three types of Nobel
prizes. (DOCX) (XLSX)
S3 Table. 76 scientific domains that have had no key papers for the three types of Nobel
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2019; 1:301–303. 15. Klavans R, Boyack KW. Research portfolio analysis and topic prominence. Journal of Informetrics. 2017; 11(4):1158–1174. 16. Author Contributions Conceptualization: John P. A. Ioannidis, Kevin W. Boyack. Data curation: Ioana-Alina Cristea, Kevin W. Boyack. Formal analysis: Kevin W. Boyack. Funding acquisition: Kevin W. Boyack. Investigation: John P. A. Ioannidis. Methodology: John P. A. Ioannidis, Ioana-Alina Cristea, Kevin W. Boyack. Project administration: John P. A. Ioannidis. Project administration: John P. A. Ioannidis. Project administration: John P. A. Ioannidis. 9 / 11 PLOS ONE | https://doi.org/10.1371/journal.pone.0234612
July 29, 2020 PLOS ONE Clustering of Nobel prizes to few fields Resources: Kevin W. Boyack. Software: Kevin W. Boyack. Supervision: John P. A. Ioannidis. Validation: Ioana-Alina Cristea. Visualization: Kevin W. Boyack. Writing – original draft: John P. A. Ioannidis. Writing – review & editing: Ioana-Alina Cristea, Kevin W. Boyack. Resources: Kevin W. Boyack. Software: Kevin W. Boyack. Supervision: John P. A. Ioannidis. Validation: Ioana-Alina Cristea. Visualization: Kevin W. Boyack. Writing – original draft: John P. A. Ioannidis
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journal.pone.0039464 PMID: 22808037 11 / 11
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Supplementary Figure S5 Supplementary Figure S5 0,00
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Produção e qualidade da videira 'Superior Seedless' sob restrição hídrica na fase de maturação
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Pesquisa Agropecuária Brasileira
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Production and quality of 'Superior Seedless' grapes under irrigation
restrictions during berry maturation Abstract – The objective this work was to evaluate the effect of water defi cit conditions, during the maturation
phase of grapes, on the production and quality of the 'Superior Seedless', between July and November of
2007. The experiment was carried out in a randomized block design, with four replicates, in a (3x3) + 1
factorial arrangement: three times of alteration of the irrigation depths (21, 13 e 5 days before harvest); three
irrigation depths (100, 50 e 0% of crop evapotranspiration); and a control treatment, which was the producer’s
irrigation management scheme. Irrigation timing and depth infl uenced berry fi rmness and titrable acidity. The
management with cut-off irrigation depths at 13 or 21 days before harvesting and the control had the same
yield, grape quality and water use effi ciency, and may be adopted to save water for irrigation in the São
Francisco Valley region. Index terms: Vitis vinifera, water stress, grape quality, yield. alternativas que racionalizem o uso de água na irrigação,
a fi m de aumentar a competitividade desta região em
relação a outras tradicionalmente produtoras de uva. No Submédio do Vale do São Francisco, os
viticultores não têm empregado padrões adequados de
defi cit hídrico, na fase fi nal de maturação da uva de
mesa. Estratégias de imposição do defi cit hídrico só
devem ser adotadas se a economia de água não tiver
impacto negativo na produtividade e na qualidade da
uva (Netzer et al., 2009). Produção e qualidade da videira 'Superior Seedless'
sob restrição hídrica na fase de maturação
Lígia Borges Marinho(1), José Julio Vilar Rodrigues(1), José Monteiro Soares(2),
Maria Auxiliadora Coelho de Lima(2), Magna Soelma Beserra de Moura(2),
Elieth Oliveira Brandão(2), Thieres George Freire da Silva(3) e Marcelo Calgaro(2) (1)Universidade Federal Rural de Pernambuco, Departamento de Tecnologia Rural, CEP 52171-900 Recife, PE. E-mail: ligia.bmarinho@gmail.com,
juba.vilar@oi.com.br (2)Embrapa Semiárido, Caixa Postal 23, CEP 56310-000 Petrolina, PE. E-mail: monteiro@cpatsa.embrapa.br,
magna@cpatsa.embrapa.br,
maclima@cpatsa.embrapa.br,
elieth.brandao@cpatsa.embrapa.br,
marcelo.calgaro@cpatsa.embrapa.br
(3)Universidade Federal Rural de Pernambuco, Unidade Acadêmica de Serra Talhada, CEP 56900-000 Serra Talhada, PE. E-mail: thieres@uast.ufrpe.br Resumo – O objetivo deste trabalho foi avaliar o efeito das condições de defi cit hídrico, na fase de maturação da
uva, sobre a produção e qualidade da uva 'Superior Seedless' entre julho e novembro de 2007. O experimento
foi realizado em delineamento de blocos ao acaso, com quatro repetições, em arranjo fatorial (3x3) + 1: três
épocas de alteração da aplicação das lâminas de irrigação (21, 13 e 5 dias antes da colheita); três lâminas
de irrigação (100, 50 e 0% da evapotranspiração da cultura); e um tratamento controle (manejo de irrigação
adotado pelo produtor). As épocas de irrigação e as lâminas de irrigação utilizadas infl uenciaram a fi rmeza
das bagas e a acidez titulável. A interrupção da irrigação, aos 13 ou 21 dias antes da colheita, resultou em
produtividade, qualidade de frutos e efi ciência do uso da água semelhante às obtidas pelo produtor, assim, pode
ser adotada para economia da água de irrigação na Região do Submédio do Vale do São Francisco. Termos para indexação: Vitis vinifera, estresse hídrico, qualidade da uva, rendimento. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Index terms: Vitis vinifera, water stress, grape quality, yield. Produção e qualidade da videira ‘Superior Seedless’ 1683 Segundo Ávila Netto et al. (2000), a restrição
hídrica durante as duas primeiras fases de crescimento
das bagas pode reduzir o tamanho dos frutos e
atrasar o seu amadurecimento. Serman et al. (2004),
em experimento com a cultivar Apirênia Superior
Seedless, irrigada sob diferentes percentagens da
evapotranspiração, verifi caram diminuição do número
de cachos comercializáveis, nos tratamentos com defi cit
hídrico, apesar de não terem observado diferenças
signifi cativas nos sólidos solúveis. No entanto, no
Submédio do Vale do São Francisco, Bassoi et al. (1999) avaliaram a suspensão total da irrigação na
cultivar Itália, num período de até 30 dias antes da
colheita, e não constataram redução signifi cativa na
qualidade ou na produtividade da uva. De acordo com
Ferreyra et al. (2006), a aplicação de defi cit hídrico
à cultivar Crimson Seedless proporcionou diferenças
signifi cativas apenas quanto à produtividade, sobretudo
a partir do segundo ciclo de cultivo, possivelmente em
razão dos efeitos cumulativos dos diferentes anos de
restrição de irrigação. três épocas (E) de alteração da aplicação de diferentes
lâminas de irrigação, em relação à colheita – 21 (E21),
13 (E13) e 5 (E5) dias antes da colheita (DAC) –; três
lâminas de irrigação (L) – 100% (L100), 50% (L50) e
0% (L0) da evapotranspiração da cultura (Etc) –; mais
um tratamento controle, correspondente ao manejo
adotado pelo produtor (LP), com irrigação com cerca
de 95% da Etc, até um dia antes da colheita (L95–E01);
quando foi totalmente suspensa. q
p
No talhão selecionado, foi escolhida uma área de
2.240 m2 (28 x 80 m), constituída por oito fi leiras com
40 plantas cada, no total de 320 plantas, onde foram
distribuídos os blocos. Em cada bloco, havia quatro
linhas com seis plantas por tratamento, em que foram
consideradas as quatro plantas centrais como unidades
experimentais, no total de 160 plantas úteis. As lâminas
de irrigação, até os 21 DAC, foram quantifi cadas pelo
produtor com base em dados de evapotranspiração
de referência (ETo), provenientes de uma estação
meteorológica automática situada a aproximadamente
2 km da área experimental, e com base nos dados
do coefi ciente de cultura (Kc) defi nidos para a fase
de maturação (0,8 para o período entre 85 e 92 dias
após a poda – DAP –; 0,6, entre 93 e 100 DAP; e
0,4 entre 101 e 104 DAP) conforme Soares & Costa
(2000). Produção e qualidade da videira ‘Superior Seedless’ Para estimar a Eto, foi utilizada a equação de
Penman-Montheith parametrizada pela FAO (Allen
et al., 1998). O objetivo deste trabalho foi avaliar o efeito da
irrigação defi citária no período de maturação sobre
a produção e a qualidade da cultivar de uva de mesa
Superior Seedless, no Submédio do Vale do São
Francisco. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Introdução alternativas que racionalizem o uso de água na irrigação,
a fi m de aumentar a competitividade desta região em
relação a outras tradicionalmente produtoras de uva. A 'Superior Seedless', também conhecida por
'Sugraone' (Vitis vinifera L.), é a principal cultivar de
uva sem sementes produzida no Submédio do Vale do
São Francisco (Grangeiro et al., 2002). Nas condições
desta região vinícola, com clima semiárido, o uso de
irrigação é indispensável. No Submédio do Vale do São Francisco, os
viticultores não têm empregado padrões adequados de
defi cit hídrico, na fase fi nal de maturação da uva de
mesa. Estratégias de imposição do defi cit hídrico só
devem ser adotadas se a economia de água não tiver
impacto negativo na produtividade e na qualidade da
uva (Netzer et al., 2009). Em razão da escassez dos recursos hídricos e do
alto custo dos insumos, cada vez mais, têm-se buscado Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Produção e qualidade da videira ‘Superior Seedless’ Produção e qualidade da videira ‘Superior Seedless’ Material e Métodos O índice de fertilidade real de gemas foi
obtido pela divisão do número total de cachos pelo
número total de gemas (varas e esporões), conforme
Leão & Silva (2003). Esta avaliação foi realizada em 16
plantas por tratamento, antes da desbrota dos ramos. Por meio da relação entre a quantidade total de uva
produzida e a lâmina de água aplicada, acumulada
entre a poda e a colheita, calculou-se a efi ciência de
uso da água (EUA) (Doorenbos & Kassam, 1994). Aos 2, 5, 9 e 14 DAC, foram feitas amostragens de
seis bagas por cacho, de cada parcela experimental. Após a coleta, as amostras foram armazenadas em
isopor com gelo e transportadas para o Laboratório de
Pós-Colheita da Embrapa Semiárido, em Petrolina, PE,
onde foram realizadas as seguintes análises químicas:
teor de sólidos solúveis (SS), por meio de refratômetro
digital (Hanna, Modelo – HI – 96801, Milliminas
Limitada, Belo Horizonte, Brasil); ácidez titulável
(AT), por meio da titulação da polpa das bagas com
NaOH 0,1N, expresso em gramas de ácido tartárico por
100 mL de suco, conforme Pregnolatto & Pregnolatto
(1985); relação SS/AT. Os dados foram submetidos à análise de variância,
para se determinar a interação entre os fatores e
comparar as médias conforme Yassin et al. (2002). As médias dos tratamentos foram comparadas pelo teste
de Duncan, a 5% de probabilidade. Por meio de teste
F (p<0,05), obteve-se a signifi cância do contraste, pela
comparação da média dos tratamentos do fatorial com
o controle e, quando signifi cativas, foram comparadas
as médias do tratamento adicional às médias dos
fatoriais, pelo teste de Dunnett, a 5% de probabilidade. Utilizou-se o programa SAS versão 9.0 for Windows
(SAS Institute, 2002). Logo após a colheita da uva, no dia 24/10/2007
(aos 105 DAP), em conformidade com a programação
da fazenda, quantifi cou-se: o diâmetro de baga, com
paquímetro digital (Stainless Hardened, VTC, Ribeirão
Preto, Brasil), em oito cachos por tratamento e três
bagas por cacho (uma baga localizada no ápice, uma
no meio e outra na extremidade inferior do cacho),
no total de 240 amostragens; o peso médio de cachos
(em g), por meio de balança digital (capacidade de
6.100 g, sensibilidade de 0,1 g, Marte, Brasil); o número
total de cachos por planta; o peso total de cachos por
planta (em kg); e a produtividade (Mg ha-1). Material e Métodos O sistema de irrigação utilizado foi o gotejamento,
com uma linha lateral por fi leira de plantas, e emissores
autocompensantes espaçados em 30 cm. A frequência de
irrigação foi diária, exceto aos domingos. Realizou-se a
avaliação do coefi ciente de uniformidade de distribuição
de água, conforme Karmeli & Keller (1975), com
valor médio de 94,4%, e vazão média de 2,89 L por
hora. Diariamente, realizou-se o monitoramento do
potencial mátrico do solo, por meio de tensiômetros
instalados a 20 e 40 cm de profundidade. A partir da
curva de retenção da água no solo (Marinho, 2008), os
valores em umidade volumétrica (θ) foram convertidos
em base de cm3 cm-3. O experimento foi realizado na Fazenda Agrobrás
Tropical do Brasil S/A, no Município de Casa Nova,
BA (9o19'36"S, 40o47'53"W e a 399 m de altitude), na
região semiárida do Submédio do Vale do São Francisco,
de julho a novembro de 2007. O clima local é do tipo
BSwh, segundo Köppen, com estação chuvosa limitada
aos meses de janeiro a abril, e precipitações escassas
de distribuição irregular, com média anual em torno de
400 mm (Hargreaves, 1974; Reedy & Amorim Neto,
1993). O solo da área experimental é classifi cado como
Argissolo Vermelho-Amarelo (Embrapa Semiárido,
2007). A poda, realizada no dia 11/7/2007, foi do tipo
mista com varas e esporões. Foram mantidas as varas
que tinham de 10 a 16 gemas e os esporões com duas
ou três gemas. Logo após a poda, os ramos foram
pulverizados com calcianamina hidrogenada (Dormex,
formulada pela Basf, fabricada pela AlzChem Trostberg
GmbH, Trostberg, Alemanha), à concentração 5% v/v Utilizou-se a cultivar Superior Seedless (Vitis
vinifera L.), enxertada sobre a cultivar SO4, com quatro
anos de idade e segundo ciclo de produção, cultivada
no espaçamento de 3,5 m x 2,0 m e conduzida no
sistema de latada. O delineamento experimental foi blocos ao acaso
com quatro repetições, em arranjo fatorial (3x3) + 1: Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 1684 L.B. Marinho et al. cinco bagas cada quanto à fi rmeza da polpa, sólidos
solúveis, acidez titulável e relação SS/AT. A fi rmeza da
polpa da baga foi determinada com um penetrômetro
(TR, Modelo – FT 327, Gold Lab, Ribeirão Preto,
Brasil). para quebra de dormência das gemas e uniformização
da brotação. Material e Métodos Nesse
momento, também foram separados quatro cachos
representativos de cada parcela, tendo-se utilizado
16 plantas por tratamento, dos quais foram avaliadas Resultados e Discussão (2000) (333,6 mm), em estudo no Submédio
do São Francisco, com a cultivar Itália, sob regime
de defi cit hídrico. No Chile, Ferreyra et al. (2006)
obtiveram lâmina média aplicada de 376,90 mm para
videiras 'Crimson Seedless' irrigadas com 50% da ETc,
durante todo o ciclo produtivo. Lâminas maiores (entre
649 e 1.060 mm por ano) foram determinadas para a
videira 'Superior Seedless', por Serman et al. (2004),
que trabalharam com a aplicação de defi cit hídrico com
base na ETc, na Argentina. Entretanto, vale salientar
que o ciclo da cultura tem maior duração na Argentina
e no Chile do que no Brasil, em razão das diferentes
condições climáticas. Seedless, por Leão & Silva (2003). Essa superioridade,
possivelmente, é resultante de que, no presente trabalho,
as podas foram mais longas e, consequentemente,
analisaram-se até 16 gemas nas varas. Não houve diferença signifi cativa para os sólidos
solúveis (SS), em função das épocas de alteração da
irrigação em relação à colheita e das lâminas, nas datas
amostradas, ou das diferenças das médias dos fatoriais
comparadas ao tratamento controle (LP) (Tabela 3). Porém, ao se considerarem as datas de amostragem
(Tabela 4), houve aumento progressivo de SS, que
alcançou os maiores valores aos 2 e 5 DAC, e os
menores aos 9 e 14 DAC. Estes resultados indicam que
esse incremento de SS pode ser atribuído à modifi cação
metabólica na translocação do açúcar, que foi acumulado
nas bagas, na fase de maturação. Os sólidos solúveis
tendem a aumentar acentuadamente com o crescimento
da baga até alcançar um ponto de equilíbrio, com
valores que dependem da cultivar, tamanho da baga,
produção por planta e das condições climáticas durante
a maturação da baga. O teor de sólidos solúveis tende a
aumentar com a maturação da baga, em consequência
da degradação dos polissacarídeos (Chitarra & Chitarra,
1990), e do conteúdo de água no solo. O conteúdo de água no solo, durante o ciclo
produtivo da videira 'Superior Seedless', está
apresentado na Figura 1. Até 84 DAP, a umidade
volumétrica θ (cm3 cm-3) variou pouco na camada
do solo de 0 a 20 cm de profundidade, com valores
médios de 0,244 cm3 cm-3. Contudo, depois dos 89
DAP, o tratamento E21–L0 teve conteúdo de água no
solo de 0,129 cm3 cm-3, próximo ao ponto de murcha
(0,117 cm3 cm-3) e, nos demais tratamentos, os valores
de θ foram superiores a 0,150 cm3 cm-3. Resultados e Discussão Durante o período experimental, a temperatura média
do ar oscilou em torno de 25,3±1,57oC, com umidade
relativa média de 56,5±6,62%, e com evapotranspiração
de referência média de 5,37±0,88 mm por dia. As lâminas aplicadas, acumuladas na fase de
maturação e no ciclo produtivo da uva 'Superior
Seedless', e o defi cit de irrigação, em relação ao
tratamento LP, podem ser observadas na Tabela 1. A diminuição de aplicação de água, na fase de
maturação da uva nas E21–L0, E21–L50 e E13–L0, em Tabela 1. Lâminas acumuladas de irrigação, durante a fase de maturação e o ciclo produtivo completo da cultivar de videira
Superior Seedless. (1)E, época de alteração da lâmina de irrigação, em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21 dias antes da colheita; L, lâminas de irrigação
aplicadas: L0, L50 e L100, lâminas de 0, 50 e 100% da evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor: irrigação com cerca de
95% da Etc, até um dia antes da colheita (E1–L95). adas de irrigação, durante a fase de maturação e o ciclo produtivo completo da cultivar de videira acumuladas de irrigação, durante a fase de maturação e o ciclo produtivo completo da cultivar de videira Tabela 1. Lâminas acumuladas de irrigação, durante a fase de maturação e o ciclo produtivo completo da
Superior Seedless a 1. Lâminas acumuladas de irrigação, durante a fase de maturação e o ciclo produtivo completo da cultiv
i
S
dl (1)E, época de alteração da lâmina de irrigação, em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21 dias antes da colheita; L, lâminas de irrigação
aplicadas: L0, L50 e L100, lâminas de 0, 50 e 100% da evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor: irrigação com cerca de
95% da Etc, até um dia antes da colheita (E1–L95). Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Produção e qualidade da videira ‘Superior Seedless’ Produção e qualidade da videira ‘Superior Seedless’ 1685 relação ao tratamento controle (LP), ocasionou defi cit
de irrigação, respectivamente, de 19,5, 8,9 e 8,7%, que
resultou na economia de água de 53,4, 24,1 e 23,50 mm. Esta economia é representativa sob o ponto de vista
econômico. As lâminas aplicadas durante todo o ciclo
produtivo da videira variaram de 334,14 a 399,36 mm
e foram semelhantes às encontradas por Ávila Netto
et al. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Resultados e Discussão Esses resultados
indicam que após o começo da alteração de aplicação
das lâminas, as plantas estavam expostas à umidade
do solo inferior à capacidade de campo (CC), como
era previsto. Nos tratamentos E21–L0 e E5–L100, a
umidade do solo variou entre 44,6 e 80,15% da CC
e entre 55,8 a 87,3% da CC, respectivamente. Aos
93 DAP, o tratamento E13–L0 registrou o mínimo de
água no solo. Valores semelhantes de umidade do solo
(entre 59 e 83% CC) foram observados em tratamento
com lâmina calculada a 50% da Etc, por Ferreyra et al. (2006), que trabalharam com uva 'Crimson Seedless',
em parreiral espanhol. Na L0, houve diferenças signifi cativas em acidez
titulável (AT) (Tabela 3) apenas na amostragem
aos 2 DAC na E21, em comparação com a E13 e
E5; ao se considerarem as épocas de diferenciação,
observou-se que a lâmina L50 apresentou maior acidez
titulável na E5, em comparação L0 e L100. Valores
de acidez titulável altos são benéfi cos sob o ponto de
vista microbiológico, pois inibem o crescimento de
patógenos nocivos à saúde humana, sem comprometer
a qualidade sensorial do produto (Mattiuz et al., 2004). Os resultados do presente trabalho estão de acordo
com essa afi rmação para os parâmetros produtivos,
em que o tratamento E5 mostrou-se infl uenciado pelas
alterações da irrigação. Com isso, entende-se que ao
ocorrer defi cit de irrigação antes dessa época, a planta
se ajusta e não permite reduções signifi cativas dos seus
atributos produtivos e de AT e SS/AT, antes da colheita,
e a alteração da irrigação às épocas E13 e E21 pode,
então, ser adotada com vistas à economia de água. Não houve diferenças signifi cativas entre os fatoriais nos
índices de fertilidade real de gemas (Tabela 2); entretanto,
observou-se diferença entre as médias dos fatoriais e o
tratamento controle (LP), pelo teste F. Os valores de
fertilidade de gema de todos os tratamentos foram 10%
superiores àqueles obtidos para a cultivar Superior Analisando-se os valores médios de AT, em relação
às datas de amostragem (Tabela 4), verifi ca-se que
são inversos aos de SS, pois são inicialmente altos,
diminuem aproximadamente 20% a cada dia com a
evolução da maturação e atingem valores máximos e
mínimos aos 14 e 2 DAC. A redução da AT pode estar Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 L.B. Marinho et al. L.B. Marinho et al. Resultados e Discussão 1686 relacionada ao fato de os ácidos tartárico e málico serem
sintetizados pelas folhas e pelas bagas verdes que, no
início da maturação apresentam elevado teor de AT. Com a evolução da maturação, a demanda por energia aumenta e, muitas vezes, os ácidos são utilizados
como fonte de energia na respiração celular. Além
disso, fatores como a diluição dos ácidos orgânicos
em consequência do aumento do tamanho da baga, Figura 1. Umidade do solo na camada de 20 cm, em função das épocas de alteração das lâminas de irrigação em relação
à colheita e das lâminas de irrigação. LP, lâmina do produtor: irrigação com cerca de 95% da evapotranspiração da cultura
(Etc), até um dia antes da colheita (E1–L95). E, épocas de alteração das lâminas de irrigação, em relação à colheita: E21, 21
dias, E13, 13 dias e E5, 5 dias antes da colheita. L, lâminas de irrigação aplicadas: L100, L50, e L0, lâminas a 100, 50 e 0%
da Etc, respectivamente; CC: capacidade de campo; PMP, ponto de murcha permanente. ç
ç
,
p
g
q
g , Figura 1. Umidade do solo na camada de 20 cm, em função das épocas de alteração das lâminas de irrigação em relação
à colheita e das lâminas de irrigação. LP, lâmina do produtor: irrigação com cerca de 95% da evapotranspiração da cultura
(Etc), até um dia antes da colheita (E1–L95). E, épocas de alteração das lâminas de irrigação, em relação à colheita: E21, 21
dias, E13, 13 dias e E5, 5 dias antes da colheita. L, lâminas de irrigação aplicadas: L100, L50, e L0, lâminas a 100, 50 e 0%
da Etc, respectivamente; CC: capacidade de campo; PMP, ponto de murcha permanente. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Produção e qualidade da videira ‘Superior Seedless’ Produção e qualidade da videira ‘Superior Seedless’ 1687 teste F, dois dias antes da colheita (Tabela 3). Ao se
considerarem as datas de amostragem, percebe-se que
a relação SS/AT teve semelhança com a evolução do
teor de SS, com baixos valores no início da maturação
e aumento progressivo até o período próximo à
colheita. Resultados semelhantes da evolução de SS/AT
foram encontrados por Sato et al. (2009), em estudo
sobre a evolução da maturação e as características
físico-químicas da uva 'Isabel' sobre diferentes
porta-enxertos, na região norte do Paraná. Resultados e Discussão a migração de bases e a consequente salifi cação dos
ácidos orgânicos também contribuem para a redução
no teor de AT (Rizzon et al., 2000). Os valores de SS/AT não apresentaram diferenças
signifi cativas, em função das épocas de alteração da
irrigação e lâminas. Entretanto, observou-se diferença
entre as médias e o tratamento controle (LP), pelo Tabela 2. Fertilidade de gemas da cultivar de videira
Superior Seedless, em função das épocas de alteração das
lâminas de irrigação em relação à colheita e das lâminas de
irrigação(1). Para diâmetro de baga, peso médio, número médio de
cachos e peso total de cachos por planta e produtividade,
não houve diferença signifi cativa, pelo teste F, entre
os tratamentos e o tratamento controle (LP). O uso de
diferentes épocas e lâminas poderá ser adotado pelo
produtor, sem efeitos negativos no manejo da irrigação,
sempre com vistas à economia de água. Assim, para
estes atributos de produção, foram comparadas apenas
as médias dos tratamentos (Tabela 5). O diâmetro das
bagas e o peso médio do cacho por planta não diferiram
signifi cativamente, a 5% de probabilidade, em função
das épocas, lâminas e interação entre os fatores. Todos os valores obtidos de diâmetro de bagas e peso
médio de cacho por planta foram superiores ao padrão g ç
(1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas
nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probabilidade. **Média do tratamento LP em relação à média dos tratamentos signifi cativa,
pelo teste F, a 1% de probabilidade. (2)Épocas de alteração da lâmina de
irrigação em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21dias
antes da colheita. (3)L0, L50 e L100, lâminas de irrigação a 0, 50 e 100% da
evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor:
irrigação com cerca de 95% da Etc, até um dia antes da colheita (E1–L95). (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas
nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probabilidade. **Média do tratamento LP em relação à média dos tratamentos signifi cativa,
pelo teste F, a 1% de probabilidade. (2)Épocas de alteração da lâmina de
irrigação em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21dias
antes da colheita. Resultados e Discussão Segundo Ferreyra et al. (2006), é importante detectar
um período em que o defi cit de irrigação é moderado,
pois se sabe que a falta de água, durante o crescimento
da uva mesa, limita a produção e a qualidade da fruta,
particularmente se o defi cit hídrico se iniciar entre a
fl oração e a pinta. mínimo, exigido pelo mercado externo para uva sem
semente, que é de 19 mm e de 250 g (Brazilian Grapes
Marketing Association, 1999). Resultados semelhantes
de peso médio de cacho de uva 'Superior Seedless'
variaram de 370 a 490 g, em regime de defi cit hídrico
aplicado ao longo do ciclo fenológico, na Argentina Tabela 4. Sólidos solúveis (SS, oBrix), acidez titulável
(AT, g ácido tartárico por 100 mL de suco) e relação SS/AT
da cultivar de videira Superior Seedless, aos 14, 9, 5 e 2 dias
antes da colheita(1). (1)Médias seguidas de letras iguais, nas colunas não diferem entre si pelo
teste de Duncan, a 5% de probabilidade. Tabela 4. Sólidos solúveis (SS, oBrix), acidez titulável
(AT, g ácido tartárico por 100 mL de suco) e relação SS/AT
da cultivar de videira Superior Seedless, aos 14, 9, 5 e 2 dias
antes da colheita(1). ç
p
Houve interação entre as épocas e lâminas quanto
ao número médio de cachos e peso total de cachos
por planta, produtividade e efi ciência de uso de água
(Tabela 5). Verifi ca-se que, apenas para a época E5,
a lâmina L100 apresentou maior número de cachos
e peso total de cachos por planta que a L0, não
tendo diferido da lâmina L50. Nas demais épocas
(E13 e E21), não houve diferença estatística para o
número médio de cachos e peso total de cachos por
planta, tendo-se obtido uma economia de água de
53,38 mm, quando a irrigação foi suspensa 21 dias
antes da colheita. Todavia, as diferenças estatísticas
do presente trabalho devem-se também ao raleio das
bagas das uvas – efetuado de maneira irregular entre
as plantas no Submédio do Vale do São Francisco –,
visto que não houve diferença estatística na fertilidade
de gemas (Tabela 2), nem no peso médio de cachos
por planta, pois, na fase de maturação, o número de
cachos não se altera mais. Resultados e Discussão (3)L0, L50 e L100, lâminas de irrigação a 0, 50 e 100% da
evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor:
irrigação com cerca de 95% da Etc, até um dia antes da colheita (E1–L95). Tabela 3. Evolução de sólidos solúveis (SS, oBrix), acidez titulável (AT, g de ácido tartárico por 100 mL de suco) e relação
SS/AT, da cultivar de videira Superior Seedless, em função das épocas de alteração das lâminas de irrigação em relação à
colheita e das lâminas de irrigação, aos 14, 9, 5 e 2 dias antes da colheita(1). SS/AT, da cultivar de videira Superior Seedless, em função das épocas de alteração das lâminas de irrigação em relação à
colheita e das lâminas de irrigação, aos 14, 9, 5 e 2 dias antes da colheita(1). (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probabilidade. ns e **Média do tratamento LP em relação à média dos tratamentos não signifi cativa e signifi cativa, respectivamente, pelo teste F, a 1% de probabilidade. (2)Épocas de alteração das lâminas de irrigação em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21dias antes da colheita; (3)L0, L50 e L100, lâminas
de irrigação a 0, 50 e 100% da evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor: irrigação com cerca de 95% da Etc, até um dia
antes da colheita (E1–L95). (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probabilidade. ns e **Média do tratamento LP em relação à média dos tratamentos não signifi cativa e signifi cativa, respectivamente, pelo teste F, a 1% de probabilidade. (2)Épocas de alteração das lâminas de irrigação em relação à colheita: E5, 5 dias; E13, 13 dias e E21, 21dias antes da colheita; (3)L0, L50 e L100, lâminas
de irrigação a 0, 50 e 100% da evapotranspiração da cultura (Etc), respectivamente; LP, lâmina do produtor: irrigação com cerca de 95% da Etc, até um dia
antes da colheita (E1–L95). Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 1688 L.B. Marinho et al. (Serman et al., 2004). O diâmetro de baga e o peso
de cacho por planta, na fase de maturação da uva,
mostraram-se pouco sensíveis ao defi cit hídrico que
pode ser adotado em estratégias de economia de água. (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas
nas linhas, não diferem entre si pelo teste de Ducan, 5% de probalidade.
nsMédia do tratamento LP em relação à média dos tratamentos, não
signifi cativa pelo teste F, a 1% de probabilidade. (2)Épocas de alteração
das lâminas de irrigação em relação à colheita: E5, 5 dias; E13, 13 dias
e E21, 21dias antes da colheita; (3)L0, L50 e L100, lâminas de irrigação a
0, 50 e 100% da evapotranspiração da cultura (Etc), respectivamente; LP,
lâmina do produtor: irrigação com cerca de 95% da Etc, até um dia antes
da colheita (E1–L95). Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Resultados e Discussão Menores valores de número
de cachos e peso total de cachos da cultivar Itália, para
os tratamentos que obtiveram a irrigação suspensa
aos 16 DAC e infl uência do raleio das bagas nestes
parâmetros, foram observadas por Bassoi et al. (1999),
no Submédio do Vale do São Francisco. O número médio
de cachos obtido por planta não apresentou diferenças
signifi cativas nos tratamentos com defi cits hídricos,
nas diferentes fases de cultivo, em comparação ao
tratamento com irrigação plena, em videira 'Sultanina',
no Sul da África (Myburgh, 2003), provavelmente por
não se realizar o raleio de bagas nessa região. (1)Médias seguidas de letras iguais, nas colunas não diferem entre si pelo
teste de Duncan, a 5% de probabilidade. (1)Médias seguidas de letras iguais, nas colunas não diferem entre si pelo
teste de Duncan, a 5% de probabilidade. Tabela 5. Número de cachos por planta, peso total de cachos
por planta, produtividade e efi ciência de uso de água da
cultivar de videira Superior Seedless, em função das épocas
de alteração das lâminas de irrigação em relação à colheita e
das lâminas de irrigação(1). Ao se considerarem as lâminas de irrigação,
observa-se que apenas a época E5 apresentou
diferenças signifi cativas quanto à produtividade
(Tabela 5). Quando aplicada a lâmina L100, as
videiras apresentaram, estatisticamente, maior valor
(34,9 Mg ha-1) que L0. Valores de produtividade
semelhantes foram observados por Serman et al. (2004), em estudo realizado para avaliar o efeito do Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Produção e qualidade da videira ‘Superior Seedless’ Produção e qualidade da videira ‘Superior Seedless’ 1689 defi cit hídrico na 'Superior Seedless', em que obtiveram
produtividade entre 20,53 e 25,21 Mg ha-1. entre as diferentes lâminas nas épocas E13 e E5. Esta
resposta é altamente desejável pois a fi rmeza ou turgidez
da baga é um atributo físico bastante importante para
avaliar a qualidade da uva na pós-colheita, por permitir
maior resistência ao transporte e conservação em
câmara fria. As diferenças de produtividade também estão
relacionadas ao número de cachos por planta e,
consequentemente, ao peso total de cachos por planta. Essas respostas, de alguma maneira, podem ter sido
ocasionadas pelo raleio das bagas e pelo manejo
da videira, realizado no ano anterior, uma vez que a
alteração das lâminas de irrigação ocorreu apenas na
fase de maturação da uva. Resultados e Discussão Porém, a falta de diferenças
signifi cativas de produtividade, para as épocas E13
e E21, pode ser resultado da regulação da perda de
água por transpiração, principalmente nas horas de
maior demanda, conforme Ferreyra et al. (2006). Isto
pode levar mais de cinco dias para acontecer e, por
isso, as plantas que tiveram 13 e 21 dias conseguiram
evitar perdas evapotranspirométricas e não tiveram
perdas signifi cativas de produtividade. Segundo Bidin
et al. (2005), as plantas sujeitas a defi cit de água no
solo, em comparação às plantas sob irrigação plena,
realizaram ajustes na taxa de transpiração para
minimizar as respostas ao estresse, tendo-se verifi cado
um decréscimo na taxa de transpiração 14 dias após
o início do experimento. Pode-se observar que, para
a época E5, a lâmina L100 apresentou os maiores
valores de efi ciência de uso de água (EUA), e que a
lâmina L50 igualou-se estatisticamente à L0, com
os menores valores (Tabela 5). Para a lâmina L0, a
época E21 teve as melhores médias de EUA, tendo
diferido de E5 e E13. Vale salientar que estes valores
foram obtidos considerando-se apenas uma safra por
ano. Os valores de EUA, obtidos neste trabalho, são
superiores aos encontrados por Serman et al. (2004),
que trabalharam com diferentes lâminas de irrigação
na videira 'Superior Seedless' e obtiveram valores de
EUA entre 2,62 a 3,16 kg m-3, todavia, na região de
estudos desses autores, a duração do ciclo fenológico é
maior que no Submédio do Vale do São Francisco. Não houve diferença estatística no teor de SS, na
pós-colheita em função das épocas e lâminas de
irrigação, nem entre as médias dos tratamentos e o
tratamento LP (Tabela 6), o que pode indicar uma das
estratégias de manejo a ser adotada pelo produtor para
economizar água, sem impactos negativos nos SS. Resultados semelhantes foram encontrados por Shellie
et al. (2006), em dois anos de produção (2003 e 2004). Entretanto, estes autores observaram, no ano de 2002,
no sudeste de Idaho, que as concentrações de SS foram
levemente maiores nas plantas sob irrigação com 35 ou
35–70% da ETc (iniciada com a frutifi cação até duas
semanas depois da colheita). No presente trabalho,
os valores médios de SS oscilaram entre 15,2oBrix e
16,8oBrix. Estes resultados foram semelhantes ao valor Tabela 6. Resultados e Discussão Atributos físico-químicos da cultivar de videira
Superior Seedless, na pós-colheita, em função das épocas
de alteração das lâminas de irrigação em relação à colheita e
das lâminas de irrigação(1). das â
as de
gação . (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas
nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probalidade. nsMédia do tratamento LP em relação à média dos tratamentos não
signifi cativa pelo teste F, a 1% de probabilidade (2)Épocas de alteração
das lâminas de irrigação em relação à colheita: E5, 5 dias; E13, 13 dias
e E21, 21dias antes da colheita. (3)L0, L50 e L100, lâminas de irrigação a
0, 50 e 100% da evapotranspiração da cultura (Etc); LP, lâmina do produtor:
irrigação com cerca de 95% da Etc, até um dia antes da colheita (E1–L95). Os resultados dos atributos de qualidade da uva,
obtidos na pós-colheita, podem ser observados na
Tabela 6. Houve diferença estatística, pelo teste
Duncan (p<0,05), quanto à fi rmeza da baga da uva
pós-colheita, em função da época e das lâminas, o que
não foi observado entre as médias dos tratamentos e o
tratamento LP. Ao se considerar a época de alteração,
nota-se que houve diferença de fi rmeza apenas quando
utilizada a lâmina L0, tendo-se alcançado os melhores
resultados na E21. Não houve diferença signifi cativa (1)Médias seguidas de letras iguais, maiúsculas nas colunas e minúsculas
nas linhas, não diferem entre si pelo teste de Ducan, a 5% de probalidade. nsMédia do tratamento LP em relação à média dos tratamentos não
signifi cativa pelo teste F, a 1% de probabilidade (2)Épocas de alteração
das lâminas de irrigação em relação à colheita: E5, 5 dias; E13, 13 dias
e E21, 21dias antes da colheita. (3)L0, L50 e L100, lâminas de irrigação a
0, 50 e 100% da evapotranspiração da cultura (Etc); LP, lâmina do produtor:
irrigação com cerca de 95% da Etc, até um dia antes da colheita (E1–L95). Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 1690 L.B. Marinho et al. 'Superior Seedless', apenas aos cinco dias antes da
colheita. encontrado (17,3oBrix) por Grangeiro et al. (2002),
que trabalharam com a cultivar Superior Seedless no
Submédio do Vale do São Francisco, sem condição
de supressão da irrigação. Referências ALLEN, R.G.; PEREIRA, L.S.; RAES, D.; SMITH, M. Crop
evapotranspiration: guidelines for computing crop water
requirements. Rome: FAO, 1998. 310p. (Irrigation and drainage
paper, 56). Para a relação SS/AT, na pós-colheita, constatou-
se que houve diferença estatística apenas para L50,
com os maiores valores na E13 e E21 (Tabela 6). Entretanto, todas as médias dos tratamentos e do
tratamento LP apresentaram valores acima de 20:1,
limite desejável para a exportação (Beinroth, 1993;
Choudhury, 2000). Sabe-se que a relação SS/AT é
um importante atributo qualitativo, por indicar o
sabor do produto, o qual é resultado da contribuição
dos componentes responsáveis pela acidez e doçura
(Mattiuz, 2002). ÁVILA NETTO, J.; AZEVEDO, P.V. de; SILVA, B.B. da; SOARES,
J.M.; TEIXEIRA, A.H. de C. Exigência hídrica da videira na Região
do Submédio São Francisco. Pesquisa Agropecuária Brasileira,
v.35, p.1559-1566, 2000. BASSOI, L.H.; ASSIS, J.S. de; LIMA FILHO, J.M.P.; RIBEIRO,
H.A.; SILVA, M.R.; MIRANDA, A.A. Interrupção da
irrigação no período de maturação da uva cv. Itália. Petrolina:
Embrapa-CPATSA, 1999. 5p. (Embrapa-CPATSA. Comunicado
técnico, 79). BEINROTH, E.W. Determinação do ponto de colheita. In:
GORGAATI NETO, A.; GAYET, J.P.; BEINROTH, E.W. (Ed.). Uva para exportação: procedimentos de colheita e pós-colheita. Brasília: Embrapa-SPI: Frupex, 1993. p.20-21. (Frupex. Publicações
técnicas, 2). Agradecimentos À Universidade Federal Rural de Pernambuco e à
Embrapa Semiárido, pelo apoio técnico-científi co e
fi nanceiro; à Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior, pela concessão de bolsa; e à
Fazenda Agrobrás, pelo apoio técnico. Resultados e Discussão Valores inferiores de SS
foram observados para esta mesma cultivar, sob defi cit
hídrico, na Argentina (Serman et al., 2004), e para
cultivar Itália no Submédio do Vale do São Francisco
(Bassoi et al., 1999). 3. Há infl uência das épocas de alteração da irrigação
e lâminas de irrigação sobre a fi rmeza das bagas, a
acidez titulável e a relação entre sólidos solúveis e
acidez titulável. 3. Há infl uência das épocas de alteração da irrigação
e lâminas de irrigação sobre a fi rmeza das bagas, a
acidez titulável e a relação entre sólidos solúveis e
acidez titulável. 4. A redução das lâminas, na fase de maturação da
uva 'Superior Seedless', benefi cia a qualidade da uva
no Submédio do Vale do São Francisco. Diferenças signifi cativas na AT, na pós-colheita,
foram observadas em função dos fatores épocas e
lâminas de irrigação, sem diferenças entre as médias
dos tratamentos e o tratamento LP (Tabela 6). Ao se
considerar a época de diferenciação da irrigação em
relação à colheita, houve diferenças nos valores de
AT quando foram utilizadas as lâminas L0 e L50,
tendo-se obtido maior AT com essas lâminas na
época E5. Quanto às lâminas de irrigação, verifi ca-se
que apenas a E21 apresentou diferenças estatísticas,
com os menores valores de AT para L0 e L50. Estes
resultados indicam que quanto maior o defi cit de
irrigação e a sua duração, maior a redução de acidez
titulável na uva 'Superior Seedless'. Redução aparente
de AT também foi observada em videiras 'Merlot'
submetidas a defi cit de irrigação, no sudeste de Idaho
(Shellie et al., 2006). Essa redução da acidez titulável,
associada ao defi cit hídrico, pode ser atribuída à
redução de malato (Matthews & Anderson, 1988;
Esteban et al., 1999). 5. A estratégia de defi cit hídrico, na fase de maturação
da uva 'Superior Seedless' aos 13 ou aos 21 dias antes
da colheita, permite produtividade, qualidade da uva
e efi ciência de uso de água semelhante ao do manejo
adotado pelo produtor. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Conclusões Petrolina:
Embrapa- CPATSA, 1993. 280p. FERREYRA, R.E.; SELLES, G.; SILVA, H.; AHUMADA,
R.; MUÑOZ, I.; MUÑOZ, V. Efecto del água aplicada em las
relaciones hídricas y productividad de la vid 'Crimson Seedless'. Pesquisa Agropecuária Brasileira, v.41, p.1109-1118, 2006. locais e classifi cação climática do Nordeste do Brasil. Petrolina:
Embrapa- CPATSA, 1993. 280p. RIZZON, L.A.; MIELE, A.; MENEGUZZO, J. Avaliação da uva
cv. Isabel para elaboração de vinho tinto. Ciência e Tecnologia de
Alimentos, v.20, p.115-121, 2000. GRANGEIRO, L.C.; LEAO, P.C. de S.; SOARES, J.M. Caracterização fenológica e produtiva da variedade de uva Superior
Seedless cultivada no Vale do São Francisco. Revista Brasileira
de Fruticultura, v.24, p.552-554, 2002. SAS INSTITUTE. SAS user’s guide. Version 9.0. Cary: SAS
Institute, 2002. SATO, A.J.; SILVA, B.J. da; BERTOLUCCI, R.; CARIELO,
M.; GUIRAUD, M.C.; FONSECA, I.C. de B.; ROBERTO, S.R. Evolução da maturação e características fi sico-químicas de uvas da
cultivar Isabel sobre diferentes porta-enxertos na Região Norte do
Paraná. Semina: Ciências Agrárias, v.30, p.11-20, 2009. HARGREAVES, G.H. Climate zoning for agricultural production
in Northeast Brazil. Logan: Utah State University, 1974. 6p. KARMELI, D.; KELLER, J. Trickle irrigation design. California:
Rain Bird Sprinkler Manufacturing Corporation, 1975. 133p. LEÃO, P.C. de S.; SILVA, E.E.G. da. Caracterização fenológica
e requerimentos térmicos de variedades de uvas sem sementes no
vale do São Francisco. Revista Brasileira de Fruticultura, v.25,
p.379-382, 2003. SERMAN, F.V.; LIOTTA, M.; PARERA, C. Effects of irrigation
defi cit on Table grape cv. Superior Seedless production. Acta
Horticulturae, n.646, p.183-186, 2004. SHELLIE, K.C. Vine and berry response of Merlot (Vitis vinifera L.)
to differential water stress. American Journal of Enology and
Viticulture, v.57, p.514-518, 2006. MARINHO, L.B. Defi cit hídrico regulado na fase de maturação
da uva “Superior Seedless” na região do Submédio São
Francisco. 2008. 106p. Dissertação (Mestrado) - Universidade
Federal Rural de Pernambuco, Recife. SOARES, J.M.; COSTA, F.F. da. Irrigação da cultura da videira. In: LEÃO, P.C. de S.; SOARES, J.M. (Org.). A viticultura no SOARES, J.M.; COSTA, F.F. da. Irrigação da cultura da videira. In: LEÃO, P.C. de S.; SOARES, J.M. (Org.). A viticultura no
Semi-Árido brasileiro. Petrolina: Embrapa Semiárido, 2000. p.147-212. MATTHEWS, M.A.; ANDERSON, M.M. Fruit ripening in Vitis
vinifera L.: responses to seasonal water defi cits. American Journal
of Enology and Viticulture, v.39, p.313-320, 1988. YASSIN, N.; MORAIS, A.R. de; MUNIZ, J.A. Análise de
variância em um experimento fatorial de dois fatores com
tratamentos adicionais. Conclusões técnicas, 2). BIDIN, M.; BELLESI, S.; ORLANDINI, S.; FIBBI, L.;
MORIONDO, M.; SINCLAIR, T. Infl uence of water defi cit
stress on leaf area development and transpiration of Sangiovese
grapevines grown in pots. American Journal of Enology and
Viticulture, v.56, p.68-72, 2005. 1. As épocas de alteração das lâminas de irrigação,
em relação à colheita e as lâminas de irrigação não
afetam o diâmetro de bagas e o peso médio de cachos
por planta. 2. Lâminas de irrigação têm efeitos diferentes
sobre o número e o peso total de cachos por planta,
produtividade e efi ciência de uso de água da uva BRAZILIAN
GRAPES
MARKETING
ASSOCIATION. Instrutivo: controle de qualidade: safra II/99. Petrolina: BGMA,
1999. Paginação irregular. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Produção e qualidade da videira ‘Superior Seedless’ 1691 MATTIUZ, B.-H.; MIGUEL, A.C.A.; NACHTIGAL, J.C.;
DURIGAN, J.F.; CAMARGO, U.A. Processamento mínimo de
uvas de mesa sem semente. Revista Brasileira de Fruticultura,
v.26, p.226-229, 2004. CHITARRA, M.I.F.; CHITARRA, A.B. Pós-colheita de frutos e
hortaliças: fi siologia e manuseio. Lavras: ESAL: FAEPE, 1990. 320p. CHOUDHURY, M.M. Colheita, manuseio pós-colheita e qualidade
mercadológica de uvas de mesa. In: LEÃO, P.C. de S.; SOARES,
J.M. (Ed.). A viticultura no Semi-Árido brasileiro. Petrolina:
Embrapa Semiárido, 2000. p.347-368. MYBURGH, P.A. Responses of Vitis vinifera L. cv. Sultanina to
water defi cits during various pré- and post-harvest phases under
semi-arid conditions. South African Journal of Enology and
Viticulture, v.24, p.25-33, 2003. DOORENBOS, J.; KASSAM, A.H. Efeito da água no rendimento
das culturas. Campina Grande: UFPB, 1994. 306p. (FAO. Estudo
FAO. Irrigação e drenagem, 33). NETZER, Y.; YAO, C.; SHENKER, M. Water use and the
development of seasonal crop coeffi cients for Superior Seedless
grapevines trained to an open-gable trellis system. Irrigation
Science, v.27, p.109-120, 2009. EMBRAPA
SEMIÁRIDO. Registro
de
observações
meteorológicas. Petrolina: Embrapa Semiárido. Disponível em:
<http://www.cpatsa.embrapa.br:8080/servicos/dadosmet/estacoes/
bebnovembro.html>. Acesso em: 24 out. 2007. PREGNOLATTO, W.; PREGNOLATTO, N.P. (Coord.). Normas
analíticas do Instituto Adolfo Lutz: métodos químicos e físicos
para análise dos alimentos. 3.ed. São Paulo: Instituto Adolfo Lutz,
1985. 533p. ESTEBAN, M.A.; VILLANUEVA, M.J.; LISSARRAGUE,
J.R. Effect of irrigation on changes in berry composition of
Tempranillo during maturation. Sugars, organic acids, and mineral
elements. American Journal of Enology and Viticulture, v.50,
p.418-434, 1999. REEDY, S.J.; AMORIM NETO, M. da S. Dados de precipitação,
evapotranspiração potencial, radiação solar global de alguns
locais e classifi cação climática do Nordeste do Brasil. Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009 Recebido em 16 de setembro de 2009 e aprovado em 22 de novembro de 2009 Conclusões Ciência e Agrotecnologia, edição especial,
p.1541-1547, 2002. MATTIUZ, B.-H. Efeitos de injúrias mecânicas e do
processamento mínimo na fi siologia pós-colheita de goiabas. 2002. 120p. Tese (Doutorado) - Universidade Estadual Paulista,
Jaboticabal. Recebido em 16 de setembro de 2009 e aprovado em 22 de novembro de 2009 Pesq. agropec. bras., Brasília, v.44, n.12, p.1682-1691, dez. 2009
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https://zenodo.org/record/7805402/files/TANGENTE%20ENTRE%20O%20DIAGN%C3%93STICO%20DE%20TRANSTORNO%20DE%C2%A0%20PERSONALIDADE%20BORDERLINE%20E%20OS%20DEMAIS%20TRANSTORNOS%20DE%C2%A0PERSONALIDADE%C2%A0%20%E2%80%93%20ISSN%201678-0817%20Qualis%20B2.pdf
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TANGENTE ENTRE O DIAGNÓSTICO DE TRANSTORNO DE PERSONALIDADE BORDERLINE E OS DEMAIS TRANSTORNOS DE PERSONALIDADE
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Zenodo (CERN European Organization for Nuclear Research)
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TANGENTE ENTRE O DIAGNÓSTICO DE TRANSTORNO DE
PERSONALIDADE BORDERLINE E OS DEMAIS
TRANSTORNOS DE PERSONALIDADE
Ciências da Saúde, Edição 121 ABR/23 / 06/04/2023
TANGENT BETWEEN THE DIAGNOSIS OF BORDERLINE PERSONALITY
DISORDER AND OTHER PERSONALITY DISORDERS
REGISTRO DOI: 10.5281/zenodo.7805402
ISSN 1678-0817 Qualis B2
Revista Científica de Alto Impacto. Caroline Mioranza Veit¹
Pedro Zabot²
Rogélio Rocha Barros³ Caroline Mioranza Veit¹
Pedro Zabot²
Rogélio Rocha Barros³ RESUMO INTRODUÇÃO: Os aspectos que cada padrão comportamental e emocional que
os indivíduos expressam e sentem diante a situações cotidianas ou de
dificuldade caracterizam os transtornos de personalidade, que foram divididos
em 3 grupos, cada um apresentando um parecer que se relacione às
peculiaridades do transtorno pertencente, como excêntrico, emocional e
ansioso, respectivamente. Até os dias atuais o TPB era classificado como uma
ampla categoria, pelos diversos sintomas envolvidos, como sensação extrema de
vazio, submissão e manipulação a fim de ganhar atenção e afeto, entre outros,
que podem ou não apresentarem semelhanças com outros transtornos de
personalidade, que dificultam ainda mais a identificação e diagnóstico. As fases de desenvolvimento tendem a aflorar os sintomas característicos, que se
expressam ao adentrar na vida adulta, podendo afetar diversas áreas na vida
pessoal do indivíduo. OBJETIVO: Busca-se caracterizar e analisar as
peculiaridades dos indivíduos com Transtorno de Personalidade Borderline, bem
como diferenciá-lo dos demais transtornos de personalidade que confundem o
diagnóstico clínico. METODOLOGIA: Para o referido estudo, foi utilizado uma
pesquisa bibliográfica, por meio de ferramentas de busca on-line de artigos
científicos em inglês e português, como: PubMed, ERIC, MedScape e Scielo, com
filtros de ensaios clínicos, estudos randomizado e textos completos, no intervalo
de tempo de 2010 a 2021. CONCLUSÃO: Nota-se grandes semelhanças entre os
critérios diagnósticos do DSM-5 acerca dos transtornos de personalidade, mas
que se diferenciam pela motivação acerca do comportamento, sendo
característico com cada diferente traço de personalidade, fazendo-se possível a
distinção entre eles. ABSTRACT INTRODUCTION: The aspects that each behavioral and emotional pattern that
individuals express and feel in everyday or difficult situations characterize
personality disorders, which were divided into 3 groups, each one presenting an
opinion that relates to the peculiarities of the disorder belonging, as eccentric,
emotional and anxious, respectively. Until the present day, BPD was classified as
a broad category, due to the various symptoms involved, such as extreme
feelings of emptiness, submission and manipulation in order to gain attention
and affection, among others, which may or may not present similarities with
other personality disorders, which make identification and diagnosis even more
difficult. The stages of development tend to bring out the characteristic
symptoms, which are expressed when entering adulthood, and can affect
several areas in the individual’s personal life. OBJECTIVE: The aim is to
characterize and analyze the peculiarities of individuals with Borderline
Personality Disorder, as well as to differentiate it from other personality disorders
that confuse the clinical diagnosis. METHODOLOGY: For this study, a
bibliographic search was used, using online search tools for scientific articles in
English and Portuguese, such as: PubMed, ERIC, MedScape and Scielo, with filters for clinical trials, randomized studies and texts complete, in the time
interval from 2010 to 2021. CONCLUSION: There are great similarities between
the diagnostic criteria of the DSM-5 about personality disorders, but they differ
by the motivation about the behavior, being characteristic with each different
personality trait , making it possible to distinguish between them. 1. INTRODUÇÃO Transtornos de personalidade (TP) caracterizam-se por padrões
comportamentais e emocionais do indivíduo, sua percepção, frente a situações
cotidianas, relacionamentos profissionais ou pessoais, até mesmo a forma como
lida com suas próprias emoções, sendo persistentes e inflexíveis. Cada indivíduo
possui traços de personalidade, quando algum deles se sobressaem e passam a
prejudicar a vida do indivíduo, o mesmo deixa de ser um traço/característica e
torna-se um transtorno de personalidade. (BANON, 2013) De acordo com o National Epidemiologic Survey on Alcohol and Related
Conditions, que realizou um estudo com a população estadunidense, entre 2001-
2002, estima-se que cerca de 15% dos indivíduos adultos possuíam algum
transtorno de personalidade. (GOODMAN et al., 2014) Até o TBP realmente ser categorizado, passou por diversas considerações
bibliográficas, onde muitos, até hoje, o chamam de transtorno limítrofe, já que
sua peculiaridade era o limite entre a neurose e a psicose, demonstrando
características de ambos, mas sem que seja possível diagnosticar um ou outro. Dentre todos os rodeios envolvendo a nomenclatura borderline, que em 1890
recebeu sua primeira consideração, sendo esta, alterada frequentemente até
1994, quando finalmente o DSM-IV inclui e manteve as características
envolvendo o transtorno, sendo essas, renovadas em 2014 pelo DSM-V. (GOODMAN et al., 2014) Após mais de cem anos de considerações, o TPB ainda é considerado um
desafio no âmbito diagnóstico, por mais que a prevalência estimada seja quase
6% da população, as queixas assemelham-se a de diversos outros TP, sendo,
muitas vezes, confundidos e tratados inadequadamente. (AGNOL et al., 2019) A complexidade de diagnóstico de TPB muitas vezes depende da evolução em
fases de desenvolvimento, já que a cada avanço, novas responsabilidades e
exigências surgem na vida do indivíduo, ficando mais evidente seu desarranjo
emocional, muitas vezes resultando em sérios quadros de dependência
emocional, envolvendo a manipulação de terceiros, como forma de buscar
“apoio” e “aprovação” que proporcionam errôneo ‘aconchego’ e ‘segurança’ para
enfrentar os respectivos desafios da vida adulta, principalmente quando a
principal característica é a sensação extrema de vazio. O DSM V descreve essa
busca por terceiros como: “esforços desesperados para evitar abandono real ou
imaginário”, que inclusive, trata-se de um dos critérios para diagnóstico do TPB. (PIMENTEL, 2019) Dessa forma, é possível afirmar que o diagnóstico do TPB depende de padrões
estáveis, além de persistentes, por isso, geralmente, a identificação do transtorno
ocorre na transição da adolescência para a vida adulta. 1. INTRODUÇÃO Diante disso, o
diagnóstico do transtorno de personalidade borderline tende a ser demorado, já
que as discrepâncias de comportamentos normais são identificadas ao longo da
terapia e uma das características dos indivíduos acometidos pelo transtorno são
as grandes taxas de abandono do acompanhamento terapêutico. (AMORIM,
2000) Diante das semelhanças existentes entre os diversos critérios de diagnóstico,
também é percebido inúmeras motivações que as envolve, sendo esta, a
principal característica para diferenciar um transtorno de outro, sendo únicas e
inconfundíveis. De acordo com o próprio manual de diagnóstico dos transtornos
mentais, as motivações variam entre afeto, reconhecimento, dinheiro, entre
outros, sendo possível diferenciar os ‘ganhos’ nos critérios semelhantes,
facilitando o diagnóstico e melhorando a qualidade de vida dos indivíduos
acometidos, já que poderão usufruir de um tratamento eficaz. (VAZQUEZ et al.,
2018) Diante das semelhanças existentes entre os diversos critérios de diagnóstico,
também é percebido inúmeras motivações que as envolve, sendo esta, a
principal característica para diferenciar um transtorno de outro, sendo únicas e
inconfundíveis. De acordo com o próprio manual de diagnóstico dos transtornos
mentais, as motivações variam entre afeto, reconhecimento, dinheiro, entre
outros, sendo possível diferenciar os ‘ganhos’ nos critérios semelhantes,
facilitando o diagnóstico e melhorando a qualidade de vida dos indivíduos
acometidos, já que poderão usufruir de um tratamento eficaz. (VAZQUEZ et al.,
2018) 2. METODOLOGIA Para este referido estudo, foi utilizada uma pesquisa bibliográfica, baseado em
artigos na íntegra, achados em ferramentas on-line de busca de artigos
científicos em inglês, como: PubMed, sendo filtrado na pesquisa avançada:
ensaios clínicos, estudo completo randomizado, textos completos gratuitos e
pagos, com dois ou mais termos, associados; ERIC – Educational Resources
Information Center, utilizando como filtro de inclusão, apenas textos completos
disponíveis. Para este referido estudo, foi utilizada uma pesquisa bibliográfica, baseado em
artigos na íntegra, achados em ferramentas on-line de busca de artigos
científicos em inglês, como: PubMed, sendo filtrado na pesquisa avançada:
ensaios clínicos, estudo completo randomizado, textos completos gratuitos e
pagos, com dois ou mais termos, associados; ERIC – Educational Resources
Information Center, utilizando como filtro de inclusão, apenas textos completos
disponíveis. Busca de artigos científicos em português, contidos em ferramentas de buscas
como: Scientific Eletronic Library Online (Scielo), Google Acadêmico e MedScape,
no intervalo de 2000 a 2020, alguns referindo-se ao século XIX, especificamente,
a partir de 1890. Para escolha da literatura consideramos os seguintes descritores
vigentes na língua portuguesa, inglesa e espanhola: Transtornos de
Personalidade, Transtorno de Personalidade Borderline, aspectos clínicos do
Transtornos de Personalidade associados ao Borderline, entre outros. Predominantemente as bibliografias foram produzidas nas duas últimas
décadas, sendo descartadas aquelas incompletas ou que não contribuíram no
conteúdo estudado e/ou literaturas revisadas. Busca de artigos científicos em português, contidos em ferramentas de buscas
como: Scientific Eletronic Library Online (Scielo), Google Acadêmico e MedScape,
no intervalo de 2000 a 2020, alguns referindo-se ao século XIX, especificamente,
a partir de 1890. Para escolha da literatura consideramos os seguintes descritores
vigentes na língua portuguesa, inglesa e espanhola: Transtornos de
Personalidade, Transtorno de Personalidade Borderline, aspectos clínicos do
Transtornos de Personalidade associados ao Borderline, entre outros. Predominantemente as bibliografias foram produzidas nas duas últimas
décadas, sendo descartadas aquelas incompletas ou que não contribuíram no
conteúdo estudado e/ou literaturas revisadas. A pesquisa bibliográfica levou em consideração o grupo amostral a ser estudado,
que envolverá indivíduos com transtorno de personalidade borderline e suas
características. A justificativa da escolha se dá a partir do próprio objetivo do
respectivo estudo, que visa especificar as características borderline, além de
diferenciá-las dos demais transtornos para que venha a agregar maior
simplicidade frente ao diagnóstico clínico. Por meio da leitura e análise das publicações citadas, as obras científicas foram
criteriosamente escolhidas, a fim de elaborar um trabalho a partir de uma leitura
informativa sistemática. 2. METODOLOGIA Os artigos foram ordenados pelos objetivos, resultados e
conclusão. Assim, os mesmos foram analisados e utilizados para a produção. 3. RESULTADOS E DISCUSSÕES 3.1 Evolução histórica do conceito borderline Desde os primórdios da psiquiatria houve a necessidade da criação de
categorias para enquadrar sintomas de ‘loucura’ em distúrbios mentais
específicos. O transtorno de personalidade Borderline passou a ser introduzido
ao final do século XIX, onde características clínicas passaram a ser nomeadas, até
receber seu conceito formal pelo DSM IV, o mesmo recebeu 10 terminologias
diferentes até então. (BANON, 2013) Kahlbaum e Edwald Hecker criaram o conceito de hebefrenia, a partir disso, o
psiquiatra alemão Hecker, descreveu detalhadamente a Hebefrenia, sendo uma
‘loucura juvenil’, onde apresentaram grandes oscilações comportamentais,
mudanças incoerentes de pensamento, ou perturbações do mesmo, além dos
delírios, o afeto que é considerado imaturo e infantil, Hecker ainda salientou a
existência de quadros mais leves desta mesma loucura, que posteriormente
nomeou como Heboidofrenia, caracterizada pela alienação juvenil, onde notam-
se sérias alterações de pensamento e raciocínio, evidenciando a incompreensão
a regras morais, sendo comum a indivíduos delinquentes, onde associou-se aos
traços do, hoje conhecido, transtorno de personalidade borderline, e nomeou
como heboidofrenia. (HADDAD et al., 2021) O próprio criador do tema heboidofrenia ressaltou que a mesma é menos
catastrófica que a hebefrenia, já que a última se faz ausente das capacidades
cognitivas básicas, além da confusão e deficiência mental. Visto que a
Heboidofrenia se apresenta por repentinas oscilações de humor, com rápida
flatulência entre estados de tristeza profunda a estados de expansividade
emocional, com ausência de delírios, é determinada então, como a
nomenclatura para o que hoje chama-se transtorno de personalidade
borderline. (COLLI et al., 2015) Sequencialmente o psiquiatra Suiço Eugen Bleuler, em 1911, afirma que alguns
casos de esquizofrenia leve não se diferenciavam da ‘heboidofrenia’, já que os
mesmos apresentavam comportamentos convencionais e comuns, porém,
elementos subjacentes de esquizofrenia eram identificados. Bleuler denominou,
o que até então era ‘heboidofrenia’, como “esquizofrenia latente”, que foi
reafirmada 10 anos depois por Hermann Rorschach. (COLLI et al., 2015) A utilização do termo borderline só aconteceu em 1938, por Stern, em um texto
sobre “Terapia e investigação psicanalítica do grupo das neuroses borderline”. Consequentemente, quatro anos depois, em 1942, Deutsch revisou quadros
discretos entre a neurose e a psicose, concluindo que os indivíduos acometidos
pelo transtorno A utilização do termo borderline só aconteceu em 1938, por Stern, em um texto
sobre “Terapia e investigação psicanalítica do grupo das neuroses borderline”. 3. RESULTADOS E DISCUSSÕES Consequentemente, quatro anos depois, em 1942, Deutsch revisou quadros
discretos entre a neurose e a psicose, concluindo que os indivíduos acometidos
pelo transtorno apresentavam uma personalidade que se flexionava entre os relacionamentos
para adequar-se. O nomeou de “Personalidade como se”. (LIEBMAN et al., 2013) Assim, portanto, em 1949, dois autores, Hoch e Polation, introduziram uma nova
nomenclatura, os dois passaram por grande hesitação ao tentar associar o
transtorno como uma pré-esquizofrenia e por fim, a definiu como “Esquizofrenia
Pseudoneurótica”, descrevendo assim uma condição específica que se finda
pela combinação de uma “Pan Neurose” e uma “Pan Psicose”, já que os quadros
clínicos eram insuficientes para diagnóstico de neurose e psicose propriamente
dita, porém, apresentando ambas características, além de discretas
características esquizofrênicas. (MÖLLER et al., 2018) Diante disso, a nomenclatura sempre estava associada a algum tipo de
esquizofrenia, que só mudou após o trabalho de Robert Knight onde a
terminologia ‘borderline’ passou a se concretizar entre todos os pensadores. O
trabalho de Knight, chamado de “Estados Borderline” apontava que os
indivíduos com o respectivo transtorno não poderiam ser diagnosticados como
quadros neuróticos ou até mesmo psicóticos, já que apresentavam
características semelhantes a ambos os quadros, mas não o pertenciam a
nenhum deles. (GOODMAN et al., 2014) Com a repercussão do trabalho de Knight, a nomenclatura foi abrangida pelo
CID-9, que passou a ser classificada como “Esquizofrenia Borderline”. O próprio
código internacional de doenças afirmou que a descrição não era
completamente aceitável e desaconselhou que fosse usada de forma
generalizada. (ANDERSON et al., 2014) Finalmente, em 1980, o DSM-III introduziu o transtorno de personalidade
borderline, com mudanças significativas para um diagnóstico, com cinco eixos para avaliação, que deveria envolver transtornos psiquiátricos ou de
personalidade, doenças físicas ou estressores psicossociais e por último, nível de
adaptação social. Em 1992 o CID-10 abrangeu o até então ‘Transtorno de
Personalidade Borderline’, como ‘Transtorno Esquizotípico’ com duas
subdivisões, do tipo impulsivo ou borderline. (ANDERSON et al., 2014) O Transtorno de Personalidade Borderline foi finalmente reconhecido como
terminologia somente em 1994, onde o mesmo passou a pertencer ao DSM-IV,
abrangendo critérios de diagnóstico, além de ser inserido em um grupo
específico para transtornos emocionais (SKODOL et al., 2011). Todas as
terminologias dedicadas ao borderline ao decorrer dos anos foram resumidas na
tabela 1. TABELA 1: Evolução Histórica da nomenclatura borderline. 3. RESULTADOS E DISCUSSÕES ANO
AUTOR
Nomenclatura
1890
Kahlbaum
Heboidofrenia
1911
Bleuler
Esquizofrenia Latente
1921
Rorschach
Esquizofrenia Latente
1938
Stern
Neuroses Borderline
1941
Zilborg
Esquizofrenia Ambulatorial
1942
Deutsch
Personalidade “como se”
1949
Hoch e
Polatin
Esquizofrenia Pseudoneurótica
1953
Knight
Estados Borderline
1976
CID-9
Esquizofrenia Latente
1980
DSM-III
Transtorno de Personalidade Borderline TABELA 1: Evolução Histórica da nomenclatura borderline. 1992
CID-10
Transtorno de personalidade emocionalmente
instável
1994
DSM-IV
Transtorno de Personalidade Borderline 3.2 TRANSTORNOS DE PERSONALIDADE O TP é padrão comportamental persistente que pode envolver diversas áreas,
como a cognição, afetando diretamente a percepção e interpretação do
indivíduo com os acontecimentos, com as pessoas, até com ele mesmo; A
afetividade, que expressa intensidade nas relações interpessoais e respostas
emocionais variadas; O funcionamento interpessoal e o controle de impulsos,
onde o mesmo pode ou não ter controle sobre seus desejos e sentimentos. (BARTTEL et al., 1995) Esses padrões comportamentais apresentam persistência de longa data, além
de prejudicarem o indivíduo em todos âmbitos, social, cultural, profissional,
familiar, entre outros que possam ser afetados diante da inflexibilidade presente
nos TP. (FAUSTINO, 2014) Os traços de personalidade são presentes durante a vida toda, de todos os
indivíduos e só se tornam um transtorno de personalidade, quando esses traços
passam a prejudicar a vivência de um indivíduo, causando-lhe sofrimento, seja
por qualquer motivo. (FAUSTINO, 2014) Geralmente esses traços de personalidade são identificados como transtornos
de personalidade no início da vida adulta, quando o indivíduo passa a assumir
mais responsabilidades e suprir exigências. Normalmente ao adentrar a vida
adulta, passa-se por várias dificuldades, onde a existência de um transtorno de
personalidade torna-se mais evidente, sendo possível a sua percepção. Cabe ao
profissional, diferenciar se o comportamento da pessoa está associado a situações de estresse, ou trata-se realmente de traços de personalidade que
caracterizam um transtorno em si. (BACH et al.,2016) situações de estresse, ou trata-se realmente de traços de personalidade que
caracterizam um transtorno em si. (BACH et al.,2016) De acordo com a quinta edição do manual de diagnóstico e estatística dos
transtornos mentais (DSM-V), os transtornos de personalidade são subdivididos
em três grupos, baseado nas semelhanças apresentadas por cada um, sendo
eles representados na tabela 2: Tabela 2: Divisão dos transtornos de personalidade em grupos de acordo
com DSM-V
Grupo
Característica do grupo
Transtornos pertencentes
GRUPO
A
Características excêntricas
-TP Esquizóide
-TP Esquizotípico
-TP Paranóide
GRUPO
B
Características Dramáticas e
impulsivas
-TP Borderline
-TP Antissocial
-TP Narcisista -TP
Histriônica
GRUPO
C
Características ansiosas e
apreensivas
-TP Obsessivo-Compulsivo
-TP Evitativa
-TP Dependente 2: Divisão dos transtornos de personalidade em grupos de acordo
SM-V FONTE: AUTORIA PRÓPRIA. Diante disso, é desejável, de acordo com o DSM-V, que cada transtorno de
personalidade apresenta semelhanças somente aos demais que pertençam ao
grupo, mas a realidade é que os TP podem apresentar critérios semelhantes aos
do mesmo grupo, ou de grupos diferentes. No que tange os critérios clínicos dos diferentes transtornos de quaisquer
grupos, sabe-se que a possibilidade de erro diagnóstico é evidentemente presente, já que queixas podem ser comuns nos mais diferentes casos. Evidencia-se, portanto, a dificuldade do diagnóstico clínico tangenciando o
Transtorno de Personalidade Borderline, principalmente se levado em
consideração as queixas iniciais, na qual representam, em sua maioria,
comportamentos depressivos, seguidos por ideações suicidas, geralmente
associado aos relacionamentos afetivos. (MACHADO et al., 2014) Evidencia-se, portanto, a dificuldade do diagnóstico clínico tangenciando o
Transtorno de Personalidade Borderline, principalmente se levado em
consideração as queixas iniciais, na qual representam, em sua maioria,
comportamentos depressivos, seguidos por ideações suicidas, geralmente
associado aos relacionamentos afetivos. (MACHADO et al., 2014) A partir disso, é possível estimar como esses quadros são tratados inicialmente,
já que o risco suicida é alarmante e de intervenção imediata, interferindo no
diagnóstico do transtorno em si, inclusive se levado em consideração as
características dos indivíduos borderline, que apresentam altos índices de desistência terapêutica,
onde a melhora dos sintomas não se apresentou de forma evidente, afinal,
muitas vezes o tratamento abrange depressão associada a ideação suicida, não
incluindo as oscilações emocionais, acarretando em um tratamento ineficaz e
persistência dos sintomas de vazio e abandono, que podem levar o indivíduo a
repetir as tentativas de mutilação e suicídio. indivíduos borderline, que apresentam altos índices de desistência terapêutica,
onde a melhora dos sintomas não se apresentou de forma evidente, afinal,
muitas vezes o tratamento abrange depressão associada a ideação suicida, não
incluindo as oscilações emocionais, acarretando em um tratamento ineficaz e
persistência dos sintomas de vazio e abandono, que podem levar o indivíduo a
repetir as tentativas de mutilação e suicídio. 3.3 Aspectos do transtorno de personalidade borderline Diante do exposto, nota-se em indivíduos com transtorno de personalidade
borderline, a caracterização de quadros padronizados, envolvendo, na maioria
das vezes, senão em todas, instabilidade emocional, onde se faz presente
oscilações de emocionais recorrentes, além de impulsividade e queixas
compulsivas, a self do indivíduo é subestimada, geralmente associada a quadros
depressivos, tendo a dependência emocional como agravante. (ANDO et al.,
2019) Dentre todos aspectos já citados, é comum observar nestes indivíduos
autodepreciação, autodestruição, abuso e dependência de substâncias lícitas
e/ou ilícitas, sensação de vazio (muitas vezes crônica), associado ao medo do
abandono, relacionamentos interpessoais totalmente instáveis, que geram crises
inesperadas, tornando seu comportamento imprevisível e característico pela manipulação, onde geralmente associa-se tentativas suicidas, ou apenas
ameaças como moeda de troca, a fim de receber consolo e aprovação. (MÖLLER
et al., 2018) Além das tentativas falhas na busca por afeto, os indivíduos borderline,
geralmente envolvem-se em atividades que possam promover riscos ou danos
pessoais, como andar em alta velocidade, envolver-se em brigas, automutilação e
até mesmo a ideação suicida se enquadra em tentativas autodestrutivas. Diante
disso, destacam-se também quadros compulsivos, que envolvem alimentação,
ingestão de álcool, dependência por nicotina, promiscuidade sexual, entre
outros que abrangem os quadros secundários assumidos como consequência
ou agravante do transtorno de personalidade borderline. (MÖLLER et al., 2018) 3.4 Diagnóstico borderline: a partir do DSM-V 3.4 Diagnóstico borderline: a partir do DSM-V Diante a todas as dificuldades envolvidas no diagnóstico de transtorno de
personalidade, os profissionais, em sua maioria, optam pelos critérios
apresentados no DSM-V, sendo eles representados na tabela 3: Tabela 3: Critérios diagnósticos do DSM-V para transtorno de personalidade
borderline
Critério
1
“Esforços desesperados para evitar abandono real ou imaginário”
(DSM-V, 2014, p.663). Critério
2
“Um padrão de relacionamentos interpessoais instáveis e intensos
caracterizados pela alternância entre extremos de idealização e
desvalorização” (DSM-V, 2014, p.663). Critério
3
“Perturbação da identidade: instabilidade acentuada e persistente
da autoimagem ou da percepção de si mesmo” (DSM-V, 2014,
p.663). Critério
4
“Impulsividade em pelo menos duas áreas potencialmente
autodestrutivas” (DSM-V, 2014, p.663). Tabela 3: Critérios diagnósticos do DSM-V para transtorno de personalidade
borderline Critério
5
“Recorrência de comportamento, gestos ou ameaças suicidas ou de
comportamento automutilante” (DSM-V, 2014, p.663). Critério
6
“Instabilidade afetiva devida a uma acentuada reatividade de
humor” (DSM-V, 2014, p.663). Critério
7
“Sentimentos crônicos de vazio” (DSM-V, 2014, p.663). Critério
8
“Raiva intensa e inapropriada ou dificuldade em controlá-la” (DSM-
V, 2014, p.663). Critério
9
“Ideação paranóide transitória associada a estresse ou sintomas
dissociativos intensos” (DSM-V, 2014, p.663) FONTE: DSM-V Critério 1: Segundo Maranga (2002) o indivíduo borderlaine sempre irá,
frequentemente, desenvolver novos investimentos para um amor incondicional. A característica desses “investimentos amorosos” se dão principalmente pela
distorção do próprio self, onde o mesmo regularmente subestima-se, se fazendo
necessário uma incansável busca por apoio, afeto e aprovação, geralmente
inserindo esses indivíduos em relacionamentos abusivos, no qual toleram a
submissão por medo da solidão, ou por se sentir incapaz de viver sem o/a
parceiro(a). (KROLL et al., 2016) Critério 2: Os indivíduos borderline inconscientemente ressignificam suas
relações, tornando-as muito intensas ou intensificando os problemas associados,
aproximando-se demais por necessidade de não se sentir vazio e ao mesmo
tempo afastando-se por problematizar esse relacionamento. Os investimentos
afetuosos são proporcionais a ruptura de vínculos nos relacionamentos desses
indivíduos. Essas determinadas características de instabilidade emocional e
hipersensibilidade afetam todos os relacionamentos negativamente, já que as
então características não são comuns apenas em relacionamentos afetuosos,
mas em todos, seja ele pessoal ou profissional (LIEB et al., 2004) Critério 3: De acordo com o DSM-V, 2013, a angústia que o indivíduo borderline
apresenta sobre sua autoimagem, impede o mesmo de transmiti-la
integralmente, gerando uma contradição entre a autoimagem, imagem
transmitida e a consciência da percepção de terceiros sobre a mesma imagem. A baixa auto estima e a subestimação, apesar de não ser uma realidade, é
percebida de tal forma pelo indivíduo, tornando-o, muitas vezes, conformado
com tratamentos indignos, já que não se sentem capazes de conquistar méritos
próprios. (KROLL et al., 2016) Critério 4: Devido a intensa dependência emocional, o indivíduo tende a
impulsividade, a fim de que o prazer gerado, possa suprir a ausência de prazeres
ausentes. Geralmente apresentam tendências a compulsão alimentar, ou
impulsividade em decisões arriscadas, a fim de que resulte em emoção. Áreas
autodestrutivas se fazem presentes, principalmente em estados depressivos,
onde buscam realizar atividades que tragam risco à vida, já que não encontram
sentido para a existência, ou entregam-se a compulsividade, podendo trazer
vícios, como etilismo e tabagismo (FARIA., 2003) Critério 5: A automutilação, tentativas suicidas, ou ameaças do indivíduo
borderline, são uma forma de recuperar a atenção ou apoio perdido, já que o
mesmo sente-se dependente da presença de terceiros, não consegue cogitar a
possibilidade da ausência deles. O Borderline capta os sentimentos e sensações
de forma intensificada, gerando enorme sofrimento, recorrendo a mecanismos
automutilantes a fim de aliviar a forte angústia (FARIA., 2003). FONTE: DSM-V Critério 6: A intensidade dos sentimentos do borderline, associado à constante
oscilação de humor, contribuem para a instabilidade emocional do indivíduo, o
caracterizando pelo ‘tudo ou nada’, já que ele apresenta imenso sentimento por
determinada pessoa, mas um único ato insignificante é capaz de mudar seu
humor, fazendo-o se sentir prejudicado ou excluído, opondo instantaneamente o
sentimento existente pelo respectivo indivíduo. (OLIVEIRA et al., 2020) Critério 7: O sentimento de vazio é uma das principais características dos
indivíduos borderline. As necessidades afetuosas, instabilidades em
relacionamentos e as mais diversas características, originam-se pelo sentimento
de vazio. A busca incansável do indivíduo borderline provoca comportamentos
impulsivos, compulsivos, submissos, até mesmo agressivos como uma forma de
amenizar a sensação de estar só, muitas vezes, buscando em terceiros aquilo
que já tem. (MAZER et al., 2017) Critério 8: A intensificação das situações cotidianas são os pré-requisitos da
intensa raiva, já que a mesma, conscientemente é proporcional ao ocorrido,
sendo que a intensificação do mesmo ocorreu inconscientemente. Um ato
pequeno é percebido como grandioso e intenso, sendo benéfico, será percebido
como uma imensa forma de carinho, amizade e amor, sendo maléfico, o
indivíduo perceberá como um ato imperdoável, uma traição, afastamento, entre
outros. (PANIGRAHI et al., 2022) Critério 9: Os indivíduos borderline apresentam uma intensa atividade
imaginária, com inserção de ocorridos fictícios a situações passadas, além de
ideações ao futuro, geralmente comuns a quadros de ansiedade presente
nesses indivíduos, intensificando dificuldades passadas ou superestimando
dificuldades futuras, o que causa grande insegurança ao indivíduo, fazendo-o
acreditar em possibilidades inexistentes. (SIMONI et al., 2018) 3.5 Semelhanças no diagnóstico de transtorno de personalidade borderline com
os demais transtornos de personalidade Cada transtorno de personalidade possui características/critérios próprios, que
apresentam muita semelhança com critérios de outros transtornos de
personalidade, visto que, cada um, conta com motivações únicas, que
rotineiramente são confundidos na psiquiatria clínica, onde o paciente relata
brevemente o que está acontecendo e cabe ao psiquiatra encaixar o que foi dito
pelo paciente nos critérios específicos dos transtornos, para que seja possível a
realização de um tratamento eficaz. FONTE: DSM-V (FAUSTINO, 2014) De acordo com o conselho federal de medicina, é aconselhável que médicos e
especialistas que atendam em CAPS, UBS e UPA, exceto em situações de
emergência, 3 pacientes por hora, ou seja, cada consulta tem duração média de
20 minutos, com retorno aproximado de 30 dias, quando será possível visualizar a eficácia ou não
do tratamento prescrito, o que deixa o paciente suscetível a um diagnóstico
errôneo, juntamente com tratamento ineficaz, além do uso medicamentoso
estendido. (ZIMMERMAN, 2020) Diante do exposto, é visível a falha no atendimento ao público, principalmente
no sistema público, onde o profissional não dispõe de tempo suficiente para
realizar uma adequada análise das queixas do paciente e diferenciá-las de
outros transtornos. Alguns TP necessitam de enquadramento apenas de parte dos critérios para
realizar o diagnóstico, existindo a possibilidade que mais de um transtorno de
personalidade seja diagnosticado ao mesmo tempo. Vale destacar a importância
da correta associação entre as queixas e os critérios, a fim de evitar uma
conclusão desnecessária, levando o paciente a realizar tratamento para
transtornos de personalidade não cabíveis ao indivíduo. As motivações envolvidas nos critérios são extremamente importantes, visto
que, por exemplo, enquanto um transtorno apresenta determinados
comportamentos a fim de se beneficiar, outros buscam atenção, por isso se faz
essencial diferenciá-lo dos demais. 3.5.1 Borderline X Transtorno de Personalidade Histriônico O transtorno de personalidade histriônico ganha o pódio no ranking de erro
diagnóstico envolvendo o transtorno de personalidade borderline, ou vice versa,
os dois são constantemente confundidos na psiquiatria clínica, visto que a base
diagnóstica são, na maioria das vezes, senão todas, os critérios do DSM-V, onde
cada transtorno conta com uma série de critérios a serem enquadrados. (BACH
et al., 2016) O transtorno de personalidade Histriônico e Borderline recebem grande
destaque no âmbito da manipulação e oscilações emocionais, onde os critérios,
apesar de não existirem referências diretas um com o outro, apresentam
características semelhantes no que diz respeito aos critérios do DSM-V,
observadas na tabela 4: Tabela 4: Comparação entre os principais critérios do DSM-V para TP
borderline e TP histriônico. Critérios
TP BORDERLINE
Critérios
TP HISTRIÔNIC
5
“Recorrência de comportamento,
gestos ou ameaças suicidas ou de
comportamento automutilante” (DSM
-V, 2014, p.663). 6
“Mostra
autodramatizaç
teatralidade e
expressão exag
das emoções.” (
V, 2014, p.667)
6
“Instabilidade afetiva devida a uma
acentuada reatividade de
humor” (DSM-V, 2014, p.663). 3
“Exibe mudança
rápidas e expre
superficial das
emoções” (DSM
2014, p.667) FONTE: AUTORIA PRÓPRIA. O critério 6 do TP Borderline assemelha-se ao critério 3 do TP Histriônico, onde
as oscilações de humor são frequentes, muitas vezes abruptas, quando
relacionadas a pessoas do meio. As oscilações de humor são causadas por
motivos diferentes nos dois TP, enquanto a causa do borderline associa-se ao
medo do abandono e vazio, a causa do histriônico é a sensação de perder o posto de centro das atenções, sendo assim, o primeiro associado à afetividade e
o segundo à vanglorização. posto de centro das atenções, sendo assim, o primeiro associado à afetividade e
o segundo à vanglorização. As oscilações de humor são as principais causas para comportamentos
manipulativos, a fim de evitar a perda, ou recuperar aquilo que perdeu. Os
extremos de humor fazem com que o indivíduo se sinta completo, tendo aquilo
que quer, porém, a estabilidade de humor não é constante, fazendo com que o
completo se torne insuficiente, obrigando o indivíduo a tomar uma atitude, no
caso, a manipulação. O critério 5 do TP borderline demonstra uma manipulação perigosa, já que as
tentativas de suicídio podem causar a morte. De acordo com o Manual de
Diagnóstico e Estatísticas de Transtornos Mentais de 2014, as tentativas podem
resultar em suicídio em até 10% dos indivíduos, o que torna a manipulação do
histriônico bem mais leve, se comparado, já que o risco de suicídio, de acordo
com a mesma fonte, é desconhecido, afinal esses indivíduos usam o exagero de
emoções, como muito choro e muita dor, para chamar a atenção, até mesmo
envergonhar terceiros para se sobressair em diversas situações. Ambos buscam atenção total, além das grandes e frequentes oscilações de
humor. Umas das maiores semelhanças existentes entre os dois transtornos é
a intensidade emocional, excesso de demonstrações de afeto ou atenção, porém,
quando tratamos de borderline, estamos envolvidos por dois extremos:
intensidade emocional e o total descaso emocional, já que o indivíduo busca
atenção desesperadamente, mas é capaz de perceber quando não a terás,
mudando totalmente o comportamento para com esse indivíduo. FONTE: AUTORIA PRÓPRIA. O histriônico busca emoção imediata, sendo o mesmo capaz de restabelecer
sentimentos de muito carinho e muita raiva por pessoas de seu meio, por
períodos tenta agradar, presentear ou elogiar excessivamente pessoas que não
são íntimas o suficiente para tal comportamento, da mesma forma que se
chateiam pela falta de retribuição desses indivíduos, resultando em expressões
dramáticas, seguidas de afastamento, que pouco dura, já que em novas
tentativas de chamar a atenção, o histriônico pode até inventar histórias convictas, concordar com opiniões divergentes, sendo regularmente
sugestionáveis, a fim de atrair o foco da mesma pessoa na qual estava
ressentido. (HASLAM et al., 2012) A partir disso, é possível perceber que histriônico faz uso de diversas formas de
manipulação, a fim de atrair a atenção que pensa ter perdido, por consequência
de suas frequentes oscilações de humor. Além das formas dramáticas e
entusiasmadas de manipulação, o indivíduo busca chamar a atenção pela
aparência física, preza por roupas chamativas e extravagantes, muitas vezes
vulgares, que torna a sexualidade uma característica marcante deste transtorno. Além dos pontos citados, o histriônico apresenta-se como um indivíduo
poliqueixoso, regularmente apresentando reclamações diferentes, relacionadas
a sintomas físicos e psicológicos, onde os relatam com a intensidade
exageradamente aumentada, para coagir todos ao seu redor a fornecer os
cuidados que desejam. (HASLAM et al., 2012) Sendo assim, entendível a diferença existente entre ambos os TP, sendo possível
identificar o que se difere nas motivações e extremos expressos, a fim de chamar
a atenção ou manipular indivíduos, em cada um dos casos, porém, se os
aspectos do indivíduo se enquadrar em ambos os transtornos de personalidade,
os dois podem ser diagnosticados. 3.5.2 Transtorno de Personalidade Antissocial x Borderline O antissocial e o Borderline apresentam manipulação constante, a fim de obter
benefício, no caso do antissocial, a manipulação é consciente, o indivíduo tem
total conhecimento e planeja como usará tal meio ao seu favor, geralmente
envolvendo ganhos, como, por exemplo, uma forma de conseguir mais reconhecimento ou
lucro, enquanto o borderline manipula inconscientemente, acreditando
depender de um indivíduo e de sua total atenção, fazendo-o se compadecer
com seu sofrimento, o obrigando a fornecer aquilo que o borderline deseja:
afeto. (NUNES et al., 2018) Ao ser questionado sobre sua manipulação, o indivíduo antissocial não
apresenta remorso, são indiferentes ao sofrimento que causou em terceiros,
acreditam e afirmam que são merecedores dos privilégios obtidos mediante
fraude ou mentiras. Enquanto o borderline, quando questionado sobre mentiras
e manipulações, reagem de forma totalmente diferente, demonstrando intensa
dificuldade em controlar as oscilações de sentimentos, geralmente
apresentando intensa raiva, que pode chegar até a agressão física, já que os
mesmos não enxergam isso como manipulação, mas sim como uma
necessidade vital que não está sendo fornecida. (LIEBMAN et al., 2013) As características de manipulação envolvendo TP antissocial e TP borderline são
semelhantes e diferem-se pela consciência do ato, onde o primeiro planeja,
executa e usufrui, sem se importar com as consequências, mas tendo noção
total que se trata de uma manipulação. Enquanto o segundo acredita estar
apenas expressando seus sentimentos, sua necessidade de atenção, podendo
chegar a tentativas suicidas, a fim de demonstrar que precisa do afeto que não
está recebendo. (ANDO et al., 2019) Os ganhos envolvidos na manipulação dos dois transtornos diferem-se pelo fato
do antissocial buscar status social e bens materiais, que acreditam merecê-los,
enquanto o borderline acredita necessitar da atenção e apoio de terceiros. (BACH
et al.,2016) 3.5.3 Transtorno de Personalidade Esquizotípica X Borderline 3.5.3 Transtorno de Personalidade Esquizotípica X Borderline Um indivíduo com transtorno de personalidade esquizotípica expressa
pensamentos paranóides, isolamento social, afeto inapropriado, e períodos
dissociativos, que podem parecer semelhantes ao borderline, mas a diferença
existe na constância e duração deste comportamento. (AGNEW-BLAIS et al.,
2018) O indivíduo borderline sofre diversas oscilações emocionais, que podem, muitas
vezes, resultar em repetidos comportamentos agressivos e de intensa raiva,
prejudicando os relacionamentos, causando, muitas vezes, afastamento de
terceiros. (FAUSTINO, 2014) O intenso estresse pode causar, no indivíduo borderline, sintomas transitórios e
dissociativos, ligados a mudanças em seus relacionamentos afetuosos,
caracterizando a sensação de distanciamento de seu próprio pensamento ou
corpo, uma despersonalização e desrealização, que duram, geralmente, poucas
horas. (MACHADO et al., 2014) O intenso estresse pode causar, no indivíduo borderline, sintomas transitórios e
dissociativos, ligados a mudanças em seus relacionamentos afetuosos,
caracterizando a sensação de distanciamento de seu próprio pensamento ou
corpo, uma despersonalização e desrealização, que duram, geralmente, poucas
horas. (MACHADO et al., 2014) A ideação paranóide ocorre com mais frequência, principalmente pelos
sintomas crônicos de vazio, onde o mesmo, ao considerar-se dependente, teme
pelo afastamento, o que possibilita diversos pensamentos paranóides e
consequentemente atitudes impulsivas a fim de evitar o que imagina que pode
acontecer. (VAZQUEZ et al., 2018) A maior diferença existente entre os dois transtornos são as características
impulsivas e manipuladoras do borderline, que são raramente apresentadas por
esquizotípicos. Apesar do borderline apresentar sintomas semelhantes, a
duração se difere, sendo esta característica duradoura em indivíduos
esquizotípicos, chegando a serem quase constantes, enquanto o borderline
apresenta-se nesta posição somente em situações extremas. (RESENDE et al.,
2019) Alguns casos de isolamento social podem surgir no borderline, mas não por
escolha própria e sim de terceiros, já que alguns comportamentos agressivos e a
constante mudança de humor afasta todos ao seu redor, o obrigando a viver
períodos de isolamento. Os dois transtornos podem apresentar-se juntos no
mesmo indivíduo, sendo quase impossível distinguir os comportamentos
providos de cada um dos transtornos, sendo necessário reavaliação do indivíduo
quando os sintomas dissociativos e transitórios causados por estresse da
personalidade borderline desapareçam. (TYRER et al., 2019) 4. CONCLUSÃO Portanto, a partir da dificuldade em diagnósticos clínicos convencionais para o
Transtorno de Personalidade Borderline, surgiu a necessidade de
esclarecimento sobre as características específicas do determinado transtorno. Por consequência deste cenário comum em ambientes psiquiátricos, a partir disso nota-se os critérios de avaliação pessoal fazendo com que a avaliação do
possível transtorno seja mais tangível e assim ter a oportunidade do tratamento
e acompanhamento pessoal. disso nota-se os critérios de avaliação pessoal fazendo com que a avaliação do
possível transtorno seja mais tangível e assim ter a oportunidade do tratamento
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borderline-tpb>. Acesso em: 11 nov. 2022. Discente do curso de medicina da UNIFIMCA
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The Southwest Silk Road: artistic exchange and transmission in early China
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Bulletin of the School of Oriental and African Studies
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© The Author(s), 2024. Published by Cambridge University Press on behalf of SOAS University of London. This is an Open Access
article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.
0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly
cited. Abstract In examining wares discovered from the cultures of Sanxingdui and Jinsha and from the former site
of the ancient kingdom of Dian in Sichuan and Yunnan provinces, this article highlights a number of
shared features and trends that suggest a continued artistic, technological and cultural transmission
through time and space. The article aims to supplement established theories on the rich material
culture of this region. It will look in particular at the development of its striking bronze metallurgy,
largely deriving from the established traditions of the Yellow River valley in China’s Bronze Age. It
highlights the function of a dense network of trading routes, referred to in modern scholarship as
the “Southwest Silk Road”, as an important facilitator of cultural and artistic exchange and recip-
rocation from ancient times. Keywords: Southwest Silk Road; Sanxingdui; Jinsha; Dian; material culture The Southwest Silk Road: artistic exchange and
transmission in early China Hajni Elias
University of Cambridge, Cambridge, UK
Email: hpe20@cam.ac.uk Hajni Elias Bulletin of the School of Oriental and African Studies (2024), 1–26
doi:10.1017/S0041977X24000120 Bulletin of the School of Oriental and African Studies (2024), 1–26
doi:10.1017/S0041977X24000120 Bulletin of the School of Oriental and African Studies (2024), 1–26
doi:10.1017/S0041977X24000120 Bulletin of the School of Oriental and African Studies (2024), 1–26
doi:10.1017/S0041977X24000120 https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Introduction Sanxingdui 三星堆, Jinsha 金沙and Dian 滇, in today’s Sichuan and Yunnan provinces,
were the centres of significant artistic and bronze casting traditions in southwest China
(Figure 1). The site of the ancient civilization of Sanxingdui, situated 40 kilometres north-
east of present-day Chengdu city, has been dated to the late Shang period (c. 1300–1050 BCE)
(von Falkenhausen 2003: 191). Archaeological finds, primarily from two pits discovered in
1986, confirm the presence of an advanced culture in the region, referred to as ‘the
Southwest’ in early Chinese sources.1 For reasons that remain unknown, the people of
Sanxingdui abandoned their walled city along the Jian River 湔江, deliberately burning 1 Some of the important textual sources that include information on the Southwest may be found in the geo-
graphical treatises (dili zhi 地理志) section of the Hanshu 漢書and the Hou Hanshu 後漢書. See Tan 2001 for a
collection of annotations on the treatises on administrative geography in the standard histories. Another import-
ant textual source for the Southwest is the Huayang guo zhi yizhu 華陽國志(Record of the Kingdoms South of
Mount Hua) compiled by Chang Qu 常璩(fl. 347 CE). Its comprehensive geographical, historical, political and bio-
graphical account of the former territories of the Ba 巴, Shu 蜀, Hanzhong 漢中and Nanzhong 南中command-
eries in early and medieval times provides detailed surveys of the Southwest’s mountains, rivers, wildlife,
produce, people, customs and culture. It is also a biographical account of the lives of some of its eminent persons
and worthy men and women from antiquity to the fourth century of the Eastern Jin period (265–420 CE). In add-
ition to the two pits discovered in 1986 at Sanxingdui, six further ritual pits have been unearthed since 2020. A joint excavation team from several universities and research institutions in China have unearthed more https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 2 Figure 1. Map of the locations of the Sanxingdui, Jinsha and Dian cultures in early China Figure 1. Map of the locations of the Sanxingdui, Jinsha and Dian cultures in early China ritual vessels and paraphernalia in sacrificial pits. The Jinsha site, located on the outskirts
of Chengdu, was discovered in 2001 and is considered the final phase of the Sanxingdui
culture (Ye 2011). than 500 artefacts, including gold masks and a large number of fine bronzes and bird-shaped gold ornament
pieces. As these finds have not yet been officially published, they are not included in this article. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Introduction Finds from Jinsha have been dated to 1000–650 BCE by archaeologists,
which corresponds to the Western Zhou period 西周(eleventh century–770
BCE)
(Chengdu Municipal Institute of Antiquity and Archaeology 2013). The Dian people
were settled in the region of Lake Dian 滇池in present-day Yunnan province, located
south of Sichuan, and were active from around 500 BCE until 109 BCE, when they were con-
quered and attached as a vassal state to the Western Han Empire (202 BCE–9 CE) (Yao 2005:
381). Archaeological excavations at the two principal sites of Shizhaishan 石寨山and
Lijiashan 李家山revealed them as a highly complex and localized kingdom with a society
of significant traditions. This article aims to supplement established theories that consider the Southwest’s
early material culture as largely deriving from the established traditions of the Yellow
River valley in the central plains of China. Through an examination of ritual wares discov-
ered from Sanxingdui and Jinsha and from the former sites of the Kingdom of Dian, the
article highlights a number of shared artistic preferences and metallurgical practices
that show a flourishing interaction between the sedentary and pastoral societies in the
region which facilitated local transmission and exchange, resulting in the development
of a number of advanced artistic traditions over time. This exchange was aided by a net-
work of trading and communication routes, referred to in modern scholarship as the
Southwest Silk Road; from early on it played a central role in bringing people with estab-
lished bronze technology and tradition to the region. While the cultures of Sanxingdui and
Jinsha preceded the civilization of the Dian people by several centuries and their centres
are at a great distance from each other (over 800 kilometres), we may assume that the https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS BSOAS BSOAS 3 movement of people in the region was continuous and active until the founding of the Qin
(221–206 BCE) and Han (206 BCE –220 CE) dynasties when central military and government
control over the region was established and consolidated. movement of people in the region was continuous and active until the founding of the Qin
(221–206 BCE) and Han (206 BCE –220 CE) dynasties when central military and government
control over the region was established and consolidated. Introduction A nuanced understanding of local and regional developments challenges arguments
that presume the overriding influence of dominant cultures, such as that found in the
Yellow River valley, and underplays the possibility of local indigenous developments.2
In China’s case this paradigm views the Southwest, and indeed most of the early cultures
of Southeast Asia – the territory encompassed by modern day Myanmar, Thailand, Laos,
Vietnam and Cambodia – as dependent on China for the origin of most technological and
artistic innovations. Especially in the field of metallurgy, these views trace the spread of
early bronze making from the elite and sophisticated Shang and Zhou cultures to the less
complex societies of the Southwest via networks of contact and exchange (White and
Hamilton 2009: 357–8).3 Following an examination of some of the key routes associated with the Southwest Silk
Road, the article highlights the nature of societies in the region and introduces estab-
lished theories on the early transfer of metallurgy to the Southwest. After this, it focuses
on the cultures of Sanxingdui, Jinsha and the ancient Kingdom of Dian, looking at some of
the shared features and trends that indicate a number of related artistic and material tra-
ditions facilitated by the presence of different social and ethnic groups and a well-
developed network of trading routes in the Southwest. 2 For examples of Sino-centric studies on the cultures of the Southwest, see Cao 2016, Li 2018, Qiu 2013 and
Wang 2002.
3 In their analysis, White and Hamilton 2009: 358 question Sinocentric models for the source of Southeast
Asian bronze technology as flawed for chronological, technological and conceptual reasons.
4 For studies on the Southwest Silk Road, see Cao 2016; Fang 2015; Hu 1989; Li 2018; Lin 2008; Luo 1993; Qiu
2013; Wang 2002; Wang and Dai 2020; Yang 2004, 2018; and Zhang 2018. The Southwest Silk Road does not des-
ignate a single unbroken passage but refers to a network of interconnected routes that passed through distinct
regions. Bin Yang’s study on the use of cowrie shells as money among Indian, Chinese, Southeast Asian and West
African societies is an example of research on the impact of the Southwest Silk Road in the region. See Yang 2004,
2009, 2011 and 2018. Asian bronze technology as flawed for chronological, technological and conceptual reasons.
4 For studies on the Southwest Silk Road, see Cao 2016; Fang 2015; Hu 1989; Li 2018; Lin 2008; Luo 1993; Qiu
2013; Wang 2002; Wang and Dai 2020; Yang 2004, 2018; and Zhang 2018. The Southwest Silk Road does not des-
ignate a single unbroken passage but refers to a network of interconnected routes that passed through distinct
regions. Bin Yang’s study on the use of cowrie shells as money among Indian, Chinese, Southeast Asian and West
African societies is an example of research on the impact of the Southwest Silk Road in the region. See Yang 2004,
2009, 2011 and 2018. 3 In their analysis, White and Hamilton 2009: 358 question Sinocentric models for the source of Southeast
Asian bronze technology as flawed for chronological, technological and conceptual reasons. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press The Southwest Silk Road Studies of the Silk Road, a network of overland routes that connected the continents of
Europe and Central Asia with northern China across the Eurasian Steppe, and also of
the Maritime Silk Road, a number of sea routes that linked southern China with
Southeast Asia, the Indian subcontinent and reaching as far as the Arabian peninsula
and Europe, are well established. These studies have overshadowed a third system of trad-
ing routes constituted by overland passages stretching through the mountainous areas of
the eastern Tibetan Plateau and the provinces of Sichuan, Guizhou and Yunnan through-
out the Yunnan-Guizhou Plateau and into the neighbouring states of Southeast Asia. Labelled as the Southwest Silk Road in modern scholarship, this complex network of trav-
ersable roads played a key role in the exchange of goods; however, its contribution to the
transmission of culture and art on a trans-regional level in early times remains to be
explored.4 Although named as the Southwest Silk Road in association with the great
trade routes – the Northern and Maritime Silk Roads – there is little evidence that silk
was ever exchanged along it. The term has come to be used as a short reference for
the routes of trade and cultural exchange across the region. g
g
Rivers and traversable plateaus in the Southwest were key to traffic from early on,
among which the Yunnan-Guizhou Plateau, a southern extension of the Tibetan
Plateau, was possibly one of the most heavily crossed routes employed by the many 2 For examples of Sino-centric studies on the cultures of the Southwest, see Cao 2016, Li 2018, Qiu 2013 and
Wang 2002. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 4 nomadic and semi-nomadic tribes in the region. It served as an interaction zone between
the main cultural centres in the northern, eastern and the southwestern parts of the
region (Yang 2004: 315). The Tibetan Plateau itself is a vast area that extends over 2.5 mil-
lion square kms, and comprises parts of Qinghai, Gansu, Sichuan and Yunnan provinces, as
well today’s Tibetan Autonomous Region (Guedes and Aldenderfer 2020: 340). Along with
land routes, rivers were also of key significance to anyone traversing this region. The Southwest Silk Road We find
that the major rivers in the Southwest, the Yangtze 揚子江, Pearl 珠江, Mekong 湄公河
and Hong rivers 洪江, mostly originate from the Tibetan Plateau with their main tribu-
taries passing through Sichuan and Yunnan and flowing south towards Southeast Asia. These rivers and their many tributaries functioned as passages for the movement of peo-
ple as well as goods, ideas and the arts (Hignam 1999: 1). Joyce White and Elizabeth
Hamilton (2009: 390), in their examination of the transmission of early bronze technology
to Southeast Asia, note how the complex river systems extending out of the southeastern
foothills of the Himalayas may have aided the direct and swift spread of the Eurasian
Steppe metallurgical traditions, especially the lost-wax casting of ornaments to the
south and southwest, reaching today’s Thailand as early as 2000 BCE. The dating of the dif-
ferent branches of the Southwest Silk Road remains a matter of debate among scholars,
some of whom believe that the route to India across the Southwest, referred to in
early historical accounts, may in fact have emerged well before the third century BCE
(Yang 2009: 34). The earliest mention in Chinese textual sources of an active trade route in the
Southwest may be found in the Shiji 史記where the explorations of the official and dip-
lomat, Zhang Qian 張騫(138 –126 BCE), are recorded as follows: 及元狩元年, 博望侯張騫使大夏來, 言居大夏時見蜀布、邛竹杖, 使問所從來, 曰
「從東南身毒國, 可數千里, 得蜀賈人市」。或聞邛西可二千里有身毒國。騫因
盛言大夏在漢西南, 慕中國, 患匈奴隔其道, 誠通蜀, 身毒國道便近, 有利無害。於
是天子乃令王然于、柏始昌、呂越人等, 使閒出西夷西, 指求身毒國。至滇, 滇王
嘗羌[3]乃留為求道西十餘輩。歲餘, 皆閉昆明, 莫能通身毒國。 及元狩元年, 博望侯張騫使大夏來, 言居大夏時見蜀布、邛竹杖, 使問所從來, 曰
「從東南身毒國, 可數千里, 得蜀賈人市」。或聞邛西可二千里有身毒國。騫因
盛言大夏在漢西南, 慕中國, 患匈奴隔其道, 誠通蜀, 身毒國道便近, 有利無害。於
是天子乃令王然于、柏始昌、呂越人等, 使閒出西夷西, 指求身毒國。至滇, 滇王
嘗羌[3]乃留為求道西十餘輩。歲餘, 皆閉昆明, 莫能通身毒國。 In the first year of yuanshou (122 B.C.E.) Zhang Qian, the Bowang marquis, returned
from his mission to the land of Daxia (Bactria) and reported that while he was
there he had seen cloth produced in Shu and bamboo canes from Qiong. On inquiring
how they had arrived in Daxia, he was told, “They come from the land of Shendu
(India), which lies some several thousand li west of here. We buy them in the
shops of the Shu merchants there.” He was told that Shendu was situated some
2,000 li west of Qiong. “Daxia, which is situated southwest of our country,” Zhang
Qian reported to the emperor with enthusiasm, “is eager to open relations with
China and is much distressed that the Xiongnu are blocking the road in between. 5 Shiji 116.2996; Watson 1993: II, 256. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press The Southwest Silk Road If we could find a new route from Shu via the land of Shendu, however, we would
have a short and convenient way to reach Daxia which would avoid the danger of
the northern route!”5 This passage confirms the presence of an established road between Sichuan and Bactria
via India by the Han dynasty, used by traders in the Southwest but not familiar to or
explored yet by the Han themselves. Indeed, the mention of Shu 蜀merchants selling
their goods in India suggests the presence of developed trading relations between local https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 5 BSOAS BSOAS societies in the Southwest and distant regions that must have flourished well before Sima
Qian’s 司馬遷(c. 145–86 BCE) writing of the Shiji.6 societies in the Southwest and distant regions that must have flourished well before Sima
Qian’s 司馬遷(c. 145–86 BCE) writing of the Shiji.6 A further passage in the Shiji refers to the attempts made by Han emissaries to locate a
safe and more direct route to Bactria in order to avoid dangers encountered by the Qiang
羌people in the Tibetan Plateau and the Xiongnu 匈奴in the north. 昆明之屬無君長，善寇盜，輒殺略漢使，終莫得通。然聞其西可千餘里有乘象
國，名曰滇越，而蜀賈姦出物者或至焉，於是漢以求大夏道始通滇國。初，漢
欲通西南夷，費多，道不通，罷之。及張騫言可以通大夏，乃復事西南夷。 昆明之屬無君長，善寇盜，輒殺略漢使，終莫得通。然聞其西可千餘里有乘象
國，名曰滇越，而蜀賈姦出物者或至焉，於是漢以求大夏道始通滇國。初，漢
欲通西南夷，費多，道不通，罷之。及張騫言可以通大夏，乃復事西南夷。 The Kunming tribes have no rulers but devote themselves to plunder and robbery,
and as soon as they seized any of the Han envoys they immediately murdered
them. Thus none of the parties were ever able to get through to their destination. They did learn, however, that some 1,000 or more li to the west there was a state
called Dianyue whose people rode elephants and that the merchants from Shu some-
times went there with their goods on unofficial trading missions. In this way the Han,
while searching for the route to Daxia, first came into contact with the Kingdom of
Dian.7 Another passage in the Hanshu 漢書records how Emperor Wu 漢武帝(r. 141–87 BCE) dis-
patched envoys in search of the route to India via the Southwest: 於是天子乃令王然于、柏始昌、呂越人等十餘輩間出西南夷，指求身毒國。至
滇，滇王當羌乃留為求道。四歲餘，皆閉昆明，莫能通。滇王與漢使言：「漢
孰與我大？」及夜郞侯亦然。各自以一州王，不知漢廣大。使者還，因盛言滇
大國，足事親附。天子注意焉。 The emperor therefore ordered Wang Ranyu, Bo Shichang, Lü Yueren and others, ten
or more, to go on a secret expedition to the region of the Southwestern Yi barbar-
ians, instructing them to search for the Kingdom of Shendu. The expedition reached
as far as Dian. The King of Dian, Changqiang made them stay and told them that he
would send out a party to search for the road to Shendu. 6 The region known in early textual sources as the Southwest (xinan 西南) primarily occupies the combined
areas of northwestern Guizhou, Sichuan and northeastern Yunnan provinces today. It encompasses the geo-
graphical landscape referred to as the Ba-Shu 巴蜀territory, a peripheral region in early Imperial times,
which combined the two states or kingdoms known as Ba and Shu within the greater Sichuan Basin. Ba was
where today’s eastern Sichuan lies, with its capital Jiangzhou 江州(present-day Chongqing city) on the banks
of the Yangtze River; while Shu, with its capital Chengdu 成都, occupied the lowlands of the Chengdu Plain
and the adjacent mountainous territories of the western part of the province. Mention of the Shu people refers
to those living in the former kingdom of Shu. For a detailed account on the early history of Sichuan, see Sage
1992. 7 Shiji 123, 3166; Watson 1993: II, 236–7.
8 Hanshu 95.3841. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias From these textual records it is evident that although there was a route from the
Western Han capital of Chang’an 長安to Yunnan via Sichuan, the stretch of road from
Yunnan westwards to Bactria in Central Asia via the region of present-day Myanmar
and India was blocked by the local ethnic tribes who may have considered the Han as
intruders rather than “friends”. Over time, Han government missions deployed to search
for a route to Bactria via the Southwest proved not only dangerous but financially costly. As noted in the Shiji, “Earlier the Han had tried to establish relations with the barbarians
of the Southwest, but the expense proved too great and no road could be found through
the region and so the project was abandoned (初, 欲通西南夷, 多道不同, 罷之).”9 What is also evident from early writings is the highly localized nature of interaction
between different societies in the Southwest and the difficulties encountered by those,
such as the Han, who as “outsiders” may have been viewed as encroaching upon their
established affairs. Although there was interest in the Southwest and the territories
beyond the Han Empire’s borders, primarily for economic purposes, it never became a pri-
ority, possibly due to contentious relations between the Han government and the
nomadic steppe tribes, united under the Xiongnu and occupying much of the territory
north of the empire’s borders, and which had a decisive influence on its political, eco-
nomic and military life (Di Cosmo 1994). y
The Southwest Silk Road comprised a number of key sections. A route labelled in mod-
ern scholarship as the Sichuan-Yunnan-Burma-India road linked Chengdu with Kunming
in the east and Dali 大理in the west of Yunnan province (Yang 2004: 287).10 From Dali the
road crossed the Bonan Mountain 博南山pass to today’s Myanmar and Thailand, even-
tually reaching India and was thus labelled the “Ancient Road of Bonan (Bonan gudao
博南古道)” (Yang 2004: 287). Another branch of the Southwest Silk Road connected
Chengdu with Kunming and then forked southeast towards Vietnam following the course
of the Hong River that flows to northern Vietnam. The third major route connected
Sichuan and Yunnan with the regions of today’s Laos, Thailand and Cambodia. Key to
the discussion in this article is a fourth route that joined Sichuan, Yunnan and the
Tibetan Plateau with the north. Shiji 123, 3166; Watson 1993: II, 237.
10 See Yang 2004 for a description of the different network of routes that comprised the Southwest Silk Road.
11 Shiji 116.2993 (巴蜀民或竊出商賈，取其筰馬、僰僮、髦牛，以此巴蜀殷富). 10 See Yang 2004 for a description of the different network of routes that comprised the Southwest Silk Roa
11 Shiji 116.2993 (巴蜀民或竊出商賈，取其筰馬、僰僮、髦牛，以此巴蜀殷富). 9 Shiji 123, 3166; Watson 1993: II, 237.
10 The Southwest Silk Road After more than four years
of waiting, all the roads were closed off by the inhabitants of Kunming and the search
party was not able to get through. The King of Dian told the Han envoy, “Which is
greater, my domain or that of the Han ruler?” The Marquis of Yelang asked the same
question. They both thought of themselves as kings of one vast region and did not
know the vast greatness of the Han. The Han envoys returned and made an effort
to claim that the Dian Kingdom was large and should be good enough to have a
close relation and binding to the Han. The emperor paid close attention to this
matter.8 https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 6 Hajni Elias g
p
11 Shiji 116.2993 (巴蜀民或竊出商賈，取其筰馬、僰僮、髦牛，以此巴蜀殷 Hajni Elias Entire horse skeletons placed in “sacrificial features”, similar to
the horse sacrificial burials known from across the Eurasian Steppe, have been discovered,
suggesting that people in the region engaged in ritual practices that were formed among
the nomadic steppe peoples of Central Asia.14 Jade Guedes and Mark Aldenderfer (2020:
376) note how the introduction of the horse most likely changed the way humans occu-
pied the Tibetan Plateau in several ways. Transport on horseback made it easier to cross
larger distances in shorter amounts of time, which increased people’s ability to engage in
long-distance patterns of trade and exchange that came to characterize subsistence on the
Tibetan Plateau. Indeed, representations of horses and riders on bronze vessels, showing horsemen with
a cape similar to that worn by the Yi 彝people in the Liangshan 凉山region of southern
Sichuan today, are prominent in the arts of the Dian people.15 The modern Yi are the des-
cendants of the ancient Di 氐and Qiang ethnic tribes, the former from the lowlands of
northwest Yunnan and the latter from the highlands of Tibet.16 The cost or value of a
horse is recorded on a Dian tally plaque unearthed from a tomb at Shizhaishan and
dated to the height of the Dian Kingdom. This tally contains an unusual engraved drawing
in the form of an inventory list. Along with a horse head, there are representations of
slaves, heads of sheep and ox and cowrie shells, all of which appear to represent forms
of moveable wealth. The inclusion of cowrie shells on the plaque is noteworthy, especially
because the large quantities of these small sea snails found at the sites of Sanxingdui and
Dian have raised scholars’ interest in their role and meaning for the region’s early soci-
eties.17 While cowries have been found at the Shang and Zhou sites in Central China, its
prevalence in the Southwest and the production of elaborate bronze vessels for their stor-
age, suggest their significance to local societies in the region. The most frequent cowrie
type found in the Southwest is the Gold Ring cowrie which came primarily from the
Indian Ocean, more specifically from the Maldive Islands. They were probably brought
to the Southwest by traders who followed the land route that connects Sichuan and
Yunnan with Thailand and Burma, extending to India and thereby reaching the shores
of the Indian Ocean and the Maldives (Pirazzoli-t’Serstevens 1990: 47). Hajni Elias The Yunnan-Guizhou Plateau, mentioned earlier, is a nat-
ural corridor for the northern part of this route. Much later, in the Ming dynasty (1368–
1644), tea became an important commodity traded along this route. It was exported from
Sichuan and the Puer region in Yunnan, via Dali to Lhasa and from Lhasa to Nepal and
India (Yang 2009: 32–3). Known at the time as the “Tea Horse Route”, the
Yunnan-Tibet connection started much earlier, even before the custom of tea drinking
began among the Tibetan people in the Tang period (618–907) (Yang 2009: 33). 筰都 Long before the tea trade, horses from the Zuodu 筰都people, who lived west of
Sichuan at the Tibetan-Yunnan borders, were traded along the fourth major network of
routes mentioned above. We read in the Shiji how Ba and Shu traders made good profits
from the purchase of Zuodu horses, slaves and oxen in the region.11 The earliest geo-
graphical treaties in the Southwest – the Huayang guo zhi, 華陽國志(Records of the
Kingdoms South of Mount Hua) compiled by Chang Qu 常璩(c. 291–361 CE) – mentions
the presence of “divine horses (shenma 神馬)” in the region as follows: 滇池縣郡治。故滇國也。有澤水，周回二百里。所出深廣，下流淺狹，如倒流，
故曰滇池。長老傳言，池中有神馬，或交焉，即生駿駒，俗稱之曰“滇池駒”. 滇池縣郡治。故滇國也。有澤水，周回二百里。所出深廣，下流淺狹，如倒流，
故曰滇池。長老傳言，池中有神馬，或交焉，即生駿駒，俗稱之曰“滇池駒”. 滇池縣郡治。故滇國也。有澤水，周回二百里。所出深廣，下流淺狹，如倒流，
故曰滇池。長老傳言，池中有神馬，或交焉，即生駿駒，俗稱之曰“滇池駒”. The commandery administration is located in Dianchi county, seat of the ancient
Dian Kingdom. There is a large lake with a circumference of two-hundred li. The https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS
7 7 BSOAS BSOAS source of the lake is deep and wide and at the lower course it becomes shallow and
narrow. It is as if it has a reverse flow thus called Dianchi. Rumours according to the
chiefs and the elders say that there are spirit horses in the lake. When these horses
are bred with other horses then they give birth to spirit colts that are commonly
referred to as the “Dianchi colts”.12 The Hou Hanshu also documents a special breed of horse to be found at Lake Dian.13
Archaeological evidence shows that horse husbandry was practised in the Southwest
from early times and these legends suggest that high-quality horses were present in
the region well before the Qin and Han occupation (Yang 2009: 49). The importance of horses to societies settled on the Tibetan Plateau is evident from
archaeological findings. 12 Huayang guozhi yizhu, 4.267–8.
13 Huayang guozhi yizhu 4.153; Hou Hanshu 86.2847.
14 See Guedes and Aldenderfer 2020: 376, where the authors note that, while there is no direct radiocarbon
date associated with these finds, nevertheless, horses have been unearthed from the region’s cist tombs that
have been dated to between 2710 and 2360 BCE.
15 See Figure 3 which is examined in more detail later.
16 On the subject of ethnic tribes in the Southwest, see Peters 2002 and Harrell 2001.
17 Although to date no cowrie shells have been unearthed at the Jinsha site, we have an example of a jade
carving in the form of a shell that suggests its continued importance at the time. The shell-form jade carving
is in the collection of and on display at the Jinsha Museum in Chengdu city. 12 Huayang guozhi yizhu, 4.267–8. Huayang guozhi yizhu 4.153; Hou Hanshu 86.2847.
14 See Guedes and Aldenderfer 2020: 376, where the authors note that, while there is no direct radiocarbon
date associated with these finds, nevertheless, horses have been unearthed from the region’s cist tombs that
have been dated to between 2710 and 2360 BCE.
15 See Figure 3 which is examined in more detail later.
16 On the subject of ethnic tribes in the Southwest, see Peters 2002 and Harrell 2001. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press g
16 On the subject of ethnic tribes in the Southwest, see Peters 2002 and Harrell 2001. 17 Although to date no cowrie shells have been unearthed at the Jinsha site, we have an example of a jade
carving in the form of a shell that suggests its continued importance at the time. The shell-form jade carving
is in the collection of and on display at the Jinsha Museum in Chengdu city. Hajni Elias In the
Southwest, at least, they appear to have functioned as a form of exchange in a society https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 8 Hajni Elias 8 that did not have coins or any other form of currency and had ritual or religious connota-
tions. Their long journey is a testament to their significance as a valued commodity avail-
able primarily through trade along the Southwest Silk Road.18 p
y
g
g
Another important commodity produced and transported via the road and river net-
works in the Southwest, especially along the fourth route mentioned above, was metal
ore. Today’s Yunnan and the region of Myanmar contain some of the richest deposits
of copper, lead and tin in the wider region.19 A recent discovery of primary metallurgical
activities at six smelting sites dated to the middle to late second millennium BCE in
Yunnan highlight the early exploitation of ores in the Southwest (Yao et al. 2020: 2). It
is worth noting that the production of quality bronze work requires a copper content
of about 90 per cent and a tin content of about 10 per cent. While copper was readily
available throughout the region, in Sichuan and Yunnan, tin was more scarce and a far
more precious material, with deposits found primarily in Yunnan and today’s
Myanmar.20 This suggests that early cultures and societies in the region, such as the
three examined in this article, must have been in contact with metal traders along the
Sichuan-Yunnan branch of the Southwest Silk Road, obtaining precious raw material
from local deposits. Furthermore, as noted by Rubin Han and Li Xiaocen (2009: 181) in
their examination of early metallurgies in the Southwest, in particular the ancient sites
of the Dian, “the appearance of tinned bronzes (and other products) unquestionably docu-
ments experimentations with the appearance of an ‘outsider’ technology. The tinning
technique can be seen as one important invention of the bronze cultures in the steppe
area of the Northern Frontier.” The use of tin-plating or the application of tin-enriched
surfaces, giving objects a shiny and attractive appearance, required tin that was available
and sourced locally from mines in the Southwest. Buoyant trade along the Southwest Silk Road also connected nomadic and semi-
nomadic societies with sedentary ones. Hajni Elias Pastoral nomadism does not normally exist in iso-
lation from farming communities, as the pastoral nomadic economy cannot provide all
basic necessities, and their contact, commercial exchange and mutual dependency with
settled people played an important role in the shaping of early societies in China (Di
Cosmo 1994: 1092). Below let us examine some of the theories on the transfer of bronze
metallurgy in the Southwest. 18 For an in-depth study on cowrie shells in early China, see Yang 2004, 2011 and 2018.
19 On the Southwest’s deposits and the locations of casting moulds discovered, see Han and Li 2009.
20 See Han and Li 2009: 183, who discuss the Southwest, in particular Yunnan province, as a region rich in
mineral resources. They note that the region’s rich mines and the presence of ancient moulds demonstrate
the possibility and conditions for bronze manufacturing in the region.
21 See von Falkenhausen 2003 and Xu 2001b. 18 For an in-depth study on cowrie shells in early China, see Yang 2004, 2011 and 2018.
19 https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 19 On the Southwest’s deposits and the locations of casting moulds discovered, see Han and Li 2009. Transfer of bronze metallurgy in the Southwest While there is an ongoing debate over the exact dating of the transfer and development of
metallurgy to societies in the Southwest, it is commonly asserted that there was contact
with “outside” that served as the main stimulus for local metallurgical experimentation.21
Established views explain the appearance of bronze production in the Southwest by look-
ing north to the early states of the Yellow River in the Central Plains and their sophisti-
cated bronze tradition. However, the metallurgy of the Central Plains had a prior source in
the Eurasian Steppe, entering China via the north and northwest where cultures such as
the Qijia 齊家(2200–1800 BCE) and Siba 四垻(1950–1550 BCE) were settled along the Gansu
corridor and interacted with the steppe peoples from Eurasia from the late third https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS BSOAS BSOAS 9 millennium BCE.22 Mei Jianjun (2009: 10–14) notes how many of the metal objects associated
with these two cultures, made of copper, tin bronze or leaded tin bronze and in the form of
knives, axes, spearheads and smaller accessories, show a similarity in typology to metal
objects found in the Eurasian Steppe which strongly suggests cultural connections. He fur-
ther observes how various steppe features from different areas coexisted among the early
bronze cultures in the Qinghai-Gansu region, suggesting that contacts between northwest
China and the Eurasian Steppe were made over an extensive period rather than in the
form of a direct influence due to a specific migration. This argument suggests a more
local or regional development that was aided by, but not dependent on, “outside” sources
with a high level of bronze metallurgical know-how. It represents a pattern of interregional
interaction rather than a simple process of one-way diffusion (Mei 2009: 40–41). p
p
y
Scholarship on the anthropology of technology transmission can help us understand
the complex questions of how and why certain technologies move or transfer from one
society to another. Transfer of bronze metallurgy in the Southwest White and Hamilton alert us to the importance of differentiating tech-
nology – the application of knowledge of the material properties of physical things to
achieve practical purposes – from a technological system that refers to the way knowledge
is implemented in a specific context.23 During the second and first millenniums BCE, states
in China’s Central Plains and cultures in the Southwest undeniably had a high level of
knowledge of bronze technology, but the technological systems for producing and
using bronze vessels and artefacts in the two regions differed. The amount of knowledge
and the skills involved in metal production are complex and the transfer of any, even the
simplest, technology to a society with no prior experience of working with metals is
almost impossible. Therefore, transmission of complex metal technologies to an area
with no prior experience in metalworking is not likely to have occurred by mere exposure
to the idea of smelting, particularly in areas lacking evidence of a period of experimen-
tation (White and Hamilton 2009: 361). White and Hamilton further note how the smelt-
ing of copper and the production of bronze artefacts are part of a complex technological
system that involves the acquisition and manipulation of ores and fuels, the creation of
refractory ceramics, the refining of molten metal, alloying, casting, fabrication and
manipulation of moulds and the management of post-casting treatments such as working. To determine the source of the knowledge of metalworking in a culture requires not
merely looking at who produced the geographically nearest metal artefacts in a suitable
period of time, but who produced the nearest artefacts using a similar technological sys-
tem (White and Hamilton 2009: 360–01). If there was no similar system employed, then
the technology was indeed special to that culture or cultures within a region. We shall
see how this aptly applies to the Southwest where techniques, such as the lost-wax pro-
cess, and decorative styles not commonly employed in the Central Plains were used. 22 See White and Hamilton 2009: 373, for a discussion on the Qijia culture where it is mentioned that the
metallurgy of the Central Plains had a prior source in the Eurasian Steppe, entering China via the north and
northwest where cultures such as the Qijia and Siba were settled. j
23 See White and Hamilton 2009: 360, for a detailed analysis of this concept and argument. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Transfer of bronze metallurgy in the Southwest Peng
Peng’s study of the use of lost-wax technique in Bronze Age China highlights its import-
ation from the Eurasian Steppe along with other metallurgical processes such as tinning,
gilding, chasing and inlay, strengthening the argument that they were not only intro-
duced to the Southwest via exchange with the northern nomadic steppe people, but
also that the communication routes of the Southwest Silk Road may have played a role
in its transfer to other regions within China and Southeast Asia (Peng 2017, 2020). It
appears that key to the transfer of bronze technologies is the movement of peoples
and interaction between sedentary and non-sedentary societies of the Southwest, the sub-
ject of our next discussion. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 10 24 I have hesitated to term these cultures “multi ethnic”, since the meaning of ethnicity in that time and con-
text is a topic fraught with difficulties. My aim is to simply highlight the coexistence of peoples in the Southwest
with distinct characteristics (at least as represented in their art) as opposed to cultures where one ethnic group is
dominant to the apparent exclusion of others 25 Hanshu 95.3837. The Hanshu provides a detailed description of the different social and cultural groups in the
Southwest. Research into the identity of these groups is both complex and inconclusive. On the Di and Qiang in
the Southwest, see Wang 1992, 1999. Early societies in the Southwest In our attempt to understand the Southwest’s population during the period of our exam-
ination, we have to rely on information from later textual sources, such as the Hanshu,
which mentions the complex amalgam of ethnic groups in the region before its conquest
by Qin and Han forces. While these accounts are from a later period, they nevertheless
provide us with valuable insight into the complex nature of societies in the region in earl-
ier times, a situation that continues to exist to this day.24 The many ethnic tribes who
subsisted in different ways are described in the Hanshu as follows: ［西南］夷君長以十數, 夜郞最大。其西, 靡莫之屬以十數, 滇最大。自滇以北, 君
長以十數, 邛都最大。此皆椎結, 耕田, 有邑聚。其外, 西至桐師以東, 北至葉楡, 名
為巂、昆明, 編髮, 隨畜移徙, 亡常處, 亡君長, 地方可數千里。自巂以東北, 君長以
十數, 徙、莋都最大。自莋以東北, 君長以十數, 冉駹最大。其俗, 或土著, 或移
徙。在蜀之西。自駹以東北, 君長以十數, 白馬最大, 皆氐類也。此皆巴蜀西南外
蠻夷也。 There are dozens of chiefs ruling amongst the Yi (Southwest) barbarians, but Yelang
amongst them is the greatest. To the West of Yelang live the chiefs of Mimo in their
dozens, amongst them the Dian are the greatest (or most important). North of the
Dian there are dozens of chiefs and amongst them the Qiongdu are the greatest
(or most important). All of these tribes wear their hair in the mallet-shaped fashion,
work the fields and gather in their own cities and settlements. Beyond them, in the
West from Tongzhi going East, to the north one reaches Yeyu where all the tribes are
called Sui and Kunming. People here braid their hair, move from place to place fol-
lowing their herds of domestic animals, and do not have a fixed place to live and
chieftains. Their land measures several thousand li. From Sui heading towards the
north-east there are dozens of chiefs amongst whom the Xi and Zuodu are the great-
est (or most important). Northeast of Zuo, there are a dozen of chiefs amongst which
the Ran and Mang are the greatest (or most important). Their custom include those
who are settled on the land and those who move about from place to place. Their
territory is west of Shu. Northeast of Ran and Mang there are a dozen of chiefs
amongst which the Baima are the greatest (or most important). They all belong to
the category of the Di tribe. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Early societies in the Southwest These are all the foreign Yi barbarian groups of the
Southwest of Ba and Shu.25 Collectively called the Southwestern Yi (Xinan Yi 西南夷), inhabitants of the Southwest
were ethnically, culturally, linguistically and in their appearance distinguished from the
Han in early historiography, with a clear separation of “us” versus “them” or “civilized”
versus “barbarian”. While they may be called various names in different sources, the
Southwest’s indigenous population can be broadly divided into three different economic
and cultural groups. Those working the fields and tied to their land, such as the Yelang,
the Dian and the Qiongdu; those with a nomadic lifestyle included the Sui and the
Kunming; and those leading a semi-nomadic semi-agricultural existence were the Xi, Collectively called the Southwestern Yi (Xinan Yi 西南夷), inhabitants of the Southwest
were ethnically, culturally, linguistically and in their appearance distinguished from the
Han in early historiography, with a clear separation of “us” versus “them” or “civilized”
versus “barbarian”. While they may be called various names in different sources, the
Southwest’s indigenous population can be broadly divided into three different economic
and cultural groups. Those working the fields and tied to their land, such as the Yelang,
the Dian and the Qiongdu; those with a nomadic lifestyle included the Sui and the
Kunming; and those leading a semi-nomadic semi-agricultural existence were the Xi, 24 I have hesitated to term these cultures “multi ethnic”, since the meaning of ethnicity in that time and con-
text is a topic fraught with difficulties. My aim is to simply highlight the coexistence of peoples in the Southwest
with distinct characteristics (at least as represented in their art) as opposed to cultures where one ethnic group is
dominant to the apparent exclusion of others. 25 Hanshu 95.3837. The Hanshu provides a detailed description of the different social and cultural groups in the
Southwest. Research into the identity of these groups is both complex and inconclusive. On the Di and Qiang in
the Southwest, see Wang 1992, 1999. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS BSOAS BSOAS 11 the Zuodu, the Ran and Mang. All these are subgroups of the Di and the Qiang who were
important groups in early migration. Early societies in the Southwest Interestingly, a possible ethnic relatedness between
the Qijia in the north, mentioned earlier, and the Qiang ethnic peoples in the west and
southwest, may be seen when we look at the burial practices of these two groups. The
discovery of cremated burials in the Qijia site of Mogou 魔沟in Gansu province confirms
the use of cremation by the Qijia in the Bronze Age. The Lüshi chunqiu 呂氏春秋(The
Spring and Autumn [Annals] of Mr Lü) compiled by Lü Buwei 呂不韋(c. 290–235 BC) men-
tions how the Qiang also used cremation as a form of burial ritual. According to this
text, when captured, the Qiang did not grieve for their relations but were anguished at
the notion that they were not going to be cremated.26 More specifically, the discovery
of the custom of piling white stones in Qijia burials, a practice continued to this day
by the Qiang, further confirms a cultural connection between the two (Guedes and
Aldenderfer 2020: 369). The link between the Qijia and the Qiang is significant, especially
in the context of the early dissemination of bronze technologies and production. As men-
tioned earlier, northern pastoralists would have made their way along the eastern rim of
the Tibetan Plateau to the metal-rich Southwest in order to obtain necessary raw material
for their craft. Their nomadic way of life facilitated long-distance travel and, with their
advanced metalworking abilities and trading skills, as well as bringing highly valued
domesticated animals, such as horses, they were invaluable to societies in the region. y
g
Another group of significance for this overview are the Sui people (mentioned above)
who led a nomadic form of existence in the area of Yuexi 越雟, located in the northwest
territories of Yunnan province and along the eastern borderland of the Tibetan Plateau
(Huang 2020).27 The Sui played an intermediating role in the Southwest’s cultural exchange,
forming relations with societies along a “Crescent-Shaped Cultural-Communication Belt”, a
term coined by the late historian Tong Enzheng (1935–1997) (Huang 2020: 101). Tong
explains how a crescent-shaped belt, containing territories stretching from northeast and
northwest China, along the Tibetan borderlands to Yunnan in the southwest, formed a far-
reaching network of exchange across an area where parallel practices and cultural traits
may be found due to similarities in ecological, topographical and typological conditions. 26 Lüshi chunqiu xin jiaoshi (氐羌之民，其虜也，不憂其係纍，而憂其死不焚也；皆成乎邪也). For the
importance and meaning of the act of piling white stones in Qiang culture, see Su 2018: 291.
27 Yuexi commandery was established in 111 BCE on the orders of Emperor Wu. The character 雟may be read
as sui or xi. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 27 Yuexi commandery was established in 111 BCE on the orders of Emperor Wu. The character 雟may be re
sui or xi. 26 Lüshi chunqiu xin jiaoshi (氐羌之民，其虜也，不憂其係纍，而憂其死不焚也；皆成乎邪也). For t
portance and meaning of the act of piling white stones in Qiang culture, see Su 2018: 291. Early societies in the Southwest Along this belt different social economies were formed, with a high degree of migration,
fusion and exchange between various cultural groups that had similar needs and material
conditions (Tong 1990: 266–7). The Sui are known to have utilized the network of passages
across the eastern part of the Tibetan Plateau within the belt. For example, Kazuo Miyamoto
sees the emergence of bronze working in the Southwest as a direct result of the active
exchange that took place between the Sui and other social groups, including those from
the northern steppe. He notes how this exchange is reflected in the shared artistic forms
and the use of the lost-wax technique seen in the region’s metallurgy (Miyamoto 2014:
79–80). Miyamoto’s examination of the contents of grave sites along the upper and middle
Yalong River 雅礱江in the eastern rim of the Tibetan Plateau confirms that the bronze
objects found there originated from northwest China, today’s Gansu and Qinghai provinces,
and date to the fifteenth–twelfth centuries BCE, a period considerably earlier than formerly
ascribed to the first bronze culture in the region and which predates interaction with the
Zhou cultural sphere of the ninth–eighth centuries BCE (Miyamoto 2014). Significantly for
our study here, these finds are dated slightly earlier than the Sanxingdui culture of the
Chengdu Plain and proposes that the beginnings of the Southwest’s bronze tradition may https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 12 well have developed not only earlier but independently from the Shang and Zhou practices,
and that it is connected with the bronze working cultures of the north and northwest. One part of the “Crescent-Shaped Cultural-Communication Belt” is the “Tibetan-Yi
Corridor” mentioned first by Fei Xiaotong in his examination of early migration move-
ments in the Southwest. 28 See Fei 1982, in which the author uses the label “Tibetan-Yi Corridor” because in China today the Tibetan
and Yi peoples are the two most populous groups in the corridor. This corridor is also known as the
Tibeto-Burman Corridor which reflects more accurately its ethnic connotation. For further information, see
Shuo 2018: 2, and Feuchtwang et al. 2010: 904. Early societies in the Southwest Fei notes how the Qiang and Di played a key role along this cor-
ridor, spreading from eastern Qinghai and southwestern Gansu in the north through to
western Sichuan and northwestern Yunnan in the southwest.28 Over a period of time,
stretching from the late Neolithic to the Bronze Age, these peoples relocated southwards,
first establishing a number of relatively large settlements along the Upper Mekong, Dadu
大渡and Min 岷rivers in the northern part of the “Tibetan-Yi Corridor”, forming a
mature and prosperous culture, and thereafter migrating further south along the river
valleys and establishing exchange and relations with the population of the Yangtze
River basin and in southwestern and central Yunnan (Shuo 2018: 4). In summary, we see three aspects that are key to the development of early bronze cast-
ing traditions in the Southwest: first, the movement and flow of peoples from the north-
west and northern regions along the “Crescent-Shaped Cultural-Communication Belt” and
the “Tibetan-Yi Corridor”; second, the multi-ethnic nature of societies who relied on trade
and interaction with each other for their livelihood; and third, the availability of precious
metal ore in the region for the development of its metalworking tradition. It may also be
said that different societies in the Southwest appear to have coexisted with each other. Their presence may be seen in the many artefacts discovered at the sites of
Sanxingdui, Jinsha and Dian, which is examined below. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom g
y p
As already mentioned, some scholars are keen to emphasize the nature of the
Sanxingdui culture as one that evolved against the backdrop of developments in
Central China. According to Jay Xu, the century from 1300 to 1200 BCE was marked by
regional diversification (commonly referred to by archaeologists as the “transition per-
iod”) and China’s Bronze Age civilization spread out from the Central Plains and diversi-
fied regionally over the next three centuries (Xu 2001a: 27–8). Although the Sanxingdui
finds are accepted to be radically different, and as such represent a unique culture that
is in sharp contrast with that of the Central Plains, it is nevertheless suggested that
there was heavy borrowing and importing from the middle Yellow River valley, the mid-
dle Yangtze valley and the northern region of modern day Gansu and Shaanxi provinces. Advocates of this theory see this as the ultimate source for Sanxingdui’s bronze casting
technology (Xu 2001a: 32). We shall return to this theory after a brief examination of
the Jinsha and Dian sites below. The settlement at Jinsha, discovered in 2001, occupies an area of about 3 square kms
and is believed to be contemporaneous with the late Shang to the early Western Zhou
periods (Zhu et al. 2003: 248). The site itself can be divided into four separate areas:
the eastern part reserved for religious and ceremonial activities and workshops; the
south and central areas of a residential nature with a cemetery; and the area in the north-
east was most likely reserved for the elite, as it includes the remains of a large palace
structure. Current scholarship in China considers Jinsha as the political, cultural and eco-
nomic centre of the ancient Shu state in the Chengdu Plain during the late Shang and
Western Zhou periods (Chengdu Municipal Institute of Antiquity and Archaeology 2013:
13). Since its discovery, more than 2,000 artefacts have been unearthed at Jinsha, includ-
ing approximately 40 gold objects, more than 700 bronze items, over 900 jade pieces,
nearly 300 stone carvings and more than 40 ivory and bone artefacts, in addition to a
large number of elephant tusks and approximately 10,000 pottery vessels and sherds
(Zhu et al. 2003: 261). Decorative motifs found on objects include the prominent use of
birds, fish and the sun, all of which are notable features on objects found at
Sanxingdui. he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom The small village of Sanxingdui, where the remains of the ancient city and culture of
Sanxingdui were discovered, is located in today’s Guanghan city 廣漢市. It covers an
area of approximately 10–17 square kms determined by the distribution of walls, founda-
tions and artefacts found since excavations started in 1980. The main finds at the site were
placed in two pits, known as Pit 1 and Pit 2, which were accidentally exposed during exca-
vations in the summer of 1986, and contained hundreds of bronzes, stone and jade imple-
ments, gold objects and elephant tusks (Xu 2001a: 25). Although a further six pits have
been discovered at the site more recently, their contents have not yet been officially pub-
lished. The contents of the original two pits represent the height of a culture that is not
recorded nor was known until this discovery. Some of the findings in the two pits are
highly unusual and fantastic in nature. Bronzes of a kind never seen before include an
impressive human figure over 2.5 metres high, bronze trees soldered with figures and
giant bronze human heads covered with gold foil masks. In addition to finished objects,
the pits also contained raw material, half-finished products and even waste material
and stones used for grinding. These findings suggest the existence of workshops for pro-
ducing stone and jade wares located at the site or nearby; however, no bronze foundry has
been discovered to date (Xu 2001a: 27). Objects in both pits were arranged in a purposeful and orderly fashion, suggesting that
they were intentionally destroyed and not in haste (Chen 1999: 171). Thus it has been sug-
gested that the pits were most likely of a sacrificial ritual nature, which involved either
the strategic renunciation of wealth, as was often the case in ethnographically documen-
ted potlatching behaviour, or the proper disposal of religious objects, an important https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS BSOAS BSOAS 13 procedure for controlling the supernatural power invested in religious objects so that they
do not harm the community. Rowan Flad and Pochan Chen (2013: 213–14) note how the
bronze figures and anthropomorphic heads were almost certainly important ritual objects
used in public display and played critical roles in ritual representation, a feature of
Sanxingdui material culture that sets it distinctly apart from the traditions of North China. 29 Shiji 116.2997 (滇王離難西南夷，舉國降，請置吏入朝。於是以為益州郡，賜滇王王印，復長其民). https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom The decoration of birds and fish pierced by arrows on a gold leaf band
from the Jinsha site is almost identical to that on a gold sheath from Pit 1 at
Sanxingdui. However, most of the objects from Jinsha, especially bronze wares, are
much smaller in size compared to those from Sanxingdui. An example is a bronze
human figure about 20 cm in height standing on a base. With arms stretched out in
the gesture of holding an object, its pose closely resembles some of the magnificent stand-
ing figures from Sanxingdui’s Pit 2. There is little doubt that the Jinsha culture was sub-
stantially derived from, or at least very closely related to, Sanxingdui. It is reasonable to
suggest that Jinsha became a major political, economic and cultural centre on the
Chengdu Plain as a consequence of the collapse of the Sanxingdui site. The discovery of a richly furnished royal tomb at Shizhaishan in December 1956, con-
taining the golden seal of the Dian king, proved the existence of the Dian Kingdom as
recorded in the Shiji. Sima Qian describes how in 109 BCE the chief of the Dian Kingdom
received a gold seal from Emperor Wu, acknowledging its position as a vassal state and
tributary kingdom to the Han.29 The gold seal bears the characters “Seal belonging to
King of Dian (Dian wang zhi yin 滇王之印)”, accurately corroborating Sima Qian’s account https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 14 of events at the time. Our knowledge of the Dian people comes primarily from historical
texts such as the Shiji, Hanshu and the Huayang guo zhi. From these writings it is evident
that the Dian were much advanced in their social and political organization, settled in the
region around the shores of Lake Dian and were led by a ruler with a large following. They
wore their hair pulled up in a mallet-shaped bun, worked the fields and lived in cities and
settlements. Early writings indicate that the wider region around Lake Dian was inhabited
by a number of different ethnic groups (just as today), such as the Sui and Kunming who
braided their hair and subsisted on pastoralism, moving around with their herds and lead-
ing a nomadic life without a fixed place or, according to the texts, a chieftain. They were
part of the Di tribe who led a semi-nomadic lifestyle. he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom The Di lived primarily in the high-
lands near the Jinsha River in the west, northwest of the Mimo territory. The Mimo were a
confederation of ethnic groups who were settled in the region corresponding to today’s
southern Sichuan, eastern Yunnan and western Guizhou.30 According to records in the Hanshu, the first king of Dian derived originally from the
state of Chu 楚國who settled in the region, taking over their custom and habits and
becoming their ruler prior to the invasion of the Qin. Events from this time are documen-
ted as follows: 始楚威王時, 使將軍莊蹻將兵循上, 略巴、黔中以西。莊蹻者, 楚莊王苗裔也。蹻
至滇池, 方三百里, 旁平地肥饒數千里, 以兵威定屬楚。欲歸報, 會秦擊奪楚巴、
黔中郡, 道塞不通, 因乃以其眾王滇, 變服, 從其俗, 以長之。 始楚威王時, 使將軍莊蹻將兵循上, 略巴、黔中以西。莊蹻者, 楚莊王苗裔也。蹻
至滇池, 方三百里, 旁平地肥饒數千里, 以兵威定屬楚。欲歸報, 會秦擊奪楚巴、
黔中郡, 道塞不通, 因乃以其眾王滇, 變服, 從其俗, 以長之。 In earlier times, when King Wei ruled the state of Chu, he dispatched his general
Zhuang Qiao to lead an army along the upper reaches of the Yangtze River and
invade west of Ba and Qianzhong commanderies. This Zhuang Qiao was a descendant
of King Zhuang of Chu. Zhuang advanced reaching the Lake of Dian, a body of water
of 300 li in circumference surrounded by several thousand li of fertile rich flatland. By means of his military might he subdued the region and brought it under Chu rule. Zhuang Qiao wished to return to report his achievements but encountered the Qin
army that attacked Chu and seized the commanderies of Ba and Qianzhong and
blocked the road not allowing him to pass through. Because of this he returned to
Lake Dian and with the men under his command he made himself King of Dian. He changed his clothes and followed the Dian custom and acted as their chief.31 There is an argument made for some possible Chu influence in Dian art, such as the use of
bronze drums that appear to have been vital to both cultures; however, the greater part of
Dian material draws from the indigenous cultures of the Southwest, borrowing from those
who had migrated down the narrow mountain passes of Sichuan and the corridors of the
Tibetan Plateau (Mei 2009: 12). It is a culture of a multifaceted hybrid society of pastoral
nomads and sedentary agriculturalists with mixed economies, lifestyle, customs and tra-
ditions. In the arts of the Dian, nomadic steppe influence may be seen in the prevalence of
animal combat scenes on plaques (Figures 2–3). 30 See Hanshu 95.3837 on the different categories of ethnic population in the region.
31 Hanshu 95.3838. 31 Hanshu 95.3838. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom However, Dian artists presented this kind
of subject matter in a more natural fashion, stripping away some of the opulence created
through gilding and precious stone inlay characteristic of the northern steppe tradition. The composition of Dian animal sculptures is, on the whole, well balanced and extremely
detailed, displaying the craftsman’s understanding of the subject matter (Li 1999: 156). p y
g
g
j
Among some of the most striking Dian bronze ritual objects are the bronze kettle-
drums, typical of the rice-cultivating cultures of Southeast Asia, which included the https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS
15 BSOAS 15 Figures 2 (left) and 3 (right). Bronze plaques depicting scenes of animal combat, Western Han period (206 BCE–
24 CE), excavated from Shizhaishan (left) and Lijiashan (right), Yunnan. Yunnan Provincial Museum, Kunming. Images
reproduced with permission from the Yunnan Provincial Museum. Figures 2 (left) and 3 (right). Bronze plaques depicting scenes of animal combat, Western Han period (206 BCE–
24 CE), excavated from Shizhaishan (left) and Lijiashan (right), Yunnan. Yunnan Provincial Museum, Kunming. Images
reproduced with permission from the Yunnan Provincial Museum. cultures of present-day Myanmar, Thailand and Vietnam. Known as the “Shizhaishan
Drums” or Heger Type I drums, in Dian culture these musical instruments came to be
placed in an inverted position in graves to store precious cowrie shells (Han 1998: 16). Bronze vessels were also made specifically to contain cowrie shells, some of which had
lids decorated with realistic narrative scenes in a three-dimensional form. These bronze
containers show lively genre scenes of warfare, markets, ritual sacrifices, tribute proces-
sions, weaving and other images covering a wide range of subject matter that appears to
document aspects of life in Dian society (Figures 4 and 5a) (TzeHuey 2008: 226). Apart
from cowrie containers and drums, large quantities of agricultural implements and weap-
ons have also been found at the Dian culture sites, many of which contain elaborate dec-
oration, suggesting their use as ritual or grave goods rather than as utilitarian wares
(Zhang 1993). An important aspect to note is the technology used in the production of the Dian
bronzes which suggests a substantial metalworking tradition that existed prior to the
Han conquest. The prevalent use of lost-wax casting, mentioned earlier, is distinct to
Dian. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom Although the technique was familiar in the Shang and Zhou bronze tradition of
the Warring States period (475–221 BCE) and Western Han times, it was not adapted on
a wide scale, certainly not as we see it in Dian, until much later (Peng 2017, 2020). The
fluid and intricate modelling of human figures and animal forms, often in freestanding
relief, is evidence of the use of lost-wax casting. Scholars remain divided on the origins
of lost-wax casting in the Southwest, with some convinced that, as no local technical trad-
ition is known, it must have been imported, possibly from the Eurasian Steppe, most likely
with other metallurgical techniques such as tinning, gilding, chasing and inlay (Peng 2017:
18). However, the construction of objects in a piecemeal manner, whereby sculptural fig-
ures and architectural forms are all cast separately and then assembled by the process of
soldering, was also extensively employed at Sanxingdui, suggesting that these techniques
were well established in the wider Southwest region. We see this especially on the bronze
tree which shall be discussed below (Figure 6). Dian bronze casters, perhaps inspired by
their example, created sculptural forms in component parts, but with the use of the lost-
wax technology which allowed more varied and complex designs. Interestingly, after the
Han takeover of the Dian in 109 BCE, characteristic features of Dian art and culture were
completely abandoned. Iron implements and weapons replaced bronze ones, and bronze
vessels were made in imitation of Han models or were imported from the Central Plains to
be placed in tombs (Fong 1980: 327). https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 16
Hajni Elias Hajni Elias 16 Figure 4. Bronze cowrie container showing scene of a
rider with cattle, Western Han period (206 BCE–24 CE),
excavated from Shizhaishan, Yunnan. Yunnan Provincial
Museum, Kunming. Image reproduced with permission
from the Yunnan Provincial Museum. Figure 4. Bronze cowrie container showing scene of a
rider with cattle, Western Han period (206 BCE–24 CE),
excavated from Shizhaishan, Yunnan. Yunnan Provincial
Museum, Kunming. Image reproduced with permission
from the Yunnan Provincial Museum. Figures 5a and 5b (detail). Bronze cowrie container with scene depicting a ritual offering, Western Han period
(206 BCE–24 CE), excavated from Shizhaishan, Yunnan. Yunnan Provincial Museum, Kunming. Image reproduced with
permission from the Yunnan Provincial Museum. Figures 5a and 5b (detail). he Sanxingdui and Jinsha cultures and the ancient site of the Dian Kingdom Bronze cowrie container with scene depicting a ritual offering, Western Han period
(206 BCE–24 CE), excavated from Shizhaishan, Yunnan. Yunnan Provincial Museum, Kunming. Image reproduced with
permission from the Yunnan Provincial Museum. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS
17 BSOAS
17 Figure 6. Bronze tree, twelfth century BCE, excavated from Sanxingdui Pit
2, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with
permission from the Sanxingdui Site Museum. BSOAS
17 Figure 6. Bronze tree, twelfth century BCE, excavated from Sanxingdui Pit
2, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with
permission from the Sanxingdui Site Museum. Figure 6. Bronze tree, twelfth century BCE, excavated from Sanxingdui Pit
2, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with
permission from the Sanxingdui Site Museum. Figure 6. Bronze tree, twelfth century BCE, excavated from Sanxingdui Pit
2, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with
permission from the Sanxingdui Site Museum. 33 See Su et al. 2018: 157, where the authors explain how Carlin-type gold deposit, named after a type of gold
found in Carlin, Nevada, may be characterized by being an invisible gold that can only be found through chemical
analysis. 32 See So and Bunker 1995 for illustrations of artefacts from the northern steppe cultures decorated in gilt and
made of gold.
33 See Su et al 2018: 157 where the authors explain how Carlin-type gold deposit named after a type of gold 32 See So and Bunker 1995 for illustrations of artefacts from the northern steppe cultures decorated in gilt and
made of gold.
33 See Su et al. 2018: 157, where the authors explain how Carlin-type gold deposit, named after a type of gold
found in Carlin, Nevada, may be characterized by being an invisible gold that can only be found through chemical https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 32 See So and Bunker 1995 for illustrations of artefacts from the northern steppe cultures decorated in gilt and
made of gold.
33 See Su et al. 2018: 157, where the authors explain how Carlin-type gold deposit, named after a type of gold
found in Carlin, Nevada, may be characterized by being an invisible gold that can only be found through chemical
analysis. Continuity and parallels Figures covered in gold leaf are
also a distinct feature of Dian bronzes. Some of the prominent figures in scenes welded
on to the lids of cowrie containers are wrapped in gold leaf. A particularly fine example
is found on the cover of a bronze container with a large gilded figure on horseback sur-
rounded by cattle (see Figure 4). The composition is not only impressive for its sculptural
style, but the gold leaf draws the viewer’s attention to the rider, marking his form with a
sense of importance and luxury. p
y
The stylistic preference for the use of sculptural components that are welded onto ves-
sels and ritual objects, mentioned earlier, may be seen on Sanxingdui and Dian bronzes. Pre-eminent examples are the bird ornaments that formed part of the “spirit tree” exca-
vated from Sanxingdui (see Figure 6). A tree from Pit 2 consists of at least a hundred sep-
arate compositions, mostly made in two-part moulds then joined and cast together. This
impressive tree-form sculpture has nine branches attached to the trunk in groups of three
with each branch bearing blooming flowers at the top of its arc and a bird seated on it. Jay
Xu suggests that the bronze tree must have been heavily decked with movable pendants
and ornamental components in various media at some stage, hanging from the branches
or from the beaks of the birds (Xu 2001b: 118). There are conflicting opinions on the use of
this fascinating bronze object, with some suggesting that it was made for display on a sac-
rificial altar as an embodiment of worship, while others propose that it was developed by
the ancient Shu people and is linked to their legendary “cosmic tree”. In Shu culture birds
were regarded as symbolic of the sun and thus composites of this type may have been
seen as tools of communication between Heaven and Earth (Sanxingdui Museum 2006:
69–70). The Sanxingdui tree may have also been the precursor for the later, Eastern
Han period (25–220 CE) bronze trees known as “money trees” discovered in tombs in
Sichuan.34 The technique of soldering different components onto a main bronze piece and creat-
ing a complex composition of multiple parts is described by some as unlike anything ever
attempted in the Central Plains (Xu 2001b: 62). Continuity and parallels It has been suggested that bronze casters of the bronze casting tradition of Sanxingdui
were in close touch with Shang centres, evidenced by the presence in the pits of bronzes
of common Shang shapes made in North China since Erligang times (c. 1500–1300 BCE)
(Pirazzoli-t’Serstevens 1990: 52). Although there may well have been contact and influence
from northern and Central China, such a Sinocentric view can obscure the important con-
nection between the different cultures of the Southwest. A number of distinctive features
and artistic preferences that are not mainstream in the early bronze tradition of Central
China are evident in the arts of the Southwest. For example, the employment of gold leaf
decoration is a common feature seen in Sanxingdui, Jinsha and Dian but was rarely (if
ever) used in the Central Plains’ bronze tradition. The practice of employing gold on
bronze wares is most likely to have derived from the influence of the northern steppe cul-
tures where gold and the technique of gilding was readily employed for the decoration of
small objects, such as jewellery, ornaments and plaques.32 On the sourcing of gold ore,
scholars have noted how the western part of Yunnan is particularly rich in copper, tin,
iron, lead and gold, much of which was exploited from early times (Zhang 1954). To
this day, the junction of Yunnan, Guizhou and Guangxi provinces is known as the
“Golden Triangle” as it has one of the largest concentrations of Carlin-type gold deposits
in the world (Su et al. 2018: 157).33 Six of the bronze heads from Pit 2 at Sanxingdui have
mask coverings made of gold leaf. Gold leaf about 0.2 mm thick was pressed against the https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 18 bronze head and rubbed to make it adhere to the surface. The gold mask covered the
entire face expect for the eyes and eyebrows. The use of gold undoubtedly enhanced
the value of the object, which may have had other religious or auspicious connotations,
perhaps associated with local sun worshipping traditions (Bagley 2001: 91). The employment of gold leaf as a decorative technique remained a popular choice for
the people at Jinsha where an especially large number of gold artefacts have been
unearthed. Gold was used for jewellery and for the making of masks, although substan-
tially smaller in scale compared to those at Sanxingdui. 34 On Eastern Han money trees, see Su 2004, He 2006 and Erickson 1994. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Representations of social groups The bronze culture of the Southwest was the outcome of the merging of different bronze
production technologies and cultures, most likely influenced by the migration of peoples
over many centuries who brought their skills and know-how with them (Han and Li 2009:
170). Among Sanxindui bronze heads there is a clear distinction between those that have
their hair pleated and those who do not. These are stylistic markers that may have been
intended to set apart groups of different ethnic or social status, or perhaps both. We have
already noted how early texts described the Di and Qiang peoples as wearing their hair in
mallet-shaped buns, while the Sui and Kunming wore theirs in plaits. These texts go fur-
ther in their demarcation of distinctive traits such as clothing, noting on which side it is
buttoned, and body features that include the presence of tattoos and facial hair. What
seems apparent is that a number of the distinctive traits – a particular hairstyle, a tattoo,
a mode of dress, a type of hat or piece of personal adornment – were used by bronze
makers at Sanxingdui to distinguish between different peoples (Peters 2002: 86). g
g
p
p
(
)
So who were those memorialized on Sanxingdui bronzes? A bronze head discovered in
Pit 1 is a comparatively realistic modelling of a face that sets it apart from more stylized
heads. It shows a hairline that is clipped straight across the back of the head and pulled
back into a bun under a headdress that is now lost (Figure 7). However, a different hair-
style may be seen on another head from Pit 2, where the hair is formed into a long pigtail
at the back (Figures 8a–b). There are further examples where headdresses are cast with
the head in a number of styles and shapes. Square tall-form caps appear to be common,
such as the example decorated with a pattern of rectangular spiral design seen on a head
from Pit 2 (Figure 9) where the hair is tied up in a bun under the cap. Another type of
headdress is the distinct braided crown or garland seen on a head from Pit 2
(Figure 10). Continuity and parallels On the casting of the many birds standing
on flowers hanging from the tree branches, scholars note how a metal worker from
Anyang would probably have cast the bird in one piece, using a complex mould, while
the Sanxingdui caster seems to have cast it in four separate pours of metal, each made
of a simple two-part mould. The bird’s wings were joined onto its shoulders, its head
attached to its neck by a collar of solder and solder beneath its claws joins it to the flower
on which it stands (Xu 2001b: 62). A more developed form of the technique seen on
Sanxingdui bronzes for the placement of sculptural components may be seen on Dian
bronzes where lost-wax casting was employed for this purpose. The raison d’être for lost-
wax casting is to produce complex shapes that are impossible or difficult to make by
piece-mould casting as seen at Sanxingdui. Some of the most realistic and highly three-
dimensional bronzes in lost-wax casting were made by Dian craftsmen who, as mentioned
earlier, are likely to have acquired their skills from the nomadic steppe cultures that read-
ily employed different metallurgical techniques in their art (Peng 2017: 18). Tzehuey
Chiou-Peng notes how perceptible signs of incipient copper-based metallurgical activities https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS BSOAS BSOAS 19 at second-millennium sites in western and northwestern Yunnan point to steppe-related
cultures as the source for the inspiration of metallurgical activities in other parts of the
region, which commenced during the latter part of the second millennium BCE. The arrival
of metallurgical technology revolutionized the tool-making industry in the region, and
knowledge of metal production and the making of artefacts were also disseminated
through interconnected valleys and flat lands along the eastward-flowing Jinsha River
(Tzehuey 2009: 83). It is worth noting that Tzehuey’s dating coincides with the height
of the Sanxingdui culture, which suggests the existence of a direct transmission route
from Sichuan where similar stylistic choices were made in the use of sculptural ornamen-
tation. Dian craftsmen were aided by imported metallurgical know-how but were also cre-
atively selective in their employment of different and unusual techniques that had a more
localized origin. Apart from the use of lost-wax casting, they also incised bronzes with
sharp tools as evident from the excavated bronze tally plaque mentioned earlier
(Whitfield and Wang 1999: 154–5). https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Representations of social groups Image reproduced with permission from the Sanxingdui Site Museum Figure 7. Bronze head, thirteenth–twelfth century BCE, excavated
from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site Museum gold leaf, with his hair tied in a topknot and dressed in a distinctive cloak over trousers on
the lid of a cowrie container (see Figure 4). A member of the Kunming with loose hair may
be seen on the cover of another cowrie container decorated with a scene of sacrificial
offering and ritual celebration (see Figures 5a–b). Following Wang’s explanation, this per-
son should be a prisoner or a war victim. However, in the same scene we see another male
figure with his hair in a bun tied to a post, perhaps waiting to be sacrificed or punished. The theory that those wearing their hair in a bun represent the Dian elite is therefore
problematic. A cowrie container decorated with a scene of 17 figures dressed in different
styles of costumes and wearing their hair in varying ways is a good example of the range
of appearance across societies in the region (Figures 11 a–b). A line drawing of the scene
(see Figure 11b) illustrates the distinctive hats, turbans and even a type of headdress with
an ornament attached to the front. Hair may be seen worn pulled up in a bun or left long
in plaits in the back. Both hairstyles are worn by figures of apparent status, carrying
Image reproduced with permission from the Sanxingdui Site Museum
Figures 8a and 8b. Bronze head,
twelfth century BCE, excavated from
Sanxingdui
Pit
2,
Guanghan
Sanxingdui Site Museum, Sichuan. Images reproduced with permission
from the Sanxingdui Site Museum. Figures 8a and 8b. Bronze head,
twelfth century BCE, excavated from
Sanxingdui
Pit
2,
Guanghan
Sanxingdui Site Museum, Sichuan. Images reproduced with permission
from the Sanxingdui Site Museum. Figures 8a and 8b. Bronze head,
twelfth century BCE, excavated from
Sanxingdui
Pit
2,
Guanghan
Sanxingdui Site Museum, Sichuan. Images reproduced with permission
from the Sanxingdui Site Museum. Figures 8a and 8b. Bronze head,
twelfth century BCE, excavated from
Sanxingdui
Pit
2,
Guanghan
Sanxingdui Site Museum, Sichuan. Images reproduced with permission
from the Sanxingdui Site Museum. gold leaf, with his hair tied in a topknot and dressed in a distinctive cloak over trousers on
the lid of a cowrie container (see Figure 4). Representations of social groups Below the garland the hairline is indicated all the way around the head,
clipped short over the forehead, trimmed to modest sideburns at the temples and des-
cending at the back as far as the bottom of the ear (Bagley 2001: 100). The multi-ethnic make up of the Dian Kingdom is represented in the variety of figures
portrayed on the many bronze drums and cowrie receptacles which differentiate between
a number of ethnic or social groups. Wang Ningsheng has analysed Dian figures on the
basis of their hairstyle and costumes, labelling those with their hair tied up in a bun
as the dominant population in the Dian region and thus members of “the kinds of
Me-mo” (better known as the Mimo), and others with braided or loose hair belonging
to “the kinds of Kun-Ming” (better known as the Kunming) (Wang 1979). An example
of a typical Dian figure of the Mimo type is the rider on horseback, decorated with Figure 7. Bronze head, thirteenth–twelfth century BCE, excavated
from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site Museum
20
Hajni Elias 20
Hajni Elias Hajni Elias 20 gold leaf, with his hair tied in a topknot and dressed in a distinctive cloak over trousers on
the lid of a cowrie container (see Figure 4). A member of the Kunming with loose hair may
be seen on the cover of another cowrie container decorated with a scene of sacrificial
offering and ritual celebration (see Figures 5a–b). Following Wang’s explanation, this per-
son should be a prisoner or a war victim. However, in the same scene we see another male
Figure 7. Bronze head, thirteenth–twelfth century BCE, excavated
from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site Museum
Figures 8a and 8b. Bronze head,
twelfth century BCE, excavated from
Sanxingdui
Pit
2,
Guanghan
Sanxingdui Site Museum, Sichuan. Images reproduced with permission
from the Sanxingdui Site Museum. head, thirteenth–twelfth century BCE, excavated
it 1, Guanghan Sanxingdui Site Museum, Sichuan. with permission from the Sanxingdui Site Museum Figure 7. Bronze head, thirteenth–twelfth century BCE, excavated
from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site Museum Figure 7. Bronze head, thirteenth–twelfth century BCE, excavated
from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Representations of social groups A member of the Kunming with loose hair may
be seen on the cover of another cowrie container decorated with a scene of sacrificial
offering and ritual celebration (see Figures 5a–b). Following Wang’s explanation, this per-
son should be a prisoner or a war victim. However, in the same scene we see another male
figure with his hair in a bun tied to a post, perhaps waiting to be sacrificed or punished. The theory that those wearing their hair in a bun represent the Dian elite is therefore
problematic. A cowrie container decorated with a scene of 17 figures dressed in different
styles of costumes and wearing their hair in varying ways is a good example of the range
of appearance across societies in the region (Figures 11 a–b). A line drawing of the scene
(see Figure 11b) illustrates the distinctive hats, turbans and even a type of headdress with
an ornament attached to the front. Hair may be seen worn pulled up in a bun or left long
in plaits in the back. Both hairstyles are worn by figures of apparent status, carrying gold leaf, with his hair tied in a topknot and dressed in a distinctive cloak over trousers on
the lid of a cowrie container (see Figure 4). A member of the Kunming with loose hair may
be seen on the cover of another cowrie container decorated with a scene of sacrificial
offering and ritual celebration (see Figures 5a–b). Following Wang’s explanation, this per-
son should be a prisoner or a war victim. However, in the same scene we see another male
figure with his hair in a bun tied to a post, perhaps waiting to be sacrificed or punished. The theory that those wearing their hair in a bun represent the Dian elite is therefore
problematic. A cowrie container decorated with a scene of 17 figures dressed in different
styles of costumes and wearing their hair in varying ways is a good example of the range
of appearance across societies in the region (Figures 11 a–b). A line drawing of the scene
(see Figure 11b) illustrates the distinctive hats, turbans and even a type of headdress with
an ornament attached to the front. Hair may be seen worn pulled up in a bun or left long
in plaits in the back. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Representations of social groups Both hairstyles are worn by figures of apparent status, carrying https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS
21 BSOAS
21 Figure
9. Bronze
head,
thirteenth–twelfth
century
BCE,
Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site
Museum. Figure
9. Bronze
head,
thirteenth–twelfth
century
BCE,
Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site
Museum. Figure
9. Bronze
head,
thirteenth–twelfth
century
BCE,
Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum, Sichuan. Image reproduced with permission from the Sanxingdui Site
Museum. Figure 10. Bronze head thirteenth–twelfth century BCE, exca-
vated from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. Figure 10. Bronze head thirteenth–twelfth century BCE, exca-
vated from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. Figure 10. Bronze head thirteenth–twelfth century BCE, exca-
vated from Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. swords suspended from their sides with a shoulder strap. There is an air of ceremonial
formality to the scene, lending credence to the theory that this is a procession expressing
fealty (Peters 2002: 95). Finally, a small bronze figure of a kneeling man from Pit 1 at Sanxingdui may be iden-
tified as “special” for its unusual hairstyle, with the front fringe combed back but then
swept into a curl in reverse (Figure 12). The figure is dressed in a robe with distinct striped
cuffs. Remarkably, centuries later, the same unusual hairstyle may be found on figures
depicted on Dian bronze plaques, an example of which is a scene of three male figures https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press 22
Hajni Elias Hajni Elias 22 Figures 11a and 11b. Bronze cowrie container with scene depicting a procession of tribute bearers, with a line
drawing showing detail, Western Han period (206 BCE–24 CE), excavated from Shizhaishan, Yunnan Provincial
Museum, Kunming. Image reproduced with permission from the Yunnan Provincial Museum; line drawing by the
author. Figures 11a and 11b. Bronze cowrie container with scene depicting a procession of tribute bearers, with a line
drawing showing detail, Western Han period (206 BCE–24 CE), excavated from Shizhaishan, Yunnan Provincial
Museum, Kunming. Representations of social groups Image reproduced with permission from the Yunnan Provincial Museum; line drawing by the
author. Figure 12. Bronze seated human figure, thirteenth–twelfth cen-
tury BCE, Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. leading a bull (Figure 13). All three figures wear their hair in a similar fashion and are
clothed in robes and wear striped cuffs, reminiscent of the Sanxingdui figure and suggest-
ive that this type of hairstyle and attire may have been worn by a specific group of people
over a long period of time. d
if i
l
h i
b
d
d
i
i
f
d i
l
l
Figure 12. Bronze seated human figure, thirteenth–twelfth cen-
tury BCE, Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. Figure 12. Bronze seated human figure, thirteenth–twelfth cen-
tury BCE, Sanxingdui Pit 1, Guanghan Sanxingdui Site Museum,
Sichuan. Image reproduced with permission from the Sanxingdui
Site Museum. leading a bull (Figure 13). All three figures wear their hair in a similar fashion and are
clothed in robes and wear striped cuffs, reminiscent of the Sanxingdui figure and suggest-
ive that this type of hairstyle and attire may have been worn by a specific group of people
over a long period of time. Identifying early ethnic groups based on descriptions found in early textual sources
may not be possible as these texts are often prejudiced and restricted in their views. As noted by Heather Peters (2002: 98), the nature of ethnicity is subjective, flexible and
dynamic, and is better expressed in terms of the ethnic identities or ethnic roles a https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press BSOAS
23 BSOAS 23 particular group holds or plays at a particular period in time. What we can say about the
variety of visual representations in the arts we have examined is that societies in the
Southwest were made up of a rich mixture of peoples, even if their precise identification
is not possible. Figure 13. Bronze plaque with a
scene showing three men and an
ox, Warring States period (475–
221
BCE),
Yunnan
Provincial
Museum, Kunming. Image repro-
duced with permission from the
Yunnan Provincial Museum. Figure 13. Bronze plaque with a
scene showing three men and an
ox, Warring States period (475–
221
BCE),
Yunnan
Provincial
Museum, Kunming. Representations of social groups Image repro-
duced with permission from the
Yunnan Provincial Museum. particular group holds or plays at a particular period in time. What we can say about the
variety of visual representations in the arts we have examined is that societies in the
Southwest were made up of a rich mixture of peoples, even if their precise identification
is not possible. particular group holds or plays at a particular period in time. What we can say about the
variety of visual representations in the arts we have examined is that societies in the
Southwest were made up of a rich mixture of peoples, even if their precise identification
is not possible. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Concluding remarks Examining the three sites of Sanxingdui, Jinsha and Dian, this article set out to explore
some of the possible traits and influences that may have connected them over time
and geography. It has been argued that the ancient network of trading routes known
as the Southwest Silk Road played a key role not only in the transmission of commodities
and goods, but also that the movement of people, especially those with established metal-
lurgical technologies, had a special part in the development of bronze cultures in the
Southwest. Secondly, the multi-ethnic nature of the Southwest, inherent in its topog-
raphy, was a significant factor in the transmission and sharing of culture, art and technol-
ogy, in particular bronze metallurgy. The employment of a new technological system, that
is, the lost-wax production and the use of multiple sculptural components, born out of
established practices but advanced independently in order to produce the desired effect,
reflect exceptional workmanship and is distinct to the Southwest. Thirdly, the Tibetan-Yi
corridor inhabited by nomadic and semi-nomadic peoples with long-standing connections
with the steppe cultures in Central Asia probably contributed to the development of
bronze technology in the Southwest. This corridor seems to be a likely, or likelier,
route for transmission to the Southwest than that conventionally assumed from the
Central Plains of China. Finally, the richness of the region in scarce minerals such as
lead, gold and especially tin (the rarest constituent in bronze metallurgy) makes the
Southwest a natural place for the development of bronze technology. Given the expertise
provided by the movement of the nomadic and semi-nomadic tribes, with their long-
standing links to the steppe cultures, the appearance of distinctly local metallurgical cul-
tures should not surprise anyone. y
Many of the ideas presented in this article suggest the need for further investigation. Any substantial bronze culture needs not only the knowledge and practice of bronze min-
ing, metallurgy and casting, but also the resources and organization to support and man-
age it. Although steppe cultures may have had the technical know-how, it was only when
they came into contact with sedentary societies with considerable resources that more https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Hajni Elias 24 substantial bronze manufacture was enabled. Primary literature Hanshu 漢書. Compiled by Ban Gu 班固(32–92 CE). Beijing: Zhonghua, 1962. Hanshu 漢書. Compiled by Ban Gu 班固(32–92 CE). Beijing: Zhonghua, 1962. Hou Hanshu 後漢書. Compiled by Fan Ye 范曄(398–445 CE) et al. Beijing: Zhonghua, 1965. Huang guo zhi yizhu 華陽國志譯註(Record of the Kingdoms South of Mount Hua). Compiled p
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)
司馬遷(
) Annotated by Chen Qiyou 陳奇猷. Shanghai: Guji chubanshe, 2002. Shiji 史記Begun by Sima Tan 司馬談(d 112 BCE) primarily composed by Sima Qian 司馬遷(c 145–c 86 BCE) 史記. Begun by Sima Tan 司馬談(d. 112 BCE), primarily composed by Sima Qian 司馬遷(c. 145–c. 86 BCE). ing: Zhonghua, 1959. Beijing: Zhonghua, 1959. Concluding remarks Therefore, an important next step in this
research is to understand more fully the requisite structural features of sedentary soci-
eties that were able to embrace bronze culture successfully in the Southwest. Given the
lack of textual records for the period examined and the uncertainties inherent in
researching and understanding the cultural movements of multi-ethnic peoples, it is
hoped that this article may be regarded as part of a much larger body of study that awaits
further investigation by comparative research. The recent announcement of the discovery of a further six sacrificial pits at
Sanxingdui, reported to contain over 500 artefacts and cultural relics, is exciting news. At the time of writing this article, the archaeological report detailing the new finds
has not been published. It is hoped that the finds will provide new information and evi-
dence that will give further insight into some of the hypotheses discussed in this article. Acknowledgements. I wish to express my deepest gratitude to the Leverhulme Trust for their generous fund-
ing of my research on the Southwest Silk Road. The completion of this article would not have been possible with-
out the support the Trust offered over the past three years. I also wish to thank the two anonymous reviewers of
this journal for their insights and constructive comments which helped greatly improve the content of this art-
icle. In addition, I thank those in the field for the advice I received and my husband, Hugo Macey, for his endless
patience and encouragement. https://doi.org/10.1017/S0041977X24000120 Published online by Cambridge University Press Secondary literature “Xinan sichou zhi lu 西南絲綢之路”, Lishi jiaoxue 8, 15–19. Huang, Wei 黃維. 2020. “Zai lun Dian wenhua de jinshu shijian 再論滇文化的金屬飾件”, Sichuan Cultural Relics 4,
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https://pubs.rsc.org/en/content/articlepdf/2023/ma/d3ma00589e
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English
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Band-gap engineering in methylammonium bismuth bromide perovskites for less-toxic perovskite solar cells
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Materials advances
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a Department of Materials, Loughborough University, Loughborough, LE11 3TU, UK.
E-mail: s.r.pering@lboro.ac.uk
b Loughborough Materials Characterisation Centre, Loughborough, LE11 3TU, UK
c CREST, Loughborough University, Loughborough, LE11 3TU, UK
d Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK
† Electronic supplementary information (ESI) available: Experimental Section
and additional data. CCDC 2265208. For ESI and crystallographic data in CIF or
other electronic format see DOI: https://doi.org/10.1039/d3ma00589e
‡ Current address: WMG University of Warwick, 6 Lord Bhattacharyya Way,
Coventry, CV4 7AL, UK. Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024
This article is licensed under a Creative Commons Attribution 3.0 U Bismuth-based perovskites could be a viable and efficient alternative to lead-based perovskite materials. To widen possible applications, it is necessary to be able to alter the band gap of the absorber material
(i.e. for water splitting or multijunction cells). In this work we show the possibility of colour-
management
in
methylammonium
bismuth
halide
perovskites. When
synthesised
using
DMSO,
methylammonium bismuth bromide is characterised and identified as possessing a zero-dimensional
perovskite type structure with a formula of MA3BiBr6 DMSO solvate, and a band gap of 2.51 eV. An
increasing mole fraction of iodide ions into methylammonium bismuth bromide is shown to produce a
single-phase with a decreasing band gap, with an associated colour change from yellow (2.51 eV) for
methylammonium bismuth bromide to red (1.88 eV) for methylammonium bismuth iodide. The
methylammonium bismuth iodide structure is tolerant to high degrees of bromide substitution, up to
40%, before significant effects in band gap or morphology are observed. Halide substitution was also
found to aid thin-film stability over 10 weeks in air. The insights obtained from this study could provide
additional stability at a reduced cost to lead-free bismuth halide perovskite materials. Received 24th August 2023,
Accepted 27th November 2023
DOI: 10.1039/d3ma00589e
rsc.li/materials-advances Received 24th August 2023,
Accepted 27th November 2023
DOI: 10 1039/d3ma00589e Received 24th August 2023,
Accepted 27th November 2023 Cite this: Mater. Adv., 2024,
5, 625
Introduction
Renewable, low-carbon ene
societal dependence on fossi
Received 24th August 2023,
Accepted 27th November 2023
DOI: 10.1039/d3ma00589e
rsc.li/materials-advances
Materials
Advances
PAPER
Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Materials
Advances View Article Online
View Journal | View Issue View Article Online
View Journal | View Issue Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Mater. Adv., 2024, 5, 625–631 | 625 Band-gap engineering in methylammonium
bismuth bromide perovskites for less-toxic
perovskite solar cells† Cite this: Mater. Adv., 2024,
5, 625 Samuel R. Pering,
*a Hunaynah Abdulgafar,‡a Madeleine Mudd,a Keith Yendall,b
Mustafa Togayc and Mark R.J. Elsegood
d Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Band gap engineering has been used throughout perovskite
solar cell research to improve device performance, and can also
be used to form an ideal material for certain applications, e.g. in tandem cells or for building integrated photovoltaics, and
halide mixing has been demonstrated to be an effective way of
altering the band-gap/colour of a material.17,40–42 In this article
we introduce a previously unreported structure of the material
methylammonium bismuth bromide, including single crystal
data. The effect of halide mixing on bismuth perovskites is then
examined, using various ratios of iodide to bromide from
MA3Bi2I9 to MA3Bi2Br9, analysing the structural, optical and
morphological effects to both assess any improvements in
material performance, and observe any similarities to band-
gap engineering in lead-based perovskites. Fig. 1
(a) Photograph of the crystal fragment used for the single crystal
X-ray diffraction study, (b) The formula unit in the crystal structure of 1,
with minor DMSO and methyl ammonium disorder components omitted
for clarity and (c) Packing plot for 1 showing the extensive H-bonded
network of interactions between cations, anions and the DMSO of crystal-
lisation. Structure viewed parallel to b. Fig. 1
(a) Photograph of the crystal fragment used for the single crystal
X-ray diffraction study, (b) The formula unit in the crystal structure of 1,
with minor DMSO and methyl ammonium disorder components omitted
for clarity and (c) Packing plot for 1 showing the extensive H-bonded
network of interactions between cations, anions and the DMSO of crystal-
lisation. Structure viewed parallel to b. cations the two ends were positionally disordered i.e. C/N swap
places. Layers of cations and anions are linked via an extensive
network of H-bonds involving all structural components. The
BiBr6
3 anions are almost perfectly octahedral and do not connect
with each other (0D). The monoclinic, C2/m structure characterised from these
experiments is not a typically observed perovskite structure, nor
is it the same as previous characterisations of methylammonium
bismuth bromide. A study by Djokic et al. Introduction opportunity for solar technologies.3 Abundant starting materi-
als and simple processing methods are significant advantages
of these materials; the latter enabling the fabrication of flexible
perovskite solar cells (PSC).4–8 From a 3% efficient cell reported
for the original material, methylammonium lead iodide (MAPI)
in 2009, the record efficiency for perovskite solar cells now lies
at over 25%, competitive with commercially established solar
cell technologies such as silicon.3,9 A major part of improving
device performance was tailoring the constituents of the per-
ovskite by the inclusion of additives at the A or X-site (from an
ABX3 general structure).10–12 This could involve small ions such
as Br, with halide mixing proving to improve stability and aid
in the control of the material band-gap.13–15 An easily con-
trolled band gap has opened the possibility of implementing
perovskite materials in multijunction cells, as complementary
band gaps to those of other materials for maximum absorption
can be designed.16,17 Additionally the incorporation of larger
cations can improve material stability, for example the most
stable cells use longer chain organic compounds that form a
more stable 2D perovskite structure.18–20 Renewable, low-carbon energy sources are vital for reducing
societal dependence on fossil fuels and mitigating the effects of
carbon emissions. Reducing both start-up and implementation
costs is key to the uptake of new technologies to decrease our
environmental impact. With increasingly reducing energy-
payback times, solar power has become an attractive alternative
energy source. Its flexibility, finding use in both 4100 MW
solar farms and smaller rooftop arrays means that it is acces-
sible to a range of applications. New materials can widen these
possibilities further for building-integration, such as photovol-
taic windows.1,2 In the past 10 years, perovskite-structured photovoltaic
materials have established themselves as an exciting new However, the long-term stability of perovskite solar cell
devices has been significantly less than commercially estab-
lished technologies, which is further complicated by the
potential release into the environment of the toxic element
lead.21–25 The exploration of lead-free materials is therefore Mater. Adv., 2024, 5, 625–631 | 625 © 2024 The Author(s). Published by the Royal Society of Chemistry 625 Fig. Methylammonium bismuth bromide Single crystal analysis determined that the structure obtained
was a DMSO solvate crystal structure. Large, single, crystals of
methylammonium bismuth bromide dimethyl sulfoxide sol-
vate, 1, were grown using a 2 : 1 ratio of methylammonium
bromide:bismuth bromide in a mixed solvent of g-butyro-
lactone and dimethyl sulfoxide, using a solvent evaporation
method. An image of the crystal fragment used for the data
collection is shown in Fig. 1a. Fig. 1b and c show the formula
unit and packing motifs in the crystal structure of 1. Fig. S1 and
S2 (ESI†) show packing plots in different orientations. All
crystal data is in Table S2 (ESI†). Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. produced a more
expected MA3Bi2Br9 material, with 2D layered structure belonging
to the space group P%3m1, similar to previous studies on bismuth
and antimony halide perovskites.43,44 It is also unlike the crystal
structure of methylammonium bismuth iodide, which usually
possesses a structure in which two face-sharing octahedra form
the main part of the repeating unit.45 This difference is likely due
to the synthesis method of the single crystals, a slow, solvent
evaporation-based method that allows plenty of time for the
crystallisation of the material to include the DMSO solvent. Introduction 1
(a) Photograph of the crystal fragment used for the single crystal
X-ray diffraction study, (b) The formula unit in the crystal structure of 1,
with minor DMSO and methyl ammonium disorder components omitted
for clarity and (c) Packing plot for 1 showing the extensive H-bonded
network of interactions between cations, anions and the DMSO of crystal-
lisation. Structure viewed parallel to b. Materials Advances
View Article Online Materials Advances Materials Advances Paper important to further development of perovskite solar cell
technology. Recently lead-free perovskite solar cells have seen
significant progress, albeit with lower efficiencies than lead-
based analogues.26,27 The next element up in group 14, tin, is
the most widely analysed alternative, but its toxicity, efficiency,
and stability have not shown improvements over lead.28,29 Recently, bismuth has been employed as a lead replacement
in the B-site; its most common oxidation state of +3 has led to a
variance in structures, for example double perovskites are
formed when used in conjunction with a +1 ion such as
silver.30–32 Silver–bismuth double perovskite solar cells have
reached efficiencies of over 2% in thin-film solar cells, and over
4% when the perovskite is converted into quantum dot
form.33,34 Functioning solar cells can also be produced when
bismuth is used as the solitary B-site cation, although efficien-
cies remain mostly below 1%, with the highest of these
obtained with caesium as the A-site cation.35–38 Improving the
performance of A3Bi2X9 materials is therefore paramount to
establish bismuth as a potential competitor to lead. For exam-
ple, by using a two-step deposition method, cells exhibiting
3.17% efficiency for a methylammonium bismuth iodide cell
have been produced.39 Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Halide mixing in bismuth halide perovskites To investigate the effect of halide mixing, powders of methy-
lammonium bismuth halide with different ratios of iodide to
bromide were prepared for powder X-ray diffraction (PXRD)
analysis. These were prepared with an increasing molar ratio of
bromide by 0.2 in each solution, to provide a broad picture of
the potential band-gap engineering available in bismuth-based [(BiBr6
3)(H3CNH3
+)3]2((CH3)2SO) (1) is the moiety formula
for the crystallised material, and one quarter of this represents the
asymmetric unit. The DMSO and methylammonium cations were
substantially disordered. In the case of the methylammonium © 2024 The Author(s). Published by the Royal Society of Chemistry 626 | Mater. Adv., 2024, 5, 625–631 626 View Article Online Materials Advances Fig. 2
Powder X-ray diffractograms (normalised) for methylammonium bismuth halide with varying iodide:bromide ratio: (a) full diffractogram, and (b)
zoomed-in image of shaded area, tracking the (1,0,2)46 peak. Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Fig. 2
Powder X-ray diffractograms (normalised) for methylammonium bismuth halide with varying iodide:brom
zoomed-in image of shaded area, tracking the (1,0,2)46 peak. Fig. 2
Powder X-ray diffractograms (normalised) for methylammonium bismuth halide with varying iodide:bromide ratio: (a) full diffractogram, and (b)
zoomed-in image of shaded area, tracking the (1,0,2)46 peak. ms (normalised) for methylammonium bismuth halide with varying iodide:bromide ratio: (a) full diffractogram, and (b)
tracking the (1,0,2)46 peak. Fig. 3
(a) Photograph of methylammonium bismuth halide films with
varying iodide:bromide ratio, from left: 100% I, 80% I, 60% I, 40% I, 20% I,
100% Br and (b) Kubelka–Munk Analysis from Diffuse Reflectance Spectro-
scopy of methylammonium bismuth halide films data of materials (dashed lines
show extrapolation for band gap calculation). This article is licensed under a Creative Commons At Fig. 3
(a) Photograph of methylammonium bismuth halide films with
varying iodide:bromide ratio, from left: 100% I, 80% I, 60% I, 40% I, 20% I,
100% Br and (b) Kubelka–Munk Analysis from Diffuse Reflectance Spectro-
scopy of methylammonium bismuth halide films data of materials (dashed lines
show extrapolation for band gap calculation). There is little change in the overall diffractogram from
MA3Bi2I9 to MA2Bi2(I0.8Br0.2)9 suggesting that the structure is
potentially tolerant to high levels of substitution. Halide mixing in bismuth halide perovskites As BiBr3 can
be significantly cheaper than BiI3 (at lower purities, BiBr3: d175/
100 g (Z 98%) BiI3: d270/100 g (99%) (Merck) in May 2023),
these findings could greatly reduce the cost of bismuth-based
perovskite solar cells, if the other major properties such as
band gap and device efficiency can be maintained at these
substitution levels. At 40% bromide substitution and above,
there is a more significant shift in peak positions, this more
pronounced change matching the change in the colour of the
powders. A single-step spin-coating method was employed to produce
thin-films for analysis to reduce procedural complexity and to
ensure observed morphology differences are due to the material
composition as opposed to deposition method. An image of the
thin films is shown in Fig. 3a. UV/Vis analysis of these films
shows that the band gap has been successfully altered through
varying the halide composition (Fig. 3b). Fig. 3
(a) Photograph of methylammonium bismuth halide films with
varying iodide:bromide ratio, from left: 100% I, 80% I, 60% I, 40% I, 20% I,
100% Br and (b) Kubelka–Munk Analysis from Diffuse Reflectance Spectro-
scopy of methylammonium bismuth halide films data of materials (dashed lines
show extrapolation for band gap calculation). Analysis of the band-gap extracted from linear fitting of the
first visible transition in the diffuse reflectance spectroscopy
echoes the trends obtained from PXRD measurements; i.e. the
material is tolerant to high levels of bromide substitution
without significant change (Fig. S4, ESI†). Table 1 below shows
the band gaps extracted from UV/Vis analysis. perovskite materials. An immediate colour difference in the
powders was observed, from a deep red for MA3Bi2I9, through
shades of orange to yellow in MA3BiBr6 (Fig. 3a displays this
colour difference in the thin-films). This echoes the trends
shown by lead halide perovskites, in which increasing the
proportion of bromide in the material increases the band
gap.13 The PXRD results obtained from the powders are shown
in Fig. 2 and a comparison with the starting materials for the
100% iodide and 100% bromide material are included in Fig. S3 (ESI†). These show distinct peaks, separate from those of the
starting materials, however a lack of complete conversion is
observed. The diffractograms show no obvious peak separation,
so a single phase of mixed halide methylammonium bismuth
perovskite is produced in each case. © 2024 The Author(s). Published by the Royal Society of Chemistry Halide mixing in bismuth halide perovskites An enhanced image
tracking the (1,0,2) peak46 of MA3Bi2I9 shows a gradual shift
to higher 2y values as the proportion of bromide increases,
suggesting that the inclusion of the smaller bromide ion is
reducing the overall size of the unit cell (see Fig. 2b). For MA3Bi2I9 a band gap of 1.88 eV is obtained, which is
consistent with previously reported results.46–48 A slight shift is Mater. Adv., 2024, 5, 625–631 | 627
Table 1
Values for band gap extracted from Kubelka Munk analysis of
reflectance spectroscopy
Material
Band gap (eV)
MA3Bi2I9
1.88
MA3Bi2(I0.8Br0.2)9
1.91
MA3Bi2(I0.6Br0.4)9
1.93
MA3Bi2(I0.4Br0.6)9
1.98
MA3Bi2(I0.8Br0.2)9
2.08
MA3BiBr6
2.51 Table 1
Values for band gap extracted from Kubelka Munk analysis of
reflectance spectroscopy © 2024 The Author(s). Published by the Royal Society of Chemistry Materials Advances
View Article Online Materials Advances
View Article Online View Article Online Paper Materials Advances Materials Advances seen at low percentages of bromide substitution, however as
the percentage of bromide in the lattice increases further, there
is a starker change in band gap. MA3Bi2(I0.4Br0.6)9 possesses a
band gap of 1.98 eV, increasing to 2.08 eV for MA3Bi2(I0.8Br0.2)9. Finally, the 100% Br-containing material has a measured band
gap of 2.51 eV. The UV/Vis data establishes that the band-gap of
methylammonium bismuth halide perovskites can be con-
trolled through halide substitution, a property that could prove
useful for their deployment as a top cell in multijunction solar
cells. Compared with methylammonium lead iodide perovs-
kites, methylammonium bismuth iodide requires greater bro-
mide substitution to enact similar degrees of band gap shift.13
A
plot
of
bromide
mole
fraction
against
band
gap (Fig. S4b, ESI†) produces a curve which appears to show an
exponential trend. To test this trend an additional sample was
made and measured with 90% bromide (Fig. S4c and d, ESI†). The band gap for MA3Bi2(I0.1Br0.9)9 was measured at 2.18 eV,
which fits with the observed trend, and this is likely due to the
significant shifts in crystalline structure at higher mole frac-
tions of bromide as seen in the PXRD measurements. The stability of the thin-films when left in atmospheric
conditions was observed over 10 weeks using both XRD
(Fig. 4) and UV/Vis (Fig. S6, ESI†). Firstly, the thin-film XRD
shows significantly less disorder than the powder, and for all
ratios of iodide/bromide appears to be relatively stable through-
out the 10 week period, with little change in the major peaks. Halide mixing in bismuth halide perovskites Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:5
This article is licensed under a Creative Commons Attribution 3.0 Unported Fig. 4
10 week stability study of thin-films through X-ray diffraction. Graph headings correspond to the proportion of iodide or bromide in the sample. Fig. 4
10 week stability study of thin-films through X-ray diffraction. Graph headings correspond to the proportion of iodide or bromide in the sample. 4
10 week stability study of thin-films through X-ray diffraction. Graph headings correspond to the proportion of io in-films through X-ray diffraction. Graph headings correspond to the proportion of iodide or bromide in the sample © 2024 The Author(s). Published by the Royal Society of Chemistry 628 | Mater. Adv., 2024, 5, 625–631 View Article Online Paper Materials Advances analysis. All films show high surface roughness and a film
thickness of between 700 nm to 1 mm, with low surface cover-
age. For MA3Bi2I9 (Fig. 5a and Fig. S7a, ESI†) flat grains of 1 mm
length populate the surface. Films containing 20% and 40%
bromide show similar morphologies, and as the proportion of
bromide increases further the grains become more rod-like and
increase in size (Fig. 5d, e and Fig. S7c–e, ESI†) towards the
large, 42 mm size grains that form MA3Bi2Br9. Improving the
film morphology of these less-toxic perovskite materials is vital
for performance, and should be the subject of further study. Fig. 5
SEM Images at 5000x magnification of methylammonium bismuth
halide films: (a) MA3Bi2I9, (b) MA3Bi2(I0.8Br0.2)9, (c) MA3Bi2(I0.6Br0.4)9, (d)
MA3Bi2(I0.4Br0.6)9, (e) MA3Bi2(I0.2Br0.8)9, and (f) MA3BiBr6. p
j
y
Methylammonium bismuth halide solar cells were fabri-
cated, using polyethylenedioxythiophene:polystyrene sulfonate
(PEDOT:PSS) as the hole-transport material and phenyl-C61-
butyric acid methyl ester (PCBM) as the electron transport
material (Fig. S9 and S10, ESI†). These materials were chosen
as they had the simplest fabrication procedures and lowest
cost, to maintain the key advantage of simple processing that
makes perovskite solar cells attractive. Previous studies looking
at MA3Bi2I9 solar cells produced devices with efficiencies of up
to 3.17%.36,39,46,49 6 devices were fabricated for each material,
with few showing measurable efficiency. The new material
MA3BiBr6 exhibited some, albeit minimal photovoltaic activity,
in the range of pA cm2 JSC and o0.05 V VOC displayed in Fig. S9f (ESI†). Similar performance was observed across the halide
substitution range (Fig. Halide mixing in bismuth halide perovskites S10, shown alongside dark measure-
ments, ESI†), therefore direct comparisons of the effects of
halide mixing on methylammonium bismuth halide solar cells
are not possible in this case. This likely has multiple causes: the
poor film coverage, uneven film morphology, and zero-
dimensional crystal structure, particularly of the MA3BiBr6
materials leading to inefficient charge transport. Improving
the morphology of MA3Bi2(I1xBrx)9 could lead to improved
performance at a reduced cost compared with MA3Bi2I9. Other
solvents to DMSO should be explored, as the formation of the
DMSO solvate crystal into a zero-dimensional structure, as
opposed to the previously reported 3-D crystal structures, likely
hampers performance.43,44 Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58
This article is licensed under a Creative Commons Attribution 3.0 Unported Fig. 5
SEM Images at 5000x magnification of methylammonium bismuth
halide films: (a) MA3Bi2I9, (b) MA3Bi2(I0.8Br0.2)9, (c) MA3Bi2(I0.6Br0.4)9, (d)
MA3Bi2(I0.4Br0.6)9, (e) MA3Bi2(I0.2Br0.8)9, and (f) MA3BiBr6. Interestingly in the first few weeks for MA3Bi2I9 (100% iodide
on Fig. 4), there is a split peak at B12.51 highlighted in Fig. S6
(ESI†). This suggests that there are two competing phases
within the material, which also appears as two separate absor-
bance changes in the UV/Vis spectra (Fig. S6, ESI†). This
apparent phase separation disappears after 4 weeks in both
the XRD and UV/Vis suggesting that a single, dominant phase is
present. However, in the UV/Vis this is manifested as an
increase in the initial band-gap, meaning that less overall light
is absorbed. This will likely have implications for device per-
formance, and therefore these phases should be explored in
more detail to determine the origin and if it is possible to
isolate and maintain the lower band gap phase. This splitting
does not occur in any of the mixed iodide:bromide samples. Additionally, there is the appearance over time of a peak at
B101, attributed to the methylammonium halide starting
material, suggesting material degradation. This is significantly
more pronounced in the pure bromide and iodide samples
than the mixed halides. An increase in phase stability from
halide
mixing
has
also
been
observed
in
lead-based
perovskites.13,14 These results suggest that halide-mixing could
also be a useful tool for bismuth-based perovskites to improve
both phase stability and long-term stability. An additional
factor is that at low bromide loading the impact on band gap
is minimal for a potential increase in long-term stability. © 2024 The Author(s). Published by the Royal Society of Chemistry References F. De Angelis, M. Graetzel and M. K. Nazeeruddin, Nat. Commun., 2017, 8, 15684. 1 M. Batmunkh, Y. L. Zhong and H. Zhao, Adv. Mater., 2020,
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lographic data for 1.46 SRP thanks the University of Loughbor-
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This article is licensed under a Creative Commons Attribution 3.0 Un L. Korte, B. Rech, M. B. Johnston, L. M. Herz and
H. J. Snaith, Science, 2016, 351, 151–155. Conclusions The crystal structure of the new material methylammonium
bismuth bromide dimethylsulfoxide solvate is reported, which
shows a zero-dimensional, monoclinic C2/m structure. Methy-
lammonium bismuth halide perovskites are then studied
through halide mixing to explore the effects on band-gap and
structure. MA3Bi2I9 displays a high tolerance to halide mixing
on structure and band gap, which show small changes at
bromide substitutions of o40%. Halide substitution has been
shown to improve the stability of the materials over 10 weeks in
air, suggesting that, this could be a method to increase material
lifetime whilst not compromising on band gap. This report
contains the first attempted synthesis of a methylammonium
bismuth bromide solar cell, which recorded minimal photo-
voltaic activity; this is attributed to film morphology and the
zero-dimensional
crystal
structure
obtained
through
the Thin-film morphology was analysed in closer detail using
both SEM (Fig. 5 and Fig. S7, ESI†) and AFM (Fig. S8, ESI†) © 2024 The Author(s). Published by the Royal Society of Chemistry Mater. Adv., 2024, 5, 625–631 | 629 629 View Article Online Author contributions 15 M. Saliba, T. Matsui, J.-Y. Seo, K. Domanski, J.-P. Correa-
Baena, M. K. Nazeeruddin, S. M. Zakeeruddin, W. Tress,
A. Abate, A. Hagfeldt and M. Gra¨tzel, Energy Environ. Sci.,
2016, 9, 1989. Open Access Article. Published on 29 November 2023. Downloaded on 10/24/2024 5:40:58 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. SRP: conceptualisation, funding acquisition, project adminis-
tration, methodology, supervision, writing – original draft. HA,
MM, KY, MT & ME data curation, formal analysis, investigation,
resources and writing – review and editing. ME – crystallo-
graphic analysis. 16 D. P. McMeekin, G. Sadoughi, W. Rehman, G. E. Eperon,
M. Saliba, M. T. Horantner, A. Haghighirad, N. Sakai,
L. Korte, B. Rech, M. B. Johnston, L. M. Herz and
H. J. Snaith, Science, 2016, 351, 151–155. 16 D. P. McMeekin, G. Sadoughi, W. Rehman, G. E. Eperon,
M. Saliba, M. T. Horantner, A. Haghighirad, N. Sakai,
h
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A comparison of temporal pathways to self-harm in young people compared to adults: A pilot test of the Card Sort Task for Self-harm online using Indicator Wave Analysis
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Frontiers in psychiatry
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TYPE Original Research
PUBLISHED 12 January 2023
DOI 10.3389/fpsyt.2022.938003 TYPE Original Research
PUBLISHED 12 January 2023
DOI 10.3389/fpsyt.2022.938003 TYPE Original Research
PUBLISHED 12 January 2023
DOI 10.3389/fpsyt.2022.938003 CITATION Background: Self-harm is complex, multifaceted, and dynamic, typically starts
in adolescence, and is prevalent in young people. A novel research tool
(the Card Sort Task for Self-harm; CaTS) offers a systematic approach to
understanding this complexity by charting the dynamic interplay between
multidimensional factors in the build-up to self-harm. Sequential analysis
of CaTS has revealed differences in key factors between the first and the
most recent episode of self-harm in adolescence. Rates of self-harm typically
decline post-adolescence, but self-harm can continue into adulthood. A comparison between factors linked to self-harm in young people vs. adults
will inform an understanding of how risk unfolds over time and clarify age-
specific points for intervention. A pilot online adaptation (CaTS-online) and a
new method (Indicator Wave Analysis; IWA) were used to assess key factors in
the build-up to self-harm. Lockwood J, Babbage C, Bird K,
Thynne I, Barsky A, Clarke DD and
Townsend E (2023) A comparison
of temporal pathways to self-harm
in young people compared to adults:
A pilot test of the Card Sort Task
for Self-harm online using Indicator
Wave Analysis. Front. Psychiatry 13:938003. doi: 10.3389/fpsyt.2022.938003 OPEN ACCESS OPEN ACCESS
EDITED BY
Oswald David Kothgassner,
Medical University of Vienna, Austria
REVIEWED BY
Joanna Anderson,
University of Cambridge,
United Kingdom
Yuanyuan Xiao,
Kunming Medical University, China
*CORRESPONDENCE
Joanna Lockwood
Joanna.lockwood@
nottingham.ac.uk
SPECIALTY SECTION
This article was submitted to
Adolescent and Young Adult
Psychiatry,
a section of the journal
Frontiers in Psychiatry
RECEIVED 21 June 2022
ACCEPTED 12 December 2022
PUBLISHED 12 January 2023 OPEN ACCESS
EDITED BY
Oswald David Kothgassner,
Medical University of Vienna, Austria
REVIEWED BY
Joanna Anderson,
University of Cambridge,
United Kingdom
Yuanyuan Xiao,
Kunming Medical University, China
*CORRESPONDENCE
Joanna Lockwood
Joanna.lockwood@
nottingham.ac.uk
SPECIALTY SECTION
This article was submitted to
Adolescent and Young Adult
Psychiatry,
a section of the journal
Frontiers in Psychiatry
RECEIVED 21 June 2022
ACCEPTED 12 December 2022
PUBLISHED 12 January 2023 Joanna Lockwood1*, Camilla Babbage1, Katherine Bird2,
Imogen Thynne2, Andrey Barsky3, David D. Clarke2 and
Ellen Townsend2 Joanna Lockwood1*, Camilla Babbage1, Katherine Bird2,
Imogen Thynne2, Andrey Barsky3, David D. Clarke2 and
Ellen Townsend2 1National Institute of Health Research MindTech MedTech Co-operative, School of Medicine,
University of Nottingham, Nottingham, United Kingdom, 2School of Psychology, University
of Nottingham, Nottingham, United Kingdom, 3School of Computational Biology, University
of Birmingham, Birmingham, United Kingdom RECEIVED 21 June 2022
ACCEPTED 12 December 2022
PUBLISHED 12 January 2023 A comparison of temporal
pathways to self-harm in young
people compared to adults: A
pilot test of the Card Sort Task
for Self-harm online using
Indicator Wave Analysis A comparison of temporal
pathways to self-harm in young
people compared to adults: A
pilot test of the Card Sort Task
for Self-harm online using
Indicator Wave Analysis Introduction Yet, while less common in adulthood, self-harm is
nonetheless present and also on the rise in adult groups
(15,
16). In
fact,
rates
and
risk
factors
for
self-harm
across adult populations, particularly, in older adulthood
remain under-researched, especially within community-based
studies. There may be distinctions in risk profiles that
underlie adult- vs. adolescent-presenting self-harm. Self-harm
in older adults compared to adolescents certainly appears
associated with higher lethality, conferring a 67 times greater
risk of completed suicide (17). Diminishing self-harm in
adulthood may also relate to the substitution of self-harm
with other risky behaviours, such as problematic drinking
(13). Arguably, self-harm, which continues into adulthood
or adult-incident self-harm, may be characterised by distinct
emotional, behavioural, or environmental self-harm pathways
from adolescent-only self-harm, which suggest opportunities for
targeted intervention and treatment. Self-harm across adolescence and
adulthood Self-harm
(non-fatal
intentional
self-injury
or
self-
poisoning regardless of the motivation or intent associated
with the act) (1) is a complex and common behaviour in
adolescence (the developmental stage from around 11–25 years
of age) which is recognised to correspond to the social,
psychological, neurodevelopmental, and biological growth
undertaken between childhood and adulthood (2). Around
one in five youth report having self-harmed at least once (3),
although this figure is likely to underestimate true prevalence
given that for many young people self-harm remains hidden
at a community level (4). Self-harm behaviour typically starts
and peaks during early- (11–14 years) to mid-adolescence
(15–18 years) and is associated with risk of repetition, potential
life-long adverse outcomes, future mental health conditions,
and, substantially increased likelihood of suicidal thoughts and
behaviour (3, 5–9). Rates of self-harm are also higher among
adolescent than child or adult populations, particularly in mid
and late adolescent groups, and have risen sharply in recent
years (10, 11). Population-based cohort studies charting the
natural history of self-harm clearly indicate that the frequency
of self-harm substantially decreases during the transition
from late adolescence to early adulthood (9, 12–14). The
prevalence, lifelong consequences, and the risk to life in youth
underscore the importance of a research focus on clarifying self-harm, adolescence, adulthood, card sort, Indicator Wave Analysis, CaTS-online,
digital interventions, co-development COPYRIGHT © 2023 Lockwood, Babbage, Bird,
Thynne, Barsky, Clarke and Townsend. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s)
are credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms. Methods: Community-based young people (n = 66; 18–25 years, M = 21.4;
SD = 1.8) and adults (n = 43; 26–57 years, M = 35; SD = 8.8) completed
CaTS-online, documenting thoughts, feelings, events, and behaviours over
a 6-month timeline for the first ever and most recent self-harm. A notable
interdependence between factors and time points was identified using IWA. Results: Positive emotion at and immediately after self-harm exceeded
the threshold for both groups for both episodes. Feeling better following
self-harm was more pronounced for the first-ever episodes. Impulsivity was Frontiers in Psychiatry 01 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 10.3389/fpsyt.2022.938003 an important immediate antecedent to self-harm for both groups at both
episodes but most markedly for young people. Acquired capability was
notable for adults’ most recent episodes, suggesting this develops over time. Burdensomeness was only more notable for adults and occurred 1 week prior
to a recent episode. Both groups revealed patterns of accessing support that
were helpful and unhelpful. Conclusion: Commonalities and differences in the temporal organisation of
factors leading to and following self-harm were identified in young people and
adult pathways which shed light on age-specific factors and possible points
of intervention. This has implications for clinical support and services around
approaches to positive feelings after self-harm (especially for first-ever self-
harm), feeling of burdensomeness, impulsivity, and acquired capability leading
up to self-harm. Support is provided for card-sort approaches that enable the
investigation of the complex and dynamic nature of pathways to self-harm. risk and protective factors for self-harm salient during this key
transitional phase. Introduction KEYWORDS Risk factors across the life-span A substantial body of empirical and theoretical work
supports an increased understanding of the influencing factors
associated with self-harm and suggests self-harm results
from a complex interplay between various genetic, biological,
psychological, psychiatric, cultural, and sociodemographic
factors that act in concert to confer risks (18) and which are
developmentally charged and fluid. Psychiatric disorders, Frontiers in Psychiatry 02 frontiersin.org 10.3389/fpsyt.2022.938003 Lockwood et al. 10.3389/fpsyt.2022.938003 particularly mood and anxiety disorders, and psychological
factors
(including
low
problem-solving,
low
self-esteem,
impulsivity, vulnerability to hopelessness, and a sense of
entrapment) are recognised as contributing to vulnerability
to
self-harm
across
the
lifespan
(19–22). Psychological
vulnerability for self-harm in young people is proposed to
relate to developmental changes in childhood and adolescence,
which undermine emotional control and coping with stress
(12),
with
pubertal
stage—rather
than
age—the
critical
contributory factor (23). By adulthood protective factors
such as affective stability, emotion regulation and increased
behavioural inhibition may typically temper this vulnerability
(24). Psychological vulnerability for self-harm in older adults
is characterised by feelings of burdensomeness, isolation,
loneliness, hopelessness and loss of control and the impact of
factors (physical/social/economic) preceding self-harm which
relate to older life-stage challenges (17, 25, 26). Consistent
evidence has clarified that self-harm often occurs in the
context of one or multiple negative life events that are typically
social/interpersonal and which also differ by age, such as
family and peer group problems in children and younger
adolescents, or spouse/partner problems in older adolescence
and adulthood (5). The Card Sort Task for Self-harm (CaTS) (30) is a research
tool that takes a dynamic approach to map the influence of
multiple potential distal and proximal biopsychosocial factors
that precede an episode of self-harm. CaTs offers a way of
examining patterns of thoughts, feelings, events, and behaviours
experienced as salient at an individual level through the
positioning of cards along a timeline, providing a nuanced
understanding of how and when the risk for self-harm emerges
and progresses. The approach reflects important contemporary
explanatory models that account for the multidimensional
nature of self-harm and the transition from vulnerability, to
thinking about self-harm (ideation) and to acting on those
thoughts (behavioural enaction) (31–34). In a first test of
the CaTS, Townsend et al. used a lag sequence analysis
statistical technique to identify the important sequences of
items leading to a first-ever and the most recent episode of
self-harm in a sample of 45 young people. Risk factors across the life-span This distinction
in episodes allows reflection on the transition from ideation
to behavioural enaction for the first onset of self-harm and
highlights maintained factors of risk over time. Sequence
statistical approaches, such as lag sequence analysis, analyse the
transitions between one event (antecedent) and the following
event (the sequitur) and enabled Townsend and colleagues
to show that factors most proximal to self-harm in young
people were negative emotions, impulsivity, and having access to
means. They also identified important distinctions in significant
sequential structures between the first-ever and most recent self-
harm. For example, hopelessness was an important antecedent
of behaviour in the most recent episode of self-harm, but while
the first-ever self-harm was associated with feeling better after
self-harm, this was no longer the case by the most recent
episode. Additional examination of temporal dynamics in self-
harm using the CaTS tool within research settings could extend
the examination of pathways to self-harm in adolescents versus
adult groups and offer a method of targeting developmentally
specific points for intervention in the self-harm pathway. Longitudinal cohort studies have advanced understanding
of the developmental history of self-harm and improved
the identification of biopsychosocial causes for self-harm
over time, charting distinct behavioural and emotional risk
profiles. Moran et al. revealed that although most self-
harm spontaneously resolves by adulthood, persistence into
adulthood is associated with high anxiety and depressive
symptomatology in adolescence (12). Research that continues to
elucidate how characteristics of self-harm unfold over time may
help to pinpoint salient intervention points. The current study Despite considerable research focus on potential factors
influencing self-harm, the accurate prediction of who is likely
to self-harm and when they are likely to do so remains poor
(27). In part, this may be due to a methodological over-reliance
on simple cross-sectional associative studies and examination of
factors associated with self-harm in isolation, which limits their
predictive utility (27, 28). Such approaches fail to account for
the complexity of risk factors or the dynamic temporal context
in which these factors are likely to confer their risk. In response,
recent strides in novel research approaches are improving our
ability to understand, predict, and prevent self-harm, including
those employing real-time monitoring methods which follow
the dynamic course of self-harm within a natural environment
at an individual level (29). This study uses an internet-mediated version of the CaTS
(CaTS-online) to systematically compare the dynamic interplay
of factors that lead to self-harm in young people (18–25 years)
and adults using a longitudinal design. Traditionally, CaTS is a
manual task with cards presented along a timeline in a tabletop
manner. An online adaptation of CaTs could offer increased
functionality and scope, including a more efficient process of
recording, coding, and tracking the order and frequency of
cards, and the capacity to allow for multiple uses of the same
card at different time points, which was not a feature of the
manual version. Previous tests of the CaTS have focused on
relatively small, clinical, or targeted populations. An online
version extends the capacity to access a wider, more diverse Frontiers in Psychiatry 03 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 10.3389/fpsyt.2022.938003 participant pool (35) and allows the task to be performed
anonymously and in less-formal settings (36). Given the remote
nature of CaTS-online, the study will draw on adult and late
adolescent (18+) groups, herein specified as “young people.” through gatekeepers (national self-harm support organisations). Undergraduate students at the University of Nottingham were
also invited to take part in return for course credits. Participants
received an online information sheet and completed the
online consent form and were then invited to complete CaTS
online. This research adhered to and was approved by the
University of Nottingham, School of Psychology Research Ethics
Committee (Ref: F967). Novel approaches to analyse the multi-dimensional nature
of risk over time are necessary to advance the understanding of
when, why, and who is at risk of self-harm. Research questions 1. Is there an association between cards that are selected as
part of the CaTS and the timepoint leading up to and after
self-harm episodes in adults and young people? 2. Do items at time points leading up to and after self-harm
differ between adults and young people? 3. Do items at time points leading up to and after self-harm
differ between the first ever and the most recent episode of
self-harm for adults and young people? The current study A limitation of the
sequence analysis approach previously employed by Townsend
et al. (30) was that the use of the same card at multiple time
points was prohibited, a restriction noted by young people in
anecdotal feedback and in Patient Public Involvement work
used to develop the original CaTS (30). To address this issue,
the present study uses Indicator Wave Analysis (IWA) as
a method of temporal measurement, which allows multiple,
simultaneous, and sequential events to be analysed across
varying time spans (37). In addition, IWA produces easy-to-
interpret wave diagrams (known as indicator wave diagrams)
that provide a profile of the factors (indicators) absent or
prevalent relative to other indicators at a time point (37). The
use of IWA in psychological methods is novel, but as a method of
allowing complex data to be plotted and examined in simplified
diagrams, it is an attractive approach to aid the interpretation
and discourse of the fluctuating and complex nature of self-
harm and suited to analyse the CaTS-online data. As IWA is a
novel approach, and there is limited data specifically comparing
adults and young people who self-harm, no specific predictions
are made concerning the absence or presence of items across
time. An additional aim of this study was to explore what can we
learn from CaTS-online as a research tool and the potential for
application of IWA as an analysis technique to support further
development of CaTS. Adaptation of CaTS The CaTS is a card sort task of 117 cards grouped broadly
into sub-sets describing thoughts, feelings, events, behaviours,
services and support, and items relevant to and after self-
harm. Groupings allow participants to easily navigate the cards
provided. CaTS was developed in conjunction with academic
and clinical experts and an advisory group of young people
with lived experience, and it draws on insight from key
theoretical models and empirical evidence. During the task,
the participant is asked to select and organise cards that are
salient to a specific self-harm episode chronologically along a 6-
month sequential timeline. Timestamps are provided (6 months
before, 1 month before, 1 week before, 1 day before, 1 h before
self-harm, and afterwards) [Refer Ref. (30) for more detailed
information about CaTS]. The CaTS-online was intended to replicate the manual
version of CaTS with a modification to the format which
extended the timeline to run over 6 months before, 6 months
before, 1 month before, 1 week before, 1 day before, 1 h before,
just before self-harm, immediately afterwards, and a later on
after. This modified timeline was suggested by a PPI focus
group with young people that explored ways to develop the
original CaTS. The timeline was presented graphically as a table
with timestamps as the heading of each column, as shown in
Figure 1. Each sub-set was presented above the timeline screen. When clicked, items in the sub-set would appear in a drop-
down menu in random order. The participant could then drag
and drop cards from each sub-set into the relevant timeline
column. Participants were able to delete cards that were placed
incorrectly. As with the manual version, participants were able
to use as many or as few cards as they wanted and were able
to create their own cards by selecting “custom card” at the
bottom of the drop-down list. Uniquely, CaTS-online allowed
participants to use the same card multiple times. On completion
of the task, a custom string of data including the time point and
cards selected during the task was created. These data were only
accessible to the research team. Frontiers in Psychiatry Recruitment As
CaTS-online
is
completed
remotely,
signposting
information with contact details for the available support
organisations (including those acting as gatekeepers to the
study) was included at the bottom of each of the CaTS-
online windows, along with contact details for the Principal Individuals with lived self-harm experience and access
to the internet, and aged 18 years or more were invited
to participate in the study via social media advertisements Frontiers in Psychiatry 04 frontiersin.org 10.3389/fpsyt.2022.938003 Lockwood et al. FIGURE 1
A screenshot of the first ever and most recent episode of self-harm tasks for CaTS-online. FIGURE 1
A screenshot of the first ever and most recent episode of self-harm tasks for CaTS-online. FIGURE 1
A screenshot of the first ever and most recent episode of self-harm tasks for CaTS-online. Investigator (ET). An initial prototype of CaTS-online, which
was created and piloted with Undergraduate students at
the University of Nottingham and members of the research
team (ET, IT) and PPI group necessitated no format or
delivery changes. than two hundred and if they had used “self-injury,” “self-
poisoning,” or “other” methods of self-harm [adapted from
Wadman et al. (38)]. An open-response box could be used to
record other methods of self-harm. Open-response boxes were
also used to measure participant estimations of how long ago
they had first and most recently self-harmed in years, months,
and days. Data were collected between December 2017 and
February 2018. All data, including consent, and completion of
the card-sort task was captured by the CaTS-online programme
in the same session. Frontiers in Psychiatry Study procedure At the start of the study, participants were asked for
their demographic information (age, date of birth, sexuality,
gender, ethnicity and country of residence, and current
employment/education status). Closed response questions asked
participants to estimate how many times they had self-harmed
across 9 options increasing incrementally from once to more Participants were asked to complete the CaTS-online task
twice, reflecting on their first-ever and most recent episode of
self-harm in line with previous studies, as shown in Figure 1
(30, 38). 05 frontiersin.org 10.3389/fpsyt.2022.938003 Lockwood et al. Lockwood et al. comparable graphs due to differences in the number of cards
selected between the four conditions (Figure 2). In order to monitor the impact of taking part in the study,
participants were required to rate their current emotional state
at the start and end of the study by completing a Visual Analogue
Scale (VAS) presented as a scale ranging from 0 (illustrated
with an unhappy face) to 10 (illustrated with a smiling face). Participants were provided with the prompt: “How are you
feeling right now?.” They were asked to reflect on their VAS
rating and any change in their mood and were provided with
signposting information and prompts for self-care. Cute animal
pictures were also included at the end of the task as part of
the final debrief in line with recommended practice to support
mood mitigation in sensitive research (39). Finally, to produce standardised residuals (SRs), a chi-
square analysis was conducted in SPSS (2021, Version 28.0) for
young persons’ and adults’ most recent and first-ever self-harm
episodes. SRs are used as descriptive variables giving a measure
of the strength of the difference between observed and expected
values to highlight points of interest by indicating when an event
is happening more or less frequently than would be expected
by chance. Requirements for the chi-square are not presented
here as the outcome of the chi-square statistic is not required
for this method. These identified which categories were disproportionately
more or less likely to occur than might be expected by chance
at specific time points, suggesting an association of cards within
a category being selected at a time point more frequently than
would be picked up by chance. A threshold value of ≥2.0 was
used to identify an association, in line with the convention for
the evaluation of categorical data using chi-square (40). Study procedure All data
were input by CB and checked by KB for inconsistencies. Data collation and pre-statistical manipulation Data were downloaded as a.CSV file and imported into a
spreadsheet programme. Participants were divided into two age
categories, young people (18–25 years) and adults (26 years and
over). Data were organised into separate time points across the
timeline, for the most recent and first-ever self-harm episode. Incomplete data Individual analysis of each card would be too complex for
IWA, given the high volume of cards in the CaTS (n = 117)
(37). Therefore, the complexity of data analysis and figures was
reduced [as in previous sequence-based approaches (30, 38)]
by grouping items into categories. This process was initially
completed by two Psychology Undergraduates, who were part
of the research team, and then reviewed further with the wider
research team, leading to 17 categories being developed such as
“negative life events or social problems” and “exposure” (refer
to Supplementary material 2 for details of which cards were
placed into which categories). A total of 89 (76%) of the 117
cards were categorised. In the interests of parsimony, cards were
prioritised, which fitted conceptually into categories or were
retained where they were considered of theoretical relevance for
the current study, as agreed by consensus in the research team. In total, 101 participants completed the CaTS for their first-
ever self-harm episode, and 96 participants completed the CaTS
for their most recent self-harm episode. This sample size is
consistent with previously published research utilising CaTS
and sequence analysis techniques (30, 38). There was a low level
of missing data; four out of 66 young people and four out of
43 adults did not complete the CaTS for their first-ever episode
of self-harm. A total of 11 young people and two adults did
not complete the CaTS for their most recent self-harm episode. Analysis proceeded on the remaining completed CaTS data. Frontiers in Psychiatry Indicator Wave Analysis Indicator Wave Analysis (IWA) can be used to assess
whether an event is interdependent on another by analysing
multiple behaviours and events along a time scale (37). A total of 109 people participated, aged 18–57 years
(M = 26.8 years; SD = 8.7). In the young people group (N = 66;
Age: M = 21.4 years; SD = 1.8), there were 58 women (87.9%), 4
men (6.1%), 3 transgender individuals not identifying as either
male or female (4.5%), and 1 transgender male (1.5%). The
adult group (N = 43; Age: M = 35 years; SD = 8.8) included
30 women (69.8%), 10 men (23.2%), 2 transgender individuals
not identifying as male or female (4.7%), and 1 participant who
was unsure (2.3%). The process of IWA begins with “unitisation” to divide
items into related categories. Second, items were organised into
timepoints, e.g., “1 h before,” along the timeline. Frequencies
were then calculated for items in each time point, leading up
to the action/behaviour. For each card, the frequency of that
card occurring at a particular time point was calculated for both
age groups during their most recent and first-ever episode of
self-harm. A frequency table of the number of occurrences of
cards within a category across the timeline was also produced. For each of the four groups, percentages were calculated based
on the total number of cards within that category to produce Across
both
groups,
participants
self-reported
as
“heterosexual” (56.9%), “bisexual” (23.9%), and “homosexual”
(10.1%). Participants reported their ethnicity as “White British”
(79.8%) or “Other White” (11.9%). A total of 51.4% were in 06 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 FIGURE 2
A graph displaying the frequency of cards, pooled as a percentage of cards in each category, across each of the four groups. A graph displaying the frequency of cards, pooled as a percentage of cards in each category, across each of the four groups. full time education, 38.5% were employed, and 10.1% were not
employed. Supplementary material 3). Out of 66, 33 young people (47%)
and 30 out of 43 adults (70%) reported self-harm in the last
6 months. All participants reported repeat self-harm except 2
adolescents who reported only one episode of self-harm, and 2
participants who did not provide a response. Frontiers in Psychiatry Frequency analysis The age at the first self-harm episode ranged between 7
and 21 years (M = 14.6 years; SD = 3.1) for young people
and between 7 and 46 years (M = 17.5 years; SD = 8.4) in
the adult group. The average duration was 5 years 6 months
for young people (range 1 month–13 years, 4 months), and
15 years 7 months (range 1 month–48 years) for adults. Almost all participants across the total sample had their
first self-harm episode in adolescence, with only 4/43 (9%)
reporting adult incident self-harm. Self-injury was the most
common method of self-harm, reported by all participants. Additionally, 16 young people (24.2%) and 14 adults (32.6%)
reported using self-poisoning (other methods of self-harm,
reported by 13 participants completing the CaTS, are detailed in In total, young people selected 1,977 and 1,233 cards, and
adults selected 818 and 814 cards in relation to their first-
ever and most recent self-harm, respectively. The frequency
percentage of cards selected in each category for each group
is displayed in Figure 2. The category “Negative Emotion”
accounted for the largest percentage of cards selected across
all groups, with a peak of 31.96% of total cards selected by
young people distributed within this category for most recent
self-harm. Table 1 presents the top 10 most frequently selected cards for
both groups at both time points. Notably, for the first and most Frontiers in Psychiatry 07 frontiersin.org 10.3389/fpsyt.2022.938003 10.3389/fpsyt.2022.938003 Lockwood et al. recent episode of self-harm, feelings of depression and sadness
were frequently reported by both adults and young people, and
self-hatred was also a prominent shared selection, markedly for
young people. Both groups also reported not being able to tell
anyone how they were feeling, and this was highly selected for
the first-ever and most recent self-harm. “I felt exhausted” and “I
was angry” were often selected by both adults and young people
in relation to the most recent, but not the first-ever, self-harm. Other highly occurring card selections for both groups included
wanting to die, feeling anxious, and feeling worthless. across timestamps is included in Supplementary material 5. IWA graphs summarising all categories, i.e., including those
where SRs did not exceed the threshold, are included in
Supplementary material 6. For key categories of interest, Indicator Wave graphs are
presented (Figures 6, 7) displaying the SRs for young people
and adults at each time point for the category. Indicator Wave Analysis graphs Standardised residuals, obtained from the chi-squared
statistic, are used to develop a (category × timepoint) frequency
matrix and to enable the development of IWA graphs as a guide
to points of interest rather than to report an association between
variables. Nonetheless, the chi-squared statistic is presented in
the following text (Table 2), detailing the significant association
between categories and time for each group. Frequency analysis These graphs
visually highlight key indicators of relative importance at time
points and allow for comparison across groups. For example,
the card category “accessed support that didn’t help” exceeded
the threshold, occurring more often than might be expected
by chance relative to other indicators, immediately after self-
harm, and this was the case for both groups for the first-
ever but neither group for the most recent episode of self-
harm. For adults, there is a notable spike reaching above the
threshold at the “accessed support that helped category” on both
timelines (Indicator Wave graphs for all remaining categories
are presented in Supplementary material 7). Frequencies for all cards, including those that were not
chosen by participants across either self-harm episode, can be
seen in Supplementary material 4–Frequency of Individual
Cards. Examination of item frequencies outside of those most
frequently endorsed is also noteworthy in highlighting the
differential relevance of individual items for age groups and
self-harm episodes where categories include multiple items. For example, frequency data suggest that mental abuse and
bullying within the category “Negative life events and social
problems” are more prominent items for the first-ever self-
harm in young people than for recent self-harm. Relatively,
low-level endorsement of cards among participants is also of
importance. For example, in general, endorsement of items
relating to support, irrespective of whether it was helpful or not,
was low, indicating modest levels of support seeking broadly
and, in particular, little endorsement of support through formal
(clinical/education) settings. Visual Analogue Scale The mean score on the emotional state VAS before
completing the CaTS for young people was 5.32 (SD = 2.13) and
4.79 (SD = 1.97) after completion. The mean emotional state
score for adults was 4.93 (SD = 2.79) before completion and
4.50 (SD = 2.79) after completion. Thus, scores persisted around
the mid-range of the scale for both groups before and after
completion. For young people, this represented a significant
decrease in mood [t(56) = 2.49, p = 0.02], but no significant
change in VAS scores was observed for adults [t(39) = 1.50,
p = 0.14]. Frontiers in Psychiatry Discussion This exploratory study reports early findings using a novel
analysis approach (Indicator Wave Analysis) to chart and aid
understanding of the temporal dynamics of biopsychosocial
factors associated with self-harm. Using the prototype CaTS-
online, we were able to describe the salient factors building
up to and following self-harm for young people and adults’
first-ever and most recent self-harm pathways. Our findings
indicate that there is an association between factors leading up
to self-harm episodes in adults and young people at specific time
points and suggests similarities and differences between these
groups that unfold over time. This replicates and extends earlier
work demonstrating the sequential pattern of self-harm using
CaTS (30). Across the 17 categories, 13 categories had SRs that indicated
cards in the card category were selected more frequently than
would be expected by chance, at particular time points along the
timeline for an adult’s first-ever episode of self-harm. Similarly,
12, 11, and 12 card categories reached the notable threshold for
adults’ most recent, young people’s first ever, and young people’s
most recent episodes of self-harm, respectively. This suggests
an association between cards relating to particular thoughts,
feelings, events, and behaviours leading up to and after self-
harm, across adults and young people. For the categories where
an SR reached a higher or lower than expected frequency,
an IWA graph is presented (Figures 3, 4) and these are
narratively described in a snapshot wave profile in Figure 5. An
Indicator Wave frequency matrix showing the SRs of categories
occurring more or fewer times than expected by chance While raw frequencies support an understanding of which
multiple factors are consistently identified as associates of
self-harm, the IWA analysis allows an examination of their
temporal importance, relative to other indicators, in the Frontiers in Psychiatry 08 frontiersin.org 10.3389/fpsyt.2022.938003 Lockwood et al. TABLE 1 A table displaying the most frequently selected cards, across the four groups. TABLE 1 A table displaying the most frequently selected cards, across the four groups. Discussion p
y
g
q
y
g
p
Position
Card #
Card description
Frequency
Adult first ever
1
B04
I felt depressed and sad
53
2
A09
I could not tell anyone how I was feeling
48
3
B10
I hated myself
47
4
B20
I felt like I did not belong
36
5
B14
I felt trapped
35
6
F06
I felt better after self-harm
35
7
D12
I isolated myself from others
34
8
A01*
I wanted to die
32
9
A03
There was no one to turn to for help
32
10
A04
I could not trust anyone
29
Adult most recent
1
B10
I hated myself
54
2
B04
I felt depressed and sad
42
3
B05
I felt very anxious
42
4
B03*
The mental pain was unbearable
39
5
A09
I could not tell anyone how I was feeling
38
6
D12
I isolated myself from others
37
7
B08*
I felt exhausted
36
8
B01
I was angry
34
9
B06
I felt worthless
32
10
A03
There was no one to turn to for help
30
Young people first ever
1
B04
I felt depressed and sad
132
2
B10
I hated myself
104
3
B06
I felt worthless
96
4
A03*
There was no one to turn to for help
89
5
A09
I could not tell anyone how I was feeling
84
6
B05
I felt very anxious
81
7
A01*
I wanted to die
77
8
B03
The mental pain was unbearable
71
9
B25*
I felt numb
60
10
B07
I felt disgusting
57
Young people most recent
1
B05
I felt very anxious
61
2
B08*
I felt exhausted
47
3
B04
I felt depressed and sad
99
4
B06
I felt worthless
59
5
A09
I could not tell anyone how I was feeling
50
6
B10
I hated myself
73
7
B01
I was angry
45
8
B16
I felt I could not escape from feelings or situations
49
9
A01*
I wanted to die
67
10
B18*
I felt very hopeless about the future
44
*Indicates cards that were not categorised. *Indicates cards that were not categorised. the temporal distribution of relevance to established affect
regulation models of self-harm (41, 42). Positive emotions
(feeling energised) first reach the positive threshold value from months, weeks, days, hours, and moments preceding and
after self-harm. Frontiers in Psychiatry Discussion In terms of negative and positive emotions,
the Indicator Wave diagrams provide a clear indication of 09 Frontiers in Psychiatry Frontiers in Psychiatry frontiersin.org 10.3389/fpsyt.2022.938003 Lockwood et al. TABLE 2 The chi-squared statistic of associations between categories and time points for each group with violations reported. TABLE 2 The chi-squared statistic of associations between categories and time points for each group with violations reported. Condition
Chi-squared value (to one d.p.)
Degrees of freedom
Significance level
Young people, ≤25 years (Most recent)
815.8a
144
p < 0.001
Young people ≤25 years (First ever)
1202.5b
144
p < 0.001
Adults, ≥26 years (Most recent)
652.2c
144
p < 0.001
Adults, ≥26 years (First ever)
738.9d
144
p < 0.001
a104 cells (61.2%) have an expected count of less than 5. The minimum expected count is 0.32. b73 cells (42.9%) have an expected count of less than 5. The minimum expected count is 0.51. c119 cells (70.0%) have an expected count of less than 5. The minimum expected count is 0.56. d122 cells (71.8%) have an expected count of less than 5. The minimum expected count is 0.33. FIGURE 3
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for young people first ever
and most recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. FIGURE 3
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for young people first ever
and most recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. FIGURE 3
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for young people first ever
and most recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. FIGURE 3
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for young people first ever
and most recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. emotions following self-harm indicated in the most recent adult
self-harm. Discussion This pattern is noticeable in an item specifically
targeting “feeling better after self-harm,” which clearly shows
a stronger endorsement for improvement in feelings post self-
harm for the first-ever in comparison to the most recent self-
harm in both age groups. just before and at the point of self-harm and continue to
rise before diminishing in value. Of note, for young people’s
first-ever self-harm, the peak in positive emotions relative
to other indicators at the point of self-harm is higher than
the peak for positive emotions relative to other indicators
for most recent self-harm. This is consistent with previous
data from sequential analyses, which reveal an attenuation
in feeling positive following self-harm associated with repeat
behaviour (30) and which could be associated with habituation
(43). Similarly, adult presentations indicated a peak in positive
emotions following self-harm for the first-ever episode, which
is in marked contrast to the large fall in the SRs for positive In terms of negative emotion, despite the high frequency
with which items were selected by all groups, profiles at
individual time points did not reach the notable threshold in
the build-up to self-harm, with the exception of the adult’s first
ever self-harm which was notable 1 day prior to behaviour. As
such, support for negative affect regulation functional accounts Frontiers in Psychiatry Frontiers in Psychiatry 10 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 FIGURE 4
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for adult first ever and most
recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. FIGURE 4
Indicator Wave graphs showing the temporal organization of categories where at least one time point reached ± 2 for adult first ever and most
recent episode of self-harm, SRs ± 2 indicating higher or lower frequency than would be expected by chance. no longer present. A deeper dive into what “better” and
“worse” constitutes could be achieved in card-sort models which
zoom into time points, particularly given the complex and
multifactorial nature of the emotional response to self-harm. Findings overall underscore a mixed emotional response but
suggest a degradation in the function of self-harm as a means
of affect regulation, which emerges with repeated self-harm and
is relevant for a long time post self-harm. Discussion of self-harm which hold that individuals are motivated to self-
harm to reduce aversive negative emotions receives only partial
support in the IWA. We might for example expect to see self-
harm preceded by a spike in negative emotions, followed by a
reduction in negative mood state, as demonstrated in real-time
EMA data (44). There are potential explanations for this. In
initial frequency analyses, negative emotion was indeed a high-
frequency category and demonstrated a high distribution at all
time points prior to and following self-harm, and thus may not
have emerged with a greater likelihood of occurrence at any
particular time point in IWA. In addition, CaTS permits a highly
individualistic representation of self-harm, and consequently,
a variety of different forms of negative affect were included
within the category. In terms of developmental differences between young people
and adult pathways to self-harm, an interesting distinction is
demonstrated in terms of impulsivity, here, specifically the
concept of low premeditation or acting on the spur of the
moment. This facet of impulsivity is recognised as a risk factor
in adolescent and adult self-harm (22, 46) and also plays a
prominent role as a key volitional moderator in ideation to
enaction models (31), i.e., those who self-harm are more likely
to be impulsive than those who have only thought about self-
harm (47). The IWA highlights a pattern of an increased
likelihood of endorsing impulsivity just before and at the
point of self-harm, which is consistent across all groups and
which is relevant at the first-ever onset and maintained at
the most recent occurrence. These findings extend those from
sequence analysis techniques that identify impulsivity as the
only immediate precursor to both a first and most recent episode
of self-harm to a broader age span (30). Of note, the peak
of impulsivity was markedly higher for adolescents at both Different forms of negative affect may have salience
across time (45) and it would be helpful to separate out
affect presentations in future examinations. In terms of the
specific question relating to “feeling worse after self-harm,”
response profiles show a clear indication of worsening feelings
immediately post-episode for all groups, except again in adult’s
first ever self-harm, where feeling worse did not immediately
reach the threshold until a later time-point after self-harm. Frontiers in Psychiatry Discussion Again, endorsement of feeling worse following self-harm was
higher in most recent than the first-ever self-harm for both
groups, and by the most recent account of adult self-harm,
the absence of feeling worse immediately post self-harm was 11 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 ofiles based on notable category selection by time point. Frontiers in Psychiatry FIGURE 5
Snapshot wave profiles based on notable category selection by time point. Frontiers in Psychiatry Snapshot wave profiles based on notable category selection by time point. self-harm. In addition, burdensomeness exceeded the threshold
in most recent adult self-harm at 1 week prior to behaviour. This is consistent with recent review evidence suggesting that
such factors commonly characterise self-harm in older adults
and may be a particular feature of self-harm at an older
life stage (17). In fact, loneliness, isolation, and entrapment
were similarly interdependent with a time point proximal to
self-harm for young people; however, burdensomeness was
not and appears to be a particular feature of self-harm at
an older age. Interestingly, acquired capability also reached
the threshold (at the point of self-harm) for an adult’s most
recent self-harm only. Theoretically, it is plausible that an
acquired capability to overcome a natural fear of death or
pain, would be associated with repeated rather than the
first onset of self-harm, and this replicates previous findings time points, than for adults, which is in line with previous
findings of a developmental difference in levels of impulsivity
as associated with self-harm (48) and is consistent with the
suggestion that impulsivity is heightened in adolescence (49). Interestingly, premeditation also exceeded the threshold (albeit
at a much lower level than impulsivity) for all groups just prior
to and at the point of self-harm. Although seemingly at odds,
this is consistent with some research that has shown that for
some young people a deliberative thought-through plan for
self-harm can be delayed if the situation is not suitable, and
then subsequently acted on without the need for additional
planning (50). Our data suggested that feelings of isolation, loneliness,
and entrapment were marked in pathways for adult self-harm
with a notable interdependence 1 h prior to the most recent 12 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 FIGURE 6
Indicator Wave graphs comparing standardised residuals (SRs) for each group across the timeline, for the categories: Positive emotions,
premeditation, feeling positive after self-harm, and impulsivity. FIGURE 7
Indicator Wave graphs comparing the standardised residuals (SRs) for each group across the timeline, for the categories: Acquired capability,
burdensomeness, accessed support that didn’t help, and accessed support that helped. (43). Our findings provide temporal evidence consistent with
prominent models of suicide and self-harm (31, 33) of the
transition through motivational phase moderators (entrapment
indicate that this pathway may be of particular importance in
adult behaviour. This limitation could be addressed through a more collaborative
digital implementation, e.g., within a therapeutic session. episode of behaviour. However, accessing unhelpful support
did not reach the threshold post self-harm in either case of
recent self-harm. Indeed, most recent self-harm behaviours were
associated with a sharp rise in accessing support that was classed
as “helpful” immediately following self-harm and continued to
rise later on after. As such, while there are endorsements for
an experience of support that is helpful and unhelpful, there
appears to be a different pattern and more positive evaluation of
support for more recent presentations. Notably, support access
of whatever quality did not feature notably, or reach a nadir,
at earlier stages in the timeline. These temporal findings could
indicate support for functional motivations of self-harm as a
“cry for help” (51), which secures support following self-harm. It is possible that contemporary help-seeking experiences
of young people do qualitatively differ from those of an
adult’s first-ever experience of self-harm dating from many
years previously. It is also true that there are myriad types
of help and support (including informal and formal, online,
and face-to-face) and a considerable range in the quality and
suitability of this provision, which will differ for individuals
and by episode. Recent co-produced avenues of prevention
and intervention support, e.g., reaching young audiences by
directing support within online social spaces and new media
avenues (52, 53) may be contributing to recent improved
access and response to support, particularly in young people. Importantly, the findings suggest that groups are help-seeking. There is nonetheless an opportunity to increase targeted support
at earlier stages in self-harm pathways, e.g., through universal
prevention programmes. Importantly, the broad categorisation
of helpful or unhelpful support also masks the salience of
individual support-related items. Inspection of frequencies of
card selection (Supplementary material 1) reveals that items
relating to formal support seeking through dedicated services
such as GPs or teachers were endorsed less frequently than
informal sources of support such as friends and partners. Increased participatory approaches would support an improved
understanding of barriers and facilitators to support seeking
and engagement and improve the design and implementation
of service provision. For example, recent work focused on
improving the experience of visiting a GP and preparing young
people for their GP consultation (54) models how youth-
oriented involvement and co-production can facilitate improved
formal service use. Our analyses identified interesting patterns of category FIGURE 6 FIGURE 6
Indicator Wave graphs comparing standardised residuals (SRs) for each group across the timeline, for the categories: Positive emotio
premeditation, feeling positive after self-harm, and impulsivity. premeditation, feeling positive after self-harm, and impulsivity. FIGURE 7
Indicator Wave graphs comparing the standardised residuals (SRs) for each group across the timeline, for the categories: Acquired capability,
burdensomeness, accessed support that didn’t help, and accessed support that helped. Indicator Wave graphs comparing the standardised residuals (SRs) for each group across the timeline, for the categories: Acquired capability,
burdensomeness, accessed support that didn’t help, and accessed support that helped. (43). Our findings provide temporal evidence consistent with
prominent models of suicide and self-harm (31, 33) of the
transition through motivational phase moderators (entrapment,
burdensomeness, and social isolation) at time points prior
to self-harm, which can lead to ideation, to volitional phase
moderators (acquired capability) at the point of self-harm, and
describing the translation of ideation into action. Our findings indicate that this pathway may be of particular importance in
adult behaviour. Our analyses identified interesting patterns of category
selection in relation to accessing support. In terms of support
classed as “unhelpful,” both young people and adult pathways
demonstrated a sharp increase in accessing unhelpful support
immediately after self-harm, peaking later on after their first 13 Frontiers in Psychiatry frontiersin.org 10.3389/fpsyt.2022.938003 10.3389/fpsyt.2022.938003 Lockwood et al. timeframe, may be open to question. Having said this, the
first-ever experience of self-harm is a focal event that is
likely to be subject to easier recall than other experiences. While caution is advocated in the interpretation of findings as
discussed, responses provided show consistent parallels with
key theoretical frameworks. There were also commonalities
occurring across groups indicate a shared pattern of behaviour. It is noteworthy nonetheless that overall adults selected half the
number of cards that younger participants selected, which could
indicate difficulties with recall. Lower card usage by adults could
also relate to reluctance or difficulty engaging with the online
tool. In addition, the online and anonymous nature of the CaTS-
online tool limited the ability to understand reasons for failure
to complete the task (e.g., lack of interest, not being able to
remember details, lack of understanding, and wanting to exit the
task) and precluded the ability to sense check with participants. While our aim was to identify similarities and differences
between self-harm in young people and adults and hence we
distinguished groups at a cut-offof 25 years in accordance
with
established
categorisations
of
adolescence
(2),
this
may nonetheless represent fairly arbitrary segregation at a
developmental level and as such our groups may not be
sufficiently distinct. In the vast majority of cases, adult
participants also indicated an adolescent first incidence of
self-harm, and as such, adult first ever and young person
first ever were both representations of self-harm onset pre-
adulthood. However, it is also important to recognise that
contemporary risk factors, attitudes towards, experiences of
support for self-harm, etc., are likely to differ considerably
between these groups at the time of the first incidence. For
example, young people today are living in extraordinarily
stressful times, with unprecedented social and online pressure,
increased psychological distress, and high levels of self-
dissatisfaction (10), particularly among girls. A larger or more
targeted sampling frame could allow for the comparison
of adolescent/young person incident vs. adult incident self-
harm. There are also limitations to discuss in relation to the IWA
approach as employed to analyse CaTS data. Grouping cards
into categories in the first stage of IWA facilitates relatively
simple data outputs for the ease of analysis and presentation
but necessarily removes some of the complexity and nuance
associated with the multi-card task. In some cases, related
concepts were included in a shared category (e.g., loneliness,
isolation, and entrapment) which reduces their specificity. Arguably, the IWA can be used to pinpoint areas that warrant
examination at greater granulation. It would be informative
to explore in more detail the importance of individual items
that show variable prominence at time points or age groups
within a multi-item category. A strength of the original CaTS
development was the involvement of young people with lived Frontiers in Psychiatry Limitations An
additional limitation of the approach as applied to self-harm
items in this study was the inclusion of two cards that included
a time reference (feeling positive after self-harm or feeling
negative after self-harm) that were not, therefore, independent
of timing. It is, however, possible to draw comparisons on
the selection of either card across groups. Finally, it should
be noted that young participants were offered participation
in exchange for course credit which may have introduced
incentivised bias. • The adoption of IWA supports calls for innovative
approaches and techniques to account for the complexity
and dynamic nature of self-harm (29). Using IWA with
a card-sort task is novel, and we look now to refine
and improve this process. The IWA does not provide
a prediction of behaviour, but rather a “characteristic
signature” visible at time points in relation to self-harm,
for example, a week before. Such an approach may support
the early identification of “warnings signs” to be picked
up and monitored. However, turning the patterns of peaks
and troughs into a statistically valid prediction (given the
measure is derived from standard residuals rather than raw
frequencies) is something still being explored. • The adoption of IWA supports calls for innovative
approaches and techniques to account for the complexity
and dynamic nature of self-harm (29). Using IWA with
a card-sort task is novel, and we look now to refine
and improve this process. The IWA does not provide
a prediction of behaviour, but rather a “characteristic
signature” visible at time points in relation to self-harm,
for example, a week before. Such an approach may support
the early identification of “warnings signs” to be picked
up and monitored. However, turning the patterns of peaks
and troughs into a statistically valid prediction (given the
measure is derived from standard residuals rather than raw
frequencies) is something still being explored. Creating
CaTS-online
brought
benefits
in
terms
of
increasing reach and access to a large community-based
sample and increased functionality (i.e., being able to select a
card multiple times), but there are ethical limitations with a
task that explores complex and sensitive topics in a detailed
approach, remotely, and outside of support. Factors were
included to mitigate risk, including an 18+ age range, and
signposting. Nonetheless, we report a decline in VAS scores
at the completion of the task though this was significant for
young people only. Limitations In fact, this finding is consistent with other
studies that have reported a reduction in mood following
participation in self-harm research, but which have also
indicated that changes are often short-lived and while the
mood is impacted, this is not necessarily judged as distressing
(55, 56). Clinical implications • In line with previous CaTS examinations, we identify what
factors might be indicators of risk (such as increased
impulsivity) and an understanding of when in relation
to other complex factors these factors are likely to
become most salient. As such, the findings offer targeted
and time-specific points for intervention. Many of the
factors identified are modifiable and exist as treatment
targets within therapeutic approaches (e.g., DBT-A). The
use of a tool such as CaTS within a clinical setting
could support clinicians with a needs-based assessment
in line with recently published NICE guidelines (58) and
supports decision-making on the timing and pertinence
of therapeutic support. In addition, there may be value in
the mapping of individual risk profiles via visual diagrams
which are simple to generate, readable, and can support
collaborative discussion and shared understanding between
patients and practitioners within and across care settings. Limitations There are limitations associated with the nature of the
CaTS-task itself which relies on retrospective recall. It is
recognised that for adult participants, in particular, this may
have required recalling an episode of self-harm occurring
many years previously, and as such the accuracy of recall, in
particular, in terms of the placing of items against a pinpointed 14 frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 10.3389/fpsyt.2022.938003 • We address calls for greater representation of community-
based adult samples (17) and point to commonalities
and differences in the characteristic pattern of indicators
noted for adults and young people, suggesting that some
indicators, e.g., the nature of belonging for young people or
the nature of burdensomeness for adults are of heightened
relevance prior to self-harm (relative to other multiple and
shared risk factors). The characteristic profiling approach
adopted here speaks to wider approaches that seek to
delineate distinctive psychological risk profiles [e.g., (57)]
in order to provide more targeted treatment options
throughout the self-harm cycle. • We address calls for greater representation of community-
based adult samples (17) and point to commonalities
and differences in the characteristic pattern of indicators
noted for adults and young people, suggesting that some
indicators, e.g., the nature of belonging for young people or
the nature of burdensomeness for adults are of heightened
relevance prior to self-harm (relative to other multiple and
shared risk factors). The characteristic profiling approach
adopted here speaks to wider approaches that seek to
delineate distinctive psychological risk profiles [e.g., (57)]
in order to provide more targeted treatment options
throughout the self-harm cycle. experience in the identification of card items. Continued
development of the CaTS would benefit from further co-
production and expert involvement work to refine and update
item selection, potential category membership, and analysis
approach. An advantage of IWA is that participants were able
to use cards multiple times. In some cases, this resulted in
multiple uses of the same card (e.g., “I felt depressed and
sad”) at every time point preceding self-harm, and thus IWA
only showed limited notable interdependence for the category
of negative emotion at time points. It is also possible that
low mood is an ever-present indicator leading to self-harm,
which is not notable at any one particular time point. Research implications • Our findings offer support for prominent theories and
models, including the Interpersonal Theory of Suicidal
Behaviour e.g., (33) and the IMV (31), and contribute to
an understanding of the relative interplay between multiple
factors associated with risk for self-harm over a period
of time. By also comparing pathways between the first-
ever and most recent self-harm, we identify the patterns
that emerge over repeated behaviour, including notably
changed experiences of support. Further work delineating
factors associated with “helpful” or “unhelpful” support at
stages of the self-harm pathway are particular points of note
resulting from this work. frontiersin.org Conflict of interest Due to the sensitive nature of this topic, supporting data is
available with conditions. Further information about the data
and conditions for access are available at the University of
Nottingham data repository (doi: 10.17639/nott.72). The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. Funding JL, CB, and ET acknowledged the support of the UK
Research and Innovation (UKRI) Digital Youth Programme
award (MRC project reference: MR/W002450/1) which was part
of the AHRC/ESRC/MRC Adolescence, Mental Health and the
Developing Mind programme. JL and CB also acknowledged
the financial support of National Institute of Health and
Care Research MindTech MedTech Co-operative and National
Institute of Health and Care Research Nottingham Biomedical
Research Centre. This work was also supported by the Wellcome
Trust (202668/Z/16/Z). Acknowledgments We
would
like
to
acknowledge
the
contributions
of our PPI participant group at Café Connect and Lee
Melton for IT support. Publisher’s note The
studies
involving
human
participants
were
reviewed
and
approved
by
University
of
Nottingham,
School
of
Psychology
Research
Ethics
Committee. The
patients/participants provided their written informed consent
to participate in this study. All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher. Conclusion The CaTS offers a systematic approach to understanding
the complex interplay between thoughts, feelings, events, and
behaviours in the build-up to self-harm. A pilot test of CaTS-
online using a novel analytical approach (IWA) successfully
captured and visually presented the multidimensional and
dynamic pattern of risk across young people and adults’ first-
ever and most recent pathways. Key indicators of risk and
intervention points are identified and indicate the changing
profile of risk with repeat self-harm. Work to extend these
pilot findings should further develop the potential for digital
application, particularly, in clinical settings. Next steps • This study used a prototype version of CaTS-online and
provides a pilot test of this initial digital iteration of
CaTS. Developing the task into a digital innovation was
anecdotally discussed within our PPI group. As a first test,
the study shows at a practical level that participants were • This study used a prototype version of CaTS-online and
provides a pilot test of this initial digital iteration of
CaTS. Developing the task into a digital innovation was
anecdotally discussed within our PPI group. As a first test,
the study shows at a practical level that participants were 15 Frontiers in Psychiatry frontiersin.org Lockwood et al. 10.3389/fpsyt.2022.938003 the manuscript. JL, CB, IT, KB, and ET were responsible for
interpreting results. DC devised the original CaTS and Indicator
Waves techniques as part of an earlier project on self-harm led
by ET. All authors contributed to preparing and approving the
final manuscript. able to engage with and complete the task in this format,
and the extracted data was sufficient for analyses. As such,
the further development of CaTS as a digital tool (e.g., an
online version or a mobile app) merits exploration. Work
is now needed to explore in greater depth how that tool
might look, function, or be implemented, and build an
understanding of acceptability, usability, and feasibility. As
part of this, we might revisit the cards and card categories
in the original CaTS to consider new markers of risk and
how to group the cards. Such work should be driven by a
strong co-production focus (59). Frontiers in Psychiatry References Life
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opment
o. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Internat
Developm
Vol. 8, No. 4, Usage of Metacognitive Strategy in Reading Skill of Malay
Essay Text Full Terms & Conditions of access and use can be found at
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Essay Text
Ruzanita Sarman, Azhar Md. Sabil, Shamsudin Othman and Rozita Radhiah
Said
To Link this Article: http://dx.doi.org/10.6007/IJARPED/v8-i4/6903 DOI:10.6007/IJARPED/v8-i4/6903
Received: 20 October 2019, Revised: 30 November 2019, Accepted: 11 December 2019
Published Online: 30 December 2019
In-Text Citation: (Sarman et al., 2019)
To Cite this Article: Sarman, R., Sabil, A. M., Othman, S., & Said, R. R. (2019). Usage of Metacognitive Strategy in
Reading Skill of Malay Essay Text. International Journal of Academic Research in Progressive Education and
Development, 8(4), 1043–1052. Copyright: © 2019 The Author(s)
Published by Human Resource Management Academic Research Society (www.hrmars.com)
This article is published under the Creative Commons Attribution (CC BY 4.0) license. Anyone may reproduce, distribute,
translate and create derivative works of this article (for both commercial and non-commercial purposes), subject to full
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Vol. 8(4) 2019, Pg. 1043 - 1052
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JOURNAL HOMEPAGE Published Online: 30 December 2019 International Journal of Academic Research in Progressive Education and
Development
Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS
Usage of Metacognitive Strategy in Reading Skill of Malay
Essay Text
Ruzanita Sarman, Azhar Md. Sabil, Shamsudin Othman and Rozita Radhiah
Said
To Link this Article: http://dx.doi.org/10.6007/IJARPED/v8-i4/6903 DOI:10.6007/IJARPED/v8-i4/6903
Received: 20 October 2019, Revised: 30 November 2019, Accepted: 11 December 2019
Published Online: 30 December 2019
In-Text Citation: (Sarman et al., 2019)
To Cite this Article: Sarman, R., Sabil, A. M., Othman, S., & Said, R. R. (2019). Usage of Metacognitive Strategy in
Reading Skill of Malay Essay Text. International Journal of Academic Research in Progressive Education and
Development, 8(4), 1043–1052.
Copyright: © 2019 The Author(s)
Published by Human Resource Management Academic Research Society (www.hrmars.com)
This article is published under the Creative Commons Attribution (CC BY 4.0) license. Anyone may reproduce, distribute,
translate and create derivative works of this article (for both commercial and non-commercial purposes), subject to full
attribution to the original publication and authors. The full terms of this license may be seen
at: http://creativecommons.org/licences/by/4.0/legalcode International Journal of Academic Research in Progressive Education and
Development
Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS
Usage of Metacognitive Strategy in Reading Skill of Malay
Essay Text
Ruzanita Sarman, Azhar Md. Sabil, Shamsudin Othman and Rozita Radhiah
Said
To Link this Article: http://dx.doi.org/10.6007/IJARPED/v8-i4/6903 DOI:10.6007/IJARPED/v8-i4/6903
Received: 20 October 2019, Revised: 30 November 2019, Accepted: 11 December 2019
Published Online: 30 December 2019
In-Text Citation: (Sarman et al., 2019)
To Cite this Article: Sarman, R., Sabil, A. M., Othman, S., & Said, R. R. (2019). Usage of Metacognitive Strategy in
Reading Skill of Malay Essay Text. International Journal of Academic Research in Progressive Education and
Development, 8(4), 1043–1052. Copyright: © 2019 The Author(s)
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http://hrmars.com/index.php/pages/detail/publication-ethics 1043 Usage of Metacognitive Strategy in Reading Skill of
Malay Essay Text Ruzanita Sarman, Azhar Md. Sabil, Shamsudin Othman
Rozita Radhiah Said Ruzanita Sarman, Azhar Md. Sabil, Shamsudin Othman and
Rozita Radhiah Said
Faculty of Educational Studies, University Putra Malaysia, 43400 UPM, Serdang, Selangor
Darul Ehsan, Malaysia. Rozita Radhiah Said
of Educational Studies, University Putra Malaysia, 43400 UPM, Serdang, Selangor
Darul Ehsan, Malaysia. Abstract This concept paper aims to identify learning using a metacognitive strategy in reading skill. The
skill of reading and understanding text is a key goal to enhance knowledge and the key to success
for an individual. In fact, in the learning of reading skill, a focus must be given to the aspects of
comprehension and reasoning to achieve success in reading. In addition, the reader needs to
know that the reading process is conscious and provides meaning to the reader. The reader needs
to create awareness of his reading while focusing on the content of the text being read. By using
an effective strategy while reading, the students may know and identify the level of reading
comprehension. The metacognitive strategy needs to be applied during the reading process to
make sense of the text. The metacognitive means the awareness of thinking or thinking about
thought. The metacognitive strategy, too, refers to a way of improving the reading skill which is
awareness that includes planning, monitoring, and evaluation. Students can apply the
metacognitive strategy and control their learning through the process of designing what they
want to learn, monitoring their learning progress and students can evaluate what they learn. The
strategy found in the metacognitive can enhance students' learning and intelligence. Keywords: Metacognitive, Planning, Monitoring, Evaluation, Reading Skill, Education ywords: Metacognitive, Planning, Monitoring, Evaluation, Reading Skill, Education tional Journal of Academic Research in Progressive Education a
ment
2019, E-ISSN: 2226-6348 © 2019 HRMARS Internat
Developm
Vol. 8, No. 4, Introduction Reading and understanding a text is something that is intertwined. Reading is one of the sources
of knowledge and the foundation towards achieving knowledge for self-formation (Rahman
et.al., 2017). By mastering the reading skill, a student can understand the content of the text
information being read. However, reading comprehension is often influenced by the teaching
effectiveness of a teacher because the ability to read and understand the text is a fundamental
skill that needs to be taught in the Malay language subject. Reading and understanding are not
only important for students to improve the performance of the Malay language subject, but other
subjects are also important to master. 1044 Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Reading skill is one of the four essential language skills an individual possesses in the
language teaching and learning process. This skill is also a continuation of other basic skills such
as listening, speaking and writing. The purpose of reading is to help broaden thoughts,
experiences, digest ideas and to enhance the creativity of an individual in various fields. Through
mastering this language skill, students are able to communicate in a variety of situations more
effectively. Through reading skill, students can improve vocabulary while developing reading
interest (Peng, 2016). Reading is also a process of finding information. In accordance with the
needs of students who must read, they access the information contained in the reading text. The
reading process is in line with students' need to expand existing information in completing tasks
(Othman, 2008). Reading and understanding text is not an easy task for an individual to master. In the
process of reading the text, the reader needs to understand each word, and the information
contained or what the author would like to deliver. Without understanding the text being read,
the reader is not considered to master the reading skill Mahzan (2008). He also pointed out that
the reading skill is not limited to text comprehension skill and the ability to answer a variety of
comprehension questions only. This is because the reading skill also needs to involve the skills of
using the information contained in solving problems, relating information to the situation,
commenting and making judgments and conclusions based on information obtained from
reading materials. International Journal of Academic Research in Progressive Education and
Development
Vol 8 No 4 2019 E ISSN: 2226 6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS for example, can improve readers' understanding by the methods of planning, monitoring, and
evaluating. In addition, students who are poor at reading comprehension will have difficulties in learning,
causing their thinking ability to be limited, and thus achieving a less favorable level of
achievement in their learning. This leads to problems of not interested in learning, hopelessness
and further discontinuance from the learning that happens in the classroom (Safiah, 1989). Apart
from that, the weakness of the candidates who do not understand the requirements of the
questions in the public examination will cause the candidates to be unable to provide content
that meets the title (Zamri, 2016). Therefore, the lack of mastery of reading comprehension skill
is one of the reasons why students are not able to master the reading comprehension skill at a
higher level (Kyairaniah, 2017). By choosing the right strategy, the goal of the reader to master
the text quickly and effectively can be realized. A proper reading skill will help improve comprehension with more effective. A student
who can read but does not understand what is read is still considered as not able to read (Yunus,
2016). A variety of activities or assignments can be provided by the teachers so that the effective
reading process can be implemented. Hence, reading behavior can be defined as a complex
behavior and an individual who reads is required to think, feel and imagine what they are reading. Through reading, the students are able to acquire knowledge that cannot be gained through
experience and help to develop ideas and enhance one's thinking ability in various fields. The education system has now changed with the implementation of Primary School
Curriculum (KSSR) that brings changes in the curriculum content and practice in the primary
school system is the responsibility of educators and the students to master the reading skill
holistically. In line with the implementation of this new KSSR curriculum, it is more empowered
through a variety of teaching and learning activities inside and outside of the classroom. These
include activities and campaigns related to reading programs. The content of Curriculum and sment Standard Document (DSKP) 2014, KSSR Primary School Malay Language out tives of the reading skill to ensure the students know and capable as follows: 1. Read and understand sentences containing affix words from various sources with
the correct pronunciation. Reading Skill Reading skill needs to be mastered by each student. Therefore, reading and understanding of the
text are crucial in determining learning success, critical and creative thinking ability, academic
achievement, and individual intellectual ability. The importance and mastery of this skill are very
important in the education system that values academic achievement as a measure of an
individual's educational success (Surat, 2012). However, in order to master the reading skill, teachers need to know various reading
strategies especially for primary school students. Metacognitive strategy is one of the strategies
that can be used to help students improve to the maximum their comprehension of the text they
are reading (Lasan, 2017). In this regard, the Malay language teachers should redouble their
teaching efforts to help students mastering the reading skill and to understand the content of
the text. Students need to be exposed to a variety of reading materials such as literary and non-
literary reading, electronic and non-electronic reading. Teachers need to teach reading
techniques such as mekanis, mentalist, intensive and extensive reading. A student's weakness in his effort of doing reading activities will negatively affect his or
her individual language skills and may adversely affect his or her achievement in other subjects
(Othman, 2003). According to Jamian (2011), the problem of mastering reading and writing skills
has caused students to become weak and they are uninterested in the Malay language as a result
of their inability to master it. Therefore, students need to understand their learning style with
the guidance of teachers to adapt easily, have a positive attitude towards learning and achieve
higher achievement (Mohamad et.al., 2013). In consequence of that, students need to use a
variety of appropriate strategies to achieve their goals in learning. The metacognitive strategy, 1045 Reading Skill Concept The concept of reading skill refers to the ability of a student to speak with correct pronunciation,
intonation, pause, and fluency. According to Kamarudin (1996), reading comprehension is a
complex activity that involves several key elements, namely, the reader, the text read, and the
context and task of reading. The concept of reading comprehension is the same as the concept
of reading, which will only be complete and perfect with the presence of the text comprehension
process (Osman, 1990; Savage, 1998; Arshad, 2008). The process of understanding this text
requires the reader to respond to the text being read in order to formulate and define the
meaning of the text based on their cognitive experience. According to Yusoff (2014), the process of understanding or constructing this text can be
divided into three main categories, namely, create, interpret and evaluate meaning. The same
view is presented by Yahya Othman (2008), who views reading comprehension as a cognitive
process that involves the integration of new information from text with the reader's existing
(schematic) information. Besides that, cognitive activities such as word recognition, choosing
appropriate meanings, associating ideas with experiences and schemas, formulating ideas,
generalizing and evaluating, all occur simultaneously in a process of reading comprehension
(Yusuff, 2014). Therefore, the main factor is to understand the text by designing the reading
activity and choosing the right type of reading. In addition, the concept of reading skill covers mastery of basic alphabet recognition skill
as well as the mastery of high-level cognitive skills, such as inference skills, assessment and
appreciation of texts, the process of understanding and constructing meaning by the reader
through the interaction of existing knowledge (schema) with the author's ideas. This publishing
activity demands the active role of readers in integrating their schemata with linguistic
backgrounds. Nambiar et. al. (2004), on the other hand, considers comprehension as the essence
of reading activity and the importance of teaching comprehension is as important as the
introduction of alphabet and spelling in mekanis reading activity. According to Elers, et. al. (2006) reading comprehension is a complex activity that involves several
key elements, namely, the reader, the text read, and the context and task of reading. The process
of understanding this text requires the reader to respond to the text in order to formulate and
define the meaning of the text based on their cognitive strength. International Journal of Academic Research in Progressive Education and
Development
Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS 1. Read and understand sentences containing affix words from various sources with
the correct pronunciation. 2. Read various materials that contain different types of sentences in mekanis with
smooth, clear pronunciation and right intonation. 3. Read and understand explicit and implicit information to identify key ideas and
ancillary ideas, generate ideas and evaluate correctly. 4. Read, understand and reason explicit and implicit information from prose material
and transfers it to poetry form correctly. 5. Reads and understands literary and non-literary materials to enhance creative
thinking and to identify their value. In addition of KSSR through Malaysian Education Development Plan (PPPM) 2013 until 2015 via
second shift, touches on strengthening Malay language proficiency among primary school
students. By mastering the reading skill at the primary school level, student excellence can have
a significant impact on the country (KPM, BPK 2015). 1046 Definition and Element of Metacognitive Metacognitive originates from the Greek word which is Meta that means anything that can be
covered or achieved by the individual. Meta also involves higher understanding, more abstract
and everything outside of individual coverage Flavell (1981). Cognitive refers to thinking, mental
and reasoning processes. In addition, metacognitive is a process by which an individual thinks
about his or her mind during meaningful and effective cognitive activity (Flavel 1976, 1978). Metacognitive is also a process of thinking that governs and controls how one exercises his or
her mind at a high level of thinking. Flavel also divides metacognitive into metacognitive
knowledge and metacognitive experience. Metacognitive knowledge refers to a person's
knowledge of cognitive process, which is knowledge that can be used to control cognitive
processes. He also divided into three categories which are knowledge of self or individual,
knowledge of assignments or activities on learning strategy. Metacognitive is a term that means awareness of what is known and what is unknown. A person's
metacognitive awareness varies by individual (Carreker, 2004). This reading skill based on the
metacognitive awareness is not only believed to be born naturally but can be expected to be
learned from one's learning experience. The metacognitive strategy refers to ways to improve
thinking skills in the learning process. Therefore, when such awareness exists, an individual can
control his or her mind by planning, executing, monitoring and evaluating. Reading activity is a
very important learning activity and has been practiced since elementary school. The use of
metacognitive strategy in teaching the reading comprehension has also been widely used by
researchers in order to create maximum impact in teaching. According to Savia (2008), students
with poor metacognitive status will benefit if given metacognitive training. Whereas, good
metacognitive students show better academic achievement than the poor metacognitive
students (Surat, 2012). Fogarty (1994) states that metacognitive is the awareness of what is known and what is unknown. Metacognitive is the awareness and control of one's own thinking behavior. He lists three key
components of metacognition, namely planning, detection and evaluation. Planning involves
thinking about the whole problem-solving process. Detection involves thinking about rules and
steps in solving problems and assessing / evaluating, including thinking about the processes used
and their effectiveness. The metacognitive benefit for teachers and students is to emphasize self-
monitoring and responsibility from teachers and students. International Journal of Academic Research in Progressive Education and
Development is a process of constructing active meanings from written texts and are relevant to the reader's
experience and knowledge. Marohaini (2014); Pragasam, Singh, Singh, Mostafa, Ja’afar,
Abdullah, Khaja, (2018); Pihie, Dahiru, Basri, & Hassan, (2018), on the other hand, describes the
process of reading as a complex process that must generate comprehension other than word
recognition and utterance of words, involving the process of thinking, feeling and imagining what
is read, not happening with empty thoughts that are without purpose, expectation, the
knowledge or experience of the reader and involves a number of tasks in the reading process
that require active thinking. The true reading skill also means a skill that can help the reader to
understand and not just involve the process of uttering letters or words (Sakiah, 2016). Reading Skill Concept Therefore, before discussing
the teaching and learning practices of the reading skill, a teacher should understand what the
reading skill means. Understanding of this reading skill is important for teachers as teachers are
the most important factors that determine the success or failure of a teaching and learning
reading (Marohaini, 2014). Next, Marohaini (2014), also stated that teachers' understanding of the reading skill will also
influence teachers' choice of teaching methods, materials, and tools used as well as determine
techniques and focus on teaching the reading skill. There are several meanings given to reading. Azhar (2004), states that reading has a lot of meaning and depends on context and type of
reading. According to Savia (2008), reading is a meaningful interpretation of printed or written
verbal symbols. While reading comprehension is the result of the interaction between the
perceptions of a graphic symbol representing a person's language and knowledge. The concept of reading skill will only be understood if the students are able to achieve
their learning goals through their own efforts. Heilman et. al. (2002), states that the reading skill 1047 Metacognitive Strategy in Malay Language Learning Metacognitive is known as a construct that describes one's ability to reflect on thought, thinking
about thought, knowing what is known and can be used to enhance learning activities (Surat,
2012). In Malay Language subject, during reading activity, the metacognitive strategy can be used
to understand the content of text. The metacognitive strategy used is to plan, monitor and
evaluate. In learning as teachers and educators, teachers can develop and direct students'
metacognitive behaviors. Fogarty (1994), proposing the strategy to strengthen the students'
metacognitive behaviors where there are four stages in classroom learning i.e. (i) Teaching For
Thinking (satisfactory), (ii) Teaching of Thinking (Good), (iii) Teaching With Thinking (Excellent),
dan (iv) Teaching about Thinking (Superior). All these four strategies can guide students'
metacognitive behaviors that can be incorporated into the classroom learning process. Teaching
about thinking is the best learning about thinking, in which the teacher provides instruction in
thinking skill (converting cognitive to metacognitive). As a teacher and educator in the learning process, they can foster and guide students'
metacognitive behavior. Fogarty (1994); Triantafyllia & Katerina, (2015) explains in fostering and
guiding students' metacognitive behavior using a calm and serious model, and true, a fantastic
classroom model, which shows that we teach for, from, with, and about to think new ideas begin
to understand teaching quality. The teachers use class model full with thought that shows the
teachers teach; teaching FOR thinking (satisfactory), teaching Of thinking (good), teaching WITH
thinking (excellent), and teaching ABOUT thinking (superior). Teaching for Thinking is called a satisfied teacher. In classroom, the satisfied teachers set
a condition where students will take care about being good of themselves and able to build
confidence and belief in their abilities. This teacher observes the affective and cognitive
development of students. Teaching of Thinking is referred to as a good teacher who is a teacher
who sets a thoughtful atmosphere. This teacher discusses the ability to think and strictly teaches
critical thinking and creative thinking in a live instruction model to ensure that students have
skills and tools for lifelong learning. Teaching with thinking is called a diamond teacher. Diamond
teachers not only create a caring and warm atmosphere in their skills, but also work to create
strategies for a truly interactive classroom with their thinking. Teaching about thinking is called
a great teacher. Great / superior teachers know the setting of teaching from cognitive to
metacognitive. Definition and Element of Metacognitive Metacognitive strategy is the awareness belongs to the students about their
metacognitive knowledge and regulation. According to Beyer (1997), competent thinking 1048 Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS involves two types of cognitive operations simultaneously; cognitive and metacognitive. Cognitive operation is an operation that uses various combinations of skills and strategies to
achieve meaningful thinking goals. Whereas, the metacognitive operation is an operation that
controls and directs the meaningful strategy and skill. During cognitive and metacognitive
operations such as planning, monitoring, and evaluation are applied to cognitive skills to control
the thinking process. This cognitive operation consists of the operations used to plan and find
meaning. Cognitive operation involves a variety of complex strategies such as decision-making
and problem-solving, analyzing, synthesizing, reasoning, and critical thinking. International Journal of Academic Research in Progressive Education and
Development Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Corresponding Author Corresponding Author
Ruzanita Sarman
Faculty of Educational Studies,
University Putra Malaysia,
43400 UPM,Serdang, Selangor
Darul Ehsan, Malaysia. Email: izaneryna74@gmail.com Email: izaneryna74@gmail.com Email: izaneryna74@gmail.com International Journal of Academic Research in Progressive Education and
Development discussion strategy to make sense of learning for students. By paying particular attention to not
only what they do, but also how and why they do the activity (Fogarty 1994). Metacognitive Strategy in Malay Language Learning Great / superior teachers know that setting the atmosphere for thinking and
teaching explicit skills through cooperative learning should be accompanied by a reflective 1049 Conclusion Reading skill should be mastered by each individual and should not be overlooked by every
student. There are three phases used through the metacognitive strategies used in reading skills,
namely the planning, monitoring and evaluation phases. These phases include statements of
metacognitive awareness used during reading. Students can easily understand the text by using
the phase. The reader is prepared by designing the readings so that the information required is
easily understood. Readers are free to read through their own goals. The text monitoring aspect
can also have a deeper impact on the reading process. Besides that, the aspect of assessment is
also an important element in the implementation of metacognitive strategies. Repeated
exposures will help readers improve their ability to understand text. Therefore, every student
needs to know the right strategies for reading skill as this skill is vital in the learning process. The
use of metacognitive reading can explicitly and implicitly increase the comprehension of a text. Choosing a strategy can also help readers plan and further evaluate the extent to which they are
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4 2019 E ISSN 2226 6348 © 2019 HRMARS Vol. 8, No. 4, 2019, E-ISSN: 2226-6348 © 2019 HRMARS Lumpur: International Journal of
Academic Research in Business and Social Sciences, 8(12), 258–274. Pihie, Z. A. L., Dahiru, A. S., Basri, R., & Hassan, S. A. (2018). Relationship between Entrepreneurial
Leadership and School Effectiveness among Secondary Schools. International Journal of
Academic Research in Business and Social Sciences, 8(12), 258–274. 1052 1052
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https://openalex.org/W2973388696
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English
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Stress analysis of a second stage gas turbine blade under asymmetric thermal gradient
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Mechanics & industry
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1 Introduction models. Among numerical studies done, we can note the
physical effect of the flow in the cooling hole on the heat
transfer in turbine blade [13], improvement and develop-
ment of turbulence models, in order to accurately predict
heat transfer from the surface of the turbine blade with
cooling and without cooling [14]. However, most of the
numerical simulations conducted in this matter are 2
dimensional or does not applied on near-real conditions. So
a thorough assessment considering the real geometry and
near-real boundary conditions needs to be done. One of the important components of gas turbines is their
moving blades which are under mechanical and thermal
stresses due to high-speed rotation and exposure to high
temperatures. To improve turbine efficiency, gas turbine
inlet temperature should be increased [1,2]. On the other
hand, the temperature of the turbine blades needs to be
kept lower than a certain value because of the limitations of
the material properties at high temperatures. In order to
achieve ideal conditions in the design and manufacture of
gas blades, the accuracy in the measurement of the
temperature distribution of the blade is very important. So,
in recent years, many studies have been done to estimate
temperature and stress distribution of the turbine blade [3],
turbulence intensity of the streamline [4,5], the Reynolds
number and Mach number [6,7], to experimentally study
the effect of cooling temperatures and mass flow on the heat
transfer distribution on the turbine blades [8], swirl effects
of unsteady vortices [9,10] as well as the tip and shape of the
blade [11,12]. In addition to these experiments, numerical
studies have been carried out using CFD codes developed
based on the Navier-Stokes equations and boundary layer In this study, numerical analysis is conducted in order
to estimate thermal stresses due to temperature gradient
and stresses caused by aerodynamic and centrifugal effects
on a fractured blade. Figure 1 shows the fractured blade, as it can be seen
from this illustration. Received: 1 July 2018 / Accepted: 11 July 2019 Abstract. In this study the main causes of the failure of a GE-F9 second stage turbine blade were investigated. The stress distribution of the blade which has 6 cooling vents in three modes (with full cooling, closure of half of
the cooling channels, and without cooling) was studied. A three dimensional model of the blade was built and the
fluid flow on the blade was studied using the FVM method. The stress distribution due to centrifugal forces
applied to the blade, temperature gradients and aerodynamic forces on the blade surface was calculated by the
finite element model. The results show that the highest temperature gradient and as a result the highest stress
value occurs for the semi-cooling state at the areas near the blade root and this status is true for the full cooling
mode for the regions far from the root. However, the field observations showed that the failure occurred for the
blade with the semi-cooling state (due to closure of some of the channels) at areas far from the root. It is discussed
that the main factor of the failure is not the stress values being maximum because in the state of full cooling mode
(the state with the maximum stress values) the temperature of the blade is the lowest state and as a result the
material properties of the blade show a better resistance to phenomena like hot corrosion and creep. Keywords: turbine blade failure / blade cooling / thermal stress / stress analysis / finite element modelling Mechanics & Industry 20, 607 (2019)
© AFM, EDP Sciences 2019
https://doi.org/10.1051/meca/2019041 Mechanics & Industry 20, 607 (2019)
© AFM, EDP Sciences 2019
https://doi.org/10.1051/meca/2019041 Mechanics & Industry 20, 607 (2019)
© AFM, EDP Sciences 2019
https://doi.org/10.1051/meca/2019041 Mechanics & Industry 20, 607 (2019)
© AFM, EDP Sciences 2019
https://doi.org/10.1051/meca/2019041 * e-mail: khavasi@znu.ac.ir Mechanics
&Industry Available online at:
www.mechanics-industry.org Available online at:
www.mechanics-industry.org REGULAR ARTICLE 3.1 Fluid flow analysis meshing. For this purpose, several meshing with different
numbers of elements was built by Gambit 2.4.6 software
and mesh independency was investigated. In order to
analyze the fluid flow, the sector volume around the blade
was calculated considering the arrangement of 93 adjacent
turbine blades of the second stage. A total of 3,287,137
structured elements were used, 1,482,314 elements of which
are for the blade body (Fig. 2), and the rest for the
environment around the blade and 6 cooling holes (Fig. 3). It should be noted that according to Figure 2 a boundary
layer mesh was used in areas near surface of the blade. The uniform distribution of the force from the fluid
pressure from bottom to top of the blade is of great
importance. Unequal distribution of the force makes the
gases flow over the blade with different speed and pressure. The difference in rotational speed at the hub and tip of the
blade reduces the gases relative speed at the tip, so less
force is applied to the tip of the blade compared with hub. So, modern gas turbines use blades that have impaction at
the hub and reaction at the tip. Figure 5 shows the distribution of static pressure on the
blade. Pressure drop required for the blade reaction
appears at the tip, and gradually changes to the conditions
without drop for the impaction at the hub. High pressure at
the tip makes the gases move toward the roots of the blade;
this effect is opposed to centrifugal forces which flow gases
into the tip. As a result, a uniform force distribution occurs
across the entire blade. Boundary conditions used in this study is based on
measurements done in the power plant. According to
Figure 4 the inlet mass flow rate is 4 kg/s with the
temperature of 1149 °K. In the case of cooling channels, the
inlet cooling fluid mass flow rate from the compressor is
7.2 104 kg/s for each channel, and its temperature is
620 Kelvin. Periodic boundary condition is used for the
lateral boundaries; the output pressure boundary condition
is used for the outlet surface. Figure 6 shows the static pressure coefficient which is
obtained by Cp = [Px Pref]/[1/2 pV 2
b], where Px and Pref
are the static pressure on the mid-surface of the blade and
the reference pressure on the stagnation point, respectively. Vbisthespeedatthebladeinputthatisusedasareferencefor
dynamic pressure term. 3.1 Fluid flow analysis The differenceoftheresultsfrom the
present study and the result from reference [3] is due to the
physical conditions of the flow. Since the flow around the turbine blade is turbulent, k
–e model was used to simulate the flow. The convergence
criteria determined to be 10‒6 for the residuals. The material properties of the GTD 111 nickel-base
alloy are shown in Table 1. 3 Results and discussion In the sight of theory, the thermal stresses, static and
dynamic forces that affect the performance of the turbine
blades are as follows: 2 Geometry, boundary conditions and
material properties The model of blade was designed using CAD software. Since there are several effective parameters such as
complex geometry of the blade, the unsteady nature of
the flow, relative motion of the components and turbulence
in order to obtain accurate results, there is a need for proper J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 2 Fig. 3. Mesh the surrounding environment of the blade and
cooling holes. Fig. 1. Broken blades of the second stage of power plant and
obstruction of one of the cooling channels. Fig. 1. Broken blades of the second stage of power plant and
obstruction of one of the cooling channels. Fig. 1. Broken blades of the second stage of power plant and
obstruction of one of the cooling channels. Fig. 2. GEF9 turbine blade meshing using boundary layer mesh. Fig. 3. Mesh the surrounding environment of the blade and
cooling holes. In this part these that the effect of each parameter on
the blade performance will be explained. Fig. 2. GEF9 turbine blade meshing using boundary layer mesh. meshing. For this purpose, several meshing with different
numbers of elements was built by Gambit 2.4.6 software
and mesh independency was investigated. In order to
analyze the fluid flow, the sector volume around the blade
was calculated considering the arrangement of 93 adjacent
turbine blades of the second stage. A total of 3,287,137
structured elements were used, 1,482,314 elements of which
are for the blade body (Fig. 2), and the rest for the
environment around the blade and 6 cooling holes (Fig. 3). It should be noted that according to Figure 2 a boundary
layer mesh was used in areas near surface of the blade. 3.2 Heat transfer analysis Figure 7 shows the comparison of the heat transfer
coefficient in the middle part of the blade in the recent
study and the amount of mass and heat transfer coefficient
in the previous studies conducted by others [3,4,5,9,10]. – the aerodynamic forces of flow; – the stresses resulting from temperature gradient; – forces due to centrifugal effect. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 3 Fig. 4. Boundary conditions of the flow variables with 6 cooling channels. Fig. 4. Boundary conditions of the flow variables with 6 cooling channels. Table 1. Properties of the alloy GTD-111 [15]. Ultimate tensile strength (21 °C)
0.2% yield strength (21 °C)
MPa
Ksi
MPa
Ksi
Mechanical properties at room temperature
GTD-111
1095
159
950
135
Density
(g/cm3)
Melting
point (°C)
Specific heat (J/kg K)
Thermal conductivity
(W/m K)
Thermal expansion
(106/K)
21 °C
538 °C
1093 °C
538 °C
1093 °C
93 °C
538 °C
Physical properties
GTD-111
8.11
1230–1315
420
565
710
17.7
27.2
11.6
14 Table 1. Properties of the alloy GTD-111 [15]. The highest amount of heat transfer occurs due to collision
of the main flow on the stagnation point at leading edge. The lowest amount of heat transfer coefficient occurs due
to the development of thermal boundary layer at the
trailing edge. The highest temperature is observed at the
blade tip. results is the condition in which the flow passes the blade
surface. results is the condition in which the flow passes the blade
surface. Since the effect of temperature gradient on stress
distribution occurring in the blade is much more than the
pressure of the fluid on the blade, and with respect to
blades’ working conditions, there is blocking probability in
some cooling channels, therefore, for better comparison,
simulation is done in three modes of (1) full cooling with 6
cooling channels; (2) cooling assuming the blockage of half of
thecooling channels (Fig.8); (3) assuming theblockage of all
cooling channels. Since the effect of temperature gradient on stress
distribution occurring in the blade is much more than the
pressure of the fluid on the blade, and with respect to
blades’ working conditions, there is blocking probability in
some cooling channels, therefore, for better comparison,
simulation is done in three modes of (1) full cooling with 6
cooling channels; (2) cooling assuming the blockage of half of
thecooling channels (Fig.8); (3) assuming theblockage of all
cooling channels. 3.2 Heat transfer analysis In this study, the Reynolds number is considered to
be equal to 1.07 106. One of the reasons for the different
results in some parts is the difference in the blade
geometry studied by other researchers. Of course,
another thing that has impact on the change of these J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 4 three modes but the temperature gradient is reduced at any
section. On the other hand with reduces the temperature
gradient we can also see decrease of corresponding stresses. Figure 12 shows the section 3 at the distance of two In order to find the temperature distribution and Stress
caused by temperature gradients in the blade, 4 sections are
considered with similar distances in the blade according to
Figure 9 for all three cooling modes. Figure 12 shows the section 3 at the distance of two
third of the blades’ length from hub of the blade. The blade
without cooling is subjected to relatively little temperature
changes. In blades with cooling channels, as height
increases the cooling fluid impact reduces, so the section
temperature will be increased. The maximum temperature
of the section (3) happens at the trailing edge of the blade in
all three modes, and the highest temperature is in the mode
without cooling. In this section also a reduction in the
stresses caused by the temperature gradient in three
sections can be seen. Figure 10 shows the temperature distribution and
stress caused by temperature gradients in section 1 for all
three modes. In the full cooling with 6 cooling channels,
maximum blade temperature is significantly lower than
the other two conditions. The highest temperature
gradient is in the half-cooling mode and is equal to 74
Kelvin.The maximum stresses caused by the temperature
gradient in this section is related to half-cooling state. Figure 11 shows the section 2 at the distance of one
third of the blades’ length from hub of the blade. With
increasing altitude, average temperature is increased in all Figure 13 shows near the blade tip, i.e. section (4). Compared to all sections, the maximum temperature
occurred in this section, and in all cases, the trailing edge of
the blade is in high temperature which is due to the cooling
fluid warming and its low impact in this height of the
blades. On the other hand, the temperature difference
between the three modes is reduced. 3.2 Heat transfer analysis On the other hand the
thermal stress at this section is the lowest and is near
together in three states. Fig. 5. Distribution of pressure on both sides of the blade. g
Figure 14 shows the temperature distribution on the
wall attached to the cooling fluid with 6 cooling channels. The results show that with increasing altitude, cooling fluid
gets warmer and the wall temperature goes higher. 3.3 Centrifugal force This force is a function of the rotor rotation speed, turning
radius and mass of blades. This force is a harmful one for
the blades so, designers are always trying to reduce mass of
blades to minimize its amount. In order to calculate Fig. 5. Distribution of pressure on both sides of the blade. Fig. 6. Static pressure coefficient on the mid-surface of the blade. Fig. 6. Static pressure coefficient on the mid-surface of the blade. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 5 Fig. 7. Comparing the local heat transfer on the middle part of the blade in previous researches with the current study. Fig. 7. Comparing the local heat transfer on the middle part of the blade in previous researches with the current study. Fig. 9. Plotted sections for blade temperature analysis. Fig. 8. Cooling channels in semi-open mode (2, 4 and 6 are
closed). Fig. 8. Cooling channels in semi-open mode (2, 4 and 6 are
closed). Fig. 9. Plotted sections for blade temperature analysis. analytically the function of the changes in stress distribu-
tion caused by the centrifugal force along a blade with
variable cross-section, we act as follows [16]: is a piece of the blade, which is applied in the area between
section r and blade end radius Rtip with rotational speed of
3000 rpm. In order to calculate the Fbl for the airfoil,
according to Figure 15, considering a longitudinal element,
centrifugal force is achieved. sr ¼ Fr=Sr
ð1Þ
Fr ¼ FblðrÞ þ Fb
ð2Þ sr ¼ Fr=Sr
ð1Þ ð1Þ FblðrÞ ¼ ∫l
rRHubrv2SðjÞðRHub þ jÞdj:
ð3Þ Fr ¼ FblðrÞ þ Fb
ð2Þ ð3Þ ð2Þ To compute the integral in equation (3) area function
(S(j)) needs to be obtained. To evaluate S(j) the area of
forty different sections of blade obtained and interpolated. S(j) is achieved as follow: where Fr is the amount of centrifugal force and Sr is the area
function at any section of the blade, both of which are
defined as functions of the turning radius of blades. According to Figure 15, Rhub = the radius of the blade hub
and Rtip = the radius of the blade tip. In relation 2, Fb
parameter is the centrifugal force of the Shroud Banding
which is considered to be zero for this kind of blade due to
the lack of Shroud Banding part. 3.3 Centrifugal force Centrifugal force of Fbl(r) SðjÞ ¼ 3:02 105j3 þ 1:36 102j2 9:9 103j
þ2:58 103: J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 6 Fig. 10. Temperature distribution and normal stress caused by temperature gradients in section (1) near the hub in the modes (a)
without cooling, (b) half-cooling, (c) full cooling. Fig. 10. Temperature distribution and normal stress caused by temperature gradients in section (1) near the hub in the modes (a)
without cooling, (b) half-cooling, (c) full cooling. Consequently Fr can be obtained: To examine the stress on the blade from the fluid, the
results of the fluid analysis, including temperature and
pressure distribution on the blade, are inserted as boundary
conditions; and the stresses obtained in different sections of
the blade are investigated by applying a 3000 rpm rotation
on the blade Figure 17 shows the overall stress that applied
on the blades in half cooling state. Fr ¼ 4:837103r5 þ 2:730106r4 þ 9:34105r3
2:851 106r2 þ 2:022 106r: Finally, having the area and force functions, the stress
distribution function can be obtained in accordance with
equation (1) which is shown by solid line in Figure 16. To
ensure the validity of the results obtained by numerical
simulation, the stress distribution due to centrifugal force
compared by analytical results. Numerical results (the
average stress in each section) are also illustrated by circles
in this figure. The agreement between the results is suitable
and the differences can be because of assumptions have
been made in the analytical method; normal stress
distribution in each section is assumed to be constant
and the deformation of the blade is ignored. Field surveys of the second stage blade fracture surfaces
show that the fractures occurred at the section 2 and lower
sections of the blade, started to grow and finally caused the
failure of the blade. Thermo-mechanical analyses also show
the fact that the maximum stress occurred in the hub. It
seems this is because of high temperature gradients in this
area due to the proximity of these pages to the inlet opening
of the cooling fluid on the one hand, and inability of
deformation as a result of root constraint, on the other
hand. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 7 Fig. 11. 3.3 Centrifugal force Temperature distribution and normal stress caused by temperature gradients in section (2) at the distance of one third of the
blades’ length from hub of the blade in the modes (a) without cooling, (b) half-cooling, (c) full cooling. Fig. 11. Temperature distribution and normal stress caused by temperature gradients in section (2) at the distance of one third of the
blades’ length from hub of the blade in the modes (a) without cooling, (b) half-cooling, (c) full cooling. – It can be said about the pressure that in three modes of
6- and 3-channel cooling and without cooling, there is
no significant change in the pressure on the blades, and
the pressure is almost equal in all modes, and the
highest pressure is at the stagnation point near the
peak leading. Another important point is that the
influence of this parameter is very low compared to the
impact of stresses caused by rotation and temperature
gradient. – It can be said about the pressure that in three modes of
6- and 3-channel cooling and without cooling, there is
no significant change in the pressure on the blades, and
the pressure is almost equal in all modes, and the
highest pressure is at the stagnation point near the
peak leading. Another important point is that the
influence of this parameter is very low compared to the
impact of stresses caused by rotation and temperature
gradient. 4 Conclusion Internal cooling of GEF9 turbine blade was presented and
investigated in this paper. In the first step, the cooling air
flow inside the channel was simulated and evaluated. In the
next step, normal stresses were evaluated in four sections
using the results obtained from the fluid analyses and
cooling system effect on the temperature parameters. According to the results presented in this report, the
following cases can be presented as the conclusion: According to the results presented in this report, the
following cases can be presented as the conclusion: Investigating the four sections cut on the blade, it can be
concluded about the applied stress that the stress will be
reduced gradually with increasing distance from the
blade root, and the maximum stress occurs in the section
near the blade root. These stresses are caused by
applying blade rotation, temperature gradient and fluid
pressure on the blade. Comparing the three modes
above, it can be found that highest stress is related to
the 6-channel cooling mode. Stress difference between
cooling and without cooling modes is at maximum at the
blade root. – Investigating the four sections cut on the blade, it can be
concluded about the applied stress that the stress will be
reduced gradually with increasing distance from the
blade root, and the maximum stress occurs in the section
near the blade root. These stresses are caused by
applying blade rotation, temperature gradient and fluid
pressure on the blade. Comparing the three modes
above, it can be found that highest stress is related to
the 6-channel cooling mode. Stress difference between
cooling and without cooling modes is at maximum at the
blade root. – Using
cooling system
as
a
channel
in
the blade
significantly reduces the temperature in all parts of the
blade. Results showed that maximum temperature is in
the mode without cooling at all sections, and the
temperature difference is more tangible in the modes
of cooling and without cooling in the blade root, and this
difference decreases with increasing altitude; but in
general, the temperature increases with increased blade
height, and maximum temperature occurs in the upper
part of the blade. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 8 8 Fig. 12. Nomenclature g
– It can be said blade in full cooling mode provides turbine
blade function optimal conditions compared to the half-
cooling and without cooling modes. Thanks to cooling,
the blade temperature operating range is decreased and
as a consequence, the material can tolerate higher
stresses. Cp
Local pressure coefficient, [Px ‑ Pref]/[1/2 pV 2
b]
Cx
Blade axial chord length
Px
Local pressure
Pref
Reference pressure
Fr
Centrifugal force as a function of blades’ radios
Sr
Area of a cross section of the blade as a function of
blades’ radios
Rhub
Radios of the blade at hub
Rtip
Radios of the blade at tip
Fb
Centrifugal force of the Sherrod bonding area
Fbl(r)
Centrifugal force of a section of the blade that is
between r cross section and r of tip of blade p
Cx
Blade axial chord length Local pressure 4 Conclusion Temperature distribution and normal stress caused by temperature gradients in section (3) at the distance of one third of the
blades’ length from hub of the blade in the modes (a) without cooling, (b) half-cooling, (c) full cooling. Fig. 12. Temperature distribution and normal stress caused by temperature gradients in section (3) at the distance of one third of the
blades’ length from hub of the blade in the modes (a) without cooling, (b) half-cooling, (c) full cooling. Fig. 12. Temperature distribution and normal stress caused by temperature gradients in section (3) at
blades’ length from hub of the blade in the modes (a) without cooling, (b) half-cooling, (c) full coolin – In this study, cooling channels was considered alter-
nately closed, however, due to the expected weather
conditions, channels would be closed consecutively
which leads to create a more intense temperature
gradient. – Another solution is regular oversee of the hot paths of the
turbine. – Another solution is regular oversee of the hot paths of the
turbine. 4.1 Solutions to prevent such events – Some infiltration filters can be installed in the way air
flow to the compressor to prevent the entrance of dusts
and impurities. These filters should be visited periodi-
cally. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 9 Fig. 13. Temperature distribution and normal stress caused by temperature gradients in section (4) at tip of the blade in the modes (a)
without cooling, (b) half-cooling, (c) full cooling. Fig. 13. Temperature distribution and normal stress caused by temperature gradients in section (4) at tip of the blade in the modes (a)
without cooling, (b) half-cooling, (c) full cooling. to the
Fig. 15. Schema of a moving blade having Sherrod bonding with
corresponding coordinates [16]. t to the
Fig. 15. Schema of a moving blade having Sherrod bonding with
corresponding coordinates [16]. Fig. 14. Temperature distribution on the wall adjacent to the
cooling fluid with 6 cooling channels. Fig. 15. Schema of a moving blade having Sherrod bonding with
corresponding coordinates [16]. Fig. 14. Temperature distribution on the wall adjacent to the
cooling fluid with 6 cooling channels. Fig. 15. Schema of a moving blade having Sherrod bonding with
corresponding coordinates [16]. J. Rahimi et al.: Mechanics & Industry 20, 607 (2019) 10 Fig. 16. The normal stress from centrifugal force. [3] K.M. Kim, J.S. Park, D.H. Lee, T.W. Lee, H.H. Cho,
Analysis of conjugated heat transfer, stress and failure in a
gas turbine blade with circular cooling passages, Eng. Fail. Anal. 18, 1212–1222 (2011) [4] L. Zhang, J.-C. Han, Influence of mainstream turbulence on
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(1999) [1] J. Polezhaev, The transpiration cooling for blades of high
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[14] G. Medic, P.A. Durbin, J. Turbomach. 124, 193–199 (2002) [15] J.R. Davis, ASM specialty handbook: heat-resistant materi-
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Dynamic response of carbon storage to ecological restoration measures in Liupanshui City, Mountain, Water, Forest, Field, Lake and Grassland
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Dynamic response of carbon storage to ecological
restoration measures in Liupanshui City, Mountain,
Water, Forest, Field, Lake and Grassland Jiajing Ning
Guizhou University
Hu Wang
Guizhou Chuyang Ecological Environmental Protection Technology Co., Ltd
Qiong Yang
Guizhou University
Tengbing He
Guizhou University
Tianling Fu
(
tlfu@gzu.edu.cn
)
Guizhou University
Article
Keywords: Mountains, rivers, forests, fields, lakes and grasses; Ecological restoration; Carbon storage;
Land use type change
Posted Date: June 5th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-2862194/v1
License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License Abstract To verify the impact of ecological restoration of mountains, forests, fields, lakes and grasses on carbon
stocks, the implementation of ecological restoration of mountains, forests, fields, lakes and grasses in the
karst region of southwestern China, the ecologically fragile area of Liupanshui City, western Guizhou
Province, was analyzed by means of RS and GIS, corresponding to the carbon stocks in the region. The
results showed that the carbon stocks in the study area in 2015, 2018 and 2020 were 424.05 × 106 t,
426.46 × 106 t and 436.91 × 106 t, respectively, and the carbon stocks in the area where ecological
restoration actually occurred in 2015, 2018 and 2020 were 28.85 × 106 t, 29.31 × 106 t and 30.63 ×106 t,
all showing an increasing trend, with a cumulative increase of 12.86 ×106 t in the study area and 1.78
×106 t in the actual occurrence area of ecological restoration, and analyzed the effects of different
implementation measures on carbon stock changes, among which, afforestation (non-shrub) had the
best effect on regional carbon stock increase, afforestation (shrub) was not obvious, while soil
improvement works for crop health had There is no significant effect on carbon stock. It can be
concluded that the carbon stock of Liupanshui city responded positively to the ecological restoration
measures of landscape, forest, field, lake and grass. Article License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. License:
This work is licensed under a Creative Commons Attribution 4.0 International
License. Read Full License Page 1/23 Page 1/23 Page 1/23 1. Introduction Global climate change is an increasingly serious problem, posing a major challenge to human survival
and sustainable development. Carbon storage in terrestrial ecosystems is an important part of global
carbon storage [1], which effectively regulates regional climate by absorbing and releasing greenhouse
gases from the atmosphere, and plays a crucial role in mitigating global warming [2]. As a major source
of greenhouse gases, carbon emissions are gradually aggravating global warming, and in order to
achieve the goal of carbon peaking and carbon neutrality, countries around the world are formulating
relevant policies and implementing low-carbon development strategies according to their own national
conditions [3]. 2020, the 75th session of the United Nations General Assembly, China put forward the goal
of reaching carbon peaking by 2030 and carbon neutrality by 2060 [4]. China has implemented a series of
comprehensive national land remediation and ecological protection and restoration efforts to cope with
the adverse effects on natural ecosystems caused by unreasonable development and construction
activities in the process of rapid urbanization and industrialization, and has achieved certain results [5]. However, most of the previous remediation and restoration efforts were sectoral projects implemented for
a single element and a single goal, which were not systematic, holistic and comprehensive enough, which
restricted the effect of remediation and restoration [6]. After the 18th Party Congress, China put forward
the concept of "mountain, water, forest, field, lake, grass, and sand are a community of life" for the
problems of scattered departments, single remediation tasks, weak overall system, and poor remediation
and restoration effects in remediation and restoration, and systematically promoted the integrated
protection and restoration of mountain, water, forest, field, lake, grass, and sand, and Positive progress
has been achieved. 1. Introduction Page 2/23 Mountain, water, forest, field, lake, grass and lake have changed land use types on a large scale through
large-scale ecological restoration, including various measures linked together, leading to land use change
[7], and as land use change occurs, it will subsequently lead to many situations, such as land use change
plays a key role in ecological processes such as water cycle, carbon and nitrogen cycle, and ecosystem
services [8], and some studies have shown that land use change affects greenhouse gas emissions
mainly through land use category conversion [9], for example, conversion from forest or grassland to
agricultural land may reduce carbon stocks [10], and in recent decades, dramatic climate change and
human activities have led to significant land use/change, such as glacial melting, grassland
development, afforestation, desertification management, and agricultural expansion [11]. This study
focuses on the dynamic response of carbon stocks by exploring the large land use changes that have
resulted with the ecological restoration of mountains, water, forests, fields, lakes and grasses. The traditional field survey method mainly uses regional carbon density profiles of different vegetation
and soil types to estimate carbon stocks, which is relatively simple and accurate, but the applicable area
is small and the assessment results cannot reflect the dynamic changes of carbon stocks [13]. The use of
models can simulate, predict and assess carbon stocks at different scales, such as global, national and
regional, among which the InVEST model is the most widely used, and previous studies have shown that
the InVEST model can estimate carbon stocks in a simple and reliable way [14]. storage [14], and the
model is based on land use type maps and carbon density, and estimates carbon stocks using four
carbon pools: aboveground biomass, belowground biomass, soil carbon density, and dead organic
carbon, and has been widely used by many scholars to assess regional carbon stocks and their spatial
and temporal distribution patterns [15]. 2.1 Overview of the study area As shown in Fig. 1,the study area is located in the karst region of southwestern China and the ecologically
fragile area of Liupanshui City in western Guizhou Province, with a total land area of 9,914 km2. It
belongs to the north subtropical - warm temperate climate zone, with abundant rainfall, the average
annual rainfall is 1363.39 mm, and the rainfall is mostly concentrated between May and October. Due to
the undulating terrain, the temperature vertically changes significantly, and there are large differences in
light, radiation and heat in various places, and the ecological environment is complex and diverse. Liupanshui City carried out the ecological restoration project in the Wumeng Mountains, and the actual
ecological restoration occurred mainly in the coal mining concentration area of Dahe Town in Zhongshan
District, which is one of the major projects of ecological restoration in the Wumeng Mountains of Guizhou
Province. Through the ecological environment survey, there are seven major ecological problems in
Dahue Town: geological disasters, land suppression and destruction problems, vegetation degradation,
soil erosion, river destruction (siltation), surface water pollution, and soil pollution problems. This study
mainly focuses on the changes of carbon stock in Dahue town of Liupanshui City, where the ecological Page 3/23 Page 3/23 restoration project of Zhongshan District, i.e., Liupanshui City, was implemented, and the dynamic
response of the main project measures of the project to the carbon stock of Liupanshui City. 2.2 Data sources Data sources: (1) land use data from the Geographic State Monitoring Cloud Platform
(http://www.dsac.cn/); (2) land use type data from the Chinese Academy of Sciences Land Use/Cover
Standard; (3) basic geographic information data from the 1:1 million national basic geographic database
published by the National Basic Geographic Information Center (http://www) .webmap.cn), including
administrative boundaries, roads, railroads, rivers, and rural settlements in Liupanshui; (4) meteorological
data from the China Meteorological Data Network (http://data.cma.cn/); (5) elevation data from the
Geospatial Data Cloud (https://www.gscloud.cn/search), using the is ASTERGDEMV2 version data. The
spatial resolution of all data used in this paper is 30m, and the spatial coordinate system is
Krasovsky_1940_Albers. The aboveground carbon density of national horizontal cropland, forest land and grassland was obtained
according to the relevant studies of Xu Quan et al [16] and Xie Xianli et al [17]; the belowground carbon
density of national horizontal cropland, forest land and grassland was determined according to the study
of Xie Xianli et al [17]; the soil carbon density of national horizontal cropland, grassland and forest land
was determined according to the studies of Li Kejan and Ma Qinyan et al [18, 19]; the soil carbon density
of national horizontal cropland, grassland and forest land was obtained according to the study of Tui
Xiaowei [20], the above-ground carbon density and soil carbon density of watershed, urban and rural
industrial and mining construction land in Guizhou province were obtained, and the subsurface carbon
density was defaulted to 0. Then, by referring to the data provided by the national meteorological data
network, the multi-year average temperature of the whole country, Guizhou province and Liupanshui city
was obtained, and finally, the model on the relationship between biomass carbon density and soil carbon
density and temperature and precipitation, respectively, from the studies of Chen Guangshui et al [21] and
Zeng Weisheng et al [22] was adopted to obtain the relationship between biomass carbon density and
soil carbon density. Finally, the relationship models of biomass carbon density and soil carbon density
with temperature and precipitation, respectively, from the studies of Chen Guangshui et al. The specific
data are shown in Table 1. 2.2 Data sources Page 4/23 Table 1
Carbon density of various parts of different land use types(t/hm2)
Land Use
Type
Above-ground
biogenic carbon
stocks
Subsurface biogenic
carbon stocks
Soil
carbon
density
Carbon density of
dead organic matter
Arable
land
5.70
0.68
90.56
0.00
Woodland
26.50
4.27
84.03
0.00
Grassland
3.40
11.70
101.27
0.00
Waters
1.00
0.50
46.90
0.00
Residential
land
0.00
0.00
50.65
0.00
Unused
land
0.00
0.00
0.00
0.00
2.3 Research Methodology Table 1 arbon density of various parts of different land use types(t/hm2) 2.3 Research Methodology In this study, the InVEST model was used to estimate regional ecosystem carbon stocks. The model
consists of a series of sub-modules that can simulate the effects of land use change on ecosystem
service functions, in which the carbon stock module divides the carbon stock of each land use type into
four basic carbon pools: aboveground biogenic carbon (
), below-ground biogenic carbon (
),
soil carbon (
), dead organic matter carbon (
). The model combines the land use data and the
carbon pool data corresponding to each land use type to generate the spatial distribution map of carbon
stocks. According to the classification of land use, the average carbon density
of different land use
types are calculated and counted separately, and the calculation formula is as follows:
Cabove
Cbelow
Csoil
Cdead
Ctotal Ctotal = Cabove + Cbelow + Csoil + Cdead 1 Based on the carbon density and land use data of different land use types, the total carbon stock of each
land use type in the study area was calculated: Based on the carbon density and land use data of different land use types, the total carbon stock of each
land use type in the study area was calculated: Ctotali = (Cabovei + Cbelowi + Csoili + Cdeadi) × Ai 2 2 where :
is the average carbon density of aboveground biogenic carbon, and
is the average
carbon density of belowground biogenic carbon, and
is the average carbon density of soil carbon,
and
is the dead organic matter carbon, and
is the area of the land use, and
is the total
carbon stock of each land use type. Cabovei
Cbelowi
Csoili
Cdeadi
Ai
Ctotali where :
is the average carbon density of aboveground biogenic carbon, and
is the average
carbon density of belowground biogenic carbon, and
is the average carbon density of soil carbon,
and
is the dead organic matter carbon, and
is the area of the land use, and
is the total
carbon stock of each land use type. Cabovei
Cbelowi
Csoili
Cdeadi
Ai
Ctotali Page 5/23 Page 5/23 Data processing: (1) According to the land use data of three time points in Liupanshui City and the actual
situation of project implementation, the ecological restoration project was divided into project
implementation stage (2015–2018) and ecological benefit generation stage (2018–2020) respectively. 2.3 Research Methodology The carbon stock images outputted by the carbon storage module were used for carbon stock change
statistics according to the administrative division of Liupanshui City by using the regional statistics tool
in ArcGIS software, so as to analyze the changes in the spatial distribution of carbon stocks in
Liupanshui City and recount the area of each category; then the total carbon stocks of the three phases
were obtained by combining with the land use distribution map. And according to the same approach, the
carbon stocks of the actual occurrence area of ecological restoration during 2015–2020 were estimated
separately by using the carbon stock module of InVEST model. 3. Results and Discussion The carbon stocks in the study area during 2015–2020 are shown in Fig. 2. The total carbon stocks in the
study area in 2015, 2018 and 2020 are 424.05×106 t, 426.46×106 t and 436.91×106 t, respectively, with an
overall increasing trend and a cumulative increase of 12.85×106 t in 2020 compared with 2015. The
specific data are shown in Table 2. Table 2
Whole change of carbon storage from 2015 to 2020
ProjectItem
2015
2018
2020
Change volume
2015–2020
Variation/106 t
Rate of change
2015–2020
Change rate/%
Total Carbon
Reserves
/106 t
424.05
426.46
436.91
12.86
3.03
Average carbon
stock
/(t-hm²)
782.31
786.43
794.13
11.82
1.51 The carbon stock of forest land has been dominant during 2015–2020. The carbon stocks of woodlands
and grasslands showed an increasing trend. Among them, the carbon stock of forest land increased
prominently with a growth rate of 13.2%; the carbon stock of cropland and watershed showed a
decreasing trend, among which the carbon stock of cropland decreased most prominently with a
decrease rate of 5.29%; the carbon stock of unused land did not change (Table 3). Page 6/23 Page 6/23 Table 3
Carbon storage change for each land use types from 2015 to 2020
Land type
Arable
land
Woodland
Grassland
Waters
Residential
land
Unused
land
Carbon stock in
2015/106 t
119.21
211.97
80.56
9.03
3.28
0
2018 carbon
stocks/106 t
117.37
216.52
81.19
8.38
3.00
0
Carbon stock in
2020/106 t
113.92
225.17
86.74
8.11
2.97
0
Carbon stock change
/106 t
-5.29
13.2
6.18
-0.92
-0.31
0 Table 3 The carbon stocks of the ecological restoration actual occurrence area for the period 2015–2020 were
estimated separately using the carbon stock module of the InVEST model, and the results are shown in
Table 4. In terms of quantity, the total carbon stocks in the ecological restoration actual occurrence area
in 2015, 2018 and 2020 were 28.85×106 t, 30.00×106 t and 32.13×106 t, respectively, with an overall
increasing trend and a cumulative increase of 3.28×106 t. The total carbon stocks in the ecological
restoration actual occurrence area in 2015, 2018 and 2020 were estimated as 28.85×106 t, 30.00×106 t
and 32.13×106 t, respectively. 3. Results and Discussion Table 4
Carbon storage change for each land use types from 2015 to 2020
ProjectItem
2015
2018
2020
Amount of change
Variation/106 t
Rate of change
Change rate/%
Carbon stock
/106 t
28.85
29.31
30.63
1.78
6.20
Average carbon stock
/(t-hm²)
778.67
784.91
799.26
20.59
2.64
During 2015–2020, the carbon stock of forest land was equally dominant in the areas where
ecological restoration actually occurred. The carbon stocks of woodlands and grasslands showed an
increasing trend. Among them, the carbon stock of grassland increased prominently with a growth
rate of 21.69%, and the carbon stock of forest land increased with a growth rate of 17.61%; the carbon
stock of cropland and water area showed a decreasing trend, among which the carbon stock of
cropland decreased most prominently with a decrease rate of 9.02%.(Table 5) During 2015–2020, the carbon stock of forest land was equally dominant in the areas where
ecological restoration actually occurred. The carbon stocks of woodlands and grasslands showed an
increasing trend. Among them, the carbon stock of grassland increased prominently with a growth
rate of 21.69%, and the carbon stock of forest land increased with a growth rate of 17.61%; the carbon
stock of cropland and water area showed a decreasing trend, among which the carbon stock of
cropland decreased most prominently with a decrease rate of 9.02%.(Table 5) During 2015–2020, the carbon stock of forest land was equally dominant in the areas where
ecological restoration actually occurred. The carbon stocks of woodlands and grasslands showed an
increasing trend. Among them, the carbon stock of grassland increased prominently with a growth
rate of 21.69%, and the carbon stock of forest land increased with a growth rate of 17.61%; the carbon
stock of cropland and water area showed a decreasing trend, among which the carbon stock of
cropland decreased most prominently with a decrease rate of 9.02%.(Table 5) During 2015–2020, the carbon stock of forest land was equally dominant in the areas where
ecological restoration actually occurred. The carbon stocks of woodlands and grasslands showed an
increasing trend. 3. Results and Discussion Among them, the carbon stock of grassland increased prominently with a growth
rate of 21.69%, and the carbon stock of forest land increased with a growth rate of 17.61%; the carbon
stock of cropland and water area showed a decreasing trend, among which the carbon stock of
cropland decreased most prominently with a decrease rate of 9.02%.(Table 5) Page 7/23 Table 5
Carbon storage change for each land use types in the actual area of ecological restoration from 2015 to
2020
Land type
Arable
land
Woodland
Grassland
Waters
Residential
land
Unused
land
Carbon stock in
2015/106 t
6.32
16.13
4.38
1.26
0.76
0
Carbon stock in
2018106 t
6.18
16.87
4.62
1.31
0.72
0
Carbon stock in
2020/106 t
5.95
17.67
4.93
1.39
0.69
0
Carbon stock change
/106 t
-0.37
1.54
0.55
0.13
-0.07
0
3.2 Dynamic response of carbon stocks to ecological
restoration measures
3 2 1 Vegetation restoration and greening 3.2 Dynamic response of carbon stocks to ecological
restoration measures 3.2.1 Vegetation restoration and greening As shown in Fig. 3,the project is mainly deployed in Dahebian coal mine gangue mountain, no main
gangue mountain, Dahebian coal mine gangue mountain area of 5.31 hm2, take the side discharge, side
treatment method for management, mainly using gangue mountain slope reduction cutting, retaining
wall, drainage ditch and vegetation restoration and greening and other projects for management. Related
measures include site leveling about 0.330 hm2, covering soil area about 6800 m2, planting 365 trees,
grass seeding area about 0.35 hm2. The carbon stocks of the three project sites were obtained by remote sensing images combined with
aerial photography interpretation by UAV using the InVEST model, as shown in the figure, and the specific
data are shown in the Table 6, the vegetation restoration and greening project implementation sites,
during the period of 2015–2018, did not change significantly, and the carbon stocks increased by
0.63×106 t from 2018 to 2020. The specific data are shown in Fig. 4. Table 6
Changes in vegetation restoration and green carbon stock from 2015–2020
ProjectItem
2015
2018
2020
2015–2020 Variation/106 t
Carbon stock/106 t
5.62
5.71
6.34
0.72 3.2.2 Vegetation degradation re-greening 3.2.2 Vegetation degradation re-greening 3.2.2 Vegetation degradation re-greening Page 8/23 As shown in Fig. 5,The project is located in the northern part of Dadi Village and the vegetation
degradation area caused by Wangjiazhai and Naluo coal mines, with a total treatment area of
292.71hm2. The relevant measures include setting up protection areas, planting shrubs (tea trees) as the
main measures, including the main sub-projects: shrub planting, construction of production roads,
construction of machine farming roads, construction of water reservoirs, construction of irrigation
pipeline network and other measures. Completion of revegetation 330 hm2. As shown in Fig. 5,The project is located in the northern part of Dadi Village and the vegetation
degradation area caused by Wangjiazhai and Naluo coal mines, with a total treatment area of
292.71hm2. The relevant measures include setting up protection areas, planting shrubs (tea trees) as the
main measures, including the main sub-projects: shrub planting, construction of production roads,
construction of machine farming roads, construction of water reservoirs, construction of irrigation
pipeline network and other measures. Completion of revegetation 330 hm2. 3.2.1 Vegetation restoration and greening The carbon stocks of the three project sites were obtained by remote sensing images combined with
aerial photography interpretation by UAV using InVEST model, as shown in the figure, and the specific
data are shown in the Table 7, the vegetation degradation regeneration project implementation sites,
during the period of 2015–2018, the carbon stocks increased by 0.19×106 t, and during the period of
2018–2020, the carbon stocks increased by 0.13×106 t. The specific data are shown in Fig. 6. Table 7
Change in carbon stock of vegetation degradation re-greening, 2015–2020
ProjectItem
2015
2018
2020
2015–2020 Variation/106 t
Carbon stock/106 t
4.99
5.18
5.31
0.32 Table 8
Change in carbon stock for soil improvement projects, 2015–2020
ProjectItem
2015
2018
2020
2015–2020 Variation/106 t
Carbon stock/106 t
2.17
2.17
2.18
0.01 3.3 Analysis of the contribution of ecological restoration to
carbon stocks 3.2.3 Soil improvement works As shown in Fig. 7,The soil improvement project is mainly arranged in the arable land within the Dazhai
bag in Dazhai Village, totaling 51.34 hm2. The project uses in-situ passivation restoration + low
absorption vegetable species planting to reduce the activity of heavy metals in the soil, reduce the
accumulation in vegetables, ensure the safety of agricultural products and realize the safe use of soil. Under the premise of crop quality safety, try to ensure normal agricultural production; realize the
production and restoration of the dam area at the same time. The main project includes: in-situ
passivation restoration + low absorption vegetable species planting: 450 mu of leafy vegetables (lotus
white, cabbage, lettuce, cilantro, shallot, garlic seedlings, coronary, celery, spinach, pea tips, etc., fishy
grass), 150 mu of melon vegetables (zucchini, pumpkin) and 170 mu of bean vegetables (beans, peas,
beans). The carbon stocks of the three project sites were obtained by remote sensing images combined with
aerial photography interpretation by UAV using the InVEST model, as shown in Fig. The specific data are
shown in the Table 8, the soil improvement project implementation sites, during 2015–2018, there was no
significant change in carbon stocks, and during 2018–2020, the carbon stocks increased by 0.01×106 t. The specific data are shown in Fig. 8 Page 9/23 3.3 Analysis of the contribution of ecological restoration to
carbon stocks It is obvious from the data that the growth of carbon stock in the study area is 12.86×106 t with a change
rate of 3.03%, and the growth of carbon stock in the area where the ecological restoration actually
occurred is 1.78×106 t with a change rate of 6.20%, where the proportion of carbon stock in the area
where the ecological restoration actually occurred in the whole study area increased from 6.80–7.01%,
and the change accounts for the total change 13.74%.(Table 9) Table 9
Comparison of carbon stock changes from 2015–2020
ProjectItem
2015
2018
2020
Amount of
change
Rate of
change
Variation/106
t
Change
rate/%
Carbon stock in the study area/106 t
424.05
426.46
436.91
12.86
3.03%
Carbon stock in the area where ecological
restoration actually occurs/106 t
28.85
29.31
30.63
1.78
6.20%
Percentage/%
6.80
6.87
7.01
13.74
/
By analyzing the proportion of the increase in carbon stock of each land type in the actual occurrence
area of ecological restoration to the total study area, we obtained the data as shown in Table 10, the
contribution of forest land to the increase of carbon stock in ecological restoration reached 11.67%, and
the contribution of grassland to the increase of carbon stock reached 8.89%, which is mainly due to the
large area of afforestation caused by the reforestation and revegetation. Table 9
Comparison of carbon stock changes from 2015–2020
ProjectItem
2015
2018
2020
Amount of
change
Rate of
change
Variation/106
t
Change
rate/%
Carbon stock in the study area/106 t
424.05
426.46
436.91
12.86
3.03%
Carbon stock in the area where ecological
restoration actually occurs/106 t
28.85
29.31
30.63
1.78
6.20%
Percentage/%
6.80
6.87
7.01
13.74
/ Table 9
Comparison of carbon stock changes from 2015–2020 By analyzing the proportion of the increase in carbon stock of each land type in the actual occurrence
area of ecological restoration to the total study area, we obtained the data as shown in Table 10, the
contribution of forest land to the increase of carbon stock in ecological restoration reached 11.67%, and
the contribution of grassland to the increase of carbon stock reached 8.89%, which is mainly due to the
large area of afforestation caused by the reforestation and revegetation. 3.3 Analysis of the contribution of ecological restoration to
carbon stocks By analyzing the proportion of the increase in carbon stock of each land type in the actual occurrence
area of ecological restoration to the total study area, we obtained the data as shown in Table 10, the
contribution of forest land to the increase of carbon stock in ecological restoration reached 11.67%, and
the contribution of grassland to the increase of carbon stock reached 8.89%, which is mainly due to the
large area of afforestation caused by the reforestation and revegetation. By analyzing the proportion of the increase in carbon stock of each land type in the actual occurrence
area of ecological restoration to the total study area, we obtained the data as shown in Table 10, the
contribution of forest land to the increase of carbon stock in ecological restoration reached 11.67%, and
the contribution of grassland to the increase of carbon stock reached 8.89%, which is mainly due to the
large area of afforestation caused by the reforestation and revegetation. Page 10/23 Table 10
Carbon stock contribution of the actual occurrence area of ecological restoration, 2015–2020
ProjectItem
Volume of change in the
study area /106 t
Actual occurrence of zone
change /106 t
Change volume as a
percentage
Arable land
-5.29
-0.37
6.99%
Woodland
13.2
1.54
11.67%
Grassland
6.18
0.55
8.89%
Waters
-0.92
0.13
14.13%
Residential
land
-0.31
-0.07
22.58%
Unused
land
0
0
0.00% By analyzing the impact of each measure on the change of carbon stock, it can be found that the
vegetation restoration and greening measures have changed the land use type the most, mainly because
of the large number of trees and land leveling, while the vegetation degradation restoration is also a large
number of trees, but the tree species chosen is mainly shrubs (tea tree), which has a low carbon density,
resulting in little change in carbon stock. The soil improvement project did not have much impact on
carbon stock before and after the implementation, mainly because the restoration goal of the soil
improvement project is to reduce the activity of heavy metals in the soil, reduce the accumulation of
vegetables, ensure the safety of agricultural products, and realize the safe use of soil. This shows that the
land use type was not changed, resulting in little change in carbon stocks. 4.1 Effect of carbon density data on estimation results The accuracy of carbon stock estimation results is mainly influenced by the input parameter data, so the
selection of reasonable carbon density data is the key to model simulation. The carbon density data used
in this study are mainly from previous related carbon density studies, and the selected data are processed
to obtain carbon density data in Liupanshui area by carbon density correction formula. The carbon
density data obtained in this study were compared with the carbon density data obtained by the actual
measurement method in similar areas, and the results were relatively similar. 4. Discussion Many studies have shown that [23]. that the increase of forest land is beneficial to the increase of
regional carbon stock, and the present study reached a similar conclusion, which is mainly related to the
increase of forest land driven by the implementation of landscape, water, forest, field, lake and grass
projects. It is worth noting that although the increase in the area of watershed and residential land is not
conducive to the increase of regional carbon stock, its impact on carbon stock is not significant, mainly
because the amount of area of these two types of land is much smaller than the increase in forest land,
which is an important factor leading to the overall trend of increasing carbon stock in the region. At the
same time, this also fully indicates that with the further effect of the ecological restoration project of
mountains, water, forests, fields, lakes and grasses, the carbon stock in the region will continue to
increase in the future period. Conversion of cropland to forest land exhibits strong carbon sink [24] The conversion of arable land to
construction land will reduce the regional carbon sequestration capacity, which is influenced by
mountainous terrain, with dry land mostly distributed on steep slopes and paddy land mostly distributed Page 11/23 Page 11/23 on dams. Under the coupling effect of the ecological restoration project of mountains, water, forests,
fields, lakes and grasses and rapid urbanization, a large amount of dryland is converted to forest land
and paddy land is converted to construction land, which makes the transfer of dryland have a positive
effect on the increase of regional carbon stock, while the transfer of paddy land has a negative effect. If
this scenario is developed, the contribution of dryland transfer to regional carbon stock increase will
always be positive in the future, while the transfer of paddy land will continue to maintain the negative
effect. 4.2 Impact of land use change on carbon stock The results of this study show that the carbon stock in the study area increased by 12.85×106 t from
2015 to 2020, showing an overall increasing trend, indicating that the carbon sequestration function of
the ecosystem in the Liupanshui region has improved. Due to the model setting, the change of carbon
stock mainly depends on the interconversion between different land types in the region. Liupanshui area
is an ecologically fragile area because of the long-term mining exploitation, and its ecological
environment is easily changed by external disturbance, while in recent years is the implementation of
ecological management and protection projects also lead to significant changes in land use in the region. First, land use change is a complex process influenced by multiple socioeconomic and natural drivers. The time span of carbon density data used in this study is 2015–2020, which does not consider the
temporal changes of carbon density of different land use types. Meanwhile, the carbon stock module of
the InVEST model only considers the carbon density variation of different land use types, ignoring the
spatial heterogeneity of carbon density within the same land use type. Therefore, the carbon density
should be validated in future studies with the measured data. The implementation of the ecological restoration project of landscapes, forests, fields, lakes and grasses
has caused changes in land use, which affects the carbon sequestration capacity of the ecosystem by
changing the structure (species composition, biomass) and function (biodiversity, energy balance, carbon
cycle, etc.) of the ecosystem. During the conversion of forest and grassland to cropland and cropland to
urban construction and industrial land, the humus entering the soil decreases, and tillage practices also
destroy the conservation of soil organic matter, increase the mineralization of soil humus, and reduce soil
carbon storage. This is more consistent with the findings of Rong Yuejing et al. (2016) on the Taihu River
basin in the lower reaches of the Yangtze River and Gao Hongjuan et al. (2016) on the Wujiang River Page 12/23 Page 12/23 Page 12/23 basin in the upper reaches of the Yangtze River. The carbon density of different land use types is an
important factor influencing land use change on carbon stock changes, and carbon density is influenced
by multiple factors such as climate, hydrological conditions, topography, and soil type (Xiqiao Liu et
al.,2017). 4.2 Impact of land use change on carbon stock When existing studies use the InVEST model to assess carbon stocks, most of them are based
on the carbon density that comes with the model and are modified by combining field surveys and related
studies, which greatly improves the universality and scientific validity of the InVEST model (Jinpu Li et
al.,2020). To further improve the estimation accuracy, monitoring and investigation of carbon density of
different land use types need to be strengthened in future studies to obtain long-term and dynamic
observation data to reduce the uncertainty brought by carbon density. The impact of land use change on
carbon stock is ultimately driven mainly by human social activities (Ting-Hui Wang et al.,2021), such as
administrative orders and related laws that have a direct impact on land use types (Jiayi Fu et al.,2020). 5. Conclusion In this study, based on RS and GIS means, with the help of InVEST model carbon stock module, we
assessed the impact of land use changes on carbon stock under the mountain, water, forest, field, lake
and grass restoration model in the karst region of southwest China, the ecologically fragile area of
Liupanshui City, western Guizhou Province during 2015–2020, and came to the following main
understandings:(1) the carbon in the study area in 2015, 2018 as well as 2020 The carbon stocks in the
study area in 2015, 2018 and 2020 were 424.05×106 t, 426.46×106 t and 436.91×106 t, respectively, and
the carbon stocks in the ecological restoration actual occurrence area in 2015, 2018 and 2020 were
28.85×106 t, 29.31×106 t and 30.63×106 t, respectively, all of which showed an increasing trend, with a
cumulative increase of 12.86×106 t in the study area and a cumulative increase of 1.8×106 t in the
ecological restoration actual occurrence area. (2) Forest land and cropland are the most important carbon
pools in the study area, and their carbon stocks account for 83.86% of the total carbon sequestered by all
land use types in the study area; (3) the total area of the actual ecological restoration area accounts for
less than 7% of the total area of the study area, but it contributes 13.74% to the increase of carbon stocks
in the study area; (4) the ecological restoration work in the landscape, forest, field, lake and grass
Ecological restoration efforts have an overall positive effect on regional carbon stocks, but each measure
contributes differently to carbon stocks, with afforestation (non-shrub) having the best effect on regional
carbon stock increase, afforestation (shrub) being insignificant, and soil improvement works for crop
health having no significant effect on carbon stocks. Institutional Review Board Statement: Not applicable. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Informed Consent Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The data presented in this study are available in article and
supplementary material. Acknowledgments: We thank the Guizhou Academy of Agricultural Sciences for providing experimental
site support for us. Acknowledgments: We thank the Guizhou Academy of Agricultural Sciences for providing experimental
site support for us. Acknowledgments: We thank the Guizhou Academy of Agricultural Sciences for providing experimental
site support for us. Conflicts of Interest: The authors declare no conflict of interest. Declarations Supplementary Materials: The following supporting information can be downloaded at:
www.mdpi.com/xxx/s1, Figure S1: title; Table S1: title; Video S1: title. Author Contributions: T.F.,J.N. and H.W. contributed to the study conception and design. The first draft of
themanuscript was written by J.N. and all authors commented on previous versions of the manuscript.All Page 13/23 authors have read and agreed to the published version of the manuscript authors have read and agreed to the published version of the manuscript
Funding: This research was supported by the National Natural Science Foundation of China
(No. 4216070281). Funding: This research was supported by the National Natural Science Foundation of China
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Figure 2
Whole change of carbon storage from 2015 to 2020 Figure 2 Figure 2 Whole change of carbon storage from 2015 to 2020 Page 17/23 Page 17/23 Figure 3 Aerial Photo of Actual Mine Restoration in the Stydy Area Aerial Photo of Actual Mine Restoration in the Stydy Area Page 18/23 Figure 4
Carbon Storage of Comprehensive Treatment Project of Mine Environment Figure 4 Carbon Storage of Comprehensive Treatment Project of Mine Environment Page 19/23 Figure 5 Figure 5 Aerial Photo of Vegetation Degradation and Greening in the Stydy Area Page 20/23 Page 20/23 Figure 6
Carbon Storage of Vegetation Degradation and Greening Projects Figure 6 Figure 6 Carbon Storage of Vegetation Degradation and Greening Projects Page 21/23 Figure 7 Aerial Photo of Soil Improvement Project in the Stydy Area Page 22/23 Figure 8
Carbon Storage of Soil Improvement Project Figure 8 Carbon Storage of Soil Improvement Project Page 23/23
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Canine Adenovirus 1 Isolation Bioinformatics Analysis of the Fiber
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Frontiers in cellular and infection microbiology
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cc-by
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Canine Adenovirus 1 Isolation
Bioinformatics Analysis of the Fiber
Ben Wang 1, Minchun Wang 2, Hongling Zhang 1, Jinfeng Xu 2, Jinyu Hou 2,3
and Yanzhu Zhu 2,3* 1 Animal Science and Technology College, Jilin Agriculture Science and Technology University, Jilin, China, 2 Institute of
Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China, 3 College of Veterinary
Medicine, Jilin Agricultural University, Changchun, China Canine adenovirus type 1 (CAdV-1) is a double-stranded DNA virus, which is the causative
agent of fox encephalitis. The Fiber protein is one of the structural proteins in CAdV-1,
which mediates virion binding to the coxsackievirus and adenovirus receptor on host cells. The suspected virus was cultured in the MDCK cells, and it was determined through the
cytopathic effects, sequencing and electron microscopy. The informatics analysis of the
Fiber was done using online bioinformatics servers. The CAdV-1-JL2021 strain was
isolated successfully, and were most similar to the CAdV-1 strain circulating in Italy. The
occurrence of negative selection and recombination were found in the CAdV-1-JL2021
and CAdV-2-AC_000020.1. Host cell membrane was its subcellular localization. The
CAdV-1-JL2021 Fiber (ON164651) had 6 glycosylation sites and 107 phosphorylation
sites, exerted adhesion receptor-mediated virion attachment to host cell, which was the
same as CAdV-2-AC_000020.1 Fiber. The Fiber tertiary structure of the CAdV-1-JL2021
and CAdV-2-AC_000020.1 was different, but they had the same coxsackievirus and
adenovirus receptor. “VATTSPTLTFAYPLIKNNNH” were predicted to be the potential
CAdV-1 B cell linear epitope. The MHC-I binding peptide “KLGVKPTTY” were both
presented in the CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber and it is useful to
design the canine adenovirus vaccine. Edited by:
Zhanbo Zhu,
Heilongjiang Bayi Agricultural
University, China
Reviewed by:
Yufei Zhang,
Huazhong Agricultural University,
China
Xijun He,
State Key Laboratory of Veterinary
Biotechnology, Harbin Veterinary
Research Institute, Chinese Academy
of Agricultural Sciences, China
*Correspondence:
Yanzhu Zhu
zyzzu@126 com Edited by:
Zhanbo Zhu,
Heilongjiang Bayi Agricultural
University, China Reviewed by:
Yufei Zhang,
Huazhong Agricultural University,
China
Xijun He,
State Key Laboratory of Veterinary
Biotechnology, Harbin Veterinary
Research Institute, Chinese Academy
of Agricultural Sciences, China Reviewed by:
Yufei Zhang,
Huazhong Agricultural University,
China
Xijun He, *Correspondence:
Yanzhu Zhu
zyzzu@126.com Keywords: canine adenovirus 1, phylogenetic tree, bioinformatics analysis, B cell epitope, T cell epitope, Fiber *Correspondence:
Yanzhu Zhu
zyzzu@126.com BRIEF RESEARCH REPORT BRIEF RESEARCH REPORT BRIEF RESEARCH REPORT
published: 13 June 2022
doi: 10.3389/fcimb.2022.879360 INTRODUCTION Specialty section:
This article was submitted to
Clinical Microbiology,
a section of the journal
Frontiers in Cellular and
Infection Microbiology Canine adenovirus type 1 (CAdV-1) is a double-stranded DNA genome virus belonging to the
mastadenovirus genus of the adenoviridae family. This virus is the etiologic agent of fox encephalitis
(Balboni et al., 2019). CAdV-1 is transmitted by saliva, feces, urine (Yang et al., 2019). Foxes infected
with CAdV-1 present with fever, cough, depression, vomiting, diarrhea, anorexia, convulsions, and
the characteristic clinical sign of blue eye (corneal edema) (Sun et al., 2019). The large-scale use of
the CAdV-2 live attenuated vaccine has reduced the prevalence of CAdV-1. However, CAdV-1 also
circulates in wildlife with high pathogenicity and a broad host range (Verin et al., 2019; Zhu et al.,
2020). Surveillance for new genetic variants is necessary to evaluate the potential impacts of CAdV-1
on wildlife species. Received: 19 February 2022
Accepted: 25 April 2022
Published: 13 June 2022 Keywords: canine adenovirus 1, phylogenetic tree, bioinformatics analysis, B cell epitope, T cell epitope, Fiber Polymerase Chain Reaction Polymerase Chain Reaction
Following infection, DNA was extracted from MDCK cells using
the MagicPure® Simple 32 Viral DNA/RNA Kit (EC311-32-11). Amplification of the 508bp CAdV-1 fragment was accomplished
using previously published primers (Hu et al., 2001) (Forward
primer-HA1:5’-CGCGCTGAACATTACTACCTTGTC-3’ and
Reverse primer-HA2:5’-CCTAGAGCACTTCGTGTCCG
CTT-3’). Reactions were run in a 50 µL sample volume
consisting of 1 µL of DNA template, 25 mL of 2×EasyTaq®
PCR SuperMix (Transgen Biotech, AS111-01), 1 µL of forward
and reverse primers each, and 22 µL of sterile deionized nuclease
free water. The thermocycling profile for amplification was as
follow: 5 min of denaturation at 95°C followed by 35 cycles of
1 min of denaturation at 95°C, 15 s of annealing at 58°C, and 30 s
of extension at 72°C, with a final 5 min of extension at 72°C. Amplicons were resolved using1.0% agarose gel electrophoresis
and stained with GelStain (Transgen Biotech, GS101-01) to
visualize the product. An immunogenic protein, the Fiber protein is an attractive
candidate for use in the development of subunit vaccines (De
Luca et al., 2020). Fiber protein subunit vaccines have been
demonstrated to protect fowl against fowl adenovirus serotype 4
(Ruan et al., 2018) and FAdV-8b (Gupta et al., 2017). Limited
data have been reported demonstrating efficacy of Fiber protein
vaccines against CAdV-1. The bioinformatics may have
important applications in the newly discovered and emerging
viruses prediction (Foroutan et al., 2018). Bioinformatics analysis
of the ROP8 protein was conducted during the design process of
a vaccine targeting Toxoplasma gondii (Foroutan et al., 2018). Bioinformatic analysis of the Fiber will be the first step to design
the vaccine. In the present study, a CAdV-1 isolated from a sick fox on a
farm was characterized and the resulting Fiber sequence data
were analyzed using bioinformatics. The resulting data provides
a rational and theoretical starting point for the development of
CAdV-1 control measures and vaccine development. PCR amplification using the CAdV-1 Fiber primer pair
(Fiber-F:5’-ATGAAGCGGACACGAAGTGCT-3’; Fiber-R:5’-
TCATTGATTTTCCCCCACATAGGTGAAG-3’) yielding a
1063 bp fragment. The target region PCR reactions were
performed six times in 50 µL reaction volumes containing 1
µL denatured DNA template, 5 mL of buffer, 2 mL of 25mM
MgSO4, 1 µL of each primer (10 pmol/µL), 5 mL of 2 mM
dNTPs, 1 mL of KOD plus (TOYOBO, KOD-201, 1.0 U/µL)
and 34 µL of sterile deionized water. Polymerase Chain Reaction The thermocycling profile
used was as follows: 5 min denaturation at 95°Cfollowed by 30
cycles of 30 s denaturation at 95°C, 30 s annealing at 60°C, and
1 min extension at 72°C, with a final 5 min extension at 72°C. The amplicons were resolved using 1.0% agarose gel
electrophoresis and stained with GelStain (Transgen Biotech,
GS101-01). Ethics Statement This experiment was approved by the ethics committee at the
Jilin Agriculture Science and Technology University, and the
procedures complied with IACUC guidelines on the animals’
care and use for scientific purposes. Preparation of Liver Tissue A fox presenting with clinical encephalitis was collected from a
farm in Jilin. One part of the liver was stained by hematoxylin
and eosin (H&E) (Lin et al., 2018). The other part of the liver was
homogenized in 1 mL of sterile phosphate buffer (PBS), and was
centrifuged for 10 min at 8000 g/min. The supernatants were
collected and filtered through a filter with a 0.22 µ M pore size
and stored at - 80°C. Citation: Wang B, Wang M, Zhang H,
Xu J, Hou J and Zhu Y (2022)
Canine Adenovirus 1 Isolation
Bioinformatics Analysis of the Fiber. Front. Cell. Infect. Microbiol. 12:879360. doi: 10.3389/fcimb.2022.879360 The CAdV-1 genome is 32 kb in length and contains 30 open reading frames (Pizzurro et al.,
2017). The Fiber protein is the main capsid protein. The Fiber protein is composed of 3 domains,
referred to as the tail, shaft, and knob (Schoehn et al., 2008). During CAdV-1 replication, the Fiber
protein binds to the receptor, destroys the binding integrity of the receptor, allowing for viral entry June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org Canine Adenovirus 1 Isolation Wang et al. into the host cell, and subsequent dissemination between cells. This cell to cell spread helps the virus minimize time in the
extracellular environment, greatly limiting detection by the
immune system (Walters et al., 2002). When CAdV-1 is
detected and identified, Fiber nucleotide sequences are usually
selected for homology and similarity analysis in CAdV-1 and
CAdV-2 (Balboni et al., 2022). distinct CPE were further characterized by negative-stain
transmission electron microscopy (TEM) to determine
morphological characteristics of the infecting virus (Prasad
et al., 2020). Bioinformatics Analysis of Fiber Protein
Physical and Chemical Properties, Phosphorylation,
and Glycosylation Sites Protparam (Walker, 2005) was used to predict the instability
coefficient, average water absorption coefficient, relative
molecular weight, amino acid composition and isoelectric
point of charged amino acids in the Fiber protein. The
Protscale with Hphob./Kyte & Doolittle (Walker, 2005) was
used to predict the hydrophilicity and hydrophobicity of the
Fiber protein. Phylogenetic and Homology Analyses y
g
gy
y
Electrophoretically resolved amplicons from the PCR reactions
were eluted from the gel matrix using the EasyPure® Quick Gel
Extraction Kit (TransGen, EG101-01), and cloned into an
amplification plasmid using the pMD™18-T Vector Cloning
Kit (TaKaRa, 6011). Sequencing of the purified plasmids was
performed using Sanger sequencing by the Comate Bioscience
Co., Ltd. The sequences were assembled and aligned according to
the CAdV-1 reference sequences in GenBank, and were
translated into amino acid sequences using BioEdit 7.2.5. The
resulting Fiber nucleotide sequence (CAdV-1-JL2021 strain) was
blasted in the NCBI database and compared to the 14 most
similar Fiber nucleotide sequence of all CAdV strains. Based on
the sequences, a phylogenetic tree was constructed using the
MEGA 7.0.20 software with the neighbor-joining method. The reliability of the phylogenetic tree was verified through the
bootstrap method with 1,000 replicates. Cytopathic Effect and Virus Morphology
CAdV-1 infection was performed in Madin-Darby Canine
Kidney (MDCK) cells (ATCC CCL-34, derived from normal
kidney of Canis familiaris). MDCK cells were cultured at 37°C in
Dulbecco’s modified Eagle’s medium (DMEM) containing 10%
of fetal bovine solution (FBS) and 1% Penicillin-Streptomycin in
a 5% CO2 incubator. Confluent MDCK cells (70-90%) were
washed with PBS (pH 7.2), and inoculated with 100 µL of filtered
liver homogenate supernatant at 37°C for 1 h. Nine milliliters of
fresh DMEM containing 5% FBS was added, and the plate was
incubated at 37°C in 5% CO2. The cytopathic effect (CPE) was
observed and photographed daily. The MDCK infected cells with June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org Canine Adenovirus 1 Isolation Wang et al. T and B Cell Epitope Prediction p
p
The BCpred method (El-Manzalawy et al., 2008) (Methods:
Fixed length epitope prediction- BCPred, Epitope length-20,
Specificity-75%, report only non-overlapping epitopes) was
used to predict potential B cell epitopes. MHC-I binding
peptides were obtained using the IEDB Analysis Resource
(Vita et al., 2019) (Sort peptides by-Predicted Score (descend),
Output format-XHTML table). The MHC allele selected for the
analysis was DLA-8803401, and the length was 14 aa, with the Transmembrane Region, Signal Peptide, Secondary
and Tertiary Structure Prediction y
In the CAdV-1-JL2021 Fiber, CAdV-2-AC_000020.1 Fiber, the
transmembrane region was predicted using TMHMMServer 2.0
(Krogh et al., 2001) (Extensive, with graphics). SignalP 5.0 Server
(Nielsen et al., 2019) (Eukarya, Long output) was used to predict
the signal peptide. Potential secondary structure characteristics
were predicted using SOPMA (Deléage ALIGNSEC, 2017)
(Number of conformational states-4 (Helix, sheet, turn, coil),
Similarity threshold-8, Window width-17). The tertiary structure
of CAdV-1-JL2021 Fiber, CAdV-2-AC_000020.1 Fiber and the
Coxsackievirus and adenovirus receptor _XP_038299179 were
predicted using Robetta (Nerli and Sgourakis, 2019). The Fiber Selective Pressure Analysis
Negative selective pressure was identified in 375, 281, 292, 170
sites of CAdV-1-JL2021 Fiber (Figures 2C–F). Negative selective
pressure was identified in 22 sites of CAdV-2-AC_000020.1 Fiber
(Figures 2C’–F’). The Fiber Recombination Analysis
The evidence of recombination breakpoint was found in the
CAdV-1-JL2021 and CAdV-2-AC_000020.1Fiber GARD
analysis. The CAdV-1-JL2021 alignment contained 42 potential
breakpoints and 1 inferred breakpoint (Figures 2G–I). The
CAdV-2-AC_000020.1 alignment contained 148 potential
breakpoints and 2 inferred breakpoint (Figures 2G’–I’). The Fiber Recombination Analysis
The evidence of recombination breakpoint was found in the
CAdV-1-JL2021 and CAdV-2-AC_000020.1Fiber GARD
analysis. The CAdV-1-JL2021 alignment contained 42 potential
breakpoints and 1 inferred breakpoint (Figures 2G–I). The
CAdV-2-AC_000020.1 alignment contained 148 potential
breakpoints and 2 inferred breakpoint (Figures 2G’–I’). Protein Subcellular Localization and
Function Prediction Virus Isolation and Identification
The CPE was observed in MDCK cells. The typical “grape cluster
morphology” of CPE was observed while control monolayers
remained intact (Figures 1A, B). CAdV-JL2021 caused a series
of morphological changes in fox liver, such as cell swelling and
necrosis (Figure 1C). The cell with CPE were further examined
by TEM, PCR, and sequencing. Characteristic adenoviral
particles were observed by TEM (Figure 1D). A 508 bp
fragment of the E3 gene was amplified for primary detection. It indicated that the CAdV-1 strain was first isolated. Next, a
1632 bp (Figure 1E) target band consistent with the Fiber gene
was amplified and submitted to the GeneBank (ON164651). The Protein subcellular localization of CAdV-1-JL2021 Fiber and
CAdV-2-AC_000020.1 Fiber was predicted by Virus-mPLoc in
Cell-PLoc 2.0 (Chou and Shen, 2008). The Fiber function of the
CAdV-1-JL2021 and CAdV-2-AC_000020.1 were predicted by
EMBL-EBI (Madeira et al., 2022). Bioinformatics Analysis of Fiber Protein
Physical and Chemical Properties, Phosphorylation,
and Glycosylation Sites The Fiber Phylogenetic and
Homology Analyses Three different clusters were identified through the phylogenetic
analyses of the Fiber gene sequences accessioned in GenBank. The CAdV-1-JL2021 strain belongs to CAdV-1, and apparently
has a close relationship with CAdV-1 strain (accession number,
KP840546). This present study revealed the unique nature of the
new strain (Figure 2A). The NetPhos 3.1 Server (Blom et al., 1999) (Residues to
predict serine-all three, Output format-classical, Generate
graphics) was used to predict the potential phosphorylation
sites of the Fiber protein. The potential glycosylation sites of
the Fiber protein were predicted using the NetNGlyc 1.0 Server
(Gupta and Brunak, 2002) with generate graphics. The protein sequences of the CAdV-1 Fiber gene (1632 bp in
length, 543 amino acid residues) were compared with CAdV
Fiber gene sequences available from NCBI (Figure 2B). The
sequence of the Fiber gene was determined and was more similar
with isolates from Italy (KP840546), suggesting that the isolated
virus was CAdV-1. The virus identified in this study also shared
97.8 to 99.82% identity with other CAdV-1 strains. Transmembrane Region, Signal Peptide, Secondary
and Tertiary Structure Prediction Selective Pressure and Recombination
Analysis MHC source species being dog. Binding predictions of MHC-II
performed using IEDB Analysis Resource as well. The prediction
method used was IEDB recommended 2.22. The selected MHC
allele was DRB1*01:01. Based on the CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber
nucleotide sequence, the selective pressure and recombination
analysis were conducted through SLAC (Kosakovsky Pond and
Frost, 2005) and GARD (Kosakovsky Pond et al., 2006) method
in Datamonkey. Fiber Protein Subcellular Localization and
Function Prediction The predicted location of the CAdV-1-JL2021 Fiber was host cell
membrane (Figure 2J). The predicted location of the CAdV-2-
AC_000020.1 Fiber was host cell membrane and host cytoplasm June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 3 Canine Adenovirus 1 Isolation Wang et al. FIGURE 1 | The isolation and identification of the canine adenovirus 1. (A) Normal MDCK; (B) MDCK with CPE; (C) HE staining of liver; (D) Electron microscopy
observation of the adenovirus particles; (E) Amplification of the Fiber gene and identification of adenovirus. FIGURE 1 | The isolation and identification of the canine adenovirus 1. (A) Normal MDCK; (B) MDCK with CPE; (C) HE staining of liver; (D) Electron microscopy
observation of the adenovirus particles; (E) Amplification of the Fiber gene and identification of adenovirus. (Figure 2J’). CAdV-1-JL2021 and CAdV-2-AC_000020.1Fiber
exerted adhesion receptor-mediated virion attachment to
host cell. (Figure 2J’). CAdV-1-JL2021 and CAdV-2-AC_000020.1Fiber
exerted adhesion receptor-mediated virion attachment to
host cell. phosphorylation sites, 47 potential threonine phosphorylation
sites and 8 tyrosine phosphorylation sites. However, the Fiber
protein in CAdV-1-JL2021 and CAdV-2-AC_000020.1 were not
expected to have either a transmembrane region or signal peptide,
as were shown in Figures 3E, E’, F, F’, respectively. Prediction on Fiber Secondary and
Tertiary Structure The number of amino acids in the Fiber protein was 543, the
molecular weight was 56974.49 g/mol, the isoelectric point was
6.26, and the instability coefficient was 39.33. There were 143
amino acids in the hydrophobic region (> 0.5), 168 amino acids
in the hydrophilic region (< - 0.5), suggesting that CAdV-1-
JL2021 Fiber was a hydrophilic protein. (Figure 3A). According
to the CAdV-2-AC_000020.1 Fiber, the average hydrophobicity
of the Fiber protein is -0.092. There were 129 amino acids in the
hydrophobic region (> 0.5), 161 amino acids in the hydrophilic
region (< - 0.5), suggesting that CAdV-2-AC_000020.1 Fiber was
a hydrophilic protein (Figure 3A’). Prediction on Fiber Secondary and
Tertiary Structure
The CAdV-1-JL2021 Fiber protein a- Helix (Hh), extended
chain (EE), b- proportions of angle (TT) and irregular curl
(CC) were 0.92%, 34.81%, 6.45% and 57.83% respectively
(Figure 3D). The CAdV-2-AC_000020.1 Fiber protein a-
Helix (Hh), extended chain (EE), b- proportions of angle (TT)
and irregular curl (CC) were 1.29%, 36.53%, 4.24% and 57.93%
respectively (Figure 3D’). The Fiber tertiary structure of the
CAdV-1-JL2021 and CAdV-2-AC_000020.1 was different, but
they had the same coxsackievirus and adenovirus receptor
(Figures 3G–I). Their binding models were also predicted
(Figures 3J, K). Fiber Prediction of Phosphorylation and
Glycosylation Sites (A) CAdV-1-JL2021 Fiber Phylogenetic tree; (B) CAdV-1-JL2021 Fiber Homology analyses; (C) CAdV-1-JL2021
Selective pressure-Partition information; (C’) CAdV-2-AC_000020.1 Selective pressure-Partition information; (D) CAdV-1-JL2021 Selective pressure-SLAC site
graph; (D’) CAdV-2-AC_000020.1 Selective pressure-SLAC site graph; (E) CAdV-1-JL2021 Selective pressure-SLAC Phylogenetic alignment; (E’) CAdV-2-
AC_000020.1 Selective pressure-SLAC Phylogenetic alignment; (F) CAdV-1-JL2021 Selective pressure-Fitted tree; (F’) CAdV-2-AC_000020.1 Selective pressure-
Fitted tree; (G) CAdV-1-JL2021 Recombination detection-General information; (G’) CAdV-2-AC_000020.1 Recombination detection-General information; (H) CAdV-
1-JL2021 ecombination detection-Left: the best placement of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the
improvement in the c-AIC score between successive breakpoint numbers (log scale). (H’) CAdV-2-AC_000020.1 Recombination detection-Left: the best placement
of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the improvement in the c-AIC score between successive breakpoint
numbers (log scale). (I) CAdV-1-JL2021 Recombination detection-Model-averaged support for breakpoint placement; (I’) CAdV-2-AC_000020.1 Recombination
detection-Model-averaged support for breakpoint placement. (J) CAdV-1-JL2021 Subcellular localization; (J’) CAdV-2-AC_00020.1 Subcellular localization. FIGURE 2 | The nucleotide analysis of the Fiber. (A) CAdV-1-JL2021 Fiber Phylogenetic tree; (B) CAdV-1-JL2021 Fiber Homology analyses; (C) CAdV-1-JL2021
Selective pressure-Partition information; (C’) CAdV-2-AC_000020.1 Selective pressure-Partition information; (D) CAdV-1-JL2021 Selective pressure-SLAC site
graph; (D’) CAdV-2-AC_000020.1 Selective pressure-SLAC site graph; (E) CAdV-1-JL2021 Selective pressure-SLAC Phylogenetic alignment; (E’) CAdV-2-
AC_000020.1 Selective pressure-SLAC Phylogenetic alignment; (F) CAdV-1-JL2021 Selective pressure-Fitted tree; (F’) CAdV-2-AC_000020.1 Selective pressure-
Fitted tree; (G) CAdV-1-JL2021 Recombination detection-General information; (G’) CAdV-2-AC_000020.1 Recombination detection-General information; (H) CAdV-
1-JL2021 ecombination detection-Left: the best placement of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the
improvement in the c-AIC score between successive breakpoint numbers (log scale). (H’) CAdV-2-AC_000020.1 Recombination detection-Left: the best placement
of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the improvement in the c-AIC score between successive breakpoint
numbers (log scale). (I) CAdV-1-JL2021 Recombination detection-Model-averaged support for breakpoint placement; (I’) CAdV-2-AC_000020.1 Recombination
detection-Model-averaged support for breakpoint placement. (J) CAdV-1-JL2021 Subcellular localization; (J’) CAdV-2-AC_00020.1 Subcellular localization. CAdV-2. The haemagglutination and neutralization tests do not
provide definitive differentiation between CAdV-1 and CAdV-2
isolated from the digestive tract (Timurkan et al., 2018). However,
PCR is a powerful tool for the differentiation of CAdV-1 and
CAdV-2 (Balboni et al., 2019; Oleaga et al., 2021). The genomic
region encoding the E3 gene and flanking sequences were selected
as the target for a pair of primers to diagnose and differentiate the
two serotypes of CAdV (Hu et al., 2001). Fiber Prediction of Phosphorylation and
Glycosylation Sites The resulting PCR
product produced bands 508 bp of CAdV-1 E3 gene, and 1632 bp
of CAdV-1 Fiber gene, which will identify the occurrence of
CAdV-1 in fox using sequencing and phylogenetic analysis. the 432, 202, 80 sites of CAdV-2-AC_000020.1 were
simultaneously predicted. CAdV-1-JL2021 and CAdV-2-
AC_000020.1 Fiber did not have the same B cell linear
epitopes. CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber
had 3 and 2 discontinuous epitopes, respectively (Figures 4B–F). CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber had 9
MHC-I binding peptides, respectively. Importantly, the peptide
“KLGVKPTTY” were both presented in the CAdV-1-JL2021 and
CAdV-2-AC_000020.1 Fiber (Figures 4G, H). CAdV-1-JL2021
and CAdV-2-AC_000020.1 Fiber had 7 MHC-II binding
peptides, respectively (Figures 4I, J). the 432, 202, 80 sites of CAdV-2-AC_000020.1 were
simultaneously predicted. CAdV-1-JL2021 and CAdV-2-
AC_000020.1 Fiber did not have the same B cell linear
epitopes. CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber
had 3 and 2 discontinuous epitopes, respectively (Figures 4B–F). CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber had 9
MHC-I binding peptides, respectively. Importantly, the peptide
“KLGVKPTTY” were both presented in the CAdV-1-JL2021 and
CAdV-2-AC_000020.1 Fiber (Figures 4G, H). CAdV-1-JL2021
and CAdV-2-AC_000020.1 Fiber had 7 MHC-II binding
peptides, respectively (Figures 4I, J). Double-stranded DNA viruses tend to have lower mutation
rates than RNA genome viruses (Sanjuán and Domingo-Calap,
2016). Nucleotide sequence alignment between the CAdV-1-
JL2021 strain and 14 reference strains showed high identities
ranging from 97.8 to 99.82%. A phylogenetic tree of 23 Fiber
nucleatide acid sequences found that the CAdV-1-JL2021 strain
was included in the KP840546 strain containing subgroup. The
study of this virus strain can provide an alternative strain for the
diagnosis and prevention of fox encephalitis. Fiber Prediction of Phosphorylation and
Glycosylation Sites T and B Cell Epitope Prediction in Fiber
11 and 14 of B cell linear epitopes were predicted in the Fiber of
CAdV-1-JL2021 and CAdV-2-AC_000020.1, respectively
(Figure 4A). The peptides in the 1, 9, 433, 198, 168, 272, 71
sites of CAdV-1-JL2021 were simultaneously predicted. Importantly, the peptide “VATTSPTLTFAYPLIKNNNH” was
both predicted by the IEDB, BCPred and ElliPro. The peptides in In Figure 3B, 6 glycosylation sites (242, 319, 375, 438, 450 and
493) were identified in the Fiber protein. It can be seen in
Figure 3C. CAdV-1-JL2021 Fiber had 59 serine phosphorylation
sites, 42 potential threonine phosphorylation sites and 6 tyrosine
phosphorylation sites. In Figure 3B’, 4 glycosylation sites (125,
320, 437, 449) were identified in the Fiber protein. It can be seen in
Figure 3C’, CAdV-2-AC_000020.1 Fiber had 42 serine June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org Canine Adenovirus 1 Isolation Wang et al. A
B
D
D’
E
E’
F
F’
G
G’
I
I’
H
H’
J
J’
C
C’
FIGURE 2 | The nucleotide analysis of the Fiber. (A) CAdV-1-JL2021 Fiber Phylogenetic tree; (B) CAdV-1-JL2021 Fiber Homology analyses; (C) CAdV-1-JL2021
Selective pressure-Partition information; (C’) CAdV-2-AC_000020.1 Selective pressure-Partition information; (D) CAdV-1-JL2021 Selective pressure-SLAC site
graph; (D’) CAdV-2-AC_000020.1 Selective pressure-SLAC site graph; (E) CAdV-1-JL2021 Selective pressure-SLAC Phylogenetic alignment; (E’) CAdV-2-
AC_000020.1 Selective pressure-SLAC Phylogenetic alignment; (F) CAdV-1-JL2021 Selective pressure-Fitted tree; (F’) CAdV-2-AC_000020.1 Selective pressure-
Fitted tree; (G) CAdV-1-JL2021 Recombination detection-General information; (G’) CAdV-2-AC_000020.1 Recombination detection-General information; (H) CAdV-
1-JL2021 ecombination detection-Left: the best placement of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the
improvement in the c-AIC score between successive breakpoint numbers (log scale). (H’) CAdV-2-AC_000020.1 Recombination detection-Left: the best placement
of breakpoints inferred by the algorithm for each number of breakpoints considered. Right: the improvement in the c-AIC score between successive breakpoint
numbers (log scale). (I) CAdV-1-JL2021 Recombination detection-Model-averaged support for breakpoint placement; (I’) CAdV-2-AC_000020.1 Recombination
detection-Model-averaged support for breakpoint placement. (J) CAdV-1-JL2021 Subcellular localization; (J’) CAdV-2-AC_00020.1 Subcellular localization. D’
E’
F’
G
G’
I
I’
H
H’
J
J’ D
D
E A D’ D D’ G G’ G’ E F’
I
I’
H
H’
J
J’ B B B
F
C
C’ F C I’ FIGURE 2 | The nucleotide analysis of the Fiber. DISCUSSION The size and shape of CAdV particles were similar to those of
CAdV-1 and CAdV-2 strains isolated from fox (Choi et al., 2014;
Tamukai et al., 2020). However, virus isolation is a very time-
consuming diagnostic test, which further necessitates additional
molecular tests to classify the etiologic agent as either CAdV-1 or June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 5 Canine Adenovirus 1 Isolation Wang et al. A
A’
B
B’
E
E’
F
F’
G
I
H
J
K
C
D
D’
C’
GURE 3 | The structure prediction of the Fiber protein. (A) CAdV-1 JL2021 Fiber Hydrohilicity and hydeophobicity; (A’) CAdV-2-AC_000020.1 Fiber Hydrohilicity
nd hydeophobicity; (B) CAdV-1 JL2021 Fiber N-glycosylation potential position; (B’) CAdV-2-AC_000020.1 Fiber N-glycosylation potential position; (C) CAdV-1
L2021 Fiber Phosphorylation potential position; (C’) CAdV-2-AC_000020.1 Fiber Phosphorylation potential position; (D) CAdV-1 JL2021 Fiber secondary structure;
D’) CAdV-2-AC_000020.1 Fiber secondary structure; (E) CAdV-1 JL2021 Fiber Signal peptide; (E’) CAdV-2-AC_000020.1 Fiber Signal peptide; (F) CAdV-1 JL2021
ber transmembrane region; (F’) CAdV-2-AC_000020.1 Fiber transmembrane region; (G) CAdV-1 JL2021 Fiber Three-dimensional structure; (H) Coxsackievirus
nd adenovirus receptor (CAR) Three-dimensional structure; (I) CAdV-2-AC_000020.1 Fiber Three-dimensional structure; (J) Interaction between CAdV-1 JL2021
ber and CAR; (K) Interaction between CAdV-2-AC_000020.1 Fiber and CAR. A
A’
B
B’
E
E’ A
A’
B
B’
E
E’ C C
C’ I
H
D’ G
H
D D G
H
D D’ J I H K G FIGURE 3 | The structure prediction of the Fiber protein. (A) CAdV-1 JL2021 Fiber Hydrohilicity and hydeophobicity; (A’) CAdV-2-AC_000020.1 Fiber Hydrohilicity
and hydeophobicity; (B) CAdV-1 JL2021 Fiber N-glycosylation potential position; (B’) CAdV-2-AC_000020.1 Fiber N-glycosylation potential position; (C) CAdV-1
JL2021 Fiber Phosphorylation potential position; (C’) CAdV-2-AC_000020.1 Fiber Phosphorylation potential position; (D) CAdV-1 JL2021 Fiber secondary structure;
(D’) CAdV-2-AC_000020.1 Fiber secondary structure; (E) CAdV-1 JL2021 Fiber Signal peptide; (E’) CAdV-2-AC_000020.1 Fiber Signal peptide; (F) CAdV-1 JL2021
Fiber transmembrane region; (F’) CAdV-2-AC_000020.1 Fiber transmembrane region; (G) CAdV-1 JL2021 Fiber Three-dimensional structure; (H) Coxsackievirus
and adenovirus receptor (CAR) Three-dimensional structure; (I) CAdV-2-AC_000020.1 Fiber Three-dimensional structure; (J) Interaction between CAdV-1 JL2021
Fiber and CAR; (K) Interaction between CAdV-2-AC_000020.1 Fiber and CAR. Selection is an essential component of any evolutionary system
and analyzing this fundamental force in evolution can provide
relevant insights into the evolutionary development of a population
(Haasdijk and Heinerman, 2018). DISCUSSION negative selection removed
amino-acid changes that reduced fitness, positive selection
maintained amino-acid changes that increase virus fitness. Neutral selection was that the fitness was not affected by the
amino-acid changes. In this experiment, negative selective
pressure was identified in 375, 281, 292, 170 sites of CAdV-1- JL2021 Fiber and in the 22 sites of CAdV-2-AC_000020.1. The
presence of negative selection implies that the sites were functionally
important in the virus evolution. The sites in the CAdV-1-JL2021
Fiber were less than that of CAdV-2-AC_000020.1. The less negative
selection site maybe that the numbers of nucleotide substitutions (cS
1 cN) observed were insufficient for detecting statistically significant
differences between cS and cN. More sequence data should be
collected in the future. The negative selection identified in CAdV-1-
JL2021 and CAdV-2-AC_000020.1 protein may help the June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org Wang et al. Canine Adenovirus 1 Isolation A
B
D
E
F
G
I
H
J
C
FIGURE 4 | The epitope analysis of the Fiber protein. (A) Table 1 B cell linear epitope prediction; (B–D) CAdV-1 JL2021 Fiber discontinuous epitopes; (E, F) CAdV-
2-AC_000020.1 Fiber discontinuous epitopes; (G) Table 2 CAdV-1-JL2021 Fiber MHC-I-binding prediction; (H) Table 3 CAdV-2-AC_000020.1 Fiber MHC-I-binding
prediction. (I) Table 4 CAdV-1-JL2021 Fiber MHC-II Binding Prediction; (J) CAdV-2-AC_000020.1 Fiber MHC-II Binding Prediction. A B B D
C G D C G H E H J FIGURE 4 | The epitope analysis of the Fiber protein. (A) Table 1 B cell linear epitope prediction; (B–D) CAdV-1 JL2021 Fiber discontinuous epitopes; (E, F) CAdV-
2-AC_000020.1 Fiber discontinuous epitopes; (G) Table 2 CAdV-1-JL2021 Fiber MHC-I-binding prediction; (H) Table 3 CAdV-2-AC_000020.1 Fiber MHC-I-binding
prediction. (I) Table 4 CAdV-1-JL2021 Fiber MHC-II Binding Prediction; (J) CAdV-2-AC_000020.1 Fiber MHC-II Binding Prediction. The subcellular location of a protein is highly related to its
function (Pan et al., 2020). Identifying the location of a given
protein is an essential step for investigating its related function. The host cell membrane was the subcellular location of the
CAdV-1-JL2021 and CAdV-2-AC_000020.1. But host cytoplasm
was also the subcellular location of the CAdV-2-AC_000020.1. It
indicates that they may have different function during the virus
infection. It predicted that CAdV-1-JL2021 and CAdV-2-
AC_000020.1Fiber exerted adhesion receptor-mediated virion
attachment to host cell. More evidences need to further find
the function difference between the CAdV-1 and CAdV-2. DISCUSSION In the prokaryotic expression and purification of Fiber
protein, the corresponding test scheme can be formulated
according to its hydrophilic characteristics. was both a viral receptor and cell adhesion protein (Readler
et al., 2019). CAV-2 had been shown to use CAR as a primary
receptor (Soudais et al., 2000). But limited data showed the
interaction between Knob of the Fiber and the CAR. The CAdV-
1 and CAdV-2 fiber–knobs may share a common receptor as
evidenced by the ability of the CAdV- 1 knob to inhibit
Ad5Luc1-CK2 function (Stoff-Khalili et al., 2005). In our
experiment, The Fiber in CAdV-1-JL2021 and CAdV-2-
AC_000020.1, CAR were predicted. The binding model
between Fiber and CAR was also predicted. It will be helpful to
clarify the interaction between Fiber and CAR. The B cell linear peptide “VATTSPTLTFAYPLIKNNNH” in
CAdV-1-JL2021 was predicted by the IEDB, BCPred and ElliPro. It indicates that this peptide had high potential in the epitope vaccine
design. The B cell linear peptides “STGNINSTTTWGEKPWGNNT”
of CAdV-2-AC_000020.1 were both predicted by the IEDB and
BCPred. CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber did not
have the same peptide. It indicates that B cell linear epitope vaccine
should be developed in the CAdV-1-JL2021 and CAdV-2-
AC_000020.1, respectively. Importantly, the T cell peptide
“KLGVKPTTY” were both predicted in the CAdV-1-JL2021 and
CAdV-2-AC_000020.1 Fiber. It indicates that T cell epitope vaccine
maybe both efficient for the CAdV-1-JL2021 and CAdV-2-
AC_000020.1, respectively. Protein phosphorylation is crucial for multiple biological
processes including signal transduction, regulation of cell cycle
and gene expression through post-translational modifications
(Luo et al., 2019; Mehrpouyan et al., 2021). For example, the N
protein phosphorylation impairs porcine reproductive and
respiratory syndrome virus growth efficiency in porcine
alveolar macrophages (Chen et al., 2019). Thus, it is important
to predict protein phosphorylation sites in the Fiber protein. It
was predicted that CAdV-1-JL2021 Fiber protein had 107
phosphorylation sites. The phosphorylation of Fiber protein is
related to its antigenicity and virulence. Like phosphorylation,
glycosylation is also an important post-translational
modification, which affects the structure and function of
proteins (Macedo-da-Silva et al., 2021). The glycosylation of
the Newcastle disease virus (Kosakovsky Pond et al., 2006)
resulted in a virus that was able to proliferate faster than that
of the vaccine (Schön et al., 2021). The CAdV-1-JL2021
Fiber protein has six glycosylation sites, suggesting that it is
related to the virus titer and proliferation rate of CAdV-1. DISCUSSION identification of highly conserved regions useful to implement new
future diagnostic protocols. Natural recombination is an important strategy for viruses to
adapt to new environmental conditions and hosts. Besides
evolving through nucleotide substitution, viruses frequently
also evolve by genetic recombination which can occur when
related viral variants co-infect the same cells (Varsani et al.,
2018). More CAdV genome sequences were added to GenBank,
CAdV-1 and CAdV-2 sequences arising from different parts of
world. Therefore, it is necessary to find the recombination for
genetic variability, and it will be helpful to understand the
evolutionary process of the CAdV genome (Eltahir et al.,
2011). In our experiment, recombination break-point were
observed in the 143 site of CAdV-1-JL2021 Fiber, and 397,
1558 site of CAdV-2-AC_000020.1. In the evolution of the
CAdV-1 populations, the recombination was not a common
event. The genetic diversity of CAdV-1 evolutionary maybe
attribute to the recombination. During the infection, the same
animal maybe infected by different CAdV genotypes, and this
condition will contribute to the CAdV recombination. In the process of CAdV infection, the Fiber protein interacts
with the host cell receptor to adsorb on the host cell. While much
of the current literature focuses on analysis of the Fiber gene
nucleic acid sequence of virus isolates (Schoehn et al., 2008), few
have gone so far as to predict the molecular characteristics of the
Fiber protein. The isoelectric point was predicted to be 6.26. When pH of the environment was 6.26, the net surface charge of
CAdV-1-JL2021 Fiber protein was 0. At this time, the Fiber
proteins repeled each other in solution, the force between June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 7 Canine Adenovirus 1 Isolation Wang et al. molecules was weakened, and Fiber precipitation occured
readily. Thus, at the isoelectric point, Fiber protein was easy to
obtain because of its low solubility. When the instability
coefficient of the protein was greater than 40, it was considered
to be an unstable protein (Dong et al., 2021). The total average
hydrophobicity of the hydrophilic protein was less than 0 (Zhou,
2016). The average hydrophobicity of the CAdV-1-JL2021 Fiber
protein was -0.092, suggesting that it was a hydrophilic protein. Protein dissolution in supernatant was an ideal result of
prokaryotic expression, but the specific distribution of protein
in supernatant and precipitation still need to be analyzed by SDS-
PAGE. CONCLUSION In this experiment, the CAdV-1-JL2021 strain was isolated
successfully, and were most similar to the CAdV-1 strain
circulating in Italy. The occurrence of negative selection and
recombination were found in the CAdV-1-JL2021. Host cell
membrane was its subcellular localization. The CAdV-1-JL2021
Fiber (ON164651) exerted adhesion receptor-mediated virion
attachment to host cell, which was the same as CAdV-2-
AC_000020.1 Fiber. “VATTSPTLTFAYPLIKNNNH” were
predicted to be the potential CAdV-1 B cell linear epitope. The MHC-I binding peptide “KLGVKPTTY” were both
predicted in the CAdV-1-JL2021 and CAdV-2-AC_000020.1
Fiber, and it is useful to design the canine adenovirus
epitope vaccine. The secondary structure prediction results showed that the
extended chain and irregular curl accounted for the majority of
the Fiber protein secondary structure. The irregular curl is
responsible for a protein’s enzymatic activity and protein
specific functions (Simm et al., 2021). It was also observed
that the CAdV-1-JL2021 and CAdV-2-AC_000020.1 Fiber
protein contains a large number of antigenic determinants,
which is consistent with the prediction results of antigenic
determinants. Antigenic determinants can specifically bind to
corresponding antibodies or B cells. Since the Fiber protein is
the main capsid protein on the adenovirus surface, its antigenic
determinants can cause strong neutralization reactions. Therefore, predicting the antigenic determinants of Fiber
protein and the dominant B cell epitopes is helpful to
understand the mechanisms of viral neutralization via
responses to the Fiber protein. DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in
the article/supplementary files. Further inquiries can be directed
to the corresponding author. DISCUSSION The phosphorylation sites and glycosylation sites of CAdV-1-
JL2021 Fiber protein is the same as that of CAdV-2-
AC_000020.1 Fiber protein. It indicates that they have the
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Agriculture Science and Technology College and the
procedures complied with IACUCS guidelines on the animals’
care and use for scientific purposes. The Knob of the adenovirus Fiber protein is used for
attachment of the virus to a specific receptor on the cell
surface. The coxsackievirus and adenovirus receptor (CAR) June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org Canine Adenovirus 1 Isolation Wang et al. FUNDING BW and MW conduct the experiment. HZ, JX, and JH analyze
the data and draw the picture. YZ designed and provide the grant
for this experiment. YZ also reviews the manuscript. All authors
contributed to the article and approved the submitted version. This work was supported by grants from the Science and
Technology department of Jilin Province (20200402045NC)
and the Doctoral Start-up Fund Project of the Jilin Agriculture
Science and Technology College (20200002). Hu, R. L., Huang, G., Qiu, W., Zhong, Z. H., Xia, X. Z., and Yin, Z. (2001). Detection and Differentiation of CAV-1 and CAV-2 by Polymerase
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598–603. doi: 10.1177/1040638720934809 Publisher’s Note: All claims expressed in this article are solely those of the authors
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article distributed under the terms of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original
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Recombination and Reassortment in Multipartite/Segmented Viruses. Curr. Opin. Virol. 33, 156–166. doi: 10.1016/j.coviro.2018.08.013 Verin, R., Forzan, M., Schulze, C., Rocchigiani, G., Balboni, A., Poli, A., et al. (2019). Multicentric Molecular and Pathologic Study On Canine Adenovirus June 2022 | Volume 12 | Article 879360 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 10
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Back to the Future. ISPI Report 2023
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ISPI REPORT 2023 THE FUTURE
edited by Alessandro Colombo and Paolo Magri
conclusion by Giampiero Massolo BACK TO
THE FUTURE ISPI Report 2023 edited by Alessandro Colombo and Paolo Mag
conclusion by Giampiero Massolo edited by Alessandro Colombo and Paolo Magri
conclusion by Giampiero Massolo © 2023 Ledizioni LediPublishing
Via Antonio Boselli, 10 – 20136 Milan – Italy
www.ledizioni.it
info@ledizioni.it
Back to the Future. ISPI Report 2023
Edited by Alessandro Colombo and Paolo Magri
First edition: February 2023
Image cover by Francesco Fadani
The opinions expressed herein are strictly personal and do not necessarily reflect the
position of ISPI. Print ISBN 9788855268691
ePub ISBN 9788855268707
Pdf ISBN 9788855268714
DOI 10.14672/55268691
ISPI. Via Clerici, 5
20121, Milan, Italy
www.ispionline.it
Catalogue and reprints information: www.ledizioni.it © 2023 Ledizioni LediPublishing
Via Antonio Boselli, 10 – 20136 Milan – Italy
www.ledizioni.it
info@ledizioni.it Back to the Future. ISPI Report 2023
Edited by Alessandro Colombo and Paolo Magri Back to the Future. ISPI Report 2023
Edited by Alessandro Colombo and Paolo Magri Image cover by Francesco Fadani The opinions expressed herein are strictly personal and do not necessarily reflect th
position of ISPI. Catalogue and reprints information: www.ledizioni.it The ISPI Report 2023 was published thanks to the financial
support of Fondazione Cariplo. Editors: Alessandro Colombo, Paolo Magri
Project and editorial coordination: Matteo Villa
Translation from the Italian version of the ISPI Report 2023
Ritorno al futuro edited by Grace Hason
Editorial coordination and editing: Renata Meda Editors: Alessandro Colombo, Paolo Magri
Project and editorial coordination: Matteo Villa
Translation from the Italian version of the ISPI Report 2023
Ritorno al futuro edited by Grace Hason
Editorial coordination and editing: Renata Meda Table of Contents Table of Contents Introduction
Alessandro Colombo, Paolo Magri.......................................... 9
Part I – General Evolution
of the International System Introduction Introduction
Alessandro Colombo, Paolo Magri.......................................... 9
Part I – General Evolution
of the International System
1. The War in Ukraine and the Unstoppable
Decline of the Post-Twentieth Century
International Order
Alessandro Colombo............................................................... 23
2. Back to the Future? NATO in 2022
Andrea Carati................................................................................ 33
3. Are We Heading Back to an Age
of Traditional Wars Between Major Powers
Valter Coralluzzo......................................................................... 43
4. The Nuclear Threat is Back
Luciano Bozzo.............................................................................. 57
5. Return of Inflation
Franco Bruni................................................................................... 71 9 Part I – General Evolution
of the International System 6. The Three-Dimensional Features
of the Global Energy Crisis
Francesco Sassi.......................................................................... 85
7. Are We Heading Towards De-Globalisation? Lucia Tajoli...................................................................................... 95
8. The Return of Poverty and Hunger
Giovanni Carbone, Lucia Ragazzi.................................. 107
9. The Non-Aligned Movement is Back? Ugo Tramballi............................................................................. 123
Part II – Evolution of the Single Regional Areas
10. The Never-Ending MENA Region Crises
Armando Sanguini................................................................... 137
11. The New Militarisation of East Asia
Francesca Frassineti, Giulia Sciorati............................ 159
12. The Return of the Left to Latin America
Antonella Mori............................................................................ 173
Conclusion
Giampiero Massolo......................................................................... 183
About the Authors.......................................................................... 191 Introduction No sooner had the Covid-19 pandemic begun to retreat than
the outbreak of war in Ukraine delivered a fourth global
shock to the XXI century’s already fragile international order
– following the traumas of the September 11 2001 terrorist
attacks on America, the 2007-08 economic and financial crisis,
and, of course, the pandemic itself, which struck between late
2019 and early 2020. Even more than the jolts that preceded
it, catastrophic war in the middle of Europe appeared to put
an end to all illusions of a New World Order, heralding instead
a return to the past in international politics. This idea of
regression is echoed in the use of terms like “XIX century” to
define and discredit the policies of states like Russia and China. A sense of going backwards certainly sums up the experience of
the last 30 years: after promising an unstoppable “transition”
to democracy, economic openness, multilateral governance of
globalisation, respect for human rights, new sources of energy
and, above all, an end to war, we are now seeing a sudden
“relapse” to a condition in which all improvements seem to
have ground to a halt or even reversed their direction.h This presumed “return to the past” is the focus of our
present volume. In it, we examine various aspects of this
apparent reversal in post-Cold War expectations: the return of
conventional warfare, the renewed threat of nuclear war, the
revitalisation of alliances, the re-appearance of “non-aligned”
nations, and, on the economic side, the return of inflation, fossil
fuels and poverty, along with the spectre of de-globalisation. 10 Back to the Future We also ask whether the phenomena we are seeing today
actually constitute a return to the past or not. Were they really
“laid to rest” in the golden age of the new liberal order? Does
their re-emergence point to a reversal of previous dynamics or
merely a new equilibrium? And to what extent, if at all, do the
“regressions” of recent months really constitute a “return to the
past” rather than stem from entirely or partly new processes? These questions are raised in the very first chapter, devoted
to the significance and impact of the war in Ukraine. Rather
than the cause, the present conflict should be seen as a result
of an ongoing crisis in the post-bipolar international order – a
crisis to which ISPI has presciently devoted all recent annual
reports. Introduction The present situation seems to replicate the disruptive
and conflictual phenomena that have always accompanied the
decline of hegemonic orders: struggles to redistribute power
and prestige; attempts by rising challengers to construct spheres
of influence or buffer zones outside the global influence of the
declining hegemon, and the latter’s attempt to prevent them
from doing so or even to widen its own sphere of influence; and
the calling into question of fundamental principles, norms and
institutions of international coexistence. What makes things worse is that the war in Ukraine seems
destined to dramatically accelerate this already pervasive crisis. Firstly by exacerbating and generalising the trend towards
militarisation in inter-state relations which, for the past two
decades, has been limited to highly contended regions such
as the Middle East and East Asia and has not assumed global
proportions (the European continent certainly being spared). Secondly by giving the international system a further push
towards bipolarisation, especially since the war in Europe runs
in parallel with a deterioration in relations between the United
States and China. Thirdly and most importantly by reversing
or at least correcting the trends that seemed central to the “new
era” that began in the late XX century: economic, social and
cultural globalisation in the first two decades of the post-Cold
War era (already severely undermined by the economic and 11 Introduction 11 financial crisis of 2007-08 and the Covid-19 pandemic); the
growth of an inclusive and tendentially universal multilateral
fabric (now being replaced by coexisting, alternative and
in principle competitive multilateralisms constructed on a
global or regional scale by the hegemonic powers and, most
importantly, open only to their allies; and the very ability to
adopt a concerted approach to what are by definition common
issues – climate change and the environment in general. g
g
However, the practical and symbolic crux of this “return
to the past” – or return to how international politics has
always been, as “realist” scholars see it – is a reaffirmed quest
for “security”. This finds expression firstly in a renewed fear
of war between the major powers, i.e. precisely the type of
war whose disappearance was eagerly celebrated for decades. Valter Coralluzzo examines this issue in his chapter. He points
out that the Russo-Ukrainian conflict has seriously called
into question many deep-seated beliefs about war, its recent
transformations, and its future evolution. Introduction These beliefs had
been matured over decades of intense debate, especially in the
field of strategic and international studies, and are based on
two assumptions that received broad if not unanimous support
among scholars: the disappearance of traditional wars between
states and that of major wars between great powers. Giving the
lie to the expectations embodied in the term “decline of war”,
the conflict in Ukraine constitutes a classical, conventional,
symmetric, high-intensity, and large-scale war between regular
armies (albeit flanked by private military groups) seeking to
conquer territory and establish positions of advantage through
the widespread use of armour and heavy artillery. In short, the
conflict has suddenly brought traditional warfare back to the
heart of Europe, in a form that in many respects resembles the
two world wars.l On the other hand, the Russo-Ukrainian conflict also
presents many aspects of so-called “new war” or, to use another
popular term, “hybrid war”: the presence alongside regular
forces of private and semi-private troops (foreign fighters, 12 Back to the Future Wagner Group mercenaries, and Chechen kadyrovtsy), the
extension of the battlefield to the whole of Ukrainian society,
the use of a wide variety of non-conventional weapons (the
weaponisation of energy, the use of energy supplies to apply
pressure), the massive use of drones and hi-tech weapon systems,
and the increased importance of cyber dominance (hacking)
and psychological operations (psyops). In some respects, it can
be claimed that the conflict (on the Ukrainian side even more
than the Russian) is projecting us into the future, into the next
and final frontier of contemporary warfare: war for control of
the minds of the masses (not transient and partial, but semi-
permanent and total). The renewed spectre of war between the great powers is
accompanied by an explicit revitalisation of the nuclear question
– the theme of Luciano Bozzo’s chapter. The events of 1989-
91 led to a general blackout, or at least a radical reassessment
of the risks of nuclear conflict. The key question inherent in
the “global and endless” war on terrorism, for example, was
whether and how a nuclear deterrent could be used against
international terrorist networks belonging to no single state. No less important was the debate on how the threat of a
nuclear strike could possibly deter other emerging, inherently
non-attributable but potentially devastating challenges: cyber
attacks. Introduction Since 24 February last year, the nuclear factor has reassumed
a central role in the war in Ukraine as a result of Putin’s more
or less explicit references to the possibility of nuclear escalation. This has deeply affected the course of the war in at least two
ways. For the present, the rediscovered nuclear dimension
has led to a unique condition of “double sanctuarisation” in
the strategic theatre: the Russians cannot strike the lines that
feed the Ukrainian war effort where they originate beyond
the borders of Ukraine; for the same reason, the Allies are
begging the Ukrainians to avoid, or at least limit, attacks on
Federation territory, excluding, of course, the regions annexed
by Moscow. Looking ahead, taboos against the use of nuclear Introduction 13 weapons appear to have lost their force in the minds of national
leaders and indeed in public opinion. Worse still, thanks to
progress in miniaturisation, reductions in the power of tactical
nuclear weapons and a corresponding increase in the power of
conventional weapons, the boundary between the two forms of
warfare has become so vague that escalation in the field looks
much easier. War and rearmament, however, are not the only instruments
of security in international politics. Another instrument whose
return has been observed (and even celebrated) in recent months
is that of alliance. While late 2021 saw the launch of AUKUS
in the Indo-Pacific, 2022 saw the rebirth of NATO in Europe. Andrea Carati examines the significance and ambivalence of
this relaunch. On the one hand, there is no doubt that 2022
saw a turning point in the recent history of NATO. Compared
to the gloomy prognosis commonly attributed to it until the
end of 2021, the ongoing conflict at its borders has allowed
NATO to re-establish itself as an indispensable security tool
for Americans and Europeans alike. On the diplomatic front
the allies have united in condemning Russian aggression
and in clearly rejecting direct involvement in the conflict. On the military level, the Alliance has reinforced its eastern
flank and shipped massive quantities of arms to the Ukrainian
government. Finally, on the institutional level, NATO has been
strengthened by enlargement to Sweden and Finland. Introduction g
y
g
Despite the undoubted effectiveness with which it has
influenced the military balance between Ukraine and Russia,
NATO’s present revival has nevertheless not solved key problems
from the past: that of burden-sharing, or European tardiness
in implementing agreed NATO standards (not only the target
of defence spending at 2% of GDP, but the modernisation of
armaments and defence sector reforms too); and differences
between heterogeneous security demands and expectations of
what NATO can actually do (differences destined to become
more acute once the war in Ukraine ends). 14 Back to the Future Back to the Future While the revitalisation of transatlantic solidarity seems to
confirm the transition towards a new, bipolarised international
system, we cannot overlook the fact that such a development is
being resisted by many states. This has prevented the formation
of a united front against Russian aggression, as when a large
number of states (including populous nations like India and
Indonesia) abstained in United Nations votes condemning
Russian aggression and applying subsequent sanctions. This
hypothetical “return” of Non-Alignment is the subject of Ugo
Tramballi’s chapter. While avoiding the emphasis that many
commentators place on the birth of a new “Global South”,
Tramballi recognises that something completely new is indeed
happening in global geopolitics and in relations between the
Global South and North, not only between emerging nations
and the West (i.e. the US and EU), but between the South on
the one hand and the West, Russia and China on the other. The
new dividing line seems to lie between the established Great
Powers and the Rest of the World, with the latter claiming a
new autonomy. y
Various considerations combine to explain this distancing:
past colonialism; memories of the Soviet Union’s support
for anti-colonial liberation movements; a pandemic during
which, at least early on, African nations were forced to beg
vaccines and medicines from a preoccupied Europe; and
Russian disinformation. But the most important reason is
that the conflict in Ukraine is perceived and represented as a
specifically European war, and as another sign – probably the
most significant – of the radical changes occurring in relations
between Europe and the rest of the world. The same interplay of continuity and discontinuity is
repeated in the field of economics. Here, the first phenomenon
to return was inflation, which is dealt with in Franco Bruni’s
chapter. Introduction Inflation began rising again in the second half of 2021,
then surged rapidly in the latter part of 2022 to levels last
seen 40 years ago. Virtually the entire world has been hit by
renewed inflation as a result of a lively post-pandemic economic 15 Introduction 15 recovery. Consumer demand and investment gave back to the
markets the purchasing power that had been forcibly restrained
during months of anti-Covid precautions and lock-downs,
while households and businesses received significant public
cash injections. Large public deficits have also continued to
stimulate economies. The inflationary effect of demand has
been heightened by continuing problems in international
supply chains, partly as a legacy of the pandemic. Significant
rigidity has emerged in energy supply chain, raising prices. To all this must be added the vast liquidity created by years of
super-expansionary monetary policies. p
p
y
y p
The return of inflation has led to the reappearance of interest
rate rises in response. Central banks were slow in reacting to
rising prices, but eventually did so by tightening monetary policy
in a way reminiscent of the radical approach to disinflation
adopted by Volcker in 1979. Short-term interest rates, almost
all close to zero, remained in place for the first quarter of 2022. The US Federal Reserve only began to tighten policy in March,
when inflation already exceeded 8% on an annual basis. In the
Eurozone, the ECB waited until July to revise its rates, by which
time consumer price inflation was already touching 9%. By the
end of the year, central-bank-controlled rates were raised from
zero to 4.5% in the US and to 2.5% in the Eurozone. Though
falling slowly, consumer price inflation remains high at present:
over 7% in the US, around 10% in the Eurozone. At the same time, the war in Ukraine and the spectre of
separation between competing economic spaces have combined
to fuel speculation about the future of globalisation. This topic
is addressed in the chapter by Lucia Tajoli. Over the last 15
years, world trade has been more volatile than ever before. After
nearly half a century of continuous growth in the value and
volume of global trade, and particularly rapid growth in the first
decade of the millennium, international trade has slowed and
become increasingly erratic since 2009. Introduction WTO statistics show
that annual average growth for world trade (volume) between
2010 and 2019 was less than 3%, well below the figure for the 16 Back to the Future previous decade and, more to the point, below annual average
growth in real GDP. Globalisation was defined by increasingly
open markets and growing economic integration, leading to
growth in trade being systematically higher than growth in
GDP. The latest figures have therefore given rise to talk of de-
globalisation. The age of continuous and rapid expansion in
trade certainly seems to have ended for now. For the moment, however, the chance of globalisation
actually failing seems remote, partly because the system of
global trade seems to have weathered the storm, despite the
problems of the last two years, from Covid to supply chain
bottlenecks, soaring freight and international transport costs. More importantly, breaking up and reorganising the many
international supply chains and global value chains that drive
the process of globalisation would prove extremely costly,
especially in the short term. The most likely scenario is that
we shall see a limited decoupling in certain strategic areas of
industry characterised by advanced technology and the use of
semiconductors: globalisation between geographic areas will
likely be more fragmented and selective, but the phenomenon
will not extend to global trade as a whole. g
In parallel with the partial regression of globalisation, the
dream of eradicating global poverty has faded in recent years. Giovanni Carbone and Lucia Ragazzi tackle this subject. In
the modern world, poverty levels have followed a definite
and virtuous trajectory since at least the 1950s: the number
of poor in the world has gradually declined, along with the
share of global population they represent. The percentage of
the world’s population living in extreme poverty has also fallen
from almost 60% in 1950 to less than 10% today. Progress
accelerated rapidly in the 1980s – albeit with a slowdown in
the second half of the 2010s – driven by rapid transformations
in China and India, the world’s two most populous nations. By
way of example, in the 35 years between 1981 and 2016, the
total number of people living in poverty fell from 1.8 billion to
750 million. Introduction 17 The Covid-19 pandemic put an end to this gradual but
constant reduction in poverty and halted a trend established
for over seventy years. Introduction The almost immediate result was that
extreme poverty – the share of the world’s population living
on less than $2.15 a day – increased by 11% in 2020, reaching
9.3% (up from 8.4% in 2019). The same applies to hunger,
defined as the prevalence of chronic malnutrition, a condition
in which daily food consumption is insufficient for a healthy,
active life. Progress in the gradual reduction of global hunger,
from 12.3% of the world’s population in 2005 to 7.8% in
2014, first stalled and then, over only two years, from 2019
to 2021, saw a dramatic reversal, the figure jumping by almost
two percentage points to 9.8%. p
g p
Finally, international political and economic circumstances
have had a major impact on energy transition, and have refocused
attention on energy security. The chapter by Francesco Sassi is
dedicated to these developments. Though completely different
in nature, the shock of the pandemic and that of the Russo-
Ukrainian conflict have had very similar consequences for the
energy sector. Over the last three years, global energy supply
chains have been subjected to repeated commercial shocks
of a physical nature, caused by delays and disruptions, or by
imbalance between supply and demand. This has disrupted
entire national and regional energy systems.h The interruption of climate talks, cancelled because of
tensions over Taiwan, and only restarted in extremis during
COP27, risks exacerbating the competitive nature of this
process. The race between the West and China to achieve energy
transition will affect commodity dependencies, condition
essential supply chains in a low-carbon world, and influence
access to resources in different regions of the Earth. This goes
to show that energy geopolitics will remain a core issue for
decades to come, whether we are talking about fossil fuels or
critical raw materials. Neither does this competitive spiral spare
relationships between allies and partners. One need only think
of the chorus of protests aroused by the German government’s 18 Back to the Future vast programme of energy subsidies to industry and citizens,
and by Germany’s decision to use the full capacity of its coal-
fired power stations to minimise its consumption of natural gas. This strategy, of course, is counterbalanced by the confirmed
closure of German nuclear power plants in 2023. Introduction While international politics and economics do seem to have
resumed the competitive dynamics of the past, these dynamics
are now expressed in disparate ways in different regional
contexts. Francesca Frassineti and Giulia Sciorati’s chapter deals
with the Indo-Pacific region, which seems destined to remain
pivotal to international relations in coming years. This region
is characterised by continuously evolving security dynamics,
including growing threats to public health like Covid-19 and
ever more frequent extreme weather phenomena. However,
the proliferation of weapons of mass destruction, territorial
and maritime disputes, and demographic decline are the
main factors influencing debate on military spending and the
modernisation of defence systems and the armed forces. h y
The Korean peninsula, the Taiwan Strait and the South China
Sea are all potential flashpoints in the region. The concentration
of military resources in geographically limited areas increases
the risk of escalation both as a result of technical errors and
through misinterpretation of the opponent’s intentions. This
has almost led to dramatic consequences on various occasions
on the Korean Peninsula recently. The most important aspect
of this situation, however, remains what the authors call the
“systemic dimension” of regional insecurity, namely the role
that the world powers – China and the US – play in the process
of regional militarisation. Fuelled by a growing US presence
in the region and China’s intensifying military activism, this
dynamic has been aggravated in recent years by the infrequency
of diplomatic meetings between the parties. Latin America seems to have “returned to the past” in a
completely different way. The chapter by Antonella Mori deals
with developments in this region. The current prevalence of
left-leaning governments recalls the political situation in the 19 Introduction 19 region at the beginning of the millennium, though the nuances
are greater and the prospects for stability probably poorer
today. In this context, there is a contrast between three groups
of left-wing governments with quite different propensities:
authoritarian, social-democratic and populist. The authoritarian
group includes Cuba, Nicaragua and Venezuela. The social-
democratic group is made up of leaders like the Chilean
President Boric, Colombian President Petro, and Brazilian
President Lula, who represent a renewed Latin American left
and combine progressive vision with a pragmatic willingness
to compromise. The Mexican AMLO, Peruvian Castillo, and
Bolivian Arce make up the group of populist left-wing leaders. Introduction p
g
p
p p
g
Behind the electoral success of the last two categories is very
often the failure of previous governments to manage Covid
and, more generally, growing frustration with the quality of
democracy and its inability to provide adequate solutions to real-
life problems. Corruption, impunity and social inequality top
the list of voter complaints. Rather than an ideological choice
by the population, this second wave of left-wing governments
seems to channel dissatisfaction – a factor that regularly
drives citizens to vote against any incumbent government and
therefore makes the tenure of the current governments fragile
and reversible too. Finally, the Middle East has also experienced some significant
“returns”: Netanyahu’s re-election to government in Israel; the
crisis of democratic transition in Tunisia; and the latest wave
of protests in Iran, largely instigated by women, which has
spread to all classes of the population and, though lacking
clear leadership, has placed severe strains on the regime of the
Ayatollahs. But, as Armando Sanguini points out in his chapter,
any attempt to lump the mosaic of countries that make up
the MENA (Middle East and North Africa) geopolitical area
into the same basket runs the risk of ignoring their internal
peculiarities and dynamics and the extent to which they are
affected by the regional and international influences that
traverse the region. 20 Back to the Future Back to the Future Russia’s invasion of Ukraine has clearly exemplified these
differences. Apart from absorbing the political attention
of Europe and of the West in general, the war has severely
jeopardized the supply of cereals, of which the region is the
world’s largest importer, while proving particularly advantageous
to its oil and gas-producing nations and, lastly, accentuating
internal tensions that the region could well do without.i g
At the end of the day, though superficially appealing, the
suggestion of a “return to the past”, is questionable. This, at
least, is the conclusion that Giampiero Massolo reaches at the
end of the volume. To begin with, he points out that the shocks
of the war in Ukraine, and Covid-19 before it, fell upon an
international order already shaken by a crisis of confidence and
legitimacy that extends to all major governments. Introduction That same
international order was also already rattled by the failure of the
two great ambitions to which the West, victorious in the Cold
War, had directed its expectations and policies: the inclusion of
Russia and China in an expanded liberal international order,
and globalisation as an engine of limitless and unstoppable
economic progress. p
g
The present process of change does not necessarily imply a
return to an “old world order”. On the contrary, the prospect
of a new bipolar order between the United States and China
seems to be masking a broader and historically unprecedented
juxtaposition: a new duality between “the West and the Rest.” Alessandro Colombo
Paolo Magri 1 On the leap from the rhetoric of the “end of history” to the pervasive
psychology of siege, allow me to refer to A. Colombo, Il governo mondiale
dell’emergenza. Dall’apoteosi della sicurezza all’epidemia dell’insicurezza, Milano R.
Cortina, 2022.
2 C.A. Kupchan, “Realpolitik’s Revenge”, The National Interest, September-
October 2022, pp. 33-42. See also R. Haas, “The Dangerous Decade. A Foreign
Policy for a World in Crisis”, Foreign Affairs, September-October 2022, 101, 5,
pp. 25-39. 1. The War in Ukraine and
the Unstoppable Decline of the Post-
Twentieth Century International Order
Alessandro Colombo In those same months when the great global fear of the Covid-19
pandemic seemed to subside, the war in Ukraine nipped in the
bud the rather wishful idea of reviving that historical and political
imaginary of the liberal international order that accompanied
the change from the XX to the XXI centuries.1 During the
golden age of the New World Order, the entire (political and
legal) edifice of international coexistence might have been able
to construe that it was on the threshold of a “new era” – perhaps
even the “end of history” – but the Ukrainian war has clearly
stood out as sealing the “return” of international politics to the
situation that existed before such promises: “power politics”, the
primacy of strategic considerations over “liberal values”,2 the
subordination of the much celebrated economic “openness” to
ties of friendship and political enmity, the return to borders, the
new-found centrality of States, and even the Cold War – this 24 Back to the Future time, though, two different cold wars,3 one (between NATO and
Russia) that has already degenerated into open confrontation,
but only on a regional scale with a lower-level challenger; the
other (between the United States and China) that is still only
looming, but quite capable of impacting the entire international
system and exposing it to the challenge of an entity that both
the United States and Europe recognise as a genuine “systemic
rival”,4 “the only competitor with both the intent to reshape the
international order and, increasingly, the economic, diplomatic,
military, and technological power to do it”.5 If this is not enough, even in military terms the war in
Ukraine has had the power to instantly sweep away the reality
and rhetoric of the “new wars”,6 once again bringing to the
fore a type of war that is politically and strategically closer to
the great wars between nations of the past than to that of the
“humanitarian”, “low-intensity”, “surgical”, and “zero-cost”
wars of the past 30 years. 3 R. Legvold, “The New Cold Wars”, The National Interest, September-October
2022, pp. 22-32. 3 R. Legvold, “The New Cold Wars”, The National Interest, September-October
2022, pp. 22-32.
4 EU, Strategic Compass, Brussels 2022, p. 18.
5 White House, US National Security Strategy, Washington DC, 2022, p. 23.
6 On how war has changed and the concept of “new wars”, see among others
M. Van Creveld, The Transformation of War, New York, The Free Press, 1991; M.
Kaldor, New and Old Wars. Organized Violence in a Global Era, Polity Press, 1999;
R. Smith, The Utility of Force: The Art of War in the Modern World, London, Penguin
Books, 2006. 1. The War in Ukraine and
the Unstoppable Decline of the Post-
Twentieth Century International Order
Alessandro Colombo This is a war in which not one, but
both sides, are fighting for fundamental interests and values
(territorial integrity for Ukraine, maintaining “great power”
status for Russia); both sides can inflict significant damage
and losses on the other; both sides accept this possibility as an
ineradicable part of the conflict; in line with this, both sides are
prepared to “take the war to the extreme”, without the slightest
thought of an exit strategy, solely a fight until victory or defeat. i
It comes as no surprise, then, that a trauma of such magnitude
could be seen as a clear break in post-XX-century international
relations. Of course, 11 September 2001, the financial and
economic crisis of 2007-08 and, in more recent times, the The War in Ukraine and the Unstoppable Decline... 25 pandemic of 2020-21 have also been given the same tag – and
this definitely raises a few questions. To really understand how
and to what degree the war actually marks a “break”, one must
bear in mind the liberal international order so openly challenged
by Russia’s attack on Ukraine has arguably been suffering from
an irreversible crisis for at least 15 years – that is, at least since
the double shock of the political and military failure in Iraq in
2004 and 2005 and the financial and economic crisis in 2007
and 2008. It is no coincidence that ISPI has focused all its
recent Annual Reports on various aspects of this crisis. War in Ukraine as a Summary Since the war in Ukraine is better understood as an expression
of an ongoing international order crisis, rather than its cause,
the first question to tackle is how the two relate. What factors of
disaggregation for the liberal international order were “released”
in the outbreak of hostilities in Ukraine? Plus, once again, why
do these factors of disaggregation seem to be “taking us back”
to those factors that have always accompanied the declining
phases of hegemonic orders? p
g
The first and most obvious connection relates to, whether
one wants it or not, the dimension of power. The disruption of
the patently clear hierarchy of the immediate post-Cold War era
– a hierarchy dominated by the inordinate power of the United
States and its allies, coupled with a lack of any true competitors
– has already triggered a dash, with rather foregone conclusions,
for a redistribution of power and prestige fuelled by objective
changes (China’s spectacular growth, the increasing success of
other Asian countries, especially India, Indonesia and Vietnam,
and the simultaneous decline of Europe) and visible in the
increasing assertiveness of the leading challengers (China and
Russia above all) and in the unprecedented elbowing for space
in which to manoeuvre by all the others (from India to Brazil,
and from the Arab countries to that increasingly anomalous ally
of the United States, Turkey). 26 Back to the Future This great dash has contributed to the Ukraine catastrophe
in at least two ways. On the one hand, the competition to gain
or not to lose positions in the hierarchy of power has made
all actors more sensitive about the related benefits, while
exacerbating uncertainty about the (peaceful or aggressive)
intentions of others. As often happens in the most competitive
phases of international politics, this dual drive can trigger
“security dilemmas”,7 such as the one that has caused a
progressive deterioration over the last two decades of relations
between NATO and Russia8 or the one that threatens to make
the United States and China fall into Thucydides’s Trap in the
future.9 In such spirals, each side becomes convinced the other
already has already or is on the verge of aggressive intentions. To
prevent this perceived threat, it accumulates defensive resources
in advance, particularly weapons and allies, but this only serves
to confirm the other’s suspicions, leading it to do the same or,
worse, strike first. 7 On the notion of “security dilemma” see H.J. Herz, International relations in the
atomic 1978, age, New York, Columbia UP, 1959; R. Jervis, “Cooperation under
the Security Dilemma”, World Politics, vol. 30, no. 2, pp. 167-214.
8 Ibid.
9 G. Allison, Destined for War. Can America and China escape Thucydides’s Trap?, 2017.
10 R. Gilpin, War and Change in International Politics, Cambridge UP, Cambridge
1981
11 H. Morgenthau, Politics among Nations, New York, Knopf, New York 1948. 7 On the notion of “security dilemma” see H.J. Herz, International relations in the
atomic 1978, age, New York, Columbia UP, 1959; R. Jervis, “Cooperation under
the Security Dilemma”, World Politics, vol. 30, no. 2, pp. 167-214.
8 Ibid. 11 H. Morgenthau, Politics among Nations, New York, Knopf, New York 1948. 9 G. Allison, Destined for War. Can America and China escape Thucydides’s Trap?, 2017.
10 R. Gilpin, War and Change in International Politics, Cambridge UP, Cambridge
1981 War in Ukraine as a Summary The flip side of this is an equally growing sensitivity
to considerations of prestige, which are another constant
macroscopic element in international politics. In all historical
phases in which a mismatch has arisen between the hierarchy of
prestige inherited from the past and the emerging hierarchy of
power,10 those actors that worry about a decline take all possible
steps to defend even the ceremonial structure of the existing
international order, using diplomatic and military means or
drawing on what Hans Morgenthau called “ideologies of the
status quo”.11 By contrast, those nations that believe they are on
the upward trajectory are anxious that their status be recognised The War in Ukraine and the Unstoppable Decline... 27 in the hierarchy of international prestige,12 perhaps through the
battle for admission to major international organisations (the
G20 is a good example), through a redistribution of offices
within such organisations or, more traditionally, through
various forms of diplomatic or military activism – those that
have united Russia and China in the past decade provide an
example of this. h p
This can be linked to the second major connection between
the Ukraine war and the pre-existing crisis of the international
order. As is always the case in international politics, the
redistribution of power has immediate (though, in turn,
intricate) spatial or geopolitical implications. In general
terms, this can be seen in the most common questions that
policymakers, scholars and commentators often ask about
the geopolitical configuration of the near future: where will
the political, economic and strategic centre of gravity of the
international system shift to? Will the XXI century actually be
characterised, as everything would seem to suggest, by a shift
in geopolitical centrality from the Atlantic to the Indo-Pacific? Or will the Atlantic and Indo-Pacific remain what they were
to some degree throughout the last century: the two poles of
international relations?13 Plus, regardless of where this centre
of gravity is, how will the relationships between different
regional spheres evolve, and how will they relate to the global
arena? Will regional dynamics gradually regain prominence at
the expense of global dynamics, as has been increasingly seen
over the last three decades? Or will the mounting competition
between the United States and China be powerful enough to
partially or totally reverse this trend? 12 D.W. Larson and A. Shevchenko, “Status Seekers. Chinese and Russian
Responses to U.S. Primacy”, International Security, vol. 34, no. 4, 2010, pp. 63-95.
13 As already noted by O. Young, “Political Discontinuities in the International
System”, World Politics, vol. 20, no. 3, April 1968, pp. 369-92. 14 This conflict dynamic is explicitly recognised in the US National Security
Strategy of the past year: “Beijing has ambitions to create an enhanced sphere
of influence in the Indo-Pacific and to become the world’s leading power”. As
such, “Competition with the PRC is most pronounced in the Indo-Pacific, but it
is also increasingly global” - White House (2022) pp. 23-24.
15 A. Osiander, The States System of Europe, 1640-1990. Peacemaking and the Conditions
of International Stability, Oxford, Clarendon Press, 1994; I. Clark, Legitimacy in
International Society, Oxford - New York, Oxford UP, 2005. 15 A. Osiander, The States System of Europe, 1640-1990. Peacemaking and the Conditions
of International Stability, Oxford, Clarendon Press, 1994; I. Clark, Legitimacy in
International Society, Oxford - New York, Oxford UP, 2005. 14 This conflict dynamic is explicitly recognised in the US National Security
Strategy of the past year: “Beijing has ambitions to create an enhanced sphere
of influence in the Indo-Pacific and to become the world’s leading power”. As
such, “Competition with the PRC is most pronounced in the Indo-Pacific, but it
is also increasingly global” - White House (2022) pp. 23-24. War in Ukraine as a Summary At the heart of the impact
of this competition for power on geopolitics lies the challengers’
already continuous attempts to build spheres of influence or
buffer zones that are not subject to the global influence of the 28 Back to the Future United States and Europe – and the efforts by these latter two
to prevent this or, even, enlarge their own sphere. This is the
same conflict that has caused the catastrophic consequences
seen in Ukraine. The same dynamic looks likely to also play out
in East Asia and, on a larger scale, in the Indo-Pacific.14 gi
Finally, a transformation in power relations and geopolitical
configuration of this magnitude cannot happen without also
calling into question all the fundamental principles, norms
and institutions of international coexistence – those that set
out who are the legitimate actors in the system, the basic rules
of their coexistence (particularly, whether and under what
circumstances they can legitimately resort to war)15 and who
has the right to speak on behalf of the entire international
community, dictating the political, economic and ideological
standards for full membership and defining, as part of the same
power, the degrees of non-membership as well. h This is the least noted, but in all likelihood most unwieldy
dimension of the war in Ukraine. This dimension was already
part of an undoubted and clearly extensive questioning of the
existing principles and norms of international coexistence. Indeed, so extensive was this that it has not even spared a
surreptitious re-legitimisation of the use of force and, above all,
it has led the international community to split into factions in
every major international crisis of the past two decades, from the
“humanitarian war” in Kosovo in 1999 to the Anglo-American
aggression in Iraq in 2003, from the NATO intervention in
Libya in 2011 to the Russian invasion of Crimea in 2014. This
instability in the rules of coexistence has dramatically increased The War in Ukraine and the Unstoppable Decline... 29 29 the space for the opportunistic strategies of various actors. 16 G. Ferrero, Potere. I Geni invisibili della Città, Milano, Sugarco, 1981, pp. 255-305.
17 The three most important strategy documents published in the past year all
converge on this: UE (2022); NATO, Strategic Concept, Bruxelles, 2022; White
House (2022). War in Ukraine as a Summary This
happens in cases of what Guglielmo Ferrero called, during
the tormented period between wars, the conditions of quasi-
legitimacy.16 When two or more alternative principles face off
without one ever managing to impose itself definitively, an
actor that violates the rules can justify this by drawing, from
time to time, on the principle that most suits it, thus trying to
avoid, at least in part, the reputational price it would otherwise
have had to pay in a more orderly situation. From Continuities to Discontinuities Still, this does not change the fact the war in Ukraine seems
destined to really accelerate this general crisis of order. For
starters, it looks set to aggravate and generalise the trend towards
the “securitisation” of relations between States that, over the
past two decades, was already found in highly competitive
regional areas, such as the Middle East and East Asia, but had
not yet become a trend (sparing, in particular, the European
continent). The manifestations of such “regression” are the
same as in all competitive phases of international politics: an
increase in military spending, the formation of new alliances
and the revival or enlargement of others (NATO, notably), the
definitive shift in strategic planning from minor wars (which
was, in spite of everything, the “global war on terror”) to the
potential for direct confrontation between major powers, the
consequent investment in cutting-edge military technologies
which, in recent months, has not stopped even in the face of an
express return to nuclear.17 Next, the seemingly permanent breakdown in relations
between NATO and Russia will probably add impetus to the 30 Back to the Future bi-polarisation of the international system, particularly because
it has already become intertwined with the simultaneous
deterioration of relations between the United States and China. This bi-polarisation remains uncertain diplomatically and
strategically, with many countries resistant to it (including
almost all the “champions” of their respective regions: India,
Brazil, South Africa, Saudi Arabia, Egypt, etc.) and reluctant to
take sides in the emerging confrontation, seeking to maintain
relations with all parties instead.18 However, in the meantime,
the bi-polarisation of the international system has already
become fully fledged in terms of the world’s languages and
representations, as can be seen in the Euro-American rhetoric
of the clash between democracies and autocracies19 and the
Russian and Chinese rhetoric of the clash between Westerners
and non-Westerners. Consistent with this dualistic portrayal,
bi-polarisation has already resulted in a call to “close ranks”
against real and potential adversaries, and a call to order for
those allies suspected of seeking “dangerous” relations outside
their own camp. It is no coincidence that this line of fracture tends to
further hold back the economic and political globalisation of
the opening two decades of the post-Cold War era, after the
other brakes applied by the 2007-08 financial and economic
crisis and the Covid-19 pandemic in the last three years. 18 S. Menon, “Russia’s War in Ukraine May Bring Nonalignment Back”, Foreign
Policy, Summer 2022. For the especially important case of India, see S.L. Jagtiani,
S. Wellek, “In the Shadow of Ukraine: India’s Choices and Challenges”, Survival,
2022, vol. 64, no. 3, pp. 29-48. 19 This dualistic portrayal is ubiquitous in political rhetoric and news reporting,
and it occupies an increasing place in scholarly works. Some of the most recent
accounts are R. Kagan, “A Free World, If You Can Keep It. Ukraine and
American Interests”, Foreign Affairs, 2023, 102, 1, pp. 39-53.. 18 S. Menon, “Russia’s War in Ukraine May Bring Nonalignment Back”, Foreign
Policy, Summer 2022. For the especially important case of India, see S.L. Jagtiani,
S. Wellek, “In the Shadow of Ukraine: India’s Choices and Challenges”, Survival,
2022, vol. 64, no. 3, pp. 29-48.
19 This dualistic portrayal is ubiquitous in political rhetoric and news reporting,
and it occupies an increasing place in scholarly works. Some of the most recent
accounts are R. Kagan, “A Free World, If You Can Keep It. Ukraine and
American Interests”, Foreign Affairs, 2023, 102, 1, pp. 39-53.. 20 It is no coincidence that the saying the “weaponisation of interdependence” is
found in the opening pages of the European Union’s Strategic Compass, cit., p. 5.
21 On the nature and limits of the project, B.R. Rubin, “Geography Lessons:
American Decline and the Challenge of Asia”, Survival, 2022, vol. 64, no. 1, pp.
121-30; J. Crabtree, “Competing with the BRI: The West’s Uphill Task”, Survival,
2022, vol. 63, no. 4, pp. 81-88. From Continuities to Discontinuities Some
restrictive repercussions are already fully in place: the drive
(more political than economic) to “bring back home” activities
that were previously relocated abroad, at least in newly declared
“strategic” sectors like healthcare and energy; the promise to The War in Ukraine and the Unstoppable Decline... 31 31 “enclose” and “secure” the borders of individual States and
regional organisations (including the European Union), the
renewed focus on the strategic need for autonomy, coupled
with the even more significant reinterpretation of economic
interdependence as a possible (and always looming) “weapon”;20
and, as a solution to all this, the temptation to “disassemble”
and, potentially, “reassemble” globalisation in smaller spaces and
only around actors, principles and projects that are compatible
with their own. This geopolitical disassembly has significant institutional
repercussions. On the one hand, it looks likely there will be a
worsening in the crisis that, for at least 15 years, has already been
affecting those international institutions with universal reach –
that is, not only the major international political and economic
organisations such as the United Nations, the World Trade
Organization and the World Bank, but also the sets of agreed
principles, norms, rules and decision-making procedures for
trade, finance and environmental and military matters. On the
other hand, in the place of such inclusive multilateralism that
tends towards universalism – it is no coincidence this is reflected
in the unitary notion of the “international community” – the
current trend is for a coexistence of alternative multilateralisms. In principle, such multilateralisms compete with each other
and they are built at the initiative of hegemonic powers on a
global or regional scale. Most importantly, though, they are
only open to their respective allies – as in the Western Build
Back Better World project launched in June 2021 by the G7 in
response to the Chinese Belt and Road Initiative21 or, even more
as a consequence, the establishment of AUKUS (the United
States, the United Kingdom and Australia) a few weeks later. 32 Back to the Future Back to the Future The most worrying and potentially most destructive
outcome of this laceration is a weakening of the capacity for
concerted management of shared problems and emergencies. 22 White House, National Security Strategy, cit., p. 6. White House (2022), p. 6. 1 “Emmanuel Macron warns Europe: NATO is becoming brain-dead”, The
Economist, 7 November 2019.
2 A. Carati, “La Nato e la straordinaria persistenza di un’alleanza obsoleta”, in A. From Continuities to Discontinuities This has been seen in the last three years in how Covid-19 was
dealt with, as the situation rapidly degenerated into a battle
of efficiency and recriminations between the United States
and China (like the one that reopened at the end of 2022 in
the wake of the rise in infections in China). The same looks
likely to be repeated in the face of other major issues that are
by definition common or shared, such as climate change and,
more generally, the environment. This potential consequence
is candidly acknowledged in the latest US National Security
Strategy. Indeed, it precisely sees the relationship between the
decline of the international order and the growth of “common”
emergencies as the political and strategic conundrum of the
current moment in history: “We face two strategic challenges. The first is that the post-Cold War era is definitively over and
a competition is underway between the major powers to shape
what comes next. ... The second is that while this competition is
underway, people all over the world are struggling to cope with
the effects of shared challenges that cross borders – whether
it is climate change, food insecurity, communicable diseases,
terrorism, energy shortages, or inflation... But we must be
clear-eyed that we will have to tackle these challenges within
a competitive international environment where heightening
geopolitical competition, nationalism and populism render this
cooperation even more difficult and will require us to think and
act in new ways”.22 2. Back to the Future? NATO in 2022 Andrea Carati 2022 will go down as a watershed in the history of NATO,
not only because the war in Ukraine refocused the spotlight
on European security but, more importantly, because of
the dramatic change in the way the public at large and, to a
great extent, political élites too perceive the organisation. The
relevance attributed to NATO today is in complete contrast
to the way in which the Alliance was viewed until late 2021. While NATO appeared to languish in a critical condition in
the two or three years leading up to the Russian invasion of
Ukraine, today the organisation has re-established itself as the
principal anchor for European security. The transition from presumed obsolescence to evident
resilience has been rapid. As recently as 2019, in a hard-hitting
interview with the Economist, President Emmanuel Macron of
France declared the Alliance “brain dead”; the United States
was seen to be abandoning its European allies and the latter
showed no sign of commitment to the continent’s security.1
Macron’s analysis seemed to echo that of Donald Trump, the
first American president to threaten a US withdrawal from
NATO and the first to question the strategic reasoning that
tied the United States to multilateral regional agreements
considered inefficient and disadvantageous for Washington.2 34 Back to the Future The withdrawal from Afghanistan in 2021 had an even more
significant impact on the public’s perception of the Alliance
as moribund. Traditionally estranged from international
affairs, the European public at large, along with political
commentators and leaders viewed NATO’s disengagement
from Afghanistan as the result of a spontaneous decision by
the Biden administration. On the surface, the abandonment
of Afghanistan to the Taliban confirmed not only the military
inefficiency but the political unreliability of NATO, and clearly
signalled the need to relaunch the European defence project.3 In only a few weeks, the war in Ukraine turned public opinion
on its head, with one exaggerated view (the obsolescence of
NATO) being replaced by its opposite (extraordinary resilience). The truth is that the conflict raging on the borders of the Alliance
confirms that despite the many crises it has faced in recent years,
NATO remains what it has always been, namely an essential
security instrument for Americans and Europeans alike. Colombo and P. Magri (Eds.), La fine di un mondo. La deriva dell’ordine liberale, ISPI
Report, Milan, Ledizioni, 2019.
3 O. David, “NATO and the Future of Europe-US Relations after Afghanistan”,
The RUSI Journal, vol. 166, n. 5, 2021, pp. 44-48. 4 For the official declarations issued by the Secretary General and Councils of
NATO, see the section entitled Russia’s Invasion of Ukraine – NATO’s response in
the official website of the North Atlantic Treaty Organisation. 2. Back to the Future? NATO in 2022 At
the same time, setting aside the effectiveness with which it has
changed the balance of military power between Ukraine and
Russia, the problems facing NATO allies remain unchanged:
the dilemma of burden sharing; Europe’s reluctance to conform
to agreed standards (not only the defence spending target of
2% of GDP but the modernisation of military equipment and
defence sector reforms); and differences between heterogeneous
security demands and expectations of NATO capabilities (a
problem destined to become even more acute after the war in
Ukraine). Unsurprisingly, the contrast between NATO’s resilience and
its persistent problems has emerged in all the main events of
2022 discussed in this article. It is naturally most evident in
the Alliance’s reaction and policy towards the Russian attack
on Ukraine; it is also apparent in the new Strategic Concept Back to the Future? NATO in 2022 35 adopted at the Madrid Summit (28-30 June); and finally it is
evident in the process of northward expansion initiated by the
membership applications of Sweden and Finland. NATO and the War in Ukraine In response to the Russian Federation’s military offensive
against Ukraine on 24 February, NATO immediately adopted a
policy of opposition that has remained substantially unchanged
until the present day. NATO has reacted on three fronts:
1) condemnation of Russian aggression accompanied by a
clear refusal to become directly involved in the conflict; 2)
reinforcement of the Alliance’s eastern borders; 3) massive arms
supplies to the Ukrainian government. pp
g
To begin with, on a political level, NATO categorically
condemned the Russian invasion on 24 February. The declaration
issued by Jens Stoltenberg, Secretary General of the North
Atlantic Council, and the joint declaration of NATO Heads of
State and Government issued 24 and 25 February assume an
identical tenor that has been maintained for the duration of the
conflict so far. In a consistent script, NATO “condemns in the
strongest possible terms Russia’s brutal and unprovoked war of
aggression against Ukraine”, defines the military operation as
a “blatant violation of international law”, and “stands with the
people of Ukraine and … will always maintain its full support
for the territorial integrity and sovereignty of Ukraine”.4 Even in the face of unanimous condemnation, however,
NATO has been equally clear in its political and strategic decision
not to join the war against Russia. To begin with, the allies have
repeatedly pointed to the distinction between NATO members
(the only countries for which the organisation is obliged to go
to war) and partner countries like Ukraine, for which NATO Back to the Future 36 limits itself to providing indirect military aid while doing
everything possible to avoid direct involvement. On top of this,
NATO has committed itself to preventing or at least containing
the risk of escalation, both horizontal (the geographic spread
of conflict) and vertical (the step from conventional to nuclear
warfare). It was made clear from the outset that, in the case of
Ukraine, NATO would adopt neither of the instruments it has
utilised in other crises over the last thirty years: boots on the
ground and either aerial bombardment or the imposition of a
no-fly zone. l y
In keeping with this response, NATO has committed itself
only on the two fronts mentioned above: reinforcement of
its eastern borders and the supply of arms to Ukraine. 5 NATO, Statement by NATO Heads of State and Government on Russia’s attack on
Ukraine, 25 February 2022.
6 Statement by NATO Heads of State and Government, 24 March 2022. NATO and the War in Ukraine In the
Extraordinary Virtual Summit of NATO Heads of State and
Government of 25 February, an immediate decision was taken
to reinforce the Alliance’s eastern flank.5 With this in mind,
SACEUR (the Supreme Allied Commander Europe) was
charged with drawing up plans for the deployment of a rapid
reaction force to the eastern quadrant. In the Extraordinary
Summit of 24 March, the leaders of NATO further agreed to
station 40,000 men along the eastern flank and to deploy four
additional battle groups to Bulgaria, Hungary, Romania and
Slovakia.6 This reinforcement leverages policy adopted by NATO
following the 2014 crisis in Ukraine, and therefore represents an
acceleration of ongoing deployments rather than a completely
new approach. The policy in question is the EFP (Enhanced
Forward Presence), first elaborated at the NATO summit in
Wales in 2014 and enacted later in 2017. This foresees four
multinational battalions stationed in Poland and the three
Baltic nations, led by the United Kingdom, Canada, Germany
and the United States, and more than triples the forces present Back to the Future? NATO in 2022 37 at the start of the conflict.7 In a similar manner, the Tailored
Forward Presence launched in 2017 has reinforced ground,
naval and air capabilities in the Black Sea region to the south
east.8 After the 2014 crisis, NATO’s greater engagement in the east
was accompanied by an intensification of US commitment. The Obama administration had already launched the European
Reassurance Initiative (later renamed the European Deterrence
Initiative) establishing a rotating presence of 7,000 men in
central and western Europe. In February 2022, the Biden
administration reinforced the American contingent with an
additional 15,000 men, taking the total number of US troops
in Europe to around 100,000.9 p
In addition to reinforcing Europe’s eastern flank, NATO
countries immediately boosted arms supplies to the government
in Kyiv. Western aid proved decisive in enabling Ukraine’s armed
forced to withstand the Russian offensive and, later, to retake
some occupied territory. All NATO countries have provided
military aid with the exception of Bulgaria and Hungary. Arms
have been supplied in vast quantities and have included anti-
tank weapons, air defence systems (particularly the famous
Stinger, Patriot and Javelin missiles), helicopters, drones,
howitzers, tanks, military vehicles, small artillery, ammunition
and various types of non-lethal military supplies (protective
armour, equipment, communication systems, etc.). 7 P. Belkin, Russia’s Invasion of Ukraine: NATO’s Response, Congressional Research
Service, CRS Insight no. 11866, 21 March 2022.
8 See the dedicated portal in NATO’s official website: NATO’s military presence in
the East of the Alliance.
9 A. Cordesman, “The Ukraine War: Preparing for the Longer-term Outcome”,
Center for Strategic and International Studies (CSIS), Washington DC, 2022.
10 D. Kunertova and N. Masuhr, “The War against Ukraine Shapes NATO”, Policy Perspective, CSS Eth Zurich, vol. 10, no. 4, June 2022, p. 3.
11 J. Master and W. Merrow, How Much Aid Has the U.S. Sent Ukraine? Here Are Six
Charts, Council on Foreign Relations, 16 December 2022.
12 G. Sarcina, “Lo scontro con Putin, l’America unita su Kiev”, Corriere della Sera,
21 December 2022. NATO and the War in Ukraine Far more
cautious if not completely withheld have been military supplies
potentially capable of triggering dangerous escalation, such as
long-range missiles or bombers. The supply of MIG-29 jets
was blocked, for example.10 The Czech Republic, Poland and 38 Back to the Future Slovakia felt particularly exposed, as their Russian and Soviet-
made arms were the only ones compatible with many Ukrainian
military systems. In late Spring, as the conflict dragged on and
a war of attrition began to look inevitable, NATO members
intensified the supply of western-made arms, accompanied by
new training programmes for Ukrainian military personnel. Most arms supplies have come from the United States,
though US military aid has not exceeded that of the other allies
taken together. Estimates vary significantly but many sources
quantify US aid in 2022 at around 48 billion dollars11 – more
than the US spent on their own war in Afghanistan (around 46
billion per annum). More generally, the NATO members who
have contributed most (excluding the United States) are the
United Kingdom (around 4 billion dollars), Germany (around
2 billion euros) and, proportionally to their economies, Poland
and the Baltic states. Comparatively speaking, the other major
European nations have contributed far less: France only 470
million euros and Italy only 310 million, for example.12 13 A. Colombo, Il governo mondiale dell’emergenza. Dall’apoteosi della sicurezza all’epidemia
dell’insicurezza, Milano, Cortina, 2022.
14 Active Engagement, Modern Defence. NATO Strategic Concept 2010.
15 NATO Strategic Concept 2022. NATO’s New 2022 Strategic Concept In addition to the war, the big news in 2022 was NATO’s
adoption of a new Strategic Concept at the Madrid Summit
(28-30 June). The latest version of the Alliance’s most important
strategy document completely rewrote rather than merely
updating the previous concept issued in 2010. It presented
numerous innovations, some of which were evidently responses
to the most dramatic events of the war in Ukraine while others
pointed to longer term developments. The latter come as a
response to the parabola traversed by the liberal international Back to the Future? NATO in 2022 39 order, whose perception of NATO had deteriorated from that
of undisputed security guarantor in the Euro-Atlantic area
to that of an organisation plagued by increasing instability.13
Compared to its 2010, 1999 and 1991 antecedents, the 2022
Strategic Concept confirms this trajectory: while NATO was
deemed an exceptionally secure alliance in the ’90s, by 2010 it
was facing new challenges and today feels openly threatened. The 2022 Strategic Concept makes this even too clear: NATO
feels directly challenged in Europe – the geopolitical space it
is most clearly obliged to defend – and by a formidable threat
that for the very first time could seriously endanger the allies’
security. y
While NATO’s enemies were never defined in the 1999 and
2010 documents, the new Strategic Concept draws crystal clear
lines between those inside and those outside the Alliance. The
biggest change is seen in the approach to Russia. In the 2010
concept, the Russian Federation was described as a partner with
whom “a common space of peace, stability and security” could
be established and one with whom NATO, far from being in
conflict, should rather seek “a true strategic partnership”.14 The
relationship described in the 2022 Strategic Concept is totally
different. Following brief notes on the aims of the Alliance, the
very first point made in the Strategic Environment section points
an accusing finger at Russian aggression. Soon after, we read
that “the Russian Federation is the most significant and direct
threat to Allies’ security and to peace and stability in the Euro-
Atlantic area”.15 This is the clearest statement of antagonism
ever made. Back to the Future 40 16 J.J. Mearsheimer, “The Causes and Consequences of the Ukraine War”,
Horizons, no. 21, Summer 2022, pp. 12-27.
17 See A. Wolff, “The future of NATO enlargement after the Ukraine crisis”,
International Affairs, vol. 91, no. 5, 2015, pp. 1103-121. NATO Membership for Sweden and Finland Another key development in 2022, again as a result of the war,
was the application of Sweden and Finland to join NATO. The decision of both countries to abandon their traditional
neutrality was a direct response to the conflict in Ukraine. What
is important here is that, despite the controversy surrounding
the policy of expansion, NATO has insisted on maintaining its
so-called “open door” policy towards potential applicants. p
p
y
p
pp
By attributing full responsibility for the attack on Ukraine
to the Russian Federation, NATO has rejected the accusation
that its eastward expansion could be interpreted as one of the
causes for the conflict. Setting aside the debate raging around
expansion to the east and the kind of conflict it could trigger
with Russia, and excluding too the geopolitical considerations
that, historically, have made Ukraine’s geographic position far
more problematic than those of other east European countries,
the point worth emphasising is that, from a political and
strategic point of view, the war has not called into question
the open door policy adopted by NATO in the mid ’90s. On
the contrary, within NATO circles, the attack on Ukraine
seems to confirm the raison d’être behind expansion, which
is viewed as a means of securitising eastern Europe and as a
bulwark against an increasingly aggressive Russia.16 The Alliance
has therefore confirmed its initial reaction to the Ukrainian
crisis of 2014: in the face of Russian claims, it has abandoned
the hypothesis of Ukrainian neutrality and instead intensified
military cooperation, not only keeping Ukrainian membership
of NATO on the table but accrediting the prospect too.17 g
p
p
Against this backdrop, on 18 May 2022, when Finland
and Sweden jointly presented official applications for NATO
membership, abandoning the long tradition of neutrality Back to the Future? NATO in 2022 41 that had characterised both countries, the move was greeted
with enthusiasm by all members with the sole exception
of Turkey. The arrival of Finland and Sweden represents a
round of expansion that is profoundly different from those
of the past. For a start, both countries boast internal stability
and democratic credentials far superior to those of the east
European nations that joined NATO after 1999. Secondly,
they come from a history of formal neutrality and substantial
alignment with the West rather than from a sphere of influence
antagonistic to NATO. 18 E. Ashford, “NATO Should Think Twice Before Accepting Finland and
Sweden”, The Washington Post, 30 May 2022. 1 R. Kagan, “Il pretesto del nazionalismo”, Corriere della Sera, 21 August 2008.
2 Id., The Return of History and the End of Dreams, 2008; Italian translation Il ritorno
della storia e la fine dei sogni, Milan, Mondadori, 2008. g
,
p
,
,
g
2 Id., The Return of History and the End of Dreams, 2008; Italian translation Il ritorno
della storia e la fine dei sogni, Milan, Mondadori, 2008. 1 R. Kagan, “Il pretesto del nazionalismo”, Corriere della Sera, 21 August 2008. NATO Membership for Sweden and Finland Thirdly, Finland and Sweden boast
far more developed defence industries and armed forces than
NATO’s new members in eastern Europe, and have already
participated in many NATO missions, developing a high level
of interoperability. Their military contribution to the Alliance
will therefore be significant. i
As with all expansions, however, the integration of Finland
and Sweden will inevitably be accompanied by numerous
problems.18 An Alliance of 32 nations (twice the organisation’s
1991 membership of 16) will have to reckon with more complex
decision-making processes and with increasingly heterogeneous
security demands – problems already encountered with the
post-Cold War admissions. As in the past, expansion to these
two Scandinavian nations will inevitably exacerbate the Russian
Federation’s perception of encirclement by the West, leading to
increased antagonism and an even more strained relationship
between Moscow and NATO. In addition, combined with
increased defence spending, an expanded Alliance will accelerate
the remilitarisation of Europe and significantly reduce areas of
neutrality. Finally, while eastward expansion over the last twenty
years has driven strategic competition primarily in the region
from the Baltic nations to the Black Sea, the arrival of Sweden
and Finland will extend competition to the High North and
therefore to the Baltic Sea, Barents Sea and the Arctic in general. 42 Back to the Future Alongside the renewed protagonism of NATO referred to in
the opening sections, 2022 will therefore go down in history as
the start of an era of renewed competition and militarisation in
Europe, the outcome of which is disquietingly uncertain. 3. Are We Heading Back to an Age
of Traditional Wars Between
Major Powers?
Valter Coralluzzo Valter Coralluzzo In the aftermath of the “five-day war” between Russia and
Georgia (8-12 August 2008) ‒ which in practice was a major
offensive by Russian armed forces on Georgian territory, in the
name of defending the separatist republics of South Ossetia
and Abkhazia, of which Tbilisi was seeking to regain control
through military power ‒ Robert Kagan, a leading figure in
American neo-conservative circles, observed that the conflict
represented no less significant a turning point in recent history
than the fall of the Berlin Wall. It marked, he wrote, “the
official return of history... to an almost XIX century style of
great-power competition, complete with virulent nationalisms,
battles for resources, struggles over spheres of influence and
territory, and even — though it shocks our XXI century
sensibilities — the use of military power to obtain geopolitical
objectives”.1 Furthermore, this confirmed the central thesis of
the book that Kagan had just published,2 in which he scorned
the optimistic and widely cherished illusion that the end of the
Cold War had spawned a new international order, characterised
by the disappearance of any serious reason for conflict between
states. Instead, he argued that those years had been “just a 44 Back to the Future momentary pause in the eternal competition between peoples
and nations”3 and that in the decades to come, the traditional
geopolitical contest between major powers would return to the
fore, in a global context increasingly marked by the perennial
clash between democracies and autocracies. Kagan’s commentary on the “August War” between Russia
and Georgia is a perfect fit for the current context. Many
features of what can be rightly seen as Europe’s first (albeit
underestimated) war of the XXI century are in fact being
amplified in the ongoing war of aggression in Ukraine, which
is generally depicted as a classical, conventional, symmetrical,
high-intensity, large-scale conflict between regular armies
(albeit backed up by private military groups) striving to conquer
territory and positions of advantage by making widespread
use of armoured vehicles and heavy artillery: in other words,
a conflict that has undoubtedly brought traditional war back
to the heart of Europe, in a form that resembles the two world
wars in many respects. 3. Are We Heading Back to an Age
of Traditional Wars Between
Major Powers?
Valter Coralluzzo Public opinion, the media, political
decision-makers and various analysts were clearly taken aback:
until the very last moment and despite the US’s well-founded
forewarnings of an imminent attack by Russia on Ukraine,
many denied that such an event could actually happen. For
others, however, Russia’s attack came as a surprise only in its
form, not its substance, because it could easily be seen as a
natural (and hence predictable) step in the development of post-
Soviet Russian foreign policy, which had long been focused on
the increasingly aggressive and unscrupulous struggle to gain
recognition of its status as a major power. 3 Ivi, p. 14. 4 J. Caesar, Commentarii de Bello Gallico, Book III, 18, 6.
5 G.P. Gooch, History of Our Time, 1885-1911, London, Williams and Norgate,
1911, pp. 248-249. 5 G.P. Gooch, History of Our Time, 1885-1911, London, Williams and Norgate,
1911, pp. 248-249. 4 J. Caesar, Commentarii de Bello Gallico, Book III, 18, 6. The Decline-of-War Thesis To fully understand why there is a stubborn refusal to see a war
of the type unleashed by Putin’s Russia at dawn on 24 February
2022 as a real possibility ‒ despite the fact that this was no bolt Are We Heading Back to an Age of Traditional Wars Between Major Powers? 45 from the blue, but a sharp escalation of the conflict that had
been going on in the Donbass since 2014 ‒ it is worth bearing
in mind that all of us, like the Gauls who opposed Caesar,
tend to be bound by the logic under which “men willingly
believe what they wish”.4 It is no coincidence that the cognitive
sciences used for the purposes of prediction and strategic
decision-making warn of the danger posed by factors (such as
beliefs, values and illusions) that act as a filter on the impartial
examination of facts, thus undermining our ability to question
our beliefs and causing us to fall into cognitive traps (giving
credence only to information that confirms our expectations,
or fitting incoming information to our existing world-views)
that generate a skewed picture of reality. In this case, the Russia-
Ukraine conflict seriously calls into question a number of deep-
seated beliefs about war, its recent transformations and its
future development. Shaped by the lively debate on these issues
over recent decades, especially in strategic and international
studies, these beliefs are based on two assumptions that have
gained broad (but not unanimous) consensus among scholars:
firstly that the age of traditional wars between sovereign states
is over, and secondly that wars between major powers have
been consigned to history. Usually lumped together under the
more general and inclusive heading “the decline of war”, these
assumptions, which appear to accurately reflect the historical
experience of the Cold War and post-bipolar eras, warrant
careful consideration. 6 T.P.M. Barnett, The Pentagon’s New Map, New York, G.P. Putnam’s Sons, 2004,
p. 271.
7 M. Singer and A. Wildavski, The Real World Order. Zones of Peaces, Zones of Turmoil,
Chatham (NJ), Chatham House, 1993.
8 Battle-related deaths include military and civilian fatalities caused by traditional
battlefield fighting, guerrilla activities and bombardments of all types. The Decline-of-War Thesis Over a century has passed since George Gooch, a British
historian, wrote: “We can now look forward with something
like confidence to the time when war between civilised nations
will be as antiquated as the duel”.5 The most authoritative
conflict datasets give reason to believe that this time has come,
which is why, a few years ago, Thomas Barnett claimed that Back to the Future 46 “state-on-state war has gone the way of the dinosaur”.6 These
datasets clearly show that since 1945, despite a large rise in the
number of states, the number of classical international wars
‒ i.e. conventional, symmetrical conflicts between sovereign
states fought around a military front by regular armies using
comparable weapons, tactics and strategies – has fallen so
drastically, that such wars have become rare and, in certain
parts of the world, a thing of the past. This has spawned the
idea of a world of two halves, in which zones of peace (within the
confines of the Euro-Atlantic security community), benefiting
from economic development, political stability and liberal
democracy, co-exist with zones of turmoil (the rest of the world),
where in “strong” states (i.e. states capable of fulfilling their
sovereign functions), power politics and the security dilemma
dictate the rules of the game, and in “weak” states (i.e. states
unable to acquire legitimacy by providing security and other
services), civil wars and territorial fragmentation proliferate7. While the two-worlds narrative may look somewhat
contrived, the fact remains that the few interstate conflicts
fought in recent decades ‒ whether minor conflicts or those
classified as full-scale wars on the basis that they have exceeded
the conventional threshold of 1,000 deaths in battle per year8
‒ have been geographically confined to peripheral or semi-
peripheral areas of the international system. Furthermore, these
conflicts have almost invariably involved minor actors. Where
they have involved the system’s major powers, they have never
developed into direct conflicts on the ground between those
powers, but only into proxy wars (i.e. wars between minor
players each protected by a major power). Alternatively, they
have involved indirect, covert, unconventional or hybrid forms Are We Heading Back to an Age of Traditional Wars Between Major Powers? 47 of warfare. In other cases again, they have pitted a major power
(perhaps at the head of a broad coalition of states) against a
minor power or non-state actors of a criminal or terrorist
nature. 9 C. Holmqvist, Policing Wars. On Military Intervention in the Twenty-First Century,
London, Palgrave Macmillan, 2014.
10 M. Kaldor, New and Old Wars. Organized violence in a Global Era, 1999.
11 Id., Global Civil Society: An Answer to War, 2003.
12 E.N. Luttwak, Towards Post-Heroic Warfare, in “Foreign Affairs”, vol. 74, no. 3,
1995
13 S. Davies, T. Pettersson, and M. Öberg, “Organized Violence 1989-2021 and The Decline-of-War Thesis This latter category takes the name “policing wars”,9 by
which western countries (first and foremost the United States)
have attempted to restore order in nations torn by civil war,
destabilise nations deemed to be “rogue states” (to the point
of regime change, by playing the Nazi card against the dictator
of the day), or counter the activity of criminal or terrorist
organisations by military means. Even Mary Kaldor, whose
best-known book10 occasionally appears to stereotype post-
bipolar wars as “new wars” ‒ which are basically domestic wars
fought in the context of failing states (failing due to the impact
of globalisation), by non-state actors in the name of identity
politics ‒ has referred to this type of conflict as “spectacle war”
and “neo-modern war”11. The former is the remote, hyper-
technological, casualty-free form of warfare typical of a “post-
heroic” western world12 whose citizens are no longer willing to
sacrifice their lives in war, but get involved in it only as distant
spectators (because it is reduced to a kind of virtual simulation
attracting a disproportionate amount of media attention). The
latter can take the form of a limited interstate war, usually
attributable to border disputes; or a counter-insurgency war
triggered by the increasing political polarisation of fear and
hatred that characterises “new wars”. Interstate war is becoming rarer, but seeing this as
confirmation of its actual or imminent demise may be wishful
thinking. The latest evidence, in fact, points to an increase in
the frequency and lethality of inter-state conflicts.13 There is 48 Back to the Future no doubt, however, that many factors militate against recourse
to this type of war. Firstly, war has become more destructive
and less cost-effective ‒ a classically liberal idea expressed by
Norman Angell at the beginning of the XX century.14 Secondly,
the use of force has gradually lost legitimacy and war itself has
become a taboo. Drone Warfare”, Journal of Peace Research, vol. 59, no. 4, 2022, pp. 593-610.
14 N. Angell, The Great Illusion: A Study of the Relation of Military Power to National
Advantage, 1910.
15 J. Mueller, Retreat from Doomsday: The Obsolescence of Major War, New York, Basic
Books, 1989, p. 240.
16 A. Colombo, “La guerra in Ucraina e il trionfo contemporaneo della guerra
giusta”, La fionda, no. 2, 2022, pp. 28-40. Drone Warfare”, Journal of Peace Research, vol. 59, no. 4, 2022, pp. 593-610. The Decline-of-War Thesis According to John Mueller, therefore, war is
not only “rationally” but also “subconsciously inconceivable”,15
to the extent that those who still have recourse to it feel obliged
to conceal it behind euphemisms such as “peace-enforcing”,
“humanitarian intervention” and “international policing
operations”, or to restore its legitimacy by opportunistically
leveraging the idea of the “just war”.16 Thirdly, under the
current international system, it has become impracticable to
pursue territorial conquest, which has always been one of the
main objectives of interstate wars but now seems to have been
eradicated, because the right to territorial integrity is so rooted
in the international political and legal order that it is obvious
to anyone that state borders cannot be unilaterally changed
and that any attempt to seize territory by force, even if it wins
domestic approval, will be considered illegitimate and seriously
damaging to the international reputation of a state, its ruling
elite or its leader. These factors ‒ alongside others, such as the
role played by democratisation, international institutions, the
deterrence mechanism and the “benevolent” hegemony of the
United States, whose “peacemaking” effect, however, appears to
have been diminishing for some time ‒ all play an important
role in explaining the decline of the classic interstate war and,
even more so, war between major powers. Many commentators,
meanwhile, have claimed that major war is a thing of the past, Are We Heading Back to an Age of Traditional Wars Between Major Powers? 49 on the basis that there is virtually no risk of such conflict
occurring today or in the foreseeable.17 But how far is this really
true? h There can be no doubt that, since 1945, humankind
has enjoyed a “long peace”,18 which the system of nuclear
deterrence based on Mutual Assured Destruction (MAD)
helped strengthen, by radically and irreversibly changing the
rational calculus of the costs and benefits of war and making
it “unthinkable”. Let us not forget, however, that history offers
other examples of long episodes of peace destined, nonetheless,
to end. The Cold War itself can certainly be regarded as a major
war, unlike all others in its form but similar in its consequences,
because it spawned a new international order built around the
hegemony of the United States. 17 The leading exponent of this school of thought is John Mueller. 20 years
after the publication of his best-known book (Retreat from Doomsday), he has
emphatically reiterated his arguments (J. Mueller, “War has almost ceased to exist:
An Assessment”, Political Science Quarterly, vol. 124, No. 2, 2009, pp. 297-321).
For an opposing opinion, see J.W. Forsyth Jr. and T.E. Griffith Jr., “Through
the Glass Darkly: The Unlikely Demise of Great-Power War”, Strategic Studies
Quarterly, vol. 1, no. 1, 2007, pp. 96-115. 20 L. Bonanate, Il futuro della guerra e le guerre del futuro, in Tullio Gregory (ed.), XXI
secolo, Roma, Istituto Enciclopedia Italiana Treccani, 2009, vol. 3, p. 434. 19 V.E. Parsi, Il sistema politico globale: da uno a molti, in Id. (ed.), Che differenza può fare
un giorno, Milano, Vita e Pensiero, 2003, p. 103. 18 J.L. Gaddis, “The Long Peace: Elements of Stability in the Postwar International
System”, International Security, vol. 10, no. 4, 1986, pp. 99-142. 17 The leading exponent of this school of thought is John Mueller. 20 years
after the publication of his best-known book (Retreat from Doomsday), he has
emphatically reiterated his arguments (J. Mueller, “War has almost ceased to exist:
An Assessment”, Political Science Quarterly, vol. 124, No. 2, 2009, pp. 297-321).
For an opposing opinion, see J.W. Forsyth Jr. and T.E. Griffith Jr., “Through
the Glass Darkly: The Unlikely Demise of Great-Power War”, Strategic Studies
Quarterly, vol. 1, no. 1, 2007, pp. 96-115.
18 J.L. Gaddis, “The Long Peace: Elements of Stability in the Postwar International
System”, International Security, vol. 10, no. 4, 1986, pp. 99-142.
19 V.E. Parsi, Il sistema politico globale: da uno a molti, in Id. (ed.), Che differenza può fare
un giorno, Milano, Vita e Pensiero, 2003, p. 103.
20 L. Bonanate, Il futuro della guerra e le guerre del futuro, in Tullio Gregory (ed.), XXI
secolo, Roma, Istituto Enciclopedia Italiana Treccani, 2009, vol. 3, p. 434. The Decline-of-War Thesis The fact that the Cold War
came to an end “without a single shot being fired in its main
theatre (Europe)”, however, “made it unable to give birth to an
actual constitutive peace: as if once again, as always and bitterly,
only a bloody victory won on the battlefield could transform
the power of the hegemon into legitimate authority”.19 To put it
another way, if a true international order can only be spawned by
a major war (which ruthlessly separates victor from vanquished,
and dominant from dominated), then “it follows that periods
of history without major wars are destined to witness great
disorder”.20 And it is an established fact that the end of the 50 Back to the Future “short century” marked the beginning of a period of increasing
disorder, complexity and unpredictability in international
politics. So in a context characterised thus far by the absence
of conflict (or even the mere expectation of war) between the
system’s major powers, how can we rule out the possibility of a
major war becoming at least “conceivable” again? j
g
g
Like Alessandro Colombo, we could also ask ourselves
whether it still makes sense to use the term “major war” solely
to describe a war between major powers on a global scale, or
whether it should also apply to war between the major powers
of each regional system. 21 A. Colombo, “Guerra e discontinuità nelle relazioni internazionali. Il dibattito
sul declino della guerra e i suoi limiti”, Rivista italiana di scienza politica», vol. XLII,
no. 3, 2012, pp. 452-453
22 A. Giannuli offers a convincing explanation of why the widespread use of the
term “proxy war” to describe the Russia-Ukraine conflict is approximate and
inadequate in Spie in Ucraina, Milan, Ponte alle Grazie, 2022, pp. 157-158 and
182-185. The Decline-of-War Thesis This changes the picture dramatically:
although the prospect of a global war does not seem plausible,
“the same is not at all true if we shift the perspective to the
level of individual regions, with the sole and usual exception
of Europe and America”.21 This exception no longer seems
to apply, however, in light of what is happening in Ukraine,
where a local dyadic conflict (with several, generally overlooked
features typical of a civil war) has been transformed (since the
attrition of the Russian army made it clear to the Americans that
Ukraine was no longer a lost cause but a strategic opportunity
to weaken and marginalise Russia) into an anomalous proxy
war22 with growing potential for global destabilisation ‒ in other
words, a proxy war between Russia, whose claims for status
have triggered a kind of anti-Western crusade in the name of
multipolarism that seems capable of uniting all the revisionist
powers against the existing international order, and the United
States, which is committed to defending a world order in which
right trumps might (despite having resorted to “might” more
than once itself) ‒ not to say a “clash of civilisations” between Are We Heading Back to an Age of Traditional Wars Between Major Powers? 51 51 the West and the non-West (see statements to this effect by
Putin and Kirill I, the Patriarch of the Russian Orthodox
Church).23 As Ian Morris points out, at present “any move that
carries a risk of open war with the United States still requires
a good dose of folly”, but in the future “the possible benefits
may look very different to the emerging powers of 2030 and
2040”, and if so, we are likely to face an era that has “much
in common with the decade after 1910”.24 This confirms the
view of John Mearsheimer, one of the most radical critics of the
decline-of-war thesis, who maintains that the end of the Cold
War “did not lead to any attenuation in the anarchic structure
of the [international] system ‒ if anything it did the opposite ‒
and there is therefore no reason to expect the major powers to
behave very differently in the new century from the way they
behaved in the previous two centuries”.25 But another issue is also worth raising. 23 M. Rubboli, La guerra santa di Putin e Kirill, Chieti, Edizioni GBU, 2022.
24 I. Morris, War – What Is It Good For?, 2014; cited by G. Breccia, La grande storia
della guerra, Rome, Newton Compton Editori, 2020, pp. 354-355.
25 J. Mearsheimer, The Tragedy of Great Power Politics, 2001; Italian translation La
logica di potenza, Milan, Università Bocconi Editore, 2003, p. 328. 23 M. Rubboli, La guerra santa di Putin e Kirill, Chieti, Edizioni GBU, 2022. The Decline-of-War Thesis It has been said that
the Russia-Ukraine conflict marks the return of traditional war
to the heart of Europe: but is this conflict really so “traditional”
and eccentric compared with the paradigm of “new wars”? The current map of organised violence features a prevalence
of conflicts ‒ regardless of whether we call them post-national
wars, peoples’ wars, wars of the third kind, hybrid wars, fourth-
or fifth-generation wars, post-heroic wars, post-modern wars
or simply new wars ‒ fought in a global, multi-dimensional
context in which the war’s connection with the Clausewitzian
trinity of state, army and people has become decidedly loose,
in the sense that these conflicts involve the presence of non-
state actors, the blurring of the boundary between battle-
space and non-battle space and the coordinated, simultaneous
use of a wide range of military and non-military instruments
(conventional weapons, irregular tactics, criminal acts, terrorism, 52 52 Back to the Future indiscriminate violence, highly sophisticated technology, classic
disinformation and propaganda techniques and acts of cyber,
communication, psycho-cognitive, economic, commercial and
financial war). If “hybrid warfare” is one of the most widely
used terms to describe the reality of today’s conflicts, this is
because those conflicts do not involve “fighting a single type
of war; instead, various categories (or ‘generations’) of wars
converge and develop simultaneously”.26 In this respect, the war in Ukraine is no exception. On
the one hand, it looks increasingly like countless past wars,
characterised by continuous, bloody confrontations that yield
no decisive victory to either party, but give rise only to a war
of attrition, whose outcome will be determined by the collapse
of the government, the economy or the will to fight, in one of
the warring countries. On the other hand, the Russia-Ukraine
war has other features ‒ including the presence of private and
semi-private entities (such as foreign fighters, Wagner Group
mercenaries and Chechen kadyrovcy), the extension of the
battlefield to the whole of Ukrainian society, recourse to a wide
range of non-conventional instruments (e.g. the weaponisation
of energy), large-scale use of drones and high-tech weapon
systems, and the increased importance of the cyber and cognitive
domains (hackering and psyops respectively) ‒ which are
entirely in line with the aforementioned predominant features
of contemporary conflicts. 26 C. Jean, La strategia nelle guerre di quinta generazione, in L. Bozzo (editor), Studi di
strategia, Milan, EGEA, 2012, p. 59. The Decline-of-War Thesis In certain respects, in fact, it could
be argued that the Russia-Ukraine conflict (with reference to
Ukraine more than Russia) is propelling us towards the future
and towards the next and final frontier of contemporary warfare:
the war to control the minds of the masses (not transiently or
partially, but semi-permanently and totally).il p
y
p
y
y
While the Gulf War of 1991 was the first conflict covered
in real time by TV cameras, and the Arab Spring saw the
first revolutions coordinated on social networks, Ukraine will Are We Heading Back to an Age of Traditional Wars Between Major Powers? 53 certainly be remembered as the first theatre of war in which
the sixth dimension of conflict – the cognitive dimension –
played an equally (or more) important role as that of the other
five dimensions (land, sea, air, outer space and cyberspace),
by generating tangible, real-world effects. In fact, the Russia-
Ukraine war is “the first conflict fought with weapons that
include memes, virtual appeals and advertising-style outputs
representing a cross between war propaganda and viral
marketing”.27 This unexpectedly and outstandingly effective mix
has enabled President Zelensky, the first online wartime leader, to
achieve two goals: firstly to generate such a vast “rallying effect”
around the Ukrainian flag as to encourage widespread, tenacious
civil resistance to Russian aggression; and secondly to awaken
the slumbering conscience of an uncertain West, to the point
of winning its firm and growing support (diplomatic, political,
economic and above all military) for the Ukrainian cause,
which in practice reversed an outcome (the rapid capitulation
of Kiev) that everyone (first and foremost Putin) had taken for
granted. In this respect, “while international relations will be
marked by a pre- and post-Ukraine demarcation line, hybrid
wars will be marked by a pre- and post-Zelensky demarcation
line”.28 Having studied the shrewd and unconstrained way
in which Zelensky has leveraged the technological advantage
afforded by the strategic use of digital platforms, Zhan Shi, a
Chinese analyst, came to describe the Russia-Ukraine war as
“the first metaverse war”: a “dispersed, digitised, interconnected
and smart” war that is being waged both online and offline
and makes “the Russian tactic, with its huge war machine,
comparable to that of the Second World War, look clumsy
and outdated”.29 But other aspects of the war in Ukraine also
appear to be steering us towards a future fraught with risks and
unknowns. 27 E. Pietrobon, Zelinskij. La storia dell’uomo che ha cambiato (per sempre) il modo di fare
la guerra, Rome, Castelvecchi, 2022, p. 74.
28 Ivi, back cover.
29 Z. Shi, “La prima guerra del Metaverso”, Limes, no. 4, 2022, p. 201. 27 E. Pietrobon, Zelinskij. La storia dell’uomo che ha cambiato (per sempre) il modo di fare
la guerra, Rome, Castelvecchi, 2022, p. 74. 29 Z. Shi, “La prima guerra del Metaverso”, Limes, no. 4, 2022, p. 201. The Decline-of-War Thesis Let us focus on just two of these. The first relates to certainly be remembered as the first theatre of war in which
the sixth dimension of conflict – the cognitive dimension –
played an equally (or more) important role as that of the other
five dimensions (land, sea, air, outer space and cyberspace),
by generating tangible, real-world effects. In fact, the Russia-
Ukraine war is “the first conflict fought with weapons that
include memes, virtual appeals and advertising-style outputs
representing a cross between war propaganda and viral
marketing”.27 This unexpectedly and outstandingly effective mix
has enabled President Zelensky, the first online wartime leader, to
achieve two goals: firstly to generate such a vast “rallying effect”
around the Ukrainian flag as to encourage widespread, tenacious
civil resistance to Russian aggression; and secondly to awaken
the slumbering conscience of an uncertain West, to the point
of winning its firm and growing support (diplomatic, political,
economic and above all military) for the Ukrainian cause,
which in practice reversed an outcome (the rapid capitulation
of Kiev) that everyone (first and foremost Putin) had taken for
granted. In this respect, “while international relations will be
marked by a pre- and post-Ukraine demarcation line, hybrid
wars will be marked by a pre- and post-Zelensky demarcation
line”.28 Having studied the shrewd and unconstrained way
in which Zelensky has leveraged the technological advantage
afforded by the strategic use of digital platforms, Zhan Shi, a
Chinese analyst, came to describe the Russia-Ukraine war as
“the first metaverse war”: a “dispersed, digitised, interconnected
and smart” war that is being waged both online and offline
and makes “the Russian tactic, with its huge war machine,
comparable to that of the Second World War, look clumsy
and outdated”.29 But other aspects of the war in Ukraine also
appear to be steering us towards a future fraught with risks and
unknowns. Let us focus on just two of these. The Decline-of-War Thesis The first relates to 54 Back to the Future the process of democratisation (or apparent democratisation?)
unleashed by the systematic use of Open-Source Intelligence
resources, which has made the progress of field operations more
transparent and made “information that used to be held secretly
in the hands of governments, which decided how much of it to
disseminate, now largely available to anyone with an internet
connection”.30 The second relates to the prominent role played
by the aerospace capabilities of private actors such as Elon
Musk, who, by granting the Ukrainian armed forces free use
of Starlink, the satellite system of SpaceX, a global corporation
that he owns, has pushed the process of privatising war to the
extreme at which a private citizen can declare de facto war on
a nation, by choosing not merely to influence, but to actually
determine the outcome of, a conflict between sovereign states. 30 M. Spagnulo, “L’invisibile battaglia spaziale nella guerra d’Ucraina”, Limes, no.
7, 2022, p. 223.
31 F. Heisbourg, The Future of War, 1997; Italian translation Il futuro della guerra,
Milan, Garzanti, 1999, p. 23. 31 F. Heisbourg, The Future of War, 1997; Italian translation Il futuro della guerra,
Milan, Garzanti, 1999, p. 23. 30 M. Spagnulo, “L’invisibile battaglia spaziale nella guerra d’Ucraina”, Limes, no.
7, 2022, p. 223. Conclusion In light of the processes in international relations that the war
in Ukraine has set in motion (or revitalised) ‒ from a worrying
re-militarisation of relations between states to a growing
bipolarisation of the international system along the lines of
democracies versus autocracies, which nonetheless looks difficult
to reconcile with the tendency to form self-sufficient regional
resource and technology blocs, spawned by the “rethinking” of
globalisation that has received a fresh boost from the war ‒ it is
likely to be remembered as the real watershed event of the first
part of the XXI century. According to Françoise Heisbourg ‒
who as far back as 1997 wrote an ominous essay on the future
of war31 ‒ the Russia-Ukraine conflict, after the fall of the
Berlin Wall and the attacks of 11 September 2001, represents
“the third major historical watershed event of the past fifty Are We Heading Back to an Age of Traditional Wars Between Major Powers? 55 years”, which posterity will see as the beginning of a new “era
of war”.32 Some even think that Putin’s decision to resolve the
“Ukrainian question” by force is “rapidly welding together
the parts of the creeping Third World War denounced by Pope
Francis”,33 bringing the world dangerously close to midnight
on the Doomsday Clock – all the more so if Russia’s threat to
use nuclear weapons materialises. Attempting to predict how
the situation will evolve, either in Ukraine or worldwide, is of
course a daunting task: there are too many variables to consider;
and too many “black swans” ‒ rare events of immense impact
that can only be seen coming with the benefit of hindsight –
have taken to the troubled waters of the post-bipolar world. What is certain is that the post-modern illusion cherished
for decades by Europe, as a “civil power”, in the belief that
neighbouring regions (and eventually the entire international
system) could be reshaped and pacified on the basis of its own
experience, has been crushed (probably beyond repair) under
the overwhelming weight of the security dilemma and the
ruthless laws of power politics, which have exposed Europe’s
strategic vulnerabilities. 32 Id., “La Russia alla perdita dell’impero”, Aspenia, no. 99, 2002, pp. 136-137.
33 V. Ilari, “Perché l’indipendenza economica non impedisce la guerra”, Domino,
no. 4, 2022, p. 105.
34 M. Evans, “From Kadesh to Kandahar: Military Theory and the Future of
War”, Naval War College Review, vol. 56, no. 3, 2003, p. 132.
35 C.S. Gray, Another Bloody Century. Future Warfare, London, Weidenfeld and
Nicolson, 2005, p. 21. 2 Id., “La Russia alla perdita dell’impero”, Aspenia, no. 99, 2002, pp. 136-137. 36 E. Morin, Penser global. L’homme et son univers, 2015; Italian translation Sette lezioni
sul pensiero globale, Milan, Raffaello Cortina Editore, 2016, pp. 113-14.
37 E. Levenson, The Ambiguity of Change, 1983; Italian translation L’ambiguità del
cambiamento, Rome, Astrolabio Ubaldini, 1985, p. 16. 4. The Nuclear Threat is Back Luciano Bozzo Among other macroscopic effects, the events of 1989-91,
the collapse of Communist regimes in Central and Eastern
Europe, the dissolution of the Warsaw Pact, and the progressive
disintegration and eventual disappearance of the Soviet Union
caused a kind of “nuclear eclipse”. Entire libraries dedicated to
nuclear war and strategies, written over decades of extraordinary
financial and scientific endeavour, suddenly seemed obsolete and
fit only for pulping. With very few exceptions, this perception
did not change significantly for the next thirty years – until 24
February last year, that is. 1 The translation is edited by F. Kaplan, the Wizards of Armageddon, Stanford, CA,
Stanford University Press, 1991. This book accurately tells the tale of the famous Conclusion As for the future of war, which now
“seems more dynamic and chameleon-like than ever before”,34
and the form that any global confrontation between the major
powers might take, Colin Gray notes that “it is a perennial
vice of unimaginative theorists to sketch out a future that is
identical to the present ‘but a bit more so’”, but “it is a parallel
mistake to predict a future that shares few points of contact
with reality as we know it”.35 So the words written by Edgar
Morin a few years ago sound more prescient than ever: “We’re
experiencing the beginning of a beginning”, so to understand 56 Back to the Future Back to the Future the meaning and direction of the changes taking place, “we must
avoid dogmatism, in other words setting our ideas in stone and
refusing to measure them against experience”.36 If, however, we
cling to the belief that our theories and certainties are beyond
question, we risk ending up “like a penguin, drifting out to sea
on a melting bed of premises”.37 “lay strategists” recruited by leading US research institutes.
2 B. Brodie, Implications for Military Policy, in Id. (ed.), The Absolute Weapon: Atomic
Power and World Order, New York, Harcourt & Brace, 1946, p. 76.
3 A. Roberts, Churchill: Biography, Turin, UTET, 2020, p. 1322.
4 C.M. Santoro, Il sistema di guerra: teoria e strategia del bipolarismo, in L. Bonanate and
C.M. Santoro (eds.), Teoria e analisi nelle relazioni internazionali, Bologna, il Mulino,
1986, pp. 315-349. The Nuclear Eclipse Between the first use of the atomic bomb on 6 and 9 August 1945
and the end of the Cold War, thousands of volumes and tens
of thousands of articles and papers gave substance to the most
convoluted strategic debates. Especially in the United States,
a conceptual castle was constructed, as vast as it was complex,
characterised by paradoxes and indeed esotericism. This castle
was the theory of nuclear deterrence. The best minds from many
fields of science, with good reason later dubbed “the Wizards
of Armageddon”1 were hired by leading American research 58 Back to the Future centres, the most prestigious being the RAND Corporation. The paradoxical task entrusted to them was to conceive and
plan for the use of the most destructive weapons ever devised
by man – nuclear weapons and, after 1952, even thermonuclear
weapons – whose use, however, had to be prevented at all costs,
given their limitless capacity for destruction. As early as 1946, Bernard Brodie predicted that the United
States would soon lose its monopoly and that the Soviet Union
would acquire nuclear weapons (as indeed it did three years later)
along with ballistic missiles, which could not be intercepted
either then or for many years after. When this happened, he
argued, the combination of the former and latter into a single
weapon system would forever change traditional military and
diplomatic thinking, and with it the very nature of political-
military relationships. In Brodie’s words: “To date, the main task
of our military apparatus has been to win wars. From now on
it must be to avoid them”.2 Throughout the Cold War, though
nuclear weapons were never used in the field, they maintained
a constant and decisive influence on political and diplomatic
debates between the Great Powers. The Nuclear Eclipse In a famous speech to the
House of Commons in 1955, Sir Winston Churchill ironically
noted that: “safety will be the sturdy child of terror, and survival
the twin brother of annihilation”.3 The threat of reciprocal
annihilation by the superpowers, codified in the late 1960s in
the American doctrine of Mutual Assured Destruction (MAD),
expressed perfectly the ultimate nature of the bipolar system of
warfare.4 It was no coincidence that the nightmare of nuclear
war and the disturbing prospects of “the day after” entered and
remained in the subconscious and imagination of the public, The Nuclear Threat is Back 59 partly as a result of numerous expressions of pop culture and
art. Nevertheless, in the West, MAD was envisaged and later
widely perceived as the mainstay of international stability: a
“balance of terror”. Not surprisingly, the end of such a system was greeted with
collective relief. The resulting nuclear eclipse was considered a
great “peace dividend” and widely celebrated in the euphoric
months of the immediate post-Cold War period. The date of 2
August 1990 – the start of the Gulf War – rudely shattered the
dream of peace. However, the collapse of the Soviet Union, the
crisis of the Russian Federation, and the international status
of China, then still a developing nation, meant that for the
duration of the 1990s the debate around nuclear weapons
remained far less intense than in preceding decades. 5 Among others see: J. Record, Defeating Desert Storm (and Why Saddam Didn’t), in
Comparative Strategy, vol. 12, no. 2, 1993, pp. 125-140. 9 S.D. Sagan, The Perils of Proliferation: Organization Theory, Deterrence Theory, and the
Spread of Nuclear Weapons, in International Security, vol. 18, no. 4, spring 1994, pp.
66-107; now expanded in Id., More Will Be Worse, in S.D. Sagan and K.N. Waltz
(1995), pp. 47-91. 8 This argument was first formulated in K.N. Waltz, The Spread of Nuclear Weapons:
More May Be Better, London, IISS, Adelphi Paper 171, 1981. It was later revived
and expanded in Id., More May Be Better, in S.D. Sagan and K.N. Waltz, the Spread
of Nuclear Weapons: A Debate, New York, London, W.W. Norton & Co., 1995,
pp. 1-45. 7 This is the case of J. J. Mearsheimer, Back to the Future: Instability in Europe After
the Cold War, in S. Lynn-Jones (ed.), The Cold War and After: Prospects for Peace,
Cambridge, MA, MIT Press, 1993, pp. 141-192.i 6 This argument was put forward by J. J. Mearsheimer before the Memorandum
was signed. See The Case for a Ukrainian Nuclear Deterrent, in Foreign Affairs, vol.
72, no. 3, summer 1993, pp. 50-66. The text of the Memorandum is available at:
https://treaties.un.org/Pages/showDetails.aspx?objid=0800000280401fbb 6 This argument was put forward by J. J. Mearsheimer before the Memorandum
was signed. See The Case for a Ukrainian Nuclear Deterrent, in Foreign Affairs, vol.
72, no. 3, summer 1993, pp. 50-66. The text of the Memorandum is available at:
https://treaties.un.org/Pages/showDetails.aspx?objid=0800000280401fbb
7 This is the case of J. J. Mearsheimer, Back to the Future: Instability in Europe After
the Cold War, in S. Lynn-Jones (ed.), The Cold War and After: Prospects for Peace,
Cambridge, MA, MIT Press, 1993, pp. 141-192.
8 This argument was first formulated in K.N. Waltz, The Spread of Nuclear Weapons:
More May Be Better, London, IISS, Adelphi Paper 171, 1981. It was later revived
and expanded in Id., More May Be Better, in S.D. Sagan and K.N. Waltz, the Spread
of Nuclear Weapons: A Debate, New York, London, W.W. Norton & Co., 1995,
pp. 1-45.
9 S.D. Sagan, The Perils of Proliferation: Organization Theory, Deterrence Theory, and the
Spread of Nuclear Weapons, in International Security, vol. 18, no. 4, spring 1994, pp.
66-107; now expanded in Id., More Will Be Worse, in S.D. Sagan and K.N. Waltz
(1995), pp. 47-91. was signed. See The Case for a Ukrainian Nuclear Deterrent, in Foreign Affairs, vol.
72, no. 3, summer 1993, pp. 50-66. The text of the Memorandum is available at:
https://treaties.un.org/Pages/showDetails.aspx?objid=0800000280401fbb
7 This is the case of J. J. Mearsheimer, Back to the Future: Instability in Europe After
the Cold War, in S. Lynn-Jones (ed.), The Cold War and After: Prospects for Peace,
Cambridge, MA, MIT Press, 1993, pp. 141-192.
8 This argument was first formulated in K.N. Waltz, The Spread of Nuclear Weapons:
More May Be Better London IISS Adelphi Paper 171 1981 It was later revived The Nuclear Weapons Debate in the Nineties In the first decade following the Cold War, as America’s hopes of
establishing a new world order underwritten by a victorious US
hyperpower gradually faded, the debate around nuclear weapons
focused on three main themes. First, it was thought that the
“lesson of the Gulf” would provide a valid and powerful reason
for nuclear proliferation among the so-called “rogue states”
of Iran, North Korea, Syria and Libya. It was widely assumed
at the time that had Saddam Hussein succeeded in acquiring
nuclear weapons, he could have dissuaded the United States
from intervening in the Gulf and liberating Kuwait.5 This same
argument has been repeated in recent months by those who
believe that Putin would never have attacked Ukraine if Kyiv
had not signed the Budapest Memorandum in December 1994
and handed over to the Russian Federation the nuclear weapons
it inherited from the Soviet Union, in exchange for Moscow’s Back to the Future 60 now evidently worthless commitment to Ukrainian security.6
Second, in the early 1990s, proponents of the transition to a
multipolar international system assumed that the emerging
powers, Germany and Japan, would likely develop their own
nuclear capabilities for reasons of status and security.7 Third, a
theoretical debate begun in the previous decade continued to
rage throughout the nineties. Kenneth Waltz, on the one hand,
maintained a traditional, heterodox position. According to this
view, nuclear proliferation, if limited to fifteen or so nations,
would actually stabilise relations between regional rivals
(e.g. Israel and Iran or India and Pakistan), as had happened
previously in the case of the two superpowers.8 Others, on the
other hand, were fearful of the serious risks associated with the
spread of nuclear weapons to developing countries governed
by authoritarian regimes deemed unable to guarantee adequate
security or control their militaries.9 11 September brought this phase to a sudden end and led to
a redefinition of the debate around nuclear weapons. 10 See NSC, The National Security Strategy of the United States of America, September
2002, p. 15; see also J. J. Klein, Deterring and Dissuading Nuclear Terrorism, in the
Journal of Strategic Security, vol. 5, no. 1, 2012, pp. 22-23, 25-26.
11 J. Arquilla and D. Ronfeldt, Cyberwar is Coming!, in Comparative Strategy, vol. 12,
no. 2, 1993, pp. 141-165.
12 M. Van Creveld, the Transformation of War, New York, The Free Press, 1991.
13 R. Smith, The Utility of Force: The Art of War in the Modern World, London, Allen
Lane, 2005. The Nuclear Weapons Debate in the Nineties With the
start of the “global and endless” war on terror, the crucial and
controversial first question became whether and how nuclear
deterrence could be effective against internationally networked 61 The Nuclear Threat is Back 61 terrorist organisations belonging to no single state.10 No less
important was the question of how a nuclear threat could
possibly deter other emerging, inherently non-attributable
but
potentially
devastating
challenges:
cyber-attacks.11
One assumption, however, was widespread throughout the
literature: future conflicts would be profoundly different from
those of the past. The inter-state wars of the industrial age
were about to be permanently superseded by asymmetric or
non-Clausewitzian “limited intensity conflicts”,12 by “non-war
military operations”, “wars among peoples” and “non-kinetic
warfare”.13 Needless to say, in each of these interpretations,
nuclear weapons, if considered at all, played only a secondary,
residual role as a dangerous and unnecessary legacy of the last
great conflict of the industrial age. h l
The conventional war between two states that began in
Europe last year has given the lie to these and similar theories
and refocused debate on the strategy of deterrence, the potential
use of tactical nuclear weapons on the battlefield, and the risk
of escalation. Terms, concepts, and doctrines first developed
during the so-called “golden age” of deterrence theory have
been revitalised as a consequence. 14 G.H. Snyder, Deterrence by Denial and Punishment, Research Monograph no. 1,
Princeton, NJ, Center of International Studies, 2 January 1959; T. C. Schelling,
Arms and Influence, New Haven, CT, Yale University Press, 1966, p. 22.
15 Schelling (1996), pp195-96.
16 P.M. Morgan, Deterrence: A Conceptual Analysis, Beverly Hills, CA, Sage, 1977,
p. 111. The Conceptual Legacy of the Early Nuclear Age The foundations of deterrence theory were laid between the
mid-1950s and the early 1960s. In the jargon then adopted, an
attack is referred to as a “first strike” and retaliation as a “second
strike”. Nuclear deterrence can be based either on the ability 62 Back to the Future to prevent an opponent achieving their objectives (“deterrence
by denial” or “deterrence by defence”) or on the ability to
inflict unacceptable damage on them, without first defeating
them and even having suffered attack by them (“deterrence by
punishment”).14 The first scenario obviously requires “first-strike
counterforce” targets, i.e. the targeting of an opponent’s nuclear
weapon sites to eliminate the possibility of a devastating second
strike. The objective of the second approach is to dissuade
the opponent from carrying out an attack in the first place, by
threatening to launch a devastating and therefore unacceptable
second strike. A further distinction is made between deterrence
and compellence, the latter being more difficult to achieve by
its very nature.15 y
To be effective, a threat must be credible, and this
presupposes firstly survival, or the relative invulnerability of
the forces responding to a surprise attack, and secondly the
ability to communicate the determination of those forces to the
enemy. Faced with an opponent like the Soviet Union (or the
Russian Federation today) capable of counterattacks on enemy
cities, a second-strike strategy is evidently suicidal and therefore
quite irrational. Yet MAD, the very cornerstone of bipolar
equilibrium, was based on exactly this kind of reciprocal threat,
despite the careful choice of civilian and military objectives
listed in the SIOPs (Single Integrated Operational Plans) for
nuclear war elaborated by the US over the years. The central
tenet of the concept was, and still is, simple and disturbing:
“a state cannot rationally […] commit to extremely irrational
behaviour, but it cannot guarantee rationality [in a critical
situation]”.16 It cannot therefore rule out the unthinkable. In
Thomas Schelling’s analysis, this allowed for the voluntarily The Nuclear Threat is Back 63 63 use of violence and extreme risk as a means of deterrence or
compellence (brinkmanship). 17 T.C. Schelling, The Strategy of Conflict, New York, Oxford University Press,
1963, pp. 187-203.
18 H. Kahn, On Escalation: Metaphors and Scenarios, New York, Praeger, 1965.
19 A scale of 44 steps and 6 thresholds is found in H. Kahn, op. cit., p. 39. 20 See H. Kahn, On Thermonuclear War, Princeton, NJ, Princeton University Press,
1961, pp. 126 and following.
21 See E. Bottome, The Balance of Terror: Nuclear Weapons and the Illusion of Security
1945-1985, Boston, MA, Beacon Press, 1986, pp. 25-31. The kiloton (kt) is
the unit of explosive power of an atomic weapon, and corresponds to 1,000
equivalent tons of the conventional explosive, trinitrotoluene (TNT). The Conceptual Legacy of the Early Nuclear Age In other words, purposefully
leaving to chance, rather than leadership decisions, the outcome
of a threat strategy (threat which leaves something to chance)
increased its credibility and its level of intimidation.17 Complete
uncertainty as to what would happen were the nuclear threshold
to be exceeded, combined with certainty of the devastation that
would follow, has therefore been the ultimate justification for
the effectiveness of deterrence strategy. f
In the Cold War years, the doctrine of deterrence formed
part of a more complex theory of escalation.18 According to the
latter, in a severe diplomatic crisis, both parties may attempt to
win the fight first by threat and then, if necessary, by increasing
the intensity of their actions across a series of “thresholds”. In theory, the action spectrum ranges from diplomatic and
economic measures to the gradual deployment of conventional
military capabilities and eventually to the nuclear threshold,
crossing it if necessary.19 This strategy, however, can only succeed
if the opponent does not respond to the escalation blow by
blow. To ensure success, “escalation dominance” must therefore
be maintained, i.e. readiness to move to the next step in the
certainty of being able to respond to the opponent’s actions
from a position of sufficient advantage. Threatening escalation
therefore has a dissuasive and coercive effect; it discourages the
opponent not only by raising the intensity of the violence, but
by highlighting the risk that the conflict may escape the control
of both parties, with catastrophic results. p
p
In any case, there is little doubt that a nuclear power would
indeed resort to the use of nuclear weapons if its survival or
vital interests were threatened. The use of threats to defend
that power’s allies (extended deterrence) or non-vital national
interests is quite another matter. 64 Back to the Future The Problem of Extended Deterrence Classic works of nuclear strategy distinguished between three
types of deterrence.20 The first, “basic deterrence”, is used by
a nuclear power to prevent a direct attack on its territory or
on vital interests on which its survival depends. Such threats
obviously have maximum credibility and effectiveness. This changes when we come to the second, “active” form of
deterrence, which aims at defending key allies. Finally, the third
type, “tit-for-tat deterrence”, identifies lesser, retaliatory threats
intended to protect friendly nations, for example. Needless to
say, the effectiveness of this last type of threat is, by its very
nature, limited. This problem became apparent to NATO in the mid-1950s,
when it was seen that the objectives agreed at the Lisbon
Conference in 1952, to increase the Alliance’s conventional
forces in Europe to counterbalance the far superior conventional
forces of the Warsaw Pact, would not, in fact, be achieved. Western Europe was enjoying a post-war recovery, and national
governments had no intention of implementing massive and
extremely expensive conventional rearmament plans. The West
therefore began the deployment of American tactical nuclear
weapons (bombs, shells, warheads and mines) for use on the
battlefield. These devices had a maximum power of 20 kilotons,
roughly equivalent to the Hiroshima and Nagasaki bombs.21
The intention was to redress the imbalance in conventional
forces with cheaper but more devastating nuclear weapons. Had war broken out and had the Soviets and Warsaw Pact
armoured battalions broken through, a result that was taken
for granted, NATO would have made a “first use” of tactical The Nuclear Threat is Back 65 65 nuclear weapons to stop them. This prospect alone, it was
believed, provided a sufficient deterrent. h The Americans and Europeans, however, had, and still have,
two very different interpretations of this strategy. This emerged
clearly in the next decade when NATO adopted the nuclear
doctrine of “flexible response”. The same divergent interpretations
continue to impact the Euro-Atlantic debate on nuclear weapons
and security even today. The Americans viewed tactical nuclear
weapons as practical instruments that, if deterrence failed, could
be used to fight a nuclear war of limited scale (i.e. limited to
Europe). According to many US analysts and academics, Henry
Kissinger first and foremost,22 doing so would restore military
“agility” and therefore political instrumentality, to weapons
otherwise so powerful as to be considered politically paralysing. The Problem of Extended Deterrence For the Europeans, however, any nuclear war fought in Europe
would be so devastating as to be unacceptable: they therefore
saw the deployment of nuclear weapons only as a powerful tool
for “coupling” European security to that of the US. Their use in
a war, they believed, would inevitably trigger escalation to the
strategic level and involve the United States and Soviet Union
in nuclear exchanges. The presence of nuclear weapons would
therefore force both superpowers to adopt extreme caution. The
French, and De Gaulle in particular, first raised the now highly
topical question of why the United States should endanger New
York to defend Paris? For the French, the answer was to develop
their own deterrent, reject the doctrine of flexible response and
withdraw from NATO’s integrated military command in 1966. 22 H.A. Kissinger, Nuclear Weapons and Foreign Policy, New York, Harper & Bros,
1957, pp. 188-190. 23 For reference documents on Russian nuclear deterrence doctrine, see L. Wachs,
Limited nuclear options and extended deterrence: adapting to the changing strategic context in
Europe, in A. Gilli and P. de Dreuzy (eds.), Nuclear Strategy in the 21st Century:
Continuity or Change?, Rome, NATO Defense College, NDC Research Paper no.
27, December 2022, p. 27. Ukraine: The Return of the Nuclear Debate Since 24 February last year, the threat of escalation has played
a key role in the war in Ukraine and refocused attention on the
political and military implications of nuclear weapons. Already Back to the Future 66 in the early stages of his “special military operation”, Putin
threatened that any third-party intervention in the conflict
would trigger a rapid response, while simultaneously reminding
the West of Russia’s nuclear arsenal. Two days later, he ordered
Russia’s nuclear deterrence system to a first stage of alert in
response to the “hostile sanctions” imposed on the Russian
Federation and the “aggressive statements” made by Western
leaders. Since then, Putin has continued to make more or less
explicit references to the possibility of nuclear escalation. Other
members of the Russian political elite have also issued regular
bombastic and sometimes ridiculous threats. This has deeply
affected the course of the war in at least two ways. f
y
Firstly, frequent threats of nuclear escalation have created a
unique condition of “double sanctuarisation” in the strategic
theatre. The Russians find themselves deterred from striking
the supply lines that feed Ukraine’s war effort where they
originate beyond that country’s borders: any attack on the
territory of a NATO member, Poland first and foremost,
would inevitably provoke a reaction by the Alliance and, as has
been repeatedly stated, trigger a nuclear third world war. On
the other side, the Ukrainians are continuously being begged
by the Allies to avoid, or at least limit, attacks on Federation
territory, excluding, of course, the regions annexed by Moscow. The restrictions imposed on the supply of long-range weapon
systems, which Kyiv has demanded with growing insistence
in recent months, are intended precisely to avoid giving the
Russian leadership cause to feel that their national security
is seriously threatened. After all, according to Russia’s 2020
Nuclear Deterrence Policy,23 the use of nuclear weapons is
envisaged: if similar or other weapons of mass destruction are
used against the Federation or its allies; if a launch of ballistic 67 The Nuclear Threat is Back 67 missiles directed at Russian or allied territory is detected, or if
installations needed to launch retaliatory strikes are hit; and
finally, if an attack on the territory of the Russian Federation
using conventional forces but no weapons of mass destruction
endangers the survival of the state. 24 TASS, Russia News Agency, 27 September, available at: https://tass.com/
politics/1513883 Ukraine: The Return of the Nuclear Debate hf The second effect of the nuclear threat is that, since before the
start of hostilities, Putin has practised a strategy of consciously
limiting the options available to him, and hence the courses of
action open to him, in the shadow of that threat. It is our belief
that the Russian leader has cleverly employed brinkmanship,
burning bridges and raising the stakes as he goes, in a show of
determination and in an attempt to strengthen his negotiating
position. His recognition on 21 February 2022 of the Donbas
republics of Donetsk and Luhansk that declared independence
in May 2014 should be seen in this light. The same applies to
the Russian Federation’s annexation of the two republics and
of the occupied territories of Kherson and Zaporizhzhia on 30
September last year. Just three days earlier, Dimitry Medvedev,
to name one of many, had insisted that NATO would not
react to the Federation’s use of nuclear weapons in response
to Ukrainian aggression. His point was that the security of
Washington, London and Brussels is far more important than
the fate of a dying Ukraine.24 This argument is a rhetorical one,
however, and obviously refers back to the “New York is worth
more than Paris” argument that raged within NATO over
the use of tactical nuclear weapons in the 1960s. One major
consequence of the present war is therefore that the question
of extended deterrence has once again become central to Euro-
Atlantic security. The debate has become particularly heated since the
Ukrainian oblasts were annexed by the Federation, but the
question was also raised when Russia annexed Crimea in
March 2014. Given the 2020 Nuclear Deterrence Policy, could Back to the Future 68 a sudden collapse of the Russian front and Ukraine’s recapture
of its annexed territories force Moscow into the use of tactical
nuclear weapons? And if so, how would NATO react? Rather
than real military significance, the use of such weapons would
have a symbolic value: they would demonstrate the Kremlin’s
determination and its willingness to employ brinkmanship and
escalation despite the associated risks. Things would, of course,
be different were the survival of the state – or perhaps that of its
leader – really at stake. y
Two critical facts have emerged from this ongoing war. 25 Council on Foreign Relations, Lessons from History Series: A Conversation with
Henry Kissinger, New York, 30 September 2022, available at: https://drive.google.
com/drive/folders/1_Ia5KdTiGylUWzHhafGsIwz2O_ia0i6t?usp=sharing
26 K.N. Waltz (1981), op. cit., p. 29. Ukraine: The Return of the Nuclear Debate In
the year since hostilities began, references to the possible use
of nuclear weapons on the battlefield have been made on many
occasions. The taboo against nuclear weapons seems to have
weakened in the minds of the leaders and the public at large. Furthermore, given progress in miniaturisation and reductions
in the power of tactical nuclear weapons, now rated at mere
fractions of kilotons, and a corresponding increase in the power
of conventional weapons, the boundary between the two forms
of warfare has become extremely blurred, opening the door to
easier escalation in the field. Conclusion On 30 September last year, Henry Kissinger, speaking at the
headquarters of the Council on Foreign Relations in New York,
where he published Nuclear Weapons and Foreign Policy in 1957,
warned that nuclear escalation in Ukraine could easily upset the
international system.25 Back in 1995, Kenneth Waltz pointed
out that: “a nation with nuclear weapons cannot be asked to
surrender”.26 The “double sanctuarisation” of the strategic
theatre in Ukraine has so far confirmed the effectiveness The Nuclear Threat is Back 69 of deterrence both for NATO and the Russian Federation. Attempts at coercion against Ukraine have, on the contrary,
failed miserably. Russia has not even succeeded in deterring
Ukraine from launching a counter-offensive in the annexed
territories. However, what would happen if the offensive were
to be extended to Crimea remains unclear. Regardless of the outcome of the war, the serious human and
material losses suffered by the Russian Federation, the effects of
sanctions, the unity of NATO and significant increases in the
defence budgets of certain Member States, as well as membership
applications from Sweden and Finland are all factors that weaken
Russia’s conventional strength. This will inevitably lead to its
leadership relying more on their nuclear arsenal. This could
have a significant effect on future developments. The war has
brought to light unexpected risk propensity along with blatant
errors of perception and calculation by the Kremlin. All this
means that Russia’s future actions are now far less predictable
and that the effect on Moscow of any nuclear deterrent may be
significantly reduced. gi
y
In view of all this, the question remains how the United States
can exercise credible extended deterrence in favour of its allies
given the risk that Russia might make a limited use of nuclear
weapons. The old dialectic between deterrence and reassurance
has been given a new lease of life. There are two sides to the
problem of extended deterrence credibility: the degree of US
resolve and the operational capabilities available. Against 1,900
to 2,000 Russian tactical nuclear weapons, NATO has deployed
between 100 and 150 to allied bases in Europe, including
Aviano. Some 7,000 were available in the mid-1970s. These
are B-61 gravity bombs, carried by multirole aircraft that are
vulnerable on the ground, whose deployment would be subject
to NATO decision-making and which, if used, would still have
to penetrate Russian air defences. 27 L. Wachs, op. cit., pp. 29-30. Conclusion This first weapon system
is backed up by the low-yield W76-2 warheads of missiles
carried by Trident submarines, which are almost invulnerable
and well capable of getting through enemy defence systems. 70 Back to the Future Back to the Future Warheads of this type have been kept in deployment by
President Biden despite the nuclear rearmament cuts imposed
by his predecessor.27 However, any plan to use these missiles
and warheads for extended deterrence in the European theatre
carries the risk that, as inherently strategic systems, they may
trigger immediate escalation to the level of direct confrontation
between the United States and the Russian Federation. This
obviously undermines their credibility. Failure to achieve the initial objectives of the “special military
operation”, the laborious, costly and only partial occupation
of the Donbas and subsequently annexed territories, and the
setbacks suffered since last summer have undermined Russia’s
military credibility and the reputation of the Federation
itself. In addition to the organisational limitations that its
conventional forces have shown, Russia has used a vast quantity
of ammunition and weaponry that it cannot replace easily or
quickly as a result of the embargo on “dual-use” technology. This
weakening of its conventional military forces, however, lowers
the “nuclear threshold.” Fewer taboos against the use of nuclear
weapons now combine with increased risk propensity among
a leadership intent on revisionism, not only of the European
geopolitical order that emerged from the “catastrophe” of 1989-
91, but of relations between the major powers too. The nuclear
question was all too soon forgotten, along with all the concepts,
strategic doctrines and debates associated with it: that question
has now returned to play a fundamental role in international
political relations. 5. Return of Inflation Franco Bruni Inflation returned in the second half of 2021 and rose rapidly,
such that in the latter part of 2022, it reached levels last seen
forty years ago (Figure 5.1). Interest rate hikes to stop inflation
have also returned. At first, central banks were slow to respond
to accelerating price growth, but then they introduced monetary
tightening measures reminiscent of the impetuousness of
Volcker’s disinflation in 1979. 72 Back to the Future Causes of Inflation The return of inflation to the fore has affected virtually every
corner of the globe, driven by the dynamic recoveries in
growth following the pandemic-induced crisis. Demand for
consumption and investment also meant an influx of purchasing
power into the market after it had been forcibly set aside during
the months of anti-covid measures, including lockdowns,
during which households and businesses received substantial
government aid. Large government deficits also continued to
stimulate economies. The inflationary effect of demand has
been exacerbated by the persistence of rigidities in international
production chains, which are also partly a legacy of the peak
of the pandemic. Such rigidity has been particularly evident
in energy availability, driving up prices. Such energy scarcity is
the result of a prolonged period of remarkably low prices that
provided little incentive to invest in research and production. Gas prices rose well before the war started, rebounding from a Return of Inflation 73 long period of low prices partly because post-pandemic demand
recovered, but also because Russia deliberately decreased
supplies. For example, by the end of September 2021, gas on
the Amsterdam market was already three times more expensive
than in the first half of the year. Following the outbreak of war
in Ukraine, energy costs rose dramatically in the second quarter
of 2022, with the charcteristics of energy markets contributing
to this worsening of prices for households and businesses, at
times with producers earning unjustified extra profits. In
August, gas was more than four times as expensive as at the
beginning of the year, a price to which it returned at the end of
the year. Extensive public funding to help users pay high energy
bills has been another factor in keeping prices high. p g p
g
However, all these factors would have been less likely to
ignite a raging inflationary fire without the fuel of abundant
liquidity created by many years of highly expansionary
monetary policies. Practically all short-term interest rates have
long hovered around zero, and remained as much through the
entire first quarter of 2022. In the US, the Federal Reserve
(Fed) only began tightening monetary policy in March, when
inflation was already running at more than 8% per annum. In
the eurozone, the European Central Bank (ECB) waited until
July to move rates when consumer price inflation was already
close to 9%. Causes of Inflation The ECB was also slower than the Fed to stop and
reverse its quantitative easing, that is, the purchase of long-term
bonds to boost liquidity even when interest rates are at zero. q
y
By the end of the year, central bank-controlled interest
rates had risen from zero to 4.5% in the US and 2.5% in the
eurozone. However, slowly declining consumer price inflation
remains much higher, at over 7% in the US and around 10% in
the eurozone. European real interest rates are still very negative:
more than 7 points below zero for short-term ECB lending rates
and 10-year German government bond rates, and more than 5
points below zero for 10-year Italian government bond rates. Indeed, the 10-year spread between Italian and German bonds
is over 200 points, some 70 points higher than at the beginning 74 Back to the Future of the year, as the international rise in interest rates has been
more pronounced for Italian bonds, reflecting the greater risk
of Italy’s large public debt. h The delayed reaction by central banks, together with
their failure to foresee price acceleration, makes them partly
responsible for inflation and calls into question the strategies
they have adopted for several years, which have seen their
balance sheets massively inflated with purchases of securities,
especially government bonds, in the name of quantitative
easing. Of course, in return for those purchases, ever-increasing
amounts of liquidity were poured into the markets. Before the
great financial crisis of 2008, the total balance sheet of the Fed
and the ECB as a percentage of US and eurozone GDP was 7%
and 11% respectively. Quite remarkably, in 2010 these figures
were 16% and 20% and at the end of 2021 36% and even 70%. Cost of Inflation Inflation is a general increase in prices, but this does not mean
all prices grow equally. One of the main costs of inflation is the
disruption it causes in the relationships between different prices,
which are important because they determine production and
consumption decisions. When inflation is not only high but
also highly variable, disorder turns into uncertainty, a feeling
that tends to spread from the price system to the general state
of the economy, effectively discouraging medium- and long-
term commitments and investments. Inflation thus distorts the
use of resources, reduces their productivity, and deforms the
composition of production and the structure of consumption. It
tends to benefit the profits of those with greater market power, and
the rents of those in a monopoly or oligopolistic position. One of
those prices that tends to lag behind increases in consumer prices
is the cost of labour—wages and salaries. As such, inflation tends
to eat away at real wages, but then they suddenly pick up and
this provides renewed fuel that drives the costs of goods up. This
is one of the ways in which large, unjustified redistributions of Return of Inflation 75 income take place, often in favour of profits. This phenomenon
is mirrored elsewhere, with the redistribution of wealth from
creditors, who see the real value of their receivables shrink, to
debtors, whose debts lose real value. This effect is only partly
mitigated when interest rates adjust to inflation, forcing debtors
to make increasing payments as past debts do not have their
interest rates changed until they come due.l g
y
Inflation acts as a tax between debtors and creditors,
received by the former and paid by the latter. The fact that
inflation is a hidden tax, not voted on by parliament, becomes
particularly clear when we consider its effect on government
debt, as bondholders are taxed while the government’s real debt
burden falls. This effectively means that, at the end of 2022,
the Italian state received a tax of just under 10% on its debt,
paid by domestic and foreign investors. This tax brings huge
revenue, close to 15 percentage points of the country’s GDP. Strangely, there is much more debate about whether other taxes
should be cut. Cost of Inflation This tends to reduce the ratio of public debt to
GDP, but it also ultimately encourages an increase through new
government spending, the inflationary effect of which can feed
back into a vicious circle. li Expectations can turn inflation into a self-fulfilling
“prophecy”: if those who set prices in the markets expect
inflation to accelerate, they will tend to raise prices more
quickly, eventually confirming their expectations. The self-
feeding of inflation is all the more likely and dangerous the
higher inflation is, and can lead to hyperinflation, i.e. rates of
price increases so high that they become the dominant feature
of an economy and the driving reason behind manufacturing
and consumption decisions. Once this point is reached, huge
resources are wasted on the sole task of reacting to inflation,
defending against it, profiting from it by hoarding goods and
thereby accelerating the rise in their prices (and thus fuelling
inflation even more). When inflation rises beyond certain
limits, it becomes more difficult to stop it by curbing money
creation, because money is needed in increasing quantities for 76 Back to the Future any government spending, and it is the rise in prices that causes
monetary expansion rather than the other way round. If, on the other hand, the central bank is able to curb
inflation, but inflation is already quite high, there is a new
danger, namely that the sharp rise in interest rates and the
growing liquidity shortage induced by monetary tightening
will lead to financial tensions and a crisis. Rising yields drive
down the prices of securities and, more generally, the value of
loans, creating problems for creditors who hold them in their
portfolios. Falling prices can infect the stock market and even
accelerate, potentially threatening a spread of insolvencies. On
the other hand, insolvency can also threaten bank debtors if
the interest they have to pay suddenly rises while the slowdown
in the economy induced by monetary policy reduces their
turnover. As a result, anti-inflationary monetary tightening is
still trying to strike a delicate balance between the gradualness
needed to limit the impact on financial stability and the speed
needed to prevent inflationary expectations from building up,
which could in turn hamper the reduction of inflation. Monetary Policy Delay Such a balance is easier to achieve if monetary restrictions are
introduced early. The delay at the beginning of the year has
made the whole operation trickier. Differing explanations for
the delay might exist. The “worst” would be that central banks
abandoned the independence that characterises their mandate
to maintain price stability. In such a case, their independence
is violated by facilitating the financing of large public needs
through the creation of excess money, or by propping up stock
market prices for the benefit of private investors. i
However, there are also more technical explanations that
are consistent with the goal of pursuing the primary objective
of monetary policy. The first is a misdiagnosis of the many
inflationary shocks that central banks have faced, from the
pandemic to the war and soaring energy prices. In such a Return of Inflation 77 scenario, central banks believed that such inflationary pressures
were transitory and therefore deliberately avoided confronting
them with monetary tightening that would have unnecessarily
slowed production. Then, although the price acceleration did
turn out to be prolonged and increasing, it continued to be
tolerated because of a new error, this time in the diagnosis
of inflation expectations, which were linked to the central
bank’s pursuit of a stability target of 2% on average per year. Indeed, while the median values for expectations monitored
by central banks rose very gradually, the frequency with which
high inflation rates were predicted rose definitively. Higher
inflation forecasts contributed to higher actual inflation. Monetary authorities overestimated the credibility of their own
announcements. Another mistake made by the authorities may
have been to justify keeping interest rates low by claiming that
the “neutral interest rate” – a theoretical concept that cannot
be observed directly, but measures the productivity of capital in
the medium to long term, balances saving and investment and
ensures full employment of resources – had been falling. In fact,
several estimates of the neutral rate of interest see it as stable or
increasing.1 I also believe that an appropriate interest rate increase
was postponed because monetary authorities, markets and
monetary policy commentators focused too much on the
rationale for interest rate changes rather than looking at their
levels. For example, rate hikes of 50 basis points were often
presented and commented on as applying to a normal level of
interest rates rather than, as was the case, to low or zero interest
rates. 1 Some of these types of errors are examined and documented in R. Reis, The
Burst of High Inflation in 2021–22: How and Why Did We Get Here?, London School
of Economics, June 2022. Monetary Policy Delay Reductions in the degree of expansionary monetary
policy, although still substantial, thus appeared to be effectively
restrictive manoeuvres. It was as if years of extreme expansion
had led to a loss of orientation. 78 Back to the Future Supply and Demand Inflation To combat excessive inflation, monetary policy must be restrictive
and interest rates higher. If money costs more, less will be spent
on consumption and investment, and so aggregate demand will
exert less pressure on the supply of goods and services, whose
prices will rise less or fall. As central banks adopt a restrictive
approach, one objection is often raised: if inflation is caused
by supply shortages rather than excess demand, monetary
policy has no way of correcting this and only risks causing a
recession. This objection needs to be carefully examined in the
eurozone, as some people argue that inflation in 2021-22 was
driven by supply. The argument is that European inflation then
was caused by the persistence of some production rigidities and
trade disruptions caused by the pandemic, rising energy prices
and the war in Ukraine. In such a situation, a monetary cure
would not only be unnecessary, but downright harmful. This
is in contrast to the situation in the US, where price rises are
mainly due to aggregate demand pressures, driven in part by
extremely expansionary fiscal policies. y
p
yi
p
The objection is reasonable but far from irrefutable. This
becomes clearer when looking at four counter arguments. The
first is that it is not true that cost inflation cannot be tackled
with monetary policy. In fact, restrictive demand, monetary
and fiscal policies, curb supply-side inflation just as much as
they curb demand-side inflation. The difference is that, if the
price rise is due to excessive demand, it may be possible to
rein it in without sacrificing growth, output and employment. If, on the other hand, it results from supply shortages and
rising production costs, monetary disinflation will also lead
to a slowdown in economic activity. Therefore, in order to
decide the extent to which cost inflation should be curbed
by monetary policy (obviously to the extent that this is not
convenient or cannot be done promptly with restrictive fiscal
policy), it is necessary to balance the welfare gain from slowing
prices against the loss caused by slowing the economy. 79 Return of Inflation Figure 5.2 shows aggregate demand and supply lines. Rather than correlating static quantities and prices, as such
graphs often do, this graph correlates rates of change in the
price index (inflation) with rates of change in the real quantity
of GDP produced in the economy (growth rates). Supply and Demand Inflation The faster
prices rise, the more producers will try to sell (supply curve S
with a positive slope) and the less buyers will be willing to buy
(demand curve D with a negative slope). The starting point is
the intersection of supply and demand in 1, where inflation is
2%, which is the central bank’s desired target and is considered
equivalent to “price stability”. Excess demand inflation occurs
when D becomes D’ (people buy more at all costs, for example,
because they are more optimistic about the future) and the
intersection shifts from 1 to 2. By contrast, inflation due to
oversupply occurs when S becomes to S’ (firms charge a higher
price for each unit produced, for example, because their labour
or raw material costs have risen) and the equilibrium shifts from
1 to 3. If it is not possible to manipulate supply in the short to
medium term, in order to reduce inflation in 2 by tightening
monetary policy, demand D’ must be brought back to D and
one returns to 1. On the contrary, , in order to correct inflation
in 3 by tightening monetary policy, demand must go from D
to D”, ending in 4. Is it better to be in 3 or in 4? It depends on
comparing two values: the cost of lost growth from a to b and
the well-being gain from reducing inflation from p to 2%. 80 Back to the Future Such a comparison also depends on the sensitivity of those
making the comparison to the different effects of inflation
in the economy and society, and which effects are considered
relevant. For example, if one believes that inflation increases
inequality and attaches great importance to the resulting
welfare loss from greater inequality, one is more likely to deem
positive or convenient monetary tightening that sacrifices
growth to reach 4 as worthwhile. Someone else might believe
that inflation ultimately erodes some productive capacity by
diverting resources to more speculative and less productive uses. Thus, failing to stop inflation carries the risk of a rise towards
S”, while reducing growth even more, going from 3 to 5. Supply and Demand Inflation On
the other hand, some may consider inflation so harmless that
they suggest responding to an inflationary supply shock with
expansionary monetary and/or fiscal policies, which would
again increase demand and growth, neutralising the shock and
creating even more inflation, with a move from 3 to 6. The Return of Inflation 81 81 monetary recipe for cost inflation is not easy to find and may
well involve a significant dose of monetary tightening. h i
This becomes even clearer when the second counter-argument
is examined. This argument is based on the understanding that
inflation dynamics are also linked to people’s expectations. Prices are set by decisions of both buyers and sellers, influenced
by how they think prices will move in the economy as a whole. For any decision about the maximum amount one is prepared
to spend on something, one takes into account how the price
is increasing and how much one expects it to increase. In other
words, one also takes into account general price inflation in the
future. The same process takes place when someone decides at
what price to sell. All else being equal, when sellers and buyers
expect high inflation, they tend to agree, in the various ways
that markets lead to agreement, to buy and sell at rising prices. Thus, inflation expectations feed inflation, and rising inflation
in turn leads to expectations of higher inflation in the future. Real and expected inflation feed on each other, and when
they rise it becomes a vicious circle. So the counter-argument
is that if cost inflation is not tackled with restrictive demand-
side policies, price growth may accelerate by feeding itself on
expectations. Supply and demand intersect at ever-increasing
prices (like in 7). p
The third counter-argument follows on from the second,
in that the expectations mechanism ends up blurring the
distinction between supply and demand inflation. Whatever
the initial cause of inflation, it then follows a dynamic that
depends very much on how expectations react and thus on how
the authorities manage them through their announcements. Central banks play the key role in managing inflation
expectations and containing inflation, regardless of the type of
shock that initially caused it. To achieve this, their past record
of keeping inflation low is important, as is their credibility in
promising to tighten monetary policy when inflation gets too
high. Supply and Demand Inflation By insisting for a long time on a low but positive inflation
target – such as the famous 2% – it can be assumed that if prices 82 Back to the Future grow at that rate, inflation will be stable, while if they deviate
from the target, either upwards or downwards, expectations will
tend to exacerbate the deviation. In the figure: all intersections
of supply and demand higher than 1 tend to shift both the D
and the S curves, and vice versa. Importantly, for price increases
to be sustained, there must be sufficient liquidity in the markets
to fuel transactions at rising prices. Thus, raising interest rates
reduces liquidity, makes liquidity more expensive to obtain by
borrowing, and thus takes fuel away from inflation, even if it
comes from supply. pp y
There is also a fourth counter-argument in favour of
fighting inflation in the eurozone with restrictive monetary
policy. A large part of the inflation in Europe in 2021-22 is
demonstrably demand-driven, and the idea that all or most of it
is due to the impact of post-pandemic supply rigidities, energy
shortages and war is debatable in terms of both common sense
and econometric analysis. Common sense tells us that price
dynamics and inflation expectations in the eurozone could not
have been immune to the effects on aggregate demand of very
low interest rates for such a long time, exceptionally abundant
liquidity and high government spending due to health, energy
and war emergencies. If the price of gas rises but there is no
demand to support it, the inflationary effect is limited and the
price of gas itself is constrained. Instead, while it may have
been the right option to subsidise households and businesses
extensively and for a long time to help them pay their energy
bills, it certainly did not keep inflation in check. y
pl
And there is also econometrics, which can show the demand
component of inflation in the data. Several recent studies
have exploited the fact that when a price rises due to demand
pressure, the quantity produced and traded also tends to rise
– or at least not fall – while when the rise is due to supply,
the quantity produced and traded falls – or at least does not
rise. 2 E. Gonçalves and G. Koester, The role of demand and supply in underlying inflation
– decomposing HICPX inflation into components, ECB Economic Bulletin, 7/2022; S.
Eichmeier and B. Hofmann, What drives inflation? Disentangling demand and supply
factors, Discussion Papers, Deutsche Bundesbank, No. 40/2022; A. H. Shapiro,
How much do supply and demand drive inflation, FRBSF Economic Letter 2022(15). Supply and Demand Inflation It is therefore necessary to examine how concordant or
discordant the movements of prices and quantities, of inflation
and production, were over a given period: when concordance 83 Return of Inflation 83 prevails, it is demand that moves and causes inflation; when
discordance prevails, it is supply. Studies being completed at
several central banks currently show that both in the USA and
in the euro area, inflation in 2021-22 was due to both aggregate
supply and aggregate demand; in Europe, the supply effect is
greater than in the USA, but demand contributes significantly,2
to an extent not far from half. So there are many reasons to argue that even though European
inflation is to a considerable extent supply-side driven, with
rising costs, it is right to try to stop it with restrictive monetary
policy as well. This situation is likely to continue through 2023,
although it is hoped that in the following years, after interest
rates have been raised above levels that are advisable in normal
times when inflation is under control, interest rates will fall back
a little. It is also desirable that, from now on, even in the face
of large and sudden macroeconomic shocks, monetary policy
should avoid losing its bearings by exaggerating its ambitions,
going beyond the short-term manipulation of liquidity and
pursuing monetary and financial stability, in a vain attempt to
boost real growth when it is being held back by obstacles and
problems that central banks are not responsible for removing. 6. The Three-Dimensional Features
of the Global Energy Crisis Francesco Sassi Francesco Sassi As the new year gets under way, the slight attenuation of the
energy crisis affecting Italy and Europe seems to be giving a
modest boost to the hopes of consumers and businesses, after
a season of dizzying price rises. But if we look at the long-term
dynamics, both past and future, the events of 2022 are likely to
effect a permanent change on the way we think of energy security
and energy transition, and to link these issues with national
security and market competitiveness. While 2022 was the third
consecutive year of crisis to strike the global order, accelerated
by worldwide issues such as the pandemic, climate change and
the technological and digital revolutions, 2023 is the first year in
which new political and energy-related configurations will settle
into place, with Europe at their epicentre. The choice of strategy
by which Member States will strive to resolve the fundamental
trilemma between international relations, market (in)stability
and the fight against human-induced global warming will have
repercussions well beyond national and European borders. The
dividing line in all this will be the return, or otherwise, of the
state to the centre of energy policy in this key decade for energy
transition. Back to the Future 86 1 C. Kuzemko et al., “Russia’s war on Ukraine, European energy policy responses
& implications for sustainable transformations”, Energy Research and Social Science,
vol. 93, 2022.
2 V. Anghel and E. Jones, “Is Europe really forged through crisis? Pandemic EU Pandemic, War and Economic Shocks:
How Crises Affect the Fundamental Trilemma While the pandemic and Russia’s war on Ukraine are entirely
different in nature, their impact on the energy sector has been
similar. Over the past three years, global energy supply chains
have remained constantly vulnerable to commercial shocks of a
physical nature, either as a result of delays and interrupted flows
or due to a mismatch between supply and demand, but which
nonetheless disrupt entire national and regional energy systems. In years to come, the pivotal nature of 2022 will give rise to
reams of scientific literature, regardless of whether researchers
focus on the critical, generational issue of the energy transition,
or on the key question facing governments of all political
persuasions, of how to ensure national energy security.hl The conflict between Russia and Ukraine has revealed how
the tensions surrounding the attainment of these short- and
long-term goals have been accentuated by the fact that policy is
now refocused on issues that have been culpably neglected for
a long time. With a profile that has grown higher amidst the
ashes of crisis, energy security has the potential to pit local and
national governments and multilateral organisations, such as
the EU, against each other. Although the roots of the imbalance
in energy markets can be traced back to before Russia’s invasion,
national interests and spurious political simplifications may
hinder the prospect of a truly shared approach to transition at
European level, and instead stoke the internal conflict it causes.1 l
In response to the frivolous and ephemeral assertion that
Europe, as a single, integrated political entity, has emerged
stronger from various crises, we should be asking how the
interaction between different critical junctures has spawned new
political processes.2 This tension between the various possible The Three-Dimensional Features of the Global Energy Crisis 87 87 responses to a specific matrix of events will inevitably affect the
pathway to decarbonisation chosen by the EU and Italy. It is
not yet possible to say with certainty which choices will prevail,
and the future remains unclear to observers. and the Russia – Ukraine war”, Journal of European Public Policy, 2022.
3 European Commission, REPowerEU Plan, Com(2022) 230 final, 18 May, 2022
4 F. Birol, “Europe urgently needs a new industrial master plan”, Financial Times,
5 December 2022; F. Simon and K. Taylor, “Energy crisis could worsen poverty
for millions of Europeans”, Euractiv, 22 November, 2022. Pandemic, War and Economic Shocks:
How Crises Affect the Fundamental Trilemma Despite the high-
sounding proclamations of the European Commission, it will
be up to Europe’s citizens and their leaders to take action and
withstand the vicissitudes of the international situation and the
inevitable difficulties that we will face.3h fi
The approach to addressing these challenges will have to
be sufficiently ductile and adaptable to current and future
turbulence, bearing in mind the risk that one crisis might be
followed by another that systemically amplifies the threats
arising from each. In other words, a recurrence of what
happened when the pandemic was followed by the invasion
of Ukraine. It is not a foregone conclusion, however, that the
instruments used to tackle the challenges facing Europe so far
will be as helpful again in the future. It is possible, in fact, that
today’s crisis will permanently transform Europe’s approaches,
practices and vision in relation to energy policy.h p
gy p
y
The de-industrialisation of entire sectors of the economy
and rampant energy poverty not only risk fuelling populist
sentiment and centrifugal trends among Member States, but
also further fragmenting an already composite framework of
policies and strategies for achieving Net-Zero from 27 different
energy systems.4 Countries that have already formulated an
energy strategy based on renewables will want to accelerate its
development. But the diverse range of positions and actions will
remain significantly influenced by political ideologies, specific
socio-economic contexts and party choices. h The possibility of new global shocks cannot be ruled out
either, and governments cannot anticipate which specific Back to the Future 88 strategic link between energy security and energy transition will
be affected, thus weakening the other components of national
systems. This is why now, more than ever before, we need a
multi-sectoral approach designed to strengthen national energy
security at its foundations, while at the same time ensuring
progress on the construction of low-carbon energy systems,
by targeting consumption, infrastructure, decentralisation and
social equity.5 5 J. Osička and F. Černoch, “European energy politics after Ukraine: The road
ahead”, Energy Research and Social Science, vol. 91, 2022; R.A. Huber et al., “Is
populism a challenge to European energy and climate policy? Empirical evidence
across varieties of populism”, Journal of European Public Policy, vol. 28, no. 7, 2021,
pp. 998-2017; B. Zakeri et al., “Pandemic, War and Global Energy Transitions”,
Energies, vol.15, 2022. 5 J. Osička and F. Černoch, “European energy politics after Ukraine: The road
ahead”, Energy Research and Social Science, vol. 91, 2022; R.A. Huber et al., “Is
populism a challenge to European energy and climate policy? Empirical evidence
across varieties of populism”, Journal of European Public Policy, vol. 28, no. 7, 2021,
pp. 998-2017; B. Zakeri et al., “Pandemic, War and Global Energy Transitions”,
Energies, vol.15, 2022.
6 U. Von der Leyen, 2022 State of the Union Address by President von der Leyen,
European Commission, 14 September 2022.
7 F. Sassi, “The Geopolitics of the EU-Russia Gas Trade: Reviewing Power in
International Gas Market”, in F. Taghizadeh-Hesary and D. Zhang (eds.), The
Handbook of Energy Policy, Springer Nature, 2022. 6 U. Von der Leyen, 2022 State of the Union Address by President von der Leyen,
European Commission, 14 September 2022. 7 F. Sassi, “The Geopolitics of the EU-Russia Gas Trade: Reviewing Power in
International Gas Market”, in F. Taghizadeh-Hesary and D. Zhang (eds.), The
Handbook of Energy Policy, Springer Nature, 2022. 6 U. Von der Leyen, 2022 State of the Union Address by President von der Leyen,
European Commission, 14 September 2022.
7 F. Sassi, “The Geopolitics of the EU-Russia Gas Trade: Reviewing Power in
International Gas Market”, in F. Taghizadeh-Hesary and D. Zhang (eds.), The
Handbook of Energy Policy, Springer Nature, 2022. Europe at the Heart of a Systemic Energy Crisis “This is not only a war unleashed by Russia against Ukraine. This is a war on our energy, a war on our economy, a war on our
values and a war on our future. This is about autocracy against
democracy. And I stand here with the conviction that with courage
and solidarity, Putin will fail and Europe will prevail”.6h These words alone, spoken by the President of the European
Commission during her 2022 State of the Union Address,
clearly show how many different and opposing dimensions are
bundled up in the European energy crisis and how disruptive
their effects are. First of all, there is a serious inability to think
of energy, especially gas, as an exceptionally effective lever of
political influence, despite the fact that it is destined to remain
so in the extremely volatile context in which we are now living.7
Even if we take account of the possibility of a permanent The Three-Dimensional Features of the Global Energy Crisis 89 89 break in the chain of interdependence that links the European
Union with the Russian Federation and has laid the economic
foundations of entire sectors of our economies, the Pandora’s
box now seems to be finally open. The situation between
Brussels, Europe’s capitals and Moscow is playing out against
the backdrop of a worrying polarisation between Member States
and recurrent opposition to taking an EU-wide view of possible
further-reaching initiatives to address the unprecedented prices
being paid for raw materials. g p
Take, for example, the gruelling and tortuous race to approve
the price cap on natural gas.8 The cap can be switched off before
it even comes into force and will serve little or no purpose
other than to undermine the strength of the European market
if gas shortages come back with full force to threaten Europe. From this point of view, it would therefore be an unforgivable
mistake to think that the period of instability had come to
an end. Demand for gas remains susceptible to a possible
widespread return to wintry weather and to a recovery in the
Asian economies, especially China’s. 8 C. Cooper, A. Hernandez, and V. Jack, “EU agrees on gas price cap, skeptics
denounce it as an ‘illusion’”, Politico, 19 December 2022.
9 T. Kumagai et al., “EU gas price cap could tighten LNG supplies into Europe
as Asia reassesses favorable markets”, S&P Global Platts, 21 December 2022;
Argus Media, “Viewpoint: China poised to remain LNG demand centre”, 27
December 2022; S. Stapcynski, “Winter Storm Walloping the US Threatens to
Disrupt LNG Exports”, Bloomberg, 23 December 2022. 10 “EU gas consumption down by 20.1%”, 20 December 2022; J. Fokuhl,
“Europe Set for Warmest January in Years as Gas Crisis Eases”, Bloomberg, 5
January 2023. Europe at the Heart of a Systemic Energy Crisis On the supply side, fresh
geopolitical turbulence and the domestic fragilities of producing
countries could again impede world energy flows.9 l
Having given consolidated market trends precedence over
most of its energy measures, a dependent EU earned a winter
reprieve from a combination of action and meteorological
luck or chaos (depending on your point of view). Between
August and November 2022, in fact, gas consumption fell by
20% compared with the average for 2017-2021. Following a
blast of icy weather in mid-December, January kicked off with
abnormally high temperatures, making it likely that the start 90 Back to the Future of this year will be one of the warmest in recent decades.10
A mild winter will undoubtedly help Europe wean itself off
Russian fossil fuels, but it certainly cannot be seen as a part of a
structural transformation of Europe’s energy system. Moreover,
there is nothing comforting about this weather in terms of
the challenges posed by global warming. On the contrary, it
demonstrate the need for a more concrete and urgent response. The energy and climate crises, which are interconnected
with the war in Ukraine and the precarious balance of the word
order, exacerbate the strategic dilemmas for all those countries
that still refuse to play it by ear and remain primarily interested
in establishing credible transition policies, or that are not in
such a privileged position as Europe. of this year will be one of the warmest in recent decades.10
A mild winter will undoubtedly help Europe wean itself off
Russian fossil fuels, but it certainly cannot be seen as a part of a
structural transformation of Europe’s energy system. Moreover,
there is nothing comforting about this weather in terms of
the challenges posed by global warming. On the contrary, it
demonstrate the need for a more concrete and urgent response. h g
p
The energy and climate crises, which are interconnected
with the war in Ukraine and the precarious balance of the word
order, exacerbate the strategic dilemmas for all those countries
that still refuse to play it by ear and remain primarily interested
in establishing credible transition policies, or that are not in
such a privileged position as Europe. 11 Xi Jinping, “Hold High the Great Banner of Socialism with Chinese
Characteristics and Strive in Unity to Build a Modern Socialist Country in All
Respects”, Report to the 20th National Congress of the Communist Party of
China, 16 October 2022; M. Maidan and A. Hove, “China’s 20th Party Congress
and energy: The good, the bad, and the unknown”, OIES Energy Comment,
OIES, novembre 2022; China Daily, “China seeks to balance energy needs, green
power transition”, 5 January 2023.
12 Consider the two three-dimensional aspects as fundamental components of
a single systemic framework: a) national-regional-global & b) international relations -
economy and energy markets - energy transition. E. Downs et al., “US-China Energy
Relations”, SIPA, 24 January 2022; A.J. Dlouhy and A. Cang, “China, US Resume
Climate Work in Latest Sign of Better Relations”, Bloomberg, 19 November 2022. 13 According to the International Energy Agency, the commercial value of
critical raw materials is expected to overtake that of oil and natural gas by 2050.
International Energy Agency, World Energy Outlook 2021, IEA, p. 282.
14 For more detailed analysis, see: T. Gehrke and M. Ruge, “A united front:
How the US and the EU can move beyond trade tensions to counter China”,
European Council on Foreign Relations (ECFR), 20 December 2022; Euractiv,
“Made in Europe? The EU’s response to the US Inflation Reduction Act (IRA)”,
22 December 2022; Reuters, “Italy urges EU to give strong and strategic response
to U.S. IRA”, 17 December 2022.
15 T. Wilson and J. Jacobs, “US and EU argue over claims of gas crisis profiteering”, Crisis Tests Energy Interdependence and Conflict The People’s Republic of China’s responses to this situation
reveal the depth and multiple facets of this crisis. Beijing has
decided to increase domestic coal production and speed up the
roll-out of substantial investments in renewables. Furthermore,
the historic 20th National Congress of the CPC, at which Xi
Jinping secured an unprecedented third term, saw considerably
more discussion of security than of other vital issues such as
ideology, carbon emissions and innovation. Security appeared
to take priority even over the economy, and will involve a
primary role for the state and a more marginal role for the
market and reforms. The issue of security does not end with energy, of course, but
also extends to food security and social welfare, not to mention
the well-known international issues and national security
challenges. China’s approach suggests there will be a gradual
“War on Pollution” in line with the country’s goal of reaching The Three-Dimensional Features of the Global Energy Crisis 91 91 peak emissions by 2030 and achieving carbon neutrality by
2060. In parallel, however, Beijing aims to step up its domestic
energy production in order to meet an increasing proportion of
its own demand through coal, oil and natural gas. This goal is
backed up by a commitment to decarbonising the still largely
coal-fired electricity generation sector, by recourse to solar, wind
and hydroelectric energy.11 So transition is on the agenda, but
not at the expense of energy security or economic development. All this points to the immense gap between China’s approach
and that of the European Union. In addition to domestic policy, there is also the global
chessboard to consider. Relations between Beijing and
Washington will continue to weigh disproportionately on the
huge number of decarbonisation processes and will play a vital
role in the continuation of dialogue between the Global North
and the Global South. Any loss of this dialogue would take
away a cornerstone of the entire system of international climate
diplomacy that has been built over the past three decades. Similarly, relations between China and the United States
underpin various regional balances and therefore directly affect
the stability of energy production and trading. Crisis Tests Energy Interdependence and Conflict h y
gy p
g
The breakdown of dialogue on climate issues as a result
of tensions over Taiwan, and its last-minute resumption
at COP27, shows how intrinsically and significantly the
three-dimensional features of the crisis are interlinked.12 This 92 Back to the Future industrial race to transition, between the West and China, will
affect raw materials dependencies and essential supply chains
in a low-carbon world, as well as access to resources located in
different regions of the globe. This goes to show that, whether
in relation to fossil fuels or critical raw materials, the geopolitics
of energy will remain a key issue for decades to come.13 In a world of growing interdependencies driven by the
needs of energy transition, but fragmented in nature, due to
the crisis in the international order and accelerated by Russia’s
war on Ukraine, tensions can and will emerge even in spaces
that were previously considered safe. The era-defining Inflation
Reduction Act (IRA) launched by the Biden Administration –
a historic initiative aimed at establishing an industrial base for
the green revolution in the United States by investing hundreds
of billions of dollars – is a striking example of this. Intended as
a measure to anticipate future excessive dependencies on the
People’s Republic of China, the IRA has caused direct friction
in transatlantic relations, and the Italian government seems to
be leading the ranks of European countries lobbying for a firm
response.14 These tensions between Washington, the governments of
the Member States and the EU institutions are already widely
visible. They start with the substantial price gap for liquefied
natural gas (LNG) produced in the US and exported to the EU
in increasing volumes, and end with the recalcitrance of US
companies towards the new tax regimes introduced in the EU to
tackle rising energy prices.15 These events offer further evidence The Three-Dimensional Features of the Global Energy Crisis 93 93 of how national responses to Europe’s energy crisis, supported
by EU authorities, have widened the already clear divergences
between the United States and the European Union. hi They are an equally clear sign of how economic, financial
and energy-related fire-power, in terms of production capacity
and import-export balances, have an extremely high degree of
political significance at this stage and can even affect bilateral
relations between allies, including EU Member States. Financial Times, 8 November 2022; M. Eddy, “Exxon Mobil sues to try to block a
European windfall tax”, The New York Times, 28 December 2022.
16 J. Packroff, “Energy crisis: Commission calls for more targeted government
support”, Euractiv, 22 November 2022; J. Fokhul and T. Gillespie, “Germany
Revives Coal as Energy Security Trumps Climate Goals”, Bloomberg, 22
December 2022. Crisis Tests Energy Interdependence and Conflict One
illustration of this is the chorus of protests triggered by the
German government’s extensive programme of energy subsidies
to industry and citizens, and the Commission’s concerns over
aid policy and Germany’s decision to use the full capacity
of its fleet of coal-fired power stations to minimise natural
gas consumption. This initiative is counterbalanced by the
confirmation of Germany’s strategy to shut down its nuclear
power stations in 2023.16 Even in Berlin, where the Greens are
the majority members of the current government, security takes
priority over energy transition. Energy is also at the top of France’s political agenda,
especially in the wake of the loss of credibility suffered by
Europe’s civil nuclear superpower over the past 12 months. With over half of its reactors out of action due to maintenance
or structural problems, France’s energy system has suffered a
severe blow. The forced stoppage turned the country into an
electricity importer for many months, thus undermining what
appeared to be its untouchable status. This has only exacerbated
Europe’s energy crisis. The Elysée Palace has therefore repeated
its announcements of a zero-emissions future built on a new
generation of power stations and the re-nationalisation of the
entire sector. This strategy only partially masks geopolitical and 94 Back to the Future economic intentions. On one side of the equation is the proposal
for an energy transition prototype that provides an alternative
to prototypes elsewhere in Europe, and the revival of the
national interest by exporting the French model (infrastructure,
technology and accompanying political influence) both within
and beyond Europe’s borders. On the other side, there is the goal
of ensuring cheap electricity for citizens and businesses, thereby
relaunching an economy that is struggling with high inflation
and burdened by energy insecurity.17 This demonstrates that,
even in a low-carbon future, Paris sees itself as the leading player
in its own transition and will not leave much room for market
forces to shape the contours of its energy system.h The energy crisis, which saw its annus horribilis in 2022,
is set to remain with us for a long time to come. Against
this backdrop of uncertainty, as we aim at a Net-Zero world,
energy interdependencies will not only be a bridge to facilitate
cooperation, trade and technological progress. 17 T. Wheeldon. “How France’s prized nuclear sector stalled in Europe’s hour of
need”, France24, 5 January 2023; D. Vidalon and C. Pailliez, “French government
aims to cut red tape for new nuclear reactors”, Reuters, 2 November 2022. 7. Are We Heading Towards
De-Globalisation? Lucia Tajoli Crisis Tests Energy Interdependence and Conflict We need to
become more aware that these interdependencies are an almost
inexhaustible source of economic influence and political
pressure, which can be exerted with varying degrees of intent. At the same time, politics has much to gain from a better
understanding of certain energy-related processes and dynamics
that are so disruptive and consequential that they can in no
way be ignored. From this point of view, the struggle between
the European Union and the Russian Federation will serve as a
cautionary tale for decades to come, while the state, whether it
wants to or not, is being called upon throughout Europe to face
up to an era-defining challenge dictated by the ways and time-
frames for achieving energy security and transition. 1 See Cfr. Unctad, “Global trade hits record high of $28.5 trillion in 2021, but
likely to be subdued in 2022”, 17 February 2022. 2 For an analysis of recent developments in international trade please see P. The Patchy Performance of World Trade
in Recent Years Over the past 15 years, world trade has been more volatile than
in previous decades. After almost half a century of continuous
growth in both the value and volume of world trade, including
a particular spurt in the first decade of the new millennium,
international trade growth has slowed and become less regular
since 2009 (Figure 7.1). The international financial crisis of
2008, which triggered a worldwide recession, also had a severe
impact on international trade, which dropped by about 20%
by value and 12% by volume in the year that followed. Since
then, the dynamics of world trade have not been the same. The
global shock of the Covid-19 pandemic caused a second, less
severe, major downturn in 2020, when trade shrank by about
5% by volume. 96 Back to the Future Figure 7.1 – Global Goods’ Exports Figure 7.1 – Global Goods’ Exports By as early as 2021, international trade had bounced back
vigorously: according to the data published by UNCTAD and
WTO, global trade reached a record high of well over 20,000
billion dollars, representing a rise of 25% on 2020 and 13% on
the pre-pandemic period.1 p
p
p
The growth in value was accentuated by price rises, but even
after adjusting for the major fluctuations in prices and exchange
rates in recent years, International Monetary Fund (IMF) and
World Trade Organisation (WTO) data still indicate that
international trade by volume increased by about 10% in
2021, to a higher level than before the pandemic. This means
that, despite the many problems of the past two years, from
Covid to supply-chain bottlenecks, surges in container-ship
charter rates and rising international freight prices, the global
trading system seems capable of withstanding shocks, and talk
of de-globalisation looks premature. Are We Heading Towards De-Globalisation? Are We Heading Towards De-Globalisation? 97
Figure 7.2 - Global rates growth in GDP
and trade volume (2015-21)
However, the significant change in trend and the increase in
fluctuations, clearly shown by the data, need to be assessed. Furthermore, WTO statistics show that the average annual
growth rate of world trade by volume between 2010 and 2019
was less than 3%, well below average annual growth in the
previous decade and, more significantly, below average annual
growth of real GDP (Figure 7.2). The Patchy Performance of World Trade
in Recent Years These are the figures that
have prompted commentators to talk about de-globalisation,
because the process of globalisation was marked by the
increasing openness of national economies, increasing economic
integration and trade increases that were systematically higher
than increases in GDP growth. It is this phase of continuous,
rapid trade growth that seems to have come to an end for the
time being. Most experts agree that although we are nowhere
near the end of globalisation, we are clearly seeing a change
in trade trends, in the wake of a period of vigorous growth
followed by increased volatility.2 97 Figure 7.2 - Global rates growth in GDP
and trade volume (2015-21) Figure 7.2 - Global rates growth in GDP
and trade volume (2015-21) However, the significant change in trend and the increase in
fluctuations, clearly shown by the data, need to be assessed. Furthermore, WTO statistics show that the average annual
growth rate of world trade by volume between 2010 and 2019
was less than 3%, well below average annual growth in the
previous decade and, more significantly, below average annual
growth of real GDP (Figure 7.2). These are the figures that
have prompted commentators to talk about de-globalisation,
because the process of globalisation was marked by the
increasing openness of national economies, increasing economic
integration and trade increases that were systematically higher
than increases in GDP growth. It is this phase of continuous,
rapid trade growth that seems to have come to an end for the
time being. Most experts agree that although we are nowhere
near the end of globalisation, we are clearly seeing a change
in trade trends, in the wake of a period of vigorous growth
followed by increased volatility.2 Back to the Future 98 Antràs, “De-Globalisation? Global Value Chains in the Post-COVID-19 Age”,
ECB Forum: “Central Banks in a Shifting World” Conference Proceedings, 2021.
3 See WTO World Trade Report, 2013 and 2021, and also WTO Global Value Chain
Development Report, 2021.
4 China’s exports accounted for 15% and its imports for 12% of the global totals
in 2021, representing a threefold increase since 2001. China alone therefore
accounts for over a quarter of world trade.
5 See on trade with China for example, G. Grieger, “China’s economic recovery
and dual circulation model”, European Parliament Briefing, Eprs - European
Parliamentary Research Service, 2020. Antràs, “De-Globalisation? Global Value Chains in the Post-COVID-19 Age”,
ECB Forum: “Central Banks in a Shifting World” Conference Proceedings, 2021.
3 See WTO World Trade Report, 2013 and 2021, and also WTO Global Value Chain
Development Report, 2021. 6 For data on digital exchanges among countries see Unctad, Estimates of global
e-commerce 2019 and preliminary assessment of Covid-19 impact on online
retail 2020, UNCTAD Technical Notes on ICT for Development no.18, 2021;
and for a discussion on the impact of international digital trade, L. Tajoli, “La
globalizzazione nei mercati digitali”, Rivista di Politica Economica, June 2022. Possible Reasons for the Change The resilience of globalisation and the international trade system
has been the subject of debate since the aforementioned change
in trend occurred, and many analyses have tried to identify the
reasons for the slowdown in world trade.3 Firstly, it is worth
emphasising that the vigorous growth in trade in the first decade
of the millennium was also abnormal compared with the trend
that preceded it, and difficult to sustain, despite its momentum. According to various analysts, China’s economic performance
and international trade policy, considering the substantial share
of world trade accounted for by China,4 exerted a significant
impact on both the decade of acceleration and the subsequent
slowdown. The very rapid growth in world trade until 2008 was
partly fuelled by the exponential increase in Chinese exports
and imports, especially after China’s accession to the WTO,
and by policies aimed at export-driven growth, all of which
prompted commentators to refer to this period as an era of
“hyper-globalisation”. But these policies changed over a decade
ago: the openness of China’s economy (defined as the sum of
exports and imports of goods and services in relation to GDP)
peaked in 2006, at over 60%. Since then, despite continued
growth in trade, China’s economic policy has been much
more domestically-oriented, thus contributing to an increase
in production capacity that has resulted in the replacement of
imports, especially of intermediate goods and technologies, and
less focus on exports.5 As with all large countries, after its initial Are We Heading Towards De-Globalisation? 99 growth stage, China’s economy would be expected to become
gradually less open and fall into line with the levels seen in
other large economies, and this is exactly what is happening:
the openness of the Chinese economy in 2021 stood at 38%,
down by over a third from its peak. In view of the percentage of
world trade that China accounts for, these changes have had a
major impact on world trade trends. i j
On top of the dynamics of specific countries, the change in
trend of globalisation also stems from the fading influence of
certain factors that drove the rise of globalisation at the end of
the last century and in the first decade of this one. Possible Reasons for the Change Innovations
in modes of transport, as a result of “containerisation” and the
resulting fall in trade costs, have had significant effects on world
trade, as has the spread of the Internet and telecommunications
connections, which have virtually eliminated the marginal cost
of international calls. These technological changes are now
largely complete, and while they continue to support trade, they
are unlikely to give it a further boost. This does not mean the
trend has gone into reverse; it merely means that the dynamics
have changed. One of the factors bringing fresh impetus to world trade
is digitisation and the increasing spread of international
e-commerce, which picked up pace during the pandemic. This
phenomenon is still confined to certain areas of the world,
however, and has not yet fulfilled its full potential, so still has
only a limited effect on world trade.6 It is interesting, however,
to see how digital trade is supporting global trade as a whole,
especially in the increasingly important trade in services. As Fig. 7.3 shows, while the growth rate in goods exports has slowed,
growth in digital trade in services remains vigorous, and has
sped up over the past two years. 100 Back to the Future
100
Figure 7.3 - Exports Digital-delivered services (2005-21)
Index 2005=100
The digital transition is impacting various other areas of
international trade, such as global value chains, which account
for about half of trade between countries. Global value chains
are also undergoing change, and the boost to world trade
provided by this organisation of production is influenced by
the ongoing transition. One of the key factors transforming
global value chains is the development of latest-generation
digital technologies – integrated automation and robotics,
artificial intelligence, additive manufacturing and virtual reality
– which have reduced the labour-intensiveness of the most
repetitive manufacturing processes, thereby reducing the cost-
effectiveness of relocating production to areas where labour
costs are low. At the same time, these technologies require a
higher input of services and intangible factors, which could
reduce trade, but also make it more difficult to measure the
latter’s value, because it rarely involves any physical crossing of
customs borders. At this stage of growth in the tertiarisation
and digitisation of trade, the slowdown suggested by the data
may be due to problems of recordability and measurment. Possible Reasons for the Change Back to the Future Figure 7.3 - Exports Digital-delivered services (2005-21)
Index 2005=100 Figure 7.3 Exports Digital delivered services (2005 21)
Index 2005=100 The digital transition is impacting various other areas of
international trade, such as global value chains, which account
for about half of trade between countries. Global value chains
are also undergoing change, and the boost to world trade
provided by this organisation of production is influenced by
the ongoing transition. One of the key factors transforming
global value chains is the development of latest-generation
digital technologies – integrated automation and robotics,
artificial intelligence, additive manufacturing and virtual reality The digital transition is impacting various other areas of
international trade, such as global value chains, which account
for about half of trade between countries. Global value chains
are also undergoing change, and the boost to world trade
provided by this organisation of production is influenced by
the ongoing transition. One of the key factors transforming
global value chains is the development of latest-generation
digital technologies – integrated automation and robotics,
artificial intelligence, additive manufacturing and virtual reality
– which have reduced the labour-intensiveness of the most
repetitive manufacturing processes, thereby reducing the cost-
effectiveness of relocating production to areas where labour
costs are low. At the same time, these technologies require a
higher input of services and intangible factors, which could
reduce trade, but also make it more difficult to measure the
latter’s value, because it rarely involves any physical crossing of
customs borders. At this stage of growth in the tertiarisation
and digitisation of trade, the slowdown suggested by the data
may be due to problems of recordability and measurment. i
g
g
y
– which have reduced the labour-intensiveness of the most
repetitive manufacturing processes, thereby reducing the cost-
effectiveness of relocating production to areas where labour
costs are low. At the same time, these technologies require a
higher input of services and intangible factors, which could
reduce trade, but also make it more difficult to measure the
latter’s value, because it rarely involves any physical crossing of
customs borders. At this stage of growth in the tertiarisation
and digitisation of trade, the slowdown suggested by the data
may be due to problems of recordability and measurment. 101 Are We Heading Towards De-Globalisation? 7 A debate regarding the need to reform the WTO’s methods, in light of of
the organizations lack of success, has been underway for a while P. Lamy and
N. Köhler-Suzuki, “Deglobalization Is Not Inevitable. How the World Trade
Organization Can Shore Up the Global Economic Order”, Foreign Affairs,
June 2022; and A.A.V.V., Roundabout way to multilateralism: how could regional trade
agreements and plurilaterals revitalize it?, T20 Indonesia Policy Brief, 2022. The De-Globalisation of Trade Policy:
From Multilateralism to Selective Preferential
Agreements Changing attitudes towards trade policy in many countries
has also played a significant role in reducing the drive for
globalisation: from policies of increasing trade liberalisation,
which spawned an increase in WTO membership and the
signing of many international trade agreements at the end of
the last century, there has been a shift towards more closed
and protectionist policies, and WTO negotiations have
been largely at a halt for some time. Increasingly in recent
years, trade policy has been guided by ideological issues and
geopolitical rivalries as much as by economic considerations. Each country’s use of trade policy as a means of imposing their
own standards and principles (however legitimate those may
be), and the instrumental use of economic interdependence
spawned by the rise in globalisation in past years, has made any
negotiation much more difficult, because matters of principle
are non-negotiable., This situation has made the WTO’s efforts
to promote increased openness and liberalisation of trade at
multilateral level much less effective.7 The growing complexity
and different orientation of trade-policy measures, based ever
less on traditional instruments and ever more on non-tariff
measures, such as standards and regulations, has prompted
many countries to enter into regional and preferential trade
agreements, which often involve “friendly” countries, with
which it is easier to share principles than in the multilateral
arena, but which nonetheless carries a risk of distorting global
markets in various ways. 102 Back to the Future According to some observers, furthermore, the political
climate that was conducive to trade liberalisation has changed
somewhat, due in part to increasing pressure from groups who
have been potentially disadvantaged by the redistributive effects
of globalisation, despite the overall positive net effects for all
countries).8 The return of “national security” policies also has
an impact on trade, particularly for “strategic” products, a
category revived by the Trump administration in the US, which
has become considerably wider since the Covid-19 pandemic
and even more so since the war in Ukraine, and now includes
foodstuffs, medicines, advanced technologies and supplies
considered essential for domestic industry. Fortunately, new protectionist policies had no significant
adverse effects on the already unpredictable nature of the
world market in 2022. 8 P. Antràs, A. de Gortari, and O. Itskhoki, “Globalization, Inequality and
Welfare”, Journal of International Economics, vol. 108, 2017, pp. 387-412; T.V. Paul,
“Globalization, deglobalization and reglobalization: adapting liberal international
order”, International Affairs, vol. 97, no. 5, 2021, pp. 1599-1620; D. Rodrik,
“Populism and the economics of globalization”, Journal of International Business
Policy, vol. 1, 2018, pp. 12-33.
9 See the data on All state interventions at https://wwwglobaltradealert org 9 See the data on All state interventions at https://www.globaltradealert.org. The De-Globalisation of Trade Policy:
From Multilateralism to Selective Preferential
Agreements According to Global Trade Alert data,9
after a period of increasing discriminatory measures by many
countries (first and foremost the US and China), which raised
barriers to world trade, 2022 finally saw a reduction in the
measures being taken and an increase in liberalising measures,
despite the new sanctions put in place as a result of Russia’s war
on Ukraine. Governments may have seen fit to avoid stoking
further tensions at an already difficult time, and indeed some
progress in negotiations was made at the last WTO ministerial
conference in June 2022. So although the tenor of trade policy
in recent years has put a partial brake on globalisation, last year
seems to have been better than previous years, at least in terms
of trade wars. 103 Are We Heading Towards De-Globalisation? 10 See WTO, Trade Statistics and Outlook, Press Release 909, 5 October
2022, “Trade growth to slow sharply in 2023 as global economy faces strong
headwinds”. Effects of Recent Circumstances
and Future Scenarios The war in Ukraine is another unexpected shock – the second
in less than three years – whose effects on globalisation are not
yet entirely clear. For the present, the war has clearly caused a
reduction in trade with the countries directly involved in the
conflict, partly as a result of the sanctions applied against Russia. One major difference compared with the pandemic of 2020 is
that the current shock mainly involves an area that is much less
crucial to international trading patterns, because Russia is not
comparable to China in terms of its share of world trade. However, the uncertainty unleashed on European markets in
particular, due to Russia’s invasion of Ukraine, has prompted
the WTO to downgrade its forecasts for 2022 and 2023. The
WTO forecasts that world trade in goods will increase by 3.5%
in 2022, and expects an increase of 1% in 2023 – significantly
down on the previous estimate of 3.4%.10 This slowdown in
trade is associated with weakening growth in the major world
economies for a number of reasons, ranging from the negative
impact of inflation and the resulting tightening of monetary
policies in Europe and the US, to China’s caution and the
difficulties facing many developing countries as a result of the
surge in prices of various agricultural raw materials. fi It is difficult to predict what might happen to international
trade in the medium term, but for the time being there are no
signs of any significant or permanent reversal of the trend in
globalisation, not least because the nature of the recent shocks
appears to be temporary. What we are witnessing, however,
is a slowdown in trade growth rates as a result of a series of
structural changes. Some of these changes may be the result of
shifts in the geopolitical picture due to the ongoing war, such
as increased economic cooperation between Russia and China. 104 Back to the Future Looking ahead, these two countries might reduce their ties with
the US and Europe, and increase their trade with each other:
Russia could support China’s growth with a plentiful supply
of fuels and raw materials (agricultural and non-agricultural),
while China could provide labour, technology, consumer goods
and services to Russia, and both could benefit from each other’s
sizeable markets, and perhaps strengthen their positions in
Asia and Africa. 11 N.F. Poitiers and P. Weil, “A new direction for the European Union’s half-
hearted semiconductor strategy”, Bruegel Policy Contribution, no. 17/21, 2021. Effects of Recent Circumstances
and Future Scenarios This possible separation of the Western and
Eastern blocks, known as de-coupling, would certainly trigger
a slowdown in globalisation, but it still looks unrealistic in
the medium term. This is because breaking up or reorganising
the huge number of international supply chains or global
value chains that underpin globalisation would be very costly,
especially if done quickly. p
y
q
y
The most likely medium-term scenario – which is already
beginning to emerge – is that decoupling will be limited to
certain strategic industries with a high degree of technological
input and semiconductor usage. China aspires to technological
leadership and is working to achieve this at pace. The West has
reacted by launching its own plans: the US implemented the
Chips and Science Act in July 2022 with 53 billion dollars of
funding to boost its semiconductor industry. In January 2022,
the EU passed the European Chips Act, aimed at doubling its
global market share (from 10% to 20%) between now and
2030. These policies are aimed at increasing technological
independence and may reduce trade flows.11 l
Another potentially divisive area for international trade
is environmental policy, in which the choices that individual
countries make to support certain types of production could
become barriers to international trade even within the West. As
previously mentioned, despite the crucial importance of policies
designed to limit climate change, the expansion of national
un-coordinated regulations and standards in many industries Are We Heading Towards De-Globalisation? 105 can easily become protectionist instruments that raise barriers
between countries. In addition to trade-reducing factors, however, there may
also be changes that boost foreign trade: the economic and
technological growth of several large countries to an intermediate
level of development (e.g. Turkey and India, to name but two)
could offset the reduction in trade in more advanced countries. f
In conclusion, we are very likely moving towards a more
fragmented and selective globalisation between geographical
areas, but the process will not be quick and it will not affect all
global trade. In the course of 2023, the possible deterioration of
the economic situation, especially in the West, combined with
a further rise in geopolitical tensions, could further depress
trade flows. The possibility of a renewed outbreak of the trade
war between the US and China, once the conflict in Ukraine
comes to an end, cannot be ruled out. 1 A. Deaton, La grande fuga. Salute, ricchezza e origini della disuguaglianza, Bologna, Il Effects of Recent Circumstances
and Future Scenarios A world more divided
into economic blocks therefore remains a possibility. But the
current level of economic interdependence is indispensable for
all the major players on the world stage. As such, the most likely
scenario, in a world where these actors behave rationally, is that
globalisation will continue for a long time to come, albeit in
different forms to those we have seen in recent decades. f
Certain features of world trade are certainly changing, partly
because of the more selective choices being made by businesses,
which are trying to reorganise their footprint on world markets,
in such a way as to be less exposed to the shocks that have
occurred. However, trade models have become more volatile
in recent years. Growing turbulence has led to greater caution
over the launch of new initiatives abroad, thereby slowing
down exposure to the highest-risk markets, but generally
without reducing interest in demand from foreign countries. Against this less predictable backdrop, greater diversification,
in terms of both procurement and sales markets, could play an
important role in supporting sales and profits. Mulino, 2015.
2 Unless otherwise stated, the figures for poverty are from the World Bank,
Poverty and prosperity 2022. Correcting course, World Bank, Washington, 2022.
3 M. Jerven, Poor numbers. How we are misled by African development statistics and what
to do about it, Cornell University Press, New York, 2013. 8. The Return of Poverty and Hunger
Giovanni Carbone, Lucia Ragazzi The development of poor countries – the structural
transformation and expansion of their economies, with the
associated social changes and improvements in living standards –
has long been associated with the dream of fully eradicating world
poverty. The two processes are intricately intertwined: on the
simplest level, disadvantaged societies need to increase available
resources to lift their populations out of poverty. However,
economic growth and development are clearly insufficient in
and of themselves, and they do not automatically translate into
the elimination or even a drastic reduction in poverty. To have
a tangible impact on poverty, the socioeconomic progress of a
nation must be distributed, at least to some extent, whether
this happens “naturally” through the development processes
themselves (e.g. the creation of new jobs) or through specific
government policies. In his reconstruction of the economics of
poverty and inequality, Nobel Laureate Angus Deaton shows
how “great episodes of human progress” − those moments he
calls “great escapes” from a prevalence of deprivation, disease
and premature death − have led to extraordinary increases in
life expectancy and spectacular improvements in material
living conditions, but only for certain parts of the societies
that experienced them, constantly leaving behind significant
parts of the populations involved (and thus, as Deaton points
out, creating inequality).1 This historical dynamic also applies 108 Back to the Future to more recent times. Despite a 30-year period (1990-2019)
of overall decline in both global poverty rates and the total
number of poor people, in 2019 almost a quarter (23%) of the
world’s population lived on less than $3.65 per day and almost
half (47%) on less than $6.85 per day.2 World Poverty: Measures, Estimates
and Past Trends Estimates of the prevalence of poverty are usually based on
household consumption surveys, that is, national surveys of
household consumption, which provide a basis for calculating
the equivalised value in terms of the spending capacity of
households and thus the proportion of a given population
living below (or above) a given poverty line. The World Bank’s
Poverty and Inequality Platform (PIP, formerly PovcalNet) has
systematically collected such data since 1990, while similar
information from 1950 to 1990 is based on extrapolations of
national economic growth data. However, poor countries almost
by definition suffer from a lack of data, and the data that are
available are of poor quality and reliability (this even applies to
data on GDP or inflation, which are also needed for the above
calculations), making comparisons tricky. This is part of a wider
problem with the production of statistics − etymologically the
information collected by the State − when a State’s functioning
is still plagued by considerable shortcomings.3 hi The World Bank has recently made its first estimates (referring
to 2019) using new international poverty “lines”, recalculated
using 2017 purchasing power parities (PPPs) as a baseline −
they have been updated from the earlier 2011 ones, making it The Return of Poverty and Hunger 109 possible to correctly compare living standards across countries. The new PPPs use the nominal value of the dollar in 2017, and
their changes from the past do not mean that poverty lines are
now higher in real terms. The three poverty lines correspond to
the median of the national poverty lines, respectively, for low-
income economies, which is $2.15 per day (previously it was
$1.90), below which threshold we speak of absolute or extreme
poverty; lower-middle-income economies, which is $3.65 (it
was $3.20); upper-middle-income economies, which is $6.85
(it was $5.50). For the three-year period just ended (2020-
2022), the available data come from nowcasts (“forecasts” of the
recent past, present or short-term future), that is, provisional
estimates that do not adopt the household surveys normally
used to study the prevalence of poverty, but GDP growth rates
and forecasts, and other types of indicators.4 4 Poverty and prosperity 2022. Correcting course…, cit., pp. 46ss. Pandemic and Poverty In the contemporary era, the trend in world poverty has followed
a clear, virtuous trajectory with substantial continuity since at
least the 1950s, with the number of poor people in the world
declining along with the proportion of world’s population that
is poor. The share of people living in extreme poverty has fallen
from nearly 60% of the world’s population in 1950 to less than
10% today. Progress accelerated markedly in the 1980s − albeit
with a slowdown in the second half of the 2010s − driven by
the rapid changes in China and India, the world’s two most
populous nations. For example, in the 35 years between 1981
and 2016, the total number of poor people fell from 1.8 billion
to 750 million. Such a figure is undoubtedly still far too high,
but the gradual decline has been considerable. g
As the world was on this slow but steady path of poverty
reduction, the Covid-19 pandemic struck, dealing a severe blow
to a trend that had been consolidated over more than seven 110 Back to the Future decades. Indeed, the major stumble in 2020 was “the biggest
setback [in the fight against] global poverty in decades”.5 i
Four main channels of transmission have spread the economic
impact of the pandemic to developing nations. The first was
direct in nature, dictated by the deterioration in health caused
by the spread of the virus, leading to an increase in illness and
deaths. The second was the product of the containment and
mitigation measures imposed by governments, with lockdowns,
quarantines and other forms of isolation resulting in many
businesses suspending operations, a lack of human capital
development and so on. The third was the shift in value and
trade chains as a result of the slowdown in the world’s major
economies − especially the western economies and China −
which hit energy and mining commodity exporters particularly
hard through lower prices, as well as those countries that are
heavily involved in such global value chains. The fourth and
last was a reduction in foreign financial flows, particularly in
sectors such as mining and infrastructure, development aid,
remittances and tourism. The recent surge in food and energy
inflation, which has hampered the global economic recovery,
has exacerbated these pandemic dynamics. 5 Ibid., p. xxi. Pandemic and Poverty p
y
The almost immediate result was that extreme poverty
globally, or the share of the population living on less than
$2.15 per day, increased by 11% in 2020, reaching 9.3% of the
world’s population (up from 8.4% in 2019). Figure 8.1 shows
very clearly that this is a reversal of the trend and a real “break”
in the long-term dynamics. There were as many as 71 million
new poor, adding to the 648 million already in 2019, bringing
the new total to 719 million people (from 2020 onwards, the
data are currently based on the aforementioned nowcasts). The Return of Poverty and Hunger 111 Figure 8.1 - Impact of the pandemic on poverty trends Figure 8.1 - Impact of the pandemic on poverty trends Figure 8.1 - Impact of the pandemic on poverty trends 112 Back to the Future The impact of India has heavily influenced the global trend:
in the face of a dramatic reduction in domestic GDP (-7.5%
in 2020), the country now accounts for 56 of the 71 million
new poor in the world in 2020. Economic growth trends
suffered less dramatic shocks and the associated increases in
poverty were milder in countries that already had the second
and third largest numbers of extreme poor, namely Nigeria
(with an increase of 3 million individuals linked to a -4.3%
contraction in GDP) and the Democratic Republic of Congo
(-1.4% of GDP, with 500,000 more poor people). On the
other hand, Brazil and South Africa, which are already middle-
income countries, bucked the trend and saw poverty drop due
to public policies introduced to address the hardships caused
by the pandemic. More generally, the distribution of poverty
across the world’s regions changes significantly depending on
the poverty line adopted. The largest number of the poor below
both the $3.65 and $6.85 per day lines might be found in
South Asia − the most populous area of the world − but it is
sub-Saharan Africans who make up the majority of those living
in extreme poverty, below the $2.15 per day line. p
y
p
y
Adopting a broader perspective, the systematic drop in
absolute poverty had already begun to slow before 2020, in the
five-year period from 2014 to 2019, compared with the faster
pace of reduction recorded in previous years. Recent nowcasts
show that, after the 2020 increase, poverty began to decline
again in the two-year period from 2021 to 2022, but at the same
moderate pace of the years immediately prior to the pandemic. h p
y
y p
p
The costs of Covid-19 go beyond direct “income” or
monetary costs, also having a long-term, indirect effect on
impoverishment. The pandemic has led to abrupt slowdowns,
and even sharp setbacks, for progress in health (premature
mortality due to the pandemic has led, globally, to a two-year
loss in life expectancy at birth) and education (related to young
people missing periods of education and learning during
school closures) with lasting repercussions on the lifetime
income prospects of individuals. In simple terms, poverty goes The Return of Poverty and Hunger 113 beyond monetary aspects. 6 Poverty in a rising Africa, World Bank, Washington, 2016, pp. 83ss.
7 Poverty & Human Development Initiative (OPHI) - United Nations
Development Programme (UNDP), Global Multidimensional Poverty Index 2022.
Unpacking deprivation bundles to reduce multidimensional poverty, University of Oxford,
2022.
8 Piecing together the poverty puzzle, World Bank, Washington, 2018, p. 35. Figure 8.1 - Impact of the pandemic on poverty trends The need to account for these other
aspects − such as education, health, security and so on6 − led to
the notion of multidimensional poverty and the related ways
of measuring this, such as the United Nations Development
Programme’s (UNDP) Global Multidimensional Poverty
Index,7 which combines deprivation indicators for child
mortality, schooling, access to electricity and drinking water,
housing, and so on, or the World Bank’s Multidimensional
Poverty Measure, which includes absolute poverty as a
monetary indicator, but in relation to indicators for education
and basic infrastructure services. Sub-Saharan Africa: Poverty of the Poorest In recent decades, sub-Saharan Africa has demonstrated a
far greater capacity for progress and speed of transformation
than in the past. Between 2000 and 2014, during a key time
in a durable economic revival, the region grew by about 5.5%
annually −rates far higher than those achieved between the mid-
1970s and early 1990s. This fruitful time lies at the roots of
widespread expressions like “emerging Africa” or “rising Africa”
that were coined to focus on the key transformations underway
not only for GDP, trade, foreign investment and infrastructure
improvement, but also for a number of key social indicators. For example, in 1990, infant mortality in sub-Saharan Africa
resulted in 180 children under five dying for every 1,000 births,
but this figure was less than half in 2018 (77), moving it closer
to the number found in other regions around the world.8
Primary schooling rates moved along a similar trajectory, 114 Back to the Future albeit raising questions as to the broader effectiveness of the
strategies adopted. Focusing on extreme poverty rates (i.e. the
share of people now living on less than $2.15 per day), these
have gradually declined from a peak of 58% of the sub-Saharan
population in 1993 to 35.1% in 2019.9 Economic growth has
definitely slowed and become more erratic in recent years, but
the notion of Africa rising and changing has generally held up. This explains, for example, the World Bank choosing to label
one of its 2016 reports “Poverty in a Rising Africa”. However, sub-Saharan Africa remains home to 60% of the
world’s “absolute” poor, it remains the most deprived region
on the planet, and there is little light at the end of the tunnel
as 90% of the world’s absolute poor will be in Africa by 2030. While there was a significant reduction in extreme poverty for
more than two decades starting in the early 1990s, the pace of
progress has more than halved in the last decade, from 13.1
percentage points in 2002-11 to 5.8 percentage points in 2011-
19. This slowdown has reversed the trend in the total number
of poor people, which fell from 379 million to 365 million
between 2002 and 2011, but then swung back in the other
direction to 389 million in 2019. And then the pandemic also
hit here, arriving at the same time as the “400 million threshold”
was broken. 9 The 35% estimate is 3 percentage points lower than previous analyses, but this
is because of the new baselines used-those new 2017 estimates of purchasing
power parities. Africa does continue to suffer from particularly poor data
availability and quality.
10 K. Abay, N. Yonzan, S. Kurdi, and K. Tafere, Revisiting poverty trends and the role
of social protection systems in Africa during the Covid-19 pandemic, International Food
Policy Research Institute, IFPRI Discussion Paper 02142, October 2022. 9 The 35% estimate is 3 percentage points lower than previous analyses, but this
is because of the new baselines used-those new 2017 estimates of purchasing
power parities. Africa does continue to suffer from particularly poor data
availability and quality. 10 K. Abay, N. Yonzan, S. Kurdi, and K. Tafere, Revisiting poverty trends and the role
of social protection systems in Africa during the Covid-19 pandemic, International Food
Policy Research Institute, IFPRI Discussion Paper 02142, October 2022. 11 Abay et al. (2022). Sub-Saharan Africa: Poverty of the Poorest African countries and their populations were vulnerable in
specific ways to the incredible external shock caused by Covid-19. These include structural elements such as deficiencies in health
systems, high levels of extreme poverty and food insecurity, and
limited scope for mitigation through the expansion or creation
of social protection programmes.10 Without belittling how The Return of Poverty and Hunger 115 dramatic things have been, in the cold light of day, the pandemic
in sub-Saharan Africa has had relatively limited health effects,
both compared to other parts of the world and to some of the
more catastrophic initial predictions. The situation was by no
means uniform, with some countries and their populations −
such as South Africa − suffering far more than others. f f
Looking at the economic and social effects, though, these
were felt early on, and heavily. In 2020, the sub-Saharan region
entered its first economic recession (-1.6%) in a quarter of
a century. 2021 saw a decent rebound (4.7%), but then the
war in Ukraine broke out, severely affecting the international
economy, with repercussions for the continuity of Africa’s
recovery (estimated at 3.6% for 2022, an insufficient rate for
developing countries). p g
Extreme poverty in Africa has risen − the pandemic has not
been good for anyone − but estimates vary and suffer from
inevitable uncertainty and caution required as much by the
difficulties of measuring increases in poverty as by the chronic
gaps in African statistical data. Over the course of the pandemic,
various estimates and hypotheses have calculated new figures
for the number of poor created by the pandemic − that is, the
new poor people, in addition to those who were already classed
as poor − ranging between 23 million and 120 million.11 One of
the most widely accepted assessments found that, as a result of
Covid-19, sub-Saharan Africa “gained” 28 million more poor
people over the three-year period 2020-22. In other words,
the continent currently has nearly 420 million people living
in absolute poverty. Countries grappling with armed conflict −
and Africa has more wars than any other region − tend to be the
most fragile and exposed to additional shocks, partly because of
the combined effect of a population that is already vulnerable,
if not beyond the breaking point, and state apparatuses that
are ill-equipped to provide adequate responses. 12 Ibid. Sub-Saharan Africa: Poverty of the Poorest In these already
struggling countries, the pandemic has had the greatest impact 11 Abay et al. (2022). 116 Back to the Future in increasing the spread of poverty. Moreover, using the World
Bank’s higher poverty line of $3.65 per day, the total number
of poor people in sub-Saharan Africa has never really fallen,
but has been systematically pushed upwards by the region’s
rampant population growth, such that the number of poor has
risen to encompass over 700 million people in recent years, out
of a total population in the region of 1.2 billion. g
So, nearly 30 million more people without basic and essential
resources − a huge number of poor people who are more or less
directly children of the pandemic. Still, Covid-19 could have
had a greater impact on poverty in Africa. Its impact was limited
to some extent not only by the above-mentioned smaller direct
impact on health than initially feared (a fact at least partly
attributable to the region’s average younger populations), but
also by the fact that lockdowns and other restrictive measures
had less impact in rural areas − those most at risk of poverty
− and, finally, by the capacity (albeit diminished) of African
states to implement policies to reduce poverty. Several countries
in sub-Saharan Africa already had social support programmes
in place several years before the pandemic hit, although these
had limited resources and reached only a small proportion of
the population in need, particularly in rural areas. In only a
seeming paradox, the extent of such coverage was most scarce
in those countries with the highest percentages of absolute
poor. The pandemic was clearly not a context in which it was
easy to increase resources and breadth of coverage for the most
vulnerable. But efforts were made precisely to do this. Some of
the best examples of this are Ethiopia’s Productive Safety Net
Program, which reaches about 27% of the poorest people in
rural areas, Kenya’s Universal Basic Income, Nigeria’s National
Social Safety Net Program cash transfers, and South Africa’s
Child Support Grants and the Older Person’s Grant.12 12 Ibid. 13 Poverty in a rising Africa, World Bank…, cit.; Accelerating poverty reduction in Africa,
World Bank, Washington, 2019.
14 United Nations, Sustainable Development Goals (https://sdgs.un.org/goals).
15 FAO – IFAD – WFP – WHO – Unicef, The state of food security and nutrition
in the world 2022. Repurposing food and agricultural policies to make healthy diets more
affordable,2022. Sub-Saharan Africa: Poverty of the Poorest The Return of Poverty and Hunger 117 This does not change the fact that the situation in sub-
Saharan Africa, exacerbated by the pandemic, makes it the only
region in the world that will fail to meet the target of reducing
absolute poverty to below 3% of the population by 2030 − the
first target of the Sustainable Development Goals adopted by
the international community in 2015. In 2015, the year these
targets were set, the region missed a similar target set 15 years
earlier to “halve poverty” − using 1990 as a baseline − which
was the number one Millennium Development Goal at the
time. Once again, the drop in poverty was too slow and too
limited − from 57% in 1990 to 41% in 2015 − thus preventing
sub-Saharan Africa from achieving the desired result, the only
developing region to fail to do so.13 Hunger, the Other Face of Poverty Hunger is the other side of this coin, although the full picture
would have more than just two sides. “No poverty” might rank
first among the development goals set by the international
community for 2030, but it is immediately followed by “Zero
Hunger”, which translates into “ending hunger, achieving food
security and improving nutrition, and promoting sustainable
agriculture”.14 Specific targets include eradicating hunger (goal
2.1) and “all forms of undernourishment”, particularly stunting
in children under 5 (goal 2.2), that is, reduced growth because
of inadequate nutrition that can also permanently damage
physical and cognitive development. p y
g
p
The current global trend is actually moving in precisely the
opposite direction − the wrong direction.15 Hunger, in the sense 118 Back to the Future of the prevalence of chronic undernourishment − that is, when
habitual food consumption is insufficient for an active, healthy
life16 − is on the rise. Progress had gradually reduced the portion
of hungry people globally from 12.3% in 2005 to 7.8% in 2014. However, this progress had ground to a halt, with it proving
impossible to record further reductions up to and including
2019 (8%) − and it is worth noting here the parallel slowdown
in poverty reduction over the same decade − only for it to then
leap upward by nearly two percentage points in only two years,
driven by the pandemic, touching 9.8% in 2021. In essence,
one in 10 people in the world still goes hungry. In terms of
absolute numbers, people suffering from hunger rose to 768
million in 2021, which is over 150 million more people than
the 618 million in 2019. Forecasts suggest that, by 2030, the
number could still be as high as 670 million, an estimated 78
million more than would have been the case had the pandemic
not dramatically altered the trajectory. y
j
y
This tough recent period was exacerbated by the sharp rise in
many food prices, which were already much higher throughout the
entire post-2007 period than before (Figure 8.2). The connections
among food inflation, hunger and poverty are complex. In the
short term, low-income households are hardest hit by rising prices
because the poorest spend on average two thirds of their resources
on food and so they are most vulnerable to fluctuations. City
dwellers, in particular, have to cope with rising costs without any
benefit from food inflation. 16 Ibid., Annex 7: Glossary, 2022.
17 World Bank, Poverty and prosperity 2022. Correcting course…, cit., pp. 53-54. 16 Ibid., Annex 7: Glossary, 2022. y
17 World Bank, Poverty and prosperity 2022. Correcting course…, cit., pp. 53-54. Hunger, the Other Face of Poverty Yet, over 80% of the absolute poor
live in rural areas, complicating the links and mechanisms in these
processes. Empirical evidence actually suggests an increase in food
prices becomes “a driver of poverty reduction”17 over the subsequent
five years, essentially through an adjustment in consumption (with
a shift to alternative foods), the impact of higher prices leading to
increased income for farmers and producers, wage adjustments,
new agricultural investments and so on. The Return of Poverty and Hunger 119 Of course, hunger is not evenly distributed across the world. In the rich countries of North America and Europe it affects
no more than 2.5% of the population, while at the other end
of the scale, one in five Africans (20.2%) are directly affected
by undernourishment. Once again sub-Saharan Africa is the
region with the highest prevalence of undernourishment (PoU,
an indicator that estimates the proportion of the population that
lacks access to the dietary energy required for a healthy lifestyle). Although PoU fell from 23.9% to 18.3% between 2005 and
2015 − the most robust period in the economic expansion of
‘rising Africa’ − it then began to rise again, gradually at first,
but then more decisively as a result of the pandemic. By 2021,
undernourishment had risen to 23.2%, almost back to the level
of 16 years earlier, compared with the above-mentioned world
average of 9.8%, and with the second most affected region,
South Asia, now far behind at 16.9%.18 Although the prevalence
of undernourishment is lower than in east and Central Africa,
the situation in the western and southern parts of the continent
has actually worsened compared to 2005. y
p
In sub-Saharan Africa, the number of undernourished
people has risen sharply, growing by more than 46 million
between 2019 and 2021. Once again, the difficulties in this
region are compounded by the demographic pressures of a
rapidly and steadily growing population, with more than 260
million undernourished people in 2021 compared to 174
million in 2005 (i.e. an increase of 86 million people), and
with the prospect that, with population growth, the prevalence
of undernourishment could rise to 29.4% by 2030.19 This is a
source of pressure on the continent’s food systems that intersects
with the persistence − and at times exacerbation − of other
shocks that cause or worsen food insecurity on the continent. 18 FAO – IFAD – WFP – WHO – Unicef (2022), p. 14.
19 Africa’s Pulse. Food Systems Opportunities in a Turbulent Time, n. 24, World Bank,
Washington, October 2022, p. 56. 19 Africa’s Pulse. Food Systems Opportunities in a Turbulent Time, n. 24, World Bank,
Washington, October 2022, p. 56. 20 World Food Programme, Ethiopia. Country Brief, October 2022. 1 A. Taylor, “Africa is being pushed to take sides in the Ukraine war”, The
Washington Post, 28 July 2022.
2 “The European Strategy for a “New Deal” with Africa”, European Issue n.
622, Foundation Robert Schuman, 14 February 2022. Hunger, the Other Face of Poverty Take, for example, the conflicts that disrupt food production
or access to food. This was recently the case in Ethiopia, where 120 Back to the Future an estimated 13 million people need food aid in areas affected
by the Tigray war.20 There is also the increasing incidence of
extreme weather, from floods to droughts, such as the drought
that struck the Horn of Africa for four consecutive years, or the
one that plagued Angola and Madagascar in 2022. Finally, to
take another example from earlier, there is food price volatility,
exemplified by the soaring cost of wheat in 2022, which rose
to record levels in the wake of the war in Ukraine. This has
a direct and indirect impact on the food systems of African
countries as they are largely wheat importers. All these factors
only exacerbate the effects of the 2020 economic slowdown
and the subsequent arduous search for a recovery. Thus, the
pandemic has left not only a trail of death, but also tens of
millions of people in different regions of the planet who have
slipped into the tragedy of extreme poverty and hunger. In a
situation that has become so much worse, but with much of
the world’s attention focusing on other crises, the road to the
international community’s 2030 goals has become that much
trickier to navigate. The Return of Poverty and Hunger 121 Figure 8.2 - Food price index, 1990-2022 Figure 8.2 - Food price index, 1990-2022 Figure 8.2 - Food price index, 1990-2022 9. The Non-Aligned Movement is Back? Ugo Tramballi The United States and the European Union deployed all their
diplomatic skills to achieve an outcome that unequivocally
condemned and isolated Vladimir Putin. However, on 2 March,
a week after the invasion of Ukraine, 35 countries abstained
from voting against Russian aggression at the UN General
Assembly. Of these, 17 were African nations. Another eight
from the same continent contrived to be absent from the vote. “I saw too much hypocrisy, especially on the African
continent”,1 French President Emanuel Macron said a few
days later in Cameroon, on a trip intended as a warning to
the entire continent. The vote at the U.N. Headquarter came
as an unexpected defeat for the European Union. A staunch
supporter of multilateralism and international solidarity and an
active contributor of development aid, Europe discovered that
its friends in the “Global South” were not all loyal. On 17 and 18 February, a few days before the Russian
invasion, the European Union had organised the sixth EU-
African Union summit to relaunch the “European Strategy for a
New deal with Africa”, promising energy, digital transformation,
sustainable growth, employment, peace, security, governance,
migration and mobility.2 Before the pandemic, the EU had 124 Back to the Future more than $250 billion invested in Africa, far more than the
United States (48 billion) and China (43 billion). European
trade accounted for $269 billion, twice as much as China and
five times more than the US.3 Moscow lagged far behind – and
still does. Russia nevertheless remains the largest exporter of
arms to the African continent, accounting for 44% of purchases
between 2017 and 2021.4 By the end of 2022, however, Chinese investment had grown
to $261 billion. This has targeted infrastructure, eye-catching
if not always necessary or of the highest quality, and usually
built with Chinese manpower. The acquisition of rare earths
essential to the industries of the future is another area of Chinese
involvement. For many African countries, the result has been
an exponential increase in un-repayable debt to Beijing. p
p y
j g
However, China has also had some success in the use of “soft
power”, a technique of which Beijing had previously displayed
little mastery. As the United States closed its universities to
foreign students and continued to underestimate the potential
of the continent, Beijing began opening its faculties to African
students, welcoming around 80,000 before the pandemic. 3 C. Golubski e A. Schaeffer, “The European Union unveils its new Africa
strategy”, Brookings, 14 March 2020.
4 Stockholm International Peace Research Institute, SIPRI.
5 M. Repnikova, “The Balance of Soft Power – American and Chinese Quests to
Win Hearts and Minds”, Foreign Affairs, July/August 2022. 9. The Non-Aligned Movement is Back? “Nearly two-thirds of Africans contacted in 34 countries
considered Chinese influence partly or very positive”.5 6 “No more Kofis”. It was the Bush administration which opposed appointing
Tharoor as UN General Secretary, at the end of Kofifi Annan’s mandate.
Both Annan and Tharoor opposed the US invasion of Iraq. Secretary of State
Condoleezza Rice instructed John Bolton, the then Ambassador to the UN, to
veto Shashi Tharoor: “no, we don’t want another strong General Secretary,” was
the explanation.
7 S. Tharoor, An Era of Darkness – The British Empire in India, New Delhi, Aleph
Book Company, 2016. 7 S. Tharoor, An Era of Darkness – The British Empire in India, New Delhi, Aleph
Book Company, 2016. 8 O. Scholz, “The Global Zeitenwende – How to Avoid a New Cold War in a
Multipolar Era”, Foreign Affairs, January/February 2023. Zeitenwende Response to the vote at the United Nations has been somewhat
exaggerated. Analysts have claimed that a new “Global South”
has appeared – a revamped version of the Non-Aligned
Movement formed after the Bandung Conference in 1955. In fact, only one African country actually voted against the
resolution condemning Russia at the United Nations: Eritrea. Another 28 out of 54 supported it. And not only in March
2022, but in all subsequent votes at the UN, the African Union
has consistently condemned the invasion of Ukraine and
supported the West in calling for an immediate ceasefire. i
Yet something has indeed happened. In addition to China,
the countries abstaining included India and Indonesia, two
rising economic powers with growing diplomatic influence. The
war in Ukraine has not revived the Non-Aligned Movement,
but it has given rise to something completely new in global
geopolitics and in relations between the Global South and
North, not just between emerging nations and the West (i.e. the US and EU), but between the South on the one hand and
the West, Russia and China on the other. The distinction is
between the established Great Powers and the rest of the world,
which is now claiming autonomy. “The world is facing a
Zeitenwende, an epochal tectonic change,” admitted Olaf Scholz
on Foreign Affairs. For the German Chancellor, “Russia’s war
of aggression against Ukraine has put an end to an era... In
this new multipolar world, different countries and models of
government are competing for power and influence”.8 Colonial Memories A country as important as South Africa may well have preferred
not to condemn Russia at the United Nations in appreciation
of the support once given by the Soviet Union to the African
National Congress in its fight against apartheid. After all,
Margaret Thatcher was still refusing to sanction the white The Non-Aligned Movement is Back? 125 segregationist government of Pretoria in the late 1980s. The
continent’s colonial past is not such ancient history as to be
easily forgotten. Before the Berlin Conference of 1884, 80%
of Africa was free. 30 years later, 90% would be controlled by
Europe’s seven colonial powers: France, Great Britain, Belgium,
Italy, Spain, Portugal and Germany. In addition to African nations, the 35 abstentions at the UN
included countries from all continents except Oceania. Each
of these has suffered from Western domination to a greater or
lesser extent. Vietnam, for example, endured almost thirty years
or war, first with France, later with the United States. India is
another case in point. Shashi Tharoor, former Under-Secretary
General at the United Nations6 and defeated candidate in the
election to succeed Sonia Gandhi as President of Congress,
recently proposed that the UK should pay compensation for
the damage inflicted on India by the British Empire. “At the
g beginning of the XVIII century India share of the world
economy was 23%, as large as all of Europe put together”,
Tharoor wrote. “By the time the British departed India, it
had dropped to just over 3%. The reason was simple: India
was governed for the benefit of Britain. Britain’s rise for 200
years was financed by its depredations in India”.7 Some Indian
economists have calculated that reparations could amount
to some 300,000 billion pounds sterling – the equivalent of
British GDP in 2015, but Tharoor himself would have been
satisfied with a symbolic settlement of one pound per year for
the 200 years concerned. 126 Back to the Future 9 M. Indyk, Master of the Game – Henry Kissinger and the Art of Middle East Diplomacy,
New York, Alfred Knopf, 2021.
10 R. Mohan, “Why Non-Alignment is Dead and Won’t Return”, Twitter, 10
September 2022. Not Alligned and Free During the Cold War, the Non-Aligned Movement (which
technically still exists within the UN) failed because it never The Non-Aligned Movement is Back? 127 succeeded in presenting a coherent image. When China atacked
India in 1962, Jawaharlar Nehru, one of the movement’s
founders, asked America for military aid. A decade later, his
daughter, Indira Gandhi, aligned herself closely with the Soviet
Union: Soviet-Indian relations resembled an effective alliance
though India never actually joined the Warsaw Pact. Egyptian
President Anwar Sadat began the Kippur War of 1973 in the
Soviet camp but was convinced by Henry Kissinger to end it
on the American side.9 And despite joining an anti-communist
alliance with the United States, Pakistan was regularly supported
by Mao’s China in its endless disputes with India.h y
p
The political death of the Non-Aligned Movement was
implicitly decreed by Fidel Castro, a close friend of Moscow, at
the Havana Summit in 1979. Not inconsistently, the conference
established that the Movement’s “natural ally” was the USSR:
there was simply no alternative to a bipolar order. p y
p
“For developing nations, the objective of building a non-
Western or post-Western order – part to the ideology of
nonalignment from its beginnings in the decolonization era –
has been an enduring but elusive mirage,” says Raja Mohan,
director of South Asian Studies at the University of Singapore. No new political and diplomatic front will form in the Global
South because the concept “died a long time ago. Third
Worldism and its offspring ideologies og pan-Asianism, pan-
Arabism, and pan-Islamism – was a big failure”. Nevertheless, as Raja Mohan points out, “if Western and
Eastern Europe can’t fully agree on how to respond to the war
in Ukraine, and if neither US Republicans nor Democrats see
Russia through the same eyes, why should one assume Latin
America, Africa and Asia will toe the current Western position
on Ukraine?”.10 128 Back to the Future Back to the Future Vladimir Putin must, of course, welcome abstentions in
motions condemning the war in Ukraine. Even China, though
insisting on neutrality despite the “no limits friendship” between
Xi Jinping and the Russian President, actually benefits from a
weakened Russia – an obsolete superpower reduced to the role
of fuel supplier to an increasingly assertive Beijing. A European War Non-Alignment ideology sought to transform the struggle
for decolonisation into one against the West, which it saw as
the prime culprit behind colonialism. But the Global South,
and especially African nations, now see very clearly that the
ambitions and behaviors of Russia and China are not very
different from those of earlier European colonizers. Though it
does not have the same colonial history in Africa, Russia has
ruled an empire in Central Asia and the Caucasus: it was and
remains an imperialist country – probably the last such power
on the European continent. During a UN Security Council
debate, Kenyan Ambassador Martin Kimany linked Russia’s
present actions and ambitions with Africa’s past experience and
argued that the situation in Ukraine “echoes our history; Kenya
and almost every African country was birthed by the ending of
empire.” p
China’s role is not that different. Its actions in acquiring
markets and influence in Africa and elsewhere, and in
encouraging and controlling the debt of the developing
countries it claims to be aiding, is merely a XXI century version
of XIX century colonialism. The great “Silk Road” project, One
Belt One Road, is not just an economic development plan but
an ambitious geopolitical program too.l So Africa is influenced by its colonial past, by the memory
of Soviet support for its liberation movements, by a pandemic
during which, at least early on, African nations were let to beg
vaccines and medicines from an uncaring Europe, and also by
Russian disinformation. The Non-Aligned Movement is Back? 129 All this helps explain why it proved so difficult for Europe
and the US to create a united coalition against Russian
aggression. But the real reason not only Africans but also
Indians and Indonesians have maintained a moral and political
distance from the conflict, refrained from condemning it, or
even supported it, is another: for the Global South, the war in
Ukraine is a European war.hf p
The rest of the world is of course affected by the global
economic consequences of the invasion; by the fact that Russian
and Ukrainian grain will not reach Egypt or dozens of other
developing countries (Russia and Ukraine previously accounted
for almost 30% of global grain exports);11 by uncontrolled rises
in oil and gas prices; and because the rest of the world would not
be immune to the radiation generated by a nuclear explosion or
possible escalation. 11 D. Resnick, “What does the war in Ukraine mean for Africa?”, Brookings, 25
February 2022. A European War However, from a military and geopolitical point of view,
the Russian-Ukrainian conflict is a European war, fought in a
distant and icy region of the Old Continent. Perhaps, in some
ways, the Global South may even be pleased that destructive
armed conflict has returned to Europe, the source of a thousand
years of wars, crusades and colonisation. y
Ignoring occasional nuclear jiters, the Cold War was, in a
certain sense, a period of “order” precisely because there was
no third way between the US and the USSR: Non-Alignment
failed to provide a valid alternative. The rest of the world
therefore had to support one side or the other, though it was
seldom a painless choice. p
The war was “cold” for Washington and Moscow, and though
Europe was divided by the Wall it remained substantially
at peace. In Latin America, Africa, the Middle East and the
Far East, however, conflicts, coups and revolutions – direct
consequences of the ideological and geopolitical clash between
the two superpowers – led to millions of deaths and either
prevented or delayed normal economic development. 130 Back to the Future Back to the Future In the long term, it may prove a mistake to have asked the
rest of the world to unconditionally join in condemning Russia
on every possible occasion, from the General Assembly in
New York’s Glass Palace in February 2022 to the Bali G20 in
November. Many see this approach as an extension of a Cold War
to which they have no wish to return. It is of little importance
that Beijing now also has a role to play, even stronger and
more influential than Moscow’s. Whether the clash is between
two or three, superpower ambitions extend well beyond their
geographical spheres of influence. The rest of the world will
inevitably be drawn into this kind of competition. y
p
“We must not divide the world into parts,” Indonesian
President Joko Widondo told the G20 in Bali.12 We therefore
need a new approach to international relations, to the meaning
of friendships and alliances, discussions and compromises. “We want to work and trade with everyone”,13 said Macky Sall,
President of Senegal and the African Union, in December,
before the Washington summit between the United States and
Africa. “We have suffered too much from the burden of history. 12 “Alla ricerca di un nuovo ordine”, Slow News, Il Sole 24 Ore, 18 November
2022.
13 D. Walsh, “Biden brings Africa’s leaders to U.S., hoping to make deals”, The
New York Times, 13 December 2022. 14 Z. Bar’el, “Arab countries fear fallout from Netanyahu’s ‘bombs’”, Haaretz, 2
January 2023.
15 E.R. Wald, “Why oil cuts by OPEC are warrated”, The New York Times, 25
October 2022. A European War That is why we do not want to be fertile ground for a new
Cold War.” To carry on trading and avoid becoming victims
of yet another clash between the Great Powers, we do not need
another useless Non-Aligned Movement. g
The “extraordinary” fact that a war is being fought in Europe
is a very dangerous precedent for us Europeans. To the rest
of the world, on the other hand, it signals a paradigm shift:
from now on, in a new international order in which everything
remains to be defined, decreed and established, conflicts and
alliances will be increasingly mobile, short-lived but intense. The Non-Aligned Movement is Back? 131 Arabia Felix At the Abu Dhabi Strategic Debate that ISPI atended last
November, Anwar Gargash, diplomatic advisor to Sheikh
Mohammed bin Zayed, President of the UAE, explained
how the new order was unfolding in the Gulf: “For us,
our relationship with the United States is crucial: it is the
cornerstone of our international relations and security. But we
trade with everyone. We live in a multipolar world and it is
not in our interest to take sides with any one superpower”. The
UAE therefore “maintains diplomatic relations with Iran, has
renewed relations with Turkey and abandoned the Saudi-led
coalition in the Yemen civil war; the Emirates flirt with Russia
and China while seeing themselves as allies of America”.14 g
A macroscopic and probably more complex example of this
new approach is the clash between Joe Biden and Mohammed
bin Salman, known as MbS, crown prince but de facto ruler
of Saudi Arabia. The US President requested an increase
in oil production to lower the price of crude: the call was
precipitated by the war in Ukraine and intended to counter
Putin’s weaponisation of energy. But along with the Russians,
MbS and OPEC actually cut production by one million barrels
a day in an attempt to keep the market up or at least stabilise
it. Apart from the rebuff to Joe Biden, purposefully sought by
MbS, the Saudis were not wrong: all economic indicators point
to 2023 being a year of global recession. The last time around,
in 2008, the price of a barrel fell from $100 to $40 and as low
as $32 in only three months.15 y
Last October, OPEC were already producing 3.6 million
barrels a day under the quota of 42.2 mbd set by the oil cartel. In previous years, Saudi Arabia would never have gone against
the wishes of the President of the United States, the guarantor 132 Back to the Future Back to the Future of Riyadh’s security and that of the other Arab nations in the
highly sensitive Gulf. But the Saudis, Bahrainis and Emirates
now know they can obtain the weapons they need for regional
security from the Americans while still pursuing their energy
and trade interests with the Russians. And let us not forget Xi Jinping’s triumphant visit to Riyadh
in December 2022. “The Arab states recognise that the United
States remains an indispensable ally in the field of military
security. Arabia Felix At the same time, they hope that relations will help the
development and stability of their countries and provide them
with more effective means of putting pressure on the United
States”.16 16 Y. Guzansky and T. Gering, “Xi of Arabia: Enjoing the Favor of the King”,
Institute for National Security Studies (Inss), Tel Aviv, n. 1671, 18 December
2022. 17 “Modi tells Russia president ‘today’s era is not era of war’”, Financial Times,
17/18 September 2022. 16 Y. Guzansky and T. Gering, “Xi of Arabia: Enjoing the Favor of the King”,
Institute for National Security Studies (Inss), Tel Aviv, n. 1671, 18 December
2022.
17 “Modi tells Russia president ‘today’s era is not era of war’”, Financial Times,
17/18 September 2022. Indian Exceptionalism The most successful proponent of geopolitics on demand is
India, a nation which has many friends, a few enemies, and no
true allies. India abstained in the UN vote on Ukraine. Then,
on meeting Vladimir Putin at the summit of the Shanghai
Cooperation Organization in Samarkand, Narendra Modi
openly told the Russian president “this is not the era for war:
we have spoken many times on this subject”.17 j
But India is a key customer for Russian energy. Before the
war in Ukraine, India imported only a few barrels of Russian
oil: by August this had grown to 765,000 a day. India is also
allied with the United States, Japan, and Australia in an attempt
to contain Chinese ambitions, especially in the Himalayas. At
the same time, it is also a partner in profitable bilateral trade
with China. Last August, a small contingent of Indian troops
took part in the Vostok military exercises in Siberia along with The Non-Aligned Movement is Back? 133 Russia and China; in October, the Indian army was doing the
same with the Americans on the high peaks of the Himalayas,
on the border with China. Russia and China; in October, the Indian army was doing the
same with the Americans on the high peaks of the Himalayas,
on the border with China.fi Although Xi Jinping officially returned to Marxism-
Leninism in the last congress of the CCP, ideologies are no
longer scrupulously respected as they were during the Cold
War: Though with different nuances, the market is universally
freer even if defined as “socialist”. The impassable barriers that
once prevented geopolitical movement have disappeared.h g
“The old order is disintegrating and a new struggle is about
to begin,” says Shivshankar Menon, national security advisor
to former Indian prime minister Manmohan Singh from 2010
to 2014. “The advantage is on the side of those states that
understand the balance of power and have a clear view of a
future cooperative order that serves the common good” – not
that of a single superpower.18 g
p p
In this early part of the XXI century, geopolitics have thus
become more democratic. It is not yet certain, of course, that
super-multipolarism – the assertion of national and regional
interests – is more secure than a system governed by two or
three hegemonic powers. 18 S. Menon, “Nobody Wants the Current World Order”, Foreign Affairs, 3 August
2022. Indian Exceptionalism Until a new order is established,
similar to that imposed by the Peace of Westphalia in 1648
or the Helsinki Conference on Security and Cooperation in
Europe in 1975, permanent instability remains a risk. Armando Sanguini The countries that make up the MENA region (Middle East and
North Africa) are a patchwork, and lumping them all together
under a single heading risks overlooking their respective
peculiarities and internal dynamics, as well as the extent of the
external, regional and international influences that interweave
between them. Russia’s invasion of Ukraine is a prominent example of
this. As well as taking up most of the political bandwidth of
Europe and the West, it has seriously jeopardised the supply of
cereals of which the area is the world’s largest importer. At the
same time, it has given an additional boost to the oil- and gas-
producing countries, while also stoking internal tensions in a
region already under strain.h The Maghreb has seen no progress except in the sharing of
problems that affected the area in 2022, mainly in terms of
security, lack of integration and exposure to the presence or
influence of regional and international powers, including
Russia, China, Turkey, the Gulf monarchies and, to a decreasing
extent, the United States. Morocco has seen promising signs in the dynamics of its
traditional sectors, following the severe challenges of the
previous two years (Covid-19 and drought), thanks in part
to the initiatives taken by the governing coalition led by Aziz
Akhannouch. 138 Back to the Future Back to the Future Algeria has become a prominent partner for Italy due to
the important bilateral visits that have taken place – including
the Italian Prime Minister’s visit to Algiers and the Algerian
President’s visit to Rome – in the wake of the visit of Italy’s
President of the Republic, Sergio Mattarella, in 2021, and the
signing of partnership agreements in a vast range of areas of
mutual interest. h The authoritarian tendency that has been steadily growing
in Tunisia since the election of Kais Saied as the country’s
president, has continued to raise concerns. Tunisia was a flag-
bearer for democratic values and human rights at the time of the
“Jasmine Revolution” (2011), but there are now well-founded
doubts as to whether the parliamentary elections held there at
the end of the year will yield any benefits. y
y
yi
The ongoing conflicts in Libya, caused in part by the
opposing pressures exerted by the aforementioned regional and
international powers, have been a further source of despondency. Armando Sanguini The area to the east of the Maghreb (Mashrek) has been no
less variegated, and has also been exposed to numerous critical
factors influenced by external interference, including of a
military nature. y
y
yi
The ongoing conflicts in Libya, caused in part by the
opposing pressures exerted by the aforementioned regional and
international powers, have been a further source of despondency. The area to the east of the Maghreb (Mashrek) has been no
less variegated and has also been exposed to numerous critical i
The ongoing conflicts in Libya, caused in part by the
opposing pressures exerted by the aforementioned regional and
international powers, have been a further source of despondency. p
p
y
The area to the east of the Maghreb (Mashrek) has been no
less variegated, and has also been exposed to numerous critical
factors influenced by external interference, including of a
military nature. Egypt faced the major challenge of hosting COP27, the
United Nations Climate Change Conference, in Sharm el-
Sheikh from 6 to 18 November. The event saw the participation
of over 90 heads of state, but also the incarceration of 118
human rights activists, which clearly did nothing to disperse the
dark clouds hanging over the authoritarian regime of President
al-Sisi. It will be interesting to follow COP28, to be held in the
United Arab Emirates in November 2023. Like most of the
other countries in the MENA region, UAE is showing an
increasing commitment to action on climate change.hi The most significant event in Israel was the government
crisis (in June) and the return of Benjamin Netanyahu to the
leadership of a government expected to be made up of a right-
wing/ultra-orthodox coalition that holds little promise for the The Never-Ending MENA Region Crises 139 prospect of any constructive shift on the Palestinian question. Palestine, moreover, displayed numerous signs of proximity
to Moscow, and Mahmoud Abbas, the Palestinian President,
publicly announced that he was “happy and satisfied” with
Russia’s support (Astana 13 October). There were also significant changes in Lebanon, with the
withdrawal from politics of the former Prime Minister, Saad
Al Hariri, in early 2022; the formation of a government led by
Najib Mikati, the US-brokered agreement with Israel on the
southern maritime border, the rapprochement between Beirut
and Riyadh and the other Gulf monarchies, and the wait for
the election of a new president. Armando Sanguini Another magnet for external military and other forces, Syria
is suffering from a conflict between Turkey and Islamists in the
north and a variable-geometry arrangement of Russian and
Iranian “protection” in the rest of the country under the relative
control of Bashar al-Assad’s government, while the US still has
a presence in the central-eastern area (alongside the Kurds) and
Israel is continuing to strike at Iranian forces when the need or
opportunity arises. pp
y
Now that the Iraqi parliament has overcome its political
deadlock and formed a government (Shia bloc), the country’s
Prime Minister, Mohammad Shia al-Sudani, faces serious
challenges not only of a political and institutional nature, but
also in terms of combating corruption, reforming the security
services and leading the nation out of its economic and social
crisis. And this must be done against a continuing backdrop of
uncertainty over what action Muqtada al-Sadr might take and
how the anti-Kurdish offensive being waged by Iran and Turkey
might evolve, in the broader context of Iran’s rivalry with Saudi
Arabia. The FIFA World Cup gave the small but internationally
confident Kingdom of Qatar – which had already been
designated a “major non-NATO Ally” of the United States – a
unique opportunity to raise its profile, which was tarnished,
however, in the closing days of the tournament, by the scandal 140 Back to the Future of the huge bribes alleged to have been paid to officials of the
European Parliament.h The year was a positive one for Saudi Arabia, whose image
was burnished by visits first from the US President, Joe Biden,
and then from the Chinese President, Xi Jinping at the end of
the year, during which the kingdom was able to play the role
of first among equals among the Gulf monarchies. The country
also benefited from the rise in oil prices on the back of a surge
in demand caused by Russia’s invasion of Ukraine. Algeria Two state visits within the space of six months (Sergio Mattarella
to Algiers in November 2021 and Tebboune in May 2022); a
visit by the then Foreign Minister Luigi Di Maio with the CEO
of ENI, Claudio Descalzi, in March; an Intergovernmental
Summit in July (Algiers) and a meeting of the Joint Technical
Committee pursuant to Art. 7 of the Memorandum of
Understanding at the end of the year, also in Algiers: this
combination of events clearly illustrates the breadth and hands-
on nature of Italo-Algerian relations. g
There can be no doubt that Russia’s invasion of Ukraine
and the consequent need to ensure a suitably diversified
supply of energy played an important part in strengthening
these relations. The fact that they bore fruit so promptly and
extensively, however, remains largely attributable to the decades-
long cooperation between the two countries, which has given
rise to the Transmed-Enrico Mattei gas pipeline, followed by
the discovery, in March, of a major combined oil and gas field
in the Berkine North basin in the Algerian desert by the ENI-
Sonatrach consortium. Italy and Algeria have gradually established and implemented
a comprehensive cooperation strategy, covering manufacturing,
culture, infrastructure, transport, fishing and sustainable
mobility, to name but a few. The Never-Ending MENA Region Crises 141 Attempts have also been made to resume the search for a
political solution to the Western Sahara question, without
delay, by fully supporting for the work of Staffan De Mistura,
the personal envoy of the Secretary-General of the United
Nations, who has received recognition for his efforts to achieve
a fair, lasting and mutually acceptable solution, in accordance
with the aims and principles of the United Nations Charter. Representatives of Algeria and Italy also welcomed the renewal
of the mandate for the MINURSO mission launched in 1991, as
part of the conflict resolution programme, which began with a
ceasefire in the conflict between Morocco and the Polisario Front
(and the Sahrawi Arab Democratic Republic) over the disputed
territory of Western Sahara (formerly Spanish Sahara). This is
one of Africa’s most enduring crises and the aim of the mission
is to declare the result of a referendum on self-determination,
in which the Sahrawi of Western Sahara will choose either
integration with Morocco or independence. Algeria Hundreds of
thousands of Sahrawi refugees have been living in refugee camps
on Algerian soil for decades, cut off by the world’s longest and
most densely mined wall, as they wait to learn their fate. y
y
Unfortunately, the clashes that broke out again in November
2021 continued throughout 2022, thus reviving the tension
between Morocco and the Algerian-backed Polisario Front and
dispelling hopes of any positive outcomes in the foreseeable future. Saudi Arabia The long shadow of the assassination of Jamal Khashoggi has
not yet lifted and the kingdom still attracts criticism for its
human rights record, with particular reference to the status
of women and migrant workers, and its still embryonic level
of democracy. But against the backdrop of Russia’s invasion
of Ukraine, on which Riyadh has struck a delicate balance
between meeting the expectations of Kiev and safeguarding
relations within OPEC+, signs of politically and economically
significant dynamics remained visible throughout the year. 142 Back to the Future Back to the Future Bearing in mind that export volumes rose by 33% at the
beginning of the year compared with the same month of the
previous year, mainly on the back of crude oil and petroleum
products, the end of the year saw a significant increase (+9.7%)
in the number of small and medium enterprises, suggesting
a degree of diversification of the country’s economy, albeit
incipient.f In the political arena, the year kicked off with a major shift
in relations between Turkey and Saudi Arabia, following the
chill that fell when Recep Tayyip Erdogan publicly accused the
Crown Prince of ordering the murder of Jamal Kashoggi. h g
gg
The following month, it was the turn of the President of
the United States, Joe Biden, to travel to Saudi Arabia and be
received by the Crown Prince, in a clear sign of Biden’s (resigned)
willingness to drop the term “pariah state” – which he had used
to describe Saudi Arabia during the election campaign – and
revive the historic bilateral relationship, partly with a view
to weakening the oil axis with Moscow. This hope remained
unfulfilled, at least with regard to OPEC+ policy. i
g
p
y
Having banked this substantial achievement, Riyadh
continued to pursue its policy of forging closer relations with the
Arab countries in the area, while also fostering discreet relations
with Israel, under the impetus of the Abraham Accords. i p
No less significant was the visit to Saudi Arabia of Chinese
President Xi Jinping, during which representatives of the
MENA countries gathered for an innovative Arab-Chinese
summit. The summit was designed by Riyadh as a means of
strengthening its claim on the role of a kind of regional first
among equals in relations with Beijing. Saudi Arabia It is safe to say, however, that the United States remains
the partner of choice for Riyadh, as it is for the Emirates and
other Gulf monarchies, which depend on it for their security,
but Saudi Arabia has long been engaged in a foreign policy
designed to bring about the country’s national and ultimately
international economic and political transformation. The Never-Ending MENA Region Crises 143 Egypt Egypt’s economy showed some signs of recovery following
the slowdown caused by the pandemic and the repercussions
of Russia’s invasion of Ukraine (high commodity prices
and inflation). This was mainly due to a gradual upturn in
tourism and construction, an increase in private investment
and improvements in gas extraction processes in the Eastern
Mediterranean, with particular reference to the Zohr and Nour
fields and the reopening of the Idku and Damietta LNG plants
after an 8-year hiatus. y
The country’s social situation, however, is less promising, and
suffers from widespread inequality, consequent discontent and
an authoritarianism that often spills over into harsh repression
of internal dissent. Internationally, Egypt has continued its efforts to strengthen
its image as a strategic linchpin in the area, which declined
significantly in the years following the fall of Hosni Mubarak
(Arab Spring). At a regional level, while Egypt is in good company in terms
of its poor, not to say non-existent, human rights record –
we refer in particular, but not only, to Iran, Turkey and the
Gulf monarchies – it can leverage the support it receives from
those countries in terms of investments and deposits (Saudi
Arabia and the United Arab Emirates in particular), as well
from loans from the International Monetary Fund, the African
Development Bank and the World Bank. It is also worth noting the agreement signed on 15 June with
Israel and the European Union on the export of natural gas to
Europe in order to reduce the latter’s dependence on Russian
gas, and various interventions as a mediator between Israel and
Hamas to facilitate agreement on the Gaza Strip and rebuild its
own international standing 144 Back to the Future Iraq Following the parliamentary elections, it took almost a year
to overcome the difficulties involved in appointing a new
President of Iraq. The appointment was finally made on 17
October, and went to the Kurdish engineer Abdul Latif Rashid,
who had served as Minister for Water Resources from 2003 to
2010. The Patriotic Union of Kurdistan (PUK) and the other
major Kurdish party, the Kurdistan Democratic Party (KDP)
were involved in the appointment. pp
A month later, the problem of forming a new government
was solved. Egypt Mohammed Shia al-Sudani, a former minister in
the cabinet of Nouri al-Maliki, leader of the Coordination
Framework (a pro-Iranian Shia bloc), was appointed as Prime
Minister thanks to an alliance between the Coordination
Framework and the majority of Kurdish and Sunni MPs,
many of whom are former allies of Muqtada al-Sadr who have
been released from their coalition obligations following the
withdrawal of the parliament’s Sadrists (in the Iraqi institutional
system, the presidency is granted to a Kurdish candidate, while
the head of government is always a Shia Muslim). g
y
While the ending of the deadlock that lasted for most of
2022 is a positive, the new government nonetheless faces
a series of major challenges, first and foremost its relations
with Iran, from which the Prime Minister is by no means
independent, followed by combating corruption, reforming
the security services and leading the nation out of its economic
and social crisis. Furthermore, the appointment of Al-Sudani
was so hotly contested that when the coalition proposed him as
a potential candidate to head the government, hundreds of Al
Sadr’s supporters stormed the Iraqi parliament and occupied it. Muqtada al-Sadr is another major unknown quantity. As politically significant as he is controversial, he is a direct
descendent of Mohammed, and belongs to one of the most
influential Shia dynasties in the entire Middle East. Long
branded as a radical, populist leader, and former head of The Never-Ending MENA Region Crises 145 anti-American militias in post-Saddam Iraq, he has increasingly
distanced himself from neighbouring Iran over the years. The question is what role does he intend to play, given that
his announced withdrawal from politics was accompanied by
several serious clashes with law enforcement agents and pro-
Iranian factions. He enjoys wide support, as borne out by his
clear victory in the October 2021 consultations (where he won
73 seats out of a total of 329). Another unknown quantity at a regional level is the anti-
Kurdish offensive being waged from one side by Iran and from
the other by Turkey, which shares a border of about a thousand
kilometres and continues to regard the Kurdish armed forces as
supporters of the Kurdistan Workers’ Party (PKK), probably with
a view to driving them out of their mountain strongholds and
handing over control to the Peshmerga of the Kurdish regional
government, which has excellent relations with Ankara. Egypt And this
is partly motivated by the forthcoming elections in 2023. Iran Although passed by a measured majority (29 votes in favour,
8 against and 16 abstentions), the United Nations Economic
and Social Council’s decision, on 14 December, to remove
Iran from the Commission on the Status of Women, is a
political and moral endorsement of the sanctions adopted by
the US, Canada and the European Union, against the Tehran
government’s brutal reaction to the wave of protests triggered in
September (and still ongoing) by the killing of Mahsa Amini.h Although passed by a measured majority (29 votes in favour,
8 against and 16 abstentions), the United Nations Economic
and Social Council’s decision, on 14 December, to remove
Iran from the Commission on the Status of Women, is a
political and moral endorsement of the sanctions adopted by
the US, Canada and the European Union, against the Tehran
government’s brutal reaction to the wave of protests triggered in
September (and still ongoing) by the killing of Mahsa Amini.h p
g
g
g
This endorsement, furthermore, cannot be entirely separated
from the Ayatollahs’ worrying determination to carry on
enriching uranium and their refusal to consider any conditions
that might lead to the US rejoining the Iranian nuclear
agreement. It is worth remembering that after 16 months of arduous
negotiations, Josep Borrell, the EU High Representative for
Foreign Affairs, has presented a “definitive” compromise text 146 Back to the Future (in its intentions) for both sides. But negotiations have ground
to a halt despite the fact that under the proposed agreement,
Iran would put a stop to further uranium enrichment, which
is already over 60% (the JCPOA establishes a limit of 3.67%),
and the US would commit to lifting the sanctions. This would
have enabled Tehran to return to international markets.h The United Kingdom, France and Germany released a joint
statement pointing out that, in their opinion, Iran had decided
not to take this decisive diplomatic opportunity, but to carry
on stepping up its nuclear programme far beyond what could
be justified on civil grounds. Iran ji
g
But perhaps the most worrying news is the announcement
by the Head of the Islamic Revolutionary Guard Corps’ Air
Force that Tehran is in possession of a hypersonic ballistic
missile capable of flying both within and beyond the Earth’s
atmosphere and “reaching Tel Aviv in less than 4 minutes.” h g
This new Iranian threat appears to be part and parcel of its
essential unwillingness to soften the overall regional policy
that Iran is continuing to implement, directly and indirectly,
through the “Axis of Resistance” strategy designed to legitimise
its intervention in other countries in the region, including
Lebanon, Syria, Iraq and Yemen, as well as in the intra-
Palestinian conflict between Al-Fatah and Hamas.h l
The shadows over Iran have also grown longer and darker
in connection with Tehran’s increasingly clear involvement
with Russia, in the latter’s war against Ukraine, not only with
drones, but also with surface-to-air missiles. h The year drew to a close on as aggressive a note as it started,
but in different terms, namely with the launch of a series of
executions of young people found guilty of taking part in the
wave of protests triggered by the aforementioned killing of
Mahsa Amini. This wave is showing no signs of diminishing
and could have unprecedented outcomes. The Never-Ending MENA Region Crises 147 Lebanon Although expected, the former Prime Minister Saad Al Hariri’s
announcement of his withdrawal from politics in early 2022
nonetheless marked a political milestone. Rumours that the wealthy Najib Mikati might also leave the
stage, however, were soon dispelled. Following the elections in
May, President Michel Aoun appointed Mikati (for the fifth
time) to form a government, which won a vote of confidence
from parliament in September with a membership that reflects
Lebanon’s political and religious make-up (11 Christians, 10
Muslims and 2 Druze). h The Mikati government faces the enormous challenge of
rebuilding acceptable economic and social conditions in the
country, first by implementing the reforms required by the
International Monetary Fund, and then by responding to the
discontent of a population that has been showing increasing
signs of protest. Meanwhile, the presidential term of Aoun Michel, a Maronite
Christian, who took office in 2016, expired on 31 October,
with no designated successor in place, thereby adding to the
already considerable political and institutional uncertainty
facing the country. g
Against this backdrop, exacerbated by severe outbreaks of
cholera, it is unsurprising that the 25th anniversary of Lebanon’s
independence was celebrated with little enthusiasm. Libya The elections due to be held on 24 December 2021 appeared to
be within reach and looked set to mark a decisive turning point in
Libya’s troubled dynamics, but this was not to be, despite the fact
that some 3 million Libyans were registered on the electoral roll. fi Instead, the elections were officially postponed, the electoral
committees were dissolved and preparations for the vote were
suspended, in the subsequently unfulfilled hope that they could 148 Back to the Future be held the following month, as proposed by the Libyan High
National Elections Commission (HNEC). In the face of this failure, Aguila Saleh (President of the
Tobruk-based House of Representatives) convened his deputies
to replace the Dbeibah government with a technical executive
tasked with carrying the country through to the elections. f Stephanie Williams (UN) took a different view, however,
maintaining that it was worth striving to put in place a
democratically elected government by the end of June. All this
took place against a backdrop of deep internal divisions, fuelled
by the presence of numerous armed groups and foreign troops in
Libya, all of whom are firmly committed to standing their ground. h yi
y
g
g
The situation was certainly not helped by the appointment
of Fathi Bashagha, the former Minister of the Interior, by the
Tobruk parliament, whose term of office expired some time ago. This appointment was rejected by the Prime Minister, Abdul
Hamid Dbeibah, in his capacity as head of the UN-recognised
Government of National Accord. The country thus found itself split once again between two
parallel administrations in conflict with each other, against a
backdrop of ethnic, tribal and ideological divisions carved
deeper by the various factions’ foreign sponsors p
y
g
p
Turkey, meanwhile, is not concealing its support for western
Libya. Under their latest Memorandum of Understanding
(MoU) signed in early October, Ankara and Tripoli have once
again emphasised their intention to step up their cooperation,
especially in the energy sector. i It is significant, however, that on the sidelines of the Security
Working Group (SWG) held in Tunis on 8 December, the US
Ambassador to Libya made it clear, after many years, that the
status quo is unsustainable and that there is an urgent need
for practical action to put in place a democratically elected
government that represents all Libyans. Libya This urgency is clearly
at odds with the Libyan Premier Dbeibah’s call to lift the
sanctions imposed by the UN Security Council, the European
Union, the US State Department and the UK Foreign Office The Never-Ending MENA Region Crises 149 on Abd al Rahman al-Milad (Bija), who is accused of people
trafficking and smuggling oil, drugs and weapons. Morocco 2022 turned out to be a fairly good year for Morocco’s image on
the world stage, partly because of the attention it attracted by
becoming the first Muslim Arab nation to reach the semi-finals
of the FIFA World Cup. King Mohammed VI, meanwhile, continued to open up
his country’s international horizon with some success, starting,
of course, with sub-Saharan Africa, by making full use of the
space afforded him 5 years ago when Morocco was re-admitted
to the African Union. But together with the Prime Minister,
Aziz Akhannouch, the sovereign has also made a gradual move
towards closer relations with the Gulf monarchies and has
welcomed relations with China. Morocco’s partnership with the European Union remains in
place, of course, but with a few obstacles to trade agreements,
which the General Court of the European Union ruled illegal
in September 2021 due to the Sahrawi issue, but which the
European Council signed nonetheless. h p
g
Then, right at the end of the year, Morocco was involved
in the “Qatargate” scandal in the European Parliament, again
in connection with the serious disagreement that continues to
divide the country from Algeria. This disagreement was further
fuelled by Rabat’s decision to sign the Abraham Accords, partly
in return for US recognition of its claims on Western Sahara. On the domestic front, it is worth noting that, following the
shock of the pandemic and the drought that caused a collapse
in supply and demand for agricultural produce, Morocco
is showing signs of promise in agriculture, manufacturing,
tourism and foreign investment. Furthermore, the government has changed, and is now made
up of a coalition of three parties – RNI (liberal), PAM (centre-
left) and Istiqlal (conservative) – which, between them, hold a 150 Back to the Future substantial majority (270 seats out of 395). And it is to be hoped
that the internal dissent still being caused by the precarious social
conditions facing a large proportion of the population, and the
lack of tolerance towards Aziz Akhannouch’s government, will
gradually subside thanks to the Prime Minister’s commitment
to creating a million jobs, extending health insurance to all
Moroccans, increasing teachers’ salaries and guaranteeing
pensions for seniors. Qatar Hosting the FIFA World Cup gave Qatar an opportunity prove
its credentials as a fully-fledged citizen of the world, within
the limits imposed by the fact that it still does not guarantee
respect for human rights or have a democratic institutional
system. And to a large extent, it achieved this goal, at least until
the passion of the football and the grandeur of the logistics
were overshadowed by the “Qatargate” scandal that hit the
European Parliament. We will have to wait for the outcome of
the investigations, of course, but the pending process of justice
has already taken its toll on the expectations of this small but
immensely rich monarchy, which aspires to being a key regional
and international player and is proud to have been the first
Middle Eastern country to host this prestigious tournament. y
p
g
Qatar had recently overcome the fall-out from an
acrimonious disagreement that had relegated it to the sidelines
of the Gulf Cooperation Council because of its support for the
Muslim Brotherhood, which was welcomed by Turkey, but ran
completely counter to the political and financial line pursued
by Saudi Arabia and other Gulf monarchies. hl y
This conflicting position, however, had not threatened the
continuing presence of the large air base hosting the UK’s Royal
Air Force and the United States Air Force, which is the largest
military base in the Middle East. The base also proved to be vitally
important in the latest developments in the understanding with
the Taliban regime regarding the evacuation from Afghanistan. The Never-Ending MENA Region Crises 151 Syria Ten years on from its “own” Arab Spring, Syria is still a
kaleidoscope of military forces of various types, with differing
domestic, regional and international interests. Ten years on from its “own” Arab Spring, Syria is still a
kaleidoscope of military forces of various types, with differing
domestic, regional and international interests. g
Yes, Bashar Al Assad has managed to regain control of much
of the country, but he finds himself sharing it with the Russian
and Iranian allies who enabled him to do so and who are still
his creditors with their own Mediterranean interests. Ranged
against these are the Turkish military forces in the north-west of
the country, with militias that enjoy close relations with them,
as in the north-east of Syria, from which they are striving to
drive out the Kurds who live there because they are believed to
be allies of the PKK group. This is being done at Syria’s expense,
of course, although the extent of Moscow’s and Washington’s
apparent unwillingness to allow Turkey to create such a
“Turkish” buffer on Syrian territory remains unclear. f
y
y
Let us not forget that the Kurds were vital allies in the West’s
struggle, led by the US, against Islamic State, which kicked off
2022 by displaying a remarkable ability to resume its terrorist
activities in both Iraq and Syria, where, backed by some 10,000
fighters (UN estimate), it attacked the “Syrian Alcatraz” in
January 2022 and released over 2,500 prisoners held there. Other anti-Assad forces remain in the south and south-west of
the country. Another factor not to be underestimated is Israel’s
“preventive” action against the Iranian presence (personnel
and installations) close to their northern border, which are
estimated to number some 15,000 soldiers and Pasdaran, plus
10,000 Lebanese Hezbollah fighters. i
Against this far-from-reassuring backdrop, the proposal made by
the Turkish Foreign Minister, Mevlut Cavusoglu, on 11 August at
the 13th Ambassadors’ Conference in Ankara, for a “reconciliation”
between the Syrian regime and the opposition was decidedly
tone-deaf. Furthermore, he had already made the proposal several
months earlier to his Syrian counterpart Faisal Mekdad on the
sidelines of a summit of the Non-Aligned Movement. Syria 152 Back to the Future Back to the Future “We must bring the opposition and the regime together for
reconciliation, otherwise there will be no permanent peace”
capable of preventing the break-up of Syria, he pointed out at
the time.h The Syrians responded immediately. To a soundtrack of cries
of “No reconciliation”, they demonstrated in their thousands
in the various areas of Turkish influence in the north and
around Idlib, controlled by Hayat Tahrir al-Sham (HTS, the
group believed to have close ties to Al-Qaeda in Syria) and
they branded the proposal a violation of the political process
approved by UN resolutions, particularly Resolution 2254 of
2015. Tunisia Tunisia has seen a year of rising political and social tensions
caused by the economic and financial difficulties facing the
country and reactions to the measures that President Saied has
been taking since July 2021 to boost his own personal power. g
p
p
On 1 January, the President announced an online national
public consultation in preparation for the constitutional and
electoral reform to be submitted to a popular referendum on 25
July, and then to legislative elections on 17 December. g
In February, the Supreme Judicial Council (CSM) was
dissolved and a provisional CSM was set up in its place, which,
among other things, gave Saied the power to veto the promotion
and appointment of judges. h This was followed by the dissolution of parliament (which
had been suspended since July 2021), on grounds of the need
to “preserve the state and its institutions”. h The new constitutional charter, approved with 94% of the
votes from a low turnout (30.5%), entered into force on 18
August, turning Tunisia into a hyper-presidential republic: the
Head of State appoints and can dismiss government ministers
and the key figures in the justice system, as well as proposing
laws, ratifying international treaties and dissolving parliament. The Never-Ending MENA Region Crises 153 He is also Supreme Commander of the armed forces. A
bicameral system has been introduced: in addition to the
Assembly of the People’s Representatives, there is now also an
Upper House, known as the National Council of Regions and
Provinces. Lastly, the new Charter removes the controversial
reference to Islam as the state religion and enrols Tunisia in the
universal Islamic community (Ummah). y
Even the Electoral Commission has been changed: its nine
members have fallen to seven, three of whom are selected directly
by Saïed, with the remainder being appointed by the CSM,
controlled by the Tunisian President, who has also announced
the launch of a national dialogue on the reforms to be put to
a referendum, which included the four national organisations
that won the Nobel Peace Prize in 2015, but not the opposition
parties (including Ennahda), which has organised itself into a
significant “National Salvation Front”. Tunisia gi
It is no wonder that the country’s traditional western partners,
especially the United States and the EU, as well as the Venice
Commission (Council of Europe), have expressed concern at the
political and institutional action taken by President Saïed and
have repeatedly called for a return to democratic governance. Turkey, under President Erdogan, has echoed these criticisms,
while the United Arab Emirates, Egypt and Saudi Arabia have
continued to support President Saïed and offer loan guarantees
and investments. In view of Tunisia’s existing socio-economic and financial
difficulties, however, these guarantees have done little to make
the country less vulnerable to the repercussions of Russia’s war
on Ukraine, first and foremost in terms of energy and food
prices. As for the legislative elections of 17 December, it is worth
noting the European Parliament’s decision “not to observe them
or comment on them”. But it will be difficult not to comment
on a turnout of less than 12% of registered voters, which marks
a clear defeat for Saied, whose resignation has been widely
called for. 154 Back to the Future Turkey The level of confidence with which Turkey’s President Erdogan
pursued his foreign policy in 2022 was proportional to his
ambition to win the presidential election in June 2023, an
outcome considered relatively uncertain because of the country’s
precarious economic conditions and growing authoritarianism,
the latest manifestation of which was the adoption of the
“disinformation” law. One of the most notable examples of this is the tricky
balancing act he is pulling off in his relations with Moscow. On
the one hand, he has condemned Russia’s invasion of Ukraine,
including in the United Nations General Assembly, while on the
other, he has chosen not to subscribe to the economic sanctions
imposed by the United States and the European countries, so
as not to compromise the strong economic and energy ties that
have bound Ankara to Russia for years. Furthermore, he has
been presenting himself as a mediator in the conflict triggered
by Moscow in February, partly in the wake of his undoubted
success in facilitating the export of Ukrainian cereals, first
in July and then again in November. On top of this, he has
purchased a Russian S-400 missile defence system, at the cost
of being ejected from the F-35 development programme, while
still remaining a member of NATO. Indeed, Turkey has even
managed to make Sweden and Finland’s accession to NATO
conditional upon their extradition of a number of Kurdish
figures who have taken refuge there. i
It is also worth mentioning Turkey’s attempted rapprochement
with Saudi Arabia and with Crown Prince Mohammed bin
Salman in particular (this succeeded only formally), whom
Erdogan had publicly accused of ordering the murder of the
journalist Jamal Kashoggi in Istanbul in 2018.h Things went better with Israel and the United Arab Emirates. A decade of tension with Israel has been overcome in favour
of restoring full diplomatic relations and re-establishing
cooperation between the two regional powers. Turkey has The Never-Ending MENA Region Crises 155 reached a full reconciliation with the United Arab Emirates,
thanks to a process initiated in late 2021 and endorsed by
Erdoğan’s visit to Abu Dhabi in mid-February. Turkey h This situation contrasts with the initiative launched in 2016
and resumed in November under the name Operation Claw-
Sword, against Kurdish troops (who are accused being a military
wing of the PKK) stationed on Syrian and Iraqi soil, allegedly in
retaliation for the attack in Istanbul on 3 November, in which
the accused, however, deny all involvement. The objective is still
to create a 432 km long, 30 km deep “belt” free from Kurdish
fighters, to which a large proportion of Syria’s refugees could
realistically be transferred. y
Two pieces of good news emerged with regard to bilateral
relations between Turkey and Italy. Firstly, Dalila Procopio,
a 25-year-old Italian woman arrested in Istanbul at an
unauthorised feminist demonstration, was released; and
secondly the two countries’ Ministers of Foreign Affairs,
Mevlut Cavusoglu and Antonio Tajani, held a meeting on the
sidelines of MED22 in Rome (ISPI-MAECI), which yielded
the common objective of holding a summit between the two
countries in 2023. Yemen Yemen’s devastating, seven-year civil war has now also reached
Abu Dhabi. It had already prompted Houthi “rebels” to
attack Saudi Arabia, which leads a coalition that intervened
at the request and in support of the internationally recognised
President Hadi. But in 2022, for the first time, the conflict
extended to the capital of the United Arab Emirates, 1,200 km
away, with drones and possibly missiles deployed and claimed
by Yemen. y
Such a start to the year clearly did not encourage hopes of a
truce or future peace between the two warring factions, which
are partly a front for a more covert conflict between Iran and
Saudi Arabia. And yet a truce was reached on 1 April, although it 156 Back to the Future was only provisional (two months, to accommodate Ramadan). It was then renewed for a further two months when it expired. h Thereafter, the Houthis refused to extend it again. h
It is worth noting that the Houthis did not open the road to
Taiz, despite the fact that this was one of the basic conditions for
starting the truce. And in the face of the renewed humanitarian
disaster, there was little substance behind the hopes of the Quint
member states (Saudi Arabia, UAE, Oman, United States and
United Kingdom) for a revival of political dialogue between
the parties and the renewal of mine-clearance efforts in Yemen. hfll pf
The country is also afflicted by other local conflicts, which
cast a heavy shadow over Yemen’s future prospects. According
to the country’s Foreign Minister, Ahmed bin Mubarak, who
spoke at Med Dialogues 2022 in Rome, the EU sees the conflict
in purely “humanitarian terms” and pays no attention to any of
its other aspects, including security and the economy. In his
view, the EU should intervene more assertively, by targeting the
rebels’ financial networks and condemning their violation of
human rights, starting with women’s rights. g
g
g
The minister also pointed out that “Iran did not start
interfering in Yemeni affairs with the outbreak of the conflict
and with the entry of the coalition led by Saudi Arabia. As
early as 1987, they started funding the Houthis. And then in
2012, when everyone was sitting at the negotiating table using
peaceful means, the Iranian government provided financial
assistance and weapons to the Shia group”. 1 Although this chapter derives from work carried out jointly by both authors,
Francesca Frassineti wrote the introduction and paragraph 1, and Giulia Sciorati
wrote paragraph 2 and the conclusion. Conclusion 2022 left an array of uncertainties and critical challenges
in its wake, which were clearly accentuated by the fall-out
from Russia’s war on Ukraine, despite the fact that the war
unexpectedly had certain undeniably useful consequences,
mainly for energy-producing countries. One of the pivotal points will be Iran, which is a leading
player in the dynamics of the Middle East. The country has The Never-Ending MENA Region Crises 157 been hit by a wave of protests, backed by women, which has
spread to multiple layers of the population and, despite lacking
any clear leadership, is putting the regime of the Ayatollahs
under severe strain. Any change in this leadership could bring
change to the regional policy embraced by Iran to date, towards
Israel, of course, but also towards Iran’s rival, Saudi Arabia. Meanwhile, Iran continues to find scope for influence and
intervention in countries ranging from Syria to Lebanon, Iraq
and Yemen. Another crucial factor will be the developments in government
policy that Netanyahu will want (and be able to) pursue with
his new government, especially in relation to the Palestinian
situation – marked in December by a general strike in the West
Bank called in response to the death in prison of Nasser Abu
Hamid, leader of the Al Aqsa Martyrs’ Brigade – but also with
regard to extending the Abraham Accords, which is likely to be
less promising than it was under the previous government. 2023 will mark the centenary of the foundation of the
modern Republic of Turkey (1923), which will coincide with
the year of a general election in which Recep Tayyip Erdoğan
aims to win a new mandate for his role as the political and
spiritual leader of the New Turkey and his de-Westernisation of
the country’s leadership. The prospect of the election is pushing
him towards increasing authoritarianism in the domestic arena,
even as the country’s socio-economic conditions deteriorate. y
As the first country in the Middle East and North Africa to
ratify the Paris Agreement and commit to reducing its carbon
emissions, the United Arab Emirates will host COP28, in
the hope of achieving more promising results than those that
emerged from COP27 in Sharm el-Sheikh. 11. The New Militarisation of East Asia Francesca Frassineti, Giulia Sciorati1 The Indo-Pacific region is exposed to constantly evolving security
dynamics, including growing threats to public health, such as
the Covid-19 pandemic, and increasingly extreme weather
events. New military commitments relating, for example,
to disaster relief and humanitarian aid operations require
improved capabilities in terms of power projection, mobility,
intelligence and inter-force collaboration. The proliferation of
weapons of mass destruction, territorial and maritime disputes
and demographic decline, however, are the main factors that
influence debates on military spending and the modernisation
of national defence and the armed forces. Vladimir Putin’s obsession with nuclear weapons in the context
of Russia’s attack on Ukraine, combined with the acceleration of
Chinese and North Korean nuclear programmes, has prompted
some governments to give more serious consideration to all the
options, in the event that today’s Ukraine becomes tomorrow’s
East Asia. In South Korea and Japan, the nuclear taboo has been
decisively broken in public debate, and the idea of procuring an
autonomous deterrent is no longer the subject of behind-the-
scenes conversations or the position of a handful of individual
politicians. While the Japanese remain broadly sceptical on the
issue, for obvious historical reasons, public opinion in South 160 Back to the Future Korea has long been the opposite. Over the past 15 years,
support for both the return of US tactical nuclear weapons
to South Korea, after the completion of their withdrawal in
December 1991, and the development of a military nuclear
programme has regularly garnered support of between 60%
and 75%.2 Ultimately, the decision to take the nuclear route depends on
historical and economic factors, domestic politics and attitudes
towards international status. At present, the barriers and
estimated costs that South Korea and Japan would face should
be enough to prevent any further horizontal proliferation in
the area. These alarm bells cannot be ignored, however, and
make it imperative to conduct an in-depth assessment of
the current defence alliances’ operating processes in order to
respond more effectively to a constantly changing kaleidoscope
of threats. Last December, Kurt Campbell, the US National
Security Council Coordinator for Indo-Pacific Affairs, said
“One of the enormous achievements in Asia for decades has
been the stability and reassuring quality of our extended
deterrence of our nuclear umbrella”. 2 Data collected in December 2021 by the Chicago Council on Global Affairs
and published in early 2022 show that 71% of South Koreans interviewed
believe that acquiring its own nuclear weapons would be useful for the country’s
national security. K. Friedhoff, T. Dalton, and L. Kim, “Thinking Nuclear: South
Korean Attitudes on Nuclear Weapons”, The Chicago Council on Global Affairs, 21
February 2022. 3 K. Campbell, “Fireside Chat”, Aspen Security Forum, Aspen Institute,
Washington DC, 8 December 2022. 2 Data collected in December 2021 by the Chicago Council on Global Affairs
and published in early 2022 show that 71% of South Koreans interviewed
believe that acquiring its own nuclear weapons would be useful for the country’s
national security. K. Friedhoff, T. Dalton, and L. Kim, “Thinking Nuclear: South
Korean Attitudes on Nuclear Weapons”, The Chicago Council on Global Affairs, 21
February 2022.
3 K. Campbell, “Fireside Chat”, Aspen Security Forum, Aspen Institute,
Washington DC, 8 December 2022. 4 V. Jackson, Rival Reputations: Coercion and Credibility in US-North Korea Relations,
Cambridge, Cambridge University Press, 2016. 11. The New Militarisation of East Asia He then added: “That
is being challenged now”.3 This statement reflects widespread
anxiety in Japanese and South Korean political circles about
the credibility of Washington’s security guarantees, in light of
the somewhat alarming signals coming from the US political
world, in which the perceived value of allies in relation to US
interests has become yet another bone of contention between
the opposing factions. The New Militarisation of East Asia 161 The Korean Peninsula, the Taiwan Strait and the South
China Sea are some of the main sources of tension in the
region. The concentration of military resources for deterrence
purposes in geographically limited spaces increases the
potential for escalations triggered both by technical errors and
misinterpretations of the other party’s intentions, as we have
come close to seeing several times on the Korean Peninsula
in recent months. After conducting its military exercises on a
reduced scale for four years, and in some cases merely running
tabletop simulations of them or cancelling them altogether,
partly to encourage diplomatic efforts and partly because of the
pandemic, the US-South Korea alliance returned to full-scale
manoeuvres in 2022. Furthermore, those manoeuvres included
the most extensive aerial exercises ever, dubbed ‘Vigilant
Storm’. Ever since it first came to power, the Kim family
regime has seen these operations as part of the United States’
“hostile policy” and as preparation for a potential attack on its
territory. A large proportion of the over 90 cruise and ballistic
missiles launched by the North Korean regime over the past
year were fired concurrently with and in response to large-scale
military operations carried out by its adversaries. This plunged
the Korean Peninsula back into yet another cycle of action and
reaction. Responding to pressure with more pressure has been
the unchanging cornerstone of North Korea’s strategic culture
ever since the 1960s.4 The fact that the North Korean leader
Kim Jong Un, unlike his father, has been displaying a willingness
to accept incremental risks in order to achieve his goals further
complicates the mechanisms of extended deterrence and raises
the risk of accidental clashes. Another common feature of the three cases examined is the
fact that, historically, local dynamics have been curbed by the
constraints of the broader competition between major powers. 162 Back to the Future Back to the Future 5 “On Report Made by Supreme Leader Kim Jong Un at 8th Congress of WPK”,
KCNA, 9 January 2021.
6 “N. Korea reveals leader Kim’s daughter for first time”, Yonhap News Agency, 19
November 2022. The Multidimensional Challenges
to Stability on the Korean Peninsula The past three years have been the toughest test for Kim Jong
Un’s leadership since he took the helm in December 2011, upon
the death of his father, Kim Jong Il. Having ended its short
spell of dialogue and summits with the United States and South
Korea in October 2019 – a spell that started with the North
Korean delegation’s participation in the Winter Olympics in
Pyeongchang, South Korea in February 2018 – the regime has
closed ranks again. The resumption of intensive missile activity
in September 2021 forms an integral part of Kim Jong Un’s
efforts to achieve the goals he announced in January of that
year. In his speech to the eighth Congress of the Workers’ Party
of Korea, Kim presented new five-year plans for the economy
and the military, the latter setting out ambitious targets for
upgrading the quantity and quality of the nuclear deterrent.5 pg
g
q
y
q
y
Over the past two years, North Korean scientists and military
staff have achieved remarkable results in relation to a range of
targets set by their leader, from the first tests of hypersonic
weapons to the launch of new long-range cruise missiles and the
successful launch of the Hwasong-17 intercontinental ballistic
missile in the presence not only of Kim Jong Un but also that
of his daughter, who had never appeared in public before.6
Pending the seventh nuclear test, preparations for which have
long since been completed, according to satellite images, North
Korea’s nuclear and missile programme is progressing naturally,
and has moved beyond the stage at which the technical need
to test the operation of carriers and weapons systems is at its
most pressing, to the extent that the term “test” customarily
used to describe North Korean missile launches is no longer
appropriate. According to Ankit Panda, what we were seeing, The New Militarisation of East Asia 163 especially in the second half of 2022, was more like “operational
exercises for large-scale missile deployment”.7h The regime has pursued its military and defence objectives
almost undisturbed, and has benefited considerably from the
changes to the international scenario triggered by Russia’s
war on Kyiv. 7 A. Panda, “What’s Behind North Korea’s Growing Missile Activity?”, Prospects
& Perspectives, no. 70, 6 December 2022.
8 M. Nichols, “China, Russia veto U.S. push for more U.N. sanctions on North
Korea”, Reuters, 26 May 2022. 9 Food and Agriculture Organisation (FAO) e World Food Programme (WFP),
“Democratic People’s Republic of Korea (Dprk) - Fao/Wfp Joint Rapid Food
Security Assessment”, 2019.
10 United Nations International Children’s Emergency Fund (UNICEF),
“Further Analysis on the Democratic People’s Republic of Korea Multiple
Indicator Cluster Survey 2017”, 2019.
11 M. Noland, “North Korean Food Insecurity: Is Famine on the Horizon?”,
East-West Center, Analysis n. 154, 22 August 2022.
12 H. Smith, “Explaining Food Insecurity in North Korea: The Self-Sufficiency
Fallacy,” Global Asia, vol. 16, n. 3, 2021, p. 59. The Multidimensional Challenges
to Stability on the Korean Peninsula The Security Council is paralysed by the
obstructionism of Moscow and Beijing, which share powerful
security motives for frustrating, wherever possible, all new
initiatives promoted by Washington to condemn Pyongyang’s
conduct.8 The violation of Ukraine’s territorial sovereignty has
again called into question the effectiveness of sanctions and,
more generally, has diverted the US administration’s attention
away from North Korea, which had never been a high priority
for President Biden anyway. No consideration of the North Korean regime’s military
stance can be separated from the triple shock that the country
has suffered in recent years. North Korea saw the pandemic as
an existential threat to the nation’s survival and hence to the
regime’s survival. The fragility of the country’s health system
made it imperative to close national borders immediately, as
soon as the first cases of infection in China were confirmed. Cross-border trade, which came to a halt at the end of January
2020, resumed in the second half of 2022, but in fits and starts. Experts, meanwhile, are almost unanimous that the effects
of infection-control measures imposed by the North Korean
regime are comparable, if not greater, than those of decades of
international sanctions. No international NGOs or United Nations agencies have
been operating in North Korea since March 2021, making it
impossible to independently verify the data published by North
Korean officials. Despite the suspension of the monitoring
system, this is highly likely to have been the worst period for the 164 Back to the Future North Korean population since the famine of the mid-1990s. 13 All of the expert group’s reports are available at: https://www.
securitycouncilreport.org/un_documents_type/sanctions-committee-
documents/?ctype=DPRK%20%28North%20Korea%29&cbtype=dprk-
north-korea
14 For an in-depth analysis of the security implications of climate change, see
M. Mobjörk et al. “Climate-related Security Risks”, SIPRI e Stockholm University,
October 2016.
15 Although the historical development of the two security issues covered here
falls outside the scope of this analysis, some indication of their key features must
be given at this point to ensure that readers with a less complete knowledge of
the area are equipped to fully understand the analysis set out in this paper. As
far as Taiwan is concerned, we need only remember that the insecurity of the
island and the strait to which it lends its name is a matter of national sovereignty
whose roots lie in the conclusion of the Chinese Civil War. Following the victory
of the Communist Party of China (CPC) in 1949, members and sympathisers of
the opposition party (the Kuomintang) opted for self-exile in several Southeast
Asian countries and, primarily, on the island of Taiwan, where the Republic of
China (ROC) was founded. During the Cold War, most of the international
community recognised the legitimacy of the ROC until 1971, when Beijing
replaced Taipei on the United Nations Security Council. This marked the start
of a period of strategic ambiguity, in which the international system chose not The Multidimensional Challenges
to Stability on the Korean Peninsula In
an assessment drawn up in 2019, the FAO and WFP estimated
that 10.1 million North Koreans (about 40% of the population)
were living in conditions food insecurity.9 Although nutritional
indicators were showing signs of improvement in the period
prior to the pandemic, in 2017 one in five children in North
Korea was suffering from rickets.10 f As well as international sanctions and the effects of border
closures aimed at preventing the spread of the pandemic,
account must also be taken of climate-related events, which have
become more extreme with each passing year in this part of the
world too, thus making the ecosystem extremely vulnerable and
having a dramatic impact on living conditions in rural areas.11 g
g
Simultaneous North Korean, Chinese and Russian
quarantine measures have hindered the flow of food aid and
seed into North Korea, as well as local production of pesticides
and fertilisers, placing additional strain on an agricultural
sector that was already suffering serious adverse effects from the
resolutions adopted by the Security Council between 2016 and
2017, and defined in no uncertain terms by Hazel Smith as the
“preconditions for famine”.12 It must be remembered, in this
respect, that North Korea’s extensive use of chemical fertilisers
requires large quantities of natural gas and coal, and that
North Korea’s imports of natural gas have been banned, and
its imports of oil drastically reduced, since 2017. Pyongyang’s
dependence on energy supplies from Moscow and Beijing has
inevitably increased, and the aforementioned restrictions have The New Militarisation of East Asia 165 been frequently breached, as duly documented by the expert
group responsible for monitoring the implementation of UN
resolutions.13 When viewed through a broader lens, the case of North
Korea clearly illustrates the interconnections between security
and climate change, which is often described as a “threat
multiplier”.14 Although environmental degradation does not
currently pose any direct threat to the internal control and
stability of the regime, we cannot discount the possibility that it
could fan the flames of existing regional tensions in the future. to take a clear position between recognising Taiwan either as an integral part of
the PRC or as a sovereign state. This ambiguity cyclically foments tension and
insecurity. G. Samarani, La Cina del Novecento: Dalla Fine dell’Impero a Oggi, Torino,
Einaudi, 2008. 16 Francesca Congiu and Barbara Onnis, Fino all’Ultimo Stato: La Battaglia
Diplomatica tra Pechino e Taiwan, Carocci: 2022. 16 Francesca Congiu and Barbara Onnis, Fino all’Ultimo Stato: La Battaglia
Diplomatica tra Pechino e Taiwan, Carocci: 2022.
17 Territorial disputes in the South China Sea affect a large number of regional
actors – including the PRC and Taiwan, the Sultanate of Brunei, the Philippines,
Malaysia, Thailand and Vietnam – which claim sovereignty over a stretch of the
western Pacific Ocean measuring some 3.5 million square kilometres. Roughly
one third of the world’s maritime trade passes through this area, which is also
rich in undersea energy resources. These claims have now taken on a significant
military dimension: China, the Philippines, Malaysia and Thailand have all built
military bases on islands, atolls and reefs, thereby artificially expanding the
extent of their territory. This militarisation pushes the discussion of territorial
claims into the realm of security, thus extending the range of players involved to
outside powers. B. Hayton, The South China Sea: The Struggle for Power in Asia, Yale
University Press, 2014. 18 W. Ripley, E. Cheung, and B. Westcott, “Taiwan’s President Says the Threat
from China Is Increasing ‘Every Day’ and Confirms Presence of Us Military
Trainers on the Island”, CNN, 28 October 2021.
19 M. Raymond and D.A. Welch, “What’s Really Going on in the South China
Sea?”, Journal of Current Southeast Asian Affairs, vol. 41, no. 2, 2022. Territorial Sovereignty and the PRC Further expressions of the current insecurity issues facing East
Asia feature a leading role for the PRC. Some of these relate to
Taiwan, whose situation in recent years has become increasingly
central to the militarisation of the Indo-Pacific.15 As Francesca 166 Back to the Future Congiu and Barbara Onnis wrote in a recently published book,
“the current evolution of events concerning the island of Taiwan
can be seen as a manifestation of the complex tensions and
contrasts that now characterise relations between the People’s
Republic of China … and the United States of America” (p. 15).16 Others relate to territorial disputes in the South China
Sea, where, unlike in the rest of the Indo-Pacific, there was no
real interruption in militarisation during the pandemic.17 As history shows, these matters of insecurity generally
share the common factor of issues relating to the territorial
sovereignty of the political entities concerned, and the active
involvement of the world’s two superpowers, China and the
United States. These elements, in turn, influence those that
represent key principles for the political considerations of all
the actors involved, thereby increasing the sensitivity of the two
matters and connecting them with considerations relating to
the international system, especially within the framework of
competition between great powers. p
g
p
Today’s militarisation is at least partially attributable to the
legacy of the Covid-19 pandemic, which became enmeshed The New Militarisation of East Asia 167 with these historic security dynamics from the outset. The very
advent of the health crisis, for example, raised the expectation,
shared by various observers, that the pandemic would act as a
deterrent (positive or negative) to these dynamics. Now that
the health emergency has moved into a less acute phase, we can
draw a few conclusions based on empirical evidence relating to
the region’s security practices and their impact on the current
situation. Firstly, we need to draw a distinction between two
the types of legacy – direct and indirect – left by the pandemic
on the two sources of insecurity in question. When the two
matters are viewed through the lens of realpolitik, Covid-19’s
contribution to today’s security issues is limited by structural
constraints in the first case, but more pronounced in the second. Territorial Sovereignty and the PRC i
p
Although the Indo-Pacific is increasingly a focus of
international debate, the security practices in both matters have
involved a limited number of people, especially in terms of local
populations. The Taiwanese question, for example, still has what
might be described as a Clausewitzian configuration, in the sense
that it gives rise to a strategy of mutual containment by the actors
involved, which is mainly attributed to the involvement of the
armed forces. The main evidence that international observers
have on the Taiwanese question is the presence of Chinese or
US armed forces around Taiwanese airspace or maritime space,
and attempts to militarise Taiwan itself through the acquisition
of military materiel or the training of its national armed forces
through collaborations with the US.18 As far as the South China Sea is concerned, by contrast, the
key factor in its security dynamics is still the role of the PRC,
both in terms of the artificial expansion of islands, atolls and
reefs in the area, and the formal recognition of these territories
as Chinese administrative units.19 In May 2020, for example, 168 Back to the Future the PRC unilaterally established two new administrative
districts in areas that are disputed with Vietnam – Xisha 西沙
(Paracel Islands) and Nansha 南沙 (Spratly Islands) – as part of
Hainan Province. Beijing’s aim was to increase China’s presence
and the effectiveness of its administrative control over the area
by building new infrastructure.20f Since one of the most visible effects of Covid-19 is the
restrictions it places on the affected populations, the emphasis
on armed forces that characterises security practice in the
Indo-Pacific clearly acted as a counterbalance to the problems
generated by the pandemic, in the case of both Taiwan and
the South China Sea. This resulted in levels of militarisation
that were broadly comparable to those that preceded the health
crisis, although the spread of infection on-board at least one US
military ship slowed the traditional development of regional
security dynamics (i.e. closely linked with the presence of
armed forces) during the most acute phases of the pandemic.21 As for the pandemic’s indirect legacy on the matters in
question, two factors need to be taken into account in order
to put the processes currently unfolding into context. 20 H. Le Thu, “Fishing When the Water is Muddy: China’s Newly Announced
Administrative Districts in the South China Sea”, Asia Maritime Transparency
Initiative, 6 May 2020.
21 M. Gafni and J. Garofoli, “Exclusive: Captain of Aircraft Carrier with Growing
Coronavirus Outbreak Pleads for Help from Navy”, San Francisco Chronicle, 8
June 2020. 22 R. Cronin, “Sea of Absurdity: Sansha, China’s New Island ‘City’”, Stimson
Center, 14 October 2014.
23.A. Thayer, “COVID-19 Masks Mischief in the South China Sea”, East Asia
Forum, 13 January 2021; F. Congiu and B. Onnis, Fino all’Ultimo Stato: La Battaglia
Diplomatica tra Pechino e Taiwan, Carocci: 2022, pp. 85-92.
24 Ibid.
25 “T
T i
C ll B
k US P li
St
” BBC 3 D
b
2016 25 “Trump-Taiwan Call Breaks US Policy Stance”, BBC, 3 December 2016. Territorial Sovereignty and the PRC Firstly,
the impact that restrictions on diplomatic meetings in recent
years have had on the militarisation of the area; and secondly,
the substantial change in the US approach to China’s policy in
the south-eastern neighbourhood, especially as far as Taiwan is
concerned. In the first case, the suspension of high-level diplomatic
meetings due to Covid-19 curbed dialogue on sensitive issues, as
it did in other parts of the world, thus facilitating the adoption of
one-way practices designed mainly to further national interests, The New Militarisation of East Asia 169 as was typical in the past.22 A prime example of this trend is
the establishment of the aforementioned districts of Xisha and
Nansha, which helps fulfil China’s national objectives but takes
no account of the effects of this action on the region. As noted
by Carlyle A. Thayer, Emeritus Professor at the University of
New South Wales, in a contribution to the East Asia Forum in
January 2021, the biggest impact of the absence of high-level
diplomatic meetings on security matters in the area is that it
put a stop to negotiations on the drafting of a shared “code
of conduct” between China and all the other actors making
territorial claims in the South China Sea.23 Not only has the
absence of fresh progress led to militarisation in the area, it has
also made it more difficult to resume effective dialogue because
the common foundations negotiated between all the parties
prior to Covid-19 have now been called back into question by
unilateral practices undertaken during the most acute phases of
the health crisis. The question of the US presence in the area hinges upon
similar considerations. Washington views these unilateral acts
as examples of assertive practices undertaken by China to the
detriment of the other countries in the area. The US response
in recent years has been especially emphatic in relation to
Taiwan, although the sovereignty of the island remains a central
and inviolable condition for the continuation of diplomatic
relations between the PRC and the US.24 Although the more
active approach towards Taiwan is largely attributable to the
Donald Trump presidency – as witness the controversial phone
call to the Taiwanese President Tsai Ing-wen in December 201625
– the election of a Democratic government under Joe Biden in 170 Back to the Future 2020 has done little to divert US policy from the approach
established by the preceding Republican administration. 26 N. Price, “New Guidelines for U.S. Government Interactions with Taiwan
Counterparts”, United States Department of State, 9 April 2021.
27 N. Pelosi, “Why I’m Leading a Congressional Delegation to Taiwan”, The
Washington Post, 4 August 2022.
28 “China’s warplane incursions into Taiwan air defence zone doubled in 2022”,
The Guardian, 2 January 2023. Territorial Sovereignty and the PRC Under Joe Biden, the renewed focus on Taiwan has translated,
in operational terms, into both a higher number of passages
through the Taiwan Strait by US Navy ships and a loosening
of the rules that have governed contact between American and
Taiwanese government personnel since the 1970s.26 Although
it pertains to the US administration’s legislative branch, Nancy
Pelosi’s visit to Taipei in August 2022, while still Speaker of the
House of Representatives, is a practical example of increased
US activism and reduced adherence to structural limitations in
the country’s relations with Taiwan.27 However, in view of the
highly sensitive nature of the Taiwanese question to the PRC,
the growing presence of the United States in matters relating to
the island has elicited an equally active reaction from Beijing,
which has stepped up those practices that Washington sees as
highly detrimental to regional stability. According to several
observers, it is no coincidence that Chinese incursions into
Taiwanese airspace almost doubled in 2022 compared with the
previous year.28 These effects therefore represent the return to a militarisation
primarily linked with dynamics that relate to the international
system and therefore involve actors (such as the United States)
that have no direct involvement in the pending claims, thus
broadening the scope of regional insecurity. The New Militarisation of East Asia 171 Conclusion This chapter has examined the main sources of contention
currently affecting security in the Indo-Pacific, an area that is
becoming increasingly central to the focus of a growing number
of international actors.hi The first key factor is the link between militarisation in the
area and the restrictions that the Covid-19 pandemic has placed
on national and international governance over the past three
years. North Korea, for example, is facing what seems to be
one of the worst humanitarian crises it has experienced in its
recent history. Although these difficulties do not appear to have
directly affected the legitimacy of the regime in the eyes of the
North Korean people, Kim Jong Un is expected to underscore
the visibility of the progress his country has made on the
military front so as to project the perception, both internally
and externally, that his leadership is solid, in keeping with the
pattern of behaviour that has established itself over the past
decade. The second key factor is the systemic nature of the region’s
insecurity, due to which the world’s superpowers – China and
the United States – are prime movers in the area’s militarisation. An emblematic example of this trend is the Taiwanese question. From the Chinese perspective, the current US approach – now
less dictated by the rules negotiated with the PRC in the 1970s
– violates the core principles underpinning the status quo in
the area, thereby increasing the risk that Taiwan will make an
even more decisive shift towards independence. From the US
perspective, the loosening of policy on Taiwan has been made
necessary by the PRC’s approach, under Xi Jinping, to the future
of the island, which is seen as being particularly assertive. These
tensions between the two world powers therefore give impetus
to the tendency to militarise the Indo-Pacific, by shifting the
focal point of insecurity from regional issues to considerations
involving the international system. * This chapter was concluded on 30 December 2022. Antonella Mori The political map of Latin America is now almost entirely
uniform in colour again, following the victory of Luis Inácio
“Lula” da Silva in Brazil. The current prevalence of left-wing
governments is reminiscent of the political situation in the
region at the beginning of the millennium, although the
picture is now more nuanced and probably less stable. At the
start of the millennium, left-wing presidents could be sorted
into two groups. Now, we need at least three to accommodate
them. In the first wave, left-wing governments had multiple
consecutive terms in office, thanks in part to the favourable
economic climate fostered by high international commodity
prices. The current wave appears to be driven less by voters’
ideological convictions and more by their anger at the ruling
parties, for various reasons, ranging from mismanagement of
the pandemic to corruption and a lack of social policies. The
economic situation in 2023 is likely to be difficult, with high
inflation and low growth, so it is reasonable to expect that the
political map will start changing colour again as from the next
elections. 174 Back to the Future The First Wave of Left-Wing Governments The 1990s were characterised by the adoption of economic
policies designed to restore stability in the wake of the
recession and hyperinflation caused by the foreign-debt crisis
of the 1980s. In many countries in the region, average per
capita income in the early 1990s was worse than it had been
ten years earlier, which is why the 1980s are remembered as
Latin America’s “lost decade”. The set of economic policies
adopted in the 1990s, known as the Washington Consensus,
included policies designed to increase the market’s role in the
economy, such as liberalisation (of trade, investment and the
financial sector), privatisation and deregulation. By the end of
the century, however, poverty and inequality in the region were
still very high. The disappointing results of the Washington
Consensus, combined with the failure of President Menem’s
laissez-faire policies in Argentina, prompted the majority of
Latin Americans to reject the manifestos of right-wing parties
that were ideologically closer to the Washington Consensus,
and to vote instead for left-wing parties. A phenomenon widely
known as the “pink tide” saw the election of Hugo Chávez in
Venezuela (1999), Ricardo Lagos in Chile (2000), Lula in Brazil
(2002), Néstor Kirchner in Argentina (2003), Evo Morales in
Bolivia (2005) and Rafael Correa in Ecuador (2006).h This wave of left-wing governments in the region coincided
with the commodity boom of the early years of this century. High rates of economic growth and substantial inflows of
export earnings helped prop up the popularity of governments
and generated hopes of continuous, shared prosperity, without
any need to implement the structural reforms and investments
that might ensure lasting improvements in the health and
education services and the productivity of economic systems. Poverty and inequality declined in almost every country in the
region during this period, and many Latin Americans joined
the ranks of the middle class for the first time. The Return of the Left to Latin America 175 When commodity prices fell dramatically in the middle of the
last decade, economic growth and the availability of resources
also declined in most of these countries. Many governments
found themselves with lower tax revenues to cover public
spending, at a time when demand for better public services had
actually increased, due to the expansion of the middle class. In many countries where democratic elections were held, Latin
Americans gradually started voting against the ruling parties. The First Wave of Left-Wing Governments And so by 2018, the majority of countries were governed by
right-wing and centre-right parties. The rise of the right was
also fuelled by serious corruption scandals involving politicians
and parties throughout the region. p
g
g
In order to avoid this change, free and democratic elections
were prevented in Venezuela and Nicaragua. Venezuela is the
only country whose political colour has remained unchanged
since South America’s first wave of left-wing governments. But
the Bolivarian revolution that began under former President
Hugo Chávez has turned into an economic and humanitarian
disaster under his successor, Nicolás Maduro. The attempt to
remove Maduro and replace him with Juan Guaidó in 2018
failed, despite winning support from the United States and
many other countries. y
But the conservative wave that followed the “pink tide” has
not yet fully ebbed. In Uruguay, conservatives took control
of the government in 2019 from the left-wing Broad Front
coalition, which had been in power for a decade and a half. The conservative Guillermo Lasso won Ecuador’s presidential
elections in May 2021, while Argentina’s ruling Peronist
government suffered a severe setback in the mid-term elections
in November 2021. Right-wing and centre-right governments
therefore still control Ecuador, Uruguay and Paraguay. 176 Back to the Future Back to the Future The Return of the Left The past 12 months have seen a consolidation of the trend that
emerged in 2018, when the left started winning power in free
elections against conservative continuity candidates. In January
2022, Xiomara Castro, the wife of the defenestrated Manuel
Zelaya, won the elections in Honduras. In March, Gabriel
Boric, the former leader of the student protest movement and
a left-wing member of parliament, became Chile’s youngest
ever president. In June, Colombia followed suit when its voters
made Gustavo Petro the country’s first left-wing president. And
then, in October, Lula made a spectacular return to power in
Brazil, after defeating the ultra-conservative, far-right President
Jair Bolsonaro in an election in which many observers feared
that Brazilian democracy itself was on the ballot. This new wave of more left-leaning presidents began in 2018
with the election of Andrés Manuel López Obrador (AMLO) for
the National Regeneration Movement (MORENA), who took
over from the conservative Enrique Peña Nieto. In Argentina’s
presidential elections in October 2019, Alberto Fernández, a
moderate-left Peronist candidate, beat the incumbent President
Mauricio Macri, whose austerity measures and heavy debt
burden had triggered a profound economic crisis. In October
2020, the Movement for Socialism (MAS) returned to power in
Bolivia in the first presidential elections since the ousting of Evo
Morales. Lastly, in 2021, Pedro Castillo, a far-left teacher with
no previous government experience, won Peru’s presidential
elections, beating the right-wing candidate Keiko Fujimori by
a small margin. hf g
There are numerous differences between this second wave of
left-wing presidents and the first. h i
The left’s new presidents certainly share a similar ideology,
but they seem, for example, to have none of the enthusiasm
for regional integration that Chávez had. Perhaps Lula’s return
will push this issue higher up Latin American government
agendas again, so as to open up more opportunities for regional The Return of the Left to Latin America 177 cooperation. An example of the differences between these
left-wing presidents and how difficult it is to coordinate their
action arose in November 2022, during the election of the new
President of the Inter-American Development Bank (IDB). Chile, Argentina and Mexico failed to agree on an alternative
candidate to Ilan Goldfajn, the Brazilian candidate put forward
by Bolsonaro, and therefore missed the chance to win such a
significant position for the region. The Return of the Left gi
p
g
All of these governments have their own idiosyncrasies, so
there are limits to how far they can be classified into a few
categories. But if we attempt to do so anyway, it is fair to say
that the first wave involved two versions of the Latin American
left: one international, pro-market and social-democratic (as
in Brazil and Chile, for example); and the other nationalist,
populist and statist (as in Bolivia and Venezuela). Now, there
are three versions of the left, each with different leanings,
namely authoritarian, social-democratic and populist. The first
of the three versions includes the trio of authoritarian regimes
made up of Cuba, Nicaragua and Venezuela. Although they
try to associate themselves with the rest of the Latin American
left, and the region’s other left-wing leaders avoid criticising
them, these three countries remain in a category entirely of
their own. They do not have democratically elected leaders,
their citizens do not enjoy fundamental freedoms, and their
foreign policy is stridently anti-imperialist and anti-American. In November, in the latest of a long string of examples,
President Daniel Ortega’s Sandinista National Liberation Front
(FSLN) won 100% of Nicaragua’s mayoralties in municipal
elections, in which opposition parties were unable to take part. The opposition described the elections as an “electoral farce”,
while the executive sought to defend the result on the basis of
high turnout, which does not appear to have actually existed:
according to the independent organisation Urnas Abiertas,
turnout amounted to just 17%. V
l
h h h
h d
Ch
f Venezuela, which has had a Chavist government for over 20
years, has swapped its populist left, under Chávez, for the current 178 Back to the Future authoritarian left, under Maduro, and the situation may evolve
again. Indeed, there is considerable national and international
pressure to ensure that the next presidential elections there are
free and democratic. Over the past year, international attitudes
towards Maduro have softened, partly because of the entire
region’s shift to the left and the end of the Trump presidency, and
partly because of Venezuela’s importance in efforts to increase
oil production, in the wake of Russia’s invasion of Ukraine. Venezuela has the largest estimated oil reserves in the world, but
its current output is very low, due to a lack of investment in the
industry and US sanctions preventing the export of Venezuelan
oil. The Return of the Left The rapprochement between Petro and Maduro and the
transition from the far-right Bolsonaro government to the
incoming Lula administration are particularly important. While
there may be concerns that left-wing governments might reduce
the pressure on Maduro to tackle the profound institutional
crisis, it is equally possible that more friendly governments
might have greater leverage with which to persuade Maduro
of the need to restore democracy with free and representative
elections. The strategy of maximum pressure and isolation
launched by Trump in 2019, with harsh economic sanctions,
has been unsuccessful anyway. The humanitarian crisis has
worsened, Maduro has become stronger and the opposition has
fragmented, with interim President Juan Guaidó losing support
both in and outside of Venezuela. The Biden administration’s
approach could involve a gradual easing of economic sanctions
to nudge Maduro into taking part in serious negotiations with
the opposition, now in Mexico City, to agree the procedures for
the next presidential elections. ll
f h
l d
h
f ll
h
d p
All of the current-wave leaders who fall into the second
and third categories identify as progressive, and in many cases
their electoral success was a reaction to previous governments’
mismanagement of the Covid-19 pandemic and rising levels
of poverty and inequality. Their manifestos place a strong
emphasis on social policies and the defence of their countries’
natural resources. The second category includes leaders with The Return of the Left to Latin America 179 social-democratic leanings, including President Boric of Chile,
President Petro of Colombia and President Lula of Brazil, who
represent a new Latin American left, capable of combining
progressive vision with pragmatic willingness to compromise. Boric is a good example. Although his coalition has an
intransigent left wing, which includes the Communist Party
and the indigenous Mapuche movement, the Chilean President
seems to be following in the more moderate footsteps of his
predecessors Ricardo Lagos and Michelle Bachelet. Boric is also
one of the few left-wing leaders who openly criticise the absence
of democracy and the absence of the freedoms associated with
the rule of law even in left-wing authoritarian countries.i In Colombia, President Petro, the country’s first left-wing
president, has shown signs of moderation and pragmatism
without compromising on his commitment to giving higher
priority to the poorest and most marginalised segments of the
population. The Return of the Left His pick for the role of Minister for the Economy
is José Antonio Ocampo, a respected centre-left economist,
who had campaigned for another candidate, Sergio Fajardo,
until the latter’s elimination in the first round. Sharing the
president’s priority of implementing tax reform to increase tax
revenues, including by raising taxes for the country’s wealthiest
people, Ocampo managed to achieve this goal in his first few
months in office. Petro has promised to relaunch the FARC
agreement and to seek a broader peace with other guerrilla
formations and armed groups still operating in the country. Colombia’s fragile peace process faltered after former President
Ivan Duque’s hostility to the agreement resulted in only half-
hearted implementation of the measures established in it. Lula should also fall within this second group of social-
democratic left-wing leaders, if we consider his past experience
of government. During his first term (2003-2007) in particular,
he adhered to orthodox economic policies, showed virtually
no authoritarian tendencies, and implemented effective,
properly funded social policies. Lula can take advantage of
his Latin American allies in relation to what he has called 180 Back to the Future “climate diplomacy”: the world needs a living Amazon, and
this message is in tune with Petro and Boric’s environmental
agenda. Alongside them, Lula will be a key player in the global
debate on climate change and the policies needed to manage
it. The Brazilian President could also become a champion
of democracy, against a backdrop of high levels of popular
disaffection with democratic systems, and exert an influence
against authoritarianism both in and outside of the region,
thanks to the worldwide popularity he achieved in his first two
terms. President Fernández of Argentina also belongs to this
group, despite his more mixed record. Having inherited massive
foreign debt and high inflation from the previous government,
he has imposed price and exchange rate controls, and adopted
more populist rhetoric. p p
Ultimately, Boric, Petro, Lula and even Fernández are probably
closer to the centre than to the far left, partly because they were
elected under systems involving multiple rounds of voting,
which inevitably oblige candidates to appeal to voters beyond
their own base in order to secure a chance of winning. The cases
of AMLO in Mexico, Castillo in Peru and Arce in Bolivia are
different and constitute the third group of left-wing populist
presidents. The Return of the Left In Mexico, President AMLO has a track-record of
illiberal behaviour, involving frequent attacks on the country’s
independent institutions, including the electoral authority, the
national institute for transparency, the media and various civil
society organisations. According to many observers, Mexico’s
democracy is also threatened by corruption and militarisation. The armed forces are playing a growing role in infrastructure
projects, such as the Tren Maya, a railway construction project
on the Yucatán Peninsula. By implementing environmentally
regressive and uncompromisingly statist and nationalist energy
policies, AMLO has sought to re-establish the era of state oil
and energy monopolies. It is very difficult to put AMLO in
the second group of left-wing leaders. Boric and Petro support
environmental policies, whereas AMLO rejects them. President
Petro of Colombia has appointed a human rights defender as The Return of the Left to Latin America 181 Minister of Defence, whereas AMLO has given military leaders
a major role in his government. Minister of Defence, whereas AMLO has given military leaders
a major role in his government. President Arce of Bolivia is still close and loyal to the populist
Morales, his former boss and predecessor as Bolivian president,
while Castillo, now the ex-President of Peru, shares much of the
statist, nationalist and populist ideology espoused by the others
in the third group of left-wing leaders. Castillo, a humble teacher
from a rural area, rose to power as the representative of a far-left
party. This has made him the target of fierce opposition, due to
fears that Peru could turn into a regime like that of Venezuela
or Nicaragua. Backed into a corner by corruption trials, ex-
President Castillo tried to dissolve Congress in early December
and rule by decree, but lacked the military and political
support to do so. Congress has charged him with attempted
rebellion and appointed Vice-President Dina Boluarate as his
replacement. His removal prompted his supporters to stage
protests across Peru, resulting in dozens of deaths, and to
demand an early general election, which many see as the only
way out of the crisis. The former president was ousted due to a
combination of incapacity and corruption, and Congress used
its constitutional power to dismiss the incumbent president
on the grounds of “moral incapacity.” This dubious power has
become an established part of the country’s legal framework,
which explains why Peru has got through six presidents in the
past six years. The Return of the Left In most Latin American countries there is growing frustration
with the quality of democracy and its inability to provide
effective solutions to problems. Corruption, impunity and social
inequalities remain at the top of voters’ lists of complaints. The
second wave of left-wing governments represents the tangible
outcome of this dissatisfaction, rather than the ideological
choice of the region’s citizens, and this dissatisfaction drives
people to vote against incumbent governments – a trend that
will probably see the ousting of several leaders currently in
power, when their terms come to an end. 182 Back to the Future Back to the Future At the beginning of the century, the popularity of left-
wing governments was propped up by the benefits of high
international commodity prices, but we are unlikely to see
a return to lasting increases in these prices today, with the
exception of certain commodities that are instrumental to the
energy transition, such as lithium (found mainly in Chile,
Argentina and Bolivia), copper (in Chile, Peru and Mexico)
and nickel (in Brazil and Cuba). After a string of electoral victories for the left in Latin America,
2023 is very likely to see the return of the right. This mainly
reflects the continued unpopularity of incumbent governments
in a region facing another year of modest economic growth
and social discontent. Although at least inflation will fall in the
majority of countries in the region, thanks to the prompt action
of central banks in raising interest rates, few governments can
afford expansionary fiscal policy. Having enjoyed growth of 3.5%
in 2022, the economies of Latin America and the Caribbean
are expected to expand by only in 1.7% in 2023, according to
the IMF. Poverty and inequality have risen, tax revenues have
fallen, and recovery is taking longer than expected. There is a
risk of further outbreaks of social unrest like those that befell
several countries before the pandemic. In many cases, presidential elections are won by very slim
margins, in contests resulting in the election of Presidents
of one political orientation and sub-national government
representatives of another. These factors help explain why
there has been a tendency to swing from left-wing to right-
wing governments and vice versa in the most recent presidential
elections. Under an optimistic interpretation, this alternation is
evidence that democracy is consolidating in the region. Conclusion Giampiero Massolo The Concept of a “Return” The “return” of the ISPI report this year does not imply a
straightforward repetition of the past. Instead, it involves a
reiteration of certain parts of the past in a new context, with a
new combination of features. This should not be confused with
any kind of regression, but seen as an acknowledgement of the
fact that, although the present is undoubtedly influenced by the
past, history’s continuously unfolding successions of events are
comparable, not identical. Basically, we never step into the same
river twice, although we may get the impression that we do.h This is the impression that international dynamics have
frequently given us in recent years. The Return of the Left Since
it is likely to be a manifestation of voters’ dissatisfaction with
traditional parties, however, this alternation conceals the risk
that, sooner or later, citizens will tire of the democratic process
and decide to support more authoritarian forms of government. Return or Continuity? The Covid-19 pandemic and the war in Ukraine have had
a dramatic impact on the world. Nevertheless, it is worth
emphasising that these two events did not cause the sudden
changes we are now seeing, they simply made them happen
more quickly and amplified their effects. h The trends that developed before the pandemic and the war
were, in fact, already taking shape. Russia’s invasion of Ukraine 184 Back to the Future has certainly prompted a change in international relations. But
the signs of growing tension between the world powers pre-date
the war by a considerable margin.f Furthermore, these events have impacted different countries
and different sectors of the economy in different ways. We can
therefore define their effect as a cumulative addition to a pre-
existing set of other factors.i A prime example is the fact that governments are finding
it more difficult to meet the expectations of their voters, not
to mention the expectations of public opinion, which looks
increasingly unsettled by a world it perceives to be full of threats,
although the precise nature of those threats is not always easy
to identify. The growing complexity of the problems to be addressed
makes it harder for national governments to pursue one goal
without compromising another of equal importance. This is
because the strategic exercise of prioritising national interests
is no longer adequate. This has impaired the mechanisms that
underpin policy responses, which in turn has fanned the flames
of nationalist and populist tendencies. p p
Governments have thus been forced to focus more on
domestic affairs, often from a conservative perspective, thus
diverting energy away from international issues, which are often
wrongly perceived as secondary in terms of their impact on the
constituencies concerned. The search for global solutions to
shared problems – starting with the climate crisis – has therefore
come to a halt. The polarisation of shifts in domestic opinion, and their
repercussions on public debate, has made people less trustful
of institutions and the political class, not only in democracies
but also in authoritarian regimes, which, like their democratic
counterparts, are struggling with deficits in the legitimacy of
their mandate and the effectiveness of their action. Return or Continuity? f
Another factor that pre-dates the Covid-19 pandemic and
the war in Ukraine is the pair of losing bets that the West placed
– first on China and second on Russia – in the first two decades Conclusion 185 of this century. The essence of these bets was that, in the name
of the progress and economic prosperity that globalisation had
apparently brought within reach, these nations would abandon
their hegemonic and revisionist impulses, in favour of greater
integration into the American-led Western world order. i In the case of China, the first signs that this view was mistaken
were to be seen in its growing assertiveness, first economic
and then on the security front, encouraged by exponential
and apparently unstoppable economic growth. Thanks to its
commercial power and long-term strategic perspective, the
People’s Republic has accumulated the necessary resources
to pursue its leadership ambitions through soft power and
economic and infrastructure collaboration, especially with
developing nations, within the framework of the Belt and Road
Initiative. In Russia’s case, it became clear that the West had miscalculated
when Putin repeatedly warned the Atlantic Alliance of the
dangers that would arise if it were to expand further towards
Russian borders. With an economy that is still too dependent
on energy exports, Russia does not wield the same influence
as China, and its forays into foreign affairs are guided by a
still-strong but in many ways outdated military and security
establishment. Working to a much shorter time-horizon than
Beijing, the Kremlin found itself in the awkward position of
having to quickly take its strategic gamble to extremes in order
to safeguard the stability of the regime, thus increasing the
hostility of its stance towards NATO. The West’s attempts to build on these false premises have
led to a first rift between the world powers – the conflict in
Ukraine – and a heightening of tensions that is making it
difficult to identify collective responses to global problems, first
and foremost maintaining international peace and stability.i A third factor is globalisation’s failure to fulfil its promise to
deliver indefinite, unstoppable economic progress. i
pp
p
g
Globalisation has run out of steam for several reasons. Firstly,
labour costs have steadily grown in recent years, thus blunting 186 Back to the Future the competitive edge of a production model based largely
on low prices. Return or Continuity? Secondly, the progression of globalisation was
accompanied, in parallel, by an unprecedented concentration
of wealth and rising inequality, both between countries and
between different segments of the population within countries,
thus leading to an increase in social conflict. Globalisation has
also led to a considerable rise in economic interdependence
between states and a race to secure raw materials. This
combination of factors has increased the vulnerability of
economies that depend most on supply chains with low levels
of resilience, and increased competition between powers. p
p
The pandemic and the war in Ukraine have therefore impacted
on a global situation that was already facing critical issues,
albeit with asymmetrical effects. The consequences of Covid-19
were not all negative. On the one hand, the pandemic took a
terrible toll in human lives worldwide, while also unleashing a
dramatic economic crisis. On the other, however, it triggered a
formidable leap forward in scientific and technological progress
– particularly in the health arena – by putting the Western
economic and social system to the test. The West showed its
resilience and the effectiveness of its policy of “cohabiting”
with the virus, as opposed to the Chinese model of draconian
lockdowns. The virus therefore ended up damaging China’s
economic power more than Beijing had expected, and curbing
its regional and global leadership ambitions. hf p
p
The pandemic and the war in Ukraine have therefore impacted
on a global situation that was already facing critical issues,
albeit with asymmetrical effects. The consequences of Covid-19
were not all negative. On the one hand, the pandemic took a
terrible toll in human lives worldwide, while also unleashing a
dramatic economic crisis. On the other, however, it triggered a
formidable leap forward in scientific and technological progress
l l
h
h l h
b
h W g
g
p
The war in Ukraine was different. Russia’s largely unexpected
adventurism has spawned a brutal invasion of a sovereign state
and indiscriminate attacks on both military and civilian targets. All this has taken place on Europe’s doorstep, thus awakening
the continent from its illusion that peace had become part of
the furniture. The word “collaboration” has thus been swept
aside by the word “opposition”, which is likely to continue to
set the tone in the absence of any realistic chance of resolving
the conflict in the near future, by either military or diplomatic
means. Return or Continuity? The current deadlock has broken the thread of a 30-year
dialogue that began at the end of the Cold War. Conclusion 187 So let us look again at the original meaning of the idea of a
“return” as a reappearance of features specific to past eras, but
within a changed and self-contained general framework, not
as a linear process, but as the result of a series of transitional
phases. Is This the Road to a New World Order? So if a return is not simply a replication of the past, but a new
interpretation and adaptation of its attributes to the present
context, what kind of future are we about to “return” to? It is still too early to say, as there does not yet appear to be
any clear drive for a new overall order to replace the G-0 and
the “geopolitical recession” described by Ian Bremmer. It could
be argued, however, that the bipolarism between the United
States and China, which until a moment ago looked like the
most likely medium-term scenario, has now been replaced by
a different balance, namely the dualism between “the West and
the rest.” These two factions have two distinct natures. Despite the
differences that separate its members, the West appears to be a
bloc capable of expressing common positions based on a core of
values and interests that it sees as non-negotiable. The “rest”, by
contrast, is a patchwork of countries, which is not Chinese-led
and will not necessarily be Chinese-led, at least until Beijing
regains its economic heft. This mix of nation-states is based on
occasional rather than structural interests. A prime example
is India, which clearly represents an oscillating, but far from
schizophrenic, strategic approach, which involves siding with
the developing countries and BRICS on the one hand, and
the American-led QUAD on the other, on a variable-geometry
basis. This dualism between the West and the rest of the world
may give rise to a future scenario containing multiple world
orders, where different geographical regions and different
multilateral organisations will play equally important roles in 188 Back to the Future global geopolitics and international relations. This means that
there may not be a single, dominant order, led by a hegemonic
power, but rather an assortment of different orders, which will
coexist and interact with each other along fault-lines having
varying degrees of permeability. As countries like India and Brazil and formations like the
BRICS increase their influence, we are likely to see a closer
balance of power between the world’s major nations, and more
interaction and cooperation between emerging and developed
countries. Disparate national interests will dance together
again as they have not done since the last century, in a manner
reminiscent of the dynamics of the Peace of Westphalia and the
Congress of Vienna. This time, however, the chessboard will be
the whole world, not just Europe. Is This the Road to a New World Order? j
p
In general, the transition towards a new world order has
various complex and uncertain aspects, and will depend
on many factors, including the decisions and actions of
world leaders, international cooperation and economic and
technological developments. What is certain is that the world
order is changing right now, and that Italy, Europe and the
West will need to be ready to cope with its developments.h The future will not therefore be a simple return to the past,
to Mazarin or Castlereagh, but will contain unprecedented
new elements. Firstly, in terms of security and hard power, the
United States will continue to be a superpower. There will be
new threats to global security, however, such as growing and
widespread political instability and tensions between emerging
powers. In economic terms, China will be a key player in the
multipolar economic order of the future. If Beijing succeeds
in regaining its dominant position, it will exert a significant
influence on the world economy. If it fails to do so, however,
a more decentralised economic order shared between multiple
regional areas, is likely to take shape. On the technology front, it remains to be seen whether the
world’s big-data mega-companies will end up dictating the rules 189 Conclusion to governments or vice versa. As technology becomes more
important to society and the economy, technology companies
are steadily consolidating their pivotal influence. This is why
state actors are showing an increasing interest in regulating
them, in order to protect both national security and consumers. This is where Europe, as a regulatory power, has a role to play
and will need to show that it can do so. In environmental terms, we shall need to strike a new balance
between production and energy transition. The climate crisis
is becoming increasingly serious, underscoring the need to
find effective solutions for reducing greenhouse gas emissions
and protecting the environment. Powerful industrial forces,
however, remain enmeshed with the use of fossil fuels, which
are also interconnected with delicate socio-economic balances. It is therefore crucial to find a formula that reconciles the
priorities of the market with the needs of the environment, and
non-state actors, such as private companies, non-governmental
organisations and local communities, are set to play an
increasing role in this formula. This adds a further layer to the
already multi-layered structure of global orders. Is This the Road to a New World Order? y
y
g
The future will therefore present many challenges and
uncertainties. We will need to keep track of how the security
situation, the economy, technology and the environment
evolve, so as to understand how they will affect international
relations and the global players. g
p y
Italy and Europe have a deep well of history to draw upon in
preparation for an unprecedented new scenario. It is therefore
vital that we reflect on the past, not only to avoid replicating
its darkest episodes, but also to glean every possible lesson
from it that might help shape our future as far as possible. The
cost of failing to do so will be a future “return” to an infinitely
less comfortable state than any we have seen in recent history. Only a rigorous exercise in strategic thinking in the present can
ensure our successful “return to the future.” To achieve this, we
need astute leaders who are willing to forego cheap applause in
favour of honest public discourse. About the Authors Luciano Bozzo lectures in International Relations and
Strategic Studies at Florence University’s “C. Alfieri” School
of Political Sciences, where he is also President of the Master’s
degree course in International Relations and European Studies,
Director of the 2nd level Master’s degree course in Leadership
and Strategic Analysis, and Director of the post-graduate
specialist course in Intelligence and National Security. He also
teaches at the Carabinieri Officers’ School in Rome. Franco Bruni is Professor Emeritus of Economics at Bocconi
University. He is Vice-President and joint head of ISPI’s Europe
and Global Governance Observatory. He is also an Honorary
Member of Société Européenne de Recherches Financières
(SUERF) and the Italian Member of the European Shadow
Financial Regulatory Committee (ESFRC). He served as Lead
Co-Chair of the T20’s International Finance working group on
international financial architecture in 2021. He was Co-Chair
of the T20’s International Finance and Economic Recovery
task force for 2022, and Co-Chair of the T7’s International
Cooperation for the Global Common Good task force. Andrea Carati is Associate Professor at the University of
Milan, where he teaches International Relations and Foreign
Policy Analysis. He is an ISPI Associate Research Fellow
in the Security and Strategic Studies programme. Among 192 Back to the Future his publications on NATO are: No Easy Way Out: Origins of
NATO’s Difficulties in Afghanistan (in Contemporary Security
Policy, 2015), Responsibility to Protect, NATO and the Problem
of Who Should Intervene: Reassessing the Intervention in Libya (in
Global Change, Peace & Security, 2017); NATO and the Impact
of the Long War in Afghanistan: Avoiding a Wrong Memory About
ISAF, in M. De Leonardis (ed.), NATO in the Post-Cold War
Era. Continuity and Transformation (2022). Giovanni Carbone is Head of the Africa Programme at ISPI
and Professor of Political Science at University of Milan. His
research focus is the comparative study of politics, geopolitics
and economic development in sub-Saharan Africa, with
particular regard to political institutions. He was previously
a Research Associate at the Crisis States Programme of the
London School of Economics and the Principal Investigator of
a research project funded by the European Research Council
(ERC). His latest book is Political leadership in Africa. Leaders
and development south of the Sahara (with A. Pellegata, 2020). Alessandro Colombo is Professor of International Relations
at Milan University and manages ISPI’s Transatlantic Relations
Programme. About the Authors He has written numerous essays on the conceptual
aspects of international relations and on specific aspects of
regional security problems in Europe. His publications include:
La disunità del mondo. Dopo il secolo globale (2010); Tempi decisivi. Natura e retorica delle crisi internazionali (2014); La grande
trasformazione della guerra contemporanea (2015); Guerra civile
e ordine politico (2021); and Il governo mondiale dell’emergenza. Dall’apoteosi della sicurezza all’epidemia dell’insicurezza (2022). Valter Coralluzzo is Associate Professor of International
Relations and Foreign Policy Analysis at Turin University’s
Department of Culture, Politics and Society. He also lectures
in International Relations and Strategic Studies at SUISS (the
Interdepartmental School of Strategic Sciences) in Turin. He 193 About the Authors also teaches in the Master’s degree course in International
Strategic-Military Studies run by SUISS in collaboration with
CASD (the Centre for Advanced Defence Studies). Coralluzzo
is Director of CISP (the Inter-Disciplinary Centre for Peace
Studies). His publications include: La politica estera dell’Italia
repubblicana (1946-1992) (2000); Conflitti asimmetrici (edited
with M. Nuciari, 2006); Oltre il bipolarismo (2007); Democrazie
tra terrorismo e guerra (editor, 2008); Religioni tra pace e guerra
(edited with L. Ozzano, 2012). To be published soon: Percorsi
di guerra. Fenomenologia dei conflitti armati contemporanei
(editor, 2023). Francesca Frassineti is a Postdoctoral Research Fellow at
the University of Bologna and Associate Research Fellow at
ISPI. She is also Adjunct Professor of History of Contemporary
East Asia at Ca’ Foscari University Venice. Her research mostly
focuses on the domestic, foreign, and security policies of the
Korean Peninsula, EU-Korea relations, and public diplomacy
in East Asia. In March 2020, she was awarded a PhD in Global
and International Studies by the University of Bologna. During
her doctoral studies, she was a visiting researcher at the National
Taiwan University and Korea University. In addition to being
an Emerging Leader at the National Committee on American
Foreign Policy, in 2022, Francesca Frassineti was a Fellow for
the Korea Foundation Next Generation Policy Expert Network
of Chatham House. Paolo Magri is Executive Vice-President of ISPI and teaches
International Relations at Bocconi University. He is a member
of the Strategy Committee of the Ministry of Foreign Affairs,
a member of the Europe Policy Group of the World Economic
Forum (Davos), a member of the Assolombarda Advisory
Board, and a member of the Board of Directors of the Italy-
China Foundation. About the Authors He is also a member of the Military Centre
for Strategic Studies (Ce.Mi.S.S.) and the Italian Foundation
for Charity Donations. In his work as a current affairs journalist, 194 Back to the Future he frequently appears in radio and TV programmes as an expert
on global affairs, American foreign policy, and the Middle East. His publications include: Il marketing del terrore (with Monica
Maggioni, 2016); Il mondo di Obama. 2008-2016 (2016); Il
mondo secondo Trump (2017); Post-vote Iran. Giving Engagement
a Chance (with Annalisa Perteghella, 2017); and Four Years of
Trump. The US and the World (with Mario Del Pero, 2020). he frequently appears in radio and TV programmes as an expert
on global affairs, American foreign policy, and the Middle East. His publications include: Il marketing del terrore (with Monica
Maggioni, 2016); Il mondo di Obama. 2008-2016 (2016); Il
mondo secondo Trump (2017); Post-vote Iran. Giving Engagement
a Chance (with Annalisa Perteghella, 2017); and Four Years of
Trump. The US and the World (with Mario Del Pero, 2020). Giampiero Massolo has been President of Atlantia since
29 April 2022 and President of ISPI since 2017. Ambassador
Massolo, a career diplomat, has served as Director-General of
the Department of Information for Security under the Prime
Minister’s office (2012-16), as Sherpa for the G8 and G20
of the Prime Minister (2008-09), and as Secretary-General
of the Ministry of Foreign Affairs (2007-12). He lectures on
national security issues at the School of Government of LUISS
University in Rome and writes for La Stampa and La Repubblica
on international and security matters. Antonella Mori is Head of ISPI’s Latin America Programme. She holds a PhD in Economics from the Catholic University
of Milan, and MSc in the Economics of Latin America from
the University of London and a BA in Economics and Social
Sciences from Bocconi University. She teaches Macroeconomics
and Economic Prospects at Bocconi University and
Macroeconomics and Political Economy in the Master’s degree
course in Diplomacy at ISPI. In 2011 she received an official
award from the Italian Ministry of Foreign Affairs for having
favoured the strengthening of Italian-Latin American relations. Her main research interests are Latin American economies, and
the economic relations between the EU and Latin America. Lucia Ragazzi is a Research Fellow with the Africa Programme
at ISPI. She has previously worked in research and development
in the fields of African studies and migration. About the Authors She was a project
manager at the University of Liège and an independent editor 195 About the Authors and researcher at the African Studies Centre in Leiden. She was
a trainee at DG INTPA in Brussels, working with the EU-ACP
and EU-African Union Strategic Partnerships. Lucia Ragazzi
holds a Master’s degree in African Relations and Institutions
from the “Orientale” University of Naples. Her work deals with
the politics and international relations of African countries. Armando Sanguini is Senior Scientific Advisor at ISPI. He teaches History and Analysis of International Crises at
LUMSA University (Rome). He started his diplomatic career
as commercial attaché in Ethiopia and then in Spain as Vice-
Ambassador. Ambassador Sanguini was Head of the Italian
diplomatic mission in Chile and Italian Ambassador to Tunisia
and Saudi Arabia. He took part in several short missions in
Canada, China, Japan, Brazil, South Africa, Turkey, Russia
and Venezuela. In Italy, he worked as Deputy Director General
for the Unit responsible for Italians living abroad and foreign
citizens in Italy and as the Assistant Secretary-General for the
reform of the Ministry of Foreign Affairs. As Director General
he worked for the promotion of cultural relations abroad and
was in charge of cultural institutes and Italian schools all over
the world. Sanguini was also General Director for Sub-Saharan
Africa and Personal Representative of the President of the
Council for the entire African continent. Ambassador Sanguini
left his diplomatic post in late 2008. Francesco Sassi is a Research Fellow in energy geopolitics
and markets at RIE, Ricerche Industriali ed Energetiche. He
addresses matters concerning the policies and strategies in the
fields of energy security and diplomacy, investment trends and
global energy scenarios. His main analytical interests are the
Eurasian geopolitical dynamics, the political and economic
effects of the globalisation of the natural gas market and
the relationship between governments, state-owned energy
companies and markets. He holds a PhD in Geopolitics - Political
Science at the University of Pisa. Francesco’s research has been 196 Back to the Future published in several international peer-reviewed journals and
book chapters related to the study of energy geopolitics and the
interactions between government actors and market-based ones
in highly politicised contexts. Also, Francesco has published in several international
newspapers and magazines, and he collaborates, on an ongoing
basis, with the Energy Security Focus of the Italian Parliament
and the Italian Ministry of Foreign Affairs. and International
Cooperation. About the Authors Giulia Sciorati is a Post-Doctoral Research Fellow at
the University of Trento, a Temporary Lecturer in History
of Contemporary China at the Catholic University of the
Sacred Heart, and an Associate Research Fellow at ISPI. Her
research focuses on China’s foreign and security policy, relations
between China and its western neighbours and the country’s
peripheries. She was awarded a PhD in International Studies
by the University of Trento in September 2020. Sciorati was
a visiting researcher at the University of Nottingham (spring
2018) and the University of Oxford (autumn 2021). Lucia Tajoli is Full Professor of Economic Policy at the
Department of Management Engineering of Milan Polytechnic. She is ISPI Senior Associate Research Fellow. She was previously
a lecturer at Bocconi University and then an Associate Professor
at the Polytechnic University of Milan. She received her degree
in Political Economy in 1988 and her PhD in Economics from
Bocconi University in 1994. She currently teaches courses in
Economics, International Economics, International Markets
and European Institutions at the Polytechnic University of
Milan in the undergraduate and postgraduate (MBA, EMBA)
degree programmes. She has been a Visiting Scholar and Visiting
Professor at the University of Michigan’s Ford School of Public
Policy, Ann Arbor (USA), and a Professor in International
Trade Policy and European Integration courses. She has
been invited to many European universities, institutions and About the Authors 197 international conferences as a Speaker and Visiting Professor. Her research activity focuses on theoretical and empirical
issues related to international trade and economic integration
between countries, in particular through the international
fragmentation of production and network analysis applications. On these issues she has published hundreds of scientific papers
in national and international journals and collective volumes,
along with a series of working papers. Ugo Tramballi is a Senior Advisor to and Head of ISPI’s
India desk. He is also an editorial writer for Il Sole 24 Ore
and a member of the Institute of International Affairs. He has
also served as Middle East and Moscow correspondent for Il
Giornale and as global correspondent for Il Sole 24 Ore. He
received the Premiolino Award for journalism in 1987, the
Colombe d’Oro Peace Award in 2003, the Max David Award
in 2005, and the Barzini Award in 2008. His published works
include: L’Ulivo e le pietre: racconto di una terra divisa (2002);
Israele: il sogno incompiuto (2008); India. The Modi Factor
(with N. About the Authors Missaglia, 2017); Mother India (2019); India’s Global
Challenge (with N. Missaglia, 2019); Looking West. The Rise of
Asia in the Middle East (with V. Talbot, 2020). He edits the
Slow News blog on international affairs. Matteo Villa is Senior Research Fellow at ISPI and co-heads
the ISPI Data Lab, monitoring geopolitical and geo-economic
trends (including migration trends and the evolution of the
COVID-19 pandemic). He is a co-chair of the T20 Task
Force on Global Health and Covid-19, as well as a member
of the T20 Task Force on Migration. He undertook his Ph.D. in Comparative Politics at the Graduate School of Social and
Political Sciences at the University of Milan. Formerly, at ISPI,
he oversaw the Energy Watch, edited ISPI/Treccani’s Atlante
Geopolitico, and managed RAstaNEWS, an FP7 EMU-wide
macroeconomic project. Dr. Villa specialises in global health
governance, international migration governance, statistical
modelling, European politics, and energy issues.
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A peculiar case of Campylobacter jejuni attenuated aspartate chemosensory mutant, able to cause pathology and inflammation in avian and murine model animals
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Scientific reports
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cc-by
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A peculiar case of Campylobacter
jejuni attenuated aspartate
chemosensory mutant, able to
cause pathology and inflammation
in avian and murine model animals
L. E. Hartley-Tassell1, C. J. Day1, E. A. Semchenko1, G. Tram1, L. I. Calderon-Gomez1, Z. Klipic1,
A. M. Barry1, A. K. Lam 2, M. A. McGuckin3 & V. Korolik1 Received: 9 February 2018
Accepted: 1 August 2018
Published: xx xx xxxx An attenuated Campylobacter jejuni aspartate chemoreceptor ccaA mutant caused gross pathological
changes despite reduced colonisation ability in animal models. In chickens, the pathological changes
included connective tissue and thickening of the mesenteric fat, as well as the disintegration of the
villus tips in the large intestine, whereas in mice, hepatomegaly occurred between 48–72 hours post
infection and persisted for the six days of the time course. In addition, there was a significant change in
the levels of IL-12p70 in mice infected with the C. jejuni ccaA mutant. CcaA isogenic mutant was hyper-
invasive in cell culture and microscopic examination revealed that it had a “run” bias in its “run-and-
tumble” chemotactic behaviour. The mutant cells also exhibited lower level of binding to fucosylated
and higher binding to sialylated glycan structures in glycan array analysis. This study highlights the
importance of investigating phenotypic changes in C. jejuni, as we have shown that specific mutants can
cause pathological changes in the host, despite reduction in colonisation potential. Campylobacter infections are one of the top four key global causes of bacterial gastroenteritis world-wide1. Campylobacter jejuni is widely regarded as a commensal of the avian gut, and chickens, specifically, are consid-
ered to be the major vector for this zoonotic illness1–3. In humans, however, infection results in severe gastroen-
teritis in which the pathology presents as severe active inflammation of the intestinal mucosa with an influx of
phagocytes4–6.h g
y
There are several colonisation factors, which contribute to the infection of the human gastrointestinal tract
and colonisation of the avian gut as a commensal. These factors include chemotaxis, motility, capsule formation,
two-component regulatory systems, invasion and iron regulation (reviewed in7). Specifically, chemotaxis and
motility have been implicated in colonisation and virulence of C. jejuni8,9. During infection in humans, C. jejuni
invades and traverses the intestinal epithelium5,10, causing disruption to the epithelium and gaining access to the
basal side11. Infection also stimulates the innate immune system with upregulation of the inflammatory cytokines
Il-1β, IL-8 and nitric oxide12.hf The study of host-pathogen interactions of C. jejuni suffer due to a paucity of suitable animal models which
accurately mimic human campylobacteriosis. However, animal models of colonisation and infection, such as
chickens13–15 and mice16–18, are commonly used to elucidate interactions of C. jejuni with its hosts. www.nature.com/scientificreports www.nature.com/scientificreports www.nature.com/scientificreports 1Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia. 2School of Medicine and
Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, 4222, Australia. 3Translational
Research Institute, Mater Research, Brisbane, Queensland, 4102, Australia. Correspondence and requests for
materials should be addressed to V.K. (email: v.korolik@griffith.edu.au) Received: 9 February 2018
Accepted: 1 August 2018
Published: xx xx xxxx www.nature.com/scientificreports/ infection and disease is unrealistic compared to the immunocompetent response. Despite these limitations,
murine models are extensively used to study all aspects of C. jejuni colonisation22,23. infection and disease is unrealistic compared to the immunocompetent response. Despite these limitations,
murine models are extensively used to study all aspects of C. jejuni colonisation22,23. y
y
j j
Alternatively, study by McAuley et al.18, showed that 129/SvJ background mice were susceptible to persistent
colonisation by C. jejuni which localised in digestive and systemic organs of these mice18. While 129/SvJ mice are
useful as a colonisation and not a disease model, similar to that with other murine models, they are immunocom-
petent and can provide useful information of a mammalian immune response to colonisation with C. jejuni and
its isogenic mutants. g
One major contrast between the human and avian hosts, is that C. jejuni infection in chickens does not typ-
ically lead to the same symptoms and pathological inflammatory response as in humans24. The physiological
reasons for this are yet to be elucidated. There is however conflicting evidence as to whether campylobacters can
adhere to or invade the chicken gut, and if indeed campylobacters are a commensal2,25. C. jejuni is commonly
found in the mucus layer, and especially in the deep crypts of the caecum8, and some evidence suggests that cam-
pylobacters have the ability to traverse the intestinal epithelium, as bacteria have been recovered in the liver and
lungs of young chicks26. Recent studies have also suggested that C. jejuni infection in the chicken gut initiates an
innate immune response27 which has also been shown in avian cell lines with stimulation of pro-inflammatory
cytokine response28.hf y
p
The differences in C. jejuni relationship with its human and animal hosts had been a subject of intense specu-
lation with little evidence to support any of the theories. However, genes involved in flagella, motility and chem-
otaxis, as either receptors or other elements of chemotaxis machinery, have been shown to be important for
colonisation of the gastrointestinal tract of chickens6,15. Additionally, chemotaxis genes were shown to be differ-
entially expressed in C. jejuni cells isolated from a chicken host, as well as the genes involved in electron transport
and the central metabolic pathways29. Changes in sensory receptor gene expression have also been described for
C. Results Colonisation potential in the murine model. To analyse the colonisation deficiency of the C. jejuni
aspartate receptor mutant, the colonisation potential of C. jejuni 11168-O and 11168-OΔccaA::cat was compared
in 129/SvJ mice over a 6 day period. The post-mortem analyses of mice intestinal content on day 6 post-inocu-
lation showed that the average bacterial load in the large intestine of mice infected with wild type 11168-O was
1.2 × 104 cfu/g, while mice infected with 11168-OΔccaA::cat had an average bacterial load of 1 × 101 cfu/g. This
indicated a 3-log reduction in presence of 11168-OΔccaA::cat cells in the large intestine, when compared to that
of 11168-O wild-type (p < 0.001) (Fig. 1). It should be noted that infection with 11168-OΔccaA::cat resulted in
a reduction in colonisation for the avian host of 1.5-log, (reported previously31). Selective plating of the viable
bacteria recovered from the post-mortem intestinal content from the co-infection of the mice with wild-type and
mutant CcaA, showed that >98.8% of bacteria present in the small and large intestines was wild-type 11168-O
(p > 0.25) on day 6p.i. The average bacterial load in both the small and large intestine for the 11168-O wild-type
as sole inoculum and for co-infection with the ccaA mutant were not statistically different at day 6p.i. (students
T-test, p > 0.05). Post-mortem analysis of affected murine tissues. Importantly, when mice were sacrificed on day 6p.i.,
prominent gross pathological differences were observed in the mice infected with 11168-OΔccaA::cat, when
compared to those infected with 11168-O wild-type. Despite the reduced bacterial load, the liver of the mice
infected with 11168-OΔccaA::cat appeared noticeably larger. The livers of mice infected with 11168-OΔccaA::cat
were significantly larger in weight (p < 0.01) when compared to the other groups with mean weight of 1.3 g on day
6p.i., a 60–80% increase in liver weight. Upon dissection of the gastrointestinal tract, the mesenteric lymph nodes
were visually more prominent in mice infected with 11168-OΔccaA::cat when compared to 11168-O wild-type. Additionally, the Peyer’s patches were enlarged along the entire length of the intestine, for both 11168-O and
11168-OΔccaA::cat (not shown). Four-day time course murine infection trial. To ascertain the progression of the pathological changes
in the mice, induced by 11168-OΔccaA::cat isogenic mutant, a time course experiment was conducted at time
points of 24, 48, 72 and 96 hours post inoculation. (Table S1). www.nature.com/scientificreports/ jejuni strains 11168-O, 11168-GS, 81116 and 520 when isolated from different sources, including the intestine
of mice and chickens30. We have previously shown that a mutation of the sensory domain of the aspartate chemosensor CcaA of the
original (Skirrow) isolate of C. jejuni, NCTC 11168-O, resulted in a “run” chemotactic motility bias, a reduced
ability to colonise the gastrointestinal tract of chickens and increased efficiency in invasion of Caco-2 cells when
compared to the 11168-O wild type and ccaA−/+ complemented strains31. Since CcaA appears to play an impor-
tant role in colonisation of the chicken, the effect of a mutation in ccaA of C. jejuni 11168-O on interaction with
both the avian and mammalian hosts needed to be assessed further.f In this study, we describe systematic analysis of the effect of C. jejuni 11168-O CcaA mutation on the inter-
action of the bacteria with avian and mammalian hosts during different stages of colonisation as compared with
the parental wild type strain. Here we report the first observation and analysis of abnormal gross pathology of
the liver in a murine model, and thickening of the mesenteric fat around the intestinal connective tissue in the
chicken model, following infection with C. jejuni ccaA mutant, but not when infected with wild type or comple-
mented mutant strain, as we described previously31. We further report the of the isogenic mutant’s ability to bind
simple and complex glycans as well as the expression profiles of the pro-inflammatory cytokines in the avian and
murine model were investigated in response to infection with C. jejuni 11168-O and its isogenic ccaA mutant A peculiar case of Campylobacter
jejuni attenuated aspartate
chemosensory mutant, able to
cause pathology and inflammation
in avian and murine model animals
L. E. Hartley-Tassell1, C. J. Day1, E. A. Semchenko1, G. Tram1, L. I. Calderon-Gomez1, Z. Klipic1,
A. M. Barry1, A. K. Lam 2, M. A. McGuckin3 & V. Korolik1 The use of mice
however, as a campylobacter infection model has proven problematic, as most wild-type laboratory mouse strains
are susceptible only to a short transient infection of the gut with no discernible symptoms. In order to elicit a dis-
ease phenotype upon infection, mouse models have subsequently been adapted by employing SIGIRR-deficient
(−/−) or IL-10(−/−) mice19–21. However, these mice are immunocompromised and the establishment of 1Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia. 2School of Medicine and
Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, 4222, Australia. 3Translational
Research Institute, Mater Research, Brisbane, Queensland, 4102, Australia. Correspondence and requests for
materials should be addressed to V.K. (email: v.korolik@griffith.edu.au) ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 1 1 www.nature.com/scientificreports/ Results The bacterial counts from lungs, liver and spleen for ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 2 www.nature.com/scientificreports/ small intestine
large intestine
100
101
102
104
105
106
Log CFU/gram
103
Figure 1. Bacterial load for the small intestine and large intestine at day 6 post-inoculation. Data is displayed
as log cfu per gram of intestinal content, n = 5. 11168-O (□), 11168-OΔccaA::cat (Δ), negative non-infected
control (○), competition 11168-O WT and ΔccaA::cat (◊). Bar indicates average cfu/gram for each group. <10 cfu/gram of intestinal content was detected for 11168-OΔccaA::cat and mock infected. Broken line
indicates level of sensitivity. small intestine
large intestine
100
101
102
104
105
106
Log CFU/gram
103
Figure 1. Bacterial load for the small intestine and large intestine at day 6 post-inoculation. Data is displayed
l
f
f i t ti
l
t
t
5 11168 O (□) 11168 OΔ
A
t (Δ)
ti
i f
t d small intestine
large intestine
100
101
102
104
105
106
Log CFU/gram
103 Figure 1. Bacterial load for the small intestine and large intestine at day 6 post-inoculation. Data is displayed
as log cfu per gram of intestinal content, n = 5. 11168-O (□), 11168-OΔccaA::cat (Δ), negative non-infected
control (○), competition 11168-O WT and ΔccaA::cat (◊). Bar indicates average cfu/gram for each group. <10 cfu/gram of intestinal content was detected for 11168-OΔccaA::cat and mock infected. Broken line
indicates level of sensitivity. Figure 2. Liver weights in mice. The mean of each group is shown as a bar. 11168-O (□), 11168-OΔccaA::cat
(Δ), negative non-infected control (○). Average weight is shown as a bar for each group at each time point. *p < 0.05 ANOVA, 11168-OΔccaA::cat weights are greater than 11168-O and negative groups at 48, 72 and
96 hours post inoculation. N = 3–10 mice. Figure 2. Liver weights in mice. The mean of each group is shown as a bar. 11168-O (□), 11168-OΔccaA::cat
(Δ), negative non-infected control (○). Average weight is shown as a bar for each group at each time point. *p < 0.05 ANOVA, 11168-OΔccaA::cat weights are greater than 11168-O and negative groups at 48, 72 and
96 hours post inoculation. N = 3–10 mice. mice singly infected with 11168-O or 11168-OΔccaA::cat were not statistically different (p < 0.05), and there was
no difference in bacterial load in the duodenum, small or large intestine (p > 0.05). Results Post-mortem analysis of affected murine tissues, 4 day time course trial. Further post-mortem
analysis of mice during the time course trial, showed no difference in liver weight (as a percentage of body weight)
at 24 h p.i. when comparing the mock-infected control, 11168-O and 11168-OΔccaA::cat inoculated animals
(p > 0.18). However, at 48 h post-inoculation, the liver weight for 11168-OΔccaA::cat inoculated group was sig-
nificantly higher than those inoculated with 11168-O and negative controls (p < 0.02, Fig. 2). For the mice inocu-
lated with 11168-OΔccaA::cat, an average increase of 23% in relative liver size was observed after 48 h (Fig. 2). In
order to determine if this phenomenon persisted long-term mice, mice were sacrificed on day 14p.i. There was no
statistical difference in the relative liver size for all groups, indicating that this pathology was only present during
the acute infection period (data not shown). Histopathological analysis of the systemic and digestive organs of mice infected with C. jejuni
11168-O or 11168-OΔccaA::cat. To further examine the pathological differences seen in the mice
infected with isogenic mutant strain of C. jejuni 11168-O, histological samples for the systemic and digestive
organs were taken for each mouse at every time point (24–96 h p.i.), and scored blindly according to tissue pathol-
ogy using haematoxylin and eosin (H&E) staining.fli Pathological differences were noted in the severity of inflammatory cells infiltration into the crypts of the
mid-colon, which was found to be significantly higher in 11168-OΔccaA::cat infected mice when compared
to that of the 11168-O group and non-infected control groups (p < 0.05) as shown in Table S2. Goblet cell loss
within the small intestine was observed in all groups, in conjunction with some goblet cell hyperplasia. There was, ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 3 www.nature.com/scientificreports/ however, no statistical difference in the extent of goblet cell loss or hyperplasia dependent on inoculum or time
point (p > 0.05). Paneth cells were prominent in 11168-OΔccaA::cat-infected mice at 24 h (1/10) and 48 h (4/10),
this, however, was not statistically significant. There was also evidence of C. jejuni present within the goblet cells
of the mid and distal colon in 11168-OΔccaA::cat-infected mice, however this was not consistently observed
within the group (7/40). The liver was scored in terms of nuclei enlargement, blood vessel dilation and granula-
tion. There were no significant differences between the groups. Results jejuni in systemic organs was assessed by enumeration of bacte-
rial load within each chicken at time points of 24, 48, 72 and 96 h p.i. (Table S4). Despite the changes in gross
pathology, there was no statistical difference between the overall bacterial counts in the systemic organs, small or
large intestine for animals infected with 11168-O and 11168-OΔccaA::cat isogenic strains at any time point. The
average bacterial counts in the liver for chickens infected with 11168-OΔccaA::cat was 2.5 × 102 cfu/gram, when
compared to 11168-O which was 1 × 102 cfu/gram. There was no statistical difference in the bacteria present in
the for chickens infected with 11168-O or 11168-OΔccaA::cat. Post-mortem analysis of affected avian tissues. Since gross pathological differences were seen
in chickens, the remainder of each tissue collected from the animals during the time course experiment was
examined histologically. The H & E stained sections of the tissues were scored blindly according to tissue
pathology, Table S5. There was no significant difference in pathology between 11168-OΔccaA::cat, 11168-O
and non-infected controls for the lungs, liver, spleen, and small intestines. However, there was a statistical dif-
ference in the extent of villus epithelium shedding observed in the large intestine of chickens infected with
11168-OΔccaA::cat which was significantly higher than that for 11168-O or non-infected controls (p < 0.02). Epithelial shedding was characterised by disintegration of the tips of the villi as shown in Fig. 4. Analysis of adhesion and invasion ability of 11168-O and 11168-OΔccaA::cat mutant in cell
culture assays. Since high numbers of C. jejuni were recovered from the chicken lung homogenate, the abil-
ity of C. jejuni to adhere and invade a lung cell line was investigated. A549 human lung adenocarcinoma cell line
was used, noting that the avian lung differs to the mammalian lung, as it does not have alveoli and some surface
glycans on the cells also differ. The results from the in vitro cell culture using A549 cells showed that 11168-O was
less adherent (0.22%) when compared to 11168-OΔccaA::cat (1.15%) although the difference was not significant
(p = 0.058). There was, however, a statistically significant difference between the invasion ability of 11168-O and
11168-OΔccaA::cat, showing that 11168-OΔccaA::cat was highly invasive, with 2.24% of adhered bacteria invad-
ing the cells (p < 0.001), compared to 0.003% for 11168-O wild-type strain, as shown in Fig. 5. g
p
p
yp
g
Since viable C. Results No significant differences were noted for the lungs,
liver and spleen or in the tissues of proximal or distal colon obtained from mice infected with 11168-OΔccaA::cat,
11168-O or non-infected controls. Single-cell tracking microscopic analysis. Unlike other attenuated chemoreceptor mutants previously
reported32,33, the mutation of the aspartate receptor CcaA resulted in an increase, rather than the decrease, in
both adherence and invasion of cultured Caco-2 cells. This unusual phenotype of the CcaA mutant could be
related to a “run” chemotactic behaviour was investigated further. Single-cell tracking of wild-type, mutant and
complemented C. jejuni isogenic strains showed that the mutant had increased linear displacement over 1 second
in time (Table S3, p < 0.005) confirming a run-biased phenotype, compared to 11168-O and the ccaA−/+ comple-
ment which both showed tumbling and running phenotypes. This was further confirmed by a swarm plate assay
(Table S3). Colonisation potential in the avian model. A competitive co-infection assay was used to determine
the fitness of the isogenic mutant 11168-OΔccaA::cat. Co-infection of chickens with both C. jejuni 11168-O and
11168-OΔccaA::cat, showed that only the wild type strain could be could be recovered after 24, 48, 72 and 96 h
following inoculation (p < 0.01). g
p
It was also noted that when the chickens were sacrificed on day 5 post-inoculation, similar to that seen
in the murine host, prominent gross pathological differences were observed in the chickens infected with
11168-OΔccaA::cat, when compared to those infected with 11168-O wild-type or the ccaA−/+ complement. Despite the reduced bacterial load, the intestines were surrounded by fluid and rope-like thickening of the mes-
enteric fat (Fig. 3). Four-day time course avian colonisation trial. To ascertain the time of appearance of the pathological
changes induced by 11168-OΔccaA::cat isogenic mutant, a time course experiment was then conducted whereby
groups of ten day-old chicks, inoculated with C. jejuni mutant and wild type strains, were sacrificed and dissected
every 24 h, over a 96 h period. Histological examination revealed thickening of the mesenteric fat at 72 h with
increasing evidence at 96 h. Interestingly, no diarrhoea was noted for this group of chickens. In contrast, for the
chicks infected with 11168-OΔccaA::cat, stools appeared firm and pellet-like in contrast to typical loose cloacal
secretions normally observed for chickens colonised with wild type C. jejuni strains, including 11168-O.h The severity and extent of infection of C. Results jejuni 11168-OΔccaA::cat was recovered from mice livers with hepatomegaly, the abil-
ity of C. jejuni to adhere to and invade a liver cell line was investigated. The adherence levels of 11168 and
11168-OΔccaA::cat in vitro cell culture of Hep-G2, human hepatocellular liver carcinoma cell line were higher for
11168-OΔccaA::cat at 0.78% when compared to that for 11168-O at 0.1% (p < 0.01, Fig. 6). The isogenic mutant
11168-OΔccaA::cat was also more invasive, with 0.925% of adhered bacteria invading the cells (p < 0.001), com-
pared to 0.0457% for 11168-O. Glycan binding profile of C. jejuni isolated from avian hosts. Glycan array analysis of the bacterium
isolated from the caecum of chicks was performed in order to determine if the host glycan binding profile has ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 4 www.nature.com/scientificreports/ www.nature.com/scientificreports/ Figure 3. Pathology of the chick gut day 5 post inoculation. (A) Chick infected with C. jejuni 11168-0. (B)
Chick infected with C. jejuni 11168-0ΔccaA::cat. Arrows show areas for visual comparison of the mesenteric fat
surrounding the intestines. Figure 3. Pathology of the chick gut day 5 post inoculation. (A) Chick infected with C. jejuni 11168-0. (B)
Chick infected with C. jejuni 11168-0ΔccaA::cat. Arrows show areas for visual comparison of the mesenteric fat
surrounding the intestines. altered with the mutation of the CcaA. Glycan array analysis of whole cell C. jejuni was performed as previously
described by Day et al., 2013, whereby glycans (Table S6) were tested for binding by C. jejuni 11168-GS and
11168-O isolated from the caecal content of chicks at day 5p.i. by IMS34. The binding specificities of 11168-O
and 11168-OΔccaA::cat were compared and only statistically significant differences (p < 0.05) are described
in Table 1. C. jejuni 11168-OΔccaA::cat had reduced ability to bind type II fucosylated structures, including
lacto-N-fucopentaose II, Lewisy, blood group H type II trisaccharide and monofucosyllacto-N-hexaose III. The
mutant did however display significantly stronger binding to both 3′-sialyllactosamine and 6′-sialyllactosamine
compared to the wild type 11168-O. altered with the mutation of the CcaA. Glycan array analysis of whole cell C. jejuni was performed as previously
described by Day et al., 2013, whereby glycans (Table S6) were tested for binding by C. jejuni 11168-GS and
11168-O isolated from the caecal content of chicks at day 5p.i. by IMS34. The binding specificities of 11168-O
and 11168-OΔccaA::cat were compared and only statistically significant differences (p < 0.05) are described
in Table 1. Results C. jejuni 11168-OΔccaA::cat had reduced ability to bind type II fucosylated structures, including
lacto-N-fucopentaose II, Lewisy, blood group H type II trisaccharide and monofucosyllacto-N-hexaose III. The
mutant did however display significantly stronger binding to both 3′-sialyllactosamine and 6′-sialyllactosamine
compared to the wild type 11168-O. Immune response in the murine model - Mouse CBA inflammatory cytokine array. In order to
analyse the differences in the immune response triggered by the wild type and the aspartate mutant of C. jejuni,
inflammatory cytokine levels were examined. A significant change was seen in the levels of IL-12p70 within the
C. jejuni 11168-OΔccaA::cat group, with higher levels detected at 48 h and 72 h when compared to the levels
at 24 h p.i.(p < 0.05). There appeared to be no other differences in inflammatory cytokine levels between the
non-infected control animals and those infected with either the C. jejuni 11168-O or C. jejuni 11168-OΔccaA::cat
at 24 h, 48 h or 72 h p.i. (Fig. 7A–C). Quantitation of inflammatory cytokine expression in chicken by qPCR. Similar to the murine
host, the inflammatory response of avian host was also examined. RNA extracted from the large intestine of the
chickens at 24 h and 96 h time points, cDNA was isolated and qPCR was performed investigating the levels of the
inflammatory cytokines IL-8, IL-1β, IL-6, CXCLi1, TNFα and IFNγ. At 24 h p.i., the cytokine levels of IL-8, IL-1β,
CXCLi1 and TNFα in chicks infected with both C. jejuni 11168-O and the ccaA mutant showed no significant
change in expression. There was however a significant decrease in expression of IFNγ for both WT and mutant
infected chicks (Fig. 8A).i g
At 96 h p.i., the expression of IL-1β, IL-6, TNFα and IFNγ in WT infected chicks was significantly less than the
evels determined in the uninfected control group. The expression of these cytokines IL-1β, IL-6, TNFα and IFNγ ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 5 www.nature.com/scientificreports/ www.nature.com/scientificreports/ p
/
Figure 4. Haematoxylin and eosin (H&E) stained cross sections of the large intestine of chickens infected with
11168-OΔccaA::cat or 11168-O. (A) H&E stained section of large intestine of chicken infected with 11168-O. (B) H&E stained section of large intestine of chicken infected with 11168-OΔccaA::cat. LP: Lamina propria, C:
Crypt of villi, VT: Villi tip. Figure 4. Haematoxylin and eosin (H&E) stained cross sections of the large intestine of chickens infected with
11168-OΔccaA::cat or 11168-O. Results CcaA indicates
significantly stronger binding of 11168-OΔccaA::cat to the specific glycan compared to 11168-O. Table 1. Glycan binding profile of C. jejuni isolated from avian hosts. WT indicates significantly stronger
binding of C. jejuni 11168-O to the specific glycan compared to 11168-OΔccaA::cat. CcaA indicates
significantly stronger binding of 11168-OΔccaA::cat to the specific glycan compared to 11168-O. of known virulence genes was investigated. The analysis of gene expression profiles of porA, peb1A and cdtABC
in C. jejuni cells isolated directly from the chicken caeca and from mouse intestinal tract (by IMS) showed that
there was no difference in expression in porA or peb1A for 11168-O when compared to 11168-OΔccaA::cat when
grown at 37 °C or 42 °C in vitro (core temperature of mammals and avians respectively). Interestingly, when
grown in the chicken host, the expression of porA was not detectable in the wild type strain 11168-O whereas
porA was highly expressed in the isogenic mutant 11168-OΔccaA::cat. In the mouse host, however, both were
equally expressed. In 11168-OΔccaA::cat, there was no statistical difference in the level of expression of porA and
peb1A in vivo when compared to in vitro at 42 °C (Fig. S1). of known virulence genes was investigated. The analysis of gene expression profiles of porA, peb1A and cdtABC
in C. jejuni cells isolated directly from the chicken caeca and from mouse intestinal tract (by IMS) showed that
there was no difference in expression in porA or peb1A for 11168-O when compared to 11168-OΔccaA::cat when
grown at 37 °C or 42 °C in vitro (core temperature of mammals and avians respectively). Interestingly, when
grown in the chicken host, the expression of porA was not detectable in the wild type strain 11168-O whereas
porA was highly expressed in the isogenic mutant 11168-OΔccaA::cat. In the mouse host, however, both were
equally expressed. In 11168-OΔccaA::cat, there was no statistical difference in the level of expression of porA and
peb1A in vivo when compared to in vitro at 42 °C (Fig. S1). p
p
g
Expression of cdtA and C, but not B was significantly higher in 11168-OΔccaA::cat when compared to
11168-O when it was culture in vitro at 37 °C (p < 0.05; Fig. S1). The expression of cdtA in both 11168-O and
11168-OΔccaA::cat isolated from chickens was up-regulated. Results (A) H&E stained section of large intestine of chicken infected with 11168-O. (B) H&E stained section of large intestine of chicken infected with 11168-OΔccaA::cat. LP: Lamina propria, C:
Crypt of villi, VT: Villi tip. Figure 5. Adherence and Invasion of C. jejuni of in vitro cell culture model using A549 lung epithelial cells. Adherence analysis (black) and invasion (grey) of E. coli DH5α, C. jejuni 11168-0 and 11168-OΔccaA::cat. Results are presented as mean ± SEM adherence or invasion from six to nine wells of a 24-well plate. Two tailed
t-test showed no significant increase in adherence of 11168-OΔccaA::cat compared to wild-type, p = 0.058, and
a significant increase in invasion of 11168-OΔccaA::cat compared to wild-type (Student’s T-test, p < 0.001). Figure 5. Adherence and Invasion of C. jejuni of in vitro cell culture model using A549 lung epithelial cells. Adherence analysis (black) and invasion (grey) of E. coli DH5α, C. jejuni 11168-0 and 11168-OΔccaA::cat. Results are presented as mean ± SEM adherence or invasion from six to nine wells of a 24-well plate. Two tailed
t-test showed no significant increase in adherence of 11168-OΔccaA::cat compared to wild-type, p = 0.058, and
a significant increase in invasion of 11168-OΔccaA::cat compared to wild-type (Student’s T-test, p < 0.001). were all significantly higher for the mutant C. jejuni 11168-OΔccaA::cat group than for the WT control group,
and for IL-1β and IFNγ the expression is also statistically greater than the uninfected control levels (Fig. 8B). At no time point was there any significant change in the expression of IL-8 cytokine or the CXCLi1 chemokine. xpression of porA, peb1A cdtA, cdtB and cdtC. To ascertain if the “run” phenotype of the aspartate
eceptor mutant was responsible for the observed pathological changes in the infected animals, the expression Expression of porA, peb1A cdtA, cdtB and cdtC. To ascertain if the “run” phenotype of the aspartate
receptor mutant was responsible for the observed pathological changes in the infected animals, the expression ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 6 www.nature.com/scientificreports/ Figure 6. Adherence and Invasion of C. jejuni of in vitro cell culture model using Hep-G2 liver cells. Black)
Adherence analysis (black) and invasion (grey) of E. coli DH5α, C. jejuni 11168-0 and 11168-OΔccaA::cat. Results are presented as mean adherence from six to nine wells of a 24-well plate. Standard errors are shown
as bars above the mean. Results Two tailed t-test showed a significant increase in adherence of 11168-OΔccaA::cat
compared to wild-type, (p < 0.01) and a significant increase for invasion for the ccaA mutant compared to wild-
type (p < 0.001). Figure 6. Adherence and Invasion of C. jejuni of in vitro cell culture model using Hep-G2 liver cells. Black)
Adherence analysis (black) and invasion (grey) of E. coli DH5α, C. jejuni 11168-0 and 11168-OΔccaA::cat. Results are presented as mean adherence from six to nine wells of a 24-well plate. Standard errors are shown
as bars above the mean. Two tailed t-test showed a significant increase in adherence of 11168-OΔccaA::cat
compared to wild-type, (p < 0.01) and a significant increase for invasion for the ccaA mutant compared to wild-
type (p < 0.001). Compound
Strain
Structure
β1-6 Galactosyl-N-acetyl glucosamine
WT
ASialo GM1
Lacto-N-neohexaose
WT
Type I
Lacto-N-hexaose
WT
Type II
GalNAcα1-3Galβ1-4Glc
CcaA
Type I
β1-2 N-Acetylglucosamine-mannose
CcaA
N-type glycan
α1-3,α1-6-Mannobiose
WT
BiMan
α1-3,α1-3α,α1-6-Mannopentaose
CcaA
OligoMan
Lacto-N-fucopentaose II
WT
Type II-fucosylated
Lewisy
WT
Type II-fucosylated
Blood group H type II trisaccharide
WT
Type II-fucosylated
Monofucosyllacto-N-hexaose
WT
Type II-fucosylated
3′-Sialyllactosamine
CcaA
Type II-sialylated
6′-Sialyllactosamine
CcaA
Type II-sialylated
Colominic acid
WT
Oligo Sialic acid
ΔUA-GlucNS-6S
CcaA
Digests of GAGs
ΔUA-GalNAc-4S,6S (Delta Di-disE)
CcaA
Digests of GAGs
Table 1. Glycan binding profile of C. jejuni isolated from avian hosts. WT indicates significantly stronger
binding of C. jejuni 11168-O to the specific glycan compared to 11168-OΔccaA::cat. CcaA indicates
significantly stronger binding of 11168-OΔccaA::cat to the specific glycan compared to 11168-O. Compound
Strain
Structure
β1-6 Galactosyl-N-acetyl glucosamine
WT
ASialo GM1
Lacto-N-neohexaose
WT
Type I
Lacto-N-hexaose
WT
Type II
GalNAcα1-3Galβ1-4Glc
CcaA
Type I
β1-2 N-Acetylglucosamine-mannose
CcaA
N-type glycan
α1-3,α1-6-Mannobiose
WT
BiMan
α1-3,α1-3α,α1-6-Mannopentaose
CcaA
OligoMan
Lacto-N-fucopentaose II
WT
Type II-fucosylated
Lewisy
WT
Type II-fucosylated
Blood group H type II trisaccharide
WT
Type II-fucosylated
Monofucosyllacto-N-hexaose
WT
Type II-fucosylated
3′-Sialyllactosamine
CcaA
Type II-sialylated
6′-Sialyllactosamine
CcaA
Type II-sialylated
Colominic acid
WT
Oligo Sialic acid
ΔUA-GlucNS-6S
CcaA
Digests of GAGs
ΔUA-GalNAc-4S,6S (Delta Di-disE)
CcaA
Digests of GAGs
Table 1. Glycan binding profile of C. jejuni isolated from avian hosts. WT indicates significantly stronger
binding of C. jejuni 11168-O to the specific glycan compared to 11168-OΔccaA::cat. CcaA indicates
significantly stronger binding of 11168-OΔccaA::cat to the specific glycan compared to 11168-O. Table 1. Glycan binding profile of C. jejuni isolated from avian hosts. WT indicates significantly stronger
binding of C. jejuni 11168-O to the specific glycan compared to 11168-OΔccaA::cat. Results In contrast CdtA and B expression in 11168-O was
up-regulated in vivo compared to in vitro culture grown at 42 °C, while cdtB and C were up-regulated in vitro
for 11168-OΔccaA::cat, when gene expression levels were compared to those observed for 11168-O at 42 °C
(p < 0.05). Most importantly, however, the expression of cdtABC in vivo, in a chicken and mouse host did not
show statistical difference in expression (p > 0.05). This indicates that although the overall expressions of the
three CDT subunits results showed that gene expression is variable at different temperatures, and expression is
regulated in vivo. These genes are unlikely to be involved in the observed gross pathology. 7 ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 www.nature.com/scientificreports/ Figure 7. Proinflammatory cytokine concentrations in the small intestine of mice infected with C. jejuni. Proinflammatory cytokine concentrations were determined by CBA array at time points of (A) 24 h,
(B) 48 h and (C) 72 h, n = 7. Cytokine levels of non-infected (black), 11168-O wild-type (light grey) and
11168-OΔccaA::cat (mid grey). No statistical differences were noted (ANOVA, p < 0.05). Figure 7. Proinflammatory cytokine concentrations in the small intestine of mice infected with C. jejuni. Proinflammatory cytokine concentrations were determined by CBA array at time points of (A) 24 h,
(B) 48 h and (C) 72 h, n = 7. Cytokine levels of non-infected (black), 11168-O wild-type (light grey) and
11168-OΔccaA::cat (mid grey). No statistical differences were noted (ANOVA, p < 0.05). ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 Discussion Discussion
Mutational analyses are a classical method for determining gene function and attenuation of virulence, particu-
larly when assessing potential antimicrobial targets. C. jejuni, a commensal in poultry and pathogen in humans,
has also been a subject to many such analyses. j
y
y
Previous avian colonisation studies using various C. jejuni chemosensory pathway mutants, did not report
any pathological changes13,32,33. This study revealed that despite attenuation of colonisation in both the murine
and avian models, gross pathological changes were observed in both mice and chickens infected with the C. jejuni
aspartate chemoreceptor mutant ccaA, including connective tissue and fat roping in chickens and hepatomegaly
in mice. The ability of the ccaA mutant to produce pathological changes in animal hosts is a novel and unusual
observation.i Specifically, the appearance of intestinal roping was noted at 72 h p.i. along with the disintegration of the tips
of the villi in the large intestine of chickens infected with the ccaA mutant, which persisted throughout the entire
96 hour examination period and correlated to the chicken stools appearing unusually firm and pellet-like. This
too was unexpected as it has been well established that in humans C. jejuni infection is characterised by diarrhoea
whereas in the chickens, C. jejuni colonisation is asymptomatic.h j j
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p
The hardened appearance of the faeces in chickens infected with the ccaA mutant may be due to dis-regulation
of CDT toxin production, causing the faeces to become drier and more solid, compared to normal faeces. In
humans, the cytolethal distending toxin, CDT, is thought to destroy the mucosal epithelium, cause secretory ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 8 www.nature.com/scientificreports/ Figure 8. Cytokine levels in chickens determined by qPCR. Relative expression levels of the inflammatory
cytokines in chicken large intestines at 24 h (A) or 96 h (B), non-infected control (Black), 11168-O WT (light
grey) and 11168- OΔccaA::cat (mid grey), n = 5. Expression is standardised and the scale is shown in log
(copies per 108 28S). Statistically significant differences are indicated by *, Student’s T-test (p < 0.01). Figure 8. Cytokine levels in chickens determined by qPCR. Relative expression levels of the inflammatory
cytokines in chicken large intestines at 24 h (A) or 96 h (B), non-infected control (Black), 11168-O WT (light
grey) and 11168- OΔccaA::cat (mid grey), n = 5. Expression is standardised and the scale is shown in log
(copies per 108 28S). Discussion Statistically significant differences are indicated by *, Student’s T-test (p < 0.01). diarrhoea and necrosis of the colonic epithelium35. Although in chickens, cdt toxin genes are expressed, no symp-
toms of diarrhoea are usually observed36. The expression of the CDT toxin genes, however, may contribute toward
the usually observed appearance of semi-solid chicken faeces. This change in the consistency of the cloacal secre-
tions may contribute to the damage to the villus epithelium in the large intestine as was seen in the histological
sections. The cdtA gene expression by ccaA isogenic mutant cells isolated from chickens was up-regulated as was
the expression of cdtB in the mutant cells isolated from the mouse. This was in agreement with a previous study
showing that in chickens the cdtA/C subunits could be up-regulated34. Therefore, while it may be a contributing
pathogenicity factor, it is possible to speculate that they are unlikely to account for the observed pathology. diarrhoea and necrosis of the colonic epithelium35. Although in chickens, cdt toxin genes are expressed, no symp-
toms of diarrhoea are usually observed36. The expression of the CDT toxin genes, however, may contribute toward
the usually observed appearance of semi-solid chicken faeces. This change in the consistency of the cloacal secre-
tions may contribute to the damage to the villus epithelium in the large intestine as was seen in the histological
sections. The cdtA gene expression by ccaA isogenic mutant cells isolated from chickens was up-regulated as was
the expression of cdtB in the mutant cells isolated from the mouse. This was in agreement with a previous study
showing that in chickens the cdtA/C subunits could be up-regulated34. Therefore, while it may be a contributing
pathogenicity factor, it is possible to speculate that they are unlikely to account for the observed pathology. p
g
y
p
p
y
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p
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It is critical to note that ccaA mutant exhibits a “run” bias in its chemotaxis phenotype. It is possible to hypoth-
esise that the up-regulation of some genes in the ccaA isogenic mutant may occur to compensate for changes
in chemotactic run-bias phenotype of the ccaA mutant. This lack of ability to tumble may indeed be the main
cause of attenuation, as well as the reason for increase in invasiveness in vitro31 and bacterial presence in systemic
organs. Discussion g
In vitro cell culture assays using human cell cultures; Caco-231, HepG2 and A549 cells, have shown that the
ccaA mutant is more adherent and highly invasive compared to the wild-type. Although A549 is a human lung
cell line, it contains α2,6-sialyl structures similar to those found in the chicken gastrointestinal tract37,38. The
hyperinvasive phenotype of the ccaA mutant in A549 cells indicated that this might be similar to the events in the
avian gastrointestinal tract.i g
In addition, the ccaA isogenic mutant was found to have significantly reduced ability to bind type II fucosylated
structures, ubiquitous in all eukaryotic tissue types. A significant decrease in binding ability to structures includ-
ing lacto-N-fucopentaose II, Lewisy, blood group H type II trisaccharide and monofucosyllacto-N-hexaose III was
also observed. In contrast, ccaA isogenic mutant had significantly stronger binding to both 3′-sialyllactosamine
and 6′-sialyllactosamine. The change in this binding ability, together with the “run” phenotype, may provide some
insight into the presence of the mutant in the lung of chickens, as terminal αNeuAc2-3Gal structures are found
predominantly in the lung of chickens39. This was evident by increased infection of A549 cells by the ccaA mutant,
which could be due to increased expression of this glycan by the A549 cells. ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 9 9 www.nature.com/scientificreports/ These changes in glycan binding specificity of the ccaA mutant may contribute toward the pathology observed
in model animals. The mutant bacteria may be able not only to move unidirectionally, but also be able to bind
glycan structures differently in the avian gut, helping the bacteria to transverse the epithelium. In addition, pre-
vious studies have shown that binding to 3′- and 6′-sialyllactosamine structures by 11168-O wild-type cells, was
significantly stronger at lower temperatures, 25 °C in vitro40. The higher core temperature of the chicken, 42 °C,
the temperature at which the wild-type and mutant cells were tested using glycan arrays in this study, may account
for the lower level of sialylated glycan binding for the wild-type compared to the ccaA mutant cells. y
g y
g
yp
p
This study is the first report of gross pathological differences due to infection with an isogenic mutant,
whereby mesenteric tissue abnormalities were observed within 72 hours p.i. In humans, a characteristic feature
of Crohn’s disease is mesenteric adipose tissue hypertrophy, or fat wrapping (Reviewed in41). Discussion Mesenteric adipose
tissue is an endocrine system and is able to regulated metabolic function and inflammation41. White adipose
tissue is known to synthesise PPAR-γ and TNF-α, and release cytokines including adiponectin and IL-642,43,
hence may play a role in inflammatory response in Crohn’s disease. In chickens, IL-6 mRNA expression increases
ten-fold at day 4 of colonisation28, and this may be more evident in chickens infected with the ccaA isogenic
mutant, as in the mutant, an increase in mesenteric fat may also stimulate release of this cytokine. Although it
appears that an inflammatory response is occurring in the chicken, it is unclear as the actual cause of the mesen-
teric adipose tissue hypertrophy. It is unusual, as in many diseases (including Crohn’s disease) as this manifests
over many months, not days. Infectious colitis due to bacterial infection, including Shigella, Salmonella, Yersinia,
Campylobacter, Staphylococcus and Chlamydia, have presented symptoms in humans including inflammatory
changes in mesenteric fat44. Thus, this suggests that the increase in mesenteric fat may be a clinical sign of this
Campylobacter infection. py
Gross pathological changes were also observed in the murine model, when mice were infected with the ccaA
mutant. The liver weight increased by at least 23% within 48 hours of infection in every mouse infected with the
ccaA mutant. In addition, this persisted until at least day 6, even though there was no mutant bacterium present in
the gastrointestinal tract at this time point. Similar to the findings of Vučković et al.45 hepatomegaly was observed
in BALB/c mice, however there was no spleen enlargement, no yellowish nodes on the liver and no local tissue
necrosis of the liver was observed in enlarged livers45. Unlike the study by Vučković45, where mice were infected
with C. jejuni via intraperitoneal injection, in our study the mice were infected with C. jejuni by oral inoculation
and the method of inoculation may influence the disease pathology observed in the mouse. yl
p
gy
It is well established that one of the main roles of the liver is to remove bacteria from the blood stream and to
resist infections by producing immune factors46. During inflammatory response to infection, the primary cellular
reaction is the stimulation of monocytes and tissue macrophages46. Histological analysis revialed no statistical
difference in cellular response in the livers of mice infected with the ccaA mutant compared to uninfected mice. Discussion Analyses of cytokine levels in mock-infected, 11168-O and ccaA mutant infected mice also showed no statistical
difference in the pro-inflammatory cytokines at 24, 48 or 72 h time points. Since the mediators assessed did not
change it is therefore unlikely that they contributed to the effect of gross pathological changes that were observed
in the mouse. Interestingly, the mice infected with the ccaA mutant showed enlarged mesenteric lymph nodes, which is a
common feature of Crohn’s disease or ulcerative colitis47. However both groups of mice infected with C. jejuni had
hyperplastic Peyer’s patches. The symptom of hyperplastic Peyer’s patches, where they project into the gut lumen
as submucosal elevations, along with the enlargement of the liver, which is observed in the mice infected with the
ccaA mutant, are typical symptoms of Typhoid or enteric fever48,49. Campylobacter is one of the non-salmonella
organisms causes of infection which is clinically indistinguishable from classic enteric fever caused by S. typhi,
S. paratyphi and S. choleraesuis50,51. There is little data on the pathological features of the associated enteritis, but
similarities may exist between Campylobacter and Salmonella spp, as C. jejuni may access the submucosa via
uptake by M cells, however it is unknown if C. jejuni can translocate across the cells in the colon52,53.h p
y
j j
This study highlights the importance of an alteration of the phenotype due to irreversibly blocking or altering
key colonisation factors, and the reason that they must be fully investigated. These factors are often potential
targets for the development of new antimicrobial agents. Although there is a reduction in colonisation potential
using both avian and mammalian colonisation models, one must ensure that there are no gross pathological
changes occurring in the host due to this infection. Methods Tissue
samples for histology were prepared using a portion of organ (systemic) or half of the longitudinally cut organ
(digestive), fixed immediately in formal saline solution for at least 24 h. The samples were prepared for histology
as described in Stahl et al.55. Histopathological scoring of organ tissue. The H & E stained sections were randomly coded for blind
scoring, and the pathology of each organ was microscopically examined at 600 x magnification. The lungs, liver
and spleen were examined for abnormalities including increase in leukocytes, tissue damage or changes in cellular
arrangement. The digestive organs were examined in sections; small intestine, caecum, and proximal, mid and
distal colon, for abnormal crypt architecture, crypt length, damage, goblet cell loss or hyperplasia, inflammatory
cell infiltrate or the presence of neutrophils in the lamina propria. After scoring of each organ was performed, the
samples were decoded and the results analysed. Direct in vivo Isolation of C. jejuni using M-280 Dyna-Beads. Immunomagnetic separation (IMS) of
C. jejuni from mouse intestinal content or chicken caecal content was performed as previously described by King
et al.34. Glycan Array analysis. IMS isolated cells were labelled with CFDA-SE and glycan binding profile was ana-
ysed as described in Day et al.56. Full list of glycan structures see Table S6. Adherence and Invasion Assays. The assays were performed according to22, with the modifications
as described in31. The cell lines used in this study were A549 Human lung adenocarcinoma epithelial cell line
(ATCC); Hep-G2 Human hepatocellular liver carcinoma cell line (ATCC). Cytometric bead array for quantification of inflammatory cytokines in mice. Mice were orally
inoculated with Brucella broth, C. jejuni 11168-O or C. jejuni 11168-OΔccaA::cat at 5 × 108 CFU. After 24 hours,
submandibular punctures were performed to remove approximately 100 µL of blood. Blood was allowed to coagu-
late for 15 mins, prior to centrifugation to separate serum. The BD CBA inflammatory mouse kit was used accord-
ing to manufacturer’s instructions. After the beads were washed, data was acquired using a Beckman Coulter
Cyan Flow cytometer, using the 488 nm laser with settings for FITC, APC and PE. Data was analysed using
FlowJo software. Concentrations of cytokines were extrapolated from standard curves using Microsoft Excel. qPCR primers and primer design. C. jejuni primers were designed based on the published nucleotide
sequence of C. jejuni 1116857. Methods Bacterial strains and plasmids. The C. jejuni NCTC11168-O original strain was kindly donated by D.G
Newell, VLA, London and its isogenic mutant strain 11168-OΔccaA::cat31 were grown on Columbia agar supple-
mented with 5% defibrinated horse blood (HBA) with Skirrow antibiotic supplement (Oxoid) or Muellar Hinton
agar (MHA) (Oxoid) under microaerophilic conditions (5% O2, 15% CO2, 80% N2; BOC gases) for 48 h at 37 °C
or 42 °C where appropriate. Motility assays. Motility assays were performed as described by King et al.54. The motility phenotypes of C. jejuni 11168-O and 11168-OΔccaA::cat were ascertained by calculating the spatial displacement of single cells. Singular cells were tracked via time lapse photography using ImageJ, over a one second time frame. Ethics Statement. Animal experiments were carried out in strict accordance with the Griffith University
Animal Ethics Committee guidelines and assigned approval numbers MSC/04/08/AEC, BDD/01/07 and
GLY/02/15/AEC. All procedures involving animals were reviewed and approved by National Health and Medical
Research Council Australian code of practice for the care and use of animals for scientific purposes, 7th edition
2004. ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 10 www.nature.com/scientificreports/ Avian and murine models. Unvaccinated Ross breed chickens (Bartters, Rochdale Qld) at one day after
hatching were placed into groups of ten, pre-inoculation faecal samples were taken from the cloaca of the chick-
ens and cultured. Chickens were housed in clean barrier cages at 32 °C and supplied sterilised food and water ad
libitum for the entire experimental period. 129 × 1/SvJ background male mice (Animal Resource Centre, Western
Australia) aged between 6–8 weeks, were housed in groups of 6–10 as specified, supplied ad libitum with food
and water. The animals were inoculated by orally challenging with 30 μL of Brucella broth containing approximately
1 × 108 C. jejuni cells, as previously published31. Post-inoculation cloacal or faecal samples were taken daily and
cultured. 24–96 h post-inoculation, as specified, the animals were euthanized by cervical dislocation, and the
gastrointestinal tissues including small and large intestine as well as the systemic organs, lungs, liver and spleen,
were removed aseptically. Each organ was weighed and apportioned. An appropriate portion was placed in a 5 mL
tube with 2 mL of sterile Brucella broth, homogenised and the bacterial load enumerated by viable count. References
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4. Horton, K. M., Corl, F. M. & Fishman, E. K. CT Evaluation of the Colon: Inflammatory Disease. Radiographics 20, 399–418 (2000) ScienTific REPOrTS | (2018) 8:12594 | DOI:10.1038/s41598-018-30604-5 12 www.nature.com/scientificreports/ 45. Vuckovic, D., Abram, M. & Doric, M. Author Contributions V.K., L.H.T. and C.J.D. conceived the study, all authors contributed to the design of experiments and analysis of
data, L.H.T., C.J.D., G.T., E.A.S., Z.K., L.I.C.G. and A.M.B. performed the experiments, L.H.T. and V.K. wrote the
paper, all authors reviewed and approved the final version of the manuscript. V.K., L.H.T. and C.J.D. conceived the study, all authors contributed to the design of experiments and analysis of
data, L.H.T., C.J.D., G.T., E.A.S., Z.K., L.I.C.G. and A.M.B. performed the experiments, L.H.T. and V.K. wrote the
paper, all authors reviewed and approved the final version of the manuscript. Additional Information Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-30604-5. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-3060 Competing Interests: The authors declare no competing interests. Competing Interests: The authors declare no competing interests. Competing Interests: The authors declare no competing interests. Competing Interests: The authors declare no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps an
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Capacity estimation based on incremental capacity and Gaussian process regression for retired lithium-ion batteries
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E3S web of conferences
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Capacity estimation based on incremental capacity and
Gaussian process regression for retired lithium-ion batteries School of Environment and Energy, Peking University Shenzhen Graduate School, Shenzhen, China Abstract. Fast capacity estimation for retired batteries is necessary when batteries are recycled for echelon
utilization. Here, a fast capacity estimation method is proposed for retired LiFePO4 battery. First, a full survey
of battery pack and cells degradation after a long period of service is studied. Then the filtered ICA is used to
study degradation variation phenomenon of retired batteries, the relationship between IC curve feature and
remaining capacity was studied. Finally, a fast capacity estimation using incremental capacity and Gaussian
process regression is proposed. Our results show high efficiency and accuracy of the proposed method. 1 Introduction Then the filtered ICA is used to study degradation
variation phenomenon of retired batteries, the
relationship between IC curve feature and remaining
capacity was analyzed. Finally, a fast capacity
estimation method based on incremental capacity
and Gaussian process regression is proposed. Then the filtered ICA is used to study degradation
variation phenomenon of retired batteries, the
relationship between IC curve feature and remaining
capacity was analyzed. Finally, a fast capacity
estimation method based on incremental capacity
and Gaussian process regression is proposed. Recently, electric vehicles (EVs) have become a
significant trend in many countries for the reason of
concerns about energy security and environmentally
friendly [1]. However, lithium-ion batteries, which
is one of the core components in EVs, need to be
transposed to guarantee safe operation and sufficient
mileage when their capacity drops to 80% [2]. The
retired batteries echelon utilization can prolong the
useful battery life-span, thus reducing harmful
environmental effects and resources conservation
[3]. However, for their inconsistency, retired
batteries cannot be firsthand recycled for echelon
utilization [4], so the capacity estimation and
screening methods of retired batteries are of great
significance to the echelon utilization of retired
batteries and the healthy development of electric
vehicles. p
g
j p
g@p
© The Authors, published by EDP Sciences. This is an open access article distributed under the terms of the Creative Commons Attribution
License 4.0 (http://creativecommons.org/licenses/by/4.0/). * Corresponding author: jinpeng@pkusz.edu.cn
© The Authors, published by EDP Sciences. This is an open access article distributed under the terms of the Creative Commons Attribution
License 4.0 (http://creativecommons.org/licenses/by/4.0/). * Corresponding author: jinpeng@pkusz.edu.cn E3S Web of Conferences 338, 01006 (2022)
ESMA 2021 E3S Web of Conferences 338, 01006 (2022)
ESMA 2021 https://doi.org/10.1051/e3sconf/202233801006 © The Authors, published by EDP Sciences. This is an open access article distributed under the terms of the
License 4.0 (http://creativecommons.org/licenses/by/4.0/). d by EDP Sciences. This is an open access article distributed under the terms of the Creative Commons Attribution
ommons.org/licenses/by/4.0/). 2.1 Test setup and experimental method Our retired battery pack is received from an electric
bus which is operated for more than three years. As
is shown in Fig. 1, the experimental pack consists of
42 series-connected battery modules, 28 battery cells
are parallel-connected in each module. Air cooling
is adopted for battery heat dissipation in the whole
battery pack. In order to analyze degradation mechanism of
large scale of cells and estimate their state of health
(SOH), incremental capacity analysis (ICA) is
employed [5-7]. IC curve cannot only indicate the
subtle and slowing-changing electrochemical feature
of the electrochemical reactions inside cells, it can
also depict current acceptance capability in various
potentials. In view of the merit of convenient
properties for modeling without specific function,
Gaussian process regression has been widely
adopted in the field of machine learning and
statistics [8]. Fig. 1 Experimental retired battery pack Fig. 1 Experimental retired battery pack Fig. 1 Experimental retired battery pack In this thesis, a rapid capacity estimation is
applied for retired LiFePO4 battery. First, a
comprehensive survey of a battery pack aging and
cells after a long period of employment is studied. The
battery
cell
is
manufactured
by
OptimumNano Energy CO., LTD of China, and their The
battery
cell
is
manufactured
by
OptimumNano Energy CO., LTD of China, and their E3S Web of Conferences 338, 01006 (2022)
ESMA 2021 https://doi.org/10.1051/e3sconf/202233801006 parameters are itemized in Table 1. The 32700-type
cell is configured with LiFePO4/graphite as
electrode, whose nominal capacity is 5.0 Ah,
upper and lower limit voltages are 2.65–3.7V. All of
our tests are carried out at room temperature. An 8-
channel battery test system (Shenzhen Repower
Technology Co.,Ltd ACTS 5V-10A) whose current
range is −5A~5A and voltage range is 0~5V( ±0.02%
at full scale) is used for battery test. Fig. 2. Battery cell capacity and resistance bargraph and
probability plots Table 1 Parameters for the LiFePO4 cell. Items
Parameters
Manufacturer
OptimumNano
Group pattern
28 parallel-42 series
Cathode material
LiFePO4
Anode material
Graphite
Nominal capacity
5.0Ah
Nominal voltage
3.2V
End-of-charge
voltage
2.65V
End-of-discharge
voltage
3.7V Table 1 Parameters for the LiFePO4 cell. In order to obtain the remaining capacity, we
apply the charging current rate of 1/3 C, i.e., 1.66 A. and test the internal resistance by hybrid pulse power
characterization (HPPC) method. Fig. 2. 2.2 Test results Capacity and resistance of all 1176 retired battery
cell is surveyed by battery test system, Fig.2 shows
the distribution histogram of these batteries. As
shown in Fig.2, the capacity data of 1176 single cells
in the entire battery pack shows that most of the cells
have a capacity between 4.2Ah and 4.6Ah and obey
a normal distribution. 90.2% of the cells still
maintain the rated capacity. 80%, 98.7% batteries
maintain 70% of the rated capacity. In the
histograms, the distribution of battery capacity is
left-skewed with s=−0.755 and the distribution of
battery resistance is s=−1.18. 2.1 Test setup and experimental method Battery cell capacity and resistance bargraph and
probability plots For both battery capacity and resistance
probability plots, some cells are outside the
confidence intervals. However, normal probability
has a better fitting quality than that of Weibull
probability, for the reason that in the low resistance
range of the probability map, there are some points
far away from the lower confidence interval. Therefore, the normal distribution is more suitable
than the Weibull distribution for the batteries that we
study with parallel connections. 3.2 Gaussian process regression Based on Eq. (10), the posterior distribution can
be derived as: Gaussian process regression (GPR) is a neoteric
regression approach in machine learning, so we
explain how apply the algorithm to estimate
attenuation of battery capacity. (10) (10) Then, in the predictive distribution, we calculate First, in our training dataset D=(X, y) , the input
variable and output variable are indicated as X and y
accordingly. As the formula X={x1D,x2D,x3D,⋯xND}
shows, there are D-dimensional N input vectors in
variable X, which follows multivariable distribution
with mean function and covariance function of m(x)
and kf(x,x’), respectively. We express the properties
of f(x) as following: 𝑚𝑥𝑥𝑘𝑥𝑥𝑚𝑥𝑥𝑚𝑥𝑥 the mean y‾∗ and covariance cov(y*): (11)
(12) (11)
(12) (11) (12) Finally, a full GPR algorithm modeling is done. Finally, a full GPR algorithm modeling is done. 3.1 Incremental capacity analysis The incremental capacity is obtained from a full
charging/discharging cycle, where we get the
changing rate of capacity with the voltage as the
vertical coordinate, and the changing voltage as the
horizontal ordinate, which is shown as following: ௗொሺ௧ሻ
ௗሺ௧ሻൎοொሺሻ
οሺሻൌொሺሻିொሺିேሻ
ሺሻିሺିேሻ (1) (1) In Eq. 1,οܳሺ݇ሻ and οܸሺ݇ሻ are the rate of
electric quantity and terminal voltage during
charging/discharging, respectively. As a result, 2 https://doi.org/10.1051/e3sconf/202233801006 E3S Web of Conferences 338, 01006 (2022)
ESMA 2021 https://doi.org/10.1051/e3sconf/202233801006 οொሺሻ
οሺሻ can be described as ௗொሺ௧ሻ
ௗሺ௧ሻ when the sample
interval 𝑁𝑁 is short enough. 𝑘𝑘ሺ𝑥𝑥𝑥𝑥𝑥ᇱሻൌ𝜎𝜎
ଶp𝐼ሺ
ିሺ௫ି௫ᇲሻమ
ଶమ
ሻ (3) 𝑘𝑘ሺ𝑥𝑥𝑥𝑥𝑥ᇱሻൌ𝜎𝜎
ଶp𝐼ሺ
ିሺ௫ି௫ᇲሻమ
ଶమ
ሻ (3) οሺሻ can be described as ௗሺ௧ሻ when the sampl
interval 𝑁𝑁 is short enough. Fig. 3. (a) Initial IC curve; (b) Filtered IC curve Considering there are D-dimensional N input
vectors in variable X, we can converse Eq. (3) as
follows: 𝑘𝑥𝑥𝜎 𝑘𝑘൫𝑥𝑥, 𝑥𝑥൯ൌ𝜎𝜎
ଶp𝐼ሺെ
ଵ
ଶ∑
ሺ௫
ି௫ೕ
ሻమ
మ
ௗୀଵ
ሻ (4) 𝜎𝐼 ( )
Here, the noise covariance matrix 𝜎𝜎ଶ𝐼𝐼 is
appended into Eq. (4) as below: 𝑥𝑥𝑘𝑥𝑥𝜎𝐼 pp
q ( )
൫𝑥𝑥, 𝑥𝑥൯ൌ𝑘𝑘൫𝑥𝑥, 𝑥𝑥൯𝜎𝜎ଶ𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 (5) pp
q ( )
൫𝑥𝑥, 𝑥𝑥൯ൌ𝑘𝑘൫𝑥𝑥, 𝑥𝑥൯𝜎𝜎ଶ𝐼𝐼𝐼𝐼𝐼 (5) 𝑘
𝑥𝑥
𝜎𝐼
Considering the input variable X and the
properties of the latent function f, the distribution of
y is denoted as follows: 𝑁𝜎𝐼 pሺy|Xሻൌ pሺy|f, Xሻpሺf|Xሻ݂݀ൌ𝐼𝑁𝑁ሺͲ𝑥ܭ
𝜎𝜎ଶ𝐼𝐼ሻ (6) Then, we denote the marginal log-likelihood of y
as: as: (7) (7) Fig. 3. (a) Initial IC curve; (b) Filtered IC curve Here, for the marginal log-likelihood function,
we employ the gradient method to optimize the
hyper-parameters, and the calculation process of the
gradient descending is: As a novel technique to analysis aging
phenomenon and survey state of health (SOH) of
lithium battery, ICA is applied in fast estimation in
our essay. In order to extract capacitance features of
incremental capacity, preprocessing needs to be
conducted previously. Figure.3 illustrates the initial
IC curve contaminated by noises and filtered IC
curve using Kalman filter in the 1/3C current rate. Finally we need to record the coordinates of the
characteristic peak(P1，P2 and P3) which are highly
related to the attenuation of battery capacity. g
g
(8) (8) Here, in training dataset, we employ a small
representative subset for the sparse approximation
propose to handle GPR. The joint prior distribution
of the training output y and the test output y∗ is
deduced and expressed as [8]: p
(9) (9) Acknowledgments This work was financially supported by Shenzhen
Science
Research
Project
under
Grant
GJHZ20180928162210431. Fig.4. The error analysis of battery estimation based GPR 5 Conclusion This paper presents an efficient capacity estimation
based on ICA and Gaussian process regression for
retired lithium-ion batteries. The main contributions
are summarized as follows: (1) a detailed survey of
a retired battery pack and cells was conducted,
normal distribution is more suitable than the Weibull
distribution for the batteries that we study with
parallel connections. (2) The GPR is employed to
establish SOH estimation model and how the
algorithm works is demonstrated. (3) Our novel
method is verified by LFP retired cells charging and
discharging datasets. Verification result with a
maximum MAE and RMSE of 1.8%, 2.2% shows
strong performance. As illustrated in Table 2, error of the estimation
of battery No. 61, 62, 63, 64 and 65 are 1.76%,
1.41%, 2.59%, 1.53%,1.93%, respectively. As a
result, the battery SOH estimation of GPR shows
strong performance. In addition, we also employ the
mean absolute error (MAE) and the root mean
square error (RMSE) to analyze the performance of
the model quantitatively, whose definition is shown
as: 𝑦𝑦 ൌ
ଵ
ே∑
|𝑦𝑦െ𝑦𝑦ത
∗|
ே
ூୀଵ
(18)
ൌටሺ
ଵ
ே∑
ሺ𝑦𝑦െ𝑦𝑦ത
∗ሻଶ
ே
ୀଵ
ሻ (19) 𝑦 (18) (19) Where 𝑦𝑦ത
∗ is the estimated value, the y is the real
value, and it is worth noting that N represents how
many times battery cycles, so MAE and RMSE
could be used to assess the algorithm modelling of
different cells in view of absolute sign. 4 Validation and discussion ( )
g
൜
𝑚𝑚ሺ𝑥𝑥ሻൌܧሺ݂ሺ𝑥𝑥ሻሻ
𝑘𝑘ሺ𝑥𝑥𝑥𝑥𝑥ᇱሻൌܧሾሺ𝑚𝑚ሺ𝑥𝑥ሻെ݂ሺ𝑥𝑥ሻሻሺ𝑚𝑚ሺ𝑥𝑥ᇱሻെ݂ሺ𝑥𝑥ᇱሻሻሿ(2) In view of the proposed GPR battery screening
model mentioned above, 5 LFP retired batteries data
of 190 cycle are employed to verify the validity of
battery estimation. In our experiment, we regard the
first 80% data of charging/discharging period as the
training datasets and the rest 20% data as testing part. For the GPR algorithm, in order to express the
prior assumptions for the properties of latent funtion,
calculating the the kernel function 𝑘𝑘ሺ𝑥𝑥𝑥𝑥𝑥ᇱሻ is
necessary. We use the squared exponential
covariance (SE) to complete this step, as shown in
Eq. (3): 3 E3S Web of Conferences 338, 01006 (2022)
ESMA 2021 https://doi.org/10.1051/e3sconf/202233801006 The results for battery No. 61, 62, 63, 64 and 65 are
shown in Table. 2. The results for battery No. 61, 62, 63, 64 and 65 are
shown in Table. 2. MAE reflects the mean absolute error between
real value and estimated value in our cells SOH
estimation, we calculate MAE and RMSE of battery
No. 61, 62, 63, 64 and 65. As Fig.4 shows, battery
No.63 has the maximum MAE with 1.8% which is
not overrun 2%, while battery NO.64 has the
minimum MAE with 1.1%. In term of RMSE, all 4
LFP cells are nearly 1.7%, battery NO.63 has the
maximum RMSE with 2.2%, and battery NO.65 has
the minimum RMSE with 1.4%. As a result, our
proposed SOH fast estimation based on GPR
indicates high accuracy and reliability. Table 2 Capacity estimation results vs. real capacity of the
screening method Table 2 Capacity estimation results vs. real capacity of the
screening method
Cell
number
Estimation
results
（Ah）
Real
capacity
（Ah）
error
（%）
C61
3.94
4.04
1.76
C62
3.69
3.64
1.41
C63
4.92
4.79
2.59
C64
4.15
4.01
1.53
C65
3.91
3.96
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The complete genome sequence of Hafnia alvei A23BA; a potential antibiotic-producing rhizobacterium
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BMC research notes
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© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the
permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Abstract Objectives: The urgent need for novel antibiotics cannot be overemphasized. Hafnia alvei A23BA was isolated from
plant rhizosphere as part of an effort to recover novel antibiotic-producing bacterial strains from soil samples. The
genome of the isolate was sequenced to facilitate mining for potential antibiotic-encoding biosynthetic gene clusters
and to gain insights into how these gene clusters could be activated. Data description: Here, we report the complete genome sequence of H. alvei A23BA obtained from the hybrid
assembly of Illumina HiSeq and GridION reads. The genome, consisting of a circular chromosome and a circular plas-
mid, is 4.77 Mb in size with a GC content of 48.77%. The assembly is 99.5% complete with genomic features including
4,217 CDSs, 125 RNAs, and 30 pseudogenes. Thiopeptide, beta-lactone, siderophore, and homoserine lactone biosyn-
thetic gene clusters were also identified. Other gene clusters of interest include those associated with bioremediation,
biocontrol, and plant growth promotion- all of which are reported for H. alvei for the first time. This dataset serves to
expedite the exploration of the biosynthetic and metabolic potentials of the species. Furthermore, being the first pub-
lished genome sequence of a soil isolate, this dataset enriches the comparative genomics study of H. alvei strains. Keywords: Hafnia alvei, H. alvei, Genome mining, Biosynthetic gene clusters, Antibiotics, Rhizobacteria,
Bioremediation, Biocontrol, Plant growth-promoting rhizobacteria Hafnia alvei is a Gram-negative, rod- shaped, facul-
tatively anaerobic psychrotrophic bacterium. It is com-
monly isolated from clinical materials, gastrointestinal
tract of animals, plant surfaces, soil, and water [4]. Some
strains are commensals of the gastrointestinal tract while
others are opportunistic pathogens implicated in both
nosocomial and community-acquired infections [5, 6]. It is almost never associated with antibiotic produc-
tion except for the antimicrobial activities reported for
a strain isolated from the gut of honeybees [7]. Phyloge-
netic studies of this little-known species have shown its
pan-genome to be open and dynamic with each strain
possessing sets of unique genes [8]. Unique gene acquisi-
tion is mainly by horizontal gene transfer, and it reflects
the adaptation of strains to their remarkably diverse
natural habitats. Strains show considerable metabolic The complete genome sequence of Hafnia
alvei A23BA; a potential antibiotic‑producing
rhizobacterium Opeyemi K. Awolope1 , Noelle H. O’Driscoll1 , Alberto Di Salvo1 and Andrew J. Lamb2* Awolope et al. BMC Res Notes (2021) 14:8
https://doi.org/10.1186/s13104-020-05418-2 Awolope et al. BMC Res Notes (2021) 14:8
https://doi.org/10.1186/s13104-020-05418-2 BMC Research Notes BMC Research Notes Open Access Objective Bacterial secondary metabolites are invaluable sources of
novel bioactive compounds. Many clinically useful anti-
biotics were derived from the secondary metabolites of
soil dwelling bacteria [1]. However, only a small fraction
of all known species have had their metabolites exploited
in this way [2]. To this end, we sought to isolate novel
antibiotic-producing bacterial strains from soil samples
collected from the rhizosphere as antibiosis occurs natu-
rally within it [3]. H. alvei A23BA was recovered as part
of this effort. *Correspondence: a.lamb@rgu.ac.uk
2 Graduate School, Robert Gordon University, The Ishbel Gordon Building,
Garthdee Road, Aberdeen AB10 7QE, Scotland
Full list of author information is available at the end of the article Awolope et al. BMC Res Notes (2021) 14:8 Page 2 of 4 and one plasmid) were identified with a total length of
4,772,047 bp, N50 value of 4,687,005 bp and #N’s per
100 kbp value of 0 (data file 4) [18]. Assembly complete-
ness was assessed with BUSCO [19] v3.0.2 and found to
be 99.5% (data file 5) [20]. Identity was confirmed as H. alvei by ANI analysis using the FastANI tool [21], with
the ANI value of 97.8167. Gene and functional annota-
tions were performed with PGAP [22] v4.11 and RAS-
Ttk [23]; pathways analyses were performed using the
KEGG database [24] Rel 93.0 and the eggNOG mapper
[25] vs 2.0.0. smBGCs were identified with antiSMASH
[26] v5.0. Genome map was drawn with CGView [27] and
presented in data file 6 [28]. pathway diversity and varied biosynthetic potentials
because of the open pan-genome making them good
mining candidates for novel metabolites. Consequently, the genome of H. alvei A23BA was
sequenced to enable mining for potential antibiotic-
encoding secondary metabolite biosynthetic gene clus-
ters (smBGCs) that show little or no homology to known
smBGCs. Furthermore, assembled genomes of H. alvei
in public repositories are typically of clinical, human or
food isolates, to the best of our knowledge, the complete
genome sequence of H. alvei A23BA represents the first
published complete genome sequence of a soil isolate. i
In summary, the complete genome sequence of H. alvei A23BA is 4,772,047 bp in size with the overall GC
content of 48.77% and sequencing coverage of 256.0 x. It comprises of one circular chromosome (4,687,005 bp;
GC content 48.8%) and one circular plasmid (85,042 bp;
GC content 47.2%). Genomic features include 4,217
CDSs, 25 rRNA, 92 tRNA, 8 ncRNA, 30 pseudogenes and
2 CRISPRs. Thiopeptide, beta-lactone (both showing lit-
tle or no homology to known smBGCs) and siderophore
smBGCs were identified (data file 7) [29]. Thiopeptides
and beta-lactones are known for their antibiotic and/or
anticancer activities [30, 31], while siderophores are used
clinically as “Trojan horse” to deliver antibiotics to anti-
biotic resistant bacteria [32]. Gene clusters commonly
associated with bioremediation, biocontrol, environmen-
tal adaptation, and plant growth promotion were also
identified (data file 8) [33]. Please see Table 1 for links to
data files 1–8. Data description H. alvei A23BA was recovered from the rhizosphere of a
garden plant in Aberdeen, Scotland (57.101 N 2.078 W). It was isolated using an ultra-minimal substrate medium
(Data file 1) [9]. Upon isolation and strain purification,
isolate was cultivated in nutrient broth (Oxoid, UK) at
37 °C for 24 h. Overnight culture was centrifuged and
gDNA was extracted from pellets with the DNeasy®
Ultraclean® Microbial Kit for DNA Isolation (Qiagen,
UK). Isolate was preliminarily identified by 16S rRNA
gene sequence comparison as H. alvei with 99% identity
score. Libraries were subsequently prepared from extracted
gDNA by MicrobesNG (Birmingham, UK) for whole
genome sequencing. For Illumina sequencing, libraries
were prepared using the Nextera XT Library Prep Kit
(Illumina, USA) and sequenced with the Illumina HiSeq
system using a 250 bp paired end protocol. For GridION
(Oxford nanopore) sequencing, libraries were prepared
with Oxford nanopore SQK-RBK004 kit and/or SQK-
LSK109 kit with Native Barcoding EXP-NBD104/114
(ONT, UK) using 400-500 ng HMW DNA. Sequencing
was performed on a FLO-MIN106 (R.9.4 or R.9.4.1) flow
cell in a GridION (ONT, UK). i
Given the quality control measures applied and results
of analyses undertaken, we believe Hafnia alvei strain
A23BA chromosome, complete genome [34] represents a
high-quality dataset that would expedite the exploration
of the biosynthetic and metabolic potentials of H. alvei
A23BA and would also enrich the comparative genomics
study of H. alvei strains. Illumina sequencing run produced 4,973,530 short
reads that were trimmed and paired using Trimmo-
matic [10] v0.30 with a sliding window quality cut-off of
Q15. Ninety eight percent of reads were retained, and
quality was assessed with FastQC [11] v0.11.8. Mean
phred score across each base position was assessed with
MultiQC [12] and found to be ≥ 28 (Data file 2) [13]. GridION sequencing run produced 18,642 reads with
the mean read quality score of 10.5 (data file 3) [14] as
assessed with NanoStat [15]. Paired short reads and long
reads from GridION sequencing were assembled with
Unicycler [16] v0.4.8.0. Assembly quality was assessed
with QUAST [17] v5.0.2- two contigs (one chromosome g
This project was supported by Tenovus Scotland (Grant Number G16.04). g
This project was supported by Tenovus Scotland (Grant Number G16.04). g
j
3. Lugtenberg B, Kamilova F. Plant-growth-promoting rhizobacteria. Annu
Rev Microbiol. 2009;63:541–56. https://doi.org/10.1146/annurev.micro
.62.081307.162918. Received: 12 August 2020 Accepted: 9 December 2020 Received: 12 August 2020 Accepted: 9 December 2020 Received: 12 August 2020 Accepted: 9 December 2020 Author details 1 School of Pharmacy and Life Sciences, Robert Gordon University, Sir Ian
Wood Building, Garthdee Road, Aberdeen AB10 7GJ, Scotland. 2 Graduate
School, Robert Gordon University, The Ishbel Gordon Building, Garthdee Road,
Aberdeen AB10 7QE, Scotland. Limitationsh This dataset was generated from a hybrid assembly to
ensure accuracy and completeness. Furthermore, the
hybrid assembler (Unicycler) autocorrects read errors
and polishes final assemblies several times to ensure
accuracy. Annotations and metabolic pathway analyses
were carried out with robust and validated bioinformat-
ics tools, and smBGCs were identified with the most
comprehensive genome mining tool to date. Therefore,
the authors are currently unaware of any limitations of
the data. Awolope et al. BMC Res Notes (2021) 14:8 Page 3 of 4 Awolope et al. BMC Res Notes Table 1 Overview of data files/data sets
Label
Name of data file/data set
File types (file extension)
Data repository and identifier (DOI
or accession number)
Data file 1
Composition of ultra-minimal substrate
growth medium
Portable Document Format file (.pdf)
https://doi.org/10.6084/m9.figshare.12781
193.v [9]
Data file 2
Quality distribution of Illumina reads
Joint Photographic Experts Group file (.jpg)
https://doi.org/10.6084/m9.figshare.12643
961.v1 [13]
Data file 3
Basic quality statistics of GridION sequenc-
ing data
Portable Document Format file (.pdf)
https://doi.org/10.6084/m9.figshare.12781
280.v1 [14]
Data file 4
Quast report
Portable Document Format file (.pdf)
https://doi.org/10.6084/m9.figshare.12781
289.v1 [18]
Data file 5
Short BUSCO summary
Joint Photographic Experts Group file (.jpg)
https://doi.org/10.6084/m9.figshare.12643
937.v1 [20]
Data file 6
Circular representation of H. alvei A23BA
genome
Joint Photographic Experts Group file (.jpg)
https://doi.org/10.6084/m9.figshare.12643
949.v1 [28]
Data file 7
Predicted smBGCs of interest in H. alvei
A23BA genome
Portable Document Format file (.pdf)
https://doi.org/10.6084/m9.figshare.12781
274.v1 [29]
Data file 8
Other gene clusters of interest in H. alvei
A23BA genome
Portable Document Format file (.pdf)
https://doi.org/10.6084/m9.figshare.13309
049.v1 [33]
Data set 1
Illumina and GridION sequencing reads
Fastq file (.fastq.gz)
https://identifiers.org/ncbi/insdc.sra:SRP25
1948
[35]
Data set 2
Genome assembly of H. alvei A23BA
Fasta file (.fna)
https://identifiers.org/ncbi/insdc
.gca:GCF_011617105.1 [36] https://identifiers.org/ncbi/insdc
.gca:GCF_011617105.1 [36] Authors’ contributions The project was conceived and designed by OKA and AJL. Data acquisition
was performed by OKA. Data analysis and interpretation was performed by
OKA, NHO, ADS and AJL. The project was jointly supervised by NHO, ADS and
AJL. AJL was the principal investigator. The manuscript was written by OKA
and revised by NHO, ADS and AJL. All authors read and approved the final
manuscript. References 1. Bérdy J. Bioactive microbial metabolites. J Antibiot. 2005;58:1–26. https://
doi.org/10.1038/ja.2005.1. 1. Bérdy J. Bioactive microbial metabolites. J Antibiot. 2005;58:1–26. https://
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G Genome sequencing was provided by MicrobesNG (http://www.microbesng
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Supplemental Figure 2 Supplemental Figure 2 FIRST LINE
SECOND LINE
STUDY
MSK
cohort
AURA
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Le et al. Piotrowska
et al. Oxnard
et al. Supplemental Figure 2 Cohort size
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EGFR C797X
EGFR L792X
EGFR L718Q
EGFR G724S
EGFR S768I
EGFR Ex20ins
EGFR G796S
EGFR amp
MET amp
HER2 amp
KRAS amp
PIK3CA amp
KRASm
BRAF V600E
PIK3CAm
JAK2m
ERBB2m
MEK1m
ALK fusion
FGFR3 fusion
NTRK fusion
RET fusion
BRAF fusion
MET exon 14
Small cell trans
Squamous cell trans
Pleormorphic trans
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1 (4%)
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2 (11%)
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7 (8%)
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1 (1%)
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-
11 (15%)
2 (3%)
1 (1%)
-
-
1 (1%)
1 (1%)
9 (23%)
3 (8%)
1 (3%)
1 (3%)
-
-
-
13 (32%)
2 (5%)
1 (2%)
1 (2%)
-
-
-
9 (22%)
1 (2%)
-
1 (2%)
-
-
-
1 (4%)
2 (7%)
-
-
-
1 (5%)
1 (5%)
-
1 (5%)
-
-
14 (15%)
2 (2%)
-
-
2 (6%)
2 (6%)
-
-
-
-
14 (19%)
4 (5%)
-
3 (4%)
3 (8%)
4 (10%)
3 (8%)
2 (5%)
1 (3%)
14 (36%)
10 (26%)
2 (5%)
3 (7%)
1 (2%)
-
4 (10%)
-
-
-
1 (4%)
-
-
-
-
-
1 (5%)
-
1 (5%)
1 (5%)
1 (5%)
1 (5%)
3 (3%)
3 (3%)
6 (7%)
-
1 (1%)
-
1 (3%)
-
-
-
1 (3%)
-
1 (1%)
2 (3%)
1 (1%)
-
-
-
1 (3%)
-
2 (5%)
-
1 (3%)
-
-
-
1 (2%)
1 (2%)
-
-
2 (5%)
1 (2%)
4 (10%)
-
-
-
-
-
-
1 (4%)
1 (4%)
-
-
-
-
-
-
-
1 (1%)
-
-
-
-
-
2 (6%)
-
-
-
1 (3%)
1 (3%)
-
1 (1%)
1 (1%)
1 (1%)
-
-
-
-
-
1 (3%)
-
-
-
-
1 (3%)
2 (5%)
3 (8%)
-
1 (2%)
1 (2%)
-
1 (2%)
1 (2%)
-
1 (4%)
2 (7%)
1 (4%)
-
-
-
-
-
-
2 (6%)
3 (9%)
-
-
-
-
1 (3%)
-
-
2 (6%)
1 (3%)
-
6 (15%)
2 (5%)
-
On-target:
EGFR
Off-target:
opy-number
Off-target:
mutations
Off-target:
fusions
Histologic
nsformation SECOND LINE
|
https://openalex.org/W2604582417
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https://europepmc.org/articles/pmc5401728?pdf=render
|
English
| null |
Electrical Stimulation for Wound-Healing: Simulation on the Effect of Electrode Configurations
|
BioMed research international
| 2,017
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cc-by
| 6,668
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1. Introduction membrane of the skin’s mucosal surface, a transepithelial
potential difference (TEPD) is established [6, 7]. And once the
epidermis is broken, an electrical leak is produced since the
resistance of the wounded site is lower than that of the normal
skin. An endogenous EF is then created by reason of the net
movement of ions within the layer between the epidermis and
the dermis.h A wound is a type of injury in which the skin epithelial layer is
broken [1], and the break may go beyond the skin epidermis
to deeper layers such as the dermis, the subcutis, and muscle. In 1843, Du Bois-Reymond first measured an electric current
of 1 𝜇A flowing out of a cut on his finger [2, 3], and more
recently, currents of 35 and 10∼30 𝜇A/cm2 were recorded in
the amputated fingers of children and the wounds of guinea
pigs, respectively [4]. Since then, it has been demonstrated
that endogenous DC electric fields (EFs) occur naturally,
in vivo around wounds. An electric potential difference of
30∼100 mV, known as the transepithelial potential (TEP),
was measured between the epidermis and the dermis in
the normal skin of a cavy [4]. Nuccitelli et al. reported
that the mean lateral electric field in the space between the
epidermis and stratum corneum adjacent to a lancet wound
was around 100∼200 mV/mm, and this value was largest in
fresh wounds and slowly declined as the wound closed [5]. The TEP is known to occur as a result of the accumulations
of negative and positive charges on the surface of and inside
the epidermis, respectively. When the ion channels of Na+,
K+, and Na+/K+ ATPase distribute unevenly in the apical This endogenous EF is highly involved in the wound-
healing process mainly through its effects on protein synthe-
sis and cell migration [8–10]. G. J. Bourguignon and L. Y. W. Bourguignon exposed human fibroblasts to high voltage,
pulsed current stimulation (HVPCS) to increase the healing
rate of soft tissue injuries [11]. Hindawi
BioMed Research International
Volume 2017, Article ID 5289041, 9 pages
https://doi.org/10.1155/2017/5289041 Hindawi
BioMed Research International
Volume 2017, Article ID 5289041, 9 pages
https://doi.org/10.1155/2017/5289041 Research Article
Electrical Stimulation for Wound-Healing: Simulation on
the Effect of Electrode Configurations Yung-Shin Sun
Department of Physics, Fu Jen Catholic University, New Taipei City 24205, Taiwan
Correspondence should be addressed to Yung-Shin Sun; 089957@mail.fju.edu.tw
Received 29 November 2016; Revised 22 February 2017; Accepted 21 March 2017; Published
Academic Editor: Subhas Gupta Yung-Shin Sun Department of Physics, Fu Jen Catholic University, New Taipei City 24205, Taiwan Correspondence should be addressed to Yung-Shin Sun; 089957@mail.fju.edu.tw Received 29 November 2016; Revised 22 February 2017; Accepted 21 March 2017; Published 9 April 2017 Copyright © 2017 Yung-Shin Sun. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Endogenous electric field is known to play important roles in the wound-healing process, mainly through its effects on protein
synthesis and cell migration. Many clinical studies have demonstrated that electrical stimulation (ES) with steady direct currents
is beneficial to accelerating wound-healing, even though the underlying mechanisms remain unclear. In the present study, a
three-dimensional finite element wound model was built to optimize the electrode configuration in ES. Four layers of the skin,
stratum corneum, epidermis, dermis, and subcutis, with defined thickness and electrical properties were modeled. The main
goal was to evaluate the distributions of exogenous electric fields delivered with direct current (DC) stimulation using different
electrode configurations such as sizes and positions. Based on the results, some guidelines were obtained in designing the electrode
configuration for applications of clinical ES. 2. Materials and Methods Within the biological tissue, the electric field resulting from
constant DC can be treated as quasi-stationary over time. Steady EFs are established by flowing constant DC through
volume conductors with homogeneous and isotropic electri-
cal properties such as conductivity and relative permittivity. Under this circumstance, the distribution of electric potential
(𝑉) is governed by the Laplace equation, ∇2𝑉= 0, with
appropriate boundary conditions. In the Dirichlet boundary
condition, a fixed scalar potential, the applied voltage, is
specified on the surface of the model. i
g
Knowing that the endogenous EF is highly involved in the
wound-healing process, researchers have also demonstrated
that exogenous EFs are beneficial for the healing of wounds
in both animal and human models [18–24]. Electrotherapies
including microcurrent electrical stimulation (MES) [25]
and transcutaneous electrical nerve stimulation (TENS) [26]
have become a current trend in wound-healing applications. Depending on the type of currents, ES can be divided into
three categories: DC, alternating current (AC), and pulsed
current (PC) [8, 27, 28]. In 1968, DC was first applied on
human wounds, showing that patients with chronic leg ulcers
healed after 50∼100 𝜇A DC treatments for six weeks [29]. Car-
ley and Wainapel observed that low intensity direct current
(LIDC) in the range of 200 to 800 𝜇A yielded 1.5 to 2.5 times
faster wound-healing rates in thirty patients with indolent
ulcers located either below the knee or in the sacral area
[18]. Symmetric square wave (an AC form) and asymmetric
biphasic pulsed wave (a PC form) were applied on wounds. Baker et al. evaluated the effects of these two stimulation
waveforms on healing rates in patients with diabetes and open
ulcers. They found that electrical stimulation, given daily with
a short pulsed, asymmetric biphasic waveform, enhanced
healing by nearly 60% over the control rate of healing [21]. 2.1. The Wound Model. A three-dimensional finite element
wound model was built using the software COMSOL Multi-
physics (MI, USA). The geometry of the wound and the skin
is shown in Figure 1(a) with dimensions listed in Table 1. The
outermost layer of the epidermis, the stratum corneum, has
a thickness of 0.014 mm and is composed of 15∼20 layers of
flattened cells. The epidermis, having a thickness of 0.3 mm, is
composed of proliferating basal and differentiated suprabasal
keratinocytes. The dermis, consisting of connective tissues,
has a thickness of 2.2 mm. 1. Introduction found that primary human keratinocytes migrated randomly
on collagen substrates in EFs of 5 mV/mm or less, but in fields
greater than 50 mV/mm they migrated toward the cathode
pole of the field [16]. Cooper and Schliwa showed that, in EFs
of 0.5∼15 V/cm, single epidermal cells, cell clusters, and cell
sheets migrated toward the cathode, with clusters and sheets
breaking apart into single migratory cells in the upper range
of these field strengths [17]. g
The present study was aimed to optimize the DC stimu-
lation therapy for wound-healing enhancement. Given that
the endogenous EF is beneficial and necessary for wound-
healing, it is important to determine the parameters in exoge-
nous electrotherapy. We built a three-dimensional wound
model consisting of different tissue types in the skin layers. Using the finite element method (FEM) and the commercial
software COMSOL Multiphysics, we simulated the distribu-
tion of EF near the wounded area under different electrode
configurations and further compared these results with what
were observed in the endogenous case. The main goal of this
study was to evaluate the effects of electrode configurations,
including sizes and positions, on the EFs produced around
the wound. The total power dissipation due to Joule heating
in different skin layers was also discussed. 1. Introduction Cooper and Schliwa showed that, in EFs
of 0.5∼15 V/cm, single epidermal cells, cell clusters, and cell
sheets migrated toward the cathode, with clusters and sheets
breaking apart into single migratory cells in the upper range
of these field strengths [17]. Electrical nerve stimulation (ENS) was applied to patients
with stasis ulcers, indicating an increase in the healing
rate from 15% (sham treatment) to 42% after 12 weeks of
treatment [30]. Moreover, low voltage PC (LVPC) [31, 32] and
high voltage PC (HVPC) [33–35] electrotherapies have been
shown to accelerate wound-healing in many clinical studies. For example, doubled-peaked monophasic impulses of a total
duration of 0.1 ms, frequency of 100 Hz, and amplitude of
100 V were demonstrated to be an efficient method for better
healing of crural ulceration [36].h electrotaxis or galvanotaxis, describes the directional migra-
tion of cells toward the cathode or anode of an applied EF. There are three sequential, distinct, but overlapped phases
involved in a normal wound-healing process: the inflamma-
tory, the proliferation, and the remodeling phases. During the
inflammatory phase, the endogenous EF enhances autolysis
and phagocytosis by means of the electrotaxis of macrophages
and neutrophils. Investigators have shown that macrophages
exposed to a 1 Hz and 2 V/cm EF exhibited an induced migra-
tion velocity of around 5.2 × 10−2 𝜇m/min on a glass substrate,
possibly due to EF exposure inducing the reorganization of
microfilaments from ring-like structures to podosomes [12]. Also, Kindzelskii and Petty reported that the application of
extremely low-frequency pulsed DCEFs that were frequency-
and phase-matched with endogenous metabolic oscillations
led to greatly exaggerated neutrophil extension and metabolic
resonance [13]. As the proliferative phase begins, EF promotes
fibroplasia by guiding fibroblasts toward the wounded area. Guo et al. demonstrated that human dermal fibroblasts of
both primary and cell-line cultures migrated directionally
toward the anode in an EF of 50∼100 mV/mm [14]. Chao
et al. applied static and pulsed DCEFs to calf anterior
cruciate ligament (ACL) fibroblasts and found that these
cells showed enhanced migration speed and perpendicular
alignment to the applied EFs [15]. In the remodeling phase,
EF accelerates wound contraction and epithelialization by
directing the migration of myofibroblasts, keratinocytes, and
epidermal cells near the wounded area. Nishimura et al. 1. Introduction It was found that the rates of
both protein and DNA syntheses were significantly increased
by specific combinations of HVPCS voltage and pulse rate;
the optimal EFs of protein and DNA syntheses were measured
to be 6.7 and 10 V/cm, respectively, with a pulse rate of 100
pulses/sec and the cells located near the negative electrode,
and HVPCS intensities greater than 250 V, corresponding to
EFs higher than 33.3 V/cm, inhibited both protein and DNA
syntheses. Moreover, it has long been proposed that, near
the wounded area, cells migrate in response to the endoge-
nous EF to repair the wound. This phenomenon, known as 2 BioMed Research International electrotaxis or galvanotaxis, describes the directional migra-
tion of cells toward the cathode or anode of an applied EF. There are three sequential, distinct, but overlapped phases
involved in a normal wound-healing process: the inflamma-
tory, the proliferation, and the remodeling phases. During the
inflammatory phase, the endogenous EF enhances autolysis
and phagocytosis by means of the electrotaxis of macrophages
and neutrophils. Investigators have shown that macrophages
exposed to a 1 Hz and 2 V/cm EF exhibited an induced migra-
tion velocity of around 5.2 × 10−2 𝜇m/min on a glass substrate,
possibly due to EF exposure inducing the reorganization of
microfilaments from ring-like structures to podosomes [12]. Also, Kindzelskii and Petty reported that the application of
extremely low-frequency pulsed DCEFs that were frequency-
and phase-matched with endogenous metabolic oscillations
led to greatly exaggerated neutrophil extension and metabolic
resonance [13]. As the proliferative phase begins, EF promotes
fibroplasia by guiding fibroblasts toward the wounded area. Guo et al. demonstrated that human dermal fibroblasts of
both primary and cell-line cultures migrated directionally
toward the anode in an EF of 50∼100 mV/mm [14]. Chao
et al. applied static and pulsed DCEFs to calf anterior
cruciate ligament (ACL) fibroblasts and found that these
cells showed enhanced migration speed and perpendicular
alignment to the applied EFs [15]. In the remodeling phase,
EF accelerates wound contraction and epithelialization by
directing the migration of myofibroblasts, keratinocytes, and
epidermal cells near the wounded area. Nishimura et al. found that primary human keratinocytes migrated randomly
on collagen substrates in EFs of 5 mV/mm or less, but in fields
greater than 50 mV/mm they migrated toward the cathode
pole of the field [16]. 2. Materials and Methods This electrode
covered the whole wounded area and was grounded at 0 mV. The remaining intact skin was covered with the positive
electrode assigned an electric potential of 30 mV. In the
second configuration (Geo 2), the negative electrode, with a
diameter of 3 mm, was placed on the center of the wound. There was a ring-shaped gap of 0.5 mm between the positive
(30 mV) and negative (grounded) electrodes. In the third
configuration (Geo 3), the negative electrode covered the 2.3. Simulation Conditions. The wound model was first used
to simulate the distribution of endogenous EF around the
wounded area. A potential difference of 30 mV was estab-
lished between the top of the stratum corneum and the
bottom of the epidermis. The ground (0 V) was set on the
surface of uninjured skin and a potential of 30 mV was placed
on the interface between epidermis and dermis. Further, this
model was applied to studying the effects of arrangements
and sizes of electrodes on the distribution of exogenous EFs. We would like to find the optimal electrode configuration
that has a synergistic effect to the existing endogenous EF. The top view of the five electrode configurations is shown
in Figure 2. In the first configuration (Geo 1), the diameter
of the circular, negative electrode was 4 mm. This electrode
covered the whole wounded area and was grounded at 0 mV. The remaining intact skin was covered with the positive
electrode assigned an electric potential of 30 mV. In the
second configuration (Geo 2), the negative electrode, with a
diameter of 3 mm, was placed on the center of the wound. There was a ring-shaped gap of 0.5 mm between the positive
(30 mV) and negative (grounded) electrodes. In the third
configuration (Geo 3), the negative electrode covered the 2.2. Tissue Properties. The electrical properties of different
skin layers are listed in Table 1 [37–41]. For simplicity, the four
skin layers were modeled as homogenous, isotropic conduc-
tors with constant conductivities and relative permittivities
throughout. The conductivities of the stratum corneum, the
epidermis, the dermis, and the subcutis were 2 × 10−6, 0.026,
0.222, and 0.08 Sm−1, respectively. The relative permittivities
of these four tissues were 5 × 102, 106, 108, and 107, respectively. The conductivity and relative permittivity of the surrounding
PBS buffer were 1.4 Sm−1 and 80, respectively. 2. Materials and Methods The underlying subcutis (also
called the subcutaneous tissue or the hypodermis), with a
thickness of 3 mm, has three types of cells: fibroblasts, adipose
cells, and macrophages. The wound and the surrounding
tissue were immersed in a salty buffer, phosphate-buffered
saline or PBS, for better electrical conductance. Figure 1(b)
shows the wound model constructed in COMSOL. Viewing
from top, the wound and the skin were modeled as a cylinder
with a total thickness of 5.514 mm, and the wound itself
had a side view of a triangle with a base of 4 mm and a
height of 5.514 mm (see Figure 1(b)). Figure 1(c) shows the BioMed Research International 3 PBS
Epidermis
Subcutis
Dermis
Wound
Stratum
corneum
(a)
5mm
(b)
5mm
(c)
Figure 1: (a) The geometry of the wound and the skin (not to scale). (b) The wound model constructed in COMSOL. (c) The finite element
mesh constructed in COMSOL. PBS
Epidermis
Subcutis
Dermis
Wound
Stratum
corneum
(a) 5mm
(b) Wound (a) (b) 5mm
(c) (c) Figure 1: (a) The geometry of the wound and the skin (not to scale). (b) The wound model constructed in COMSOL. (c) The finite element
mesh constructed in COMSOL. Table 1: Parameters used in the wound model. Thickness (mm)
Conductivity (𝜎in Sm−1)
Relative permittivity (𝜀𝑟)
PBS
1.4
80
Stratum corneum
0.014
2 × 10−6
5 × 102
Epidermis
0.3
0.026
106
Dermis
2.2
0.222
108
Subcutis
3.0
0.08
107 Table 1: Parameters used in the wound model. finite element mesh made of 485,510 tetrahedral elements,
73,114 triangular elements, 3,662 edge elements, and 92 vertex
elements. 2.3. Simulation Conditions. The wound model was first used
to simulate the distribution of endogenous EF around the
wounded area. A potential difference of 30 mV was estab-
lished between the top of the stratum corneum and the
bottom of the epidermis. The ground (0 V) was set on the
surface of uninjured skin and a potential of 30 mV was placed
on the interface between epidermis and dermis. Further, this
model was applied to studying the effects of arrangements
and sizes of electrodes on the distribution of exogenous EFs. We would like to find the optimal electrode configuration
that has a synergistic effect to the existing endogenous EF. The top view of the five electrode configurations is shown
in Figure 2. In the first configuration (Geo 1), the diameter
of the circular, negative electrode was 4 mm. 2. Materials and Methods We neglected
the facts that epidermis and dermis are polarized epithelia
and there are numerous Na+/K+ pumps on the membranes
of each layer. In other words, we were most interested
in optimizing the electrode configurations when applying
external ES. A more detailed model including polarized
epithelia and ion pumps is required if one wants to elucidate
the underlying mechanism of the endogenous EF. BioMed Research International Negative electrode
No electrode
Positive electrode
Wound (4mm dia.)
+
−
+
−
+
−
+
−
+
−
4mm dia. wound)
(20mm dia. with
Geo 1
(0.5 mm gap)
Geo 2
(2mm gap)
Geo 3
(2.5 mm gap)
Geo 4
Geo 5
Figure 2: Five electrode configurations used in this study. 4mm dia. wound)
(20mm dia. with
Geo 1
(0.5 mm gap)
Geo 2
(2mm gap)
Geo 3 +
−
(2.5 mm gap)
Geo 4 Geo 5 Geo 5 (2.5 mm gap)
Geo 4 Negative electrode
No electrode
Positive electrode
Wound (4mm dia.)
Figure 2: Five electrode configurations used in this study. Figure 2: Five electrode configurations used in this stud flow, as shown in Figure 4(b), indicates a clockwise current
flow outside the skin (the top part of the black loop) and a
counterclockwise current flow inside the skin (the top part
of the black loop). It is the counterclockwise current that
could help in wound-healing because its direction is the same
as what is observed in the endogenous EF (see Figure 3(b))
[2, 42–44]. Figures 4(c) and 4(d) show the 2D and 1D EF
distributions, respectively, demonstrating a maximum EF of
around 40 mV/mm near the edge of the wound (𝑥= 8 mm
and 𝑥= 12 mm). whole wounded area (diameter = 4 mm), and there was a
ring-shaped gap of 2 mm between it (grounded) and the
positive (30 mV) electrode. In the fourth configuration (Geo
4), the positive (30 mV) and negative (grounded) electrodes
partially covered the intact skin and the wounded area,
respectively, and there was a ring-shaped gap of 2.5 mm in
between. In the last configuration (Geo 5), no electrodes were
placed on the wound, and the positive (30 mV) and negative
(grounded) electrodes covered each side of the intact skin. Figures 5(a)–5(c) show the 1D exogenous EF distributions
of the Geo 2, Geo 3, and Geo 4 configurations, respectively. 2. Materials and Methods In these three configurations, the directions of the electric
current flows are similar to that observed in Geo 1, being
a clockwise current flow outside the skin and a counter-
clockwise current flow inside the skin. Therefore, comparing
with Figure 3(b), these exogenous EFs could have synergistic
effects to the existing endogenous EF. In Geo 2, the maximum
EF strength, around 40 mV/mm, occurred near the edge of
the wound (𝑥= 8 mm and 𝑥= 12 mm). This value is close
to what is observed in Geo 1. However, in Geo 2, the EF
decreased gradually outward along the intact skin (𝑥
<
8 mm and 𝑥> 12 mm) and reached zero on the outmost
region (𝑥
< 3 mm and 𝑥
> 17 mm). In Geo 3, the EF
reached a maximum of around 13 mV/mm near the edge
of the wound and then decreased to zero right out of the
wound toward to intact skin. The EF distribution in Geo 4
is similar to what is observed in Geo 2, except that the EF had
a maximum of only about 22 mV/mm. Figure S1 of the Sup-
plementary Material shows the 1D EF distributions combing
the endogenous EF with the applied EF in different electrode
configurations (see Supplementary Material available online
at https://doi.org/10.1155/2017/5289041). Comparing all these
configurations, we concluded that (1) all configurations
resulted in the same electric current flow directions, which 3. Results and Discussion The endogenous EF due to a potential difference of 30 mV
between the top of the stratum corneum and the bottom
of the epidermis is shown in Figure 3. The EF strength
near the edge of the wound (i.e., the junction of the
wound and the intact skin) was close to the theoretical
value of 30 mV/0.314 mm, or 96 mV/mm, as indicated three-
dimensionally (3D) in Figure 3(a). Figure 3(b) shows the
direction of the electric current flow, indicating the formation
of a current loop (marked as a black loop with arrows). In
Figure 3(c), the two-dimensional (2D) EF distribution, taken
along the horizontal plane marked red in Figure 1(b) (the
middle of the epidermis layer), shows an EF value of around
96 mV/mm near the edge of the wound. In Figure 3(d),
the one-dimensional (1D) EF distribution, plotted along the
horizontal line marked red in Figure 1(b) (taken as the 𝑥-axis
from 0 to 20 mm), further verifies that the EF distributes near
the wound edge (𝑥= 8 mm and 𝑥= 12 mm) and drops to zero
outward along the intact skin (𝑥< 8 mm and 𝑥> 12 mm). Figure 4(a) represents the 3D exogenous EF distribution
in the Geo 1 configuration. Similarly, the EF strength had
a maximum near the edge of the wound, and this value
decreased sharply to almost zero right out of the wound
toward the intact skin. The direction of the electric current BioMed Research International 5 120
0
5mm
(V/m)
(a)
5mm
(b)
120
0
5mm
(V/m)
(c)
0
20
40
60
80
100
120
−10
0
5
10
(mm)
−5
(V/m)
(d)
Figure 3: (a) 3D distribution of the endogenous EF. (b) Direction of the electric current flow. (c) 2D distribution of the endogenous EF. (d)
1D distribution of the endogenous EF. (V/m) (a) 120
0
5mm
(V/m)
(c) (V/m)
(c) (c) Figure 3: (a) 3D distribution of the endogenous EF. (b) Direction of the electric current flow. (c) 2D distribution of the endogenous EF. (d)
1D distribution of the endogenous EF. 120
0
5mm
(V/m)
(a)
5mm
(b)
120
0
5mm
(V/m)
(c)
0
10
20
30
40
50
0
5
10
(mm)
−5
−10
−
+
(V/m)
(d)
Figure 4: (a) 3D exogenous EF distribution in Geo 1. (b) Direction of the electric current flow in Geo 1. (c) 2D exogenous EF distribution in
Geo 1. 3. Results and Discussion (d) 1D exogenous EF distribution in Geo 1. 120
0
5mm
(V/m)
(a)
5mm
(b) 5mm
(b) (b) (a) (b)
0
10
20
30
40
50
0
5
10
(mm)
−5
−10
−
+
(V/m)
(d) 120
0
5mm
(V/m)
(c)
0
10
20
30
40
50
0
5
10
(mm)
−5
−10
−
+
(V/m)
(d)
Figure 4: (a) 3D exogenous EF distribution in Geo 1. (b) Direction of the electric current flow in Geo 1. (c) 2D exogenous EF distribution in
Geo 1. (d) 1D exogenous EF distribution in Geo 1. 120
0
5mm
(V/m)
(c) (V/m)
(c) (d) (c) Figure 4: (a) 3D exogenous EF distribution in Geo 1. (b) Direction of the electric current flow in Geo 1. (c) 2D exogenous EF distribution in
Geo 1. (d) 1D exogenous EF distribution in Geo 1. BioMed Research International 6 BioMed Research Internationa
0
10
20
30
40
50
0
5
10
(mm)
+
−
−5
−10
(V/m)
(a)
0
4
8
12
16
0
5
10
−
(mm)
−5
−10
(V/m)
(b)
0
5
10
15
20
25
0
5
10
+
−
(mm)
−5
−10
(V/m)
(c)
Figure 5: 1D exogenous EF distributions in (a) Geo 2, (b) Geo 3, and (c) Geo 4. 0
4
8
12
16
0
5
10
−
(mm)
−5
−10
(V/m)
(b) (c) Figure 5: 1D exogenous EF distributions in (a) Geo 2, (b) Geo 3, and (c) Geo 4. and x > 12 mm). Moreover, the maximum EF strength was
only around 16 mV/mm. This was simply due to the poor
conductance of air, so it would be most helpful to keep the
wound in moist, salty surroundings. This agrees with clinical
findings that (1) cells die when they dry and (2) endogenous
and exogenously enhanced electrotaxis is enhanced in a
physiological moist wound environment. are helpful in electrotherapy applications, and (2) Geo 1 and
Geo 2 provided the highest EF strength, compared to Geo 3
and Geo 4, indicating that covering the whole unwounded
area (intact skin) with the positive electrode and the whole or
part of the wounded area with the negative electrode resulted
in the optimal configuration in such applications. The 1D EF
distribution combining the endogenous EF with the applied
EF in different electrode configurations is shown in Figure S1
of the Supplementary Material. 3. Results and Discussion Finally, we investigated the power dissipation density (in
W/m3) due to Joule heating in different skin layers, as listed
in Table 2. In the case of the endogenous EF, the power
dissipation density in the stratum corneum was 8.9 W/m3,
and this value decreased to 6.77 W/m3 in the epidermis, to
4.75 W/m3 in the dermis, and to 0.28 W/m3 in the subcutis. In Geo 1, these values were 8.05, 2.14, 2.34, and 0.12 W/m3
in the stratum corneum, the epidermis, the dermis, and
the subcutis, respectively. In Geo 2∼Geo 4, these values
were 6.02∼8.5, 0.39∼1.54, 0.64∼1.82, and 0.03∼0.07 W/m3 in
the stratum corneum, the epidermis, the dermis, and the
subcutis, respectively. In the last configuration (Geo 5), the
power dissipation densities were smaller compared to those
in other cases, being 1.48 W/m3 in the stratum corneum,
0.36 W/m3 in the epidermis, 0.13 W/m3 in the dermis, and
0.02 W/m3 in the subcutis. These results suggested that most
of the electrical energy was dissipated in the stratum corneum
since it is the thinnest layer and has the smallest conductivity. According to [45], an absorption of surface power density
less than 40 mW/cm2 was considered safe to the skin. In our
studies, a power dissipation density of 10 W/m3 corresponded pp
y
In Geo 5, with the positive and negative electrodes being
placed on each side of the intact skin, the directions of the
electric current flow were opposite outside and inside the
skin, as indicated in Figure 6(a) (see the black loop with
arrows). A clockwise current flow was established outside the
skin, and a counterclockwise one was observed inside the
skin. As shown in Figure 6(b), the EF reached a maximum of
about 20 mV/mm near the edge of the wound (𝑥= 8 mm and
𝑥= 12 mm) and decreased gradually to zero outward along
the intact skin (𝑥< 8 mm and 𝑥> 12 mm). Clearly, this
configuration was not suitable for electrotherapy applications
because in the endogenous EF and other exogenous EFs
(Geo 1∼Geo 4) there are two current loops distributed
symmetrically on each side of the wound but in the current
configuration (Geo 5) there is only one current loop. After
changing the surrounding medium from PBS to air, the
difference in the EF distributions was significant. Conflicts of Interest The author declares that he has no conflicts of interest. 4. Conclusion Knowing that the endogenous EF is beneficial and necessary
for wound-healing, we built a three-dimensional wound
model consisting of different tissue types in the skin layers to
study the effects of electrode configurations, including sizes
and positions, on the exogenous EFs produced around the
wound. According to the results, different electrode config-
urations resulted in different magnitudes and distributions of
exogenous EFs. The optimal arrangements were to cover the
whole intact skin with the positive electrode and the whole
or part of the wounded area with the negative electrode. With a potential difference of 30 mV established between
positive and negative electrodes, these optimal configurations
exhibited a maximum EF of around 40 mV/mm near the 3. Results and Discussion Finally,
by investigating the power dissipation density due to Joule
heating in different skin layers, it was concluded that these
different electrode configurations with an applied voltage of
30 mV should be harmless to the skin. The present study
is beneficial to designing the electrode configuration for
applications in clinical electrotherapies. 3. Results and Discussion As shown
in Figure 6(c), the EF strength was the highest in the edge of
the wound (x = 8 mm and x = 12 mm) and was almost zero
right outside of that edge along the intact skin (x < 8 mm 7 BioMed Research International +
−
5mm
(a)
0
5
10
15
20
0
5
10
(mm)
−5
−10
(V/m)
(b)
0
5
10
15
20
0
5
10
(mm)
−5
−10
(V/m)
(c)
Figure 6: (a) Direction of the electric current flow in Geo 5 (Ambient = PBS). (b) 1D exogenous EF distribution in Geo 5 (Ambient = PBS). (c) 1D exogenous EF distribution in Geo 5 (Ambient = air). Figure 6: (a) Direction of the electric current flow in Geo 5 (Ambient = PBS). (b) 1D exogenous EF distribution in Geo 5 (Ambient = PBS). (c) 1D exogenous EF distribution in Geo 5 (Ambient = air). Table 2: Power dissipation densities (W/m3) in different configurations. Endo. EF
Geo 1
Geo 2
Geo 3
Geo 4
Geo 5
EF (mV/mm)
96
40
40
13
22
20
Stratum corneum
8.90
8.05
8.50
7.57
6.02
1.48
Epidermis
6.77
2.14
1.54
1.10
0.39
0.36
Dermis
4.75
2.34
1.82
1.16
0.64
0.13
Subcutis
0.28
0.12
0.07
0.04
0.03
0.02 Table 2: Power dissipation densities (W/m3) in different configurations. to only 1.4 × 10−5 mW/cm2 surface power density in the 0.014-
mm-thick epidermis. Therefore, these electrotherapies with
an applied voltage of 30 mV were thought to be harmless to
the skin. edge of the wound, which could have synergistic effects
to the existing endogenous EF. The results also indicated
that it would be helpful to keep the wound in moist, salty
surroundings, comparing to the dry environment. Finally,
by investigating the power dissipation density due to Joule
heating in different skin layers, it was concluded that these
different electrode configurations with an applied voltage of
30 mV should be harmless to the skin. The present study
is beneficial to designing the electrode configuration for
applications in clinical electrotherapies. edge of the wound, which could have synergistic effects
to the existing endogenous EF. The results also indicated
that it would be helpful to keep the wound in moist, salty
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Control Mechanisms of Energy Storage Devices
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IntechOpen eBooks
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Abstract The fast acting due to the salient features of energy storage systems leads to
using of it in the control applications in power system. The energy storage systems
such as superconducting magnetic energy storage (SMES), capacitive energy stor-
age (CES), and the battery of plug-in hybrid electric vehicle (PHEV) can storage the
energy and contribute the active power and reactive power with the power system
to extinguish the rapid change in load demands and the renewable energy sources
(RES). This chapter gives an overview about the modeling of energy storage devices
and methods of control in them to adjust steady outputs. Keywords: energy storage devices, superconducting magnetic energy storage
(SMES), capacitive energy storage (CES), plug-in hybrid electric vehicle (PHEV) Control Mechanisms of Energy
Storage Devices Mahmoud Elsisi 1. Introduction With the increasing of distributed generator (DG) technologies, large numbers
of DGs are connected with the grid in different forms, such as wind and solar power
systems [1–3]. Because of the fluctuations of their output power, energy storage
devices are utilized to adjust steady outputs [4, 5]. In fact, the characteristics of the
different storage devices vary widely, including the amount of energy stored and
the time for which this stored energy is required to be retained or released [6, 7]. The superconducting magnetic energy storage (SMES), superconducting capacitive
energy storage (CES), and the battery of plug-in hybrid electric vehicle (PHEV) are
able to achieve the highest possible power densities. Each storage energy device has
a different model. Several control approaches are applied to control the energy
storage devices. In [8, 9], model predictive control (MPC) is presented for residen-
tial energy systems with photovoltaic (PV) system and batteries. Model predictive
control predicts the load and the generation over a certain time horizon into the
future and finds the optimum schedule of the battery over that period which can
minimize a desired objective. In [10], a voltage regulation in distribution feeders is
proposed using residential energy storage units. The control method is carried out
by making the charging and discharging rates of the batteries a function in the
voltage at the point of common coupling. A fuzzy logic based control method of
battery state of charge (SOC) is presented in [11]. This control method regulates the
battery SOC at expected conditions, and consequently the energy capacity of BESS
can be small. In [12], a state-of-charge feedback control technique is used to keep
the charging level of the battery within its proper range while the battery energy
storage system make the output fluctuation of a wind farm smooth. The optimal 1 Energy Storage Devices design of MPC with SMES based on the bat-inspired algorithm (BIA) is introduced
for load frequency control in [13]. This work is extended to include the MPC with
SMES and CES in [14]. Decentralized MPC with PHEVs is utilized for frequency
regulation in a smart three-area interconnected power system in [15]. 2.1 Modeling of superconducting magnetic energy storage According to the rectifier or inverter modes, the polarity of the voltage Ed is
adjusted while the direction of inductor current Id does not change. As mention in
the above section, the regulation of the thyristor firing angle is used to controlling
the direction and magnitude of the inductor power Pd. Initially, a small positive
voltage is applied to charge the inductor to its rated current according to the desired
charging period of the SMES unit. The inductor voltage is reduced to zero and the
inductor current reach to its rated value because the coil is superconducting. When
the inductor current reached to its rated value, the SMES unit can be coupled to the
power system. The error signal ∆e represent the input to control the SMES voltage
Ed. This error signal may be the change of system frequency, the change of system
voltage, or the change of system current according to the control object. The incre-
mental voltage and current changes of the SMES coil are given as follows: ΔEd ¼
Ko
1 þ sTdc
Δe
ð
Þ
(2)
ΔId ¼ 1
sL ΔEd
(3) ΔEd ¼
Ko
1 þ sTdc
Δe
ð
Þ
(2) (2) ΔId ¼ 1
sL ΔEd
(3) (3) where Tdc is the converter time constant in sec, Ko is the gain of the proportional
controller in kV/Hz and s is the Laplace operator. As reported in [19], the inductor
current reaches to its nominal value very slowly in the SMES unit. So, the fast rate
of the current to restore its rated value is required to extinguish the next load
perturbation fastly. Therefore, a negative feedback signal is used in the SMES
control loop to provide fast current recovery. Thus, Eq. 2 is rewritten in following
form: ΔEd ¼
1
1 þ sTdc
KoΔe KIdΔId
ð
Þ
(4) (4) where KIdis the negative feedback gain of the current deviation (kV/kA). In the
storage mode, the coil is short-circuited, i.e. Edo ¼ 0 and there is no power transfer. So in either phase (charging/discharging), the power is defined by Pd ¼ EdId and
the initial inductor power is Pdo ¼ EdoIdo, where Edo and Ido are the voltage and
current magnitudes previous to load disturbance. 2. Superconducting magnetic energy storage The SMES units are used to compensate the load increments by the injection of a
real power to the system and diminished the load decrements by the absorbing of
the excess real power via large superconducting inductor [16–18]. Figure 1a show a
schematic diagram of SMES unit consists of superconducting inductor (L), Y-Y/Δ
transformer, and controlled ac/dc bridge converter with 12-pulse thyristor. A power
conversion system (PCS) is used to connect the superconducting inductor with the
AC grid. The PCS is a dual-mode converter and it works as a rectifier or as an
inverter in the charging and discharging modes of the inductor respectively. Obvi-
ously, the mode of operation is detected according to the nature of load perturba-
tion. The charging phase represents the rectifier mode. In the rectifier mode,
adjusted positive voltage is applied across the terminals of the inductor. Alternatively,
the discharging phase represents the inverter mode. In the inverter mode, adjusted
negative voltage is applied across the terminals of the inductor. The controlling in the
thyristor firing angle is used to switch either rectifier or inverter modes, the converter
output voltage is expressed in kV and it is given in following equation [19]: Ed ¼ 2Eo cos α
ð Þ 2IdRc
(1) (1) Ed ¼ 2Eo cos α
ð Þ 2IdRc Ed ¼ 2Eo cos α
ð Þ 2IdRc Figure 1. The SMES unit (a) circuit diagram and (b) corresponding block diagram. Figure 1. The SMES unit (a) circuit diagram and (b) corresponding block diagram. Figure 1. The SMES unit (a) circuit diagram and (b) corresponding block diagram. Figure 1. The SMES unit (a) circuit diagram and (b) corresponding block diagram. 2 Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 where Ed is the inductor DC voltage (kV); Eo is the converter open circuit
voltage (kV); α is the thyristor firing angle (degrees); Id is the inductor current
(kA); RC is the equivalent resistance of commutation (ohm). where Ed is the inductor DC voltage (kV); Eo is the converter open circuit
voltage (kV); α is the thyristor firing angle (degrees); Id is the inductor current
(kA); RC is the equivalent resistance of commutation (ohm). 2.2 Control techniques of SMES Modern control techniques such as adaptive control, fuzzy logic control, and
model predictive control (MPC) can be applied to control the charging and
discharging of the SMES instead of the proportional controller as shown in Figure 2. The controller and SMES parameters must be adjusted by proper optimization
technique such as genetic algorithm (GA), particle swarm optimization (PSO), and
artificial bee colony (ABC),…etc. to give a good performance. 3. Capacitive energy storage The capacitive energy storage (CES) has an important role to stabilize the power
system against to the sudden change in load demand. The static operation of the
CES makes its response faster than of the mechanical systems [20–23]. Parallel
storage capacitors form the CES. Figure 3a shows a schematic diagram of a CES unit
connected with the AC grid by a PCS. The capacitor bank dielectric and leakage
losses are defined by the resistance (R). When the load demand decreases, the
capacitor charges up to its rated full value, thus releases an amount of the excess
energy in the system. Contrary, the capacitor discharges to its initial value of
voltage when the load demand rises suddenly and release the stored energy fastly to
the grid through the PCS. A gate turn-off (GTO) thyristors is used as switches to
control the direction of the capacitor current during the charging and discharging as
shown in Table 1. The controlling in the thyristor firing angle is used to switch either rectifier or
inverter modes of CES to adjust the capacitor voltage as defined in Eq. 1. Figure 2. Figure 2. The block diagram of SMES with controller. Figure 2. The block diagram of SMES with controller. Setting the parameters (L, Ko, KId and Ido) of the SMES unit to their optimistic
values can enhance its role in achieving well-damped to the responses. Herein, the
application of artificial intelligence (AI) techniques is suggested to search for the
optimal parameters of the SMES and controller simultaneously. 2.1 Modeling of superconducting magnetic energy storage The inductor power following to
the load disturbance is defined as follows: Pd ¼ Edo þ ΔEd
ð
Þ Ido þ ΔId
ð
Þ
¼ EdoIdo þ EdoΔId þ IdoΔEd þ ΔEdΔId ¼ Pdo þ EdoΔId þ IdoΔEd þ ΔEdΔId, Edo ¼ 0
(5) Pd ¼ Edo þ ΔEd
ð
Þ Ido þ ΔId
ð
Þ (5) Therefore, the real power incremental change ΔPd of the SMES unit in MW is
computed as follows: Therefore, the real power incremental change ΔPd of the SMES unit in MW is
computed as follows: ΔPd ¼ Pd Pdo ¼ IdoΔEd þ ΔIdΔEd
(6) (6) The corresponding block diagram of an SMES incorporating the negative feed-
back of the current deviation is shown in Figure 1b. The corresponding block diagram of an SMES incorporating the negative feed-
back of the current deviation is shown in Figure 1b. 3 Energy Storage Devices Setting the parameters (L, Ko, KId and Ido) of the SMES unit to their optimistic
values can enhance its role in achieving well-damped to the responses. Herein, the
application of artificial intelligence (AI) techniques is suggested to search for the
optimal parameters of the SMES and controller simultaneously. Figure 2. The block diagram of SMES with controller. Figure 2. The block diagram of SMES with controller. 3.2 Control techniques of CES Modern control techniques such as adaptive control, fuzzy logic control, and
MPC can be applied to control the charging and discharging of the CES instead of
the proportional controller as shown in Figure 4. The controller and CES parame-
ters must be adjusted by proper optimization technique such as GA, PSO, and ABC,
…etc. to give a good performance. Figure 4. g
4
The block diagram of CES with controller. and no power transfer. Hence, the power is defined by PCS ¼ EdId and the initial
CES power is PCSo ¼ EdoIdo, where Edo and Ido are the magnitudes of the voltage and
current prior to load disturbance. Following a load disturbance, the power flow into
the CES is given as follows: and no power transfer. Hence, the power is defined by PCS ¼ EdId and the initial
CES power is PCSo ¼ EdoIdo, where Edo and Ido are the magnitudes of the voltage and
current prior to load disturbance. Following a load disturbance, the power flow into
the CES is given as follows: PCS ¼ Edo þ ΔEd
ð
Þ Ido þ ΔId
ð
Þ
¼ EdoIdo þ EdoΔId þ IdoΔEd þ ΔEdΔId ¼ PCSo þ EdoΔId þ IdoΔEd þ ΔEdΔId, Ido ¼ 0
(9) (9) Thus, the real power incremental change ΔPCS of the CES unit in MW is com-
puted as follows: Thus, the real power incremental change ΔPCS of the CES unit in MW is com-
puted as follows: ΔPCS ¼ PCS PCSo ¼ EdoΔId þ ΔEdΔId
(10) (10) The corresponding block diagram of a CES unit incorporating the negative
feedback of the voltage deviation is shown in Figure 3b. The corresponding block diagram of a CES unit incorporating the negative
feedback of the voltage deviation is shown in Figure 3b. Setting the parameters (C, Kc, KEd and Edo) of the CES unit to their optimistic
values can enhance its role in achieving well-damped to the responses. Herein, the
application of artificial intelligence (AI) techniques is suggested to search for the
optimal parameters of the CES and controller simultaneously. 3.1 Modeling of superconducting magnetic energy storage The CES unit is ready to be coupled to the power system for LFC when the
rated voltage across the capacitor is attained. The current Id of CES is controlled
by sensing the error signal Δe. This error signal may be the change of system
frequency, the change of system voltage, or the change of system current according
to the control object. The incremental current changes of the CES are given as
follows: 4 Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 ΔId ¼
Kc
1 þ sTdc
Δe
ð
Þ
(7) (7) where Kc is the proportional controller in kA/Hz. where Kc is the proportional controller in kA/Hz. where Kc is the proportional controller in kA/Hz. As stated in [20], the CES voltage reaches to its nominal value very slowly. So,
the fast rate of the capacitor voltage to restore its rated value is required to extin-
guish the next load perturbation fastly. Therefore, a negative feedback signal is used
in the CES control loop to provide a fast voltage recovery. Thus, Eq. 7 is rewritten in
following form: ΔId ¼
1
1 þ sTdc
KcΔf KEdΔEd
ð
Þ
(8) (8) where KEd is the negative feedback gain of the capacitor voltage deviation
(kA/kV). In the storage mode, the capacitor represents an open circuit, i.e. Ido ¼ 0 where KEd is the negative feedback gain of the capacitor voltage deviation
(kA/kV). In the storage mode, the capacitor represents an open circuit, i.e. Ido ¼ 0 where KEd is the negative feedback gain of the capacitor voltage deviation
(kA/kV). In the storage mode, the capacitor represents an open circuit, i.e. Ido ¼ 0 Figure 3. The CES unit (a) circuit diagram and (b) corresponding block diagram. Charging mode
Discharging mode
S1, S4
ON
OFF
S2, S3
OFF
ON Figure 3 Figure 3. The CES unit (a) circuit diagram and (b) corresponding block diagram. Figure 3. The CES unit (a) circuit diagram and (b) corresponding block diagram. Charging mode
Discharging mode
S1, S4
ON
OFF
S2, S3
OFF
ON
Table 1. The modes of switches during the charging and discharging of CES unit Table 1. The modes of switches during the charging and discharging of CES unit. 5 Energy Storage Devices Figure 4. The block diagram of CES with controller. Figure 4. 4. Plug-in hybrid electric vehicle model The PHEV model is represented as first-order transfers function with very small
time constant TPHEV as shown in Figure 5(a) [24–27]. The change of PHEV output
power ∆PPHEV for charging or discharging is selected according to the control signal
Ui of the controller. In this chapter, the control signal is determined by modern
control techniques such as adaptive control, fuzzy logic control, and model predic-
tive control (MPC). The control signal depends on the error signal to adjust the
charging or discharging of PHEVs batteries. Figure 5(b) shows a bi-directional
PHEV to charging and discharging power control ‘vehicle to grid (V2G)’. According
to the change of error, this V2G release a power to the grid or drain power from the 6 Figure 5. PHEV model: (a) PHEV with controller block diagram, (b) change of PHEV output power against control
signal. Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 Control Mechanisms of Energy Storage Devices
DOI: http://dx.doi.org/10.5772/intechopen.82327 Figure 5. PHEV model: (a) PHEV with controller block diagram, (b) change of PHEV output power against control
signal. grid. The change of PHEV output power is adjusted by the control signal (U)
according to the limit range of output power deviation of PHEV as grid. The change of PHEV output power is adjusted by the control signal (U)
according to the limit range of output power deviation of PHEV as ΔPPHEV ¼
Ui, Ui
j
j≤ΔPmax
ΔPmax, Ui>ΔPmax
ΔPmax, Ui < ΔPmax
8
>
<
>
:
(11) (11) where Pmax is the maximum PHEV power. max is the maximum PHEV power. sion where Pmax is the maximum PHEV power. 5. Conclusion In this chapter, classifications of energy storage devices and control strategy for
storage devices by adjusting the performance of different devices and features of
the power imbalance are presented. The modeling of each storage energy devices is
discussed. Furthermore, the control method for each one are cleared. These energy
storage devices with modern control techniques such as adaptive control, fuzzy
logic control, and model predictive control (MPC) can be applied to extinguish the
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Mahmoud Elsisi
Electrical Power and Machines Department, Faculty of Engineering (Shoubra),
Benha University, Cairo, Egypt
*Address all correspondence to: mahmoud.elsesy@feng.bu.edu.eg
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
Energy Storage Devices Energy Storage Devices Energy Storage Devices © 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited. 8 Control Mechanisms of Energy Storage Devices
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frequency control of microgrid. IEEE
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automatic generation control with
superconducting magnetic energy
storage in power systems. IEEE
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Development of a novel clinical support tool for active surveillance of low risk papillary thyroid cancer
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Frontiers in endocrinology
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cc-by
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OPEN ACCESS EDITED BY
Joana Simões-Pereira,
Instituto Portugueˆ s de Oncologia de Lisboa
Francisco Gentil, Portugal Eleanor White 1*, Bridget Abbott 2, Geoffrey Schembri 2,3,
Anthony Glover 3,4, Roderick Clifton-Bligh 1,3 and Matti L. Gild 1,3 1Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, NSW, Australia,
2Department of Radiology, Royal North Shore Hospital, Sydney, NSW, Australia, 3Faculty of Medicine
and Health, University of Sydney, Sydney, NSW, Australia, 4Department of Endocrine Surgery, Royal
North Shore Hospital, Sydney, NSW, Australia Background: Active surveillance (AS) is an alternative to surgery in select patients
with very low risk papillary thyroid cancer (PTC). Many clinicians feel ill-equipped
in selecting appropriate patients. We aimed to 1) Develop an evidence-based
web delivered decision support tool to assist clinicians in identifying patients
appropriate for AS; and 2) Evaluate the prevalence of patients suitable for AS in a
tertiary high volume thyroid cancer centre. CITATION
White E, Abbott B, Schembri G, Glover A,
Clifton-Bligh R and Gild ML (2023)
Development of a novel clinical
support tool for active surveillance
of low risk papillary thyroid cancer. Front. Endocrinol. 14:1160249. doi: 10.3389/fendo.2023.1160249 © 2023 White, Abbott, Schembri, Glover,
Clifton-Bligh and Gild. This is an open-
access article distributed under the terms of
the Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that
the original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms. Method: A REDCap web based clinical support tool was developed utilising
evidence-based characteristics for AS suitability available to clinicals during initial
assessment. A retrospective database was interrogated for patients who
underwent hemithyroidectomy between 2012 – 2021 with final histopathology
demonstrating PTC. Patients with PTCs>2cm, missing data, benign disease on
surgical histopathology or incidental PTC were excluded. © 2023 White, Abbott, Schembri, Glover,
Clifton-Bligh and Gild. This is an open-
access article distributed under the terms of
the Creative Commons Attribution License Results: Between 2012 - 2021, 763 patients underwent hemithyroidectomy with
final histopathology confirming PTC. Of these, 316 patients were excluded
(missing data, incidental PTC, concomitant hyperparathyroidism were most
common reasons for exclusion) and 114/447 remaining patients had a pre-
operative fine needle aspirate (FNA) of Bethesda V or VI (high likelihood of
malignancy). TYPE Original Research
PUBLISHED 11 September 2023
DOI 10.3389/fendo.2023.1160249 TYPE Original Research
PUBLISHED 11 September 2023
DOI 10.3389/fendo.2023.1160249 © 2023 White, Abbott, Schembri, Glover,
Clifton-Bligh and Gild. This is an open-
access article distributed under the terms of
the Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that
the original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms. Development of a novel
clinical support tool for
active surveillance of low
risk papillary thyroid cancer OPEN ACCESS
EDITED BY
Joana Simões-Pereira,
Instituto Portugueˆ s de Oncologia de Lisboa
Francisco Gentil, Portugal
REVIEWED BY
Amirhesam Babajani,
Iran University of Medical Sciences, Iran
Tetiana Bogdanova,
National Academy of Sciences of Ukraine,
Ukraine
*CORRESPONDENCE
Eleanor White
eleanor.white@health.nsw.gov.au
RECEIVED 06 February 2023
ACCEPTED 24 August 2023
PUBLISHED 11 September 2023
CITATION
White E, Abbott B, Schembri G, Glover A,
Clifton-Bligh R and Gild ML (2023)
Development of a novel clinical
support tool for active surveillance
of low risk papillary thyroid cancer. Front. Endocrinol. 14:1160249. doi: 10.3389/fendo.2023.1160249 OPEN ACCESS
EDITED BY
Joana Simões-Pereira,
Instituto Portugueˆ s de Oncologia de Lisboa
Francisco Gentil, Portugal
REVIEWED BY
Amirhesam Babajani,
Iran University of Medical Sciences, Iran
Tetiana Bogdanova,
National Academy of Sciences of Ukraine,
Ukraine
*CORRESPONDENCE
Eleanor White
eleanor.white@health.nsw.gov.au
RECEIVED 06 February 2023
ACCEPTED 24 August 2023
PUBLISHED 11 September 2023
CITATION
White E, Abbott B, Schembri G, Glover A,
Clifton-Bligh R and Gild ML (2023)
Development of a novel clinical
support tool for active surveillance
of low risk papillary thyroid cancer. Front. Endocrinol. 14:1160249. doi: 10.3389/fendo.2023.1160249 Introduction decade and is included in the most recent ATA guidelines (7). Evidence for active surveillance dates back to 1993, through a
prospective study in Kuma Hospital where patients with low risk
PTC either underwent active surveillance or immediate surgery
(12). Patients in the AS arm had low rates of tumour growth or
development of nodal disease over 10 years. Those who had tumour
growth or nodal disease underwent rescue surgery with no
difference in mortality between groups (12). This safety data has
now been replicated by many other centres (13–15). The bulk of
studies for AS are in papillary microcarcinomas (PMC) however
there is now evidence for inclusion of tumours up to 2cm. Sakai
et al. included patients with tumours up to 2cm in their prospective
active surveillance trial, demonstrating low rates of tumour growth
and lymph node metastases in patients who underwent active
surveillance, at 7% and 3% respectively (13). Even patients who
underwent subsequent surgery from the AS arm did not
demonstrate any disease recurrence in the follow up period,
reflecting that the size criteria can be safely extended (13). This
data has also been replicated by Ho et al. (2022) (14). Incidence of thyroid cancer has increased over past decades,
largely attributed to improvement in imaging techniques and
identification of incidental thyroid nodules (1). Most of these
nodules will be benign; however, a small percentage will harbour
malignancy (1). Papillary thyroid cancer (PTC) is the most
common type of thyroid malignancy, with excellent prognosis
and 5 year survival rates over 97% (2, 3). Despite increased
diagnosis of incidental thyroid cancers, mortality rates remain
largely unchanged and are overall low, suggesting over-diagnosis
of low risk cancers (4). In addition to the psychological impact of a
cancer diagnosis, there are financial implications on the health care
industry for overdiagnosis which need to be considered. In South
Korea the economic burden of thyroid cancer increased from $257
million in 2000 to $1.7 billion by 2010, with no change in thyroid
cancer mortality (5). These figures are similarly seen in other
countries and highlight the need to balance the risk and cost of
treatment against the risk of disease progression (6). While there is robust evidence for AS for low risk PTC <2cm,
not every patient with a low risk PTC should undergo AS. Introduction Characterising both the tumour and patient features that make
patients ideal candidates has become clearer in the recent years. Tuttle et al. have described tumour and patient characteristics that
help risk stratify patients into ideal, appropriate, or inappropriate
for active surveillance (15). Presence of nodal or distant metastases,
extrathyroidal extension (ETE) or lymphovascular invasion (LVI),
or unfavourable tumour location (e.g. adjacent to a critical structure
with potential for tumour invasion) exclude active surveillance as a
suitable option (15). Lohia et al. recommended there should be
>2mm of normal parenchyma between the thyroid nodule and the
capsule to avoid potential tumour growth to nearby critical
structures and this has been adopted by some centres (15). Thyroid cancer can be classified into low, intermediate or high
risk based on tumour stage, presence of lymphovascular invasion
(LVI), extrathyroidal extension (ETE) and tumour location in
relation to the capsule (7). Low risk papillary thyroid cancer are
smaller tumours, typically less than 1cm (microcarcinoma), without
LVI, ETE or presence of nodal or distant metastasis (8). Certain
histological subtypes of papillary thyroid cancer or presence of
molecular mutations such as BRAF V600E can behave more
aggressively, and this information is typically identified in the
final histopathology report (2). The natural history of low risk PTC is indolent and slow growing,
with low rates of locoregional or distant metastasis (9). Historically
the management of these cancers has been surgical, with either total
thyroidectomy or lobectomy. Following the updated American
Thyroid Association (ATA) guidelines in 2015, hemithyroidectomy
is now an accepted surgical option for low risk differentiated cancer
(7). Potential surgical complications of hemithyroidectomy such as
wound infection, vocal cord or recurrent laryngeal nerve palsy,
temporary or permanent hypoparathyroidism, or hypothyroidism
may still occur and while these rates are low in experienced centres,
these should be considered in treatment decisions (10, 11). Despite the continuously growing body of evidence for active
surveillance, many clinicians do not feel comfortable in identifying
appropriate patients (16). Wei et al. performed a scoping review to
explore factors that influenced clinician and patients decision in
selecting either active surveillance, hemi- or total thyroidectomy for
low risk thyroid cancer (17). Patients were more likely to consider
conservative therapy if provided with adequate information (17). OPEN ACCESS Using the tool, 59/114 (52%) met criteria for AS. The majority of
patients were female (85% vs 15% male); median age 36 years (range 19 – 78). Following initial surgery, 10/59 patients had a completion thyroidectomy, with 4/
10 demonstrating malignancy in contralateral lobe and eight of those patients
undergoing I131 ablation. During a median follow up of over 3 years, 49/59 (83%)
did not require further surgery or intervention with no patients developing
recurrence. A subgroup analysis with second radiology assessment excluded
4/59 patients as meeting criteria for AS based on presence of ETE on
preoperative ultrasound. None of these 4 patients had completion
thyroidectomy. Conclusion: Our clinical support tool identifies patients with PTC potentially
suitable for AS which could be utilised during initial patient assessment. In a Frontiers in Endocrinology 01 frontiersin.org White et al. 10.3389/fendo.2023.1160249 retrospective cohort of patients who had hemithyroidectomy for PTC with a pre-
operative FNA diagnosis of Bethesda V or VI, 55/114 (48%) patients may have
been suitable for AS. Prospective validation studies are required for
implementation of the tool in clinical practice. active surveillance, low risk thyroid cancer, clinical support tool, papillary thyroid cancer,
watchful waiting, de-escalation treatment active surveillance, low risk thyroid cancer, clinical support tool, papillary thyroid cancer,
watchful waiting, de-escalation treatment Frontiers in Endocrinology frontiersin.org KEYWORDS Retrospective analysis A retrospective thyroid cancer surgery database was
interrogated for patients who underwent hemithyroidectomy
between 2012-2021 with final histopathology demonstrating PTC. This database captures information about thyroid cancer surgery
performed by endocrine surgeons at our institution and their
affiliated operating sites. Introduction Key barriers identified that prevented patients or physicians from
selecting AS included lack of published surveillance protocol/
guidelines and physician comfortability in recommending AS to Due to this epidemic of overdiagnosis, the role of active
surveillance (AS) as an alternative to thyroid surgery in the
management of low risk PTC has gained traction in the past Frontiers in Endocrinology 02 frontiersin.org White et al. 10.3389/fendo.2023.1160249 patients (17, 18). This highlights the potential role for a clinical
decision support tool to help clinicians identify if their patient is
suitable for active surveillance, which to our knowledge is not
available in the literature. findings and patient data such as presence of local or distant
metastasis, age, calcitonin level, comorbidities that would
preclude them from surgery (15). Patients were deemed suitable for active surveillance by the tool
if they were aged ≥18 years, tumour size ≤2cm, no evidence of ETE
or LVI on ultrasound, had no nodal or distant metastases and
>2mm normal gland parenchyma (Figure 1). Tumour size was
determined by the maximum tumour diameter and tumours up to
2cm were included. Methods This study was performed at the Department of Diabetes and
Endocrinology, the Department of Endocrine Surgery and the
Department of Radiology at Royal North Shore Hospital. Ethics
approval was by the local Northern Sydney Health District Ethics
Committee (2020/ETH02787). Characteristics of patients suitable for AS Most patients with BV/BVI results who were deemed suitable
for active surveillance were young females, with median age 36 years
(Table 1). Median size of nodules in this group was 10mm, with size
ranging 4mm – 19mm and majority of patients had T1a tumours
(tumour ≤1cm). Subgroup analysis with sonologist A sonologist and imaging trainee reviewed the ultrasound images
in a subgroup of 22 patients to determine if AS features were easily
identified on pre-operative ultrasound. The preoperative ultrasound
images were unavailable for the remaining 37 patients deemed
suitable for AS. The nodule of interest was assessed for presence of
LVI, ETE, proximity to critical structures and presence of 2mm
normal gland surrounding the nodule, and the tool was applied. Prevalence of AS suitability During 2012 – 2021, 763 patients underwent hemithyroidectomy
with final histopathology demonstrating PTC. Excluded from
analysis were 316 patients (see Figure 2), leaving a cohort of 447
potentially eligible patients. We analysed the cohort of 447 patients by
Bethesda category and found 114 patients (26%) had a pre-operative
Bethesda result of BV or BVI. The tool was applied to the potentially
suitable 114 patients with BV/BVI FNA and 59/114 (52%) were
found to meet criteria for active surveillance. Of the 55/114 (48%)
who were deemed unsuitable, all patients had nodule size >2cm. Assessment of all Bethesda results yielded: 353/447; 79% were
unsuitable (>2cm tumour) and 95/447 (21%) potentially suitable
for AS. 63% of those 95 patients were BV/VI reflecting that a majority
would have a high risk of malignancy from the FNA. Clinical support tool development A web based clinical support tool was developed and built on
REDCap software (Supplementary Appendix 1). It utilised evidence
based characteristics for AS suitability and generated a result
indicating whether a patient was suitable for active surveillance. The tool was designed to apply the pre-operative ultrasound Patients were excluded from analysis if; there was missing
histopathology or pre-operative ultrasound data, the histopathology
demonstrated a cancer other than PTC, the final histopathology FIGURE 1
The flowchart outlines the algorithm of the clinical support tool. IGURE 1
The flowchart outlines the algorithm of the clinical support tool. 03 03 Frontiers in Endocrinology frontiersin.org White et al. 10.3389/fendo.2023.1160249 showed an incidental PTC, they had hemithyroidectomy and
contralateral nodulectomy, or if they had concomitant
hyperparathyroidism and underwent parathyroidectomy. between the group had completion surgery versus those who had no
completion surgery as well as between the subgroup who had
evidence of malignancy on completion surgery versus those who
had no malignancy. A p value of <0.05 was considered significant. Remaining patients were stratified according to pre-operative
Bethesda category. Our cohort of interest were patients with a high
risk of malignancy on biopsy or with a pre-operative biopsy result of
either Bethesda V (BV, suspicious for malignancy) or Bethesda VI
(BVI, malignancy). The tool was applied utilising pre-operative
ultrasound reports and information from surgical database forms. Information was also extracted from surgical consultation letters,
histopathology and imaging results, referral letters and electronic
medical records where available. Given the retrospective nature of
this study, we were unable to ascertain patient willingness to
participate in active surveillance, however for the purpose of our
prevalence assessment we assumed all patients would be amenable. Patients who had further surgical
intervention We next analysed the characteristics of the cohort who went on
to have further surgical intervention to ascertain if we could predict
the need for further treatment. Most patients (49/59) did not
require any further surgical or medical intervention for a median
of 3.25 years (ranging from 0.2 – 7.35 years) follow up. After MDT
and patient discussion, ten patients went on to have completion
hemithyroidectomy. Evaluation of their initial histopathology
demonstrated higher rates of lymphovascular invasion (80%
versus 18%, p<0.01) and lymph node involvement (90% versus
27%, p<0.01) compared to patients who did not undergo
completion hemithyroidectomy. There was a trend for patients
who underwent completion surgery to be younger (median age 34
vs. 39 years, p=0.05) with bigger nodules (median nodule size 12mm
vs. 10mm, p=0.05) however these were of borderline statistical
significance. Rates of tumour multifocality or presence of ETE did
not differ significantly between groups (Table 2). patients with malignancy in contralateral lobe had multifocal
tumours in initial histopathology, compared with one out of the six
patients with benign histopathology on completion. No patients with
malignancy in contralateral lobe had an aggressive histological
subtype (such as poorly differentiated features, tall cell variant,
diffuse sclerosing etc). Histopathology from initial hemithyroidectomy showed similar
lesion size between patients who had malignancy vs. benign
pathology on completion hemithyroidectomy, with median size
11mm vs. 12mm respectively. Patients who went on to have
malignancy in contralateral lobe were slightly younger, with
median age 32.5 years versus 35.5 years. There were similar rates
of ETE in each group however higher rates of LVI in the group who
did not have evidence of malignancy in contralateral lobe (Table 3). Statistical analysis Statistics were performed in Microsoft Excel. Sample T tests
were used to analyse differences in age, and median tumour size FIGURE 2
The PRISMA diagram outlines the selection process for our study. PTC, papillary thyroid cancer; FNA, fine needle aspirate; AS, active surveillance; BV,
Bethesda V; BVI, Bethesda VI. FIGURE 2
The PRISMA diagram outlines the selection process for our study. PTC, papillary thyroid cancer; FNA, fine needle aspirate; AS, active surveillance; BV,
Bethesda V; BVI, Bethesda VI. 04 04 Frontiers in Endocrinology frontiersin.org 10.3389/fendo.2023.1160249 White et al. TABLE 2
Comparison of patients who had no completion surgery vs. completion surgery. TABLE 2
Comparison of patients who had no completion surgery vs. completion surgery. TABLE 2
Comparison of patients who had no completion surgery vs. completion surgery. Characteristic
No comple-
tion surgery
(n=49)
Completion
surgery
(n=10)
P
value
Age range
19 – 78
20 – 52
Median age
39 years
34 years
0.05
Male
Female
8/49 (16%)
41/49 (84%)
1/10 (10%)
9/10 (90%)
0.619
Pre-operative FNA
Bethesda V
Bethesda VI
23/49 (47%)
26/49 (53%)
6/10 (60%)
4/10 (40%)
Median nodule size
(range)
10mm (4-19)
12mm (8-18)
0.058
Tumour focality
Unifocal
Multifocal
41/49 (84%)
8/49 (16%)
7/10 (70%)
3/10 (30%)
0.319
Presence of ETE
9/49 (18%)
2/10 (20%)
0.905
Presence of LVI
9/49 (18%)
8/10 (80%)
<0.01
Presence of LN
involvement
13/49 (27%)
9/10 (90%)
<0.01
BRAF V600E
positivity
27/49 (55%)
8/10 (80%)
0.149
FNA, fine needle aspirate; ETE, extrathyroidal extension; LVI, lymphovascular invasion; LN,
lymph node. TABLE 1 Baseline characteristics of patients suitable for active
surveillance. Characteristic
Value
Age range
19 – 78 years
Median age
36 years
Male
9/59 (15%)
Female
50/59 (85%)
Bethesda V
29 (49%)
Bethesda VI
30 (51%)
Nodule size range
4-19mm
Nodule size
T1aN0M0 – 37/59 (63%)
T1bN0M0 – 22/59 (37%)
Median nodule size
10mm
TNM refers to American Joint Committee on Cancer (AJCC) staging tumour (T), nodes (N),
metastes (M). Frontiers in Endocrinology Imaging subgroup We next examined the characteristics of patients who were found
to have malignancy in the contralateral lobe and this was seen in 4/10
(40%) of patients who underwent completion thyroidectomy. In
these patients the average age was 36 years and median tumour
size was 11mm. All four followed up with I-131 therapy, and four
patients with benign histopathology in contralateral lobe also received
I-131 (Table S1). No patients in the study cohort had evidence of
disease recurrence at median 3.25 years follow up (0.2 – 7.35 years). Evaluation of the initial hemithyroidectomy histopathology of the
four patients with contralateral lobe malignancy demonstrated that
all had classical papillary architectures subtype. All four had lymph
node involvement on initial histopathology (Table 3). Two of the four To investigate the real world application of this tool, we conducted
a subgroup analysis of patients in whom we were able to obtain their
pre-operative ultrasound. Of the 59 patients who met criteria for active
surveillance, the preoperative ultrasound images were available for 22
patients. None of the patients in this subgroup analysis were patients
who had completion thyroidectomy. In 21/22 patients (95%), the
sonologist was unable to identify >2mm of normal gland parenchyma
between the nodule and the capsule in the saved images, identifying a
real world limitation of this tool. Nodule size ranged from 5-14mm,
with median nodule size of 9mm. ETE on pre-operative ultrasound Frontiers in Endocrinology 05 frontiersin.org White et al. 10.3389/fendo.2023.1160249 eristics of initial nodule size, histopathology, further treatment and recurrence in patients who had completion thyroidectomy. TABLE 3 Characteristics of initial nodule size, histopathology, further treatment and recurrence in patients who had completion thyroidectomy. Imaging subgroup Pt
Age
Sex
Nodule
size
Initial histopathology
Completion
Histopathology
I 131
therapy
Recurrence
1
20
F
12mm
Unifocal 12mm tumour, classical, ETE, LVI, 11/17 LN
involved, BRAF V600E positive
Benign
No
No
2
35
F
13mm
Unifocal 14mm tumour, classical, no LVI,
ETE, 3/4 LN involved, tracheal invasion, BRAF V600E
positive
0.4mm deposit in
contralateral lobe, no LN
Yes – 224MBq
No
3
52
F
18mm
Unifocal 19mm tumour, classical, no LVI, no ETE, 0/6
LN involved, BRAF not done
Benign
Yes – 1.8 GBq
No
4
30
F
12mm
Unifocal 12mm tumour, classical, LVI, no ETE, 2/4 LN
involved, BRAF V600E positive
Benign
Yes – 4 GBq
No
5
33
F
8mm
Unifocal 12mm tumour, classical, LVI, no ETE, 1/7 LN
involved, BRAF V600E positive
Benign
Yes – 1 GBq
No
6
36
M
12mm
Multifocal 13mm tumour, classical, LVI, no ETE, 2/3
LN involved, BRAFV600E positive
2mm papillary thyroid
cancer, no LN involved
Yes – 1 GBq
No
7
37
F
14mm
Unifocal 15mm tumour, mixed papillary/follicular,
LVI, no ETE, 1/2 LN involved, BRAF V600E positive
Benign
Yes – 1 GBq
No
8
32
F
14mm
Multifocal 11mm tumour, mixed papillary/follicular,
LVI, no ETE, 5/14 LN involved, BRAF V600E positive
Benign
No
No
9
32
F
11mm
Unifocal 8mm tumour, classical, no LVI, no ETE, 3/5
LN involved, BRAF V600E negative
Multifocal PTC, largest
deposit 9mm, no LVI, no
ETE, 3/5 LN involved
Yes – 4 GBq
No
10
41
F
9mm
Multifocal 9mm tumour, classical, LVI, no ETE, 1/4
LN involved, BRAF V600E positive
6mm PTC, no LN
Yes – 4 GBq
No
ETE, extrathyroidal extension; LVI, lymphovascular invasion; LN, lymph node; PTC, papillary thyroid cancer; MBq, megabecquerel; GBq, gigabecquerel. A strength of this analysis is that it includes patients with tumours up
to 2 cm. 37% of patients who were suitable for active surveillance had
tumours >1 cm, and therefore would have been excluded without the
extended 2 cm tumour diameter. There was no control group for
comparison as very few patients in our cohort have AS thus far and
the database only captures patients post surgery. was defined as extension of the nodule beyond the normal capsule
line. The sonologists identified 4/22 patients with evidence of ETE
which had not been identified on initial ultrasound report. Imaging subgroup Of these 4
patients, 1 was identified as definite ETE and 3 were deemed to have
features suggestive of ETE, rendering them unsuitable for AS
according to our protocol. It is reasonable to propose that patients who required further
surgery or medical intervention had progressive disease either distant
metastases or further lymph node disease. While we do not know if
these patients would have progressed without the initial surgery, our
tool correctly identified characteristics meeting criteria for AS with the
majority (49/59) having no further surgery. Patients who had
completion surgery were generally younger, with lymph node
involvement and presence of lymphovascular invasion on initial
histopathology. In the group who did not have completion, we are
unable to ascertain whether there was malignancy in the remaining
lobe however it is reassuring that there has been no evidence of disease
recurrence or development of nodal or distant metastases in this
cohort (as evidenced by lack of further interventions and available
progress imaging reports). Of the patients who had completion
thyroidectomy, the majority (7/10 patients) had tumour size >1cm. No patients who had evidence of malignancy on completion
thyroidectomy had evidence of disease recurrence on available
follow up data, however we are unable to ascertain if any these Discussion In this retrospective analysis of patients treated by hemithyroidectomy
for nodules with pre-operative cytology BV or BVI FNA, we have shown a
substantial proportion of patients may have been suitable for active
surveillance rather than surgery. The strongest evidence for active
surveillance is for patients with high risk of malignancy (BV or BVI
cytology) and as there is limited data for active surveillance in other
Bethesda categories, we focused our analysis on patients with pre-operative
FNA of BV or BVI. To our knowledge, there are no decision support tools
available to help clinicians identify patients suitable for AS. We present a
novel tool with real world application, outlining the experiences of using
this tool in a cohort from a tertiary centre. The demographic results for our appropriate AS cohort were
unsurprising. Most patients in our suitable active surveillance cohort
were young females which reflects known epidemiological data (19). Frontiers in Endocrinology frontiersin.org 06 White et al. 10.3389/fendo.2023.1160249 main factor that excluded patients from suitability for active
surveillance was tumour size >2 cm. patients went on to have further treatment at another treatment
location. Tumour size, multifocality, presence of ETE or LVI, presence
lymph node involvement and BRAFV600E positivity did not predict
malignancy in contralateral lobe. As hemithyroidectomy as a first line
operation for low risk cancer gains further evidence, there is a trend
away from completion thyroidectomy unless initial histopathology has
concerning features. This study was not able to identify any factors in
this cohort that predicted risk of malignancy in contralateral lobe,
though a key limitation is the small sample size. The higher rates of
LVI in the group who had completion thyroidectomy who did not
have malignancy in contralateral lobe is of doubtful relevance and
likely due to small sample size. Limitations of this study are that it is retrospective single centre
data. There is selection bias given we analysed a low risk population by
selecting patients who had been managed with hemithyroidectomy. Our follow up data was limited to information available through our
thyroid cancer database and electronic medical record. We were
unable to ascertain whether patients have gone on to receive further
treatment through other centres, which may underestimate the risk of
recurrence in our population. Thirdly, our imaging review of the 59
patients identified as being suitable for AS was incomplete as we only
had access to the images of 22 patients. Conclusion Our clinical decision support tool is a novel method of assisting
clinicians in selecting patients that are suitable for active surveillance. Utilising this tool in our single centre cohort, almost half (48%) of
patients with BV/BVI FNA and PTC on final histopathology would
have been suitable for active surveillance. No patients had evidence of
disease recurrence throughout our follow up period. Further
prospective studies are required to evaluate this tool. Furthermore in our subgroup analysis, 21/22 patients did not
have ≥2 mm between the nodule and capsule on the ultrasound. However, nodule position is inconsistently reported in ultrasound
results, making it difficult to interpret from the report alone whether
a nodule would meet this criteria and thus this represents a
limitation to the application of this tool. Collaboration with our
imaging colleagues would be necessary to develop more relevant
reporting schema. Absence of 2mm of normal gland parenchyma
does not preclude suitability for active surveillance, and future
refinement of this tool would likely eliminate this specification
and focus on more discriminatory markers such as tumour location
in relation to critical structures and tumour volume kinetics (20). Ethics statement The studies involving humans were approved by Northern
Sydney Health District Ethics Committee. The studies were
conducted in accordance with the local legislation and institutional
requirements. Written informed consent for participation was not
required from the participants or the participants’ legal guardians/
next of kin in accordance with the national legislation and
institutional requirements. This study has several key strengths. Firstly, it demonstrates a
novel idea of creating a clinical decision support tool designed to
empower clinicians in identifying patients who are potential
candidates for active surveillance as a lack of physician knowledge
has been identified as a barrier to AS implementation (19). Secondly,
it demonstrates likely numbers of patients who would be potentially
suitable for active surveillance based on the experience of a tertiary
centre. In our cohort, 59/114 (52%) of patients with Bethesda V or VI
were suitable for active surveillance based on our clinical support tool,
with 55/114 (48%) deemed suitable following imaging review. The Discussion It is likely that further patients
would have been excluded had we been able to review the entire
cohort. Acknowledging this limitation, we have attempted to estimate
prevalence of patients suitable for AS based on our available data. We next attempted to understand how the tool could work in
clinical practice, and the feasibility of interpreting findings from the
ultrasound report and original images and incorporating these into
this tool. Our subgroup analysis with our imaging specialists
highlighted some of the challenges of the real world application
of this tool. Firstly, there is inter-observer variability in detecting the
presence of ETE on ultrasound. Of the 4 patients in whom our
imaging specialists deemed there to be ETE present, there was no
comment on ETE in the original ultrasound report in three patients
and in one patient it was documented as not present. Final
histopathology for these patients demonstrated two of four had
no ETE and two had presence of ETE, reflecting ultrasound and
pathological disparity. The sonologist reviewing the subgroup
analysis had 40 years of experience. We conclude that ETE is not
feasible to be routinely analysed in a pre-operative ultrasound due
to significant heterogeneity, and in further refinement of this tool
we would focus more on tumour location in relation to critical
structures. Several features we have used to assess feasibility for
active surveillance on preoperative ultrasound (ETE, LVI, presence
of 2 mm normal gland around nodule) are not routinely reported
and a training and reporting template when looking at these
ultrasounds may be beneficial. Lastly, in the application of our clinical support tool, patient
willingness to undertake active surveillance and engage with follow
up is a key component of suitability. In applying our tool to this
retrospective data, we were unable to ascertain patient willingness to
undergo AS. Prospective studies are required to further evaluate the
effectiveness of our clinical support tool in patients who are suitable
for AS. Data availability statement The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation. Frontiers in Endocrinology Supplementary material The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1160249/
full#supplementary-material The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest. Author contributions EW: Methodology, data collection, formal analysis, writing
-original draft, writing - reviewing and editing. BA: data analysis, Frontiers in Endocrinology frontiersin.org frontiersin.org 07 White et al. 10.3389/fendo.2023.1160249 Publisher's note writing -reviewing and editing. GS: data analysis, writing -
reviewing and editing. AG: methodology, writing - reviewing and
editing. MG: Supervision, conceptualisation, formal analysis,
methodology, writing - reviewing and editing. RC-B: supervision,
conceptualisation, methodology, writing - reviewing and
editing. All authors contributed to the article and approved the
submitted version. All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher. References 1. Hoang JK, Choudury KR, Eastwood JD, Esclamado RM, Lyman GH, Shattuck
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O jogo político das lideranças do associativismo negro: alianças, conflitos e redes de proteção em Salvador na segunda metade do século XIX
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Revista Ágora
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Doutorando pelo Programa de Pós-Graduação em História Social da Universidade Federal da Bahia (PPGH-UFBA) com pesquisa
intitulada “Associativismo negro na Bahia da segunda metade do século XIX”. Bolsista da Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES). Membro da linha de pesquisa “Escravidão e Invenção da Liberdade”. E-mail:
lucasribeiroc2@gmail.com. v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 o jogo político das
lideranças do
associativismo negro:
alianças, conflitos e redes de proteção
em salvador na segunda metade do
século xix Lucas ribeiro campos
universidade federal da bahia
salvador bahia brasil A Sociedade Protetora dos Desvalidos, primeira associação civil negra
do Brasil, instalada em 1851 na cidade Salvador, se tornou um espaço
importante de negociação entre lideranças de cor e políticos baianos, na
segunda metade do século XIX. Alguns de seus associados se
destacaram como importantes lideranças e alcançaram um status de
enorme prestígio entre os trabalhadores de cor da cidade de Salvador. Este artigo tem como objetivo entender quais os sentidos das
articulações dessas lideranças com figuras importantes da Bahia. Busca-
se investigar como aqueles trabalhadores, em sua maioria artistas e
artífices, negociaram e disputaram um projeto político para os homens
de cor, com a intenção de alcançar direitos básicos enquanto cidadãos,
como educação, dignidade, assistência mútua, participação política e
pertencimento racial. resumo Palavras-chave: Associativismo negro; Sociedade Protetora dos
Desvalidos; Política dos homens de cor. The Sociedade Protetora dos Desvalidos, Brazil's first black civil
association, installed in 1851 in the city of Salvador, became an
important space for negotiation between color leaders and Bahian
politicians in the second half of the 19th century. Some of its associates
stood out as important leaders and achieved a status of enormous
prestige among the colored workers of the city of Salvador. This article
aims to understand the meanings of the articulations of these leaders
with important figures from Bahia. It seeks to investigate how those
workers, mostly artists and craftsmen, negotiated and disputed a
political project for men of color, with the intention of achieving basic
rights as citizens, such as education, dignity, mutual assistance, political
participation and racial belonging. Keywords: Black associations; Sociedade Protetora dos Desvalidos;
Politics of men of color. 1 SCHWARTZ, Stuart B. Escravos, roceiros e rebeldes. Bauru: EDUSC, 2001, p. 28-29. abstract Keywords: Black associations; Sociedade Protetora dos Desvalidos;
Politics of men of color. REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 ,
,
,
, p
2 Cf.: LARA, Silvia Hunold. Blowin’ in the wind: E. P. Thompson e a experiência negra no Brasil. Proj. História, v. 12, outubro ,
p
p
g
j
,
,
1995, p. 43-56. LARA, Silvia Hunold. Escravidão, cidadania e história do trabalho no Brasil. Proj. História, São Paulo, (16), fe
1998. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
2 O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
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2 introdução Nos últimos anos os estudos sobre escravidão e pós-abolição no Brasil passaram
por um processo intenso de transformações, com a expansão de temas, problemas,
metodologias e fontes. Ganhou força a chamada nova historiografia da escravidão,
dedicada às formas de participação política e cultural de homens livres de cor, libertos e
escravizados. De acordo com Stuart Schwartz, diferente do que acontecia nas décadas de
1950 e 1960, em que o interesse primordial eram nas consequências da escravidão como
sistema sobre a economia e toda a sociedade, essa nova tendência, que se desenvolveu
nas últimas décadas, destaca “a importância de se compreender a organização da
escravidão e seu funcionamento tanto como forma de trabalho quanto como sistema social
e cultural.”1 Dentre os novos temas dessa historiografia, que interessam a este artigo, vale
destacar a participação de pessoas livres e libertas em irmandades, associações e partidos. Na década de 1990, em sintonia com essa nova historiografia da escravidão e
muito inspirada no marxismo britânico de Edward Thompson, Silvia Lara chamou a
atenção para uma abordagem com mais prioridade na liberdade ao invés da escravidão,
ao trazer alguns elementos para que o debate não se restringisse a uma dicotomia
desnecessária e pouco producente para os estudos da experiência negra no Brasil. De
acordo com a autora, era preciso redimensionar os estudos da escravidão, ao observar
livres e libertos e inserir a experiência negra na história social do trabalho, principalmente
com a incorporação do século XIX como um período importante para a discussão.2 Para este artigo, será analisada a experiência de lideranças do associativismo
negro na Salvador da segunda metade do século XIX. Mais especificamente, a reflexão
será feita a partir da vivência dessas lideranças à frente da primeira associação civil negra
do Brasil, a Sociedade Protetora dos Desvalidos (doravante SPD), que havia sido fundada
na cidade de Salvador, em 29 de outubro de 1851. A SPD era formada, em sua maioria,
por trabalhadores da construção civil e, de acordo com seu estatuto de 1874, admitia como
sócios efetivos “todos os cidadãos brasileiros de cor preta”, com o objetivo de auxiliá-los
na doença, invalidez, prisão, velhice e, até mesmo, após a morte, através de um funeral O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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2 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. introdução 2, e-2020310204, 2020, ISSN: 1980-0096 digno. Além disso, a SPD buscava proporcionar benefícios aos dependentes dos sócios,
como pensões aos familiares dos membros falecidos, assim como supervisão e cuidado
com a educação dos órfãos.3 Neste artigo, busca-se responder as seguintes questões: quais os sentidos das
articulações das lideranças do associativismo negro com figuras importantes de Salvador
na segunda metade do século XIX? O que ganhavam esses indivíduos ao se aliarem com
políticos e pessoas de influência naquele momento? Qual era de fato o projeto político de
liberdade daqueles artistas e artífices negros? Para responder a estas questões, o artigo
tem como objetivo principal compreender como aqueles trabalhadores negociaram e
disputaram um projeto político para os homens de cor, com a intenção de alcançar direitos
básicos enquanto cidadãos, como acesso a educação, dignidade, ajuda mútua,
pertencimento racial, participação política entre outros. Em relação às fontes, foi utilizado para escrita deste artigo documentos do
Arquivo da Sociedade Protetora dos Desvalidos (ASPD), como atas de reuniões,
comunicados, pedidos de inscrição e estatutos. Além disso, as correspondências que eram
enviadas pelas lideranças da SPD ao Presidente da Província e os inventários de alguns
sócios foram consultados no Arquivo Público do Estado da Bahia (APEB). Periódicos,
almanaques e legislações foram pesquisados na Hemeroteca Digital da Biblioteca
Nacional, Biblioteca Virtual Consuelo Pondé e Biblioteca Pública do Estado da Bahia. Essas fontes foram fundamentais para a coleta de dados sobre a trajetória e atuação
política de lideranças do associativismo negro que serão apresentadas nas próximas
páginas. 3 ASPD, Estatuto da Sociedade Protetora dos Desvalidos, aprovado pelo governo da Província em 26 de agosto de 1874. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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3 alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Algumas lideranças da SPD constituíram redes de proteção, que além de envolver
seus aliados dentro da associação, incluía os chamados “sócios protetores”. A categoria
de sócio protetor era constituída, em sua grande maioria, por homens brancos, escolhidos
pela capacidade de ajudar a associação, apesar de terem influência relativamente limitada ASPD, Estatuto da Sociedade Protetora dos Desvalidos, aprovado pelo governo da Província em 26 de agosto de 1874. REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 nas operações internas da instituição. De acordo com o artigo 8º do estatuto de 1874, os
sócios protetores eram “todas aquelas pessoas que por seu coração benfazejo, segundo
suas altas representações, queiram voluntariamente proteger a esta Sociedade”.4 Entre
eles estavam políticos e figuras influentes da sociedade baiana, como presidentes de
província, senadores, deputados, desembargadores, advogados, militares, médicos e
outros. Os dirigentes da SPD estabeleceram alianças com estes protetores, que eram
sustentadas através de uma política de favores, acordos e relações de compromisso. Essas
estratégias, na maioria das vezes, decidiam as disputas pelo controle da associação, pois
aqueles que constituíam alianças mais consistentes com os protetores eram os que
estavam mais blindados no poder e permaneciam mais tempo no comando da associação. Esse foi o caso do marceneiro Manoel Leonardo Fernandes, um dos membros que
mais assumiu cargos diretivos na SPD e protagonizou acirradas disputas pelo comando
da associação, principalmente durante as décadas de 1860 e 1870. Manoel Fernandes foi
remanescente da antiga Irmandade de Nossa Senhora da Soledade Amparo dos
Desvalidos e assumiu na SPD os cargos de presidente, vice-presidente e 1º secretário. Na
lista eleitoral da Freguesia da Sé, em 1878, havia declarado ter 50 anos de idade, solteiro
e com uma renda anual de 500$000 réis.5 Morava ou trabalhava na antiga Ladeira do
Aljube, próximo de onde hoje está o viaduto da Sé, esquina com a Ladeira da Praça.6
Manoel Fernandes tinha ambições dentro da SPD e a sua presença no controle da
associação rompeu com a hegemonia de um antigo grupo no poder. Era inegável sua
atuação como uma forte liderança dentro da associação, provavelmente protegido por
diversos políticos da época. Na eleição para a nova diretoria da SPD do dia 25 de outubro de 1863, o então
vice-presidente Manoel Fernandes protagonizou uma disputa com o grupo de Joaquim de
Santana Gomes Ferrão. O MONITOR, 30/07/1878, p. 2.
6 MASSON, Camillo de Lellis. Almanak Administrativo e industrial da Bahia, para o anno de 1860. Salvador: Typographia de Camillo
de Lellis & Cia, 1860, p. 323. 5 O MONITOR, 30/07/1878, p. 2. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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4 4 ASPD, Estatuto da SPD de 1874. LUCAS RIBEIRO CAMPOS
4 alianças,
conflitos
e
redes
de
proteção
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lideranças do associativismo negro Naquela ocasião, Manoel Fernandes assumiu interinamente o
cargo de presidente e foi o responsável por ter conduzido aquela eleição, tendo em vista
que o titular do cargo, Joaquim Ferrão, estava impossibilitado de comparecer naquele dia,
por motivo de doença. Sua presença presidindo uma sessão tão importante como aquela,
despertou a desconfiança de antigas lideranças da SPD, que temiam perder a hegemonia LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 e as prerrogativas no comando da associação, construídas através de alianças políticas
cultivadas há algum tempo. Durante a sessão da eleição de 1863, Manoel Fernandes foi duramente criticado
por alguns sócios, por ter descumprido o estatuto, ao ter aceitado cédulas com votos de
associados que não estavam presentes no dia da votação. Contudo, o que provocou maior
confusão naquela sessão foi à decisão do vice-presidente de anular a chapa em que
constava o nome do sócio suspenso Francisco das Chagas e Assis para o cargo de
visitador. Houve muita confusão entre os membros, que se dividiram entre aqueles que
estavam ao lado de Francisco Assis e os que não aceitavam a presença dele naquela chapa. Embora o vice-presidente solicitasse ordem diversas vezes, a sessão seguiu em um clima
tenso, a ponto do sócio suspenso e seus correligionários – entre eles Bento Ignácio de
Oliveira, Feliciano Primo Ferreira, Damião Cardoso da Costa, Pedro Ribeiro de
Figueiredo, José Pedro do Sacramento e Gregório Joaquim de Santana –, se retirarem da
sala das sessões, dizendo em protesto “que seus pés não se cruzavam mais na sociedade”. Ao final da sessão, Manoel Fernandes foi eleito presidente, junto com alguns sócios do
seu grupo, que assumiram cargos importantes.7 No dia 27 de outubro, Manoel Fernandes enviou a lista com os nomes da nova
diretoria para o presidente da Província, o conselheiro Antônio Coelho de Sá e
Albuquerque, que era sócio protetor da SPD.8 Esse era um procedimento previsto pelo
artigo 29, parágrafo 5º, do decreto nº 2.711, de 19 de dezembro de 1860, que dizia que os
montepios seriam responsáveis pela eleição ou nomeação de seus quadros administrativos
e cabia apenas ao governo da Corte ou presidentes das províncias, nomear entre os mais
votados, quem iria presidir as associações.9 Ou seja, apesar da eleição, cabia somente a
autoridade máxima da província escolher quem realmente iria conduzir a instituição
durante o exercício de um ano. 7 ASPD, ata da Assembleia Geral de 25/10/1863. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
5 8 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d
Desvalidos (1861-1880), maço 5306, relação dos novos funcionários da Sociedade Amparo dos Desvalidos, eleitos em Assemble
Geral do dia 25/10/1863, enviada no dia 27/10/1863. ,
8 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, relação dos novos funcionários da Sociedade Amparo dos Desvalidos, eleitos em Assembleia
Geral do dia 25/10/1863, enviada no dia 27/10/1863.
9 BRASIL. Decreto nº 2.711, de 19 de dezembro de 1860. Contém diversas disposições sobre a criação e organização dos bancos,
companhias, sociedades anônimas e outras, e prorroga por mais quatro meses o prazo marcado pelo artigo 1º do Decreto nº 2.686, de
10 de novembro do corrente ano. Colleção das Leis do Império do Brazil, Rio de Janeiro, Typografia Nacional, v. 2, p. 1125-1140,
1860. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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5 7 ASPD, ata da Assembleia Geral de 25/10/1863.
8 ,
9 BRASIL. Decreto nº 2.711, de 19 de dezembro de 1860. Contém diversas disposições sobre a criação e organização dos banco
companhias, sociedades anônimas e outras, e prorroga por mais quatro meses o prazo marcado pelo artigo 1º do Decreto nº 2.686,
10 de novembro do corrente ano. Colleção das Leis do Império do Brazil, Rio de Janeiro, Typografia Nacional, v. 2, p. 1125-114
1860. ,
8 APEB, Seção de Arquivo Colonial e Provincial, Presidência da 11 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d
Desvalidos (1861-1880), maço 5306, requerimento assinado por Joaquim de Santana Gomes Ferrão em 26/10/1863. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX 10 BRAGA, Júlio. Sociedade Protetora dos Desvalidos: uma irmandade de cor. Salvador: Ianamá, 1987, p. 55, 66-68.
11 11 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, requerimento assinado por Joaquim de Santana Gomes Ferrão em 26/10/1863. BRAGA, Júlio. Sociedade Protetora dos Desvalidos: uma irmand BRAGA, Júlio. Sociedade Protetora dos Desvalidos: uma irmandade de cor. Salvador: Ianamá, 1987, p. 55, 66-68.
APEB S
ã d A
i
C l
i l
P
i
i l P
idê
i d P
í
i
C
dê
i
bid d S
i d d P
t t
d alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Esse procedimento fazia parte de uma lógica de controle, 5 LUCAS RIBEIRO CAMPOS LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 no qual as autoridades escolhiam lideranças que fossem de sua confiança para conduzirem
aquelas associações. Esse controle do governo exigia das lideranças de cor um empenho em estabelecer
boas relações com os presidentes da província, pois não bastava apenas serem eleitos
pelos sócios e terem o apoio de seus aliados dentro da associação para chegarem ao poder,
era necessário que sua capacidade de comando fosse reconhecida pela maior autoridade
provincial. Havia nesse jogo político, relações estreitas entre a SPD e o Estado Provincial,
no qual a associação se constituiu como uma instituição política importante no tabuleiro
do poder. Desse modo, as disputas internas ganharam uma dimensão mais complexa, pois
alguns sócios utilizaram essa lógica de dominação ao seu favor, para alcançarem posição
de destaque dentro da instituição, em detrimento de seus rivais. De acordo com Júlio
Braga, alguns desses sócios permaneceram durante muito tempo ocupando cargos na
diretoria da SPD, por conta de “suas habilidades políticas, prestígio pessoal ou tino
administrativo” e constituíram verdadeiras oligarquias na associação.10 No ano de 1863, os sócios que saíram insatisfeitos com o resultado da eleição,
perceberam as possibilidades de negociação dentro dessa lógica de dominação, pois
rapidamente se articularam com o presidente titular da SPD, Joaquim Ferrão, e enviaram
um requerimento para a autoridade provincial, Antônio Coelho de Sá e Albuquerque,
solicitando intervenção para a realização de nova eleição. Joaquim Ferrão tomou partido
desses membros e disse que os argumentos deles eram “plausíveis e razoáveis,” tendo em
vista a “parcialidade demonstrada pela Mesa,” ao “fazer prevalecer uma lista ou chapa
por ela imposta.” Ainda sugeriu a possibilidade dessa nova eleição ser realizada com
assistência de alguma autoridade designada pelo presidente da Província, provavelmente
como uma estratégia para acionar políticos que pudessem influenciar uma nova eleição a
favor de seu grupo.11 Esse grupo de opositores era constituído basicamente pelos membros que saíram
insatisfeitos na sessão do dia 25 de outubro. Francisco das Chagas e Assis, figura central
na confusão daquele dia, participou das reuniões da antiga Irmandade dos Desvalidos na
década de 1840 e chegou a assumir o cargo de 2º solicitador. Pedro Ribeiro de Figueiredo 6 6 6 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 12 CAMPOS, Lucas R. Sociedade Protetora dos Desvalidos: mutualismo, política e identidade racial em Salvador (1861-1894).
Dissertação (Mestrado) – Universidade Federal da Bahia, Faculdade de Filosofia e Ciências Humanas, Salvador, 2018, p. 42.
13 CASTILLO, Lisa Earl. O terreiro do Alaketu e seus fundadores: história e genealogia familiar, 1807-1867. Afro-Ásia, nº 43, 2011,
p.257. 14 APEB, Seção Judiciária, inventário. Classificação 07/3062/11. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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7 O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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7 ,
ç
,
15 CAMPOS, 2018, p. 42-43. ,
ç
,
ç
15 CAMPOS, 2018, p. 42-43. 12 CAMPOS, Lucas R. Sociedade Protetora dos Desvalidos: mutualismo, política e identidade racial em Salvador (1861-189 14 APEB, Seção Judiciária, inventário. Classificação 07/3062/11.
15 CAMPOS, 2018, p. 42-43. alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro 2, e-2020310204, 2020, ISSN: 1980-0096 ocupou o cargo de porteiro/arquivista duas vezes (1862-1863; 1866-1867) e Damião
Cardoso da Costa foi cobrador (1859-1860) e 1º secretário (1860-1861). Já José Pedro do
Sacramento foi operário da oficina de carpinteiros do Arsenal da Marinha, assumiu os
cargos de 2º cobrador (1859-1860; 1866-1867), e depois foi eleito presidente (1867). O
sócio Bento Ignácio de Oliveira exercia o ofício de empalhador e havia sido 1º secretário
(1855) e presidente entre os anos de 1860 e 1861.12 Um dos que mais se tem informações daquele grupo é Feliciano Primo Ferreira,
que era filho de africana, residia na Ladeira da Conceição da Praia e estava inserido nas
redes de sociabilidades dos candomblés.13 Em seu inventário consta que possuía dois
armazéns de madeira, com endereço na Ladeira da Preguiça, o que indica que fosse um
comerciante deste ramo. Provavelmente era uma figura que tinha fortes contatos na cidade
de Salvador, principalmente no meio dos trabalhadores da construção civil, o que lhe dava
as credenciais necessárias para assumir cargos diretivos na associação, já que a maioria
dos sócios da SPD eram desse ramo. Possuía pelo menos um escravo, que talvez
trabalhasse para ele nos armazéns. Faleceu no ano de 1868 e deixou apenas sua mãe como
herdeira.14 Assumiu o cargo de 1º secretário (1845) na Irmandade dos Desvalidos e depois
as funções de presidente (1852-1853), vice-presidente (1853-1854) e tesoureiro (1859-
1860) da SPD.15 No inventário de Feliciano ainda consta Joaquim Ferrão como seu inventariante,
o que indica uma proximidade entre aquelas duas lideranças. Joaquim Ferrão era torneiro
mecânico, também morava na Ladeira da Preguiça e, além de ter sido presidente naquela
ocasião, havia ocupado os cargos de 1º secretário (1856-1858) e tesoureiro entre os anos
de 1860 e 1861 (MASSON, 1857, p. 384). Tendo em vista sua forte influência dentro da
instituição, pode ter sido ele quem influenciou, em 1861, na entrada de seu filho, Gregório
Joaquim de Santana Gomes Ferrão, como sócio efetivo com apenas 17 anos de idade, o
que contrariava as regras do estatuto, que apenas aceitava maiores de 18. Gregório era ,
ç
,
15 CAMPOS, 2018, p. 42-43. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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7 LUCAS RIBEIRO CAMPOS LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 16 LOBO, Tânia; OLIVEIRA, Klebson. Escrita liberta: letramento de forros na Bahia do século XIX. In: CASTILHO, Ataliba de;
TORRES, Maria Aparecida; CIRINO, Sônia (Org.). Descrição, História e Aquisição do Português Brasileiro: estudos dedicados a
Mary Aizawa Kato. São Paulo: Fapesp, 2007.
17 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, ofício assinado pelo 1º secretário Manoel Salustiano Severiano Gomes em 05/11/1863.
18 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, ofício de 27/11/1863, assinado pelo 1º secretário Manoel Salustiano Severiano Gomes, 2º
secretário Guilherme Francisco Henrique, tesoureiro Antônio José Bracete, 1º cobrador João Theodoro da Soledade e o 2º cobrador
João Pereira dos Santos Godinho. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
8 O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
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conflitos
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lideranças do associativismo negro 2, e-2020310204, 2020, ISSN: 1980-0096 solteiro e, assim como seu pai, também trabalhava como torneiro mecânico e chegou a
assumir, em 1861, o cargo de 2º secretário da SPD.16 As queixas desses opositores chegaram ao conhecimento da recém-eleita diretoria
da SPD, liderada por Manoel Fernandes, que sinalizou não haver irregularidades nas
eleições, pois o pleito havia sido decidido por maioria de votos e a associação não poderia
ficar com os seus trabalhos parados.17 Em resposta, o presidente da Província solicitou o
encaminhamento de uma cópia da ata daquela eleição para ser examinada, mas a Mesa
eleita acusou Joaquim Ferrão de fazer a cópia do documento em sua casa, sem passar por
deliberação em sessão, o que era contra o estatuto.18 Existia certo receio do grupo de
Manoel Fernandes de uma possível manipulação dos fatos, que favorecesse os
argumentos dos queixosos em seu objetivo de anular aquela eleição. Contudo, Joaquim
Ferrão enviou a cópia da ata solicitada pela autoridade provincial e aproveitou a
oportunidade para reiterar os motivos que levaram aquela oposição a solicitar uma nova
eleição: Cumpre-me declarar a Vossa Excelência, que semelhante ata deixou de ser
aprovada pelas irregularidades, e oposições, que nela tiveram lugar, que
por isso deixou de ser assinada por alguns sócios antigos, que contiveram
presentes a discussão dela, por causa de tais irregularidades, e pelo
descomportamento do Vice-Presidente [Manoel Leonardo Fernandes]:
cujos argumentos de que ele se compõe são todos fabulosos [argumentos
falsos], e compostos agora a contento dos opositores para se poder
satisfazer a exigência de Vossa Excelência, que evidentemente dela verá o
quanto se tem procedido contra as disposições dos Estatutos, que rege a
Sociedade, cuja ata não estando ainda lançada no respectivo livro, deu
lugar a não ser com brevidade respondida e satisfeita a exigência de Vossa
Excelência, e fazendo constar aos sócios, que me representaram a qual
representação remeti a Vossa Excelência com o supradito oficio, eles 8 8 8 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 reprovaram completamente a composição em que se acha lançada a
referida ata, que deixou de ser aprovada pelas ditas irregularidades,
oposições sem fundamento, provável, e descomportamento do referido
Vice-Presidente. (
),
ç
,
p
q
20 MATTOS, Ilmar Rohloff de. O Tempo Saquarema: a formação do Estado Imperial. São Paulo: Editora Hucitec, 2004. APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
svalidos (1861-1880), maço 5306, oficio assinado por Joaquim de Santana Gomes Ferrão de 28/11/1863. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX Desvalidos (1861-1880), maço 5306, oficio assinado por Joaquim de Santana Gomes Ferrão de 28/11/1863.
20 MATTOS Il
R hl ff d
O T
S
f
d E
d I
i l S
P
l
Edi
H
i
2004 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, oficio assinado por Joaquim de Santana Gomes Ferrão de 28/11/1863. 19 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d
Desvalidos (1861 1880) maço 5306 oficio assinado por Joaquim de Santana Gomes Ferrão de 28/11/1863 alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Julgo ter assim satisfeito ao que me foi exigido por Vossa
Excelência de quem espero, que faça à costumada justiça para exato
cumprimento da ordem e dos Artigos dos Estatutos, que deve reger à
Sociedade respectiva.19 Ao observar a disputa entre os dois grupos, é possível perceber que houve uma
movimentação de ambos os lados para justificar o acesso ao espaço que pretendiam
ocupar, através de um discurso que buscava obter simpatia e proteção da autoridade
provincial. De um lado, os “sócios antigos”, liderados por Joaquim Ferrão, muito
preocupados com a possibilidade de perderem a hegemonia no controle da associação,
atacaram a gestão eleita e acionaram o presidente da Província, através de um discurso
que denunciava o “descomportamento” e as supostas irregularidades promovidas pelo
presidente eleito. Do outro lado, a diretoria eleita, comandada por Manoel Fernandes, se
defendia e argumentava que inexistia razão para as queixas daquele grupo, pois todo o
procedimento da eleição seguia as regras dos estatutos, e que, por sua importância, a SPD
não poderia ter os seus trabalhos interrompidos. Esse episódio revela uma disputa política complexa, que provavelmente tinha
relação com as inclinações partidárias dos sócios. Quando se instalou a SPD, como uma
instituição civil, em 1851, após o racha entre os membros da Irmandade dos Desvalidos,
no final da década de 1840, o Império brasileiro estava sob a influência dos conservadores
no poder. Esse período é tratado pela historiografia como tempo saquarema (1843-1861),
pois existia um projeto conservador de construção e consolidação do Estado imperial, no
sentido da manutenção interna dos privilégios coloniais e construção de uma classe
senhorial.20 Figuras como Francisco Gonçalves Martins (Barão de São Lourenço), João
Mauricio Wanderley (Barão de Cotegipe) e Álvaro Tibério de Moncorvo Lima,
presidiram a província da Bahia nessa época e foram matriculados como sócios protetores
da SPD. Acredito que talvez o grupo de Joaquim Ferrão, que mantinha uma hegemonia
desde a instalação da SPD em 1851, tenha se aproximado desses políticos ligados ao 9 9 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 Partido Conservador naquele período e constituíram acordos para manter o controle da
associação. 21 De acordo com Klebson Oliveira, que foi responsável por transcrever diversas atas da SPD em sua tese de doutorado, este documento
está dividido em duas partes, uma escrita por Manoel Fernandes e outra por Antônio José Bracete, durante a década de 1860, sem uma
data especifica. OLIVEIRA, Klebson. Negros e escrita no Brasil do século XIX: sócio-história, edição filológica de documentos e
estudo linguístico. Tese (doutorado) – Universidade Federal da Bahia, Instituto de Letras, Salvaor, 2006, p. 637-638, 1039.
22 O MONITOR, 30/07/1878, p. 2. CAMPOS, 2018, p. 45.
24 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, relação dos novos funcionários enviada em 06/11/1865. 21 De acordo com Klebson Oliveira, que foi responsável por transcrever diversas atas da SPD em sua tese de doutorado, este documen
tá di idid
d
t
it
M
l F
d
t
A tô i J
é B
t
d
t
dé
d d 1860 23 CAMPOS, 2018, p. 45. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
LUCAS RIBEIRO CAMPOS
10 p
CAMPOS, 2018, p. 45. alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro No entanto, algum tempo depois, com a perda da hegemonia política dos
conservadores no Brasil e na Bahia, a partir do início da década de 1860, figuras como
Manoel Leonardo Fernandes, que tinha o apoio de indivíduos ligados ao Partido Liberal,
ascenderam como fortes lideranças dentro da associação. Apesar de Manoel Fernandes
ter vencido aquela disputa, as querelas com o grupo de Joaquim Ferrão não cessaram por
aí, pois no ano de 1864, o então presidente, que agora contava com a proteção das
autoridades legais, fez um discurso que conclamava os sócios a lutarem contra “aqueles
que conosco deveriam partilhar as nossas fileiras”. Em um complemento desse mesmo
documento, Antônio José Bracete, na época membro da Comissão de Contas e aliado de
Manoel Fernandes, disse que a SPD durante seus dez primeiros anos como instituição
civil, estava entregue aos cuidados de “meia dúzia de homens inexperientes, decrépitos e
até analfabetos”, que administravam a associação como bem queriam. Bracete
provavelmente estava se referindo ao grupo de Joaquim Ferrão. Acrescentou que graças
ao decreto de 1860, que proporcionou através do governo a aprovação do estatuto da
associação, já não era “aquela Sociedade decrepita e sim a Sociedade Protetora dos
Desvalidos que socorre as viúvas e ampara seus órfãos”. Concluiu sua fala ao destacar
que seu grupo foi responsável por ter “acabado com tudo quanto era de mau”, além de ter
“acabado com este desleixo”, que era “arma mais miserável que há no mundo.”21 Antônio Bracete tinha cerca de 48 anos de idade na época, era solteiro e, assim
como Manoel Fernandes, exercia o oficio de marceneiro.22 Havia ocupado na SPD o cargo
de tesoureiro (1862-1863) e depois assumiu as funções de arquivista, entre os anos de
1864 a 1865.23 Em novembro de 1865, estava na lista dos sócios mais votados, enviada
ao então presidente da Província Manoel Pinto de Souza Dantas, importante chefe político
do Partido Liberal e sócio protetor da SPD, que o escolheu como presidente da associação
naquele ano.24 Havia sido guarda na Freguesia de Brotas desde 1839, uma espécie de 10 10 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 inspetor de quarteirão, onde também estava qualificado para eleições na época. 25 O ALABAMA, 09/08/1864, p. 4. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX LUCAS RIBEIRO CAMPOS
1 alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Tinha
muito orgulho de um batalhão ao qual serviu, ao que parece da Guarda Nacional, mas
teve que pedir dispensa em agosto de 1864, pois já se encontrava na reserva por
impossibilidade de serviço. Até o ano de 1859, era conhecido como José dos Santos
Bracete, mas por conta de ter aparecido na capital da Província outro indivíduo com este
nome, vindo do Rio de Janeiro, em 1858, passou a se chamar Antônio José Bracete. Declarou em 1864, que até então nunca havia divulgado na imprensa a mudança de seu
nome, “por ser um pobre artista” e que pouco importava que os outros o “chamassem
Pedro ou Paulo”, porém “agora qualificado na freguesia da Sé e podendo ser procurado
por alguém visto ser tempo de eleições”, achou melhor divulgar a mudança de seu nome
.25 Imagino que Bracete e Manoel Fernandes tenham adquirido uma experiência que
lhes garantiu acordos com autoridades da época, capaz de possibilitar a presença de
ambos no comando da SPD. Com o gabinete liberal no poder e os chefes locais da
província da Bahia fortalecidos, ambos ganharam confiança e assumiram uma postura de
enfrentamento com os “sócios antigos” da associação. Ao depreciar os opositores em sua
fala, Bracete tinha o objetivo de sensibilizar os sócios e os políticos locais para o
engajamento de seu grupo na liderança da SPD, através do reconhecimento de suas
capacidades de comando. Buscou diferenciar seus aliados de um tipo de indivíduo que
era indesejado pelas autoridades. Construiu assim uma imagem alinhada com o ideal de
uma liderança moralizada, instruída, qualificada em seu ofício, disciplinada e apurada
com as leis de controle do Estado, ou seja, capaz de exercer sua cidadania política. Antes
era apenas “um pobre artista”, que não se importava nem mesmo com a forma que era
chamado, desconsiderando a própria identidade de seu nome, e só sentiu necessidade de
divulgar a mudança, por conta das vantagens de sua inserção na dinâmica eleitoral
daquela instituição. Agora, Bracete vislumbrava novas possibilidades de adquirir
benefícios das autoridades políticas, como o acesso e permanência no comando da SPD. Algum tempo depois, em agosto de 1876, Manoel Fernandes protagonizou outra
disputa pelo controle da SPD. Agora com o sócio Caetano de Mattos. Em certa medida,
podemos dizer que essa querela foi decidida pelo nível de influência que os pleiteantes LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 26 ASPD, pedido de inscrição de Caetano de Mattos, indicado por Severiano Pedro da Silva, aprovado em 17/05/1893. PIMENT
Altino Rodrigues. Almanak administrativo, commercial e insdustrial da Província da Bahia para o anno de 1873, quinquagésim
segundo da Independência e do Império. Bahia: Typographia de Oliveira Mendes & C., Anno I, quarta parte, 1872, p. 25.
27 O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
12 p
29 ASPD, comunicado do vice-presidente Caetano de Mattos de 13/08/1876; ASPD, ata da Assembleia Geral de 20/08/1876.
30 O MONITOR, 13/07/1878, p. 1. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
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12 p
31 SILVA, Kátia Maria de Carvalho. O Diário da Bahia e o século XIX. Rio de Janeiro: Tempo brasileiro; Brasília: INL/MEC, 1979,
p. 29, 31, 39. ANDRADE, Humberto Santos de. Gráficos e Mutualismo: a trajetória da Associação Tipográfica Baiana (Salvador,
final do século XIX e início do XX). Dissertação (Mestrado) – Universidade Estadual Paulista, Programa de Pós-Graduação de
Mestrado em História, Assis, 2014, p. 57, 63. 26 ASPD, pedido de inscrição de Caetano de Mattos, indicado por Severiano Pedro da Silva, aprovado em 17/05/1893. PIMENTA,
Altino Rodrigues. Almanak administrativo, commercial e insdustrial da Província da Bahia para o anno de 1873, quinquagésimo
segundo da Independência e do Império. Bahia: Typographia de Oliveira Mendes & C., Anno I, quarta parte, 1872, p. 25.
27 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, relação nominal dos sócios da Sociedade Protetora dos Desvalidos que ingressariam no Liceu
de Artes e Ofícios em 19/08/ 1872.
28 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306, discurso proferido na Sociedade Protetora dos Desvalidos pelo sócio Manoel Francisco dos
Santos em 20/10/1879, p. 1.
29 ASPD, comunicado do vice-presidente Caetano de Mattos de 13/08/1876; ASPD, ata da Assembleia Geral de 20/08/1876.
30 O MONITOR, 13/07/1878, p. 1.
31 SILVA, Kátia Maria de Carvalho. O Diário da Bahia e o século XIX. Rio de Janeiro: Tempo brasileiro; Brasília: INL/MEC, 1979,
p. 29, 31, 39. ANDRADE, Humberto Santos de. Gráficos e Mutualismo: a trajetória da Associação Tipográfica Baiana (Salvador,
final do século XIX e início do XX). Dissertação (Mestrado) – Universidade Estadual Paulista, Programa de Pós-Graduação de
Mestrado em História, Assis, 2014, p. 57, 63. 27 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d
Desvalidos (1861-1880), maço 5306, relação nominal dos sócios da Sociedade Protetora dos Desvalidos que ingressariam no Lic
de Artes e Ofícios em 19/08/ 1872.
28 28 APEB, Seção de Arquivo Colonial e Provincial, Presidência da Província, Correspondência recebida da Sociedade Protetora d
Desvalidos (1861-1880), maço 5306, discurso proferido na Sociedade Protetora dos Desvalidos pelo sócio Manoel Francisco d
Santos em 20/10/1879, p. 1. alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro 2, e-2020310204, 2020, ISSN: 1980-0096 mantinham com os sócios protetores. Na época, Caetano de Mattos tinha cerca de 40 anos
de idade, exercia o ofício de funileiro e tinha uma oficina na Rua do Corpo Santo.26
Contou com o apoio de lideranças como Severiano Pedro da Silva, que também exercia
a profissão de funileiro,27 com oficina no mesmo endereço, além do pedreiro Manoel
Francisco dos Santos, antiga liderança da SPD desde 1857.28 Com a ajuda desses sócios,
Caetano de Mattos assumiu interinamente a presidência e conseguiu influenciar a
Assembleia Geral em uma deliberação que decidiu pela demissão de Manoel Fernandes,
sob alegação de que o presidente titular não merecia mais a confiança da Assembleia,
pois havia abandonado uma sessão sem justificar o motivo de sua saída.29 Naquele mesmo dia, compareceu o sócio protetor Albino Henriques da Silva,
provavelmente a convite de Manoel Fernandes. Albino tinha em torno de 44 anos de
idade, era casado, tinha filhos e exercia a profissão de tipógrafo.30 Havia sido membro da
Comissão Fiscal da Associação Tipográfica Baiana em 1871 e administrava o Diário da
Bahia desde o ano de 1864, órgão ligado aos correligionários do Partido Liberal,
especialmente nas figuras do Conselheiro Dantas, Rui Barbosa e do médico Sátiro de
Oliveira Dias, todos protetores da SPD.31 Ao que parece, Albino era um sujeito de grande
influência nos meios da imprensa, da classe trabalhadora e das autoridades públicas, o
que tornava conveniente para os interesses de Manoel Fernandes a sua presença na sessão
daquele dia, provavelmente por terem construído há algum tempo uma relação de
proteção. Albino cumpriu bem o seu papel naquela sessão, manifestou apoio ao presidente
Manoel Fernandes e registrou em ata que não existia número suficiente de sócios para se O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
LUCAS RIBEIRO CAMPOS
12 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 tomar qualquer deliberação. Ainda questionou as motivações para a realização da
Assembleia, ao dizer que se o Conselho havia sido suspenso, o vice-presidente também
deveria ser punido, pois era parte do mesmo Conselho. Em resposta, o grupo de Caetano
de Mattos argumentou que o procedimento era considerado normal e declararam que o
vice-presidente não tinha culpa de nada, pois nem sabia o que o resto do Conselho fazia. ,
34 ABREU, Alzira Alves de (Coord.). Dicionário histórico-biográfico da Primeira República [Recurso eletrônico]: 1889-193
Formato EPUB. São Paulo: FGV, 2015.
35 32 ASPD, ata da Assembleia Geral de 20/08/1876. 35 ALBUQUERQUE, Wlamyra R. de. O jogo da dissimulação: abolição e cidadania negra no Brasil. São Paulo: Companhia d
Letras, 2009, p. 258. ABREU, Alzira Alves de (Coord.). Dicionário histórico-biográfico da Primeira República [Recurso eletrônico]: 1889-1930,
Formato EPUB. São Paulo: FGV, 2015.
35 ALBUQUERQUE, Wlamyra R. de. O jogo da dissimulação: abolição e cidadania negra no Brasil. São Paulo: Companhia das
Letras, 2009, p. 258. ,
33 ASPD, ata da sessão da Assembleia Geral de 27/08/1876. ,
33 ASPD, ata da sessão da Assembleia Geral de 27/08/1876. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX 32 ASPD, ata da Assembleia Geral de 20/08/1876. 33 ASPD, ata da sessão da Assembleia Geral de 27/08/1876.
34 ABREU Al i
Al
d
(C
d ) Di i
á i
hi ó i
bi
áfi
d
P i
i
R
úbli
[R
l
ô i
] 1889 1930 alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Além disso, destacaram outras causas que justificavam a demissão de Manoel Fernandes,
como sua inadimplência com as mensalidades, a retirada de dinheiro do caixa para
empréstimos e pagamentos desconhecidos, além das irregularidades nos últimos
demonstrativos de receita e despesa. Com todos esses argumentos em mãos, Caetano de
Mattos realizou uma votação que decidiu por 9 votos contra 7 pela demissão do Conselho
e a eleição de uma nova gestão, que o tinha como presidente.32 No dia 27 de agosto foi realizada outra sessão da Assembleia Geral, na qual
Manoel Fernandes e seus aliados apresentaram um “protesto anulatório” em relação aos
trabalhos da sessão anterior. Agora contra-atacavam o grupo de Caetano de Mattos, pois
além de contarem com a presença de Albino Henriques da Silva, estava presente também
na sessão o sócio protetor Antônio Carneiro da Rocha.33 Este era filho do Major Nicolau
Carneiro da Rocha, que também era sócio protetor da SPD. Tinha uma tradição política
forte, pois havia ocupado o cargo de deputado provincial (1868-1869) e parece que
naquele momento sua aproximação com os membros da SPD tinha algum interesse na
busca de apoio para se eleger novamente, porque foi eleito para o mesmo cargo no ano
de 1878 a 1881. Era uma figura importante e, assim como seu pai, tinha uma relação
próxima com os liberais, pois haveria de ser ministro da Agricultura, no gabinete do
Conselheiro Dantas, no ano de 1884. 34 Frequentou também durante a década de 1870,
uma das mais importantes sociedades abolicionistas da capital baiana, a Sociedade
Libertadora Sete de Setembro.35 Talvez a presença desses dois protetores, que tinham uma vasta rede de
possibilidades políticas, tenha intimidado os oposicionistas de alguma forma. Manoel
Fernandes utilizou sua rede de proteção, construída há muitos anos à frente da instituição, 13 13 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 para conseguir garantir o comando da SPD naquele momento, tendo em vista as investidas
de Caetano de Mattos, apadrinhado por oposicionistas, que provavelmente não estavam
satisfeitos com a sua presença no poder. O grupo de Caetano de Mattos perdeu aquela
briga em uma votação decidida por 14 votos contra 9, pela reprovação da eleição
promovida para derrubar o presidente. 37 ANDREWS, George Reid. América Afro-Latina, 1800-2000. São Carlos: EdUFSCar, 2014, p. 124, 125. 36 ASPD, ata da sessão da Assembleia Geral de 27/08/1876. 36 ASPD, ata da sessão da Assembleia Geral de 27/08/1876. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
14 alianças,
conflitos
e
redes
de
proteção
entre
lideranças do associativismo negro Manoel Fernandes reassumiu a cadeira da
presidência e reestabeleceu o domínio legal da diretoria.36 Essa disputa, além de
evidenciar mais uma vez o quanto Manoel Fernandes tinha uma relação próxima com
políticos liberais, desde a década de 1860 – provavelmente mais forte na figura dos
Carneiro da Rocha –, demonstra como as lideranças do associativismo negro constituíram
e acionaram essas redes de proteção para atenderem os seus interesses. Estes “novos sócios”, no qual fazia parte Manoel Fernandes, Antonio Bracete e
outros, talvez tenham constituído alianças com os liberais, pois estes falavam aos grupos
subalternizados, como os negros, através de uma retórica do liberalismo, que invocava os
conceitos de igualdade cívica, democracia política e os direitos de cidadania. De acordo
com George Reid Andrews, em muitos países da América Afro-Latina, existia uma
“política negra” organizada em torno de disputas entre os conservadores e liberais. Particularmente na América espanhola, havia uma inclinação das elites tradicionais,
proprietárias de terras e comerciantes poderosos dos tempos coloniais, de se agruparem
no Partido Conservador, que defendia a preservação da herança colonial, como o
catolicismo, a hierarquia social e racial e as grandes propriedades rurais. Apesar do
Partido Liberal também ter conseguido o apoio de latifundiários e grandes comerciantes,
“seu principal apelo era a grupos sociais que haviam sido excluídos de posições de poder
e privilégio durante o período colonial e que estavam agora procurando oportunidades
para participar e ascender no novo mundo pós-independência.”37 Portanto, é possível
supor que algumas lideranças da SPD, que ascenderam no período que os liberais
ganharam força, talvez vislumbrassem nessa retórica um possível caminho para
executarem seu projeto de liberdade. LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 38 GOMES, Flávio dos Santos. Negros e política (1888-1937). Rio de Janeiro: Jorge Zahar, 2005, p. 80. O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
15 O JOGO POLÍTICO DAS LIDERANÇAS DO ASSOCIATIVISMO NEGRO: ALIANÇAS, CONFLITOS E REDES DE PROTEÇÃO
EM SALVADOR NA SEGUNDA METADE DO SÉCULO XIX
LUCAS RIBEIRO CAMPOS
15 considerações finais Ser livre no contexto escravista pode ter ganhado significados diferentes para
diversos sujeitos. A liberdade de poder constituir uma associação formada por homens de
cor, que proporcionou a constituição de uma identidade, uma assistência social e
promoveu um projeto político de trabalhadores negros, pode ser lida como uma via não
apenas de sobrevivência entre aqueles indivíduos, mas também de resistência e dignidade
em uma sociedade escravista. Cada trabalhador livre de cor que optou por apostar no
projeto político da SPD entendeu que aquele espaço era uma possibilidade de fazer com
que suas expectativas fossem alcançadas. Nas estreitas avenidas de participação política e de cidadania no Brasil, alguns
negros como Manoel Leonardo Fernandes, Antônio José Bracete, Feliciano Primo
Ferreira, Caetano de Mattos, Joaquim de Santana Gomes Ferrão e outros, exploraram ao
máximo os espaços de atuação possíveis. Esses indivíduos disputavam o jogo político e
partidário do Segundo Reinado, através de alianças e redes de proteção. Essas estratégias
consolidavam o poder de barganha de determinadas lideranças de cor, a partir de uma
agenda especifica para os negros. Ser sócio da SPD significava ter a possibilidade de lutar
por direitos básicos enquanto cidadãos, como educação, dignidade, assistência mútua,
participação política e pertencimento racial. Flavio Gomes ressalta a necessidade de atentar para o fato de que as pessoas
negras reunidas em coletividades estavam falando "de e para si mesmos". Ao tomarem
essa postura, nas palavras do autor, os negros "provavelmente não queriam apenas acesso
a direitos de uma dada cidadania. Em sindicatos, associações e projetos de partidos
políticos, agendaram a questão racial". Ou seja, "talvez não quisessem apenas debater ou
participar, mas sim definir a pauta.”38 As lideranças da SPD de fato estavam definindo a
pauta racial que melhor lhes representavam, mesmo diante de tensões, conflitos e
negociações cotidianas. Deste modo, o associativismo negro baiano deve ser lido sob uma
chave interpretativa da construção de uma resistência política dos trabalhadores negros. 15 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 ____. Comunicado do vice-presidente Caetano de Mattos de 13/08/1876. ____. Estatuto aprovado pelo governo da Província em 26 de agosto de 1874. ____. Pedido de inscrição de Caetano de Mattos, indicado por Severiano Pedro da Silva,
aprovado em 17/05/1893. ____. Seção Judiciária, inventário. Classificação 07/3062/11. ARQUIVO DA SOCIEDADE PROTETORA DOS DESVALIDOS (ASPD). Ata da
sessão da Assembleia Geral. Anos indicados. ____. Comunicado do vice-presidente Caetano de Mattos de 13/08/1876. Fontes ARQUIVO PÚBLICO DO ESTADO DA BAHIA (APEB). Seção Colonial e Provincial,
Presidência da Província, Correspondência recebida da Sociedade Protetora dos
Desvalidos (1861-1880), maço 5306; ____. Seção Judiciária, inventário. Classificação 07/3062/11. REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 HEMEROTECA DIGITAL DA BIBLIOTECA NACIONAL. O Monitor, Salvador,
1878. HEMEROTECA DIGITAL DA BIBLIOTECA NACIONAL. O Monitor, Salvador,
1878. MASSON, Camillo de Lellis. Almanak administrativo, mercantil e industrial da Bahia
para o ano de 1857. Bahia: Typ. de Camillo de Lellis Masson & C., terceiro ano, 1857; ____. Almanak Administrativo e industrial da Bahia, para o anno de 1860. Salvador:
Typographia de Camillo de Lellis & Cia, 1860; PIMENTA, Altino Rodrigues. Almanak administrativo, commercial e insdustrial da
Província da Bahia para o anno de 1873, quinquagésimo segundo da Independência e
do Império. Bahia: Typographia de Oliveira Mendes & C., Anno I, quarta parte, 1872. BIBLIOTECA PÚBLICA DO ESTADO DA BAHIA (BPEB). Brasil. Decreto nº 2.711,
de 19 de dezembro de 1860. Contém diversas disposições sobre a criação e organização
dos bancos, companhias, sociedades anônimas e outras, e prorroga por mais quatro meses
o prazo marcado pelo artigo 1º do Decreto nº 2.686, de 10 de novembro do corrente ano. Colleção das Leis do Império do Brazil, Rio de Janeiro, Typografia Nacional, v. 2, p. 1125-1140, 1860. BIBLIOTECA PÚBLICA DO ESTADO DA BAHIA (BPEB). Brasil. Decreto nº 2.711,
de 19 de dezembro de 1860. Contém diversas disposições sobre a criação e organização
dos bancos, companhias, sociedades anônimas e outras, e prorroga por mais quatro meses
o prazo marcado pelo artigo 1º do Decreto nº 2.686, de 10 de novembro do corrente ano. Colleção das Leis do Império do Brazil, Rio de Janeiro, Typografia Nacional, v. 2, p. 1125-1140, 1860. BIBLIOTECA VIRTUAL CONSUELO PONDÉ (BVCP). O Alabama, Salvador, 1864. Obras Gerais ABREU, Alzira Alves de (Coord.). Dicionário histórico-biográfico da Primeira
República [Recurso eletrônico]: 1889-1930, Formato EPUB. São Paulo: FGV, 2015. 16 16 LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 ALBUQUERQUE, Wlamyra R. de. O jogo da dissimulação: abolição e cidadania negra
no Brasil. São Paulo: Companhia das Letras, 2009. ANDRADE, Humberto Santos de. Gráficos e Mutualismo: a trajetória da Associação
Tipográfica Baiana (Salvador, final do século XIX e início do XX). Dissertação
(Mestrado) – Universidade Estadual Paulista, Programa de Pós-Graduação de Mestrado
em História, Assis, 2014. ANDREWS, George Reid. América Afro-Latina, 1800-2000. São Carlos: EdUFSCar,
2014. BRAGA, Júlio. Sociedade Protetora dos Desvalidos: uma irmandade de cor. Salvador:
Ianamá, 1987. CAMPOS, Lucas R. Sociedade Protetora dos Desvalidos: mutualismo, política e
identidade racial em Salvador (1861-1894). Dissertação (Mestrado) – Universidade
Federal da Bahia, Faculdade de Filosofia e Ciências Humanas, Salvador, 2018. CASTILLO, Lisa Earl. HEMEROTECA DIGITAL DA BIBLIOTECA NACIONAL. O Monitor, Salvador,
1878. O terreiro do Alaketu e seus fundadores: história e genealogia
familiar, 1807-1867. Afro-Ásia, nº 43, 2011, p. 213-257. CHARLOTTE, Galves; LOBO, Tânia (Org.). O português escrito por afro-brasileiros
no século XIX: as atas da Sociedade Protetora dos Desvalidos. Salvador: EDUFBA, 2019. GOMES, Flávio dos Santos. Negros e política (1888-1937). Rio de Janeiro: Jorge Zahar,
2005. LARA, Silvia Hunold. Blowin’ in the wind: E. P. Thompson e a experiência negra no
Brasil. Proj. História, v. 12, outubro de 1995, p. 43-56. ______. Escravidão, cidadania e história do trabalho no Brasil. Proj. História, São Paulo,
(16), fev. 1998. LOBO, Tânia; OLIVEIRA, Klebson. Escrita liberta: letramento de forros na Bahia do
século XIX. In: CASTILHO, Ataliba de; TORRES, Maria Aparecida; CIRINO, Sônia
(Org.). Descrição, História e Aquisição do Português Brasileiro: estudos dedicados a
Mary Aizawa Kato. São Paulo: Fapesp, 2007. MATTOS, Ilmar Rohloff de. O Tempo Saquarema: a formação do Estado Imperial. São
Paulo: Editora Hucitec, 2004. OLIVEIRA, Klebson. Negros e escrita no Brasil do século XIX: sócio-história, edição
filológica de documentos e estudo linguístico. Tese (doutorado) – Universidade Federal
da Bahia, Instituto de Letras, Salvaor, 2006. SCHWARTZ, Stuart B. Escravos, roceiros e rebeldes. Bauru: EDUSC, 2001. SILVA, Kátia Maria de Carvalho. O Diário da Bahia e o século XIX. Rio de Janeiro:
Tempo brasileiro; Brasília: INL/MEC, 1979. LUCAS RIBEIRO CAMPOS REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096
Recebido em: 15/05/2020 – Aprovado em: 14/07/2020 REVISTA ÁGORA, v. 31, n. 2, e-2020310204, 2020, ISSN: 1980-0096 Recebido em: 15/05/2020 – Aprovado em: 14/07/2020 LUCAS RIBEIRO CAMPOS
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Aberrant Expressions and Variant Screening of SEMA3D in Indonesian Hirschsprung Patients
|
Frontiers in pediatrics
| 2,020
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cc-by
| 6,062
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ORIGINAL RESEARCH
published: 11 March 2020
doi: 10.3389/fped.2020.00060 Aberrant Expressions and Variant
Screening of SEMA3D in Indonesian
Hirschsprung Patients Gunadi 1*, Alvin Santoso Kalim 1, Nova Yuli Prasetyo Budi 1, Hamzah Muhammad Hafiq 1,
Annisa Maharani 1, Maharani Febrianti 1, Fiko Ryantono 1, Dicky Yulianda 1, Kristy Iskandar 2
and Joris A. Veltman 3 Gunadi 1*, Alvin Santoso Kalim 1, Nova Yuli Prasetyo Budi 1, Hamzah Muhammad Hafiq 1,
Annisa Maharani 1, Maharani Febrianti 1, Fiko Ryantono 1, Dicky Yulianda 1, Kristy Iskandar 2
and Joris A. Veltman 3 1 Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing,
Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia, 2 Department of Child Health/Genetics Working Group,
Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, Indonesia,
3 Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom Background: The semaphorin 3D (SEMA3D) gene has been implicated in the
pathogenesis of Hirschsprung disease (HSCR), a complex genetic disorder characterized
by the loss of ganglion cells in varying lengths of gastrointestinal tract. We wished to
investigate the role of SEMA3D variants, both rare and common variants, as well as its
mRNA expression in Indonesian HSCR patients. Citation: Gunadi, Kalim AS, Budi NYP,
Hafiq HM, Maharani A, Febrianti M,
Ryantono F, Yulianda D, Iskandar K
and Veltman JA (2020) Aberrant
Expressions and Variant Screening of
SEMA3D in Indonesian Hirschsprung
Patients. Front. Pediatr. 8:60. doi: 10.3389/fped.2020.00060 Methods: Sanger sequencing was performed in 54 HSCR patients to find a pathogenic
variant in SEMA3D. Next, we determined SEMA3D expression in 18 HSCR patients and
13 anorectal malformation colons as controls by quantitative real-time polymerase chain
reaction (qPCR). Methods: Sanger sequencing was performed in 54 HSCR patients to find a pathogenic
variant in SEMA3D. Next, we determined SEMA3D expression in 18 HSCR patients and
13 anorectal malformation colons as controls by quantitative real-time polymerase chain
reaction (qPCR). Edited by:
Francesco Morini,
Bambino Gesù Children Hospital
(IRCCS), Italy
Reviewed by:
Luca Pio,
Hôpital Robert Debré, France
Risto Rintala,
Helsinki University Central
Hospital, Finland
*Correspondence:
Gunadi
drgunadi@ugm.ac.id Edited by:
Francesco Morini,
Bambino Gesù Children Hospital
(IRCCS), Italy Reviewed by:
Luca Pio,
Hôpital Robert Debré, France
Risto Rintala,
Helsinki University Central
Hospital, Finland Results:
No rare variant was found in the SEMA3D gene, except one common
variant in exon 17, p.Lys701Gln (rs7800072). The risk allele (C) frequency at rs7800072
among HSCR patients (23%) was similar to those reported for the 1,000 Genomes
(27%) and ExAC (28%) East Asian ancestry controls (p = 0.49 and 0.41, respectively). A significant difference in SEMA3D expression was observed between groups (p =
0.04). Furthermore, qPCR revealed that SEMA3D expression was strongly up-regulated
(5.5-fold) in the ganglionic colon of HSCR patients compared to control colon (1CT 10.8
± 2.1 vs. 13.3 ± 3.9; p = 0.025). *Correspondence:
Gunadi
drgunadi@ugm.ac.id Specialty section:
This article was submitted to
Pediatric Surgery,
a section of the journal
Frontiers in Pediatrics Conclusions:
We report the first study of aberrant SEMA3D expressions in HSCR
patients and suggest further understanding into the contribution of aberrant SEMA3D
expression in the development of HSCR. In addition, this study is the first comprehensive
analysis of SEMA3D variants in the Asian ancestry. Received: 28 November 2019
Accepted: 07 February 2020
Published: 11 March 2020 Received: 28 November 2019 Accepted: 07 February 2020
Published: 11 March 2020 Keywords: aberrant expression, Hirschsprung disease, Indonesia, SEMA3D, rare and common variants Keywords: aberrant expression, Hirschsprung disease, Indonesia, SEMA3D, rare and common variants INTRODUCTION Hirschsprung disease (HSCR: MIM# 142623) is a complex genetic disorder, characterized by
the lack of ganglion cells in the bowel, resulting in a functional obstruction during infancy (1). HSCR is categorized into the following types: short-segment, long-segment, and total colonic
aganglionosis (1, 2). March 2020 | Volume 8 | Article 60 Frontiers in Pediatrics | www.frontiersin.org SEMA3D Expressions/Variant in Indonesian HSCR Gunadi et al. TABLE 1 | Clinical features of the HSCR patients for SEMA3D sequencing
analysis. Clinical features
n (%); months
SEX
• Male
38 (70)
• Female
16 (30)
AGANGLIONOSIS TYPES
• Short segment
• Long segment
• Total colon aganglionosis
53 (98)
1 (2)
0
AGE AT DIAGNOSIS
34.6 ± 44.5
AGE AT DEFINITIVE SURGERY
38.7 ± 43.9
DEFINITIVE SURGERY (49 PATIENTS)
• Transanal endorectal pull-through
21 (43)
• Duhamel
12 (25)
• Transabdominal Soave
11 (22)
• Posterior sagittal neurectomy
4 (8)
• Posterior myectomy
1 (2) HSCR incidence differs among ethnic groups, with 1.5, 2.1,
and 2.8 cases per 10,000 live births in European, African, and
Asian ancestry cases, respectively (1, 2). There are at least 17
genes responsible for the development of HSCR, with most of
them being members of the RET and EDNRB signaling pathways
(1, 2). Two genetic risk factors are the RET rs2435357 and
rs2506030 variants (3, 4). Our recent studies showed that the RET
rs2435357 and rs2506030 risk alleles have higher frequency in
Indonesian ancestry cases as compared with European ancestry
cases (5, 6), which might relate to the higher incidence of
HSCR in Indonesia (3.1 cases per 10,000 live births) than other
populations (7). p p
The third signaling pathway of HSCR pathogenesis includes
class 3 semaphorins (SEMA3s), involving SEMA3D (4, 8, 9)
SEMA3D has been implicated in the development of HSCR and
contributes to risk through both common and rare variants in
European ancestries (4, 8, 9), as evidenced by (1) the detection of
both common and rare SEMA3D variants in HSCR patients; (2)
the expression of SEMA3D in the human, mouse, and zebrafish
intestines and, particularly, the enteric nervous system (ENS);
and (3) the joint effect of Ret and Sema3d loss of function in an
aganglionosis animal model. However, our recent study showed
that the effect of SEMA3 rs11766001 common variant on HSCR
depends on the ethnic background (10). MATERIALS AND METHODS Patients for SEMA3D Variant Screening
We identified 54 HSCR patients: 38 males and 16 females
(Table 1). We diagnosed HSCR in these patients in Dr. Sardjito
Hospital,
Yogyakarta,
Indonesia,
after
evaluating
clinical findings, contrast enema, and histopathology. For
histopathological findings, we used hematoxylin-eosin staining
and S100 immunohistochemistry (5–7, 10, 15, 16). DNA Genotyping DNA Genotyping
DNA genotyping was performed using Sanger sequencing
analysis. The
SEMA3D
rs7800072:A>C
(chr7:
g. 84,628,989A>C) variant was identified during the Sanger
sequencing analysis to find a rare variant in Indonesian
HSCR patients. The risk allele (C) was determined according
to
the
1,000
Genomes
Project
and
ExAC
population
databases (17, 18). RNA Extraction and Quantitative
Real-Time PCR (qPCR) The ganglionic and aganglionic intestinal specimens were
collected at pull-through surgeries from 18 HSCR patients, while
control intestinal specimens were obtained at colostomy closure
from 13 anorectal malformation (ARM) patients (Table 2). All parents signed a written informed consent form before
participating in this study. The Institutional Review Board of
the Faculty of Medicine, Public Health, and Nursing, Universitas
Gadjah Mada/Dr. Sardjito Hospital gave approval for this study
(KE/FK/1356/EC/2015). All experiments were performed in
accordance with relevant guidelines and regulations. Total RNA was isolated from colonic specimens using the
total RNA Mini Kit (Tissue) (Geneaid Biotech Ltd., New
Taipei City, Taiwan). RNA was quantified by a NanoDrop 2000
Spectrophotometer (Thermo Scientific, Wilmington, DE, USA). The OD260/280 ratios ranged from 1.8 to 2.0, indicating high
RNA purity. INTRODUCTION In addition, the allele
frequencies of common variants might differ among Asians, since
the North Asians, Han Chinese, Japanese, and Southeast Asians
can be distinguished based on their Y chromosome variants (11). Moreover, alterations in the expression of specific genes have
been implicated in the development of HSCR (12–15). Therefore,
we wished to investigate the role of SEMA3D variants, both
rare and common variants, as well as its mRNA expression in
Indonesian HSCR patients. identify sequence variants in all 17 exons of the SEMA3D gene in
HSCR patients using BigDye Terminator V3.1 Cycle Sequencing
Kits (Applied Biosystems, Foster City, CA) and a 3730xl Genetic
Analyzer (Applied Biosystems), with DNA Sequencing Analysis
Software (Applied Biosystems) 0.1 (7). The primer sequences
for SEMA3D rare variant analysis were chosen based on a
previous study (4). Polymerase Chain Reaction (PCR) and
DNA Sequencing A QIAamp DNA Extraction Kit (QIAGEN, Hilden, Germany)
was used to extract genomic DNA from whole blood from each
individual, according to the manufacturer’s instructions. We
stored the extracted DNA samples at −20◦C until analysis. PCR
was conducted using a Swift Maxi thermal cycler (Esco Micro
Pte. Ltd., Singapore), followed by Sanger sequencing analysis to SEMA3D gene expression was quantified using the BioRad
CFX Real-Time PCR System (California, USA) and the
SensiFASTTM SYBR R⃝No-ROX One-Step Kit (Bioline, Meridian
Bioscience, Memphis, USA) using the 5′-CAACGCAGCCTG
ATAAACAA-3′ (forward) and 5′-TCTTTCATCTCTTGTGGGG
AGT-3′ (reverse) (19) The primers were designed to bridge March 2020 | Volume 8 | Article 60 Frontiers in Pediatrics | www.frontiersin.org 2 SEMA3D Expressions/Variant in Indonesian HSCR Gunadi et al. TABLE 2 | Clinical characteristics of the HSCR patients for SEMA3D expression
study. Clinical characteristics
n (%); months
SEX
• Male
11 (61)
• Female
7 (39)
AGANGLIONOSIS TYPES
• Short segment
• Long segment
• Total colon aganglionosis
16 (89)
2 (11)
0
AGE AT DIAGNOSIS
16.5 ± 33.3
AGE AT DEFINITIVE SURGERY
25.5 ± 35.8
DEFINITIVE SURGERY
• Transanal endorectal pull-through
13 (72.2)
• Duhamel
3 (16.7)
• Transabdominal Soave
2 (11.1) a full-thickness rectal biopsy waiting a pull-through procedure,
respectively, with the most common definitive surgery conducted
being transanal endorectal pull-through (43%) (Table 1); and our
controls were six males and seven females, with a mean age
during stoma closure of 47 ± 45.1 months. We could not identify any rare variant in all 17 exons
of SEMA3D gene in 54 HSCR patients, but encountered one
common variant in exon 17: p.Lys701Gln (rs7800072) (Figure 1). The genotype frequencies for rs7800072 variant among HSCR
patients were as follows: AA (32/54, 60%), AC (19/54, 35%),
and CC (3/54, 5%). Subsequently, we compared the risk allele
(C) frequency of rs7800072 in 54 Indonesian HSCR cases and
the 1000 Genomes and ExAC East Asian ancestry controls
(Table 3). The risk allele (C) frequency was similar in HSCR
cases (23%) and the 1000 Genomes (27%) and ExAC (28%)
East Asian ancestry controls, with p-values of 0.49 and 0.41,
respectively (Table 3). According to the conservation score
prediction using PhyloP, the p.Lys701Gln variant did not reach
a deleterious threshold of 0.84, while the predicted deleterious
effect (Condel) showed the p.Lys701Gln variant as being
neutral (4). Furthermore, the SIFT and PolyPhen-2 analysis of
p.Lys701Gln showed the variant as being tolerated and benign,
respectively (18). DISCUSSION In this study, we have performed an in-depth genetic and gene
expression study of the SEMA3D in Indonesian HSCR patients. We did not detect any rare variants in this gene, although
previous studies in European ancestry cases have identified rare
coding variants in SEMA3D associated with HSCR. Our results
indicate that the association of such variants to the disease
may be restricted to specific ethnic groups. It may still be the
case that other semaphorin 3 genes could play a role in HSCR
pathogenesis (4, 9). A previous study showed the existence of
other genetic factors conferring risk to HSCR in specific ethnic
populations (3). For example, there were two different RET
haplotypes involving the enhancer mutation that were over-
transmitted to the HSCR offspring in the European sample,
while in the Chinese sample, only one of those haplotypes was
present (3). It might be speculated that the enhancer mutation
arose in one haplotype, which after the Asian–Caucasian split,
rearranged to also give the other haplotype, but exclusively in Polymerase Chain Reaction (PCR) and
DNA Sequencing SEMA3D exon 8 and 9 junctions (19). Glyceraldehyde-3-
phosphate dehydrogenase (GAPDH), a housekeeping gene,
was used as an endogenous control. The GAPDH primers
were 5′-GCACCGTCAAGGCTGAGAAC-3′ (forward) and 5′-
TGGTGAAGACGCCAGTGGA-3′ (reverse). qPCR reactions
contained SensiFASTTM SYBR R⃝No-ROX One-Step mix (2×)
10 µL, RiboSafe RNase Inhibitor 0.4 µL, reverse transcriptase
0.2 µL, forward primer (10 µM) 0.8 µL, reverse primer (10 µM)
0.8 µL, and total RNA 50 ng, with final volume of 20 µL. qPCR was performed for 10 minutes (min) at 45◦C for reverse
transcription process, followed by 2 min at 95◦C and 39 cycles
for 5 s at 95◦C, 10 s at 58◦C and, 5 s at 72◦C, and 1 cycle for
5 s at 65◦C, according to the manufacturer’s instructions. We
performed the gel electrophoresis for the qPCR of SEMA3D and
GAPDH (Supplemental Figure 1). Next, we compared SEMA3D expression in 18 aganglionic
and ganglionic colons of HSCR patients and 13 control colons. The distribution of SEMA3D expression data were normal for
ganglionic, aganglionic, and control colons (p = 0.2, 0.17, and
0.2, respectively). A significant different of SEMA3D expression
was observed between groups (p = 0.04). Furthermore, qPCR
showed that the SEMA3D expression was strongly up-regulated
(5.5-fold) (Figure 2) in the ganglionic colon of HSCR patients
compared to control colon (1CT 10.8 ± 2.1 vs. 13.3 ± 3.9; p
= 0.025) (Table 4, Figure 3), while the SEMA3D expression was
not significantly different between the aganglionic colon of HSCR
patients and the control colon (1CT 13.1 ± 3.0 vs. 13.3 ± 3.9; p
= 0.89) (Table 4, Figure 3). The Livak method was utilized to determine the SEMA3D
mRNA expression level (20). This method is designed to calculate
a relative gene expression and referred to as the 1CT method. The (log) expression is proportional to the negative CT value (the
lower the CT, the higher the expression) (20). Statistical Analysis SEMA3D expression was described as a mean value ± SD. The Kolmogorov–Smirnov test was used to determine the
data distribution, and a one-way ANOVA was utilized to
assess statistical differences between groups. A chi-square test
was used to establish p-value for the case-control association
analysis for SEMA3D rs7800072 variant. A p < 0.05 was
considered significant. RESULTS Another example is the NRG1 rs7835688
genetic marker, which has been originally discovered in Chinese
HSCR patients (23) and has been shown in other Asian ancestry
cases (5, 24), but is rare and shows no effect in the Caucasian
population (8, 22). Makhmudi et al. (25) also demonstrated that
the MTHFR c.677C>T is a genetic risk factor for Indonesian
gastroschisis, but not seen in Caucasians (26, 27). A recent study
showed that loss of Sema3d in null homozygotes mice had no
impact on the intestinal transcriptome (28). The authors were
unable to find evidence for Ret and Sema3d interaction affecting
survival, presence of myenteric plexus, or intestine transcriptome
(28). Furthermore, Tang et al. revealed that the effects of RET
and NRG1 variants are universal across Caucasian and Asian
ancestries, but the impact of SEMA3 variant was restricted to
Caucasian ancestries (29). It should be noted that our screening
method did not cover the promoter and enrich regions of CpG
of SEMA3D. FIGURE 2 | The SEMA3D expression was strongly up-regulated (5.5-fold) in
the ganglionic colon of HSCR patients compared to control colon (p = 0.025),
while the SEMA3D expression was not significantly different between the
aganglionic colon of HSCR patients and the control colon (p =
0.89). *p < 0.05. FIGURE 2 | The SEMA3D expression was strongly up-regulated (5.5-fold) in
the ganglionic colon of HSCR patients compared to control colon (p = 0.025),
while the SEMA3D expression was not significantly different between the
aganglionic colon of HSCR patients and the control colon (p =
0.89). *p < 0.05. ENS development is a complex process, regulated by a
large range of molecules and signaling pathways. This strictly
controlled process needs the correct regulation of ENS-specific
gene expression. The expressions of several genes implicated
in HSCR development have been shown to be regulated
by epigenetic mechanisms. RET expression was regulated by
retinoic acid through DNA methylation on this 5′-CG-3′-
rich enhancer region (30), while a significantly lower level of
EDNRB methylation was also detected in HSCR patients (31). Interestingly, our study clearly demonstrates that SEMA3D gene
expression was strongly up-regulated in the ganglionic intestines
of HSCR patients as compared to controls. RESULTS Most of our HSCR patients were male (70%) and short-segment
aganglionosis type (98%), with the mean age at diagnosis being
34.6 ± 44.5 months (Table 1). Among the 54 HSCR patients, 49,
3, and 2 children underwent a definitive surgery, a colostomy, and March 2020 | Volume 8 | Article 60 Frontiers in Pediatrics | www.frontiersin.org 3 SEMA3D Expressions/Variant in Indonesian HSCR Gunadi et al. FIGURE 1 | Sanger sequencing of exon 17 SEMA3D gene in a HSCR patient. Arrow indicates a common variant, p.Lys701Gln (rs7800072). FIGURE 1 | Sanger sequencing of exon 17 SEMA3D gene in a HSCR patient. Arrow indicates a common variant, p.Lys701Gln (rs7800072). TABLE 3 | SEMA3D common variant frequency in Indonesian HSCR and
population databases (17, 21). Variant
(risk allele)
HSCR
patients
1000
Genomes*
ExAC*
p-value
vs. 1000
Genomes
vs. ExAC
p.Lys701Gln
(rs7800072) (C)
25/108
274/1,008
2,399/8,626
0.49
0.41
*East
Asian
ancestries;
ExAC,
exome
aggregation
consortium;
HSCR,
Hirschsprung disease. TABLE 3 | SEMA3D common variant frequency in Indonesian HSCR and
population databases (17, 21). FIGURE 2 | The SEMA3D expression was strongly up-regulated (5.5-fold) in
the ganglionic colon of HSCR patients compared to control colon (p = 0.025),
while the SEMA3D expression was not significantly different between the
aganglionic colon of HSCR patients and the control colon (p =
0.89). *p < 0.05. the Caucasian (22). Another example is the NRG1 rs7835688
genetic marker, which has been originally discovered in Chinese
HSCR patients (23) and has been shown in other Asian ancestry
cases (5, 24), but is rare and shows no effect in the Caucasian
population (8, 22). Makhmudi et al. (25) also demonstrated that
the MTHFR c.677C>T is a genetic risk factor for Indonesian
gastroschisis, but not seen in Caucasians (26, 27). A recent study
showed that loss of Sema3d in null homozygotes mice had no
impact on the intestinal transcriptome (28). The authors were
unable to find evidence for Ret and Sema3d interaction affecting
survival, presence of myenteric plexus, or intestine transcriptome
(28). Furthermore, Tang et al. revealed that the effects of RET
and NRG1 variants are universal across Caucasian and Asian
ancestries, but the impact of SEMA3 variant was restricted to
Caucasian ancestries (29). It should be noted that our screening
method did not cover the promoter and enrich regions of CpG
of SEMA3D. the Caucasian (22). Frontiers in Pediatrics | www.frontiersin.org RESULTS To the best of
our knowledge, our study is the first report of the aberrant In addition, the observed SEMA3D rs7800072 variant
frequency in Indonesian HSCR patients is similar to those
reported for the 1,000 Genomes Project and ExAC East Asian
ancestry controls (17, 18). Therefore, we might conclude that
this common variant does not have a role on the development
of HSCR in Indonesia. March 2020 | Volume 8 | Article 60 Frontiers in Pediatrics | www.frontiersin.org 4 SEMA3D Expressions/Variant in Indonesian HSCR Gunadi et al. TABLE 4 | SEMA3D expressions in colon of HSCR patient and control. SEMA3D
1CT ± SD
11CT (95% CI)
Fold change
p-value
Ganglionic colon
10.8 ± 2.1
−2.5 (−4.7 to −0.2)
5.5
0.025*
Aganglionic colon
13.1 ± 3.0
−0.2 (−2.4 to 2.1)
1.1
0.89
Control colon
13.3 ± 3.9
CI, confidence interval; CT, cycle threshold; SD, standard deviation; *p < 0.05 is
considered statistically significant. FIGURE 3 | Box-plot graph of 1CT value of the SEMA3D expressions in
HSCR ganglionic colon (1CT 10.8 ± 2.1), HSCR aganglionic colon (1CT 13.4
± 2.9), and control colon (1CT 13.3 ± 3.9). Box-plot graph of 1CT value
reveals the median values as lines across the box. Lower and upper boxes are
representing the 25th percentile to the 75th percentile, while whiskers indicate
the maximum and minimum values. *p < 0.05. expressions in the ganglionic colon involve in the pathogenesis
of persistent bowel symptoms in HSCR patients following a
properly performed pull-through surgery. y
g
g y
Our results should be interpreted with some caution, however,
because they are based on overall means without accounting for
other factors generating variation in the data such as gender, age,
and degree of aganglionosis. Further studies of the methylation
pattern of the SEMA3D gene are required to investigate whether
the aberrant expression of SEMA3D in HSCR patients is due to
abnormal DNA methylation. It is also necessary to compare the
SEMA3D protein expression level between HSCR patients and
controls and to identify its location in the colon tissue to prove
the increased SEMA3D expressions. Unfortunately, we do not
have any data on the methylation pattern, protein expression, and
immunohistochemistry of SEMA3D due to resource limitations
in our institution. Furthermore, our study utilized ARM patients’
colon as controls. It has been shown that most ARM patients have
abnormal colonic motility (41) and low expression of interstitial
cells of Cajal marker (42). RESULTS Therefore, further research with
more proper control colon (e.g., autopsy bowel material from
healthy infants or trauma patients) is necessary to better confirm
the role of SEMA3D expression in the pathogenesis of HSCR. Noteworthy, however, our small sample size is a limitation of our
study and suggests that a multicenter larger sample population
needs to be studied to clarify our findings. FIGURE 3 | Box-plot graph of 1CT value of the SEMA3D expressions in
HSCR ganglionic colon (1CT 10.8 ± 2.1), HSCR aganglionic colon (1CT 13.4
± 2.9), and control colon (1CT 13.3 ± 3.9). Box-plot graph of 1CT value
reveals the median values as lines across the box. Lower and upper boxes are
representing the 25th percentile to the 75th percentile, while whiskers indicate
the maximum and minimum values. *p < 0.05. FIGURE 3 | Box-plot graph of 1CT value of the SEMA3D expressions in
HSCR ganglionic colon (1CT 10.8 ± 2.1), HSCR aganglionic colon (1CT 13.4
± 2.9), and control colon (1CT 13.3 ± 3.9). Box-plot graph of 1CT value
reveals the median values as lines across the box. Lower and upper boxes are
representing the 25th percentile to the 75th percentile, while whiskers indicate
the maximum and minimum values. *p < 0.05. In conclusion, we report the first study of aberrant SEMA3D
expressions in HSCR patients and suggest further understanding
into the contribution of aberrant SEMA3D expression in
the development of HSCR. In addition, this study is the
first comprehensive analysis of SEMA3D variants in the
Asian ancestry. FIGURE 3 | Box-plot graph of 1CT value of the SEMA3D expressions in
HSCR ganglionic colon (1CT 10.8 ± 2.1), HSCR aganglionic colon (1CT 13.4
± 2.9), and control colon (1CT 13.3 ± 3.9). Box-plot graph of 1CT value
reveals the median values as lines across the box. Lower and upper boxes are
representing the 25th percentile to the 75th percentile, while whiskers indicate
the maximum and minimum values. *p < 0.05. ETHICS STATEMENT The Institutional Review Board of the Faculty of Medicine, Public
Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito
Hospital gave approval for this study (KE/FK/1356/EC/2015). All parents signed a written informed consent form before
participating in this study. It has been shown that some HSCR patients have persistent
bowel symptoms, such as constipation, soiling, and enterocolitis,
after an appropriate pull-through procedure. Most HSCR
patients with persistent bowel symptoms do not have any
identifiable etiology for their ongoing bowel dysmotility (36). The current hypothesis is that the aberrant expression of some
genes in the ganglionic colon of HSCR patients includes SK3,
Cx26, ChAT, and nNOS (37–40). Our study presented the altered
SEMA3D expressions in the ganglionic colon of HSCR patients. Therefore, we might hypothesize that the aberrant SEMA3D DATA AVAILABILITY STATEMENT expressions of SEMA3D in HSCR patients. Another novelty
in our findings is we conducted the study on patients with
Indonesian ancestry [vs. European (4) ancestry cases]. It has
been shown that reduced sema3d expression by morpholino
resulted in severe effects on the intestine and its innervation
of zebrafish (4). In addition, sema3d bound to nrp1a to
facilitate the axonal guidance and contributed to peripheral
axon outgrowth interdependently with dpysl3 (32, 33) Binding
of Sema3d to neuropilin and plexin receptors introduced
biochemical responses in specific neurons and stimulated the
neuron migration (34, 35). Therefore, we might hypothesize that
the aberrant expressions of SEMA3D will have an impact in
our HSCR patients by affecting the neuronal guidance during
ENS development. All data generated or analyzed during this study are included
in the submission. The raw data are available from the
corresponding author on reasonable request. Frontiers in Pediatrics | www.frontiersin.org REFERENCES 14. Tang W, Li B, Xu X, Zhou Z, Wu W, Tang J, et al. Aberrant high expression
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S. SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found
online
at:
https://www.frontiersin.org/articles/10.3389/fped. 2020.00060/full#supplementary-material ACKNOWLEDGMENTS We are grateful to Program Bantuan Seminar Luar Negeri,
Ditjen Penguatan Riset dan Pengembangan, Kemenristekdikti, We are grateful to Program Bantuan Seminar Luar Negeri,
Ditjen Penguatan Riset dan Pengembangan, Kemenristekdikti,
Indonesia for providing the conference grant to present the
abstract at the 52nd Annual Meeting of PAPS in Christchurch, Supplemental Figure S1 | Gel electrophoresis of qPCR: (A) GAPDH and (B)
SEMA3D expressions for HSCR ganglionic, aganglionic, and control colons. M:
100 bp DNA ladder; G: ganglionic colon; A: aganglionic colon; C: control colon;
W: no RNA. Indonesia for providing the conference grant to present the
abstract at the 52nd Annual Meeting of PAPS in Christchurch, Indonesia for providing the conference grant to present the
abstract at the 52nd Annual Meeting of PAPS in Christchurch, FUNDING This work was supported by a grant from the Faculty of
Medicine, Public Health and Nursing, Universitas Gadjah Mada,
Yogyakarta, Indonesia (Teuku Jacob Fellowship 2015-2017:
#UPPM/202/M/05/04/09.15 and #UPPM/256/05/04/05.17 to G). This work was supported by a grant from the Faculty of
Medicine, Public Health and Nursing, Universitas Gadjah Mada, This work was supported by a grant from the Faculty of
Medicine, Public Health and Nursing, Universitas Gadjah Mada,
Yogyakarta, Indonesia (Teuku Jacob Fellowship 2015-2017:
#UPPM/202/M/05/04/09.15 and #UPPM/256/05/04/05.17 to G). Yogyakarta, Indonesia (Teuku Jacob Fellowship 2015-2017:
#UPPM/202/M/05/04/09.15 and #UPPM/256/05/04/05.17 to G). AUTHOR CONTRIBUTIONS G and KI conceived the study. G drafted the manuscript. KI and
JV critically revised the manuscript for important intellectual
content. AK, NB, and FR performed total RNA extraction and
qPCR. HH, AM, MF, and DY conducted the experimental PCR-
based work for Sanger sequencing. All authors have read and
approved the manuscript and agreed to be accountable for all
aspects of the work in ensuring that questions related to the March 2020 | Volume 8 | Article 60 5 SEMA3D Expressions/Variant in Indonesian HSCR Gunadi et al. accuracy or integrity of any part of the work are appropriately
investigated and resolved. accuracy or integrity of any part of the work are appropriately
investigated and resolved. New Zealand at March 10–14, 2019. We would like to thank
the patients, their families, and all those who were involved
and provided excellent technical support and assistance during
the study. We also thank Professor Aravinda Chakravarti (New
York University, School of Medicine) for critically reading the
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Yulianda, Iskandar and Veltman. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
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reproduction is permitted which does not comply with these terms. Copyright © 2020 Gunadi, Kalim, Budi, Hafiq, Maharani, Febrianti, Ryantono,
Yulianda, Iskandar and Veltman. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
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MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A REGIONALIZAÇÃO COMO FERRAMENTA/ MATOPIBA: Strategic Territorial Intelligence and regionalization as a tool/ MATOPIBA: la Inteligencia Territorial Estratégica y la regionalización como herramienta
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Resumo A partir dos anos 2000 observamos o aprofundamento da especialização territorial produtiva
no cultivo de commodities agrícolas voltadas ao mercado externo em porções dos cerrados
Norte e Nordeste. Diante deste processo de expansão do agronegócio nesta região do país,
o Estado brasileiro articula um conjunto de ações visando o fortalecimento da atividade
agropecuária no MATOPIBA (região que envolve porções do Maranhão, Tocantins, Piauí e
Bahia). O presente artigo1 avalia como o Estado, a partir de um conjunto de estudos
elaborados pela Embrapa, produziu uma região que pode ser considerada como uma
“ferramenta” para o planejamento de políticas públicas destinadas à promoção do
agronegócio, com fins de atribuir maior competitividade à produção regional. Tal condição
toma contorno mais preciso através da promulgação do Plano de Desenvolvimento
Agropecuário (PDA) do MATOPIBA, que confere à região o status de área estratégica de
expansão do agronegócio no país, criando de certo modo a viabilização do uso corporativo
do território. vras-chaves: Viabilidade territorial; região como ferramenta; agronegócio; MATOPIBA 1 Este trabalho resulta de pesquisa de mestrado que contou com o apoio financeiro do Fundo de Amparo à
Pesquisa de Minas Gerais (FAPEMIG), entre os anos de 2015 e 2017. MATOPIBA: a Inteligência Territorial Estratégica (ITE) e a
regionalização como ferramenta
Glaycon Vinícios Antunes de Souza
Universidade Estadual de Campinas (UNICAMP) – Campinas, São Paulo, Brasil.
e-mail: glayconantunes@hotmail.com Mirlei Fachini Vicente Pereira
Universidade Federal de Uberlândia (UFU) – Uberlândia, Minas Gerais, Brasil. e-mail: mirlei@ufu.br Resumen A partir de los años 2000, observamos que en segmentos de los cerrados Norte y Nordeste
se produce una profundización de la especialización territorial productiva en el cultivo de
commodities agrícolas, enfocadas al mercado externo. Frente a este proceso de expansión
del agronegocio en esta región del país, el Estado brasileño ha desplegado una serie de
medidas que buscan potenciar el fortalecimiento de las actividades agropecuarias en
MATOPIBA (región que abarca segmentos de Maranhão, Tocantins, Piauí y Bahia). El
presente artículo evalúa como el Estado, a partir de un conjunto de estudios elaborados por
la EMBRAPA, produjo una región que puede ser considerada como “herramienta” para la
planificación de políticas públicas destinadas a la promoción del agronegocio, con objetivo de
contribuir a una mayor competitividad de la producción regional. Dicha condición toma forma,
de manera más precisa, a través de la promulgación del Plan de Desarrollo Agropecuario
(PDA) de MATOPIBA, que entrega a la región el estatus de área estratégica de expansión del
agronegocio en el país, contribuyendo así, a una mayor viabilidad del uso corporativo del
territorio. alabras-clave: Viabilidad territorial; región como herramienta; agronegocio; MATOPIBA Abstract From the year 2000 we can observe the deepening of the productive territorial specialization
in the cultivation of agricultural commodities aimed at the foreign market in portions of the
North and Northeast Cerrados. In the face of the process of the agribusiness expansion in this
region of the country the Brazilian State is articulating a set of actions aimed at strengthening
the agricultural activity in MATOPIBA (a region that involves portions of the states of Maranhão,
Tocantins, Piauí and Bahia). This paper evaluates how the State, from a set of studies
elaborated by Embrapa, produced a region that can be considered a “tool” for the planning of
public policies destined to the promotion of agribusiness, in order to give greater
competitiveness to the regional production. Such condition takes more precise shape through
the promulgation of MATOPIBA's Agricultural Development Plan (ADP), which gives the region
the status of a strategic agribusiness expansion area in the country, creating, to some extent,
the viability of corporate use of the territory. Keywords: Territorial viability; region as a tool; agribusiness; MATOPIBA. . NERA
Presidente Prudente
v. 22, n. 47, pp. 22-45
Dossiê - 2019
ISSN: 1806-6 Rev. NERA
Presidente Prudente
v. 22, n. 47, pp. 22-45
Dossiê - 20 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Introdução Na década de 2000 configura-se um novo conjunto de relações produtivas no campo
moderno brasileiro, com o estabelecimento daquilo que Guilherme Delgado denominou como
“pacto de economia política do agronegócio” (DELGADO, 2012). Segundo o autor, esta
condição do agronegócio resulta de esforços públicos e privados, com objetivo de gerar saldos
comerciais externos para suprir o déficit da conta corrente nacional. A principal estratégia para
alcançar tal meta, visando a superação do déficit da balança comercial, deu-se através da
exportação de commodities agrícolas e minerais. Esta configuração pode ser entendida como
uma associação econômica entre a agricultura moderna, as cadeias agroindustriais, o sistema
de crédito (sendo o Estado brasileiro um dos principais financiadores do setor), além de
garantias para a formação de um novo mercado de terras, com o objetivo de promover uma
estratégia econômica própria ao capital financeiro, que busca esquemas renovados de
acumulação (DELGADO, 2012). Este pacto de economia política do agronegócio implica na reorganização do
território, sendo o aprofundamento da especialização territorial produtiva (na produção de
commodities agrícolas) em diferentes regiões do território brasileiro e em especial nos
Cerrados, uma de suas expressões mais diretas. Neste sentido, Frederico (2014, p. 2134)
considera que há o estabelecimento de um “pacto de economia política do território” fundado
no agronegócio, que pode ser entendido como a articulação dos diferentes agentes do setor
(Estado, corporações, agricultores e investidores financeiros) com o objetivo de criar 23 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA estratégias de “[...] apropriação do excedente e a utilização do capital sobreacumulado para
a incorporação e organização de espaços sob a lógica do modo de produção dominante”. Neste contexto observamos o aprofundamento da especialização territorial em
porções setentrionais dos Cerrados especialmente na produção de grãos, em áreas da Bahia,
Maranhão, Piauí e Tocantins. Esta porção do território nacional foi denominada num primeiro
momento, e com fins acadêmicos, como BAMAPITO, por Bernardes (2009) ou ainda como
Cerrados do Centro Norte, por Alves (2015). A partir de 2015 o Estado brasileiro denomina a
referida região como MATOPIBA, com a finalidade de torná-la um recorte regional estratégico
voltado ao planejamento institucional da atividade agropecuária, com caráter típico daquilo
que Elias (2013) reconhece como “agronegócio globalizado”. Dentre as articulações mais recentes provindas do esforço Estatal para o
fortalecimento do agronegócio, destaca-se a criação do Grupo de Inteligência Territorial
Estratégica (GITE) vinculado a Empresa Brasileira de Pesquisa Agropecuária, a Embrapa. Introdução O
GITE realiza uma série de estudos baseados no entendimento de Inteligência Territorial
Estratégica (ITE), podendo ser compreendido como uma ferramenta indispensável para o
monitoramento e caracterização territorial, tendo como intuito subsidiar a criação de
planejamentos voltados ao fortalecimento do agronegócio. O referido grupo foi responsável
por delimitar o recorte regional do MATOPIBA (Mapa 1), cujos critérios foram estabelecidos a
partir do levantamento e cruzamento de informações sobre o quadro natural, agrário, agrícola,
socioeconômico e de infraestrutura da região, com objetivo de caracterizar e diagnosticar as
variáveis que são importantes para sustentar a elaboração de planejamentos e políticas
públicas para o desenvolvimento do agronegócio na região. Os estudos do GITE sobre o MATOPIBA foram fundamentais para a criação do Plano
de Desenvolvimento Agrícola (PDA) do MATOPIBA. Conforme Bernardes e Maldonado (2017,
p. 76) o PDA do MATOPIBA “[...] constitui uma ação, tanto reveladora das formas como
avança o agronegócio nessa região, como impulsionadora desse agronegócio”, nos
demonstrando também como esta região torna-se um espaço importante para o Estado. O
PDA do MATOPIBA configura-se como instrumento que estimula a difusão e consolidação do
agronegócio no MATOPIBA, pois as diretrizes que dão sustentação ao plano são voltadas ao
fortalecimento de setores indispensáveis a esta atividade, tais como a melhoria das condições
de logística para a circulação de grãos, o desenvolvimento de novas tecnologias de produtos
destinados ao campo moderno e ainda a busca de um fortalecimento da chamada “classe
média” rural (BRASIL, 2015). Neste sentido a Embrapa, através do GITE, “inventa” e institucionaliza uma região
com o propósito de intervenção em setores indispensáveis para atribuir maior competitividade
ao agronegócio no MATOPIBA, conferindo-lhe um caráter de “região como ferramenta”
(RIBEIRO, 2004). Segundo Ribeiro (2004), tal tipo de compartimentação do território visa a 24 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA produção de um recorte de intervenção/planejamento para atender os interesses dos atores
hegemônicos, conduzido por um agir instrumentalizado e carregado de ideologias
dominantes, conforma-se como uma ferramenta estratégia para o uso corporativo do território
às grandes empresas. Além da institucionalização de uma região como ferramenta para o
agronegócio, a partir do PDA do MATOPIBA, observamos a criação de uma viabilidade do
território (SILVEIRA, 2003) para o setor, pois essa ação legitima a “invenção” de uma região
que visa a instrumentalização do espaço aos interesses dos agentes promotores do
agronegócio. Mapa 1: Recorte regional do MATOPIBA. Org.: SOUZA, G.V.A. MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA Portanto, nosso objetivo neste trabalho é analisar como a Embrapa, através do GITE
e a partir da ideia de Inteligência Territorial Estratégica (ITE), cria uma ferramenta
informacional indispensável para a delimitação de uma “região para o agronegócio”, e como
este grupo foi importante para subsidiar a elaboração do Plano de Desenvolvimento
Agropecuário (PDA) do MATOPIBA. Também analisamos o PDA do MATOPIBA e seu
desdobramento, buscando demonstrar como a institucionalização desta região, como área de
planejamento, é uma das formas de viabilização do território aos imperativos do mercado
globalizado. Mapa 1: Recorte regional do MATOPIBA. Org.: SOUZA, G.V.A. Org.: SOUZA, G.V.A. 25 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA mercado de terras) na busca de estratégias de capital financeiro (DELGADO, 2012). Conforme aponta Guilherme Delgado, mercado de terras) na busca de estratégias de capital financeiro (DELGADO, 2012). Conforme aponta Guilherme Delgado, [...] agronegócio na acepção brasileira do termo é uma associação do grande
capital agroindustrial com a grande propriedade fundiária. Essa associação
realiza uma estratégia econômica de capital financeiro, perseguindo o lucro e
a renda da terra, sob patrocínio de políticas de Estado. (DELGADO, 2012, p. 94). [...] agronegócio na acepção brasileira do termo é uma associação do grande
capital agroindustrial com a grande propriedade fundiária. Essa associação
realiza uma estratégia econômica de capital financeiro, perseguindo o lucro e
a renda da terra, sob patrocínio de políticas de Estado. (DELGADO, 2012, p. 94). A nova configuração da atividade agrícola, a partir de 2000, colaborou decisivamente
para a verticalização da atuação de grandes corporações atraídas pelo crescimento da
produção regional, pela menor concorrência (quando comparado com as tradicionais áreas
de produção agrícola do país), bem como pela grande demanda por grãos no mercado
internacional, conferindo possibilidades de novos processos de valorização fundiária. Em
2017, apenas quatro empresas controlam cinco unidades de processamento de soja na região
- a Bunge, em Luís Eduardo Magalhães (BA) e Uruçuí (PI), a Cargill em Barreiras (BA), o
grupo Algar, presente no município maranhense de Porto Franco e a Granol, com uma
unidade em Porto Nacional (TO). Além destas corporações, um conjunto de tradings nacionais
e internacionais estendem seus nexos produtivos a diferentes pontos da região a partir de
escritórios de exportação, tais como a Glencore, CHS, CGG, Multigrain, ADM, Amaggi & LDC,
Agrex do Brasil, entre outras. 2017, apenas quatro empresas controlam cinco unidades de processamento de soja na região
- a Bunge, em Luís Eduardo Magalhães (BA) e Uruçuí (PI), a Cargill em Barreiras (BA), o
grupo Algar, presente no município maranhense de Porto Franco e a Granol, com uma
unidade em Porto Nacional (TO). Além destas corporações, um conjunto de tradings nacionais
e internacionais estendem seus nexos produtivos a diferentes pontos da região a partir de
escritórios de exportação, tais como a Glencore, CHS, CGG, Multigrain, ADM, Amaggi & LDC,
Agrex do Brasil, entre outras. A informação como ferramenta para a definição de uma região do agronegócio:
O emprego da Inteligência Territorial Estratégica (ITE) Nas últimas três décadas observamos a constituição de uma nova fronteira agrícola
nos cerrados localizados no Norte e Nordeste do país, região esta que se afirma como um
espaço estratégico para o agronegócio, a partir da expansão de forma seletiva do meio
técnico-científico-informacional (SANTOS, 1994, 2002). A partir da década 1990 a
disseminação e utilização de objetos carregados de conteúdos técnicos, científicos e
informacionais (como os maquinários agrícolas modernos, as sementes melhoradas, uso de
fertilizantes, entre outros), juntamente com um conjunto de ações orquestradas pelo Estado
e agentes privados, possibilitou a afirmação de uma agricultura científica globaliza (SANTOS,
2001) na região, fundamentalmente voltada para a produção de commodities mais valorizadas
no mercado externo, como é o caso da soja, do milho e do algodão. É sobretudo durante os
anos 2000 que verificamos a expansão de forma mais intensa desta fronteira agrícola. Para
se ter noção da amplitude do processo, a área produzida com soja (principal commodity na
região) aumentou cerca de 310% entre os anos de 2000 (905 mil hectares) e 2015 (3,6
milhões de hectares), enquanto o crescimento entre as décadas de 1990 (407 mil hectares) e
2000 foi de 122%; a quantidade produzida saltou de 2,2 milhões de ton. para 10,7 milhões de
ton., entre 2000 e 2015 (em 1990 o volume produzido era de apenas 260 mil ton.) (IBGE/PAM,
2017). Indubitavelmente as inovações científicas e tecnológicas constituem elemento central
ao processo de produção voltado para a acumulação de grandes agentes, colaborando assim
para o aprofundamento da modernização e incorporação de novos espaços agrícolas à
região. Contudo as condições políticas são de grande relevância para a dinâmica agrícola, e
neste início de século, as relações políticas e econômicas estão sendo marcadas por um novo
pacto do agronegócio, em que há a rearticulação entre os principais agentes da agricultura
moderna do país (agricultura moderna, as cadeias agroindustriais, o sistema de crédito e o 26 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Estas corporações são responsáveis pela dinamização do circuito espacial produtivo
(SANTOS; SILVEIRA, 2010) das principais commodities produzidas na região, já que são
responsáveis pela comercialização, processamento, circulação e distribuição destes
produtos. Estes agentes estabelecem uma relação com o território de forma pontual e seletiva,
com intuito de eleger as áreas que permitam maior ampliação do seu capital, criando redes
agroindustriais (ELIAS, 2006) para o processamento e circulação de grãos. Além das tradings agrícolas, visualizamos também outros agentes do agronegócio
que estendem suas atividades ao MATOPIBA. Nos anos 2000, observamos a atuação de
forma intensa de empresas que agem no mercado de terras, muito responsáveis pela
valorização de imóveis e por um claro processo de especulação fundiária, implicando
fragmentação do território. Tal situação é fomentada por empresas que não possuíam tradição
em investir na atividade agrícola, tais como empresas de private equity, fundos de pensões,
fundos hedge e fundos soberanos, especializadas na obtenção de ganhos a partir da
especulação financeira (FREDERICO; GRAS, 2017). Esta configuração é um dos reflexos da
financeirização da economia, em que cada vez mais o capital financeiro cria novas formas
para se retroalimentar, e nesse sentido um conjunto de autores (BERNARDES et al, 2017)
reconhecem o surgimento de uma nova “safra” de capitalistas na agricultura, cuja principal 27 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA marca é a presença de agentes do capital financeiro em atividades consideradas como
“alternativas”, sendo o mercado fundiário e a especulação de terras um exemplo. Este conjunto imbricado de agentes estabelece verdadeiros círculos de cooperação
(SANTOS; SILVEIRA, 2011) com empresas que já atuam no ramo agrícola, criando novas
corporações (através de joint ventures) que buscam estratégias do capital financeiro para a
obtenção de rendimento a partir da compra, especulação e venda de terras agrícolas. O
MATOPIBA configura-se como um espaço de grandes expectativas para ganhos com
valorização fundiária, onde as corporações podem adquirir as propriedades a baixo custo e
rapidamente criar mecanismo de valorização das terras, através de uma produção agrícola
altamente tecnificada e capitalizada, visto que os preços das terras no MATOPIBA são em
geral ainda mais baixos que os praticados nas regiões agrícolas consolidadas do Centro-
Oeste, Sudeste e Sul do Brasil. Entre as empresas que atuam na exploração do mercado de
terras no MATOPIBA destacamos a Brasil Agro, SLC Agrícola, Radar S/A, Adecoagro, Sollus
Capital, entre outras. GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Segundo informações obtidas, no ano de 2017, nos sites das empresas BrasilAgro,
SLC Agrícola, Adecoagro e Sollus Capital, as mesmas possuem conjuntamente mais de 215
mil hectares de terras em diferentes porções do MATOPIBA (BRASILAGRO, 2017; SLC
AGRÍCOLA, 2017; ADECOAGRO, 2017; SOLLUS CAPITAL, 2017), sobretudo nas porções
mais preparadas às atividades do agronegócio, como o Oeste Baiano, o Sudoeste do Piauí e
o Sul do Maranhão (SOUZA, 2017). Este dado nos sinaliza que cada vez mais há
concentração fundiária sob controle de empresas que fundamentam seus lucros na
especulação fundiária, promovendo uma situação de “modernização territorial” pautada em
estratégias financeiras nesta porção do país. Diante desta condição de crescimento do agronegócio no MATOPIBA, o Estado
brasileiro articula estratégias específicas para esta região, com propósito de tornar essa
porção do território nacional ainda mais racionalizada à atividade hegemônica. Desde a
década de 1980 a Embrapa Semiárido realiza diagnósticos de áreas dos Cerrados Norte e
Nordeste favoráveis à produção em grande escala e voltada para o mercado externo. Antigo
membro da Embrapa Semiárido, o agrônomo Evaristo Miranda, atual coordenador do Grupo
de Inteligência Territorial Estratégica (GITE), relata que “Na época (1980), estávamos em
busca de áreas com potencial para a produção de alimentos [...] Foi daí que surgiu o
zoneamento agrícola para a soja, no Nordeste, quando poucos acreditavam nela como uma
cultura de peso para a região” (ONDEI, 2015). No âmbito propriamente político, observamos uma primeira organização nos anos
2012, quando o Ministério da Agricultura Pecuária e Abastecimento (MAPA) lançou uma
portaria com o objetivo de criar um grupo de trabalho para desenvolver estudos sobre o
MATOPIBA (Portaria nº 269, de 3 de abril de 2012). Este grupo foi composto por 28 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA representantes do poder executivo a partir de secretárias do MAPA, instituições como a
Companhia Nacional de Abastecimento (CONAB) e a Embrapa. Assim, percebemos que um
conjunto de especulações e interesses sobre esta região dos Cerrados estavam sendo
orquestrados desde a década de 1980, com apoio dos estudos técnicos realizados pela
Embrapa. Dentre as articulações mais recentes, provindas do esforço estatal, destacamos a
criação do Grupo de Inteligência Territorial Estratégica (GITE), vinculado a Embrapa,
responsável pela delimitação geográfica do MATOPIBA. MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA A ITE pode ser entendida como um conjunto de ferramentas e métodos
aplicados para a compreensão de um território em sua dimensão agrícola,
agrária, natural, socioeconômica e infraestrutura, através da integração de
informações provenientes de diferentes bancos de dados. Essas informações
integradas servirão para apoiar a tomada de decisão para o desenvolvimento
territorial. (EMBRAPA, 2016). Neste sentido a ITE é um recurso utilizado em estudos de caracterização territorial
de uma região, que se dá a partir de uma abordagem multifatorial, agregando as condições
agrícolas, agrárias, de infraestruturas, socioeconômica e natural da área avaliada. Para o
GITE o objetivo desta noção de ITE é ir além da mensuração e descrição das condições
territoriais, a que a contribuição de tal procedimento reside especialmente na proposição de
cenários futuros sobre as condições da atividade agropecuária. Dessa forma, cria-se uma
possibilidade de antever situações consideradas de riscos para a agricultura e assim corrigi-
las, bem como fortalecer setores avaliados como favoráveis ao crescimento econômico do
agronegócio. Esta proposição configura-se como um instrumento técnico-científico para a
ação de um planejamento tanto do Estado quanto do setor privado que, em última instância,
permite traçar “caminhos” para o aprofundamento do capitalismo no campo (como é o caso,
por exemplo, das estratégias de incorporação de novas terras e de sua valorização). Mesmo demonstrando certo interesse na dinâmica territorial da atividade agrícola, os
estudos baseados na noção de Inteligência Territorial Estratégica têm como essência o
propósito de gerar diagnósticos através de levantamentos, enumeração e mapeamento das
condições agrícolas da região. Neste sentido é um estudo que visa mostrar a configuração
territorial do MATOPIBA, noção esta que pode ser compreendida pelo conhecimento
aprofundado do [...] conjunto formado pelos sistemas naturais existentes em um dado país ou
numa dada área e pelos acréscimos que os homens superimpuseram a esses
sistemas naturais. A configuração territorial não é o espaço, já que sua
realidade vem de sua materialidade, enquanto o espaço reúne a
materialidade e a vida que a anima (SANTOS, 2002, p. 62). [...] conjunto formado pelos sistemas naturais existentes em um dado país ou
numa dada área e pelos acréscimos que os homens superimpuseram a esses
sistemas naturais. A configuração territorial não é o espaço, já que sua
realidade vem de sua materialidade, enquanto o espaço reúne a
materialidade e a vida que a anima (SANTOS, 2002, p. 62). GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA O GITE foi criado em 2013 com a
finalidade de ser um grupo de pesquisa “voltado para a temática do planejamento e do
monitoramento territorial do uso e da ocupação das terras no Brasil, com ênfase na
agricultura” (GITE, 2016). Poucos anos depois de criado, este grupo possui um banco de
dados cartográfico e icnográfico (imagens de satélites, fotos aéreas, entre outros) de todo o
território brasileiro, contendo informações necessárias para realizar diagnósticos sobre o
quadro natural, condições de infraestrutura, situação agrícola, do quadro agrário e
socioeconômico. Os diagnósticos são, em alguns casos, bases para nortear ações
governamentais, assim como para o planejamento de políticas formuladas por órgãos públicos
(Ministério da Agricultura Pecuária e Abastecimento, Ministério do Planejamento, Gestão e
Orçamento) e setor privado. Entre os trabalhos recentes desenvolvidos por este grupo de pesquisa, podemos
destacar o acompanhamento das Obras do Programa de Aceleração do Crescimento (PAC),
sobretudo no que diz respeito às obras de eletrificação rural, de construção de estradas,
portos e hidrovias que garantem o escoamento das safras; estudos sobre o impacto da
colheita mecanizada de cana-de-açúcar no Estado de São Paulo (pesquisa esta solicitada
pela Federação das Indústrias do Estado de São Paulo- Fiesp); bem como o projeto para o
MATOPIBA. Para o desenvolvimento de suas pesquisas, o GITE respalda-se no entendimento de
Inteligência Territorial Estratégica (ITE), visto como uma ferramenta importante para o
planejamento e inovação de pesquisas vinculadas com a atividade agropecuária. Em
entrevista à revista da Embrapa, Evaristo Miranda expõe que os estudos de ITE consideram
um conjunto de fatores para o desenvolvimento da agricultura, buscando “[...] os melhores
caminhos para que ela (agricultura) possa progredir e para que os produtores rurais tenham
o melhor retorno do seu trabalho [...], a inteligência e a gestão territorial focam não só o
presente, mas também perspectivas de futuro, desenham cenários evolutivos possíveis”
(MIURA, 2016, p. 1), com interesse de apresentar o “retrato territorial da agricultura em muitas
dimensões temáticas (solo, água, vegetação, cultivos), bem como em termos temporais
(evolução) e ainda em muitas escalas espaciais (detalhe de uma fazenda, de um vale ou de
uma região geoeconômica)” (MIURA, 2016, p. 1). Portanto, 29 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA de erosão; quais são as melhores localidades para implantar uma rede de
fomento agrícola ou para investir em irrigação, armazenagem e logística. (MIURA, 2016, p. 1). Um recurso criado pelo grupo de pesquisa da Embrapa (GITE), a partir dos estudos
de ITE para a produção de um banco de dados integrado, foi o Sistema de Inteligência
Territorial Estratégica (SITE). Para os membros do GITE o planejamento territorial necessita
de um SITE “[...] capaz de apoiar diversos zoneamentos, diagnósticos e aplicações, bem
como a geração e a simulação de cenários em função dos interesses e necessidades das
instituições públicas e privadas que atuam na região” (GITE, 2014, p. 3). Percebemos que a
grande preocupação do GITE é de fato elaborar trabalhos que subsidiem a produção de
planos para o desenvolvimento do agronegócio, por isso a necessidade de elaborar um
conjunto de ferramentas metodológicas para operacionalizar as pesquisas e cumprir tais
metas. O SITE figura assim como um importante recurso de investigação dentro da ITE, pois
a partir deste sistema pode criar “[...] cenários futuros e definir situações territoriais
razoavelmente parecidas ou equiproblemáticas, como também equipotenciais em termos de
desenvolvimento agropecuário, a partir desta análise multitemática” (EMBRAPA, 2016). Por ser fruto de estudos da ITE, o SITE segue os seus mesmos eixos estruturantes
(Figura 1); agrega imagens de satélite com as geotecnologias – que são programas e
softwares que trabalham com essas imagens e com a produção de mapas. Para isto o SITE
utiliza de dados governamentais de vários institutos, e têm como base para elaboração
cartográfica as normas do IBGE e da INDE – Infraestrutura Nacional de Dados Espaciais. Para a equipe técnica do GITE, o grande diferencial desde sistema de informação (SITE) é a
possibilidade de integrar as inúmeras informações inseridas nesse banco de dados, indo além
da sobreposição e armazenamento. Somando a isto, o SITE tem a capacidade de inserção
contínua de novos dados, o que torna esse sistema uma “[...] ferramenta eficiente e essencial
para ações de planejamento e gestão territorial” (GITE, 2014, p. 5). Em 2014 o GITE, juntamente com o INCRA – Instituto Nacional de Colonização e
Reforma Agrária (até então vinculado ao Ministério do Desenvolvimento Agrário),
estabeleceram uma cooperação técnica para o levantamento e sistematização de uma base
de dados territoriais sobre o MATOPIBA. MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA Deste modo os diagnósticos feitos pelo GITE deixam de lado as relações sociais que
dinamizam e atribuem funcionamento à configuração territorial a partir do uso do território, ou
seja, não considera o território usado (o espaço como um todo; o espaço banal) (SANTOS,
2005) ou as dinâmicas territoriais como um fato político. Assim, o estudo de ITE figura como
um instrumento facilitador para a ampliação do capital dos agentes hegemônicos, visto que
responde a várias “perguntas”: É como se o interessado tivesse um técnico à sua disposição para dizer qual
é o melhor lugar para plantar determinada espécie; onde existem problemas 30 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA O principal critério para a delimitação desta região
foi a ocorrência de áreas de Cerrados, bioma esse que representa cerca de 91% da área do
MATOPIBA, seguido pelo bioma Amazônia (7,3%) e com mínima área de Caatinga (1,7%) 32 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA (GITE, 2015a); sendo a atividade agrícola o segundo grande critério para a definição da
região, atividade esta que é principal responsável pelo dinamismo econômico desta porção
do território nacional. Um dos resultados deste estudo técnico (ITE) foi a elaboração do MATOPIBA
GeoWeb (lançado em dezembro de 2015), que parece exemplificar de modo mais direto a
efetivação do SITE, onde são armazenados e integrados os dados e toda a sistematização
de informação sobre a região feito pelo GITE. Na visão de Evaristo Miranda, o MATOPIBA
GeoWeb. [...] auxiliará a tomada de decisão de governantes e subsidiará estudos e
projetos de empresas e investidores privados e de instituições de ensino
superior, sendo, portanto, uma ferramenta estratégica que pode ser usada
nos programas do Ministério da Agricultura para o desenvolvimento
agropecuário da região (EMBRAPA, 2015, grifo nosso). [...] auxiliará a tomada de decisão de governantes e subsidiará estudos e
projetos de empresas e investidores privados e de instituições de ensino
superior, sendo, portanto, uma ferramenta estratégica que pode ser usada
nos programas do Ministério da Agricultura para o desenvolvimento
agropecuário da região (EMBRAPA, 2015, grifo nosso). Isto demonstra que a ITE se trata de um estudo voltado para atender interesses
específicos para o “desenvolvimento” agrícola regional do MATOPIBA, sobretudo os
interesses do setor privado. Este sistema online de informação geográfica (MATOPIBA
GeoWeb) contém mais de 200 bases de dados, agregando informações como a quantidade
de pivôs centrais, disponibilidade de armazenamento, condição logística (rodovias e
ferrovias), distribuição populacional, produto interno bruto dos municípios, entre outros; em
síntese contém dados sobre os cinco grandes eixos que caracterizam o estudo de Inteligência
Territorial Estratégica – quadro natural, agrícola, agrário, infraestrutura e socioeconômico
(MATOPIBA GEOWEB, 2016). A partir desta exposição, percebemos o quanto há uma construção técnico-científica
para promoção e a instrumentalização do território através de uma ação informatizada,
alcançada através do trabalho fomentado por um órgão de pesquisa de destaque no país, que
é a Embrapa. GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA A partir da ideia de ITE e da criação do SITE
específico para o MATOPIBA, foram elaborados diagnósticos e notas técnicas com
informações sobre as características físico-naturais, a quantidade de comunidades
quilombolas, aldeias indígenas, áreas de proteção ambiental e assentamentos de reforma
agrária, entre outras informações. Ou seja, foram mapeados os lugares e as condições que
favorecem a expansão da fronteira agrícola na região, bem como reconhecidos os possíveis
limites para a expansão do agronegócio no MATOPIBA. 31 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA Figura 1: Organização do Sitema de Inteligência Territorial do MATOPIBA. Fonte: GITE/EMBRAPA (2014) Figura 1: Organização do Sitema de Inteligência Territorial do MATOPIBA. Fonte: GITE/EMBRAPA (2014) Deste modo, foram mobilizadas para a delimitação territorial do MATOPIBA “[...]
bases multifatoriais, contemplando as dimensões agroecológicas e socioeconômicas [...] a
partir de dinâmicas do tempo passado e do presente” (GITE, 2015a), criando uma
regionalização capaz de definir um recorte que captasse a dinâmica e a expansão da
agricultura moderna no MATOPIBA. Os critérios utilizados para a delimitação da região foram:
a configuração do quadro natural (biomas, cobertura vegetal, clima, geologia, relevo,
pedologia, hidrografia, recursos minerais e energéticos), quadro agrário (unidades de
conservação, terras indígenas, áreas quilombolas, assentamentos agrários), quadro
socioeconômico (estabelecimentos agropecuários – área e renda, Índice de Desenvolvimento
Humano – IDH, população total, rural e urbana, Produto Interno Bruto – PIB), e infraestrutura
(energia, rodovias, ferrovias, hidrovias, dutovias e porto) (GITE, 2015a). O cruzamento destas informações, via procedimentos computadorizados, produziu
um recorte espacial que engloba 337 municípios dos estados do Maranhão (135), Tocantins
(139), Piauí (33) e Bahia (30), correspondendo a aproximadamente 9% do território brasileiro. O recorte territorial proposto pela Embrapa para o MATOPIBA inclui todo o estado do
Tocantins (38% da região ou 27.772.052 hectares), porções Sul e Leste do Maranhão (cerca
de 33% do MATOPIBA ou 24 milhões de hectares), o Oeste baiano (com mais de 13 milhões
de hectares – representando cerca de 11% da região) e a porção Sudoeste do Piauí (11%,
com pouco mais de 8 milhões de hectares). MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA Podemos considerar que o GITE, a partir de seus diagnósticos, torna-se uma agência
cuja finalidade é a formulação de informações especializadas para atender interesses
precisos, que são voltados para o adensamento técnico (tecnosfera) bem como na formulação
de discursos (psicosfera) que legitimem ações territoriais no MATOPIBA, pois “As ações
necessitam de legitimação prévia para ser mais docilmente aceitas e ativas na vida social e
assim mais rapidamente repetidas e multiplicadas” (SANTOS, 1994, p. 51). Toda esta
articulação informacional promovida pelo grupo de pesquisa da Embrapa (GITE) foi
fundamental para a conformação de uma proposta política criada pelo Estado, com vista de
fortalecer e incentivar a expansão do agronegócio nesta região. A proposta em questão é o
Plano de Desenvolvimento Agropecuário do MATOPIBA, que expõe as intenções e as
expectativas à esta porção do território brasileiro. GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Estes estudos apontam lugares/regiões viáveis para a produção agrícola
moderna, permitindo identificar “os polos de desenvolvimento existentes e potenciais; e
delinear o cenário geral, identificando oportunidades, necessidades de avanço de
conhecimento e de desenvolvimento tecnológico” (MATOPIBA GEOWEB, 2016). Cria-se deste modo uma densidade informacional sobre o MATOPIBA, sinalizando
as potencialidades para a expansão do agronegócio nesta região, ou seja, são identificados
os espaços estratégicos para o aumento da riqueza do setor agroindustrial, da atividade
agrícola propriamente dita, bem como da especulação/valorização fundiária. Partindo desta
perspectiva, apreende-se que o adensamento de informações sobre o MATOPIBA é um
instrumento que permite tornar essa porção do território brasileiro integrada aos interesses
globais, permitindo a atuação mais aprofundada dos agentes hegemônicos que, em parte,
são responsáveis pela implantação de novas cargas de racionalidade ao lugar. 33 O Plano de Desenvolvimento Agropecuário (PDA) do MATOPIBA: Produção da
viabilidade territorial ao agronegócio e a institucionalização de uma região como
ferramenta Em maio de 2015 foi promulgado o decreto nº 8.447, que criou o Plano de
Desenvolvimento Agropecuário (PDA) do MATOPIBA. O referido Plano foi constituído a partir
do conjunto de estudos e diagnósticos elaborado pelo GITE, incluindo o próprio recorte
territorial, que diretamente expressa o reconhecimento do Estado sobre a importância desta
região para o novo pacto de economia do agronegócio (DELGADO, 2012) desenhado para o
país neste início de século, e, dessa forma, revela a necessidade de elaborar ações para
tornar as condições materiais e imateriais competitivas ao setor. O PDA do MATOPIBA foi o mecanismo estatal privilegiado para viabilizar uma região
institucionalizada para o agronegócio, sobretudo para atender aos anseios dos agentes
hegemônicos, exemplificando aquilo que Ribeiro (2004) denominou de “regionalização como
ferramenta”. Ana Clara Torres Ribeiro (2004) aponta para a necessidade de compreendermos
processos distintos de regionalização, que normalmente se processam na tensão entre
diferentes projetos, sempre atravessados pelo poder do Estado. Segundo a proposta da
autora, podemos reconhecer situações caracterizadas ora por uma “regionalização como
fato”, ora por uma “regionalização como ferramenta”. Em linhas gerais, a regionalização como
fato deriva da ação social capaz de empreender uma estruturação histórica de regiões, a partir
de múltiplos processos que limitam a ação hegemônica (regionalização como resultado da
decantação de práticas sociais longamente elaboradas no território). Um processo oposto
seria justamente o da regionalização como ferramenta, que resulta de uma conjuntura atual
imposta sobre o espaço pretérito, quando recortes espaciais assumem o planejamento
conduzido pelo Estado, atendendo a razões hegemônicas (RIBEIRO, 2004, p. 196). “É assim 34 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA que os estudos de regionalização como ferramenta podem desvendar a estratégia de agentes
para a constituição de espaços regionais que tornem facilitadas as suas pretensões
econômicas” (PEREIRA, 2009, p. 16). Tal conformação espacial é resultado das forças econômicas e políticas que
dominam o território, fomentadas principalmente pelo Estado e pelas corporações. No atual
período técnico-científico-informacional (SANTOS, 2002), as condições técnicas e políticas
são criadas para viabilizar o uso corporativo do território e a invenção de novas regiões de
intervenção estatal a partir de instrumentos técnico-científicos configura-se como uma
estratégia de afirmação da lógica hegemônica de produção nos lugares. [...] transformação da eficácia em meta política; pela imposição do agir
instrumental e estratégico e pelo desvendamento contínuo de contextos de
inovação, (e assim) a regionalização como ferramenta adquire extraordinário
destaque, o que explica a sua utilização pelos agentes hegemônicos,
desestabilizando a estrutura espacial do país (RIBEIRO, 2004, p. 197). O Plano de Desenvolvimento Agropecuário (PDA) do MATOPIBA: Produção da
viabilidade territorial ao agronegócio e a institucionalização de uma região como
ferramenta Este plano visa dotar o MATOPIBA de maiores condições técnicas e normativas para
atribuir à região maior competitividade, visto que as três diretrizes basilares estão voltadas
para o fortalecimento de setores estratégicos para o agronegócio da região como: a) melhorar
a eficácia da infraestrutura de logística referente à circulação de mercadorias agropecuárias;
b) promover e incentivar o desenvolvimento de tecnologias inerentes ao agronegócio; c)
estimular o fortalecimento da classe média rural através de ações para mobilidade social,
buscando o crescimento da renda, do emprego e da qualificação técnica dos produtores rurais
(BRASIL, 2015). Diante destas diretrizes entendemos que, para além de uma região como ferramenta,
as intencionalidades e expectativas em torno do PDA do MATOPIBA nos permitem entender
este plano como uma flexibilidade organizacional, que possibilita “inventar” a viabilidade
territorial (SILVEIRA, 2003) para o agronegócio. Segundo Silveira (2003), a flexibilidade
organizacional pode ser compreendida pela criação, via Estado, de uma série de normas que
abrandam (tornam facilitadas) as condições jurídicas-políticas para que as grandes
corporações possam desempenhar suas atividades de forma mais eficaz. Portanto, trata-se
de uma flexibilidade organizacional que privilegia sobretudo os atores hegemônicos da
economia, tratando-se de uma flexibilidade setorial (SILVEIRA, 2003). Para o caso em análise, a flexibilidade organizacional se expressa pela criação do
PDA, cujo objetivo é o fortalecimento do agronegócio nesta região, a partir do aumento dos
investimentos nos sistemas de engenharia – ferrovias, hidrovias, rodovias e armazéns – e no
desenvolvimento tecnológico para a agricultura científica globalizada. A própria
institucionalização de uma “região para o agronegócio”, também, evidência uma ação que
busca viabilizar o território para o uso corporativo, pois as estratégias de “compartimentação
do território são formas de valorização feitas, crescentemente pelas firmas, mas com a ajuda
de um poder público devotado a ‘inventar’ a viabilidade do território para as empresas”
(SILVEIRA, 2003, p. 414). Além da questão normativa para a viabilização do território para melhor atuação das
empresas, o Estado é fundamental para a constituição da base técnica que permite maior
circulação de mercadorias, capital, ordens e informações das corporações. A fluidez torna-se
um elemento essencial no atual período de globalização, visto que a produção, distribuição e
consumo tornam-se cada vez mais dispersos e acelerados. Em áreas de novos fronts
agrícolas, caso do MATOPIBA, a atuação do Estado para constituição de sistemas de
engenharia possui peso ainda maior. O Plano de Desenvolvimento Agropecuário (PDA) do MATOPIBA: Produção da
viabilidade territorial ao agronegócio e a institucionalização de uma região como
ferramenta Nesse sentido, as
regiões muitas vezes são elaboradas para responder as demandas do capital através de
elaborações científicas, e, desse modo, vivemos em um momento histórico em que a razão
esclarecedora cede lugar para a razão instrumental (KAHIL, 2010). É assim que ocorre a A regionalização como ferramenta traduz-se na elaboração de práticas políticas do
presente, construídas por e para atores hegemônicos da política e da economia (RIBEIRO,
2004), ou seja, para aqueles que possuem acesso e controle privilegiado da informação, da
técnica e da ciência. A regionalização e a proposição de regiões como “ferramenta” se
expressam quando assumem a forma-conteúdo regida pelo planejamento de Estado, e podem
ser caracterizadas pela imposição de um acontecer hierárquico (SANTOS, 2001, 2002) muitas
vezes estranho às práticas pretéritas estabelecidas no lugar, pois obediente a lógicas
exógenas que implicam em vulnerabilidade territorial, já que “a incorporação desses nexos e
normas externas têm um efeito desintegrador das solidariedades locais então vigentes, com
a perda correlativa da capacidade de gestão da vida local” (SANTOS, 2002, p. 285). Portanto
a regionalização como ferramenta configura-se geralmente como um instrumento de
planejamento Estatal para intervenção e estruturação (política e técnica) do espaço para o
uso corporativo do território. A região delimitada pelo GITE torna-se uma “ferramenta”, uma “peça fundamental” à
operacionalização do modelo de acumulação pautado na exportação de commodities, bem
como pelos agentes de especulação fundiária, pois ela será suporte para o desenvolvimento
de ações e para a emergência de narrativas de fortalecimento dos interesses do mercado
globalizado. Por consequência, o PDA do MATOPIBA carrega consigo toda esta carga de
intencionalidade que está presente na proposta de delimitação geográfica do MATOPIBA,
ainda que oficialmente o PDA possua o objetivo de criar e desenvolver políticas públicas 35 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA voltadas para agropecuária na região, com fins de promover o “desenvolvimento econômico
sustentável do setor” (BRASIL, 2015). GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Posto isto, observamos que a infraestrutura que permite maior fluidez territorial no
MATOPIBA é uma das diretrizes bases do PDA, cujo interesse é justamente melhorar a
logística para exportação das commodities produzidas nessa região. Tal diretriz atesta a
assertiva de Castillo (2008, 2011) que considera a logística (sinônimo de circulação
corporativa) elemento indispensável para atribuir à região maior grau de competividade. Segundo o autor, a circulação corporativa se estrutura a partir de redes técnicas (rodovias,
ferrovias, hidrovias, entre outros), do acesso privilegiado a informação e pela regulamentação
normativa, tríade esta que permite ser suporte para a competitividade. Portanto as densidades
técnicas, informacionais e normativas são indispensáveis para a invenção da viabilidade
territorial à atividade agropecuária moderna no MATOPIBA, sendo o Estado o principal agente
estruturador dessa situação. Além de proporcionar maior fluidez produtiva para as grandes tradings agrícolas,
responsáveis pela circulação dos grãos produzidos na região, a construção de novos fixos
como ferrovias e rodovias, bem como a própria melhoria desses, atua como elemento de
valorização das terras na região, permitindo práticas de especulação. Como debatem Lima e Nóbrega (2015) as terras que mais se valorizaram entre 2000
a 2014 no Tocantins foram as que estão localizadas na microrregião de Gurupi, em especial
as que são próximas a BR-153 (Belém-Brasília), uma das principais rodovias que conecta o
Tocantins no sentido norte/sul e importante via para escoar a soja (permitindo o acesso a
Ferrovia Norte/Sul em diferentes pontos do estado). As autoras ainda exemplificam o quanto
o distanciamento de importantes redes técnicas para a circulação de grãos é um dos
elementos que influência diretamente no preço das terras na região do Jalapão. O preço das
terras de Cerrado nessa região girava em torno de R$ 440,00/hectare em 2013, no mesmo
ano as terras de Cerrado próximas a BR 153 (na margem leste da rodovia) alcançavam R$
1.140,00/hectare (FNP, 2015). Spadotto (2017) nos traz outro exemplo que retrata a situação de valorização das
terras próximas as vias de circulação. O Plano de Desenvolvimento Agropecuário (PDA) do MATOPIBA: Produção da
viabilidade territorial ao agronegócio e a institucionalização de uma região como
ferramenta Estas áreas possuem densidades técnicas baixas (se
comparadas aos belts consolidados), o que constitui um problema para a fluidez corporativa. 36 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Conforme o autor, a Radar S/A (uma das maiores
corporações voltadas para a especulação fundiária no MATOPIBA) adquiriu propriedades
agrícolas nos municípios de Balsas (MA) e Santa Filomena (PI), próximas a uma rodovia com
expectativa de expansão, e tal antecipação de investimentos realizada por essa empresa
garantirá a valorização de suas propriedades ao longo do tempo, demonstrando que a compra
de fazendas em áreas próximas a futuras rodovias é uma das estratégias de acumulação de
tais agentes. Percebe-se “[...] que a montagem das redes supõe uma antevisão das funções que
poderão exercer e isso tanto inclui a sua forma material, como as suas regras de gestão”
(SANTOS, 2002, p. 265), sinalizando que o acesso a informação antecipada é uma das formas
de atuação do mercado para a obtenção de maiores lucros. Logo, as rodovias e ferrovias 37 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA configuram-se como redes sociotécnicas (SANTOS, 2002), por serem objetos geográficos que
possibilitam a conexão de diferentes porções do território, e sobretudo por serem fixos que
expressam relações de poder, pois colaboram para a estruturação e no próprio ordenamento
do território. Portanto, não é por acaso que a logística se apresenta como um dos elementos
centrais no PDA do MATOPIBA, estratégia que o próprio Estado cria para a viabilização do
território para o mercado, especialmente para a atuação de grandes corporações,
representadas tanto pelas que dinamizam a circulação da produção ou por aquelas que estão
desenvolvendo estratégias de ganho a partir da indução de um lucrativo mercado de terras
na região. Tal como a necessidade de novas infraestruturas técnicas, outro ponto estratégico
do PDA do MATOPIBA é o desenvolvimento de novas tecnologias para o campo, o que é
importante para os grandes produtores agrícolas, assim como para a tradings e para as
corporações que controlam as terras, pois o aumento da produtividade agrícola implica
diretamente em maior obtenção de lucros, seja a partir da oportunidade de exportar maior
volume de commodities ou mesmo pela elevação do preço das terras, já que a viabilidade da
produção engendra o processo de valorização fundiária. Nesse sentido, desde de 2015
diferentes unidades da Embrapa (27 no total), estão desenvolvendo cerca de 80 projetos
agrícolas de Pesquisa, Desenvolvimento e Inovação (PD&I) voltados especificamente para a
região do MATOPIBA (GITE, 2015a). I – articular, apoiar e acompanhar a execução de projetos de infraestrutura e
logística para o desenvolvimento sustentável do setor agropecuário;
II – promover, coordenar, apoiar e elaborar estudos, levantamentos,
pesquisas e projetos de desenvolvimento do Matopiba;
III – articular e elaborar projetos e atividades, nos âmbitos público e privado,
de assistência técnica, extensão rural e formação profissional aos pequenos
e médios produtores rurais do Matopiba;
IV – promover a capacitação de agentes públicos e privados da região do
Matopiba com vistas à organização da base produtiva e à incorporação de
novas tecnologias agrícolas, pecuárias e gerenciais;
V – gerenciar, técnica e administrativamente, projetos de cooperação técnica
e financeira com instituições públicas e privadas nacionais e internacionais;
e VI – cooperar com o Poder Público na implementação da política de defesa
agropecuária. (BRASIL, 2016). I – articular, apoiar e acompanhar a execução de projetos de infraestrutura e
logística para o desenvolvimento sustentável do setor agropecuário; g
p
g
p
II – promover, coordenar, apoiar e elaborar estudos, levantamentos,
pesquisas e projetos de desenvolvimento do Matopiba; GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Ainda segundo o GITE (2015a), todos os projetos têm
previsão de serem finalizados até 2019, apontando a urgência de criação de produtos
carregados de conhecimento científico para o campo moderno na região. Conforme dados do GITE (2015a), o orçamento para o custeio e o investimento
destes projetos alcança R$ 124 milhões, divididos nos seguintes temas de pesquisa: a)
melhoramento genético; b) sistema de produção; c) defesa sanitária; d) temas transversais;
e) transferência de tecnologia. Mais da metade deste valor (aproximadamente R$ 70 milhões)
é destinado para o tema “melhoramento genético”, sendo que quase R$ 27 milhões do
orçamento (GITE, 2015a), é voltado para a pesquisa e inovação do cultivo de soja, commodity
de maior interesse aos grandes produtores e corporações. Ainda sobre o PDA do MATOPIBA, há uma nítida escolha dos agentes que serão
beneficiados neste processo - são os chamados produtores de “classe média”, demonstrando
o caráter seletivo que privilegia a “ampliação e fortalecimento da classe média rural” (BRASIL,
2015). Tomando como base informações do censo agropecuário de 2006, bem como o valor
do salário mínimo da época (R$ 300,00), o GITE estabeleceu quatro classes de renda bruta
(que é a produção de 2006 vendida, autoconsumo e indústria caseira) para o MATOPIBA
(GITE, 2015b). 38 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA
A primeira classe, denominada muito pobre, compreende renda bruta mensal,
entre zero, não incluído, e dois salários mínimos, dois incluído. Em símbolos,
(0, 2]. A segunda classe é denominada pobre, (2, 10]. A terceira classe,
denominada de média, (10, 200]. E, finalmente, a última classe, denominada
rica, tem renda bruta mensal maior que duzentos salários mínimos. (GITE,
2015b, p. 7, grifo nosso). GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA A primeira classe, denominada muito pobre, compreende renda bruta mensal,
entre zero, não incluído, e dois salários mínimos, dois incluído. Em símbolos,
(0, 2]. A segunda classe é denominada pobre, (2, 10]. A terceira classe,
denominada de média, (10, 200]. E, finalmente, a última classe, denominada
rica, tem renda bruta mensal maior que duzentos salários mínimos. (GITE,
2015b, p. 7, grifo nosso). A primeira classe, denominada muito pobre, compreende renda bruta mensal,
entre zero, não incluído, e dois salários mínimos, dois incluído. Em símbolos,
(0, 2]. A segunda classe é denominada pobre, (2, 10]. A terceira classe,
denominada de média, (10, 200]. E, finalmente, a última classe, denominada
rica, tem renda bruta mensal maior que duzentos salários mínimos. (GITE,
2015b, p. 7, grifo nosso). Frente a tal classificação, em que a suposta classe média recebe entre 10 e 200
salários mínimos, percebemos que este plano não se dirige aos quem mais necessitam do
apoio estatal para alcançar melhores condições materiais de vida, aqui classificados como
pobres e muito pobres. Logo, o recorte regional do MATOPIBA, imbuído de um conteúdo
carregado de intencionalidades bem declaradas, é resultado de articulações políticas do
Estado e de demandas próprias dos agentes hegemônicos (como associações, sindicatos
patronais, tradings, etc), e neste sentido, apreendemos que a compartimentação do território
é fruto da construção social que atende a interesses políticos bem definidos e que envolve
relações de poder, seja “[...] o poder de criar e estabelecer formas espaciais. E, em segundo
lugar, o poder de institucionalizar (e garantir permanência) esta forma” (RIBEIRO, 2004, p. 200). Outro desdobramento decorrente do estudo de Inteligência Territorial Estratégica
desenvolvido pelo GITE, foi a criação de uma agência regional de desenvolvimento, resultado
também do PDA do MATOPIBA. A “Agência de Desenvolvimento do Matopiba” estava
prevista no PDA do MATOPIBA, com propósito de fomentar discussões e elaborar
planos/projetos para o estímulo do setor agrícola desta região. Esta agência de
desenvolvimento surgiu com o Projeto de lei complementar nº 279 de 2016, com o intuito de
desenvolver e executar as diretrizes presentes no PDA do MATOPIBA, sendo delegada à
agência a função de operacionalizar e colocar em prática as expectativas e intencionalidades
contidas no projeto de lei que oficializa o MATOPIBA como área de interesse estatal. MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA Compreendemos que as propostas para esta agência reforçam de forma detalhada
as diretrizes do PDA do MATOPIBA, sobretudo no que diz respeito a organização de uma
logística eficiente, na ampliação do uso de tecnologias agrícolas no campo e no fomento da
capacitação técnica dos produtores rurais. Além disso, a agência MATOPIBA replica os
mesmos erros do PDA do MATOPIBA, visto que esta instituição não inclui instituições que
representam os interesses de comunidades “tradicionais” que vivem na região. A ausência de
representantes dos quilombolas, das tribos indígenas e de líderes de movimentos sociais
ligados a luta pela terra, parece ser uma estratégia de exclusão dos atores sociais
compreendidos como potenciais “entraves” para a produção de commodities agrícolas, visto
que há conflito de interesses sobre um dos principais elementos do agronegócio, a
propriedade privada da terra. Além disso, é explícita a ausência de órgãos do próprio poder
executivo como Ministério do Meio Ambiente e instituições relacionados com a questão
ambiental (Instituto Chico Mendes – ICBIO) no comitê gestor desta agência (bem como no
próprio PDA do MATOPIBA), demonstrando descaso com as implicações ambientais. Tal ausência de representantes das comunidades tradicionais (povos dos Cerrados)
e de agências nacionais voltadas ao meio ambiente revela a falta de compromisso do PDA e
do órgão gestor deste plano com relação as questões que são de grande relevância para um
projeto que em tese visa “o desenvolvimento sustentável e equilibrado” social e
ambientalmente, apontando o caráter excludente de tais políticas. Desta forma podemos inferir que esse conjunto de informações e ações estratégicas
criadas pelos os agentes hegemônicos são indícios do alto grau de alienação territorial
(SANTOS; SILVEIRA, 2011) do país e particularmente da região do MATOPIBA, visto que
privilegiam estratégias de fortalecimento de normas hierárquicas produzidas em regiões
distantes, negligenciando a diversidade e a experiência histórica e social desta região. Trata-
se, portanto, de uma clara situação de uma prática invertida, não endereçada às reais
necessidades da nação, em que se perde a dimensão do trabalho voltado aos interesses
verdadeiramente coletivos e a distinção entre o que é público e privado, impedindo práxis
sociais verdadeiramente transformadoras (PEREIRA, 2011, p. 99). Toda a construção
realizada pela iniciativa privada e pelo Estado brasileiro através dos estudos realizados a partir
da Embrapa/GITE e todos seus desdobramentos, confirmam o caráter extravertido e alienado
de todas as expectativas propostas na delimitação geográfica da região do MATOPIBA. GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA Conforme o artigo II do Projeto de lei complementar nº 279, de 2016, a Agência MATOPIBA
deverá: I – articular, apoiar e acompanhar a execução de projetos de infraestrutura e
logística para o desenvolvimento sustentável do setor agropecuário; g
p
g
p
II – promover, coordenar, apoiar e elaborar estudos, levantamentos,
pesquisas e projetos de desenvolvimento do Matopiba; g
g
p
g
V – gerenciar, técnica e administrativamente, projetos de cooperação técnica
e financeira com instituições públicas e privadas nacionais e internacionais;
e VI – cooperar com o Poder Público na implementação da política de defesa
agropecuária. (BRASIL, 2016). 39 Considerações finais As relações sociais e políticas recentes no MATOPIBA propiciaram o surgimento de
uma região com forte atuação do agronegócio e, diante disso, houve a possibilidade de
elaborar, via articulações políticas do Estado, a região como ferramenta com intencionalidade 40 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA de dotar o espaço regional das condições materiais (tecnosfera) e imateriais (psicosfera,
fluxos, ordens e informação) necessárias para a atração do investimento privado no setor, ou
seja, este plano (e o conjunto de informações organizadas pelo GITE) lança as bases para
uma nova forma de organização e ordenamento do território a partir da “invenção” regional
voltada para o incentivo à produção de commodities agrícolas. Assim, o PDA do MATOPIBA
pode ser compreendido como uma estratégia que legitimou a “invenção” de uma região como
ferramenta para viabilização territorial, em que as grandes corporações do agronegócio serão
ainda mais beneficiadas por esse plano. Sem dúvida, a situação geográfica em tela não seria constituída sem as articulações
da Embrapa, instituição de pesquisa que, para além do desenvolvimento de tecnologias para
a produção agrícola, está assumindo novas funções dentro do aparelho estatal, capaz agora
de influenciar o próprio ordenamento do território a partir da produção de conhecimento para
subsidiar políticas públicas endereçadas a agentes privados. A criação do GITE evidência a
busca desta instituição no trabalho direto de planejamento territorial, como é o caso do Plano
de Desenvolvimento Agropecuário do MATOPIBA. Assim, a Embrapa foi e é agente
fundamental para a construção de um discurso de caráter técnico e científico, conferindo
maior confiabilidade e legitimidade para os investimentos do Estado e do mercado no
agronegócio da região. Além disto, a Embrapa, neste início de século, também é responsável pela
elaboração de uma psicosfera modernizadora que busca legitimar ações para a expansão do
agronegócio globalizado no território brasileiro. Tal situação é verificada quando
pesquisadores criam uma densidade informacional para induzir e justificar os investimentos
do Estado e da iniciativa privada, em regiões consideradas estratégicas para o agronegócio. Portanto, essa configuração traduz-se no conhecimento técnico-científico, produzindo
estratégias para maior acumulação de capital à seletos agentes do mercado. Com tais propostas e procedimentos, o GITE possui uma postura conservadora das
desigualdades e das injustiças sociais no MATOPIBA, sobretudo no campo, pois as suas
ações estão alinhadas com as demandas corporativas, privilegiando setores e agentes
envolvidos com o agronegócio. Referências ADECOAGRO. Informações institucionais. Disponível em: < http://www.adecoagro.com>. Acesso em: 20 jan. 2017. ADECOAGRO. Informações institucionais. Disponível em: < http://www.adecoagro.com>. Acesso em: 20 jan. 2017. ALVES, Vicente Eudes Lemos. Prefácio. In: ALVES, Vicente Eudes Lemos (Org.). Modernização e regionalização nos Cerrados do Centro-Norte do Brasil. Rio de Janeiro:
Consequência, 2015. ALVES, Vicente Eudes Lemos. Prefácio. In: ALVES, Vicente Eudes Lemos (Org.). Modernização e regionalização nos Cerrados do Centro-Norte do Brasil. Rio de Janeiro:
Consequência, 2015. BERNARDES, Julia Adão. Fronteiras da agricultura moderna no Cerrado Norte/Nordeste:
descontinuidades e permanências”. In: BERNARDES, Julia Adão; BRANDÃO FILHO, José
Bertoldo (Org.). Geografias da soja II: a territorialidade do capital. Rio de Janeiro:
Arquimedes/CNPq, 2009. p. 13-40. BERNARDES, Júlia Adão; MALDONADO, Gabriela. Estratégias do capital na fronteira
agrícola moderna brasileira e argentina. In: BERNADES, Júlia Adão et al (Org.). Globalização
do agronegócio e land grabbing: a atuação das megaempresas argentinas no Brasil. Rio
de Janeiro: Lamparina, 2017. p.57-80. BERNARDES, Júlia Adão; MALDONADO, Gabriela. Estratégias do capital na fronteira
agrícola moderna brasileira e argentina. In: BERNADES, Júlia Adão et al (Org.). Globalização
do agronegócio e land grabbing: a atuação das megaempresas argentinas no Brasil. Rio
de Janeiro: Lamparina, 2017. p.57-80. BRASIL. Decreto nº 8.447, de 6 de janeiro de 2015. Plano de Desenvolvimento
Agropecuário do Matopiba e A Criação de Seu Comitê Gestor. Brasília, 2015. BRASIL. Decreto nº 8.447, de 6 de janeiro de 2015. Plano de Desenvolvimento
Agropecuário do Matopiba e A Criação de Seu Comitê Gestor. Brasília, 2015. ______. Projeto de lei complementar n.º 279, de 2016. Autoriza o Poder Executivo a
instituir a Agência de Desenvolvimento do Matopiba. Brasília, 2015. ______. Projeto de lei complementar n.º 279, de 2016. Autoriza o Poder Executivo a
instituir a Agência de Desenvolvimento do Matopiba. Brasília, 2015. BRASILAGRO. Informações institucionais. Disponível em: < http://www.brasil-agro.com>. Acesso em: 17 jan. 2017. BRASILAGRO. Informações institucionais. Disponível em: < http://www.brasil-agro.com>. Acesso em: 17 jan. 2017. CASTILLO, Ricardo. Agricultura globalizada e logística nos Cerrados brasileiros. In:
SILVEIRA, Márcio Rogério (Org.). Circulação, transportes e logística diferentes
perspectivas. São Paulo: Outras expressões, 2011. p.331-354. CASTILLO, Ricardo. Agricultura globalizada e logística nos Cerrados brasileiros. In:
SILVEIRA, Márcio Rogério (Org.). Circulação, transportes e logística diferentes
perspectivas. São Paulo: Outras expressões, 2011. p.331-354. ______. Região competitiva e logística: expressões geográficas da produção e da circulação
no período atual. In: Seminário Internacional sobre Desenvolvimento Regional, 4., 2008, Santa
Cruz do Sul. Anais.... Santa Cruz do Sul: Unisc, 2008. Considerações finais Mesmo sabendo da diversidade de agentes sociais que vivem
no campo, esse grupo de pesquisa desconsiderou a necessidade de promover ações voltadas
para tais agentes. Há um pensamento que considera o agronegócio como a única e a mais
cabível forma de desenvolvimento agropecuário na região, negligenciando as outras formas
possíveis de uso do território realizadas por comunidades tradicionais, o que demonstra o
caráter seletivo e hierárquico das proposições do GITE. Reconhecemos que as informações obtidas a partir da ideia de ITE possuem
potencialidade para propor outras formas de planejamento estatal, em que possa ser
considerada a diversidade existente no meio rural no MATOPIBA. Ao mesmo tempo em que 41 MATOPIBA: A INTELIGÊNCIA TERRITORIAL ESTRATÉGICA (ITE) E A
REGIONALIZAÇÃO COMO FERRAMENTA a ITE tem capacidade de formular uma região para o agronegócio, esse mesmo aparato
técnico poderia, em outras condições políticas, servir de base para o desenvolvimento de
políticas públicas mais inclusivas e endereçadas às necessidades da própria região. Potencialmente, as condições técnico-científicas estão postas, contudo há necessidade de
uma mudança de pensamento e um alargamento da política para que haja o reconhecimento
da importância de diferentes racionalidades de produção e de outras possibilidades ao futuro
do campo e das gentes na região. Referências p.1-19 ______. Região competitiva e logística: expressões geográficas da produção e da circulação
no período atual. In: Seminário Internacional sobre Desenvolvimento Regional, 4., 2008, Santa
Cruz do Sul. Anais.... Santa Cruz do Sul: Unisc, 2008. p.1-19 DELGADO, Guilherme. Do capital financeiro na agricultura à economia do agronegócio:
mudanças cíclicas em meio século (1965-2012). Porto Alegre: UFRGS, 2012. DELGADO, Guilherme. Do capital financeiro na agricultura à economia do agronegócio:
mudanças cíclicas em meio século (1965-2012). Porto Alegre: UFRGS, 2012. EMBRAPA – Empresa Brasileira de Pesquisa Agropecuária. Inteligência Territorial
Estratégica é ferramenta para transferência de tecnologia. Embrapa. [s.i]. 2016. Disponível
em:
<
https://www.embrapa.br/busca-de-noticias//noticia/13911147/inteligencia-territorial-
estrategica-e-ferramenta-para-transferencia-de-tecnologia>. Acesso em: 05 out. 2016. EMBRAPA – Empresa Brasileira de Pesquisa Agropecuária. Inteligência Territorial
Estratégica é ferramenta para transferência de tecnologia. Embrapa. [s.i]. 2016. Disponível
em:
<
https://www.embrapa.br/busca-de-noticias//noticia/13911147/inteligencia-territorial-
estrategica-e-ferramenta-para-transferencia-de-tecnologia>. Acesso em: 05 out. 2016. 42 GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA FREDERICO, Samuel; GRAS, Carla. Globalização financeira e land grabiing: constituição e
translatinização das megaempresas argentinas. In: BERNARDES, Júlia Adão et al (Org.). Globalização do agronegócio e land grabbing: a atuação das megaempresas argentinas
no Brasil. Rio de Janeiro: Lamparina, 2017. p.12-33. FNP. Agrianual: Anuário da agricultura brasileira. FNP: São Paulo, 2015. FREDERICO, Samuel. Agronegócio e dinâmica territorial brasileira no início do século XXI. In: Congreso iberoamericano estudios territoriales y ambientales, 6., 2014, São Paulo. Anais... São Paulo: USP, 2014. p. 2134 - 2154. Disponível em: <http://6cieta.org/arquivos-
anais/eixo2/Samuel Frederico.pdf>. Acesso em: 13 mar. 2015. GEOWEB
MATOPIBA. Página
na
internet. Disponível
em:
<https://www.cnpm.embrapa.br/projetos/matopiba/index.html>. Acesso em: 03 out. 2016. na GITE – Grupo de Inteligência Territorial Estratégica. Página na internet. Disponível em:
<https://www.embrapa.br/gite/quem/index.html>. Acesso em: 04 ago. 2016. ______. Um Sistema de Inteligência Territorial Estratégica para o MATOPIBA. Campinas:
Embrapa, 2014. Disponível em: < https://www.embrapa.br/gite>. Acesso 19 out. 2015. ______. Caracterização Territorial Estratégica do Matopiba. Campinas: Embrapa, 2015a. 66 slides, color. Disponível em: <https://www.embrapa.br/gite/>. Acesso em: 19 out. 2015. _____. Renda e pobreza rural na região do MATOPIBA. Campinas: Embrapa, 2015b. Disponível em: <https://www.embrapa.br/gite/>. Acesso em: 25 ago. 2016. KAHIL, Samira Peduti. Psicoesfera: uso corporativo da esfera técnica do território e o novo
espírito do capitalismo. Sociedade & Natureza, Uberlândia, v.22, p.475-485, 2010. Disponível
em:
<
http://www.seer.ufu.br/index.php/sociedadenatureza/article/view/11332/pdf_12>. Acesso em: 10 out. 2016. LIMA, Débora Assumpção; NÓBREGA, Mariana Leal Conceição. Análise do preço de terras
agrícolas no Tocantins: decifrando os caminhos do agronegócio. In: Simpósio internacional e
Simpósios nacional de geografia agrária e jornada das águas e comunidades tradicionais, 7.,
8., 2015, Goiânia. Anais..., Goiânia: UFG, 2015, p. 3379-3390. MAPA – Ministério da Agricultura Pecuária e Abastecimento. Dilma e Kátia Abreu anunciam
criação da Agência de Desenvolvimento do Matopiba. 2016. Disponível em: <
http://www.agricultura.gov.br/comunicacao/noticias/2016/05/dilma-e-katiaabreu-anunciam-
criacao-da-agencia-de-desenvolvimento-do-matopiba>. Acesso em: 29 nov. 2016. MIURA, Juliana. Inteligência territorial e os desafios do crescimento sustentável da agricultura
brasileira. XXI
Ciência
para
a
vida. Embrapa. Jan. 2016. Disponível
em:
<http://evaristodemiranda.com.br/wp-content/uploads/2016/05/XXI-Ciencia-para-a-
vida12_EvaristoMiranda.pdf>. Acesso em: 30 set. 2016. ONDEI, Vera. Terra de valor. Dinheiro Rural, S.I, v.19, set. 2015. Disponível em:
<http://dinheirorural.com.br/secao/capa/terra-de-valor>. Acesso em: 16 nov. 2015 PEREIRA, Mirlei Fachini Vicente. Potencialidades da análise regional no estudo das
tendências de modernização e fragmentação do território. Revista de Ciências Humanas,
Viçosa, v. 9, Nº 1, p. 13-22, 2009. ______. Território e política: práxis invertidas e desafios da existência. Sociedade &
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REGIONALIZAÇÃO COMO FERRAMENTA RIBEIRO, Ana Clara Torres. Regionalização: Fato e ferramenta. In: LIMONAD, Ester;
HAESBAERT, Rogério; MOREIRA, Ruy (Org.). Brasil Século XXI - por uma nova
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AGRÍCOLA. Informações
institucionais. Disponível
em:
<
https://www.slcagricola.com.br>. Acesso em: 01 fev. 2017. SPADOTTO, Bruno Rezende. Land grabbing e uso do território: capital financeiro e
apropriação de terras no sul do maranhão e Piauí (MATOPIBA). In: Encontro de Geógrafos
da América Latina, 16., 2017, La Paz. Anais..., La Paz: Universidad Mayor de San Andrés,
2017. SOLLUS
CAPITAL. Informações
institucionais. Disponível
em:<http://www.solluscapital.com.br>. Acesso em: 18 jan. 2017. GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA GLAYCON VINÍCIOS ANTUNES DE SOUZA • MIRLEI FACHINI VICENTE PEREIRA SOUZA, Glaycon Vinícios Antunes de; PEREIRA, Mirlei Fachini Vicente. MATOPIBA: a
Inteligência Territorial Estratégica (ITE) e a regionalização como ferramenta. Revista NERA,
v. 22, n. 47, p. 22-45, dossiê MATOPIBA, 2019. Sobre os autores Glaycon Vinícios Antunes de Souza – Graduação em Geografia Universidade Federal de
Uberlândia (UFU); Mestrado em Geografia Universidade Federal de Uberlândia (UFU);
Doutorando em Geografia pela Universidade Estadual de Campinas (UNICAMP); OrcID –
https://orcid.org/0000-0002-2031-5371. Mirlei Fachini Vicente Pereira – Graduação em Geografia pela Universidade Estadual
Paulista (UNESP), campus de Rio Claro; Mestrado em Geografia pela Universidade Estadual
Paulista (UNESP), campus de Rio Claro; Doutorado em Geografia pela Universidade Estadual
Paulista (UNESP), campus de Rio Claro; Docente na Universidade Federal de Uberlândia
(UFU); OrcID – https://orcid.org/0000-0002-1094-8829. Como citar este artigo Como citar este artigo Como citar este artigo 44 Declaração de Contribuição Individual As contribuições científicas presentes no artigo MATOPIBA: a Inteligência Territorial
Estratégica (ITE) e a regionalização como ferramenta, foram construídas em conjunto pelos
autores. As tarefas de concepção e design, preparação e redação do manuscrito, bem como,
revisão crítica foram desenvolvidas em conjunto. O autor Glaycon Vinícios Antunes de
Souza ficou especialmente responsável por parte do desenvolvimento teórico-conceitual,
aquisição de dados e sua interpretação e pela elaboração de elementos cartográficos; o
segundo autor Mirlei Fachini Vicente Pereira, foi o responsável por parte de alguns
elementos teóricos, inserção de argumentação conceitual e bibliografias pertinentes ao tema
do artigo, revisão textual e de elementos cartográficos e figuras presentes no texto. Recebido para publicação em 15 de maio de 2018. Devolvido para a revisão em 15 de agosto de 2018. Aceito para a publicação em 26 de setembro de 2019. Recebido para publicação em 15 de maio de 2018. Devolvido para a revisão em 15 de agosto de 2018. Aceito para a publicação em 26 de setembro de 2019. 45
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https://openalex.org/W2792212636
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Fragranced consumer products: effects on asthmatic Australians
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Air quality, atmosphere & health
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Abstract Exposure to fragranced consumer products, such as air fresheners and cleaning supplies, is associated with adverse health effects
such as asthma attacks, breathing difficulties, and migraine headaches. This study investigated the prevalence and types of health
problems associated with exposure to fragranced products among asthmatic Australians. Nationally representative cross-
sectional data were obtained in June 2016 with an online survey of adult Australians (n = 1098), of which 28.5% were medically
diagnosed with asthma or an asthma-like condition. Nationally, 55.6% of asthmatics, and 23.9% of non-asthmatics, report
adverse health effects after exposure to fragranced products. Specifically, 24.0% of asthmatics report an asthma attack. Moreover, 18.2% of asthmatics lost workdays or a job in the past year due to fragranced products in the workplace. Over
20% of asthmatics are unable to access public places and restrooms that use air fresheners. Exposure to fragranced products is
associated with health problems, some potentially serious, in an estimated 2.2 million asthmatic adult Australians. Asthmatics
were proportionately more affected than non-asthmatics (prevalence odds ratio 3.98; 95% confidence interval 3.01–5.24). Most
asthmatics would prefer workplaces, healthcare facilities, and environments that are fragrance-free, which could help reduce
adverse effects. Keywords Fragranced consumer products . Indoor air quality . Exposure . Asthma . Air fresheners . Fragrance-free policy Keywords Fragranced consumer products . Indoor air quality . Exposure . Asthma . Air fresheners . Fragrance-free policy Fragranced consumer products: effects on asthmatic Australian Received: 11 January 2018 /Accepted: 26 February 2018 /Published online: 17 March 2018
# The Author(s) 2018 Introduction (Farrow et al. 2003), reductions in lung and pulmonary func-
tion (Dales et al. 2013; Shim and Williams 1986), irritation of
the airway mucosa (Elberling et al. 2005), and exacerbation of
asthma symptoms (Kumar et al. 1995; Millqvist and
Löwhagen 1996; Shim and Williams 1986; Weinberg et al. 2017). Exposure to fragranced consumer products, such as air fresh-
eners, cleaning supplies, laundry detergents, perfumes, house-
hold items, and personal care products, has been associated
with adverse human health effects (Steinemann 2009). Effects
include headaches and migraines (Andress-Rothrock et al. 2010; Silva-Néto et al. 2013), contact dermatitis (Johansen
2003; Rastogi et al. 2007), infant diarrhea and earache In a study parallel to this one, Steinemann (2016) found
that 34.7% of adult Americans reported health problems when
exposed to fragranced products. Specifically, among Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11869-018-0560-x) contains supplementary
material, which is available to authorized users. Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11869-018-0560-x) contains supplementary
material, which is available to authorized users. 2
College of Science and Engineering, James Cook University,
Townsville, QLD 4811, Australia 2
College of Science and Engineering, James Cook University,
Townsville, QLD 4811, Australia Air Quality, Atmosphere & Health (2018) 11:365–371
https://doi.org/10.1007/s11869-018-0560-x Air Quality, Atmosphere & Health (2018) 11:365–371
https://doi.org/10.1007/s11869-018-0560-x * Anne Steinemann
anne.steinemann@unimelb.edu.au 3
Climate, Atmospheric Sciences, and Physical Oceanography, Scripps
Institution of Oceanography, University of California, San Diego, La
Jolla, CA 92093, USA Amanda J. Wheeler
Amanda.Wheeler@utas.edu.au
Alexander Larcombe
Alexander.Larcombe@telethonkids.org.au Amanda J. Wheeler
Amanda.Wheeler@utas.edu.au 4
Menzies Institute for Medical Research, University of Tasmania,
Hobart, TAS 7000, Australia 5
Respiratory Environmental Health, Telethon Kids Institute, The
University of Western Australia, Perth, WA 6008, Australia 5
Respiratory Environmental Health, Telethon Kids Institute, The
University of Western Australia, Perth, WA 6008, Australia 1
Department of Infrastructure Engineering, Melbourne School of
Engineering, The University of Melbourne, Melbourne, VIC 3010,
Australia Air Qual Atmos Health (2018) 11:365–371 366 Americans diagnosed with asthma or an asthma-like condition
(26.8%), Steinemann (2017b) found that 64.3% report one or
more types of adverse health effects, including respiratory
problems (43.3%), migraine headaches (28.2%), and asthma
attacks (27.9%), when exposed to fragranced consumer prod-
ucts. Another recent study showed that 3.8% of all work-
related asthma cases reported in California between 1993
and 2012 were associated with fragranced product exposure,
with the majority attributed to perfume or scented body prod-
ucts (Weinberg et al. 2017). Earlier studies found a higher
prevalence of adverse health effects due to air freshener or
deodorizer exposure among asthmatics (37.2%) than in the
general population (20.5%), along with a higher rate of in-
crease among asthmatics (7.5% compared with 3.0% over
3 years, 2002–2003 to 2005–2006) (Caress and Steinemann
2009). products, associated effects on health, effects on work and qual-
ity of life, awareness of fragranced product ingredients and
labeling, and preferences for fragrance-free environments. The survey contained 35 questions (outlined in the
Supplementary Material), each on its own page, with multiple
choice and open format response categories. Categories of
fragranced products evaluated in the survey included air fresh-
eners and deodorizers, personal care products, cleaning sup-
plies, laundry products, household products, and fragrances. p
y p
p
g
Drawing upon a large panel of over 200,000 Australian
participants held by Survey Sampling International (SSI),
the survey was conducted in June 2016 with 1098 adult (ages
18 to 65) Australians, representative of age, gender, and re-
gion (confidence limit = 95%, margin of error = 3%). SSI is a
survey research company and online panel provider. Participant recruitment followed a randomized process, and
all responses were anonymous. Survey completion time was
approximately 10 min. Statistical analyses The primary objective of this study was to determine the
prevalence and types of health and societal effects associated
with exposure to fragranced products in the Australian popu-
lation, with a focus on individuals with medically diagnosed
asthma or an asthma-like condition. Steinemann (2017a) re-
ports results from the general population survey of
Australians, including both asthmatics and non-asthmatics,
finding that 33% of Australians report adverse effects. This
paper extends and enriches those results by investigating the
effects specifically on the sub-population of asthmatics, and
comparing them with non-asthmatics. Descriptive statistics and cross tabulations, calculated using
GraphPad Prism v6.07 (GraphPad Software Inc.), determined
the prevalence of outcomes by different sub-populations and
demographics. Chi-squared (χ2) analyses with Yates’ correc-
tion, also calculated using GraphPad Prism v6.07, compared
the proportion of asthmatics with the proportion of non-
asthmatics who answered “yes” to survey questions to deter-
mine whether a statistically significant difference exists. Prevalence odds ratios (PORs) were calculated to measure
the strength of the association between reported health effects
and asthmatics versus non-asthmatics to determine whether
asthmatics are proportionally more affected than non-asth-
matics. All χ2 and prevalence odds ratio analyses were con-
ducted using a 95% confidence level or confidence intervals. Further details on methodology and survey data are provided
in the Supplementary Material. * Anne Steinemann
anne.steinemann@unimelb.edu.au No personal information was linked to
the survey results, and data were stored on password-protected
computers. Additional details on survey data and methodolo-
gy, including the Checklist for Reporting Results of Internet
E-Surveys (CHERRIES, Eysenbach 2004), are provided in
the Supplementary Material. Fragranced consumer products emit numerous volatile or-
ganic compounds (Steinemann 2015), and a single “fra-
grance” in a product is typically a mixture of several dozen
to several hundred chemicals (Bickers et al. 2003). However,
ingredients in fragranced consumer products do not need to be
fully disclosed to the public on either the label or safety data
sheet (Lunny et al. 2017). If any ingredients are disclosed,
they typically represent fewer than 10% of all ingredients
detected in product analyses (e.g., Uhde and Schulz 2015;
Steinemann 2017c; Steinemann et al. 2011). For instance,
Steinemann (2015) found more than 156 volatile organic com-
pounds emitted from 37 fragranced consumer products, the
most common being terpenes (e.g., limonene, alpha-pinene,
and beta-pinene). However, of over 550 volatile ingredients
emitted collectively, including hazardous air pollutants (e.g.,
formaldehyde), fewer than 3% were disclosed on the product
labels, safety data sheets, or websites. Further, even the so-
called green, organic, and natural fragranced products emitted
hazardous air pollutants, similar to regular fragranced prod-
ucts (Steinemann 2015). Out of 1098 participants, 313 (28.5%) answered “yes” to
being medically diagnosed by a doctor or healthcare profes-
sional as having asthma or an asthma-like condition. For brev-
ity, these participants will hereafter be referred to as “asth-
matics,” and the other 785 respondents (71.5%) will be re-
ferred to as “non-asthmatics.” Demographics of the survey
respondents are shown in Table 1. Results are summarized
below in four main sections: health problems associated with
exposure, effects of exposure on work and quality of life,
awareness of product emissions, and preferences for
fragrance-free environments. Health problems associated with exposure Virtually all respondents are exposed to fragranced products at
least once a week through their own use (99% for asthmatics,
97.6% for non-asthmatics), others’ use (92.3% for asthmatics,
86.4% for non-asthmatics), or both (99.7% for asthmatics,
98.1% for non-asthmatics). More than half (55.6%) of asthmatics reported health prob-
lems from exposure to one or more types of fragranced prod-
ucts, compared with approximately one quarter (23.9%) of
non-asthmatics (χ2 = (1, N = 1098) = 97.13, p < 0.001)
(Table 2 and Supplementary Material). Significantly, 24.0%
of asthmatics reported that exposure to a fragranced product
was associated with an asthma attack. Results Both asthmatics and non-asthmatics reported health prob-
lems when exposed to air fresheners or deodorizers (33.9% for
asthmatics and 9.4% for non-asthmatics), scented laundry
products coming from a dryer vent (12.1% and 3.7%, respec-
tively), being in a room after it has been cleaned with scented
products (30.7% and 9.2%, respectively), and being near
someone who is wearing a fragranced product (36.1% and
12.7%, respectively), with asthmatics proportionately more
affected than non-asthmatics (POR 3.98; 95% CI 3.01–5.24)
(see Table 3). Key findings of this study are that exposure to fragranced
products is ubiquitous in Australian society, that it is associat-
ed with a range of adverse health effects in 33% of the general
population, and that these adverse health outcomes affect asth-
matics (55.6%) more than non-asthmatics (23.9%) (POR 3.98;
95% CI 3.01–5.24). Further, in each category of adverse
health effect investigated in this study, asthmatics are propor-
tionately more affected than non-asthmatics (Table 2). Moreover, asthmatic Australians were more likely to re-
port health problems for each of the 11 categories of ad-
verse health effects investigated in the survey (χ2 = (1, N =
1098) > 14.82, p < 0.001 in all cases) (see Table 2). Respiratory problems (e.g., difficulty breathing, coughing,
or shortness of breath) and mucosal symptoms (e.g., watery
or red eyes, nasal congestion, or sneezing) were the most
frequently reported health problems for both asthmatics
(33.9% and 26.5%, respectively) and non-asthmatics
(9.8% and 9.0%, respectively). Methods Using an online national population survey, cross-sectional data
were obtained on types of exposures to fragranced consumer Air Qual Atmos Health (2018) 11:365–371 367 Asthmatic
(n, %)
Non-asthmatic
(n, %)
Total
313, 100.0%
785, 100.0%
All Males
143, 45.7%
400, 51.0%
All Females
170, 54.3%
385, 49.0%
Male 18–24
16, 5.1%
54, 6.9%
Male 25–34
34, 10.9%
75, 9.6%
Male 35–44
33, 10.5%
86, 11.0%
Male 45–54
34, 10.9%
92, 11.7%
Male 55–65
26, 8.3%
93, 11.8%
Female 18–24
26, 8.3%
60, 7.6%
Female 25–34
35, 11.2%
95, 12.1%
Female 35–44
42, 13.4%
95, 12.1%
Female 45–54
41, 13.1%
74, 9.4%
Female 55–65
26, 8.3%
61, 7.8%
Australian Capital Territory
6, 1.9%
14, 1.8%
New South Wales
98, 31.3%
262, 33.4%
Northern Territory
2, 0.6%
5, 0.6%
Queensland
66, 21.1%
151, 19.2%
South Australia
25, 8.0%
60, 7.6%
Tasmania
7, 2.2%
18, 2.3%
Victoria
77, 24.6%
201, 25.6%
Western Australia
32, 10.2%
74, 9.4% Effects of exposure on work and quality of life Fragranced products can also restrict access in society and
impose costs due to their potential to adversely affect health. The survey found 21.4% of asthmatics and 7.6% of non- Air Qual Atmos Health (2018) 11:365–371 368 Table 2 Prevalence and types of
health problems reported by
individuals who experienced
adverse health effects associated
with exposure to fragranced
products
Asthmatic
Non-asthmatic
POR (95% CI)
Prevalence (n)
Percent
Prevalence (n)
Percent
Respiratory problems
106
33.9
77
9.8
4.71 (3.38–6.56)
Mucosal symptoms
83
26.5
71
9.0
3.63 (2.56–5.15)
Skin problems
52
16.6
52
6.6
2.81 (1.86–4.23)
Migraine headaches
53
16.9
57
7.3
2.60 (1.74–3.88)
Asthma attacks
75
24.0
8
1.0
30.61 (14.55–64.36)
Neurological problems
28
8.9
21
2.7
3.57 (1.98–6.40)
Cognitive problems
27
8.6
18
2.3
4.02 (2.18–7.42)
Gastrointestinal problems
21
6.7
15
1.9
3.69 (1.88–7.26)
Cardiovascular problems
21
6.7
12
1.5
4.63 (2.25–9.54)
Immune system problems
24
7.7
12
1.5
5.35 (2.64–10.84)
Musculoskeletal problems
18
5.8
11
1.4
4.29 (2.00–9.20)
Other
5
1.6
16
2.0
0.78 (0.28–2.15)
Total
174
55.6
188
23.9
3.98 (3.01–5.24) asthmatics are unable or reluctant to use the restrooms in a
public place, because of the presence of an air freshener, de-
odorizer, or scented product (χ2 = (1, N = 1098) = 40.1,
p < 0.0001). In addition, 20.8% of asthmatics and 6.1% of
non-asthmatics are unable or reluctant to wash their hands
with soap in a public place if the soap is fragranced
(χ2 = (1, N = 1098) = 50.46, p < 0.0001). Further, 31.9% of
asthmatics and 8.3% of non-asthmatics had been prevented
from going to some place, because they would be exposed
to a fragranced product that would make them sick
(χ2 = (1, N = 1098) = 96.33, p < 0.0001). Upon entering a
business where they could smell air fresheners or a fragranced
product, 31.0% of asthmatics and 11.0% of non-asthmatics
wanted to leave as quickly as possible (χ2 = (1, N = 1014) =
63.24, p < 0.0001). In the workplace, 18.2% of asthmatics and
3.6% of non-asthmatics have lost workdays or a job, in the
past 12 months, due to exposure to fragranced products in
their work environment (χ2 = (1, N = 1098) = 65.16,
p < 0.001). Thus, in each of these exposure situations, asth-
matics were significantly more likely to report adverse effects
than non-asthmatics. Preferences for fragrance-free environments Fragrance-free environments received widespread support
from both asthmatics and non-asthmatics (Table 4). More than
half of asthmatics (50.5%) and nearly half of non-asthmatics
(39.7%) would support a fragrance-free policy in the work-
place, representing almost twice as many that would not sup-
port a policy (χ2 = (1, N = 714) = 6.921, p = 0.008). Nearly
half of both asthmatics (50.2%) and non-asthmatics (40.4%)
would prefer that healthcare facilities and healthcare profes-
sionals were fragrance-free (χ2 = (1, N = 751) = 1.779, p =
0.182). A majority of asthmatics (62.6%) and non-
asthmatics (55.8%) would prefer an airplane without scented
air pumped through the passenger cabin, representing over
three times as many that would prefer unscented air to scented
air (χ2 = (1, N = 813) = 0.082, p = 0.773). A majority of asth-
matics (60.1%) and non-asthmatics (53.8%) would prefer a
hotel without scented air, representing over twice as many that
would prefer unscented air to scented air (χ2 = (1, N = 714) =
0.124, p = 0.724). Effects of exposure on work and quality of life the product label or material safety data sheet (χ2 = (1, N =
1098) = 0.3577, p = 0.550). Similarly, most asthmatics
(70.3%) and non-asthmatics (75.0%) did not know that
fragranced products, even those called natural, green or organ-
ic, typically emit hazardous air pollutants (χ2 = (1, N =
1098) = 2.358, p = 0.125). Importantly, more than half of asth-
matics (60.1%) and of non-asthmatics (54.8%) would not con-
tinue to use a fragranced product if they knew it emitted haz-
ardous air pollutants (χ2 = (1, N = 1098) = 2.332, p = 0.127). Thus, asthmatics and non-asthmatics were similarly unaware
of fragranced product emissions of hazardous air pollutants
and would similarly cease use of a fragranced product if they
were aware of such emissions. asthmatics are unable or reluctant to use the restrooms in a
public place, because of the presence of an air freshener, de-
odorizer, or scented product (χ2 = (1, N = 1098) = 40.1,
p < 0.0001). In addition, 20.8% of asthmatics and 6.1% of
non-asthmatics are unable or reluctant to wash their hands
with soap in a public place if the soap is fragranced
(χ2 = (1, N = 1098) = 50.46, p < 0.0001). Further, 31.9% of
asthmatics and 8.3% of non-asthmatics had been prevented
from going to some place, because they would be exposed
to a fragranced product that would make them sick
(χ2 = (1, N = 1098) = 96.33, p < 0.0001). Upon entering a
business where they could smell air fresheners or a fragranced
product, 31.0% of asthmatics and 11.0% of non-asthmatics
wanted to leave as quickly as possible (χ2 = (1, N = 1014) =
63.24, p < 0.0001). In the workplace, 18.2% of asthmatics and
3.6% of non-asthmatics have lost workdays or a job, in the
past 12 months, due to exposure to fragranced products in
their work environment (χ2 = (1, N = 1098) = 65.16,
p < 0.001). Thus, in each of these exposure situations, asth-
matics were significantly more likely to report adverse effects
than non-asthmatics. Discussion would not use a fragranced product if they knew it emitted
hazardous air pollutants. This indicates that many Australians
may be using fragranced products without their awareness of
exposures. However, products without a fragrance are widely
available, and offer a practical option to reduce risks for people
adversely affected by fragranced products. Results revealed that nearly all asthmatics used a fragranced
product (99.0%) or were involuntarily exposed to others’ use
of fragranced products (92.3%), or both (99.7%), at least once
a week. Thus, the potential for exposure is widespread, espe-
cially from involuntary exposure. These results are similar to a
nationally representative US population study (Steinemann
2016) showing widespread exposure to fragranced products
from own use (98.3%), others’ use (92.1%), or both (99.1%)
(χ2 = (1, N = 618) = 0.003, p = 0.955). Our results indicate that over half of asthmatics (55.6%),
and almost one quarter of non-asthmatics (23.9%), reported
one or more types of adverse health effects associated with
exposure to one or more types of fragranced products. Asthmatics were more likely to experience adverse health ef-
fects from fragranced products (POR 3.98; 95% CI 3.01–5.24),
regardless of the type of adverse effect (Table 2). Commonly,
asthmatics experienced respiratory problems (POR 4.71; 95%
CI 3.38–6.56) and mucosal symptoms (POR 3.63; 95% CI
2.56–5.15) after exposure to a fragranced product. Similarly,
among Americans, asthmatics were more likely to experience
adverse health effects from fragranced products than non-
asthmatics (POR 5.76; 95% CI 4.34–7.64) (Steinemann
2017a). Also, in two nationally representative studies in the
USA, Caress and Steinemann (2009) found 29.7 and 37.2%
of asthmatics (in 2002–2003 and 2005–2006, respectively) An individual’s ability to avoid exposure to fragranced
products can also depend on their awareness of product emis-
sions. As prior work has demonstrated (Steinemann 2015;
Lunny et al. 2017), ingredients in fragranced products are not
fully disclosed, making it nearly impossible for the public to
make informed decisions. This problem is exacerbated because
even if products did list all their ingredients, we lack informa-
tion on which chemicals, mixtures, or reaction products could
be associated with the reported adverse effects. Awareness of product emissions Overall, the majority of asthmatics and non-asthmatics were
unaware of potentially hazardous chemicals emitted from
fragranced products, even ones called green or organic, and
would not continue to use a fragranced product if they knew it
emitted these pollutants. Nearly half of asthmatics (42.2%)
and non-asthmatics (49.2%) were not aware that a “fragrance”
in a product is a mixture of several dozen to several hundred
chemicals (χ2 = (1, N = 1098) = 4.123, p = 0.042). Most asth-
matics (67.1%) and non-asthmatics (69.2%) were not aware
that fragrance chemicals do not need to be fully disclosed on Air Qual Atmos Health (2018) 11:365–371 369 Discussion
would not use a fragranced product if they knew it emitted
h
d
i
ll t
t
Thi i di
t
th t
A
t li
Table 3 Percentage of
individuals who experienced
adverse health effects associated
with four types of exposure to
fragranced products. AF = air
fresheners or deodorizers, LP =
scent of laundry products coming
from a dryer vent, CP = being in a
room after it has been cleaned
with scented products, FP = being
near someone wearing a
fragranced product
Asthmatic
Non-asthmatic
AF
LP
CP
FP
AF
LP
CP
FP
Respiratory problems
20.8
5.1
16.6
18.2
4.5
1.5
3.8
4.3
Mucosal symptoms
13.7
4.2
13.1
15.7
3.2
0.5
3.2
4.8
Skin problems
9.3
4.8
5.1
4.2
3.1
1.0
1.9
0.8
Migraine headaches
9.9
2.2
7.0
7.3
1.9
0.9
2.0
3.9
Asthma attacks
14.1
4.5
8.3
10.5
0.6
0.1
0.1
0.5
Neurological problems
5.8
2.6
4.2
4.8
0.8
0.0
0.5
1.4
Cognitive problems
4.5
2.6
4.2
3.5
0.9
0.4
0.9
0.8
Gastrointestinal problems
3.8
3.2
4.2
2.2
0.5
0.4
0.4
1.1
Cardiovascular problems
4.2
4.2
3.8
2.9
1.0
0.3
0.3
0.5
Immune system problems
4.2
5.1
4.2
3.8
0.9
0.5
0.6
0.3
Musculoskeletal problems
3.5
2.9
2.6
3.5
0.9
0.1
0.4
0.3
Other
0.0
0.0
0.6
0.6
0.8
0.3
0.6
0.9
Total
33.9
12.1
30.7
36.1
9.4
3.7
9.2
12.7 Discussion In this study, a
majority of asthmatics and non-asthmatics were unaware of the
potentially hazardous ingredients in fragranced products, and Table 4
Percentage of individuals who prefer fragrance-free environments
Asthmatic
Non-asthmatic
Yes
No
Neutral/not sure
Decline
to answer
Yes
No
Neutral/not sure
Decline
to answer
Fragrance-free workplaces
50.5%
18.5%
31.0%
0.0%
39.7%
23.7%
36.2%
0.4%
Fragrance-free healthcare facilities
and healthcare professionals
50.2%
24.9%
24.6%
0.3%
40.4%
25.4%
33.8%
0.5%
Airplanes without scented air
62.6%
18.5%
18.8%
0.0%
55.8%
15.4%
28.5%
0.3%
Hotels without scented air
60.1%
23.3%
16.6%
0.0%
53.8%
22.4%
23.6%
0.3% Table 4
Percentage of individuals who prefer fragrance-free environments Air Qual Atmos Health (2018) 11:365–371 370 reported health problems from air fresheners and deodorizers,
compared with 33.9% of asthmatics in our study. society, that exposure is associated with a range of potentially
serious and adverse health effects, and that these effects are
more common in people with asthma or an asthma-like con-
dition. In addition to the adverse health consequences, expo-
sure to fragranced products imposes significant adverse im-
pacts on workplace productivity and quality of life, including
the ability to access public places such as restrooms. A
straightforward approach to reduce undesirable effects would
be to reduce or avoid use of fragranced products, especially in
public places that would impose involuntary risks, and to im-
plement fragrance-free policies in workplaces, healthcare fa-
cilities, and other environments. In addition to direct impacts on health, fragranced products
can also restrict an individual’s access in society, affect their
lifestyle, and have economic and workplace implications. Our
findings indicate that 18.2% of asthmatics face economic im-
plications through loss of workdays or a job, in the past year,
due to fragranced product exposure in the workplace. Over
twice as many asthmatics and non-asthmatics would support
a fragrance-free policy in the workplace (50.5 and 39.7%,
respectively), compared with those that would not (18.5 and
23.7%, respectively). Acknowledgements We thank Amy Davis, Taylor Williams, and Survey
Sampling International for their valuable contributions to this article. The
study received funding from the Clean Air and Urban Landscapes Hub, at
the University of Melbourne, through the Australia Department of the
Environment and Energy, and through the Commonwealth Scientific
and Industrial Research Organization (CSIRO) Land and Water. Dr. Wheeler’s position was supported by the NHMRC funded Centre for
Research Excellence (Centre for Air Quality and Health Research and
Evaluation, Australia). Discussion Study strengths and limitations Our survey population is rep-
resentative of the Australian population (1098 respondents, 95%
confidence level with a 3% margin of error). The 1098 respon-
dents were randomly recruited from a large Web-based panel
(over 200,000 potential participants). The proportion of respon-
dents who stated they had doctor or healthcare professional di-
agnosed asthma (16.0%) is similar to the proportion (19.0%)
reported in the 2007–2008 National Health Survey (AIHW
2011). Our survey questions were based on a study previously
conducted and published (Steinemann 2017b). Study limitations
include its cross-sectional design, being restricted to adults (18–
65 years), and reliance on self-reported data. The cross-sectional
design means that we are unable to infer temporal associations
between exposures and outcomes. Restricting respondents to
adults between 18 and 65 years of age excludes data on effects
of fragranced products on children and the elderly. Self-reports
are commonly used in survey-based research; however, respon-
dent data were not externally verified. Our lists of potential
health effects were not exhaustive; however, only 1.6% of asth-
matics and 2.0% of non-asthmatics reported health effects “oth-
er” than those included in our lists, suggesting that primary
effects were likely captured. Finally, we lack data on the severity
or frequency of adverse health outcomes, such as whether ex-
posure to a single fragranced product was associated with a
single or multiple health outcomes. Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made. References ABS (2016) Australian Bureau of Statistics. 2016 Census Data for
Australia. http://www.censusdata.abs.gov.au/census_services/
getproduct/census/2016/quickstat/036?opendocument AIHW (2011) Australian Centre for Asthma Monitoring 2011. Asthma in
Australia 2011: with a focus chapter on chronic obstructive pulmo-
nary disease. Asthma series no. 4. Cat. no. ACM 22. Canberra:
AIHW. http://www.aihw.gov.au/publication-detail/?id=
10737420159 In our survey, 28.5% of respondents answered “yes” to having
either doctor or healthcare professional diagnosed asthma
(16.0%), or an asthma-like condition (13.8%), or both. Thus,
the 55.6% of “asthmatics” in our study who report adverse health
effects due to fragranced product exposure would represent over
2.2 million adult Australians (ABS 2016). Combining this with
the 23.9% of “non-asthmatics” (71.5%) who also report adverse
health effects would represent over 4.5 million adult Australians
affected adversely by fragranced consumer products. Andress-Rothrock D, King W, Rothrock J (2010) An analysis of migraine
triggers in a clinic-based population. Headache: The Journal of Head
and Face Pain 50(8):1366–1370 Bickers DR, Calow P, Greim HA, Hanifin JM, Rogers AE, Saurat JH,
Sipes IG, Smith RL, Tagami H (2003) The safety assessment of
fragrance materials. Regul Toxicol Pharmacol 37(2):218–273 Caress SM, Steinemann AC (2009) Prevalence of fragrance sensitivity in
the American population. J Environ Health 71(7):46–50 Dales RE, Cakmak S, Leech J, Liu L (2013) The association between
personal care products and lung function. Ann Epidemiol 23(2):49–
53. https://doi.org/10.1016/j.annepidem.2012.11.006 Elberling J, Linneberg A, Dirksen A, Johansen JD, Frolund L, Madsen F,
Nielsen NH, Mosbech H (2005) Mucosal symptoms elicited by
fragrance products in a population-based sample in relation to atopy
and bronchial hyper-reactivity. Clin Exp Allergy 35(1):75–81 Conclusions Eysenbach G (2004) Improving the quality of Web surveys: the checklist
for reporting results of internet E-surveys (CHERRIES). J Med
Internet Res 6(3):e34. https://doi.org/10.2196/jmir.6.3.e34 Results from this study show that voluntary and involuntary
exposure to fragranced products is widespread in Australian Air Qual Atmos Health (2018) 11:365–371 371 Steinemann AC (2009) Fragranced consumer products and undisclosed
ingredients. Environ Impact Assess Rev 29(1):32–38. https://doi. org/10.1016/j.eiar.2008.05.002 Farrow A, Taylor H, Northstone K, Golding J (2003) Symptoms of
mothers and infants related to Total volatile organic compounds in
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Ribeiro DS, Wallace LA (2011) Fragranced consumer products:
Chemicals emitted, ingredients unlisted. Environ Impact Assess
Rev 31(3):328–333 Johansen JD (2003) Fragrance contact allergy. Am J Clin Dermatol 4(11):
789–798 Kumar P, Caradonna-Graham VM, Gupta S et al (1995) Inhalation chal-
lenge effects of perfume scent strips in patients with asthma. Ann
Allergy Asthma Immunol: Off Publ Am Coll Allergy, Asthma
Immunol 75(5):429–433 Steinemann A (2015) Volatile emissions from common consumer prod-
ucts. Air Qual Atmos Health 8(3):273–281 Steinemann A (2016) Fragranced consumer products: exposures and ef-
fects from emissions. Air Qual Atmos Health 9:861–866 Lunny S, Nelson R, Steinemann A (2017) Something in the air but not on
the label: a call for increased regulatory ingredient disclosure for
fragranced consumer products. Univ NSWLaw J 40(4):1366–1391 Steinemann A (2017a) Fragranced consumer products: effects on asth-
matics. Air Qual Atmos Health 1–7 Millqvist E, Löwhagen O (1996) Placebo-controlled challenges with per-
fume in patients with asthma-like symptoms. Allergy 51(6):434–
439 Steinemann A (2017b) Health and societal effects from exposure to
fragranced consumer products. Prev Med Rep 5:45–47 Steinemann A (2017c) Ten questions concerning air fresheners and in-
door built environments. Build Environ 111:279–284 Rastogi SC, Johansen JD, Bossi R (2007) Selected important fragrance
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56(4):201–204 Uhde E, Schulz N (2015) Impact of room fragrance products on indoor air
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18–22 Weinberg JL, Flattery J, Harrison R (2017) Fragrances and work-related
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headaches in migraine patients. Cephalalgia:0333102413495969
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A Comparison of Four Series of CISCO Network Processors
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Zenodo (CERN European Organization for Nuclear Research)
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cc-by
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Sadaf Abaei Senejani1, Hossein Karimi2 and Javad Rahnama3 Sadaf Abaei Senejani1, Hossein Karimi2 and Javad Rahnama3 1Department of Computer Engineering,
Pooyesh University, Qom, Iran
2 Sama Technical and Vocational Training College,
Islamic Azad University, Yasouj Branch, Yasouj, Iran
3 Department of Computer Science and Engineering,
Sharif University of Technology, Tehran, Iran. 1Department of Computer Engineering,
Pooyesh University, Qom, Iran
2 Sama Technical and Vocational Training College,
Islamic Azad University, Yasouj Branch, Yasouj, Iran
3 Department of Computer Science and Engineering,
Sharif University of Technology, Tehran, Iran. KEYWORDS Network processors, Network on Chip, parallel computing ABSTRACT Network processors have created new opportunities by performing more complex calculations. Routers
perform the most useful and difficult processing operations. In this paper the routers of VXR 7200, ISR
4451-X, SBC 7600, 7606 have been investigated which their main positive points include scalability,
flexibility, providing integrated services, high security, supporting and updating with the lowest cost, and
supporting standard protocols of network. In addition, in the current study these routers have been
explored from hardware and processor capacity viewpoints separately. Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 1. INTRODUCTION The expansion of science and different application fields which require complex and time taking
calculations and in consequence the demand for fastest and more powerful computers have made
the need for better structures and new methods more significant. This need can be met through
solutions called “paralleled massive computers” or another solution called “clusters of
computers”. It should be mentioned that both solutions depend highly on intercommunication
networks with high efficiency and appropriate operational capacity. Therefore, as a solution
combining numerous cores on a single chip via using Network on chip technology for the
simplification of communications can be done. The processors of network are analysed in different parts like Intended data rate and applications,
Architecture, Interface, Programmability, Implementation, Cost, and Design wins. But a practical
comparison has not been done among operational equipment of network which uses these
processors. This comparison can be done between one switch from Intel Company and a similar
counterpart in Cisco Company. In the present study the network processors of Cisco Company
will be investigated. Cisco was established in 1984 by a group of computer scientists in Stanford
University. Cisco system is a leader in network for internet. The solutions of Cisco system are
based on internet protocol (IP) which is the basis of internet, developing the activities of
companies, education and training departments, and governmental networks in the world. In
addition, Cisco provides the most extensive solutions for data transfer, and voice and video in
buildings in all universities around the world. Moreover, the solutions of Cisco provide the
possibility of the most efficient performance, security, flexibility, and reliability for private and
governmental networks. [5] DOI:10.5121/acii.2016.3402 11 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Network processor has three different with the old microprocessors [11]: Network processor has three different with the old microprocessors [11]: 1- Instruction set in many network processors is based on RISC instruction set. 2- Network Processor instruction set includes special instructions for manipulating bits,
calculating the CRC, and search operations. 3- In network processor functions some hardware blocks special accelerate packet
processing. 1. INTRODUCTION A network processor (that is harvested from its instruction set architecture), is equally important
to know which level of the network is in the network processor (the same protocol stack); the
levels that can be used in network processors are, are as follows [8]: A network processor (that is harvested from its instruction set architecture), is equally important
to know which level of the network is in the network processor (the same protocol stack); the
levels that can be used in network processors are, are as follows [8]: •
Kernel level, which contains components for high-speed production and
transmission of large amounts of data. The nodes are connected upward to
kernel-level implementation of basic services such as routing, switching and
access control. •
The edge of the network, which forms the core input and output. Core services
are complex and are implemented in higher-speed interfaces, services at this
point, including routing, switching, network flow, and access control features
quality service. •
The access network, which covers all areas of internet delivery. The end user via
campus networks, broadband connections and telephone lines becomes available. At this level, there are different protocols and technology together in a relatively
low speed. Network processors can be used both in speed and technique against different package
management, which are called level and control level. Level data is performed simple tasks, and
more rapid route packets over the network processor spend little time on network, although
management procedures are complex. [6] 2- INVESTIGATION OF FOUR SERIES OF CISCO ROUTERS The engineers of Cisco work on making advanced products and critical technologies of network
and internet like advanced router and switching, voice and image on IP, wireless optical
networks, storing networks, security, band width, and content networks. Cisco not only is an
inventor in technology and leadership of products, it is also regarded a creator regarding the way
of doing businesses. Therefore, this company is a pioneer in using internet and network for
supporting customer, selling products, training, recommendations, and financial issues
management. In the following the four series of cisco routers will be explored in separate sections and all the
characteristics of each one will be investigated. 2.1. SBC CISCO7600 SERIES [7] [2] SBC Cisco7600 series or session border controller (SBC) has been provided based on constant
performance of system and scalability of multimedia and also considering the pioneer market of
the routers of SBC Cisco7600 series. Through combining SBC with layers 2 and 3 in SBC 12 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016
Cisco7600 series, the need for covering networks and independent tools is met and the following
features will be provided: •
Protocol and interaction media •
Routing session •
Routing session •
Hosing NAT and firewall survey •
Security and AAA •
Connecting and optimizing inside and between specific virtual network •
Transcoding media with external media server SBCs do the task of controlling and managing real time of traffic among IP network borders,
signalling, data, voice, and video traffic. As part of these functions, SBC is responsible for
performing required mother IP connection functions for real time communications like accessing
control, Firewall traversal, band with police, accounting, interaction signalling, legal travelling,
and the quality of management services. Security solutions of Cisco consist of the quality of
service and secure virtualizing capacities for facilitating the support of network operations
including voice on IP (VoIP), imaging services, etc. Voip works on phone system. Telephone network is concerned analog sound data (speech). Phone
signal frequency range is almost from 0 to maximum 4 kHz. In many cases, for voice
transmission,changing the analog signal into digital data help us to make lower cost network. To
convert analog signals to digital phone, according to the Nyquist theorem, at least eight Khz
frequency is required and also according to the standard of 8-bit samples per period, to transmit
the digital broadband, the 64Kbps analog telephone line is needed. This broadband digital
telephone transmission is ideally foundation. But the allocation of 64Kbps to transfer each audio
channel requires costly, especially when it is desired network the size of Earth. With advances in
technology, especially in the computer field, new solutions to reduce communication costs were
raised that some of these solutions leads to lower bandwidth requirements on telephone transfer. On the VOIP also different standards for converting sound into digital data have been used that
they need to 64Kbps to 8.3Kbps bandwidth. 2.1. SBC CISCO7600 SERIES [7] [2] Using connector in Cisco 7600 Integrated Switching, not only makes the designing of SBC
scalable for VoIP sessions but also it is appropriate for supporting high band width of video
sessions like telepresence. Moreover, it is suitable for Service provider to service provider and
Service provider to application Service provider. SBC Cisco7600 has unified signalling position
and distributed architecture. We draw a SBE Sisco 7600 plan in figure 1. Supporting industry standard protocol and connector for VoIP and video like session initiation
protocol (SIP) and H.323 are also put in it. In addition, SBC Cisco7600 make possible
transmission support, convergence services of internet for advanced connector networks
(TISPAN IT) which is in H.248 protocol based on performing the distribution of SBC signalling
and media current. 13 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Figure 1. In this diagram adjacencies 1,2,3 have been associated with the respective DBE
locatiopns. the first (double line) call comes in over adjancency 1 and is routed over adjacency 3. the
second (single line) call comes over adjancency 2 and is routed over adjancency 3. the SBE pickes a DBE
from the appropriate location to process the call media. Figure 1. In this diagram adjacencies 1,2,3 have been associated with the respective DBE
locatiopns. the first (double line) call comes in over adjancency 1 and is routed over adjacency 3. the
second (single line) call comes over adjancency 2 and is routed over adjancency 3. the SBE pickes a DBE
from the appropriate location to process the call media. 2.2. VXR CISCO7200 SERIES [10] [1] The potentialities of
using VXR Cisco7200 include: (as shown in figure 2) 14 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 •
Multiprotocol routing of IPv4, IPv6, Internetwork Packet Exchange (IPX), DECnet,
Systems Network Architecture (SNA), etc. •
Multiprotocol routing of IPv4, IPv6, Internetwork Packet Exchange (IPX), DECnet p
g
,
,
g
(
),
,
Systems Network Architecture (SNA), etc. •
Combining IBM SNA with IP of network
•
Security-firewall of stateful. Intrusion Prevention System (IPS), hardware coding for
IPSec, Network Address Translation (NAT) and confirming identities, options and
accounting (AAA)
•
Network Based Application Recognition (NBAR)
•
Supporting data, voice, video and integration
•
Quality of services (QOS)
•
Reflecting the route
•
Multiprotocol Label Switching (MPLS)- provider of functions, virtual private networks
of (MPLS V PN MPLS, layer 2 and 3), QOS in MPLS, and traffic engineering of MPLS
(MPLS-TE)
•
Multicast
•
Mutilpoint dynamic VPNs (DMV PNs) Systems Network Architecture (SNA), etc. •
Combining IBM SNA with IP of network •
Security-firewall of stateful. Intrusion Prevention System (IPS), hardware coding for
IPSec, Network Address Translation (NAT) and confirming identities, options and
accounting (AAA)
•
Network Based Application Recognition (NBAR)
•
Supporting data, voice, video and integration
•
Quality of services (QOS)
•
Reflecting the route •
Security-firewall of stateful. Intrusion Prevention System (IPS), hardware coding for
IPSec, Network Address Translation (NAT) and confirming identities, options and
accounting (AAA) g
•
Multiprotocol Label Switching (MPLS)- provider of functions, virtual private networks
of (MPLS V PN MPLS, layer 2 and 3), QOS in MPLS, and traffic engineering of MPLS
(MPLS-TE)
•
Multicast Figure 2. VXR Cisco7200 series Architecture Figure 2. VXR Cisco7200 series Architecture 2.2. VXR CISCO7200 SERIES [10] [1] VXR Cisco7200 series provides significant adaptability and is suitable for operational programs
which need Gigabit Ethernet, OC3/STM-1 and connecting with exceptional services of IP. The
speed of processing reaches one million packets by using three connectors of Gigabit Ethernet. It
also has huge gradient of adaptor port options and incomparable amount of complicated IP
service capacities. Cisco provides the last generation of integrated services of router like cisco
series of 1800, 2800, and 3800 for applying complex services and operational programs even in
the smallest offices from distance. Final success and positioning such complex operations depend
on installing and running an efficient and scalable system in aggregation points of network. VXR
Cisco7200 is suitable for confronting this challenge and providing clear and ideal programs. The
main positive point of VXR Cisco7200 is its scalability and flexibility. VXR Cisco7200 is normally used for WAN applications, voice on IP (VoIP), security, and
different operational programs of IP and has been extended because of its noticeable routing. Scalability and cost effective supporting from the investment and maximum return of the
investment are properties which enforce any organization to use VXR Cisco7200 series in the
business for the enhancement and reinstall of cisco router. Processor motor of VXR Cisco7200 provides operational power of one Mega packet per second. VXR Cisco7200 can support at least 6 completely modular adaptors. In addition, as the most
powerful platform processing unit, VXR Cisco7200 has price-performance ratio and provides
configurations with high density of 1 mpps processing in one point and cost effective price to the
customers. Through using VPN router coded security of IP (IPsec) and scalability to 280 Megabit
per second for headend can be provided. Security capacities in VXR Cisco7200 include
supporting a stateful firewall (any firewall that performs stateful packet inspection (SPI) or
stateful inspection), prevention from intrusion, access control lists (ACL), and IPsec. Low price
of each input point port in VXR Cisco7200 makes it valuable and let customers to perform
enhancement and reinstall of their equipment in a network with high acceptability level. Moreover, processor based on system architecture in these series of products helps to assure that
new functions can be used fast and easily through updating simple software. 2.3. CISCO ISR 4451-X SERIES [4][3][9] Cisco ISR 4451-X series has an attempt to create a converged infrastructure for a virtual server,
storage and network capacity instead of allocating a series of resources to an special function of
services. In comparison to traditional and old routers and substructure switching, ISR cisco
platform has achieved 40% reduction in operation costs. Cisco ISR 4451-Xseries is a converged
substructure of a platform for creativity which provides global coordination of network,
computation and storing for unprecedented and powerful performance as ALL-IN-ONE with
extraordinary low total costs of ownership (TCO). Cisco ISR 4451-X series consists of the 15 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 solution of integrated services routers (ISR), unified computational system of cisco (UCS cisco)
and switch 24 module of cisco port. These components together have 2 gigabit calculation power,
6 cores processors, 16 gigabit RAM memory and 2 Tribute local storing capacity. They can also
support switching more powerful than Ethernet (+PoE) to achieve advanced industry goals in
cisco. Development process of ISR routers from 50 Mbps to 2 Gbps has been shown in figure 3. Figure 3. ISR routers development Figure 3. ISR routers development This platform has provided noticeable advance in router global architecture with highest
commercial and security dimensions. This model of platform has included the growth and
progressing needs of customers and makes scalability possible in future. In addition, in the future
integrated framework of rapid virtual services is put in cisco for more creativity. The solution of
converged cisco 4451-X is the biggest advance in routing, security, wireless, and calculations in
all-in-one box which can gives complete services like the following: •
Advanced routing
•
Integrated switching with +PoE
•
Secure VPN
•
View and control application (optional)
•
Controlling the route of WAN (optional)
•
Optimizing WAN (optional)
•
Control wireless networks (WLAN) (optional)
•
computing the extension of environment through supporting multi hypervisor •
Advanced routing
•
Integrated switching with +PoE
•
Secure VPN
•
View and control application (optional)
•
Controlling the route of WAN (optional)
•
Optimizing WAN (optional)
•
Control wireless networks (WLAN) (optional)
•
computing the extension of environment through supporting multi hypervisor •
Advanced routing •
Controlling the route of WAN (optional) •
Control wireless networks (WLAN) (optiona Cisco 4451-X provides ideal virtual integrated environment for performing network services in
router without any extra hardware. 2.3. CISCO ISR 4451-X SERIES [4][3][9] When extra calculation power is needed, cisco UCS E-series
adds modular servers to the system. This architecture creates the best method for providing
application programs for giving services to users. 2.4. CISCO 7606 SERIES [12] Cisco 7606 is a router with high performance in an operating system of 6 memories in the edge of
network. In this cisco multiprotocol switching label has been designed for considering the needs
of companies and service providers. These service providers enable the Ethernet carrier to
establish substructures of advanced networks through supporting extensive gradient of IP video
and media player (voice, video, and data) of system programs in both local service markets and
businesses. Through a powerful combination of speed and service in a compact agent, Cisco 7606
is a significant option for various application programs. In the present point of organizational
edge and city network edge (POP), Cisco 7606 series are new standard sets as part of progressing
industry of cisco router. Cisco 7606 with transfer rate of 240 gigabit per second distribution and
total capacitance of 480 gigabit per second provides high performance and reliability for the
processor and feeding resource. Cisco 7606 is flexible and ideal for dealing with application 16 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 programs with high efficiency. Cisco 7606 has high option capacity for supporting various
application programs. In table 1 a comparison of mentioned series in this paper has been
summarized. Table 1: a comparison of cisco series (VXR 7200, SBC7600, ISR 445-X, 7606)
feature
VXR7200
SBC7600
ISR 445-X
7606
Supporting
services
Cost
effective
supporting
Active
Yes
Yes
scalability
Yes
Yes
Yes
Yes
flexibility
Yes
Yes
Yes
Yes
business
Yes
Yes
Yes
Yes
security
Supporting stateful,
prevention
Supporting IPsec
and security
Recognizing
identity, providing
MACsec
Module-IP
(IPsec),
analysis and
identifying
system of
network
Supporting
protocol
IPV4,IPV6,.. initiation session
protocol and
H.323 , H.248
VPN
Using VPN
(+VAM2)
Via layer 3 of
network
Secure VPN
Processing
power
Operational power
of 1 Mpps
Using control
module
6 cores processors,
16 gigabyte
memory
Total power of
480 gigabit per
second
Processing
speed
One million packet
in three ports of
Ethernet gigabit
10 gigabit in each
slot of processing
capacity
Switch module of
24 port, up to 2
gigabit
performance
Transfer rate
up to 24
gigabit per
second
Integrated
services
The last generation
Yes
Rapid integration
services
Yes
QOS
Yes
Yes
Yes
Routing
Multiprotocol
routings
Routing based on
the least cost
advanced
The capacity
of routing,
protection of
processor Table 1: a comparison of cisco series (VXR 7200, SBC7600, ISR 445-X, 7606) Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 Advanced Computational Intelligence: An International Journal (ACII), Vol.3, No.4, October 2016 4. CONCLUSION Network processors are special types of central processing of CPU which are used for network
equipment like routers. They are used for the production of different kinds of network equipment
like network switching, and identifying intrusion system. In this study network processors which
are used in cisco network products have been analysed and compared. Network on a chip (NOC)
is a communication subsystem inside an integrated circuit which connects IP cores in a system on
a chip in network processors. Technology of NOC of network theory and the ways of on a chip
communication has noticeable advances in comparison to links based on gateway. These
improved architectures cause an increase in the speed of computations after 2020 (the end of
Moore’s law). Advanced services of cisco are comprehensive series of professional engineering. In this study, features like supporting network solutions, the highest level of access, quality of
services, security for a special network and returning business and investment through network
with high efficiency in different series of cisco was dealt with. 3. FUTURE WORKS In the future expansion of the Internet of Things, CPU usage also will be greater. Fast
connections with the lowest latency and the highest rate of packet sending is the perfect condition
for each network. Given that in 2020, Moore's Law will come to the end, so it will be very
difficult to make changes to the chip later on. Although methods such as Super pipeline and super
scalar and like that, partly improve the quality of processors in that time. However, due to
finishing increase of processor speed, alternative is use of network processors which has more
cost than a fast processor. Use of distributed network processors can lead to new ways of fast
connections. Also discovering new routing network algorithms can lead to processing with high
speed in the future. 17 REFERENCES [1]
Conlan, P. J. (2009). Cisco Network Professional's Advanced Internetworking Guide (CCNP
Series). John Wiley & Sons. y
[2]
IPSec, V. P. N. (2005). Catalyst 6500 Series Switches and Cisco 7600 Series Routers with IPSec
VPN SPA Module-Security Policy version 1.2. [3]
Headquarters, A. (2014). Cisco Collaboration Systems Release. [4]
Headquarters, A. (2015). Cisco Integrated Services Routers (ISR) 4400 Series Security Target. Headquarters, A. (2015). Cisco Integrated Services Routers (ISR) 4400 Series Security Target. J f
b d M
R fi
M
Kh dk i S
& Ali
d h
Z
(2012)
E
i
f C [4]
Headquarters, A. (2015). Cisco Integrated Services Routers (ISR) 4400 Series Security Target. [5]
Jafarabad, M., Rafie, M., Khodkari, S., & Alizadeh, Z. (2012). Encryption of Compressed
MultiMedia Data. International Journal of Computer Applications, 59(19), 51-55. [6]
Mikurak, M. G. (2003). U.S. Patent No. 6,606,744. Washington, DC: U.S. Patent and Trademark
Offi [5]
Jafarabad, M., Rafie, M., Khodkari, S., & Alizadeh, Z. (2012). Encryption of Compressed
MultiMedia Data. International Journal of Computer Applications, 59(19), 51-55. Mikurak, M. G. (2003). U.S. Patent No. 6,606,744. Washington, DC: U.S. Patent and Trademark
Office. [7]
Mohácsi, J. (2005). IPv6 router configuration. Diunduh tanggal, 20. [8]
Paulin, P. G., Pilkington, C., & Bensoudane, E. (2002). StepNP: A system-level exploration
platform for network processors. IEEE Design & Test of Computers, 19(6), 17-26. [8]
Paulin, P. G., Pilkington, C., & Bensoudane, E. (2002). StepNP: A system-level exploration
platform for network processors. IEEE Design & Test of Computers, 19(6), 17-26. [9]
Radan, M., & Keslassy, I. (2015, April). Tapping into the router's unutilized processing power. In
Computer Communications (INFOCOM) 2015 IEEE Conference on (pp 2569 2577) IEEE [9]
Radan, M., & Keslassy, I. (2015, April). Tapping into the router's unutilized processing power
Computer Communications (INFOCOM), 2015 IEEE Conference on (pp. 2569-2577). IEEE. [10]
Shaikh, F. A., McClellan, S., Singh, M., & Chakravarthy, S. K. (2002). End-to-end testing o
QoS mechanisms. Computer, (5), 80-87. p
[11]
Taylor, M. B., Kim, J., Miller, J., Wentzlaff, D., Ghodrat, F., Greenwald, B., ... & Ma, A. (2002). The Raw microprocessor: A computational fabric for software circuits and general-purpose
programs. IEEE micro, 22(2), 25-35. [12]
Wolchok, S., Wustrow, E., Isabel, D., & Halderman, J. A. (2012). Attacking the Washington, DC
Internet voting system. In Financial Cryptography and Data Security (pp. 114-128). Springer
Berlin Heidelberg. 18 18
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https://aacr.figshare.com/articles/journal_contribution/Supplementary_information_from_Balancing_Efficacy_and_Safety_of_an_Anti-DLL4_Antibody_through_Pharmacokinetic_Modulation/22459589/1/files/39910889.pdf
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Supplementary information from Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation
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Supplementary
Information
Supplemental
Methods
Production
of
anti-‐DLL4
F(ab’)2 Supplementary
Information Production
of
anti-‐DLL4
F(ab’)2 The
IgG-‐containing
harvested
cell
culture
(HCCF)
is
purified
through
a
series
of
chromatographic
steps,
including
immobilized
pepsin
to
generate
purified
anti-‐DLL4
F(ab’)2. The
purified
protein
was
formulated
by
ultrafiltration
and
diafiltration. Anti-‐DLL4
F(ab’)2
was
provided
as
a
single-‐use
liquid
formulation
containing
200
mg
of
anti-‐DLL4
F(ab’)2
per
glass
vial
with
a
protein
formulation
buffered
at
pH
5.5
with
stabilizers. HUVEC
fibrin
gel
bead
assay Details
of
the
assay
have
been
described
previously
(16,
28). In
the
current
study,
conditioned
medium
from
human
skin
fibroblast
(SF)
culture
was
used
instead
of
the
co-‐cultured
SF
cells
on
top
of
the
fibrin
gels. HUVEC
sprouts
were
visualized
by
staining
with
AlexaFluor488-‐phalloidin
(Invitrogen)
and
4',
6-‐
diamidino-‐2-‐phenylindole
(DAPI,
Sigma). Mouse
neonatal
retina
assay Details
of
the
assay
have
been
described
previously
(16). In
brief,
P2
CD1
mice
were
injected
IP
with
PBS,
anti-‐DLL4
IgG1,
or
anti-‐DLL4
F(ab’)2
at
a
dose
of
30
mg/kg
daily. Eyes
were
collected
on
P5,
and
dissected
retinas
were
subjected
to
immunostaining
procedure. Production
of
anti-‐DLL4
F(ab’)2 For
all
efficacy
and
safety
studies
(with
the
exception
of
the
definitive
rat
and
monkey
F(ab’)2
studies
designed
to
enable
first-‐in-‐human
dosing;
Fig. 5
and
6),
anti-‐DLL4
F(ab’)2
material
was
made
as
follows,
using
good
scientific
practices. Previously
purified
anti-‐DLL4
antibody
(YW152F,
Ridgway
et
al
2006)
was
diluted
to
5mg/mL
in
50mM
sodium
citrate
buffer,
pH
3.0,
and
porcine
gastric
mucosa
pepsin
(#P7000;
Sigma-‐Aldrich,
St. Louis,
MO)
was
added
at
a
ratio
of
1:100
(w/w). The
antibody/enzyme
solution
was
incubated
at
37ºC
for
4
hours
without
agitation. The
expected
proteolytic
site
for
pepsin
on
the
anti-‐
DLL4
molecule
is
between
leucine
positions
235
and
236
of
the
heavy
chain
portion
of
the
antibody. The
enzymatic
digest
was
halted
with
the
addition
of
a
5%
volume
of
1.5M
TRIS
buffer
at
pH
8.6,
resulting
in
a
final
pH
8.0. The
antibody
digestion
solution
was
then
filtered
using
a
0.22µm
filter
(#567-‐0020;
Nalgene,
Waltham,
MA)
and
dialyzed
into
20mM
sodium
acetate
buffer,
pH
5.0. The
F(ab’)2
solution
was
then
bound
to
SP
Sepharose
high
performance
resin
(#17-‐1087-‐05;
GE
Healthcare,
Uppsala,
Sweden),
washed
with
4
column
volumes
of
20mM
sodium
acetate,
0.1%
Triton
X-‐114,
and
washed
with
4
column
volumes
of
20mM
sodium
acetate. The
F(ab’)2
was
eluted
from
the
resin
using
a
20
column
volume
0%-‐30%
gradient
of
1M
sodium
chloride
in
20mM
sodium
acetate
and
formulated
into
10mM
histidine
sulfate
buffer,
pH
5.8,
6%
sucrose
and
0.02%
Tween-‐20
(#28320;
Thermo
Scientific,
Rockford,
IL). The
anti-‐DLL4
F(ab’)2
was
correctly
identified
by
mass
spectrometry
at
96208.07
Da
confirming
the
predicted
cleavage
site. For
the
definitive
safety
evaluations
of
anti-‐DLL4
F(ab’)2
in
rat
and
monkey
(Figs. 7,
8),
F(ab’)2
dosing
material
was
made
as
follows,
using
Good
Manufacturing
Practices
(GMP). Anti-‐DLL4
IgG1
was
expressed
by
CHO
cells
grown
in
a
non–serum
containing
chemically
defined
culture
medium,
secreted into
the
cell
culture
fluid,
and
isolated
from
cellular
debris
by
centrifugation. The
IgG-‐containing
harvested
cell
culture
(HCCF)
is
purified
through
a
series
of
chromatographic
steps,
including
immobilized
pepsin
to
generate
purified
anti-‐DLL4
F(ab’)2. The
purified
protein
was
formulated
by
ultrafiltration
and
diafiltration. Anti-‐DLL4
F(ab’)2
was
provided
as
a
single-‐use
liquid
formulation
containing
200
mg
of
anti-‐DLL4
F(ab’)2
per
glass
vial
with
a
protein
formulation
buffered
at
pH
5.5
with
stabilizers. into
the
cell
culture
fluid,
and
isolated
from
cellular
debris
by
centrifugation. Gene
expression
analysis
of
mouse
livers
after
antibody
treatment Following
antibody
treatment,
mouse
livers
were
snap
frozen
for
RNA
analysis. RNA
was
extracted
using
RNeasy
Mini
kit
(Qiagen),
and
2
μg
total
RNA
was
used
to
make
cDNA
using
the
Taqman-‐RT
kit. Gene
expression
was
analyzed
using
20
ng
cDNA,
Taqman
Gene
Expression
Master
Mix
(Applied
Biosystems),
and
gene
specific
Taqman
Gene
Expression
Assays
(Applied
Biosystems)
on
an
Applied
Biosystems
7500
RT-‐PCR
system. Probe
sets
used
for
this
analysis
were
GAPDH,
CD93,
Egfl7,
and
Lgals1. Results
were
normalized
to
GAPDH. Histological
analysis
of
mouse
liver Adult
CD1
mice
were
used
to
assess
the
liver
effect
of
various
anti-‐DLL4
antibodies. Following
completion
of
the
dosing
period,
formalin-‐preserved
liver
tissues
were
evaluated
via
microscopic
anatomic
pathology
using
hematoxylin
and
eosin
(H&E)
staining
by
a
board-‐certified
veterinary
pathologist. Development
of
xenograft
tumor
models 5X106
HM7
cells
were
inoculated
SC
into
8-‐
to
10-‐week-‐old
beige
nude
female
mice. When
the
average
tumor
size
reached
150
mm3
animals
were
sorted
into
groups
consisting
of
8-‐10
mice/group
and
subjected
to
affinity
variants
of
anti-‐DLL4
(LM1
and
HM6)
administration
for
anti-‐tumor
efficacy
evaluations. SW620
colon
carcinoma
tumors
were
maintained
by
serial
SC
transplantation
in
athymic
nude
mice
(nu/nu,
10-‐11
week
old
female
mice,
Harlan). Each
test
mouse
received
a
tumor
fragment
(1
mm3)
implanted
SC
in
the
right
flank. For
Calu-‐6
model,
10X106
tumor
cells
were
inoculated
SC
into
8-‐
to
10-‐week-‐old
beige
nude
female
mice. PK
studies
in
mice,
rats
and
monkeys PK
studies
of
anti-‐DLL4
F(ab’)2
and
IgG1
in
each
species
were
conducted
in
separate
studies. The
PK
study
in
athymic
nude
mice
was
conducted
at
Genentech,
Inc,
while
the
toxicokinetic
studies
in
Sprague-‐
Dawley
rats
and
cynomolgus
monkeys
were
conducted
at
Covance
Laboratories,
Inc. (Madison,
WI). PK
Assay
Method PK
Assay
Method For
rat
and
cyno
monkey
PK
study
samples,
recombinant
human
DLL4
extracellular
domain
(ECD)
was
diluted
to
1
µg/mL
in
carbonate
buffer
pH
9.6
and
added
to
a
96-‐well
high
binding
polystyrene
ELISA
plate
(Nunc
439454),
100
µL
per
well,
and
incubated
overnight
at
4°C. The
plate
was
washed
with
wash
buffer
(PBS/0.05%
Tween
20),
and
then
200
µL
of
assay
buffer
(PBS,
0.5%
BSA,
0.05%
polysorbate
20,
0.05%
ProClin
300,
pH
7.4)
was
added
to
each
well. After
incubation
and
washing,
100
µL
of
diluted
serum
sample
was
added
and
incubated
for
2
hours
at
room
temperature. The
plate
was
washed,
and
captured
antibodies
were
detected
by
adding
100
µL
of
monoclonal
10C4
anti-‐IgG
(GNE
IgG1
framework-‐specific
(50)
HRP
conjugate. After
incubation
and
washing,
signal
was
generated
by
adding
tetramethyl
benzidine
(TMB;
KPL)
and
the
reaction
was
terminated
with
1M
phosphoric
acid. Absorbance
was
measured
at
450
nm
using
620
nm
reference
on
a
Tecan
ELISA
plate
reader. For
mouse
PK
study
samples,
recombinant
human
DLL4
ECD
was
diluted
in
coating
buffer
and
25
µL
per
well
was
added
to
a
384-‐well
ELISA
plate
(Nunc,
Rochester,
NY;
cat
#
464718),
and
incubated
overnight
at
4°C. The
plate
was
washed
with
wash
buffer,
and
then
50
µL
of
blocking
buffer
(PBS,
0.5%
BSA,
0.05%
Proclin
300,
pH
7.4)
was
added
to
each
well. Serum
samples
were
diluted
in
sample
buffer
(PBS
pH
7.4
+
0.5%
BSA
+
10
ppm
Proclin
+
0.05%
Tween
20
+
0.25%
CHAPS
+
5
mM
EDTA
+
0.35M
NaCl). After
plate
was
washed,
25
µL
of
diluted
serum
sample
was
added
onto
the
plate
and
incubated
for
2
hours
at
room
temperature
with
gentle
agitation. The
plate
was
washed,
and
captured
analytes
were
detected
by
25
µL
of
HRP-‐
conjugated
goat
anti-‐human
IgG
F(ab’)2
fragment
specific
or
goat
anti-‐human
IgG,
Fcg
fragment
specific
reagents
(Jackson
ImmunoResearch,
West
Grove,
PA;
cat
#
109-‐036-‐097
for
anti-‐DLL4
F(ab’)2,
and
cat
#
109-‐036-‐098
for
intact
huIgG1). PK
Assay
Method After
incubation
at
room
temperature
for
1
hour
with
gentle
agitation
followed
by
washing,
signal
was
generated
by
adding
25
µL
of
3,3’,5,5’
tetramethylbenzidine
(TMB-‐E);
(Moss,
Inc;
Pasadena,
MD,
cat
TMBE-‐100)
and
the
reaction
was For
mouse
PK
study
samples,
recombinant
human
DLL4
ECD
was
diluted
in
coating
buffer
and
25
µL
per
well
was
added
to
a
384-‐well
ELISA
plate
(Nunc,
Rochester,
NY;
cat
#
464718),
and
incubated
overnight
at
4°C. The
plate
was
washed
with
wash
buffer,
and
then
50
µL
of
blocking
buffer
(PBS,
0.5%
BSA, terminated
with
25mL
of
1M
phosphoric
acid. Absorbance
was
measured
at
450
nm
using
620
nm
as
reference
on
a
MultiSkan
Ascent
(Thermo,
Waltham,
MA)
plate
reader. The
absorbance
values
were
then
analyzed
with
4-‐p
fit
equations
to
calculate
the
concentration. terminated
with
25mL
of
1M
phosphoric
acid. Absorbance
was
measured
at
450
nm
using
620
nm
as
reference
on
a
MultiSkan
Ascent
(Thermo,
Waltham,
MA)
plate
reader. The
absorbance
values
were
then
analyzed
with
4-‐p
fit
equations
to
calculate
the
concentration. Cmax=
maximum
concentration;
AUC0-‐7=
area
under
the
concentration-‐time
curve
during
the
week
following
the
first
dose
administration
(Day
0-‐Day
7). Bridging
Anti-‐Therapeutic
Antibody
(ATA)
Assay
Method g g
‐
p
y
(
)
y
Anti-‐DLL4
F(ab’)2
was
conjugated
to
biotin
(Pierce
Sulfo-‐NHS-‐LC-‐biotin,
Cat
No. 21327)
or
digoxigenin
(Invitrogen
3-‐amino-‐3-‐deoxydigoxigenin
hemisuccinamide,
succinimidyl
ester,
Catalog
No. A2952,
DIG). The
two
conjugates
were
incubated
at
a
concentration
of
2
µg/mL
in
a
1:1
stoichiometric
ratio,
with
serum
sample
or
control,
overnight,
at
room
temperature
on
an
orbital
mixer. 70
µL
of
combined
F(ab’)2-‐DIG
solution
in
assay
buffer
was
added
to
96-‐well
polypropylene
plate
(Corning
Catalog
No. 3365)
with
70
µL
of
diluted
serum
sample. The
reaction
mixture
was
then
transferred
to
a
washed
Streptavidin
High
Bind
plate
(Roche
Catalogue
No. 11989685001)
and
incubated
for
two
hours
at
RT
with
shaking. Bound
antibodies
were
detected
by
adding
100
µL
of
mouse
monoclonal
anti-‐DIG
HRP
conjugate
(125
ng/mL,
Jackson
Catalog
No. 200-‐032-‐156)
to
the
streptavidin
plate. Signal
was
generated
by
adding
tetramethyl
benzidine
(TMB;
Kirkegaard
&
Perry,
Gaithersburg,
MD),
then
the
reaction
was
terminated
with
1M
phosphoric
acid. Absorbance
was
measured
at
450
nm/630
nm
on
a spectrophotometer
(Tecan
Sunrise). Assay
Buffer
was
used
as
a
negative
control
due
to
the
pre-‐existing
anti-‐F(ab’)2
antibodies
observed
in
cynomolgus
monkey
serum. Hyperimmunized
goat
antiserum,
which
had
been
affinity
purified
to
enrich
for
anti-‐drug
CDR
reactivity
(Genentech,
South
San
Francisco,
CA),
was
used
as
a
positive
control. The
anti-‐DLL4
CDR
antibodies
were
added
to
the
assay
buffer
at
750
ng/mL
(low
control)
and
at
125
µg/mL
(high
or
titer
control). Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. Parameter
Anti-‐DLL4
IgG
Anti-‐DLL4
F(ab’)2
Dose
20
mg/kg
10
mg/kg
50
mg/kg
Cmax
(nM)
3493
1600
9160
AUC0-‐7
(day*nM)
13427
276
1500
CL
(mL/day/kg)
8
362
333
Cmax:
maximum
concentration;
AUC
0-‐7:
area
under
the
concentration-‐time
curve
during
the
week
following
first
dose
administration
(Day
0-‐Day
7);
CL:
clearance. Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. Cmax:
maximum
concentration;
AUC
0-‐7:
area
under
the
concentration-‐time
curve
during
the
week
following
first
dose
administration
(Day
0-‐Day
7);
CL:
clearance. Table
S2:
Pharmacokinetic
parameters
for
anti-‐DLL4
F(ab’)2
and
IgG1
in
rat
and
monkey. Cmax=
maximum
concentration;
AUC0-‐7=
area
under
the
concentration-‐time
curve
during
the
week
following
the
first
dose
administration
(Day
0-‐Day
7). le
S2:
Pharmacokinetic
parameters
for
anti-‐DLL4
F(ab’)2
and
IgG1
in
rat
and
monkey. Cmax=
maximum
concentration;
AUC0-‐7=
area
under
the
concentration-‐time
curve
during
the
week
following
the
first
dose
administration
(Day
0-‐Day
7). Cmax=
maximum
concentration;
AUC0-‐7=
area
under
the
concentration-‐time
curve
during
the
week
following
the
first
dose
administration
(Day
0-‐Day
7). Table
S3:
Anti-‐DLL4
F(ab’)
2
mitigates
the
occurrence
of
vascular
neoplasm
in
rats. AUC
0-‐7
(day*nM)
Dose
level
(mg/kg/wk)
Incidence
of
vascular
neoplasms
in
skin
(%)
AUC
0-‐7
(day*nM)
Dose
level
(mg/kg/wk)
Incidence
of
vascular
neoplasms
in
skin
(%)
Anti-‐DLL4
IgG1
Anti-‐DLL4
F(ab’)2
0
0
0
0
0
0
400
1
0
NT
NT
NT
907
3
7
891
10
0
4007
10
27
2710
30
0
10367
30
33
9290
100
0 Table
S3:
Anti-‐DLL4
F(ab’)
2
mitigates
the
occurrence
of
vascular
neoplasm
in
rats. Figure
S1. Generating
and
characterizing
low
affinity
anti-‐DLL4
antibodies. (A)
Sequence
alignment
of
the
original
anti-‐DLL4
IgG1
molecule
(clone
YW152F)
with
mutant
antibodies
(LM1
and
HM6,
shown
in
Fig. 1). (B)
FACS
analysis
of
antibody
binding
to
HUVECs. 2nd
only=
secondary
only
control. Figure
S1. Generating
and
characterizing
low
affinity
anti-‐DLL4
antibodies. (A)
Sequence
alignment
of
the
original
anti-‐DLL4
IgG1
molecule
(clone
YW152F)
with
mutant
antibodies
(LM1
and
HM6,
shown
in
Fig. 1). (B)
FACS
analysis
of
antibody
binding
to
HUVECs. 2nd
only=
secondary
only
control. Figure
S2. Characterization
of
anti-‐DLL4
F(ab’)2
(A)
Anti-‐DLL4
F(ab’)2
caused
a
marked
increase
of
angiogenic
sprouting
and
branching
of
HUVECs
in
fibrin
gels
with
a
similar
potency
relative
to
anti-‐DLL4
IgG1,
indicating
effective
DLL4
pathway
blockade
with
the
F(ab’)2
molecule. HUVEC
sprouts
were
visualized
by
staining
with
DAPI
and
AlexaFluor488-‐phalloidin;
Scale
bar
=
175
mm. (B)
Anti-‐DLL4
F(ab’)2
also
caused
defective
vascular
development
of
neonatal
mouse
retina. Whole-‐mount
retinas
from
P5
mice
were
stained
with
isolectin
B4. Anti-‐DLL4
F(ab’)2
treatment
resulted
a
marked
increase
of
retinal
vascular
density
(isolectin
B4),
similar
to
that
observed
with
anti-‐DLL4
IgG1. Scale
bar
=
500
mm. Figure
S2. Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. Characterization
of
anti-‐DLL4
F(ab’)2
(A)
Anti-‐DLL4
F(ab’)2
caused
a
marked
increase
of Figure
S2. Characterization
of
anti-‐DLL4
F(ab’)2
(A)
Anti-‐DLL4
F(ab’)2
caused
a
marked
increase
of
i
i
ti
d
b
hi
f
HUVEC
i
fib i
l
ith
i
il
t
l ti
t
ti‐ DLL4 Figure
S2. Characterization
of
anti-‐DLL4
F(ab’)2
(A)
Anti-‐DLL4
F(ab’)2
caused
a
marked angiogenic
sprouting
and
branching
of
HUVECs
in
fibrin
gels
with
a
similar
potency
relative
to
anti-‐DLL4
IgG1,
indicating
effective
DLL4
pathway
blockade
with
the
F(ab’)2
molecule. HUVEC
sprouts
were
visualized
by
staining
with
DAPI
and
AlexaFluor488-‐phalloidin;
Scale
bar
=
175
mm. (B)
Anti-‐DLL4
F(ab’)2
also
caused
defective
vascular
development
of
neonatal
mouse
retina. Whole-‐mount
retinas
from
P5
mice
were
stained
with
isolectin
B4. Anti-‐DLL4
F(ab’)2
treatment
resulted
a
marked
increase
of
retinal
vascular
density
(isolectin
B4),
similar
to
that
observed
with
anti-‐DLL4
IgG1. Scale
bar
=
500
mm. Figure
S3. Pharmacokinetic
profile
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
rat
toxicity
studies. Serum-‐
concentration
time
data
in
Sprague–Dawley
rats
for
(A)
anti-‐DLL4
IgG1
using
a
weekly
dosing
schedule
and
(B)
anti-‐DLL4
F(ab’)2
using
a
2
on/5
off
dosing
schedule. Figure
S3. Pharmacokinetic
profile
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
rat
toxicity
studies. Serum-‐
i
i
d
i
S
D
l
f
(A)
i‐ DLL4
I G1
i
kl
d
i
h d l Figure
S3. Pharmacokinetic
profile
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
rat
toxicity
studies. Serum-‐ Figure
S3. Pharmacokinetic
profile
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
rat
toxicity
studies. Serum-‐
concentration
time
data
in
Sprague–Dawley
rats
for
(A)
anti-‐DLL4
IgG1
using
a
weekly
dosing
schedule
and
(B)
anti-‐DLL4
F(ab’)2
using
a
2
on/5
off
dosing
schedule. Figure
S3. Pharmacokinetic
profile
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
rat
toxicity
studies. Serum-‐
concentration
time
data
in
Sprague–Dawley
rats
for
(A)
anti-‐DLL4
IgG1
using
a
weekly
dosing
schedule
and
(B)
anti-‐DLL4
F(ab’)2
using
a
2
on/5
off
dosing
schedule. Figure
S4. Mitigation
of
liver
toxicity
in
mice
with
anti-‐DLL4
F(ab’)2. (A)
Depiction
of
the
experimental
design/dosing
regimens
used
to
compare
the
impact
of
anti-‐DLL4
F(ab’)2
and
IgG1
on
mouse
liver. (B)
Liver
gene
expression
changes
previously
shown
to
be
associated
with
anti-‐DLL4
treatment
were
evaluated
as
a
direct
readout
of
DLL4
pathway
inhibition. Results
are
represented
as
fold
change
in
mRNA
levels
(mean
±
SEM),
n=5/group. Two-‐tailed
unpaired
t
test
was
used
to
calculate
P
values. Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. (C)
Liver
histopathology
was
evaluated
on
Day
40
to
assess
relative
toxicity
of
anti-‐DLL4
F(ab)’2
versus
IgG1
following
intermittent
or
continuous
exposure
at
the
same
cumulative
weekly
dose. Scale
bar=
200
uM. Left
panel,
normal
mouse
liver,
arrow
indicates
the
central
vein. Middle
panel,
minimally
dilated
hepatic
sinusoids
(arrows)
observed
following
F(ab)’2
treatment. Right
panel,
IgG1
induced
a
more
severely
dilated
central
vein
and
hepatic
sinusoids
as
well
as
a
hyperplastic
nodule
(arrow). Figure
S4. Mitigation
of
liver
toxicity
in
mice
with
anti-‐DLL4
F(ab’)2. (A)
Depiction
of
the
experimental
design/dosing
regimens
used
to
compare
the
impact
of
anti-‐DLL4
F(ab’)2
and
IgG1
on
mouse
liver. (B)
Liver
gene
expression
changes
previously
shown
to
be
associated
with
anti-‐DLL4
treatment
were
evaluated
as
a
direct
readout
of
DLL4
pathway
inhibition. Results
are
represented
as
fold
change
in
mRNA
levels
(mean
±
SEM),
n=5/group. Two-‐tailed
unpaired
t
test
was
used
to
calculate
P
values. (C)
Liver
histopathology
was
evaluated
on
Day
40
to
assess
relative
toxicity
of
anti-‐DLL4
F(ab)’2
versus
IgG1
following
intermittent
or
continuous
exposure
at
the
same
cumulative
weekly
dose. Scale
bar=
200
uM. Left
panel,
normal
mouse
liver,
arrow
indicates
the
central
vein. Middle
panel,
minimally
dilated
hepatic
sinusoids
(arrows)
observed
following
F(ab)’2
treatment. Right
panel,
IgG1
induced
a
more
severely
dilated
central
vein
and
hepatic
sinusoids
as
well
as
a
hyperplastic
nodule
(arrow). Figure
S5. Novel
toxicities
identified
with
anti-‐DLL4
F(ab’)2
in
rats. (A)
Normal
lung
in
a
vehicle-‐treated
rat;
pulmonary
small
artery
(arrow). (B)
Hypercellularity
and
hypertrophy
of
muscularis
layer
of
small
pulmonary
artery
(arrow)
in
the
lung
of
a
rat
treated
with
anti-‐DLL4
F(ab’)2
(15
mg/kg/wk;
2
on/5
off
‐
‐ Figure
S5. Novel
toxicities
identified
with
anti-‐DLL4
F(ab’)2
in
rats. (A)
Normal
lung
in
a
vehicle-‐treated
rat;
pulmonary
small
artery
(arrow). (B)
Hypercellularity
and
hypertrophy
of
muscularis
layer
of
small
pulmonary
artery
(arrow)
in
the
lung
of
a
rat
treated
with
anti-‐DLL4
F(ab’)2
(15
mg/kg/wk;
2
on/5
off
schedule). (C)
Normal
lung
and
pulmonary
artery
in
a
vehicle-‐treated
rat
after
an
8-‐week
recovery
period,
including
the
arterial
muscularis
layer
(arrowhead)
and
arterial
adventitial
layer
(arrow). (D)
Reversibility
of
lung
and
pulmonary
artery
lesions
(arterial
muscularis
layer,
arrow)
observed
in
a
rat
treated
with
anti-‐DLL4
F(ab’)2
(50
mg/kg/wk;
2
on/5
off
schedule)
after
an
8-‐week
recovery
period,
with
the
development
of
a
fibrotic
arterial
adventitial
layer
(arrowhead). All
panels
are
representative
H&E
sections
from
the
indicated
dose
group. Table
S1:
Pharmacokinetic
parameters
of
anti-‐DLL4
IgG1
and
F(ab’)2
in
mouse. Figure
S5. Novel
toxicities
identified
with
anti-‐DLL4
F(ab’)2
in
rats. (A)
Normal
lung
in
a
vehicle-‐treated
rat;
pulmonary
small
artery
(arrow). (B)
Hypercellularity
and
hypertrophy
of
muscularis
layer
of
small
pulmonary
artery
(arrow)
in
the
lung
of
a
rat
treated
with
anti-‐DLL4
F(ab’)2
(15
mg/kg/wk;
2
on/5
off
schedule). (C)
Normal
lung
and
pulmonary
artery
in
a
vehicle-‐treated
rat
after
an
8-‐week
recovery
period,
including
the
arterial
muscularis
layer
(arrowhead)
and
arterial
adventitial
layer
(arrow). (D)
Reversibility
of
lung
and
pulmonary
artery
lesions
(arterial
muscularis
layer,
arrow)
observed
in
a
rat
treated
with
anti-‐DLL4
F(ab’)2
(50
mg/kg/wk;
2
on/5
off
schedule)
after
an
8-‐week
recovery
period,
with
the
development
of
a
fibrotic
arterial
adventitial
layer
(arrowhead). All
panels
are
representative
H&E
sections
from
the
indicated
dose
group.
|
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|
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Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals
|
PloS one
| 2,007
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cc-by
| 10,081
|
UCSF
UC San Francisco Previously Published Works
Title
Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals
Permalink
https://escholarship.org/uc/item/46z4x4x5
Journal
PLOS ONE, 2(8)
ISSN
1932-6203
Authors
Stoddart, Cheryl A
Bales, Cheryl A
Bare, Jennifer C
et al.
Publication Date
2007
DOI
10.1371/journal.pone.0000655
Peer reviewed UCSF
UC San Francisco Previously Published Works
Title
Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals
Permalink
https://escholarship.org/uc/item/46z4x4x5
Journal
PLOS ONE, 2(8)
ISSN
1932-6203
Authors
Stoddart, Cheryl A
Bales, Cheryl A
Bare, Jennifer C
et al. Publication Date
2007
DOI
10.1371/journal.pone.0000655
Peer reviewed UCSF
UC San Francisco Previously Published Works
Title
Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals
Permalink
https://escholarship.org/uc/item/46z4x4x5
Journal
PLOS ONE, 2(8)
ISSN
1932-6203
Authors
Stoddart, Cheryl A
Bales, Cheryl A
Bare, Jennifer C
et al. Publication Date
2007
DOI
10.1371/journal.pone.0000655
Peer reviewed UCSF
UC San Francisco Previously Pub
Title
Validation of the SCID-hu Thy/Liv Mouse Mode
Permalink
https://escholarship.org/uc/item/46z4x4x5
Journal
PLOS ONE, 2(8)
ISSN
1932-6203
Authors
Stoddart, Cheryl A
Bales, Cheryl A
Bare, Jennifer C
et al. Publication Date
2007
DOI
10.1371/journal.pone.0000655
Peer reviewed Title
Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals
Permalink
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University of California eScholarship.org Validation of the SCID-hu Thy/Liv Mouse Model with
Four Classes of Licensed Antiretrovirals doi:10.1371/journal.pone.0000655 itation: Stoddart CA, Bales CA, Bare JC, Chkhenkeli G, Galkina SA, et al (2007) Validation of the SCID-hu Thy/Liv Mouse
icensed Antiretrovirals. PLoS ONE 2(8): e655. doi:10.1371/journal.pone.0000655 CA, Bare JC, Chkhenkeli G, Galkina SA, et al (2007) Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes o
S ONE 2(8): e655. doi:10.1371/journal.pone.0000655 PLoS ONE | www.plosone.org INTRODUCTION Academic Editor: Linqi Zhang, AIDS Research Center, Chinese Academy of
Medical Sciences and Peking Union Medical College, China Academic Editor: Linqi Zhang, AIDS Research Center, Chinese Academy of
Medical Sciences and Peking Union Medical College, China Received April 18, 2007; Accepted June 20, 2007; Published August 1, 2007 Copyright: 2007 Stoddart et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited. Funding: This project has been funded in whole or in part with Federal funds
from NIAID, NIH, under contract no. N01-AI-05418. Competing Interests: The authors have declared that no competing interests
exist. Academic Editor: Linqi Zhang, AIDS Research Center, Chinese Academy of
Medical Sciences and Peking Union Medical College, China Validation of the SCID-hu Thy/Liv Mouse Model with
Four Classes of Licensed Antiretrovirals Cheryl A. Stoddart1¤*, Cheryl A. Bales1¤, Jennifer C. Bare1, George Chkhenkeli1¤, Sofiya A. Galkina1¤, April N. Kinkade1, Mary E. Moreno1¤, Jose´ M
Rivera1¤, Rollie E. Ronquillo1¤, Barbara Sloan1¤, Paul L. Black2 1 Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, United States of America,
2 Targeted Interventions Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland, United States of America Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral
efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed
antiretrovirals. Methodology/Principal Findings. Endpoint analyses for quantification of Thy/Liv implant viral load included
ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular
staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow
cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be
productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To
determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two
drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation
antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than
lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies
pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those
used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did
not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-
resistance substitutions. Conclusion. Given the fidelity of such comparisons, we conclude that this highly reproducible mouse
model is likely to predict clinical antiviral efficacy in humans. Citation: Stoddart CA, Bales CA, Bare JC, Chkhenkeli G, Galkina SA, et al (2007) Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of
Licensed Antiretrovirals. PLoS ONE 2(8): e655. INTRODUCTION occurs with both molecular clones and clinical isolates of HIV-1 in
3–5 weeks [12–16]. This depletion includes loss of CD4+CD8+
(double-positive, DP) immature cortical thymocytes and a decrease
in the CD4/CD8 ratio in the thymic medulla. There is evidence
for both indirect, apoptotic destruction of uninfected thymocytes
and
direct
infection
and
destruction
of
CD32CD4+CD82
intrathymic T-progenitor cells, which severely disrupts thymocyte
maturation [17,18]. Infection of human thymus with HIV-1
induces IFN-a secretion from plasmacytoid dendritic cells, which
upregulates MHC class I (MHC-I) expression on DP thymocytes,
where expression is normally low [19]. The SCID-hu mouse model, in which human lymphoid organs are
implanted into severe-combined immunodeficient (SCID) mice, was
designed by McCune et al. [1] to provide a small animal model for
the study of human hematopoiesis. It has also facilitated study of the
pathogenesis of HIV-1 in human hematolymphoid organs [2–7] and
evaluation of anti-HIV-1 compounds in vivo [2,8,9]. In this model,
SCID mice are implanted with a variety of human fetal organs,
including bone, liver, thymus, lymph node, and spleen. The fetal
implants become tolerant of the mouse environment, and re-
ciprocally, growth of the human tissue is permitted by the
immunocompromised status of the recipient SCID mouse [6]. The administration of nucleoside and nonnucleoside reverse
transcriptase (RT) inhibitors to these mice results in dose-dependent The SCID-hu Thy/Liv mouse, first reported by Namikawa et
al. in 1990 [10], is generated by coimplanting human fetal thymus
and liver beneath the mouse kidney capsule. In a highly
reproducible manner, these organs fuse, become vascularized,
and grow into a stable organ termed ‘‘Thy/Liv,’’ reaching a total
mass of 100–3006106 human cells in 18 weeks. The Thy/Liv
implant reproduces the differentiation, proliferation, and function
of human hematopoietic progenitor cells derived from the fetal
liver within the human thymus. The implants possess histologically
normal cortical and medullary compartments that sustain multi-
lineage human hematopoiesis for 6–12 months [10,11], generating
a continuous source of CD4-expressing thymocytes that can serve
as target cells for HIV-1 infection and replication. Importantly for
a model of antiviral chemotherapy, 50–60 SCID-hu Thy/Liv mice
can be made with tissues from a single fetal donor, and the Thy/
Liv implant is amenable to experimental manipulation and
infection with HIV-1. Viruses The following reagents were obtained through the AIDS Research
and Reference Reagent Program, Division of AIDS, NIAID, NIH:
pNL4-3 [38] from Malcolm Martin and HIV-1 Ba-L [39] from
Suzanne Gartner, Mikulas Popovic, and Robert Gallo. A working
stock of NL4-3 was prepared in 293T cells by calcium phosphate
transfection. A T-20-sensitive NL4-3 (NL4-3 D36G) was altered
by site-directed mutagenesis to match the consensus sequence at
amino acid position 36 (aspartic acid replaced by glycine) [40,41]. The R5X4 AZT-resistant clinical HIV-1 isolate JD [42] was
kindly provided by Mike McCune, and the multidrug-resistant
(MDR) R5X4 NY index case isolate [43] by Hiroshi Morhi and
Martin Markowitz. The clinical isolates were prepared and titrated
by limiting dilution in phytohemagglutin-activated peripheral
blood mononuclear cells. The SCID-hu Thy/Liv model has also been employed by us and
by others for in vivo studies of HIV-1 pathogenesis. The roles of HIV-
1 nef [24–26], other accessory genes [24], and the Rev–Rev
responsive element [27] have been explored as well as the expression
of HIV-1 coreceptors (CXCR4 and CCR5) on thymocytes [28,29]
and the effects of coreceptor usage on viral tropism and pathogenesis
[16,28,30–32]. The CXCR4-utilizing (X4) strain NL4-3 replicates
quickly and extensively in thymocytes in the cortex and medulla,
causing significant thymocyte depletion [16]. In contrast, the CCR5-
utilizing (R5) strain Ba-L initially infects stromal cells, including
macrophages, in the thymic medulla without any obvious pathologic
consequences for 3–4 weeks, after which the infection slowly spreads
through the thymocyte populations and results in slowly progressing
thymocyte depletion after 6 weeks. In addition, three R5 viruses
isolated from rapid AIDS progressors lacking X4 strains were much
less pathogenic than NL4-3 in SCID-hu Thy/Liv mice, suggesting
that R5 virus-mediated rapid disease progression is associated with
host, not viral, factors [30]. The lab-adapted LAI/IIIB isolate and its
associated infectious molecular clones (e.g., HXB2) fail to replicate in
Thy/Liv implants, and this impairment has been mapped to
a specific amino acid change in the crown region of V3 in Env
[33,34]. The model has also been used to study immune
reconstitution and recovery of hematopoietic colony-forming activity
in HIV-1-infected implants after treatment of mice with potent
combination antiretroviral therapy [35–37]. Antiretroviral drugs and mouse dosing The antiretroviral drugs lamivudine (3TC), emtricitabine [(–)-
FTC], nevirapine, efavirenz, indinavir, and atazanavir were kindly
supplied by Opendra Sharma and the AIDS Reagent Program. Dosing solutions were prepared in sterile water for injection or
Dulbecco’s phosphate-buffered saline, and groups of 5–8 mice
were treated by oral gavage (200 ml per dose) with an 18-gauge62-
inch feeding needle twice daily at 7:00 AM and 6:00 PM for the
duration of the infection period (2–6 weeks depending on the
HIV-1 isolate). Enfuvirtide (T-20) was purchased from a pharmacy,
prepared in sterile water, and administered by twice-daily
subcutaneous injection (200 ml per dose). * To whom correspondence should be addressed. E-mail: cheryl.stoddart@ucsf.
edu * To whom correspondence should be addressed. E-mail: cheryl.stoddart@ucsf. edu ¤ Current address: Division of Experimental Medicine, Department of Medicine,
University of California at San Francisco, San Francisco, California, United States of
America The Thy/Liv implants support viral replication after inocula-
tion of HIV-1 by direct injection [3], and thymocyte depletion PLoS ONE | www.plosone.org August 2007 | Issue 8 | e655 August 2007 | Issue 8 | e655 1 Validation of SCID-hu Model performed in SCID-hu Thy/Liv mouse cohorts each made with
tissues from a single donor. We observed that the more recent
drugs in each class were significantly more potent than their
predecessors. We conclude from such comparisons with licensed
antiretrovirals that this well-established model is likely to predict
clinical antiviral efficacy in humans for other members of these
classes and possibly other drug classes as well. inhibition of HIV-1 replication, prevention of IFN-a-mediated
MHC-I upregulation, and protection of CD4+ cells within the
implanted human tissue [8,9,20]. The model has been also used to
evaluate new classes of HIV-1 inhibitors, such as bicyclam [21] and
oligonucleotide [22] inhibitors of HIV-1 entry, the nucleoside analog
29-deoxy-39-oxa-49-thiocytidine (dOTC) [20], and an oxime-piper-
idine CCR5 antagonist [23]. This is the first animal model in which
the action of candidate anti-HIV-1 compounds can be tested within
the setting of an intact HIV-1-infected human target organ. MATERIALS AND METHODS We use a standardized protocol described by Rabin et al. [8] for
evaluation of antiviral agents against HIV-1 in the SCID-hu Thy/
Liv mouse model. Drugs can be administered by various routes
(oral, subcutaneous, intraperitoneal, or by mini-osmotic pump)
before or after virus inoculation and continued for 2–6 weeks. Mice are challenged with titrated inocula of various HIV-1
isolates, and endpoint analyses include quantification of viral
protein by p24 ELISA and viral RNA by branched DNA assay,
quantification and isolation of replication-competent virus by
cocultivation after limiting dilution, and assessment of the effects
on human thymocyte subpopulations by flow cytometry [8]. Implantation and inoculation of SCID-hu Thy/Liv
mice Human fetal thymus and liver were obtained through services
provided by a nonprofit organization (Advanced Bioscience
Resources, Alameda, CA) in accordance with federal, state, and
local regulations. Coimplantation of thymus and liver fragments
under the kidney capsule to create SCID-hu Thy/Liv mice and
inoculation of the Thy/Liv implants with HIV-1 was carried out
as described [8,10]. Male C.B-17 SCID (model #CB17SC-M,
homozygous, C.B-Igh-1b/IcrTac-Prkdcscid) mice were obtained at
6–8 weeks of age from Taconic (Germantown, NY), and cohorts
of 50–60 SCID-hu Thy/Liv mice were implanted with tissues
from a single donor. Implants were inoculated 18 weeks after
implantation with 50 ml of stock virus (500–2,000 TCID50) or
RPMI 1640 medium (mock infection) by direct injection after
surgical exposure of the implanted kidney of anesthetized mice. Animal protocols were approved by the UCSF Institutional
Animal Care and Use Committee. Given the potential correlations between virus-host interactions
in the Thy/Liv implant and in humans, we wanted to determine
whether the SCID-hu Thy/Liv mouse model predicts antiretro-
viral efficacy in humans for representatives of all four classes of
currently licensed drugs. Does it, for instance, yield data that
reflect the greater potency of more recently developed drugs than
their first-generation predecessors in each class? In vivo models are
far more stringent than cell culture-based assays for demonstrating
drug activity, particularly in the case of orally delivered drugs as
they must be absorbed by the gastrointestinal tract without
degradation, enter the blood and circulate with sufficient half-lives,
and penetrate solid target organs at concentrations high enough to
be potently efficacious. The greater potency of the second-
generation drugs is likely the result of a combination of greater in
vitro potency and superior pharmacokinetics. In vitro virus-cell
culture systems would likely predict greater potency, but only in
vivo studies can demonstrate sustained plasma half-life or superior
oral bioavailability. To determine such relative potency in vivo,
head-to-head comparisons of two drugs in the same class were PLoS ONE | www.plosone.org Viral load and prophylactic antiviral efficacy are
highly reproducible among mouse cohorts each
made with tissues from a single donor g
The levels of HIV-1 RNA and p24 in the Thy/Liv implants of
untreated- and 3TC-treated SCID-hu Thy/Liv mice were highly
reproducible among seven different mouse cohorts infected with
the same stock of HIV-1 NL4-3 (Figure 1). In seven consecutive
experiments, with mice in a given cohort constructed from human
fetal tissue from a single donor, mean cell-associated HIV-1 RNA
ranged from 5.2–6.3 log10 copies per 106 cells (Figure 1A), and
mean p24 ranged from 640–1,700 pg per 106 cells (Figure 1B). There was also good correspondence between viral RNA and p24 p
g
p
g
p
p
Figure 1. Implant viral loads in untreated- and 3TC-treated SCID-hu Thy/Liv mice are highly reproducible, and 3TC treatment after HIV-1
inoculation is nearly as effective as prophylactic treatment. A, HIV-1 RNA in Thy/Liv implants of untreated mice and mice treated by twice-daily oral
gavage with 3TC at 30 mg/kg per day beginning 1 day before inoculation with NL4-3 (means6SEM) Each experiment was performed in a mouse
cohort made with tissues from a single donor. B, Implant p24 for the same groups as in panel A. C, Implant HIV-1 RNA in mice treated with 3TC
beginning on day 21, day +1, day +3, and day +7 with respect to inoculation with the indicated HIV-1 strains. D, Implant p24 for the same groups as
in panel C. Implants were collected 21 days after inoculation for NL4-3, 14 days for JD, and 42 days for Ba-L. *p#0.05, compared with untreated mice
for 5–7 mice per group. doi:10.1371/journal.pone.0000655.g001 Figure 1. Implant viral loads in untreated- and 3TC-treated SCID-hu Thy/Liv mice are highly reproducible, and 3TC treatment after HIV-1
inoculation is nearly as effective as prophylactic treatment. A, HIV-1 RNA in Thy/Liv implants of untreated mice and mice treated by twice-daily oral
gavage with 3TC at 30 mg/kg per day beginning 1 day before inoculation with NL4-3 (means6SEM) Each experiment was performed in a mouse
cohort made with tissues from a single donor. B, Implant p24 for the same groups as in panel A. C, Implant HIV-1 RNA in mice treated with 3TC
beginning on day 21, day +1, day +3, and day +7 with respect to inoculation with the indicated HIV-1 strains. D, Implant p24 for the same groups as
in panel C. Implants were collected 21 days after inoculation for NL4-3, 14 days for JD, and 42 days for Ba-L. Implant collection and viral load quantification Implant collection and viral load quantification
The Thy/Liv implants were collected from euthanized mice, and
single-cell suspensions were prepared by dispersing the implant
through nylon mesh and processed for p24 ELISA, bDNA assay,
and FACS analysis as described [8,20]. Unless specified otherwise, PLoS ONE | www.plosone August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 2 Validation of SCID-hu Model implants were collected 21 days after inoculation with NL4-3,
14 days after JD inoculation, and 42 days after Ba-L inoculation. Statistical analysis Results are expressed as the mean6SEM for each mouse group. Nonparametric statistical analyses were performed by use of the
Mann-Whitney U test. Data for mice in each group were
compared to those for untreated infected mice, and p values
#0.05 were considered statistically significant. Flow cytometry Implant cells were stained with phycoerythrin cyanine dye CY7-
conjugated anti-CD4 (BD Biosciences, San Jose, CA), phycoerythrin
cyanine CY5.5-conjugated anti-CD8 (Caltag Laboratories, Burlin-
game, CA), allophycocyanin cyanine CY7-conjugated anti-CD3
(eBiosciences, San Diego, CA), and phycoerythrin-conjugated anti-
W6/32 (DakoCytomation, Glostrup, Denmark. Cells were fixed and
permeabilized with 1.2% paraformaldehyde and 0.5% Tween 20,
stained with fluorescein isothiocyanate-conjugated anti-p24 (Beck-
man Coulter, Fullerton, CA), and analyzed on an LSR II (BD
Biosciences). After collecting 100,000 total cell events, percentages of
marker-positive (CD4+, CD8+, and DP) thymocytes in the implant
samples were determined by first gating on a live lymphoid cell
population identified by forward- and side-scatter characteristics and
then by CD3 expression. W6/32-positive mean fluorescence
intensity (MFI) of DP thymocytes was determined, and CD4/CD8
ratios were calculated by dividing the percentage of CD4+ cells by
the percentage of CD8+ cells for each individual implant. Head-to-head comparisons of antiretroviral drugs at
multiple dosage levels show relative potency p
g
p
y
In the course of preclinical antiviral drug development, it is often
important to determine whether a newly discovered agent is more
potent than an existing, perhaps licensed, drug in the same class. To
that end, we produced cohorts of SCID-hu Thy/Liv mice that were
large enough for head-to-head comparisons of two drugs at multiple
(typically three) dosage levels against one virus isolate. When the
nucleoside analogs (–)-FTC and 3TC were compared, (–)-FTC was
more potent at the same dosage levels, with greater reductions in
viral RNA at 30 mg/kg per day (p= 0.035) (Figure 4A) and greater
reductions in p24 at 10 mg/kg per day (p= 0.025) and 30 mg/kg
per day (p = 0.009) (Figure 4B). The p24 levels in mice treated with (–
)-FTC at 30 mg/kg per day were 1% that of mice treated with 3TC
at the same dose (1,300 pg per 106 cells in untreated mice versus
1.2 pg per 106 cells for (–)-FTC and 110 pg per 106 cells for 3TC)
(Figure 4B). Good protection from thymocyte depletion was
observed at all three dosage levels for both drugs (Figure 4C). Viral load and prophylactic antiviral efficacy are
highly reproducible among mouse cohorts each
made with tissues from a single donor In the seven experiments, 3TC treatment beginning 1 day
before virus inoculation reduced HIV-1 RNA in the implants by
1.2–2.1 log10 (94%–99%) (Figure 1A) and p24 by 77%–92%
(Figure 1B) compared to untreated mice in the same experiment. Importantly, HIV-1 NL4-3 replication in these mice was
genetically stable over the 21-day infection period; there was no
evidence of the RT M184V substitution in viral RNA amplified by
RT-PCR and sequenced from 32 of 32 Thy/Liv implants
collected from mice treated with 3TC in these seven experiments
(data not shown). The lack of resistance development is most likely
the result of the limited time before virus-mediated thymocyte
depletion becomes severe enough to limit the number of target
cells available for infection. We view the genetic stability of the
viruses over several weeks as an asset because our results are not
confounded by the rapid development of antiviral resistance,
particularly against drugs for which only one amino acid
substitution is sufficient for high-level resistance. Viral load and prophylactic antiviral efficacy are
highly reproducible among mouse cohorts each
made with tissues from a single donor *p#0.05, compared with untreated mice
for 5–7 mice per group. doi:10.1371/journal.pone.0000655.g001 August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 3 Figure 2. 3TC treatment of HIV-1 JD-infected SCID-hu Thy/Liv mice inhibits viral replication and protects implants from virus-mediated
thymocyte depletion. Mice were treated by twice-daily oral gavage with 3TC at 300 mg/kg per day beginning on day +1 after inoculation, and Thy/
Liv implants were collected 14, 21, and 28 days after inoculation. Antiviral efficacy was assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+
thymocytes (C), and MHC-I expression on DP thymocytes (D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability
Validation of SCID-hu Model Validation of SCID-hu Model Figure 2. 3TC treatment of HIV-1 JD-infected SCID-hu Thy/Liv mice inhibits viral replication and protects implants from virus-mediated
thymocyte depletion. Mice were treated by twice-daily oral gavage with 3TC at 300 mg/kg per day beginning on day +1 after inoculation, and Thy/
Liv implants were collected 14, 21, and 28 days after inoculation. Antiviral efficacy was assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+
thymocytes (C), and MHC-I expression on DP thymocytes (D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability
(F), percentage of DP thymocytes (G), and CD4/CD8 ratio (H) for 3TC-treated mice versus untreated mice (means6SEM). *p#0.05, compared with
untreated mice for 5–7 mice per group. doi:10 1371/journal pone 0000655 g002 August 2007 | Issue 8 | e655 4 Validation of SCID-hu Model thymocytes (Figure 2C), and IFN-a-induced MHC-I expression on
DP thymocytes (Figure 2D), compared to untreated mice at all
three times. Reductions in viral load by 3TC were accompanied
by virtually complete protection of the Thy/Liv implants from
thymocyte depletion, in terms of total cellularity (Figure 2E),
thymocyte viability (Figure 2F), percentage of DP thymocytes
(Figure 2G), and CD4/CD8 ratio (Figure 2H). Flow cytometric
analysis of representative implants obtained 28 days after in-
oculation with HIV-1 JD showed severe depletion of DP and
CD4+ thymocytes in an untreated mouse and nearly complete
protection from thymocyte depletion in one mouse treated with
3TC (Figure 3). means of implants in the same groups (i.e., lowest for untreated
mice in experiment 6 and highest for those in experiments 3 and
5). Postexposure dosing also reduces viral load and
prevents virus-mediated thymocyte depletion Initiation of 3TC treatment 1 or 3 days after NL4-3 inoculation
was nearly as effective at reducing implant viral RNA (Figure 1C)
and p24 (Figure 1D) as was prophylactic treatment with treatment
beginning 1 day before inoculation. This was also true for mice
inoculated with the clinical R5X4 isolate JD and treated with 3TC
beginning 3 days after inoculation. Treatment of mice inoculated
with the R5 isolate Ba-L, which replicates in Thy/Liv implants
with slower kinetics than does X4 HIV-1 NL4-3 [16], was highly
effective at reducing implant viral RNA and p24 even when
initiation was delayed until 7 days after inoculation. In
another
experiment,
the
nonnucleoside
RT
inhibitor
efavirenz was directly compared with nevirapine. Efavirenz was
approximately
10
times
more
potent
than
nevirapine,
as
demonstrated by similar reductions in viral RNA (Figure 5A)
and p24 (Figure 5B) and by thymocyte protection (Figure 5C) in
groups treated with 300 mg/kg per day of nevirapine compared to
30 mg/kg per day of efavirenz. To determine whether postexposure dosing also prevents
thymocyte depletion, SCID-hu mice were inoculated with HIV-
1 JD and treated twice daily with 3TC at 300 mg/kg per day in
a time-course study in which implants were collected at weekly
intervals up to 28 days after inoculation. By that point, the
implants from untreated mice had become severely depleted of
thymocytes. As expected, 3TC-treated mice had significant
reductions in viral RNA (Figure 2A), p24 (Figure 2B), Gag-p24+ Finally, the second-generation protease inhibitor atazanavir was
3–10 times more potent than indinavir in NL4-3-infected SCID- Figure 3. 3TC treatment protects HIV-1 JD-infected Thy/Liv implants from thymocyte depletion. Flow cytometric analysis of representative
implants stained for CD4 and CD8 obtained 28 days after inoculation with HIV-1 JD shows severe depletion of DP and CD4+ thymocytes in an
untreated mouse and nearly complete protection from thymocyte depletion by 3TC treatment (300 mg/kg per day beginning on day +1 after
inoculation). doi:10.1371/journal.pone.0000655.g003 Figure 3. 3TC treatment protects HIV-1 JD-infected Thy/Liv implants from thymocyte depletion. Flow cytometric analysis of representative
implants stained for CD4 and CD8 obtained 28 days after inoculation with HIV-1 JD shows severe depletion of DP and CD4+ thymocytes in an
untreated mouse and nearly complete protection from thymocyte depletion by 3TC treatment (300 mg/kg per day beginning on day +1 after
inoculation). Figure 3. 3TC treatment protects HIV-1 JD-infected Thy/Liv implants from thymocyte depletion. Postexposure dosing also reduces viral load and
prevents virus-mediated thymocyte depletion Flow cytometric analysis of representative
implants stained for CD4 and CD8 obtained 28 days after inoculation with HIV-1 JD shows severe depletion of DP and CD4+ thymocytes in an
untreated mouse and nearly complete protection from thymocyte depletion by 3TC treatment (300 mg/kg per day beginning on day +1 after
inoculation). doi:10.1371/journal.pone.0000655.g003 doi:10.1371/journal.pone.0000655.g003 PLoS ONE | www.plosone.org August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 5 Validation of SCID-hu Model Figure 4. (–)-FTC is more potent than 3TC against HIV-1 NL4-3 in
SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral gavage
ith 3TC
( ) FTC t 10 30
d 100
/k
d
b
i
i
d
Figure 5. Efavirenz is more potent than nevirapine against HIV-1
NL4-3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
gavage with nevirapine or efavirenz at the indicated dosage levels
Validation of SCID hu Model Figure 4. (–)-FTC is more potent than 3TC against HIV-1 NL4-3 in
SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral gavage
with 3TC or (–)-FTC at 10, 30, and 100 mg/kg per day beginning on day
–1. Antiviral efficacy was assessed by determining HIV-1 RNA (A) and
p24 (B), and thymocyte protection was assessed by percentage of DP
thymocytes (C) (means6SEM). *p#0.05, compared with untreated mice
for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g004
Figure 5. Efavirenz is more potent than nevirapine against HIV-1
NL4-3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
gavage with nevirapine or efavirenz at the indicated dosage levels
beginning on day 21. Antiviral efficacy was assessed by determining
HIV-1 RNA (A) and p24 (B), and thymocyte protection was assessed by
percentage of DP thymocytes (C) (means6SEM). *p#0.05, compared
with untreated mice for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g005 Figure 4. (–)-FTC is more potent than 3TC against HIV-1 NL4-3 in
SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral gavage
with 3TC or (–)-FTC at 10, 30, and 100 mg/kg per day beginning on day
–1. Antiviral efficacy was assessed by determining HIV-1 RNA (A) and
p24 (B), and thymocyte protection was assessed by percentage of DP
thymocytes (C) (means6SEM). *p#0.05, compared with untreated mice
for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g004 Figure 5. Efavirenz is more potent than nevirapine against HIV-1
NL4-3 in SCID-hu Thy/Liv mice. Postexposure dosing also reduces viral load and
prevents virus-mediated thymocyte depletion Inhibitory drug dosage levels are comparable
between SCID-hu Thy/Liv mice and humans
The SCID-hu Thy/Liv mouse has the advantage of having
human, not mouse, cells as the targets of antiretroviral uptake and
action, but the pharmacokinetics of antiretrovirals in the mouse
have the potential to be significantly different from those in
humans Small mammals usually eliminate drugs faster than large
Figure 6. Atazanavir is more potent than indinavir against HIV-1 NL4-
3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
Figure 7. T-20 causes dose-dependent reductions in viral load in HIV-
1 NL4-3 D36G-infected SCID-hu Thy/Liv mice. Mice were treated by
twice-daily subcutaneous injection with T-20 at 10, 30, and 100 mg/kg
per day beginning on day 21. Antiviral efficacy was assessed by
determining cell-associated HIV-1 RNA and p24. Data are expressed as
means6SEM; *p#0.05 for treated mice versus untreated mice by the
Mann-Whitney U test for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g007
Validation of SCID-hu Model Figure 6. Atazanavir is more potent than indinavir against HIV-1 NL4-
3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
gavage with indinavir or atazanavir at 100, 300, and 1000 mg/kg per
day beginning on day 21. Antiviral efficacy was assessed by
determining HIV-1 RNA (A) and p24 (B), and thymocyte protection
was assessed by percentage of DP thymocytes (C) (means6SEM). *p#0.05, compared with untreated mice for the number of mice
indicated under each bar. doi:10.1371/journal.pone.0000655.g006 Figure 7. T-20 causes dose-dependent reductions in viral load in HIV-
1 NL4-3 D36G-infected SCID-hu Thy/Liv mice. Mice were treated by
twice-daily subcutaneous injection with T-20 at 10, 30, and 100 mg/kg
per day beginning on day 21. Antiviral efficacy was assessed by
determining cell-associated HIV-1 RNA and p24. Data are expressed as
means6SEM; *p#0.05 for treated mice versus untreated mice by the
Mann-Whitney U test for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g007 Figure 7. T-20 causes dose-dependent reductions in viral load in HIV-
1 NL4-3 D36G-infected SCID-hu Thy/Liv mice. Mice were treated by
twice-daily subcutaneous injection with T-20 at 10, 30, and 100 mg/kg
per day beginning on day 21. Antiviral efficacy was assessed by
determining cell-associated HIV-1 RNA and p24. Data are expressed as
means6SEM; *p#0.05 for treated mice versus untreated mice by the
Mann-Whitney U test for the number of mice indicated under each bar. Postexposure dosing also reduces viral load and
prevents virus-mediated thymocyte depletion doi:10.1371/journal.pone.0000655.g007 hu mice, with a 3.1 log10 greater reduction in viral RNA
(p = 0.006) with atazanavir than with indinavir at 300 mg/kg per
day (5.3 log10 copies per 106 cells in untreated mice versus ,1.5
log10 copies per 106 cells for atazanavir and 4.6 log10 copies per
106 cells for indinavir) (Figure 6A). The p24 levels in mice treated
with atazanavir at 100 mg/kg per day were 5% (p = 0.029) that of
mice treated with indinavir at the same dose (400 pg p24 per 106
cells in untreated mice versus 19 pg p24 per 106 cells for
atazanavir and 380 pg p24 per 106 cells for indinavir) (Figure 6B). There was comparable protection from thymocyte depletion for
the drugs at 100 and 300 mg/kg per day (Figure 6C). Figure 6. Atazanavir is more potent than indinavir against HIV-1 NL4-
3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
gavage with indinavir or atazanavir at 100, 300, and 1000 mg/kg per
day beginning on day 21. Antiviral efficacy was assessed by
determining HIV-1 RNA (A) and p24 (B), and thymocyte protection
was assessed by percentage of DP thymocytes (C) (means6SEM). T-20 causes dose-dependent reductions in implant
viral load Although we did not perform this experiment as a direct
comparison with another HIV-1 fusion inhibitor, we are including
these data to complete the interspecies scaling analysis described in
the next section with a fourth class of antiretroviral (T-20). Treatment of NL4-3 D36G-infected SCID-hu Thy/Liv mice with
T-20 by twice-daily subcutaneous injection resulted in dose-
dependent reductions of both HIV-1 RNA and p24, reducing viral
RNA by 3.3 log10 copies per 106 cells and p24 to undetectable
levels at 100 and 30 mg/kg per day (Figure 7). Postexposure dosing also reduces viral load and
prevents virus-mediated thymocyte depletion Mice were treated by twice-daily oral
gavage with nevirapine or efavirenz at the indicated dosage levels
beginning on day 21. Antiviral efficacy was assessed by determining
HIV-1 RNA (A) and p24 (B), and thymocyte protection was assessed by
percentage of DP thymocytes (C) (means6SEM). *p#0.05, compared
with untreated mice for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g005 August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 6 Figure 7. T-20 causes dose-dependent reductions in viral load in HIV-
1 NL4-3 D36G-infected SCID-hu Thy/Liv mice. Mice were treated by
twice-daily subcutaneous injection with T-20 at 10, 30, and 100 mg/kg
per day beginning on day 21. Antiviral efficacy was assessed by
determining cell-associated HIV-1 RNA and p24. Data are expressed as
means6SEM; *p#0.05 for treated mice versus untreated mice by the
Mann-Whitney U test for the number of mice indicated under each bar. doi:10.1371/journal.pone.0000655.g007
Validation of SCID-hu Model Validation of SCID-hu Model hu mice, with a 3.1 log10 greater reduction in viral RNA
(p = 0.006) with atazanavir than with indinavir at 300 mg/kg per
day (5.3 log10 copies per 106 cells in untreated mice versus ,1.5
log10 copies per 106 cells for atazanavir and 4.6 log10 copies per
106 cells for indinavir) (Figure 6A). The p24 levels in mice treated
with atazanavir at 100 mg/kg per day were 5% (p = 0.029) that of
mice treated with indinavir at the same dose (400 pg p24 per 106
cells in untreated mice versus 19 pg p24 per 106 cells for
atazanavir and 380 pg p24 per 106 cells for indinavir) (Figure 6B). There was comparable protection from thymocyte depletion for
the drugs at 100 and 300 mg/kg per day (Figure 6C). T-20 causes dose-dependent reductions in implant
viral load
Although we did not perform this experiment as a direct
comparison with another HIV-1 fusion inhibitor, we are including
these data to complete the interspecies scaling analysis described in
the next section with a fourth class of antiretroviral (T-20). Treatment of NL4-3 D36G-infected SCID-hu Thy/Liv mice with
T-20 by twice-daily subcutaneous injection resulted in dose-
dependent reductions of both HIV-1 RNA and p24, reducing viral
RNA by 3.3 log10 copies per 106 cells and p24 to undetectable
levels at 100 and 30 mg/kg per day (Figure 7). DISCUSSION The SCID-hu Thy/Liv mouse is an efficient model for the study of
HIV-1 infection and for the preclinical evaluation of potential
antiretrovirals. Here we show that this model provides a validated
platform for reproducible viral infectivity and drug-mediated
reductions in viral load in vivo. We also show that the model is Table 1. Antiretroviral drug dosage levels adjusted for difference in surface area-to-body weight ratio between mice and humans
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug
Human dosage regimena
Human dosageb
(mg/kg per day)
Mouse equivalent dosagec
(mg/kg per day)
Calculated reduction in implant
HIV-1 RNAd (log10 copies)
3TC
150 mg twice daily
5.0
62
1.9
(–)-FTC
200 mg once daily
3.3
41
2.3
nevirapine
400 mg once daily
6.7
82
0.9
efavirenz
600 mg once daily
10
123
3.7
indinavir
800 mg three times daily
40
490
1.2
atazanavir
400 mg once daily
6.7
82
1.4
T-20
90 mg twice daily
3.0
37
3.2
aFrom ref. [56]. bBased on 60 kg adult human weight and 20 g mouse weight. cHuman dosage612.3 (fold difference in surface area to body weight between mice and humans; from ref. [45,46]. dCalculated by linear regression of the viral RNA data shown in Figures 3–6 at the equivalent mouse dosage level. doi:10.1371/journal.pone.0000655.t001
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibitory drug dosage levels are comparable
between SCID-hu Thy/Liv mice and humans The SCID-hu Thy/Liv mouse has the advantage of having
human, not mouse, cells as the targets of antiretroviral uptake and
action, but the pharmacokinetics of antiretrovirals in the mouse
have the potential to be significantly different from those in
humans. Small mammals usually eliminate drugs faster than large
mammals [44], and toxic endpoints for therapeutics administered
systemically to animals scale well between species when doses are
normalized to body surface area [45]. To determine whether the
doses found inhibitory in the SCID-hu Thy/Liv mouse bear any
relation to those used clinically in humans, an interspecies scaling
factor of 12.3 [46] was applied to generate mouse equivalent doses. Figure 6. Atazanavir is more potent than indinavir against HIV-1 NL4-
3 in SCID-hu Thy/Liv mice. Mice were treated by twice-daily oral
gavage with indinavir or atazanavir at 100, 300, and 1000 mg/kg per
day beginning on day 21. Antiviral efficacy was assessed by
determining HIV-1 RNA (A) and p24 (B), and thymocyte protection
was assessed by percentage of DP thymocytes (C) (means6SEM). *p#0.05, compared with untreated mice for the number of mice
indicated under each bar. doi:10 1371/journal pone 0000655 g006 August 2007 | Issue 8 | e655 August 2007 | Issue 8 | e655 7 PLoS ONE | www.plosone.org Validation of SCID-hu Model This factor reflects the 12.3-fold difference in surface area-to-body
weight ratio between mice (0.0066 m2/0.02 kg) and humans
(1.6 m2/60 kg); consequently, 12.3 times more drug is required in
the mouse to be comparable to the dose in humans. When
currently approved dosage levels for humans of each antiretroviral
drug are adjusted for this difference, the adjusted dosage levels
were similar to those that cause 0.9–3.7 log10 reductions in viral
RNA in the SCID-hu Thy/Liv mouse (Table 1). Thus, not only is
the model predictive of relative potency within these drug classes,
it might also be useful in determining approximate dosing ranges
for effective use in humans. especially valuable for direct, head-to-head comparisons of the
potency and effective dose ranges of existing antiretroviral drugs. In consecutive experiments performed in different SCID-hu
mouse cohorts infected with the same stock of HIV-1 NL4-3, we
observed a range in mean HIV-1 RNA of only 1.1 log10 copies per
106 cells. Reproducible reductions in viral load were also observed
after oral administration of 3TC. Multidrug-resistant NY index case HIV-1 replicates
and depletes thymocytes with kinetics comparable
to HIV-1 NL4-3 A key test of any new class of antiretroviral drug is a demonstration
of potent activity against HIV-1 with known drug-resistance
mutations. We reported the activity of the 3TC analog dOTC
against 3TC-resistant HIV-1 NL4-3/M184V in the SCID-hu
Thy/Liv model [20]. Here we report that the MDR NY index
case HIV-1, which was isolated from a patient with highly rapid
progression to AIDS [43], replicates with kinetics similar to HIV-1
NL4-3 in SCID-hu Thy/Liv mice (Figure 8A–D) resulting in
severe
thymocyte
depletion
by
28 days
after
inoculation
(Figure 8E–H). The lower viral loads for the NY index case
isolate compared to NL4-3 at day 28 are most likely the result of
somewhat faster thymocyte depletion and thus greater loss of
target cells for viral replication. The goal of this study was to validate the SCID-hu Thy/Liv
model for use in drug discovery efforts by determining the efficacy
of different classes of FDA-approved antiretroviral drugs. Antiviral
efficacy in this model is
demonstrated by dose-dependent
reductions in viral load as well as dose-dependent protection of
CD4+ T cells from virus-mediated depletion. Assessment of
thymocyte percentage and viability is particularly important for
proving that the observed antiviral activity is not merely the result
of cytotoxicity to the Thy/Liv implant just as the selectivity index
(ratio of cytotoxic to inhibitory concentration) is important for
assessing antiviral activity in vitro. Additional evidence that HIV-1 replication is genetically stable
within the 28-day infection period was provided by sequence
analysis of implant viral RNA showing that the MDR NY index
case isolate [43] retained the full complement of drug-resistance
amino acid substitutions of the original inoculum (data not shown). These data show that this MDR clinical isolate can readily be used
as a challenge virus in the SCID-hu Thy/Liv model for in vivo
studies of new classes of antiretroviral drugs with activity against
HIV-1 that is resistant to currently licensed antiretrovirals. As new antiretroviral drugs in existing drug classes are
developed to improve upon antiviral potency or to limit in vivo
toxicity, direct comparisons of the existing drug and the new drug
in single SCID-hu mouse cohorts represent a powerful preclinical
tool for the prediction of improved efficacy in human patients. To
accomplish this, we produced cohorts of SCID-hu Thy/Liv mice
that were large enough for comparison of two drugs at three
dosage levels against one virus isolate. Inhibitory drug dosage levels are comparable
between SCID-hu Thy/Liv mice and humans Although our standardized
protocol calls for prophylactic treatment 1 day before virus
inoculation to maximize the potential for discerning antiviral
efficacy of new drugs in initial in vivo tests, we show here that
postexposure drug initiation (beginning 1, 3, or 7 days after HIV-1
inoculation) also renders potent antiviral efficacy. Importantly,
potent therapeutic efficacy, in terms of both inhibition of viral
replication and virtually complete protection from virus-mediated
cytopathicity and thymocyte depletion, was also demonstrated in
3TC-treated mice infected with the highly cytopathic R5X4
isolate, JD. In addition, we have minimized one potential
experimental variable by inoculating the mice at a uniform time
point 18 weeks after implantation. This factor reflects the 12.3-fold difference in surface area-to-body
weight ratio between mice (0.0066 m2/0.02 kg) and humans
(1.6 m2/60 kg); consequently, 12.3 times more drug is required in
the mouse to be comparable to the dose in humans. When
currently approved dosage levels for humans of each antiretroviral
drug are adjusted for this difference, the adjusted dosage levels
were similar to those that cause 0.9–3.7 log10 reductions in viral
RNA in the SCID-hu Thy/Liv mouse (Table 1). Thus, not only is
the model predictive of relative potency within these drug classes,
it might also be useful in determining approximate dosing ranges
for effective use in humans. Multidrug-resistant NY index case HIV-1 replicates
and depletes thymocytes with kinetics comparable
to HIV-1 NL4-3 For studies of viral
pathogenesis and hematopoietic reconstitution, a relatively small
number of animals can generate sufficient replicate points for
analysis. In contrast, preclinical antiviral evaluations require
groups of animals sufficiently large to demonstrate statistical proof
of efficacy in vivo. Two-drug, three-dose comparisons are made
possible by our unique ability to construct large (50–60-mouse)
SCID-hu cohorts with tissues from a single donor, which permits DISCUSSION . . dosage levels adjusted for difference in surface area-to-body weight ratio between mice and humans
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 1. Antiretroviral drug dosage levels adjusted for difference in surface area-to-body weight ratio be
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 8 Validation of SCID-hu Model Figure 8. Multidrug-resistant (MDR) NY index case HIV-1 replicates and depletes thymocytes with kinetics comparable to HIV-1 NL4-3 in SCID-
hu Thy/Liv mice. Viral replication assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+ thymocytes (C), and MHC-I expression on DP thymocytes
(D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability (F), percentage of DP thymocytes (G), and CD4/CD8 ratio
(H) for NL4-3 versus MDR NY index case HIV-1-infected mice (means6SEM). *p#0.05, compared with untreated mice for 7 mice per group. doi:10.1371/journal.pone.0000655.g008
Validation of SCID-hu Model Figure 8. Multidrug-resistant (MDR) NY index case HIV-1 replicates and depletes thymocytes with kinetics comparable to HIV-1 NL4-3 in SCID-
hu Thy/Liv mice. DISCUSSION Viral replication assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+ thymocytes (C), and MHC-I expression on DP thymocytes
(D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability (F), percentage of DP thymocytes (G), and CD4/CD8 ratio
(H) for NL4-3 versus MDR NY index case HIV-1-infected mice (means6SEM). *p#0.05, compared with untreated mice for 7 mice per group. doi:10.1371/journal.pone.0000655.g008 August 2007 | Issue 8 | e655 PLoS ONE | www.plosone.org 9 Validation of SCID-hu Model six or seven dosing groups of 5–8 mice for optimal statistical
power. Given such group sizes and appropriate controls, it is
possible to assign effective antiviral dose ranges with statistical
precision [8]. Among animal models for HIV-1, this ability is
unique: nonhuman primate models (i.e., SIV- or SHIV-infected
rhesus macaques) cannot provide dosing groups of such size and
cannot achieve the same statistical power and relatively lower cost
per animal. There are several recent reports on the infection of
humanized Rag22/2cc2/2 (RAG-hu) [47–50] and NOD/SCID
BLT mice [51] with HIV-1, but there are no reports yet published
on the evaluation of antiretroviral efficacy in these models, and it
has not yet been demonstrated that 50–60 mice can be generated
with the CD34+ hematopoietic stem cells from a single donor. In
a recent review [52], Manz states that one of the challenges these
CD34+-reconstituted mouse models face is that usually less than 10
mice can be transplanted from one human graft. once-daily dosing [55]. Taken together, these comparisons of
licensed antiretrovirals in each major class suggest that the SCID-
hu Thy/Liv model may also predict clinical antiviral efficacy in
humans. These results extend an earlier validation of the model
with the nucleoside analogs zidovudine and dideoxyinosine [8]. The predictive nature of SCID-hu mouse efficacy is further
supported by the dosage levels required to achieve log order
reductions in implant viral load when adjusted for the difference in
surface area-to-body weight ratio between mice and humans. Upon initial examination, the effective dosage level of 1,000 mg/
kg per day for indinavir in the mice seems overly high until such
an adjustment is made and the very high human daily dosage of
2.4 g (800 mg three times a day) is taken into consideration. Predictiveness of the SCID-hu Thy/Liv model for the behavior
of HIV-1 in humans can be extended beyond antiretroviral
efficacy to simple kinetics of viral replication and virus-mediated
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IFN-alpha secretion by type 2 predendritic cells up-regulates MHC class I in the
HIV-1-infected thymus. ACKNOWLEDGMENTS We thank Sandra Bridges for longstanding support of the SCID-hu Thy/
Liv model, Opendra Sharma for supplying multiple-gram quantities of
antiretroviral drugs, Tim Schmidt for performing p24 ELISA, and Mike
McCune for helpful discussions. Author Contributions Conceived and designed the experiments: CS PB. Performed the
experiments: CB JB GC SG AK MM JR RR BS. Analyzed the data:
CS MM RR. Wrote the paper: CS. Conceived and designed the experiments: CS PB. Performed the
experiments: CB JB GC SG AK MM JR RR BS. Analyzed the data:
CS MM RR. Wrote the paper: CS. DISCUSSION AZT-resistant (JD) and MDR NY index case R5X4
clinical isolates replicate and cause thymocyte depletion with
kinetics comparable to HIV-1 NL4-3. The data presented here
show that drug-resistant clinical isolates can readily be used as
challenge viruses in the SCID-hu Thy/Liv model for in vivo studies
of new classes of antiretroviral drugs with activity against HIV-1
that is resistant to currently licensed antiretrovirals. In the experiments presented here, the second-generation
antiretrovirals in each drug class were more potent than their
first-generation predecessors. Thus, (–)-FTC was more potent than
3TC, the nonnucleoside RT inhibitor efavirenz was more potent
than nevirapine, and the protease inhibitor atazanavir was more
potent than indinavir. The greater potency of the newer drugs in
SCID-hu Thy/Liv mice is consistent with their observed greater
potency in HIV-1-infected individuals. The nonnucleoside RT
inhibitor (–)-FTC has greater potency than 3TC because the (–)-
FTC-triphosphate is incorporated 10 times more efficiently than
3TC-triphosphate during HIV-1 RT-catalyzed RNA-dependent
DNA synthesis [53]. The 10-fold greater potency of efavirenz
compared to nevirapine in SCID-hu mice is entirely predictive of
the superior oral bioavailability and plasma half-life characteristics
of efavirenz [54], which allow for once-daily dosing in humans as
the current standard of care compared with twice-daily dosing for
nevirapine. Finally, the greater potency of atazanavir over
indinavir in SCID-hu mice can be explained by a combination
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English
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Pseudo-periodic natural Higgs inflation
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Nuclear physics. B
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cc-by
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I.G. Márián a, N. Defenu b, U.D. Jentschura c,d,e, A. Trombettoni f,g,∗,
I. Nándori a,d,e I.G. Márián a, N. Defenu b, U.D. Jentschura c,d,e, A. Trombettoni f,
I. Nándori a,d,e a University of Debrecen, P.O. Box 105, H-4010 Debrecen, Hungary
b Institut für Theoretische Physik, Universität Heidelberg, D-69120 Heidelberg, Germany
c Department of Physics, Missouri University of Science and Technology, Rolla, MO 65409-0640, USA
d MTA–DE Particle Physics Research Group, P.O. Box 51, H-4001 Debrecen, Hungary
e MTA Atomki, P.O. Box 51, H-4001 Debrecen, Hungary
f CNR–IOM DEMOCRITOS Simulation Center, Via Bonomea 265, I-34136 Trieste, Italy
g SISSA and INFN, Sezione di Trieste, Via Bonomea 265, I-34136 Trieste, Italy Received 26 October 2018; received in revised form 17 March 2019; accepted 15 May 2019
Available online 17 May 2019
Editor: Clay Córdova Editor: Clay Córdova ScienceDirect Nuclear Physics B 945 (2019) 114642 www.elsevier.com/locate/nuclphysb * Corresponding author.
E-mail address: andreatr@sissa.it (A. Trombettoni). https://doi.org/10.1016/j.nuclphysb.2019.114642
0550-3213/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3. 1. Introduction Exponential expansion of the early universe can be explained by cosmic inflation, a theory
which is developed to explain major issues such as the origin of the large-scale structure, the flat-
ness of the universe, the horizon problem, the absence of monopoles and in general properties of
Cosmic Microwave Background Radiation (CMBR) [1]. A very comprehensively studied work
hypothesis is that a hypothetical scalar field, i.e., the inflaton particle, is responsible for inflation
which is caused by the slow-roll motion starting from a metastable false vacuum towards the real
vacuum [2,3]. However, it is still a matter of discussion whether a particle physics mechanism
can be associated to inflation or in general whether we have or not a reliable approach to inflation
[4,5]. The recent detection of the Higgs boson renewed research activity where the inflaton is iden-
tified with the Higgs field. Indeed, it seems to be possible to extrapolate the Standard Model
(SM) of particle physics up to very high energies, and the most “economical” choice would be
to use the same scalar field in order to describe the Higgs and inflationary physics. Nevertheless,
various issues related to Higgs-inflation, like stability of the Higgs potential or the exit from the
inflationary phase, need to be explained. As an example, it was argued in Ref. [6] that the tradi-
tional Higgs inflation can be possible within a minimalistic framework even if the SM vacuum
is not completely stable. Furthermore, the importance of renormalization group (RG) running on
the stability question is highlighted (see, e.g., Refs. [7–9]). One can also mention the possible
relation of the stability problem to unknown new physics, as in Refs. [10,11], where the analysis
is performed in a flat as well as curved spacetime background, showing that new physics can
have a significant impact on the stability condition of the vacuum. There are, however, several drawbacks of Higgs-inflation and in general cosmological infla-
tion, which require further studies and explanation. A serious problem related to the identification
of the Higgs with the inflaton is that a reliable model should work at cosmological as well as elec-
troweak energy scales. Thus, a single model should be used to explain, simultaneously, recent
data on CMBR thermal fluctuations and those measured at the electroweak scale. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3. Abstract Inflationary cosmology represents a well-studied framework to describe the expansion of space in the
early universe, as it explains the origin of the large-scale structure of the cosmos and the isotropy of the
cosmic microwave background radiation. The recent detection of the Higgs boson renewed research activ-
ities based on the assumption that the inflaton could be identified with the Higgs field. At the same time,
the question whether the inflationary potential can be extended to the electroweak scale and whether it
should be necessarily chosen ad hoc in order to be physically acceptable are at the center of an intense de-
bate. Here, we propose and perform the slow-roll analysis of the so-called Massive Natural Inflation (MNI)
model which has three adjustable parameters, the explicit mass term, a Fourier amplitude u, and a fre-
quency parameter β, in addition to a constant term of the potential. This theory has the advantage to present
a structure of infinite non-degenerate minima and is amenable to an easy integration of high-energy modes. We show that, using PLANCK data, one can fix, in the large β-region, the parameters of the model in a
unique way. We also demonstrate that the value for the parameters chosen at the cosmological scale does
not influence the results at the electroweak scale. We argue that other models can have similar properties
both at cosmological and electroweak scales, but with the MNI model one can complete the theory towards
low energies and easily perform the integration of modes up to the electroweak scale, producing the correct
order-of-magnitude for the Higgs mass. * Corresponding author. E-mail address: andreatr@sissa.it (A. Trombettoni). 2 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 1. Introduction Another issue
is, for example, the choice for the inflationary potential which means that there is a plethora of
scalar models available in the literature [12] which all work well at cosmological scales and any
choice of them seems to be ad hoc. Under the assumption of a relation of Higgs and inflationary
physics, the solution for the former problem can automatically represent a solution for the latter,
i.e., the requirement for a scalar potential viable both for inflationary and Higgs physics drasti-
cally reduces the number of admissible proposals. Indeed, a mode integration treatment can help
to relate parameters of a candidate model at both energy scales and it is expected to give us a tool
to reduce the number of viable scenarios for inflation. In order to gain insights on the previous point, an important qualitative issue is provided by the
task of understanding the structure of the inflaton potential. A simple harmonic potential φ2 has a
single minimum which is known as the quadratic large-field inflationary (LFI) potential. One can
add more minima through higher-order powers of the form φ2n. A general question is whether
and how much one has to deviate from the φ2-Gaussian form. In Ref. [13], the “φ2 or not-φ2” is-
sue was tested on the simplest inflationary potential: constraints were obtained and the relevance I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 3 of non-Gaussianity was discussed. From the opposite point of view, a very much “not-φ2” poten-
tial is the one having infinitely many minima, at the same energy. In this logic, one can explore a
periodic potential of a form having infinitely many minima, VNI(φ) = u [1 −cos(βφ)] which is
known as the Natural Inflation (NI) or pseudo-Nambu-Goldstone boson model, while in field the-
ory and condensed matter, it is denoted as the sine-Gordon model [14]. It has also been proposed
and studied as a viable inflationary scenario [15–25] and to construct a convenient scalar sector
by incorporating the periodic scalar axion potential too [25]. It was shown that the NI potential
is able to produce agreement with PLANCK results [26–28] on the thermal fluctuations of the
cosmic microwave background radiation (CMBR) with a better agreement than the simplest LFI
potential [13] and that in d = 4, it has a single phase [25]. 1. Introduction In this paper, we propose and use a relatively simple scalar model which has the advantage of
having an overall φ2 form shifted by a constant and retaining however a structure with infinitely
many minima. We show that the proposed potential (i) is a viable choice for inflation in its
large β limit, and (ii) serves as a possible extension of the SM Higgs potential. The construction
of the potential is based on the so-called massive sine-Gordon model where a term sinusoidal
in the field is added to the standard quadratic mass term; this potential has already received
significant attention in statistical field theory [29–32]. We denote our proposal as the Massive
Natural Inflation (MNI) model, φ) = V0 + 1
2m2φ2 + ucos(βφ),
(1) VMNI(φ) = V0 + 1
2m2φ2 + ucos(βφ), (1) where m is an explicit mass term, u is the Fourier amplitude, β is the frequency, and V0 is a
constant (field-independent) term which is either chosen to be equal to zero or −u or adjusted in
such a way that the global minimum value of the potential is retained at Vmin = VMNI(φmin) =
0. In general, the constant term can also be considered as a free parameter, however, we will
demonstrate that it does not modify the slow-roll analysis (comparison with PLANCK data) in
the large β limit and plays no role in the mode integration. The MNI potential (1) has, indeed,
an infinite number of minima, separated by an amount of energy depending on the ratio of the
coefficients multiplying the two terms, and ranging from the limit of infinite degenerate minima
to a single non-degenerate absolute minimum. Therefore, the MNI model appears to be an excellent candidate for cosmological inflation and
a viable extension for the SM Higgs potential. By mode integration, in the following, we show
that it is possible to relate the parameters of the model at various energy scales (cosmological and
electroweak). The next question is whether this constitutes a unique feature of the MNI model. Alternatively, one might ask if one can find, in general, other scalar models (with at least two
parameters) which have the same properties. 1. Introduction As a partial answer to this question, we observe
that, due to the fact that the studied model has two energy scales (cosmological and electroweak
ones), which are far from each other, it is expected that any suitable theory in the low-energy
(IR) limit (defined here as the electroweak scale) becomes insensitive to its high-energy (UV)
behavior (here understood as the inflationary scale). This is demonstrated by us using the above
mentioned MNI model, and we argue that this is a property shared by a number of related models. We will come back to these points in our conclusions. This paper is organized as follows: In Section 2 we discuss the application of the MNI poten-
tial at cosmological scale, considering the comparison with PLANCK data and studying in detail
the limit of high-frequency (high β). In Section 3, we consider the theory at electroweak scale,
presenting a discussion of the relation between the Higgs mass and the parameters of the MNI
model at low energies. The connection between the cosmological and the electroweak scales us- I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 4 ing the MNI model is detailed in Section 4, where we show explicitly that at low energy, the
theory exhibits UV-insensitivity. The latter is clearly demonstrated by the derivation presented
there, where the UV mass cancels out. Our conclusions are finally presented in Section 5. 2. Cosmological scale Early universe and Higgs physics are examples where scalar fields find a natural role to play in
standard models of cosmology and particle physics. Since scalar fields can mimic the equation of
state required for exponential expansion of the early universe, various types of scalar potentials
have been proposed in inflationary cosmology. The simplest of these scenarios is provided by the
slow-roll single-field models with minimal kinetic terms [12]. A good candidate for an inflation-
ary potential should have a small number of free parameters which serves as the first condition
for a reliable model, and the primary example is the well studied quadratic, LFI potential having
the form V = 1
2 m2φ2. 2
Inflationary models should be as well tested on whether (and how well) they can reproduce
the observed data of various experiments such as the PLANCK mission [26–28], which mea-
sures thermal fluctuations of cosmic microwave background radiation (CMBR). This serves as a
minimal requirement to obtain a viable scenario for the post-inflationary period. We consider, motivated by the reasons exposed in Section 1, the MNI model (1). With the
aim of performing checks on our results, we also consider three variants of the MNI model (1)
provided by V1(φ) = 1
2m2φ2 + ucos(βφ),
V2(φ) = 1
2m2φ2 + u[cos(βφ) −1] ,
V3(φ) = 1
2m2φ2 + ucos(βφ) −Vmin , V1(φ) = 1
2m2φ2 + ucos(βφ),
(2a)
V2(φ) = 1
2m2φ2 + u[cos(βφ) −1] ,
(2b)
V3(φ) = 1
2m2φ2 + ucos(βφ) −Vmin ,
(2c) V1(φ) = 1
2m2φ2 + ucos(βφ),
(2a)
V2(φ) = 1
2m2φ2 + u[cos(βφ) −1] ,
(2b)
V3(φ) = 1
2m2φ2 + ucos(βφ) −Vmin ,
(2c) (2a) (2b) (2c) where Vmin is introduced as an adjustable parameter to keep the global minimum of the potential
at zero. where Vmin is introduced as an adjustable parameter to keep the global minimum of the potential
at zero. 2.1. Slow-roll analysis Comparison of the Planck data with the slow-roll result of the MNI single-field inflationary potential (1) with the
specific choice for the constant term given in Eq. (2b), for N = 55. The best choice for the parameters is that located inside
the green region. The red line corresponds to fitted line starting from the origin. In the inset we report the comparison
for small β of the best acceptance regions (for V2 and V3). (For interpretation of the colors in the figures, the reader is
referred to the web version of this article.) should be in the range 50 < N < 60 where φi and φf are the initial and final values of the vacuum
expectation value (VeV) of the field over inflation. In a (d = 4)-dimensional field theory, the physical dimension of V has to be equal to mass4,
so one can introduce dimensionless variables accordingly. By using an arbitrary scale k which
has the dimension of mass, one has ˜V = V/k4,
˜φ = φ/k,
˜u = u/k4 ,
˜m = m/k,
˜β = kβ :
(5) ˜V = V/k4,
˜φ = φ/k,
˜u = u/k4 ,
˜m = m/k,
˜β = kβ : /
/
k,
˜β = kβ :
(5) (5) In order to obtain, from PLANCK data, the parameters of the MNI model (1), we will work in
reduced Planck units c ≡¯h ≡1 and m2
p ≡1, corresponding to choose k = mp in Eqs. (5). As
routinely done in literature, see e.g. Ref. [33], we also introduce the scalar tilt ns and tensor-to-
scalar ratio r. They are related to the slow-roll parameters by the two relations ns ≈2η −6ϵ + 1
and r ≈16ϵ [33]. From the conditions ϵ(φf,ϵ) = 1 and η(φf,η) = 1, the final value of the field
VeV can be calculated in Eq. (4) as φf ≡max
φf,ϵ,φf,η
. Knowing φf , one can determine its
initial value φi by requiring that the E-fold number should be in the range 50 < N < 60 and then
compute ns(φi) and r(φi). It is clear that the results depend on the chosen form of V : for exam-
ple, the quadratic LFI model gives ns −1 ≈−2/N and r ≈8/N, so, the relation ns −1 +r/4 = 0
holds, which is in turn almost excluded by recent results of the PLANCK mission [26–28]. 2.1. Slow-roll analysis Since we use three different values for the field independent constant, the MNI model (and
its considered variants), in addition to the usual normalization, have two adjustable parameters,
the ratio u/m2 and the frequency β. The remaining two adjustable parameters can be fixed at
cosmological scales by the standard slow-roll analysis where one has to calculate the following
parameters (see e.g., Ref. [33]), ϵ ≡1
2m2
p
V ′
V
2
,
η ≡m2
p
V ′′
V , ϵ ≡1
2m2
p
V ′
V
2
,
η ≡m2
p
V ′′
V ,
(3) (3) with the Planck mass m2
p = 1/(8πG). Inflation is in progress if the conditions ϵ ≪1 and η ≪1,
are fulfilled. If one of these parameters assumes a value on the order of unity, then inflation stops. In order to have a prolonged inflation, the E-fold number N which is defined by with the Planck mass m2
p = 1/(8πG). Inflation is in progress if the conditions ϵ ≪1 and η ≪1,
are fulfilled. If one of these parameters assumes a value on the order of unity, then inflation stops. In order to have a prolonged inflation, the E-fold number N which is defined by p
/(
)
p
g
≪
are fulfilled. If one of these parameters assumes a value on the order of unity, then
In order to have a prolonged inflation, the E-fold number N which is defined by In order to have a prolonged inflation, the E-fold number N which is defined by N ≡−1
m2p
φf
φi
dφ V
V ′ N ≡−1
m2p
φf
φi
dφ V
V ′
(4) (4) I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 5 Fig. 1. Comparison of the Planck data with the slow-roll result of the MNI single-field inflationary potential (1) with the
specific choice for the constant term given in Eq. (2b), for N = 55. The best choice for the parameters is that located inside
the green region. The red line corresponds to fitted line starting from the origin. In the inset we report the comparison
for small β of the best acceptance regions (for V2 and V3). (For interpretation of the colors in the figures, the reader is
referred to the web version of this article.) Fig. 1. 2.1. Slow-roll analysis We performed the described procedure for the potential (1) with various values for the constant
term, with an ensuing comparison to CMBR data, see Appendix A. The results are summarized
in Fig. 1. The inset shows the best acceptance regions in the small ˜β limit (for V2 and V3); these
may depend on the particular choice of V0. However, we have verified, by numerical calculations,
that in the large ˜β limit, each form of the MNI model considered by us gives the same slow-roll
result, i.e., the best acceptance region becomes a straight line which does not depend on the
specific form of the MNI model chosen. This statement holds for the region ˜β ≳1.5 and does 6 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 not change when N is varied between 50 and 60. In general, because of the automatic retention
of the minimum of the potential at zero, and because of the compact functional form, we prefer
the potential V2, but we stress that our results are general. Indeed, the straight line of Fig. 1 does not depend on the particular choice for V0 and a further
free parameter of the model can be fixed by CMBR normalization. In addition, the most important
fact that we evince from Fig. 1 is that the (dimensionless) ratio ˜u ˜β2/ ˜m2 is also fixed. We denote
it by a and we observe that, of course, ˜u ˜β2/ ˜m2 = uβ2/m2. It follows that when one extracts
the MNI parameters from a comparison with experimental PLANCK data, one does not actually
have two free parameters, but just one. In other words, the dark green “tail” (fitted by a red
straight line) of the acceptance figure is a straight line, and the ratio uβ2/m2 remains unchanged
for large β. This points to a kind of universal behavior in the large-frequency limit, i.e., at large β. In the following, we stick to this large-β region, corresponding to small field inflation, leaving a
detailed analysis of small-β region for a future work. We conclude this Section by observing that the slow-roll study of the MNI potential has been
performed preserving its sinusoidal functional form. One could, in principle, truncate the Taylor
expansion of the MNI potential keeping only the constant, quadratic and quartic terms. One may
find good agreement with the Planck data, but it would require a large explicit mass. 2.1. Slow-roll analysis However,
such a large explicit (dimensionful) mass cannot be scaled down to the required value for the
Higgs mass at the electroweak scale. We shall come back on this point in Section 3. 2.2. Unification of scales Based on the slow-roll analysis discussed above, one can fix almost all parameters of the MNI
(1) potential, and there is only a single free parameter left. In this subsection, we show how this
remaining free parameter can be determined by requiring a kind of unification of all scales at the
Grand Unification Theory (GUT) scale k = 2 × 1016 GeV. The relation uβ2/m2 > 1 holds. The dimensionless ratio a = uβ2/m2 is found to have the
following value a = ˜u ˜β2
˜m2 ≈
0.70
0.26
2
≈7.24,
(6) a = ˜u ˜β2
˜m2 ≈
0.70
0.26
2
≈7.24, (6) as extracted from the data of Fig. 1. We emphasize that the result (6), valid at large β, do not
depend on the constant term V0, as it is highly desirable. as extracted from the data of Fig. 1. We emphasize that the result (6), valid at large β, do not
depend on the constant term V0, as it is highly desirable. One can choose a particular point of that straight line where one finds the explicit mass of the
MNI model, 270
→
m ∼7 × 1015 GeV,
(7) ˜β ≈270
→
m ∼7 × 1015 GeV, →
m ∼7 × 1015 GeV,
(7) (7) in the range of the cosmological scale, i.e., kcosmo ∼1015 −1016 GeV and close to the GUT
scale. In this case the dimensionless ratio a again has the value a ≈7.24. One cannot choose
larger value for ˜β because then the explicit mass would be larger than the typical energy scale of
the system, i.e., the cosmological scale. Thus, our choice is a maximum for ˜β. With this particular choice ˜β ≈270, the initial value for the VeV of the field is around 0.02 mp
(see Fig. 2). Thus, we would like to emphasize that the MNI potential (1) requires no large field
values in the very beginning of the cosmic inflation, and so, it is more reliably supported by
GUT motivated model building rather than typical large-field inflationary models, where one has
to assume very large initial value for the VeV of the field (4 −20 mp). In addition, the initial I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 Fig. 2. The MNI potential (denoted in the text as V3) at the GUT scale. 2.2. Unification of scales The black blob denotes the initial value of the
VeV in the inflationary period. Fig. 2. The MNI potential (denoted in the text as V3) at the GUT scale. The black blob denotes the initial value of the
VeV in the inflationary period. value for the VeV of the MNI model is again in the range of the GUT scale. Therefore, by the
choice ˜β ≈270 one is somehow able to unify all scales. Finally, one should mention the following. If one would like to take into account all conse-
quences of the quantum fluctuations of the inflaton field over inflation (where the rolling down
of the VeV is basically considered as a classical process), one has to consider the RG running
where the running scale is associated to the slowly rolling field itself [34]. This can be done in
a reliable manner if the initial value for the VeV is around the momentum scale (which other-
wise has been used as the scale for RG running) typical for inflation which is the GUT scale (or
cosmological scale). The MNI model (1) with the dimensionless frequency ˜β ≈270 fulfills the
required criteria. 3. Electroweak scale There is a strong interest to find a link between these scalar fields of the Higgs and inflationary
physics [35–45]. The Standard Model (SM) Higgs field is an SU(2) complex scalar doublet
with four real components, and the underlying symmetry of the electroweak sector is SU(2)L ×
U(1)Y , thus, the SM Higgs Lagrangian reads as L = (Dμφ)⋆(Dμφ) −V (φ) −1
2Tr(FμνF μν)
(8) (8) with with V = μ2φ⋆φ + λ(φ⋆φ)2 (9) (9) and ∂μ + igT · Wμ + ig′yjBμ,
(10) Dμ = ∂μ + igT · Wμ + ig′yjBμ,
(10) Dμ = ∂μ + igT · Wμ + ig′yjBμ, (10) where the vacuum expectation of the Higgs field is either at zero field for μ2 > 0 or at √φ⋆φ =
−μ2/(2λ) = v/
√
2 for μ2 < 0 with v = 246 GeV known from low-energy experiments. The I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 8 field can be parametrized around its ground state, where the unitary phase can be dropped by
choosing an appropriate gauge. As a consequence of the Brout-Englert-Higgs mechanism [46,
47], three degrees of freedom of the Higgs scalar field (out of the four) mix with weak gauge
bosons. The remaining degree of freedom becomes the Higgs boson discovered at CERN’s Large
Hadron Collider [48,49]. The complete Lagrangian for the Higgs sector of the SM with the single
real scalar field h reads L = 1
2∂μh∂μh −1
2M2
hh2 −M2
h
2v h3 −M2
h
8v2 h4
+
M2
WW +
μ W −μ + 1
2M2
ZZμZμ
1 + 2h
v + h2
v2
,
(11) (11) where Mh =
−2μ2 =
√
2λv2. The measured value for the Higgs mass Mh = 125.6 GeV im-
plies λ = 0.13. Incidentally, we note that the latter value is close to the predicted value based
on an assumption of the absence of new physics between the Fermi and Planck scales and the
asymptotic safety of gravity [50]. Extrapolating the SM of particle physics up to very high energies leads to an interpretation
of the Higgs boson as the inflaton. Therefore, the most “economical” choice would be to use
the same scalar field for Higgs and inflationary physics. 3. Electroweak scale The Taylor expansion of the MNI model (1) recovers the SM Higgs potential (13) up to
quartic terms and the parameters can be related: VMNI ≈V0 + 1
2(m2 −uβ2)φ2 + 1
24uβ4φ4 + O(φ6),
(14)
so that
λv2 ≡(uβ2 −m2),
λ ≡1
6uβ4. (15) VMNI ≈V0 + 1
2(m2 −uβ2)φ2 + 1
24uβ4φ4 + O(φ6), (14) VMNI ≈V0 + 2(m2 −uβ2)φ2 + 24uβ4φ4 + O(φ6),
(14)
so that
λv2 ≡(uβ2 −m2),
λ ≡1
6uβ4. (15) so that so that ≡(uβ2 −m2),
λ ≡1
6uβ4. (15) λv2 ≡(uβ2 −m2),
λ ≡1
6uβ4. (15) Thus the MNI model (1) can be considered as an UV completion of the SM Higgs potential. Further details of the UV completion is shown in Appendix C. The measurable quantities are
related to the parameters of the model according to the following relations: Thus the MNI model (1) can be considered as an UV completion of the SM Higgs potential. Further details of the UV completion is shown in Appendix C. The measurable quantities are
related to the parameters of the model according to the following relations: Mh ≡m
2
uβ2
m2 −1
,
v ≡1
β
6(uβ2/m2 −1)
uβ2/m2
. (16) (16) Their low-energy/IR values are given at the electroweak scale by Their low-energy/IR values are given at the electroweak scale by Their low-energy/IR values are given at the electroweak scale by Mh,IR = 125 GeV,
vIR = 245 GeV, (17) Mh,IR = 125 GeV,
vIR = 245 GeV,
(17)
at the scale kIR ∼250 GeV. N i
h
ki
i
hi h
d
i E
(14) i
i
l
i Mh,IR = 125 GeV,
vIR = 245 GeV,
(17)
at the scale kIR ∼250 GeV. R = 125 GeV,
vIR = 245 GeV,
(17) Notice that taking into account higher order terms in Eq. (14) gives rise to results consistent
with (16), as discussed in Appendix D. Let us note, that the Higgs mass and VeV defined by (16) can be calculated also at the cos-
mological scales. For example, in the large ˜β region the slow-roll study produces values for the
Higgs mass and VeV in the same order of magnitude which serves as a high-energy/UV scale Mh,UV ∼vUV ∼1015 GeV,
(18a)
mUV ∼1015 GeV, βUV ∼10−15 GeV−1 ,
(18b) Mh,UV ∼vUV ∼1015 GeV, (18a) mUV ∼1015 GeV, βUV ∼10−15 GeV−1 , (18b) at the scale kUV ∼1015 GeV. 3. Electroweak scale These need to be scaled down (by orders of magnitude) to their
measured values at the electroweak scale (17). The integration of high-energy modes is a well-
known method which provides us this scaling down by the successful integration of the field
fluctuations. Therefore, let us discuss the integration of the high-energy modes in the MNI model
in the post-inflation period. at the scale kUV ∼1015 GeV. These need to be scaled down (by orders of magnitude) to their
measured values at the electroweak scale (17). The integration of high-energy modes is a well-
known method which provides us this scaling down by the successful integration of the field
fluctuations. Therefore, let us discuss the integration of the high-energy modes in the MNI model
in the post-inflation period. 3. Electroweak scale The action can be defined either in the
Jordan frame in which some function of the scalar field multiplies the Ricci scalar R, or in the
Einstein frame in which the Ricci scalar is not multiplied by a scalar field [51]. To perform the
slow-roll study, the action is usually rewritten in the Einstein frame and it takes the form for the
case of minimal coupling to gravity, S =
d4x√−g
m2
pR
2
−1
2gμν ∂μφ ∂νφ −V (φ)
,
V ≡λ
4
φ2 −v2 2
= M2
h
8v2
φ2 −v2 2
,
(12) (12) where the metric tensor being denoted by gμν, √−g ≡√−detg while φ ≡h and V is the
quartic-type double-well scalar potential of (11), where the metric tensor being denoted by gμν, √−g ≡√−detg while φ ≡h and V is the
quartic-type double-well scalar potential of (11), V (φ) = λ
4v4 −1
2λv2φ2 + λ
4φ4 ,
(13) V (φ) = λ
4v4 −1
2λv2φ2 + λ
4φ4 , (13) where the field variable is shifted as h →h + v. The case of non-minimal inflation is discussed
in Appendix B. Another proposal to build up the scalar sector is the Higgs inflation from false vacuum with
minimal coupling to gravity where the SM Higgs potential is extended and assumed to develop
a second (or more) minimum [35–38]. The difficulty is to achieve an exit from the inflationary
phase: one may introduce new fields, but then the attractive minimality of the model would be
lost. Another possible drawback of the Higgs-inflaton potential to its applicability is that the mea-
sured Higgs mass is close to the lower limit, 126 GeV, ensuring absolute vacuum stability within
the SM [52]. However, it was also shown [6] that traditional Higgs inflation can be possible
within a minimalistic framework even if the SM vacuum is not completely stable. Various poly-
nomial Higgs potentials have been studied by functional RG [8,9] and reported no stability
problems. I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 9 All versions of the MNI model studied by us contain two adjustable parameters (the ratio
u/m2 and the frequency β) and a normalization (the field-independent terms has been fixed by
us). 4.1. Flow equation for the potential A field theory closely related to the MNI model (1), namely, the massive sine-Gordon scalar
model, was extensively studied in d = 2 dimensions by functional RG method [29–32]. Here, we
consider d = 4 dimensions. The procedure, standard in RG approaches, consists in eliminating
the high-energy modes by integrating them. This gives an equation for the flow of the potential,
and the general fact is that this equation is a functional one. When the high-energy modes are
integrated out, the potential therefore becomes scale-dependent, V →Vk, where with the symbol
Vk we denote that the modes with momenta larger than k have been integrated out. To determine
the dependence on the scale k one has to solve the RG flow equation which has the following
form at the level of the local potential approximation where higher-order derivatives of the field
are neglected [53,54], k∂kVk(φ) = 1
2
ddp
(2π)d
k∂kRk
Rk + p2 + ∂2
φVk
,
(19) (19) where Rk = Rk(p2) is a cut-off function, which in the functional RG jargon is called regulator
function. Then, one can turn to dimensionless quantities, denoted by a tilde superscript as written
in Eqs. (5). The RG flow equation becomes where Rk = Rk(p2) is a cut-off function, which in the functional RG jargon is called regulator
function. Then, one can turn to dimensionless quantities, denoted by a tilde superscript as written
in Eqs. (5). The RG flow equation becomes
d −d −2
2
˜φ∂˜φ + k∂k
˜Vk( ˜φ) = −αd
∞
0
dy
r′ y
d
2 +1
[1 + r]y + ∂2
˜φ ˜Vk
,
(20) (20) with αd = d/(2(2π)d) and d = 2πd/2/
(d/2), where it is intended we have to put d = 4. Moreover r(y) is the dimensionless regulator defined by r(y) = Rk(p2)/p2, with y = p2/k2
and r′ = dr/dy. The integral in the right-hand-side of Eq. (20) can be performed analytically by
the appropriate choice of the regulator function, for example by using r(y) = (1/y −1)(1 −y). The results should be independent on the particular regulator which has been chosen: this issue
has been discussed in considerable detail in the functional RG literature, so we just pass to present
our results. 4. Mode integration In principle, a comprehensive study of the integration of high-energy modes requires an ac-
curate treatment of gauge and fermion fields and not just a single scalar potential. However, the
MNI model has a very important feature, namely it contains a periodic and a quadratic self-
interaction term (apart from the trivial constant term). It allows to perform explicitly, in an easy
way, the integration of modes up to the electroweak scale. The explanation is the following. The
integration of modes is done by solving the RG flow differential equation where not the action
but its Hessian (second derivative) appears on the one side [53,54]. So, even if the scalar field
couples to any gauge or fermion fields in the action (which are not higher than quadratic in the
scalar field), the Hessian remains periodic in the scalar sector. Therefore, it represents a reliable
approximation if one looks for the solution of the equation among scalar periodic functions and
neglect the effect of other fields. 10 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 4.1. Flow equation for the potential Two comments are anyway in order: i) the mode integration procedure above described give
the same results for all variants of the MNI model (V1, V2 and V3) since the derivation with
respect to the field eliminates any dependence on field-independent terms; ii) the results pre-
sented in Fig. 3 and Fig. 4, and the UV-insensitivity property, do not depend on the choice of the
regulator. Our results can be summarized by observing that one finds two phases controlled by the
dimensionless quantity ˜uk ˜β2
k/ ˜m2
k, which tends to a constant in the IR limit. In the (Z2) symmetric
phase the magnitude of this constant is arbitrary (and depends on the initial conditions), but
always smaller than one, i.e., limk→0 |˜uk ˜β2
k/ ˜m2
k| < 1 (see the blue lines of Fig. 3). In the spontaneously broken (SSB) phase, the IR value of the magnitude of the ratio is exactly
one (independently of the initial values) which serves as an upper bound, see green lines of Fig. 3. The black line separates the two phases. In other words, trajectories in the SSB phase (green lines) merge into a master trajectory
(green line parallel to the black one) of Fig. 3 which implies ¯uk ˜β2
k = 1 + ˜m2
k , (21) I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 11 Fig. 3. Flow of the MNI model showing two phases separated by a black line with a unit slope. The blue lines correspond
to the symmetric phase, while the green lines correspond to the SSB phase. Fig. 3. Flow of the MNI model showing two phases separated by a black line with a unit slope. The blue lines correspond
to the symmetric phase, while the green lines correspond to the SSB phase. and it results in the following scaling: ¯uk ˜β2
k
˜m2
k
−1 = 1
˜m2
k
=
k2
m2
UV
. ¯uk ˜β2
k
˜m2
k
−1 = 1
˜m2
k
=
k2
m2
UV
. (22) (22) This scaling relation is valid when the running is determined by the master trajectory which,
apart from the very beginning of the running, is always the case in the SSB phase. We observe
that Eq. 4.1. Flow equation for the potential (22) has been obtained with a non-perturbative approach for the MNI potential (1), but
one may expect that it is valid for other classed of inflationary potentials, as we are going to
discuss in Section 4.2 and 5. However, the MNI potential (1) is well suited to find Eq. (22) in a
particularly transparent way. Eq. (22) can be used to determine the IR value of the Higgs mass and VeV from the UV initial
conditions (18a) and compared to the known results of (17). Indeed by substituting (22) into (16)
and assuming running parameters ˜uk ˜β2
k/ ˜m2
k = ukβ2/m2, one gets Mh(k) = mUV
2
˜uk ˜β2
k
˜m2
k
−1
. (23) Mh(k) = mUV
2
˜uk ˜β2
k
˜m2
k
−1
. (23) Now, one uses Eq. (22) and obtains Mh(k) = mUV
√
2
k2
m2
UV
=
√
2
mUV
k
mUV
=
√
2k,
(24) (24) where the cancellation of the UV mass has been made evident. We observe, for absolute clarity,
that this property does not depend of the specific form of the flow (20), but is a consequence of
the fact that the slope of the master trajectory is constant. I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 12 Fig. 4. Flow of the Higgs mass from the cosmological (UV) scale to the electroweak (IR) scale obtained from the study
of the MNI model. The trajectories merge into a single line showing UV insensitivity. Fig. 4. Flow of the Higgs mass from the cosmological (UV) scale to the electroweak (IR) scale obtained from the study
of the MNI model. The trajectories merge into a single line showing UV insensitivity. Similarly, one gets v(k) =
1
βUV
6(˜uk ˜β2
k/ ˜m2
k −1)
˜uk ˜β2
k/ ˜m2
k
≈
√
6k
mUVβUV
,
(25) v(k) =
1
βUV
6(˜uk ˜β2
k/ ˜m2
k −1)
˜uk ˜β2
k/ ˜m2
k
≈
√
6k
mUVβUV
, (25) which has important consequences. Since kIR = 250 GeV, it provides the required IR values
(17), at least the same order, in accordance with measurements. Furthermore, the IR values for
the Higgs mass becomes independent of the UV initial parameter (see Fig. 4). which has important consequences. 4.1. Flow equation for the potential Since kIR = 250 GeV, it provides the required IR values
(17), at least the same order, in accordance with measurements. Furthermore, the IR values for
the Higgs mass becomes independent of the UV initial parameter (see Fig. 4). We conclude this Section by observing that the (dimensionful) Higgs mass has a weak RG
running in the framework of perturbative RG in the SM [55]. We are in agreement with this
fact, since in our model the (dimensionful) mass m has no running at all. However, with the
non-perturbative approach followed in the present paper, the Higgs mass is an effective mass and
it is not the explicit mass m. This is shown in Fig. 4 clearly demonstrating the linear dependence
of the effective Higgs mass obtained using the MNI model (1). 4.2. Comments on universality The previous derivation show that the details at cosmological scale do not influence the quan-
tities at the electroweak scale. This property manifests itself through the cancellation of the
parameter m of the MNI determined at cosmological scale using PLANCK data. In practice,
whatever is the value of m and β at cosmological scale, one gets the same value for the Higgs
mass, which depends only on the chosen energy scale at electroweak, IR scale, which we can
denote by kew. This is evident from the universality of the flow, as depicted in Fig. 4, where all
trajectories flow into the same point. Our analysis also shows that the initial condition, which
we may denote by kstart, chosen as starting point for the mode integration, also does not play a
role. 13 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 Now, the question that naturally emerges is the following: is this property specific to the MNI
alone or not? Before answering, we pause to comment that in general, the MNI is very suited
to show the property of independence of the Higgs mass from the initial conditions and from
the values of the parameters at cosmological scale, since the mode integration can be performed
straightforwardly using known results from field theory. Actually, the cancellation of the mass m
emerge naturally and with a minimally simple calculation. However, this usefulness of the MNI
does not imply that it is the only model exhibiting such features. Indeed, we expect that other
two-parameter inflationary model with Z2 symmetry will give the same results. The reason for
such expectation is three-fold: from one side, during the mode integration, all powers of the field
are generated and the interplay of the minima depends on these powers. Such a generation is
not specific of the MNI model and will be exhibited by other models: actually, we can say the
opposite, namely that if the model has an Higgs mass depending on the parameters determined
from cosmological data, then most probably it could be characterized as unphysical. So, this led
to conclude that extending an inflationary model towards low energies should produce the same
Higgs mass provided that kew is fixed, and the MNI is in our opinion just a simple model showing
this result. 4.2. Comments on universality From the other side, it is well known that mode integration makes the potential tend
to a convex form starting from a concave one, and this is in agreement with Mh(kew)/m ≪1. Finally, it should be noted that for scalar theories in four dimensions, the only relevant and
marginal couplings are the quadratic and the quartic one respectively. When considering more
complicated functional forms for the potential, the scaling arguments cannot be straightforwardly
applied, and the irrelevance of higher-order field terms is not evident from the β-functions. Even
in this case, the simple scaling arguments are expected to hold, and so we expect the irrelevance
from the UV conditions to hold even for different UV completions. 5. Conclusions and outlook This property, by contrast, is not shared by other
UV-admissible models which work at the cosmological scale. Within our assumptions, the
Higgs mass is found to be independent of the parameters found at the cosmological scale. • We argue that these properties are shared by other two-parameter inflationary models, but
our model provides an ideal framework to explicitly show it in a straightforward way. • We argue that these properties are shared by other two-parameter inflationary models, but
our model provides an ideal framework to explicitly show it in a straightforward way. We conclude that the model is valid both at cosmological and electroweak scales. We conclude that the model is valid both at cosmological and electroweak scales. Finally, we comment on the consequences of our results related to three major issues of infla-
tionary cosmology which have and are intensely discussed. The first concerns the identification
of the inflaton with the Higgs field, i.e., whether the inflationary potential can be extended to
electroweak scale in a reliable way. The second is whether the high-energy properties of the
theory affect or not the low-energy ones: when there is not such influence, one talks about UV-
insensitivity [56]. The third issue is related to the fact that many inflationary models can be and
have been proposed [12], so that it may be asked whether and how the correct model should be
chosen. The fact that one has to choose an ad hoc potential with a fine tuning of its parameters
and of the initial conditions is certainly an argument against inflationary scenarios. Our paper
brings a contribution to this on-going discussion, since our results suggest that the answer to
the first question is “yes”, in the sense that the results for the Higgs mass does not depend on
the values of the parameters at the cosmological scale and that one can explicitly build a model
valid at the cosmological and electroweak scale. The answer to the second question, looking at
the results of the MNI analysis presented in the present paper, is that there is UV-insensitivity,
as the MNI clearly shows with the cancelation of the mass m at cosmological scale in deter-
mining Mh(kew). For the third question we conclude “no”, in the sense that other models with
non-fine tuned initial conditions share the same properties. The affirmative answer to the first
question supports Higgs inflationary models. 5. Conclusions and outlook A good candidate for an inflationary potential should fulfill the following conditions, (i) have
an as-simple-possible functional form (with the smallest possible number of parameters), (ii) pro-
vide the best agreement with observations, (iii) be as “economical” as possible in term of the
formulation of the theory. In this paper, we propose the extended version of the massive sine-
Gordon theory as an inflationary potential and we refer to it as the massive Natural Inflation
(MNI) model. We show that adding the mass term to the periodic potential produces a remark-
ably improved agreement with the Planck results. We attribute such improvement to the fact that
it has infinitely many minima, but they are non-degenerate and with tunable controllable energy
difference, providing a way to be as much as possible both “φ2 and not-φ2”. The crucial point
emerging from a careful analysis of different potentials is that the inflationary potential should
have a concave region, and the mass term in the MNI potential add such an overall convexity in
presence of the many minima. To explore the issue of the convexity, we used the known renormalization group (RG) results
for the MNI model, extending them to d = 4, to perform explicitly the mode integration. We then
determined the phase diagram associated to the running determined by the slow-roll conditions
having in mind the post-inflation period. The obtained values for the ratio |˜uk ˜β2
k/ ˜m2
k| are found
in the phase of spontaneous symmetry breaking (above the critical line). Thus, the study of the
MNI model shows that slow-roll conditions represent strong constraints on the RG running i.e.,
it stays in its broken phase. Moreover, the mode integration produces a convex (dimensionful)
potential in agreement with the theoretical requirement of the convexity of the effective poten-
tial. 14 I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 In conclusion, we introduced a model for cosmological inflation, based on a UV completion
of the Higgs potential, which has the following properties: • It works at cosmological level, and its parameters can be fixed from PLANCK and BICEP2
experimental data. (This property is shared with many other models which are consistent
with available data at the cosmological scale, but still constitutes an important consistency
check of our model.) • Our model also works at the electroweak scale which means its parameter can be fixed
by comparison with experimental data. 5. Conclusions and outlook If one were to insist that a single specific model,
with uniquely determined parameters, should explain the physical properties at all scales, then
the model-independence and UV-insensitivity could be considered as an argument against Higgs
inflation. However, if one is taking an approach like the renormalization group approach à la Wil-
son, then the model-independence (and UV-insensitivity) is not only desirable, but, in a sense,
required. Summing all the radiative corrections to the quartic Higgs potential (and of course having at
disposal more experimental data) could shed light on this apparent contradiction and on the form
of the effective action at the cosmological scale. However, we think that the top-down approach
based on a guessed action at high-energies may give very useful information to clarify the prop-
erties that the UV action should have in order to fulfill the requested requirements at all scales. This approach is opposite to the more standard one bottom-up, which starts from the low-energy
properties and tries to obtain the action at high-energies, and it may give complementary infor-
mation. This is one of the reasons for which we hope that the results presented in this paper may
contribute to the discussion on the validity of specific inflationary models. I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 15 In conclusion, we found a class of MNI models which show UV insensitivity and can act as
viable candidates for an inflaton mechanism, via integration of the high-energy modes. While it
will be impossible, from low-energy experiments alone, to determine which is the correct one,
one could confirm that only rather moderate extensions of the Standard Model (in this case, the
addition of periodic terms) would be required for a consistent extrapolation to very high energy
scales, the latter being of cosmological relevance. Acknowledgements This work was supported by the János Bolyai Research Scholarship of the Hungarian
Academy of Sciences and by the ÚNKP-17-3 New National Excellence Program of the Ministry
of Human Capacities. Useful discussions with F. Bianchini, G. Gori, J. Rubio, Z. Trocsanyi and
G. Somogyi are gratefully acknowledged. Support from the National Science Foundation (Grant
PHY-1710856) also is being acknowledged. Financial support by the CNR/MTA Italy–Hungary
2019–2021 Joint Project “Strongly interacting systems in confined geometries” is gratefully ac-
knowledged. Appendix A. Inflationary predictions In this appendix we discuss the applicability of the Natural Inflation (NI) and the Massive
Natural Inflation (MNI) potentials for cosmology. The slow-roll parameters (ϵ, η, ns, r) of the
NI model reads as NI model reads as ϵ =
˜β2
2 cot2
˜β ˜φ
2
,
η =
˜β2
2
cos( ˜β ˜φ)
sin2
˜β ˜φ
2
,
N = −2
˜β2 logcos
˜β ˜φ
2
˜φi
˜φf
ns −1 ≈˜β2
1 −2sin−2
˜β ˜φ
2
,
r ≈8 ˜β2 cot
˜β ˜φ
2
ϵ =
˜β2
2 cot2
˜β ˜φ
2
,
η =
˜β2
2
cos( ˜β ˜φ)
sin2
˜β ˜φ
2
,
N = −2
˜β2 logcos
˜β ˜φ
2
˜φi
˜φf
ns −1 ≈˜β2
1 −2sin−2
˜β ˜φ
2
,
r ≈8 ˜β2 cot
˜β ˜φ
2
ϵ =
˜β2
2 cot2
˜β ˜φ
2
,
η =
˜β2
2
cos( ˜β ˜φ)
sin2
˜β ˜φ
2
, which imply the relation ns −1 + r
4 = −˜β2 which is very similar to that of obtained for the
quadratic monomial potential but having a dependence on the frequency ˜β, thus, it appears as
an additional parameter which can be tuned ( ˜β ∼0.15) to achieve a better agreement with the
Planck data, see orange line segments of Fig. 5. Appendix A. Inflationary predictions The slow-roll parameters of the MNI model (2b), The slow-roll parameters of the MNI model (2b), ϵ = 1
2
⎛
⎝
−˜u
˜m2 ˜β sin( ˜β ˜φ) + ˜φ
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
⎞
⎠
2
η =
−˜u
˜m2 ˜β2 cos( ˜β ˜φ) + 1
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
N = −
˜φf
˜φi
d ˜φ
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
−˜u
˜m2 ˜β sin( ˜β ˜φ) + ˜φ ϵ = 1
2
⎛
⎝
−˜u
˜m2 ˜β sin( ˜β ˜φ) + ˜φ
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
⎞
⎠
2
(26)
η =
−˜u
˜m2 ˜β2 cos( ˜β ˜φ) + 1
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
(27)
N = −
˜φf
˜φi
d ˜φ
˜u
˜m2
cos( ˜β ˜φ) −1
+ 1
2 ˜φ2
−˜u
˜m2 ˜β sin( ˜β ˜φ) + ˜φ
(28) (26) (27) (28) I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 16 Fig. 5. CMBR parameters, i.e., scalar tilt ns and tensor-to-scalar ratio r derived (i) for the Natural Inflation model for
various frequencies (orange line segments) and (ii) for the MNI model with fixed ratio ˜u/ ˜m2 ∼1/(0.2)2 and frequency
˜β ∼0.4 (purple line segment). Both are compared to results of the Planck mission [26–28] where dark color regions
stand for 95% CL and light color regions correspond to 68% CL. Fig. 5. CMBR parameters, i.e., scalar tilt ns and tensor-to-scalar ratio r derived (i) for the Natural Inflation model for
various frequencies (orange line segments) and (ii) for the MNI model with fixed ratio ˜u/ ˜m2 ∼1/(0.2)2 and frequency
˜β ∼0.4 (purple line segment). Both are compared to results of the Planck mission [26–28] where dark color regions
stand for 95% CL and light color regions correspond to 68% CL. depend on the ratio ˜u/ ˜m2 and the frequency ˜β. The inclusion of the explicit mass term ( 1
2m2φ2)
in the periodic (i.e., NI) potential improves the inflationary predictions of the model, see Fig. 5. Appendix B. Non-minimal inflation In this appendix we discuss the case of a large non-minimal coupling to gravity [39–45],
where the interpretation of the Higgs boson as the inflaton results in the following action in the
Jordan frame S =
d4x
−¯g
m2
p
2
F(˜h) ¯R −¯gμν∂μ ˜h∂ν ˜h −2U(˜h)
,
F(h) = 1 + ξ ˜h2, U(˜h) = m2
p
λ
4
˜h2 −v2
m2p
2
,
(29) (29) where ˜h is the dimensionless Higgs scalar (h = mp ˜h), ξ is a new parameter and ¯gμν is the metric
in the Jordan frame. Of course, by convention, √−¯g ≡√−det ¯g, while U(˜h) is the dimension-
less quartic-type double-well scalar potential with a Z2 symmetry, equivalent to the SM Higgs
potential of (11). In order to show this one has to (i) introduce a dimensionful field variable,
(ii) replace the quartic self-coupling by the Higgs mass, i.e., λ = M2
h/(2v2) as is indicated below
Eq. (11), and (iii) shift the field variable as h →h + v. To perform the slow-roll study, the action is usually rewritten in the Einstein frame and it takes
the form S =
d4x√−g
m2
pR
2
−1
2gμν ∂μφ ∂νφ −V (φ)
, S =
d4x√−g
m2
pR
2
−1
2gμν ∂μφ ∂νφ −V (φ)
,
V ≡m2
p
U
F 2 ,
dφ
d ˜h
= mp
1 + ξ(1 + 6ξ)˜h2
1 + ξ ˜h2
,
(30) V ≡m2
p
U
F 2 ,
dφ
d ˜h
= mp
1 + ξ(1 + 6ξ)˜h2
1 + ξ ˜h2
, 2
p
U
F 2 ,
dφ
d ˜h
= mp
1 + ξ(1 + 6ξ)˜h2
1 + ξ ˜h2
,
(30) V ≡m2
p
U
F 2 ,
dφ
d ˜h
= mp
1 + ξ(1 + 6ξ)˜h2
1 + ξ ˜h2
,
(30) U
2 ,
dφ
d ˜h
= mp
1 + ξ(1 + 6ξ)h2
1 + ξ ˜h2
,
(30) (30) where the metric tensor being denoted by gμν. For ξ ̸= 0, the Higgs-ξ inflaton etric tensor being denoted by gμν. For ξ ̸= 0, the Higgs-ξ inflaton potential reads metric tensor being denoted by gμν. Appendix B. Non-minimal inflation For ξ ̸= 0, the Higgs-ξ inflaton potential reads V (φ) =
m4
pλ
4ξ2
1 −exp
−
2
3
φ
mp
2
, V (φ) =
m4
pλ
4ξ2
1 −exp
−
2
3
φ
mp
2
,
(31) (31) I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 17 which is considered as a zero parameter model since the overall factor of the potential is entirely
determined by the amplitude of the CMBR anisotropies. In the framework of this inflationary
scenario, one needs to take extra precautions in order not to violate perturbative unitarity. Appendix C. UV completion Alternatively, the MNI-type UV completion of the SM Higgs potential can be formulated as Alternatively, the MNI-type UV completion of the SM Higgs potential can be formulated as V = 1
2M2φ⋆φ + u[cos(b
φ⋆φ) −1], V = 1
2M2φ⋆φ + u[cos(b
φ⋆φ) −1], φ⋆φ + u[cos(b
φ⋆φ) −1],
(32) (32) which recovers the scalar potential in (8) after its Taylor expansion with μ2 ≡1/2 (M2 −ub2)
and λ ≡1
24 ub4. Performing the same parametrization of the field used in order to get from (8)
to (11) one finds which recovers the scalar potential in (8) after its Taylor expansion with μ2 ≡1/2 (M2 −ub2)
and λ ≡1
24 ub4. Performing the same parametrization of the field used in order to get from (8)
to (11) one finds V = 1
2
M2
2 (h + v)2 + u
cos
b
√
2
(h + v)
−1
,
(33) (33) which is identical (apart from constant terms) to the MNI model (1) after shifting the field by
a constant h + v →φ and introducing m2 ≡M2/2 and β ≡b/
√
2. This validates that the MNI
model is a suitable extension of the SM Higgs potential. The broken symmetric case corresponds
to parameters where 1 < uβ2/m2 = ub2/M2, i.e., where μ2 < 0. Appendix D. Effect of higher order terms on the vacuum expectation value The vacuum expectation value (VEV) v is defined by the value of the field (φ) at the minima
of the potential: V (φ = v) = min(V ). = v) = min(V ). (34) V (φ = v) = min(V ). (34) In our case the VEV is the closest solutions to zero of the equation In our case the VEV is the closest solutions to zero of the equation dV
dφ
φ=v
= 0, dV
dφ
φ=v
= 0,
(35) (35) dφ
φ=v
= 0,
(35)
which for the MNI model writes as which for the MNI model writes as which for the MNI model writes as which for the MNI model writes as m2v −βusin(βv) = 0. m2v −βusin(βv) = 0. (36)
bt i m2v −βusin(βv) = 0. (36) (36) One obtains uβ2/m2 −1
uβ2/m2
=
1 −sin(βv)
βv
. (37) uβ2/m2 −1
uβ2/m2
=
1 −sin(βv)
βv
. −1
2
=
1 −sin(βv)
βv
. (37) (37) The left hand side is smaller than one and we remind the reader that we are looking for the
solutions for v which are the closest to zero. Thus the calculations with only the first order of the
right hand side (which is equivalent to keep only the φn terms, with n ≤4, in the potential) is a
reasonable approximation, see Fig. 6. We conclude that taking into account the higher terms changes the scaling of the VEV, which
anyway stays very close to the first order approximation written in the paper. I.G. Márián et al. / Nuclear Physics B 945 (2019) 114642 18 Fig. 6. The first order approximation of the right hand side of (37) (black line). The red line is the maximum value of the
left hand side of (37) while the blue curve is the exact result. Fig. 6. The first order approximation of the right hand side of (37) (black line). The red line is the maximum value of the
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English
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A comparison between different anti-retroviral therapy regimes on soluble inflammation markers: a pilot study
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AIDS research and therapy
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© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea-
tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo-
main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. AIDS Research and Therapy Open Access Abstract Background: Although HIV-related deaths have decreased dramatically following the introduction of antiretrovi-
ral therapy (ART), HIV infection itself causes increased morbidity and mortality for both non-AIDS-related events or
chronic inflammation and immune activation. The use of certain antiretroviral drugs can contribute to this process. Methods: We investigated 26 potential biomarkers in serum samples from HIV-1 infected patients virologically sup-
pressed under ART. The main objective of our study was to evaluate if virological suppression achieved with a triple
drug regimen containing tenofovir disoproxil fumarate co-formulated with emtricitabine (TDF/FTC) as backbone,
could correlate with a better immunological and inflammatory profile in relation to the third class of antiretroviral
drug administered. The eligible patients were then divided into 3 groups in relation to the third drug associated with
TDF/FTC: nucleoside reverse transcriptase inhibitors (NNRTI) (Group 1, n = 16), protease inhibitors (PI) (Group 2, n = 17)
and integrase inhibitors (INI) (Group 3, n = 16). Results: Inflammatory cytokines and chemokines were more represented in Group 2 than in Group 3 (IL-1Ra,
p = 0.013; IL-12p70 p = 0.039; TNF-α p = 0.041; IL-8, p = 0.027; MIP1 β, p = 0.033). Eotaxin showed lower levels in Group
1 compared to Group 2 (p = 0.010), while IP-10 was significantly lower in Group 1 compared to both Group 2 and
Group 3 (p = 0.003 and p = 0.007, respectively). Conclusions: Our results seem to discourage the administration of PI as a third drug in a virologically effective
antiretroviral regimen, as its use is linked to the detection of higher levels of pro-inflammatory mediators in compari-
son with INI and NNRTI. rds: HIV, Virological suppression, Antiretroviral therapy, Immune activation, Chronic inflammation Maritati et al. AIDS Res Ther (2020) 17:61
https://doi.org/10.1186/s12981-020-00316-w Maritati et al. AIDS Res Ther (2020) 17:61
https://doi.org/10.1186/s12981-020-00316-w AIDS Research and Therapy AIDS Research and Therapy Backgroundh as the backbone plus a base agent of another class, pro-
tease inhibitors (PI), integrase inhibitors (INI) or nucleo-
side reverse transcriptase inhibitors (NNRTI) [2], have
been shown to control viral replication [3] and represent
the gold standard for the treatment of HIV infection in
both antiretroviral-naïve and antiretroviral experienced
patients. Now, these patients live longer, although with
a higher prevalence of non-infectious comorbidities
including cardiovascular disease, diabetes, renal dysfunc-
tion and liver damage. Although these comorbidities are
quite common among the general population [4], they The introduction of antiretroviral therapy (ART) has
contributed to the reduction of AIDS-related mortality
among HIV-positive patients [1] and to the induced chro-
nicity of HIV infection. Triple drug regimens that include
two nucleos(t)ide reverse transcriptase inhibitors (NRTI) *Correspondence: mrtmtn@unife.it
1 Section of Infectious Diseases, Department of Medical Sciences,
University of Ferrara, 44124 Ferrara, Italy
Full list of author information is available at the end of the article *Correspondence: mrtmtn@unife.it
1 Section of Infectious Diseases, Department of Medical Sciences,
University of Ferrara, 44124 Ferrara, Italy
Full list of author information is available at the end of the article Maritati et al. AIDS Res Ther (2020) 17:61 Page 2 of 7 (HIV Section) University-Hospital of Ferrara. Strict
inclusion criteria were considered: (1) virological sup-
pression for at least 6 months obtained with a triple drug
regimen containing TDF/FTC as a backbone; (2) Car-
diovascular risk (CVR) ≥ 7.5%, calculated according to
the Atherosclerotic Cardiovascular Disease (ASCVD)
algorithm of American College of Cardiology/Ameri-
can Heart Association (ACC-AHA) [18], in the absence
of a regimen with statin and / or aspirin. The presence
of comorbidities (chronic inflammatory diseases, neo-
plasms, diabetes, obesity, etc.) and co-infections repre-
sented a strict exclusion criterion. are increasingly frequent in patients with ART [5] more
likely due to the inflammatory process related to HIV and
the adverse pharmacological effects of ART [6–11]. f
In this regard, the international guidelines on the man-
agement of HIV-positive patients recommend a change
in lifestyle (smoking cessation, changes in diet and physi-
cal activity) and, in case of high LDL and/or hypertriglyc-
eridemia values, the administration of statins. In addition
to these measures, it is highly recommended to move to
an antiretroviral regimen that limits the impact on lipid
metabolism, suggesting the adoption of a therapy “tai-
lored” to the needs of the patient. Clinical studies have also shown that the transition
from therapies such as PI or NNRTI (efavirenz) to inte-
grase inhibitors (INI) (e.g. raltegravir, dolutegravir) leads
to an improvement in the lipid profile, inflammatory
pattern, and chronic immune activation. In fact, HIV
infection combined with ART is directly associated with
immune activation [12, 13], even in virologically sup-
pressed patients. It is known, indeed, that the dysregula-
tion of inflammatory processes induced by HIV occurs
through multiple pathways [14], including microbial
translocation [15]. Eligible patients were then divided into groups accord-
ing to the third drug associated with TDF/FTC at the
time of enrollment: NNRTI (efavirenz) (Group 1, n = 16),
PI (atazanavir/r or darunavir/r) (Group 2, n = 17) and INI
(raltegravir) (Group 3, n = 16). This study is in line with the Code of Ethics of the
World Medical Association (Declaration of Helsinki)
and was conducted according to the guidelines for Good
Clinical Practice (European Medicines Agency). The
study was approved by The Local Ethic Committee and
written informed consent was obtained from each patient
prior to inclusion in the study. Chemokines and cytokines analysish The main outcome measures were the quantification of
cytokine concentrations and growth factors in biological
samples based on magnetic bead multiplex immunoas-
says (Bio-Plex, BIO-RAD Laboratories, Milano, Italy). Luminex multiplex panel technology was used for simul-
taneous measurement of a panel of 26 analytes including
cytokines, chemokines and growth factors (IL-1, IL-2,
IL-1ra, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13,
IL-15, TNF-α, IL-17, IL-18, IFN-γ, MIP1α, MIP1β, IL-8,
IP-10, RANTES, MCP-1, GM-CSF, G-CSF, IL-7, VEGF,
PDGF-bb) according to the method of Comar et al. 2014. Briefly, 50 μl of diluted serum samples (1:4) and reaction
standards were added, in duplicate, to a 96 multiwells
plate containing analyte beads followed by incubation
for 30 min at room temperature. After washing, the anti-
body-biotin reporter was added and incubated for 10 min To better understand this phenomenon and to optimize
therapeutic management, some authors have recently
been stimulated to seek and validate new immunological
and inflammatory predictive biomarkers. Serum sample collection Serum samples were obtained from the 49 enrolled sub-
jects. The whole blood of each subject was collected in
a covered tube without anticoagulants and left to clot
undisturbed at room temperature for 20 min. The clot
was then removed by centrifuging at 1500 × g for 10 min
in a refrigerated centrifuge. After centrifugation, the
serum was immediately transferred to a clean polypro-
pylene tube. All sera were maintained at − 80 °C until
cytokines analysis. l
So far, most studies examining changes in levels of
inflammatory biomarkers in HIV-infected individu-
als have been limited by small study populations, cross-
drawings and/or a small number of biomarkers [16]. In
this regard, recent technical advances, including the
development of multiplexed cytokine tests, have contrib-
uted to a more efficient measurement of multiple inflam-
matory biomarkers [17]. In this study, we investigated 26 potential biomarkers,
linked to systemic inflammation, immune activation and
senescence in HIV patients under ART for at least one
year and virologically suppressed (HIV-RNA < 20 cop-
ies/ml) for at least 6 months. All the enrolled patients
were treated with an ART triple drug regimen contain-
ing tenofovir disoproxil fumarate co-formulated with
emtricitabine (TDF/FTC) as backbone. The main aim of
our study was to assess whether virological suppression
can be related to a better immunological and inflamma-
tory profile, in relation to the third antiretroviral drug
administered. Study patients and design Forty-nine
caucasian
HIV-1
positive
patients
aged ≥ 40 years, who have taken ART for at least one
year, were enrolled at the Infectious Diseases Department Maritati et al. AIDS Res Ther (2020) 17:61 Maritati et al. AIDS Res Ther (2020) 17:61 Page 3 of 7 Of the 49 patients enrolled, 14 were women (28.57%) and
35 were males (71.43%). with streptavidin–phycoerythrin. Cytokines levels were
determined using the Bio-Plex array reader (Luminex,
Austin, TX). The Bio-Plex Manager software automati-
cally optimized the standard curves and returned the
reading data as Median Fluorescence Intensity (MFI)
and concentration (pg/mL). An ELISA set (Quantikine
ELISA-Human CCL5/Rantes immunoassay, RnD system,
Minneapolis, MN) with a mean minimum detectable
dose of 2.0 pg/ml was used as confirmatory test accord-
ing to manufacturer’s instruction [17]. The values of triglycerides were high (> 150 mg/dL)
in 33%, 35% and 31% of patients from NNRTI, PI and
INI group, respectively. The frequencies were not dif-
ferent between the three groups (chi-square (2) = 0.061,
p = 0.970). Total cholesterol was high (> 200 mg/dL) in 60%, 53% and
69% of patients from NNRTI, PI and INI group, respec-
tively. Also in this case, the frequencies of high total cho-
lesterol levels were not different between the three groups
(chi-square (2) = 0.863, p = 0.650).i Statistical analysish A first exploratory statistical analysis showed that one
patient, belonging to Group 1, showed extreme values
(absolute value of z-score > 1.6) for 8 (30.7%) of the 26
cytokines analyzed and, consequently, was excluded from
the analysis. The normality of distribution of continuous variables was
assessed by Kolmogorov–Smirnov test; since variables
were not normally distributed, group comparisons were
made by Kruskall-Wallis followed by the Mann–Whit-
ney U test corrected for multiple comparisons (Bonfer-
roni). To correct for possible confounding factors, such
as age, sex, smoke and disease duration, group compari-
sons were performed on natural logarithm-transformed
variables by ANCOVA, including the variables listed as
covariates. The Spearman’s Rank Test was used to ana-
lyze bivariate correlations. The categorical variables were
compared by Chi Square Test. Although statistical significance was achieved for only
few mediators, probably because of the small sample size,
our results showed that 7 of the 26 immune mediators
(18.2%), analyzed between the different groups, are influ-
enced by the type of third drug administered (Additional
file 1. Figure S1). i
As for the group of innate immunity mediators, some
traditionally inflammatory cytokines and chemokines
were more represented in PI-treated serum samples
with higher levels than those treated with INI (IL-1Ra,
p = 0.013; IL-12p70 p = 0.039; TNF-α p = 0.041; IL-8,
p = 0.027; MIP1 β, p = 0.033). Eotaxin showed lower lev-
els in Group 1 compared to Group 2 (p = 0.010), while
IP-10 was significantly lower in Group 1 compared to
both Group 2 and Group 3 (p = 0.003 and p = 0.007,
respectively). Of note, almost 47% of patients in both
NNRTI and PI groups had abnormal cytokine values
(|z-score|> 1.6), whereas 25% in the INI group showed
this behavior (Additional file 1. Table S2). However, the
difference in frequencies between groups did not reach
statistical significance (Chi-square (2) = 2.135, P = 0.344).i Data analysis was performed using SPSS Statistics for
Windows, version 21.0 (SPSS, Inc., Chicago, IL, USA). Two-tailed probability values < 0.05 were considered sta-
tistically significant. Resultsh The demographic and clinical characteristics of the pop-
ulation studied are summarized in Table 1. Table 1 Demographic
and
clinical
characteristic
of the study population
Continue variables are expressed as mean (95% Confidence Interval). Categorical
variables are expressed as percentage
Group 1
Group 2
Group 3
Age (years)
49.7 (45.9–
57.0)
52.9 (47.4–
57.1)
53.7
(45.3–
61.6)
CD4 +
857 (669–
1045)
727
(527–926)
701 (545–
857)
Sex (female, %)
44.4
50.0
33.3
Smoking status (smokers, %)
55.6
50.0
50.0
Disease Duration (years)
16.0 (11.3–
20.7)
15.5 (11.6–
19.5)
10.4 (8.7–
12.2)
Triglycerides (mg/dL)
150 (83–217)
134 (91–176)
126 (103–
149)
Total cholesterol (mg/dL)
220
(193–247)
210
(185–235)
229 (210–
248) Table 1 Demographic
of the study population Table 1 Demographic
and
clinical
characteristic
of the study population i
As shown in Table 2, statistically significant corre-
lations between disease duration and levels of some
immune mediators were found in the overall population.h The univariate analysis (ANOVA) showed that there
were no statistical differences in disease duration
between groups, although INI patients showed a ten-
dency to have lower disease duration values. In order
to correct the cytokine values for possible confounding
factors (age, sex, smoking status, duration of disease),
we used an ANCOVA approach on natural logarithm-
transformed variables. As summarized in Additional
file 1. Table S1 and Fig. 1, some of the immune mediators
tested were affected by confounding factors, in particu-
lar IL-1ra, IL12p70 and TNF-α which resulted no longer Maritati et al. AIDS Res Ther (2020) 17:61 Page 4 of 7 Page 4 of 7 Table 2 Spearman’s
correlation
coefficients
between Interleukins levels and HIV diseases duration
Interleukin
r
P value
IL-1ra
0.434
0.002
IL-7
0.371
0.010
IL-8
0.321
0.028
IL-12
0.295
0.044
G-CSF
0.325
0.026
IFNg
0.314
0.032
MCP-1
0.330
0.023
TNFa
0.402
0.005 Table 2 Spearman’s
correlation
coefficients
between Interleukins levels and HIV diseases duration cholesterol, triglycerides, and LDL-cholesterol than rec-
ommended values) that accompanies the HIV affected
patients may play a significant role in this [23]. However,
in our study the analysis conducted on total cholesterol
and triglycerides did not show statistically significant dif-
ferences between the three groups. Discussion Although HIV-related deaths have declined dramatically
since the introduction of ART, HIV infection is becoming
increasingly chronic and people infected with HIV con-
tinue to experience raised morbidity and mortality often
due to events unrelated to AIDS [19]. In fact, due to the
inability of antiretroviral drugs to eradicate the virus from
infected reservoir cells, treatment of HIV infection requires
permanent systemic therapy. However, even when success-
fully treated, HIV patients still show higher incidence of
age-associated co-morbidities than non-infected individu-
als. Chronic Immune Activation and Senescence (CIADIS),
is a process characterized by a progressive decline of
immune system function, usually detected by the expres-
sion of cellular or soluble markers derived from innate or
adaptive immune responses. Immune activation is associ-
ated with progression of HIV disease and increased mor-
bidity and mortality in HIV-infected patients despite ART
[20]. In this regard, the validation of a “CIADIS score”
based on activation, senescence, and differentiation mark-
ers, could help physicians to identify patients at high risk
for non-AIDS-related comorbidities [20]. In fact, it is strik-
ing evident that cardiovascular diseases are one of the lead-
ing non-AIDS causes of death among HIV-positive subjects
[21]. According to our findings, some inflammatory
cytokines of innate immunity (Additional file 1. Fig-
ure S1a, c, g) and two pro-inflammatory chemokines
(Additional file 1. Figure S1b, f) are more represented in
patients taking PI than those receiving INI. There are several studies comparing the effects of spe-
cific antiretrovirals and antiretroviral combinations in
ART-naïve individuals initiating their first ART regimen. In one recent ART initiation trial, INI appear to reduce
inflammation to a greater degree than NNRTI; however,
in the same study, it is not clear if there are beneficial
effects on inflammation resulting from treatment with
INI compared to PI or between PI and NNRTI [27].l It is plausible that INI may decrease inflammation and
immune activation more than other antiretroviral classes,
as INI may concentrate at higher levels in enterocytes
[28], which is important because HIV infection results
in massive depletion of immune cells within the gastro-
intestinal tract and the resultant microbial translocation
may be an important driver of immune activation in HIV. In line with this, we found that INI patients had a ten-
dency to show a lower frequency of extreme cytokine lev-
els when compared to the other groups. Fig. 1 Predicted values of cytokines (pg/ml) corrected for covariates (age, sex, smoking status and disease duration) by the ANCOVA approach.
Comparisons between groups were performed with the Sidak post-hoc test correction for multiple comparisons. Values of covariates appearing in
the model: age = 52.4 years; sex = 0.67; smoking status; 0.56; HIV duration = 13.9 years. a IL1ra; b IL-8; c IL-12; d Eotaxin; e IP10; f MIP1b; g TNF-α. Bars
and error bars denote geometric mean and 95% confidence interval
(See figure on next page.) different between the groups. On the contrary, the other
mediators were not affected by the correction. The analysis conducted in the present study reveals
that some categories of antiretroviral drugs emphasize
the residual inflammation, partly linked to HIV infection
itself [12, 13]. Resultsh This data contrasts
with what has been reported in some papers, according
to which INI are more “lipid friendly” [24, 25].i Although ART has significantly improved both the
quality and lifespan of patients, the life expectancy of
treated patients is even shorter than that of uninfected
individuals. In particular, while ART may counteract
some features of HIV-associated immunosenescence,
several anti-HIV drugs may themselves help to amplify
other aspects of immune ageing and chronic inflamma-
tion [26].h References 1. Palella FJ, Delaney KM, Moorman AC, HIV Outpatients Study Investiga-
tors, et al. Declining morbidity and mortality among patients with
advanced human immunodeficiency virus infection. N Engl J Med. 1998;338(13):853–60. 2. European AIDS Clinical Society Guidelines 2019. Version 10.0. 2019. https
://www.eacsociety.org/files/2019_guidelines-10.0_final.pdf. Accessed
Nov 2019. 3. Montaner JSG, Reiss P, Cooper D, For the INCAS Study Group, et al. A
randomized, double-blind trial comparing combinations of Nevirapine,
Didanosine, and zidovudine for HIV-infected Patients The INCAS trial. JAMA. 1998;279(12):930–7. 3. Montaner JSG, Reiss P, Cooper D, For the INCAS Study Group, et al. A
randomized, double-blind trial comparing combinations of Nevirapine,
Didanosine, and zidovudine for HIV-infected Patients The INCAS trial. JAMA. 1998;279(12):930–7. Further studies in larger cohorts are needed to confirm
the results found, to compare it to conventional markers
of inflammation, and to provide their usefulness as a sig-
nificant clinical tool to help clinicians in choosing a “tai-
lored” antiretroviral regimen. 4. Friis-Møller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy
and the risk of myocardial infarction. N Engl J Med. 2003;349:1993–2003. 5. Crum NF, Riffenburgh RH, Wegner S, et al. Comparisons of causes
and death and mortality rates among HIV-infected persons: analysis
of the pre-, early and late HAART eras. J Acquir Immune Defic Syndr. 2006;41(2):194–200. 6. Carr A, Cooper DA. Advrese effects of antiretroviral therapy. Lancet. 2000;356(9239):1423–30. Supplementary information Supplementary information accompanies this paper at https://doi. org/10.1186/s12981-020-00316-w. Supplementary information accompanies this paper at https://doi. org/10.1186/s12981-020-00316-w. Supplementary information accompanies this paper at https://doi. org/10.1186/s12981-020-00316-w. Supplementary information accompanies this paper at https://doi. org/10.1186/s12981-020-00316-w. 7. Guaraldi G, Stentarelli C, Zona S, et al. The natural history of HIV-associ-
ated lipodystrophy in the changing scenario of HIV infection. HIV Med. 2014;15(10):587–94. pp
y
org/10.1186/s12981-020-00316-w. 8. Dubé MP, Shen C, Greenwald M, Mather KJ. No impairment of endothelial
function or insulin sensitivity with 4 weeks of the HIV protease inhibitors
atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection:
a placebo-controlled trial. Clin Infect Dis. 2008;47(4):567–74. 8. Dubé MP, Shen C, Greenwald M, Mather KJ. No impairment of endothelial
function or insulin sensitivity with 4 weeks of the HIV protease inhibitors
atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection:
a placebo-controlled trial. Clin Infect Dis. 2008;47(4):567–74. Additional file 1: Figure S1. Differences in cytokine concentrations (pg/
ml) measured in patients following the therapy simplification regimen. Table S1. Crude and adjusted means of ILs values determined in study
population. Table S2. Proportion of outliers found in each group. 9. Kamin D, Hadigan C, Lehrke M, Mazza S, Lazar MA, Grinspoon S. Resistin
levels in human immunodeficiency virus-infected patients with lipoat-
rophy decrease in response to rosiglitazone. J Clin Endocrin Metabol. 2005;90(6):3423–6. Consent for publication
Not applicable. Consent for publication
Not applicable. Consent for publication
Not applicable. Competing interests The authors declare that they have no competing interests. The present study is not without limitations, first of
all with regard to the small sample size, followed by a
cross sectional design and the lack of comparison of
the immune mediators tested with other conventional
inflammatory or procoagulant markers such as CRP and
D-dimer respectively [30]. The lack of a complete set of
biomarkers hamper an exhaustive evaluation of the car-
diovascular risk and the real inflammatory profile among
the three groups and represents the main limitation of
the present study. Discussion Although not fully understood, the probable mecha-
nism involves both chronic inflammation, CD4 cell deple-
tion, endothelial dysfunction and atherosclerosis [22]. It
is undoubted that the worst lipid profile (e.g. higher total However, in contrast with the above statement, our
results show that the IFN-γ induced protein 10 (IP-10 or
CXCL-10) and eotaxin (also known as C–C chemokine Fig. 1 Predicted values of cytokines (pg/ml) corrected for covariates (age, sex, smoking status and disease duration) by the ANCOVA approach. Comparisons between groups were performed with the Sidak post-hoc test correction for multiple comparisons. Values of covariates appearing in
the model: age = 52.4 years; sex = 0.67; smoking status; 0.56; HIV duration = 13.9 years. a IL1ra; b IL-8; c IL-12; d Eotaxin; e IP10; f MIP1b; g TNF-α. Bars
and error bars denote geometric mean and 95% confidence interval
(i
g
p g ) Maritati et al. AIDS Res Ther (2020) 17:61 Page 5 of 7 Maritati et al. AIDS Res Ther (2020) 17:61 Maritati et al. AIDS Res Ther (2020) 17:61 Page 6 of 7 ligand 11, CCL1) are significantly lower in patients
treated with NNRTI compared to those belonging to the
other groups (Fig. 1e, d). This finding appears relevant
especially for IP-10, considering that this mediator is
known to be one of the first chemokines to increase fol-
lowing HIV infection [29] and it is involved in immune
cell trafficking to inflammatory sites. In particular, the
continued production of IFN-γ in the lymphoid organs
is responsible for a prolonged increase in IP-10 dur-
ing chronic HIV infection, even in patients taking ART. In fact, IP-10, by increasing the susceptibility of naive
T CD4 + T lymphocytes to HIV infection, improves the
production (constitution) of HIV reserves.hi Funding
The authors received no specific funding for this work. Author details 1 Section of Infectious Diseases, Department of Medical Sciences, Univer-
sity of Ferrara, 44124 Ferrara, Italy. 2 Department of Biomedical & Specialty
Surgical Sciences, University of Ferrara, Ferrara, Italy. 3 Department of Medical
Sciences, University of Trieste, Trieste, Italy. 4 Institute for Maternal and Child
Health – IRCCS “Burlo Garofolo”, Trieste, Italy. 5 Infectious Diseases Unit, Azienda
Ospedaliero-Universitaria di Cona (Ferrara), Ferrara, Italy. Received: 17 June 2020 Accepted: 3 September 2020 However, although with limitations, our data seem
to highlight the importance of how the choice of the
third drug in an antiretroviral regimen can promote the
imbalance of inflammation-related immune mediators. In particular, our results seem to discourage the admin-
istration of PI as a third drug in a virologically effective
antiretroviral regimen, as its use is linked to the detection
of higher levels of pro-inflammatory mediators than INI
and NNRTI.i Funding
h
h Availability of data and materials
The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request. Ethics approval and consent to participate Ethical approval for this study was obtained from the Regional Ethical Com-
mittee. The research was carried out in accordance with the ethical principles
of the Declaration of Helsinki. Written informed consent was obtained from all
subjects before the study. Authors’ contributions Martina Maritati and Carlo Contini equally contributed to the design of the
study and the writing of the manuscript; Manola Comar and Tiziana Bellini
contributed to the revision of the article and its significant intellectual con-
tent; Nunzia Zanotta and Alessandro Trentini contributed to the elaboration of
the statistical analysis and interpretation of data; Laura Sighinolfi contributed
to the collection of patient’s data and the creation of graphics. All authors
reviewed, revised and provided final approval of this manuscript before
submission. 10. Sabin CA, Darminio Monforte A, Friis-Moller N, et al. Changes over time in
risk factors for cardiovascular diseases and use of lipid-lowering drugs in
HIV infected individuals and impact on myocardial infarction. Clin Infect
Dis. 2008. https://doi.org/10.1086/528862. 10. Sabin CA, Darminio Monforte A, Friis-Moller N, et al. Changes over time in
risk factors for cardiovascular diseases and use of lipid-lowering drugs in
HIV infected individuals and impact on myocardial infarction. Clin Infect
Dis. 2008. https://doi.org/10.1086/528862. 11. Leite KME, Santos Júnior GG, Godoi ETAM, et al. Inflammatory biomarkers
and carotid thickness in hiv infected patients under antiretroviraltherapy,
undetectable hiv-1 viral load, and low cardiovascular risk. Arq Bras Car-
diol. 2019. https://doi.org/10.5935/abc.20190230. Page 7 of 7 Maritati et al. AIDS Res Ther (2020) 17:61 Maritati et al. AIDS Res Ther (2020) 17:61 23. Feeney ER, Mallon PW. HIV and HAART-associated dyslipidemia. TOCMJ. 2011;5:49–63. https://doi.org/10.2174/1874192401105010049. 12. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy
and risk of cardiovascular disease in persons with HIV-1 infection: explora-
tory analyses from the SMART trial. Antivir Ther. 2008;13(2):177–87. 24. Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C,
et al. Efficacy and tolerability of 3 non nucleoside reverse transcriptase
inhibitor-sparing antiretroviral regimens for treatment-naive volunteers
infected with HIV-1: a randomized, controlled equivalence trial. Ann
InternMed. 2014;161(7):461–71. 13. Calza L, Manfredi R, Verucchi G. Myocardial infarction risk in HIV-infected
patients: epidemiology, pathogenesis and clinical management. AIDS. 2010;24(6):789–802. 14. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune
activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17:1881–8. 25. Martinez E, Larrousse M, Llibre JM, Gutierrez F, Saumoy M, Antela A, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-
infected patients: the SPIRAL study. AIDS. 2010;24(11):1697–707.i 15. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a
cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–71. 26. Authors’ contributions Franzese O, Barbaccia ML, Bonmassar E, Graziani G. Beneficial and detri-
mental effects of antiretroviral therapy on HIV-associated immunosenes-
cence. Chemotherapy. 2018;63(2):64–75. 16. Wada NI, Jacobson Lp, Margolick JB, et al. The effect of HAART-induced
HIV suppression on circulating markers of inflammation and immune
activation. AIDS. 2015;29(4):463–71. 27. Hileman CO, Funderburg NT. Inflammation, immune activation, and
antiretroviral therapy in HIV. Curr HIV/AIDS Rep. 2017. https://doi. org/10.1007/s11904-017-0356-x. 17. Comar M, Zanotta N, Bonotti A, et al. Increased levels of C-C chemokine
RANTES in asbestos exposed workers and in malignant mesothelioma
patients from an hyperendemic area. PLoS ONE. 2014;9(8):e104848. 28. Patterson KB, Prince HA, Stevens T, Shaheen NJ, Dellon ES, Madanick RD,
et al. Differential penetration of raltegravir throughout gastrointestinal
tissue: implications for eradication and cure. AIDS. 2013;27(9):1413–9. 18. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on
the assessment of cardiovascular risk: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S49–73. 29. Jie L, Xiaowan Y, Hong S, Yongjun J. IP-10 is highly involved in HIV infec-
tion. Cytokine. 2019;115:97–103. 30. Pinzone R, Di Rosa M, Cacopardo B, Giuseppe NG. HIV RNA suppres-
sion and immune restoration: can we do better? Clin Dev Immunol. 2012;2012:515962. 19. Duffau P, Ozanne A, Bonnet F, et al. Multimorbidity, age-related comor-
bidities and mortality: association of activation, senescence and inflam-
mation markers in HIV adults. AIDS. 2018;32(12):1651–60. 20. Duffau P, Wittkop L, Lazaro E, ANRS CO3 Aquitaine Cohort Study Group,
et al. Association of immune-activation and senescence markers with
non-AIDS-defining comorbidities in HIV- suppressed patients. AIDS. 2015;29(16):2099–108. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations. Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations. 21. Islam FM, Wu J, Jansson J, et al. Relative risk of cardiovascular disease
among people living with HIV: a systematic review and meta analysis. HIV
Med. 2012. https://doi.org/10.1111/j.1468-1293.2012.00996.x. 22. Eyawo O, Brockman G, Goldsmith CH, et al. Risk of myocardial infarc-
tion among people living with HIV: an updated systematic review and
meta-analysis. BMJ Open. 2019;9:e025874. https://doi.org/10.1136/bmjop
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Optimal Design of Ship’s Hybrid Power System for Efficient Energy
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Transactions on maritime science
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cc-by
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1. INTRODUCTION The International Maritime Organization regulations on the
reduction of greenhouse gas emissions (GHGs) from ships require
efficient dealing with this complex techno-economic and highly
political problem through joint efforts of all major stakeholders
from the shipbuilding industry and ship operations. The Kyoto Protocol of 1997, paragraph 2.2, entrusted the
International Maritime Organization (IMO) (3rd IMO GHG Study,
2014) with the responsibility to regulate and reduce harmful
emissions from ship (IMO, 2017). Maritime transportation emits
approximately 1,000 million tons of CO2 annually and accounts
for about 2.5 % of the global greenhouse gas emissions (Kyoto
Protocol, 2017). The emissions of harmful contents from vessels
are anticipated to increase by 50 %-250 % by 2050, depending
on the future developments in the fields of economy and
energy. This is not in line with the international agreements to
decrease global emissions by at least 50 % by 2050 to keep the
global temperature increase under 2°C. The IMO regulated CO2
emissions by adopting Annex VI to the MARPOL Convention. Guidelines for improving energy efficiency were also laid down
with the intention to monitor and improve ships’ performances
and features with regard to various factors that may contribute
to CO2 emissions (see Figure 1). A “new” ship means a ship the
building contract for which was concluded on or after 1 January
2013 or in the absence of a building contract, the keel of which
was laid or which was in the similar stage of construction on or
after 1 July 2013 or which was delivered on or after 1 July 2015. The key problems of any research in the field of renewable
energy, including power generation, storage, transformation
and distribution, and the issues associated with limited power
generation for specific loads, are the same issues that are
experienced in the implementation of electric distribution
technologies onboard ships. This paper analyses the effects of efficient shipping using
the solar panel system and batteries to ensure continuous
power supply, regardless of the weather conditions. The logistics
chain of this control architecture is modelled by Colored Petri
Nets. The economic analysis examines the annual costs of fuel
consumption, the initial capital cost, total net cost and CO2
emissions. 2. POWER MANAGEMENT IN THE PROPOSED SHIP’S
POWER PLANT Figure 2 shows the hybrid system consisting of PV panels,
batteries, a charge regulator, AC diesel generators, converters/
inverters, and load controls. The hybrid power distributed
generation system provides four operating modes, depending on
the prevailing environmental conditions, battery charge status
and load variation. The controller switches from one mode to
another, depending on instructions determining mode selection. Mode 0: If solar energy is not available and the state of
charge (SOC) of the batteries is very low, i.e. lower than the
minimum recommended by the manufacturer (SOCmin), the
batteries should not be used and the required energy should be
provided by the AC generator. This paper is a contribution to ships’ power system energy
management in general, and to PLOVPUT’s working boat in
particular. This vessel, which served as the basis for our research
(Tech. doc. PLOVPUT) was under construction. It is a public
service workboat, fully equipped to perform a variety of marine
and hydro-submarine operations related to the maintenance of
waterways in the Croatian Adriatic. These activities include the
maintenance of existing and the construction and equipping of
new aids to navigation, e.g. marking waterways with navigation
buoys; supplying and maintaining onshore and offshore
lighthouses; transportation and installation of construction
materials onshore and under the sea, performing hydro-
submarine operations; transportation of construction machinery. Mode 1: If weather is cloudy and (SOC) is normal, the
controller allows the batteries to provide sufficient power for
the load. If the load exceeds the power of batteries, excess load
will be handled by the AC generator. This mode is maintained
while the state of charge (SOC) is above SOCmin or while power
obtained from solar energy is above threshold power. Outside
the above limits, the hybrid power system must switch either to
Mode 0 or Mode 2. Mode 2: If there is plenty of solar energy, photovoltaic
(PV) system resources are connected to the vessel’s grid and
PV-generated energy must be preferentially used to power the
loads. In the event of surplus energy (Pch), the controller puts
the batteries into charging mode until they reach maximum
charge value (SOCmax). If the power supplied by the PV system is
insufficient for the load, the necessary power should be supplied
by the batteries. KEY WORDS ~
~ Renewable power ~
~ Power management system onboard shipsfi ~
~ Energy efficiency ~
~ CO2 emissions Various studies and papers (Gudelj and Krčum, 2013;
EEDI – IMO, 2012; RSSPS, 2017; Øverleir, 2015) indicate that
environmental pollution can be significantly reduced and the
low energy efficiency of traditional marine systems improved
by the proper integration of renewable energy sources onboard
vessels where electrical power is produced by the ship’s power
plant using a diesel / turbo generator. ~
~ Multi-objective optimization a. University of Split, Faculty of Maritime Studies, Split, Croatia
e-mail: mkrcum@pfst.hr
b. University of Rijeka, Faculty of Maritime Studies, Rijeka, Croatia
e-mail: tomas@pfri.hr
This work is licensed under
doi: 10.7225/toms.v07.n01.002 Trans. marit. sci. 2018; 01: 23-32
a. University of Split, Faculty of Maritime Studies, Split, Croatia
e-mail: mkrcum@pfst.hr
b. University of Rijeka, Faculty of Maritime Studies, Rijeka, Croatia
e-mail: tomas@pfri.hr
This work is licensed under
doi: 10.7225/toms.v07.n01.002 For instance, the installation of photovoltaic (PV) systems
in the power system helps reduce greenhouse gas emissions,
improves energy efficiency and contributes to the stability of the
ship’s power system. TRANSACTIONS ON MARITIME SCIENCE 23 Trans. marit. sci. 2018; 01: 23-32 23 However, installing a PV system requires significant
attention and consideration of certain aspects, such as: unlike
land-based systems, onboard power systems are exposed
to constant load changes (Krčum et al., 2010). The frequent
presence of seawater on the deck, where photovoltaic panels are
accommodated, has a significant impact on their effectiveness;
at sea, a vessel is always under some load, which may not be the
case with shore-based PV systems; while the angle of sunlight at
a specific location on land is constantly the same, this is never the
case at sea with ever changing waves, sailing routes and courses. staying in port, electricity supply is provided by one DEA due to
reduced electricity consumption. In case of overload, the power
management system shuts down shedable, i.e. less important
consumers. The authors of this study assume that the integration of
renewable energy sources in the vessel's power system (Figure
2) may contribute to CO2 emission reduction. The basis for this
hypothesis were the results obtained by the simulation of a
hybrid marine power system on HOGA software, developed on
the basis of Colored Petri Nets (CPN) models that coordinate and
manage the flow of information. Figure 1. IMO recommendations for reducing CO2 emissions
2015-2050 Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy 2. POWER MANAGEMENT IN THE PROPOSED SHIP’S
POWER PLANT The vessels’ energy resources include: The vessels’ energy resources include: •
Three main-board voltage generators: diesel electric power
generators 190 kVA, 3x400 V, 50 Hz, one diesel electric generator
80 kVA, 3x400 V, 50 Hz and an inverter/charger; and •
Secondary-board voltage transformer, batteries and
rectifiers. If the batteries cannot handle the entire load, the excess
part of the load will be handled by the AC generator. The diesel electric aggregate (DEA) meets energy
consumption needs in all modes, depending on the balance
of electricity. In the operating mode and normal mode of
navigation, all required power is provided by one diesel electric
aggregate (1x190 kVA). In departure mode, buoy handling
mode and concrete plant operation mode, the required power
is supplied by two DEA (2x190 kVA) in parallel operation. When Mode 3: In this mode the load demand (Pload) is lower than
the available solar energy (Ppv) and the batteries are fully charged
(SOC >=SOCmax). This mode is used when there is sufficient PV
power to meet the total demand and it is maintained until the
load exceeds the available PV power. If the total load exceeds the
available PV power, the system switches to Mode 1. Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy 24 Figure 2. Hybrid ship power system configuration. Figure 2. Hybrid ship power system configuration. For modes 1, 2 and 3, if the AC generator produces more
power than required, and the power envisaged to be supplied by
the AC generator is lower than the critical power limit (Pcritical_
gen), surplus power can be used to charge the batteries up to
SOC value, the so-called SOCstp_gen (batteries SOC set point for
the AC generator). In order to present a supervising control of
the hybrid energy system, the following sections discuss the use
of Colored Petri Nets (CPNs). Since the hybrid renewable energy
system consists of several sources and involves different states
and events, the entire system is considered to be a discrete
event system (DES). The discrete dynamics of power systems are
particularly relevant for mode switching and selecting sources on
DC and AC buses depending on the available renewable energy
and load. CPNs allow us to define which actions occur in DES,
which states preceded these actions and which states will be
achieved after the actions have been performed. CPN = ( P,T,A,Σ,N,C,G,E,m0 ) (1) where, P is a finite set of places, T is a finite set of transitions;
A is a finite set of arcs. ∑ is a finite set of types called color sets. This set contains all possible colors, operations, and functions
used within a CPN. 2. POWER MANAGEMENT IN THE PROPOSED SHIP’S
POWER PLANT Colored Petri
Nets is an outstanding tool for testing the simulated environment
and avoiding the occurrence of potential forbidden states in the
real world. states. Colored Petri Net (CPN) combines the best of classical
PNs and high level programming languages (Jensen et al., 2007;
Jensen, 1991). Data, data types and transition conditions are
described by a functional programming language. The token,
with attached data value (called token color), can encode a vast
amount of information that determines transition firing. Places
are associated with color sets. A color set specifies the data type
a place can hold. A transition can be programmed using special
constructs and functions. Additional constructs can be used to
enable or disable transition firing. Input and output arcs can have
expressions and functions related to them. For a transition to be
enabled, input arcs expressions need to bind successfully with
the tokens present in the input places and the transition guard. The tokens are placed in the respective output places. A Colored Petri Net can be formally defined as a 9-tuple
(Jensen, 1991). (1)
CPN = ( P,T,A,Σ,N,C,G,E,m0 ) 2.1. Colored Petri Nets (CPNs) Petri net (PN) is a bipartite graph determined by four kinds
of objects: places, transitions, directed arcs and tokens (Gudelj et
al., 2012). In the PN model, places represent system states and
transitions represent the assessment of transition of system N:A → (P×T)U(T×P) is a node function. C is a color function
which maps places in P into color in Σ. G is a guard function TRANSACTIONS ON MARITIME SCIENCE Trans. marit. sci. 2018; 01: 23-32 25 25 The PN controller was designed using CPN tools (Version
4.0.1 (CPNTools, 2017). Taking into account the specific network
topology and net load, the model simply focuses on switching
modes of operation and estimating the batteries’ state of charge
(SOC) once an hour. Battery SOC and net load are used as
parameters for the ON/OFF control of PV and diesel generators. As stated above, CPN places consist of a set of markers called
tokens, with their attached token color. The necessary color sets
and variables are as shown in Figure 4. In the design control
strategy, hourly intervals are considered, where all the involved
variables are assumed to be constant throughout these intervals. Accordingly, the place Next_hour represents one hour which is
allocated a single token. Initially this value is 0, and is updated on
an hourly basis. defined from T into guard expressions g. The output of the
guard expression should evaluate to Boolean value true or false. E:A→[expr] is an arc expression function which maps each arc
αєA into expression e. m0 is the initial marking of CPN. For more
details and CPN theory, refer to (Jensen et al., 2007). Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy Figure 5.
Function declaration of the CHARGE and DISCHARGE
processes. Due to limited space, the process shown in CPN Tools is not
described in the paper. Figures 6 and 7 illustrate the performance
of our strategy. Figure 6 shows markings of each place Mode0,
Mode1, Mode2 and Mode3. The figure illustrates the decision made
by the PN controller coordinating operating modes. According
to the process, Figure 7 shows the power balance during the
simulation and describes the evolution of the duty cycle for PV
sources and batteries. The synchrony between consumption and
photovoltaic generation can be considered to allow the direct
use of energy. In this simulation, the weather was very sunny. Pac is power consumed by loads in the AC bus, while Pdc
denotes the power consumed by loads in the DC bus. Ppv refers
to power produced by PV renewable sources in the DC bus. K_AC/DC is the efficiency of the battery charger and Kinv is the
efficiency inverter. Pinv_max describes maximum active power
that can be produced by the inverter. This function computes the values of surplus power (Pch)
which is used to charge the batteries or the value of the load that
has not been fed (Pdis) as a function of the AC load (Pac), the DC
load (Pcd) and the energy produced by the PV sources Ppv (Dufo-
Lopez et al. 2007). If the PV renewable sources produce more
energy than required by AC/DC, surplus power Pch is calculated
on the one-hour basis. If, on the contrary, the PV system is unable
to cover DC energy demand (Ppv<Pcd) or the apparent power at
the AC/DC inverter output (Pac/Kinv), the load that has not been
fed (Pdis) is calculated. The energy deficit should be compensated
either by batteries or the AC generator to cover the AC load or DC
load. During the night, energy is supplied by batteries and the
system is in mode 1. At 8 a.m. and 5 p.m. PV panels generate
approximately 401Wh of power, which is insufficient. The
batteries are used to compensate for the gap. At 9 a.m., when the
power generated by the PV increases very rapidly and exceeds
the load, the PN switches the system to mode 2. Surplus power is
stored in batteries, which are recharged. At 2 p.m., when batteries
are full and surplus PV power can no longer be injected into
batteries, the PN switches the system to mode 3. 2.2. CPN Control System Based on the proposed hybrid power system (see
Introduction) and logistics issues related to the implementation
of renewable sources facilitating efficient shipping, algorithms
developed by the authors and C-PN rules, we designed a PN
model of a control system managing energy flow and coordinating operations of hybrid energy systems onboard
ships (see Figure 3). Figure 3. CPN control design of the ship hybrid energy system. CPN control design of the ship hybrid energy system. Figure 4. Definition of color sets and variables. The estimated state of batteries for each hour place is
modelled by Ebat. Three states for the batteries are considered
and they are defined by three token colors (S1, S2, S3) from the
colors set batStates (see Figure 3). The first color (S1) indicates
that the battery is empty (SOC<SOCmin), whereas the second
color (S2) signifies that the battery is fully charged. The latter
state is reached when the battery state of charge (SOC) becomes
equal to or higher than the maximum value (SOCmax). The third
color (S3) indicates that the battery is in an intermediate state, i.e. that its SOC is between minimum (SOCmin) and maximum value
(SOCmax). The place DIS_CH checks the system energy balance
and battery SOC at each time interval and shows whether the
system is in Charge state or in Discharge state. Charging and
discharging processes are coded by the function Discharge_
Charge (Figure 5) through a communication link with the load
layer and PV resources. Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy 26 in Section. These transmit information to one of four transitions
(PVswitchOFF,
BatswitchON,
PVswitchON,
PVswitchON1). Together with the surrounding arc inscriptions, these transitions
define how resources are reserved and released. Table 1. Conditions for selecting the appropriate operating mode. Conditions
Selected
mode
Charge/Discharge value
Battery States
Pch=0.0 and Pdis>0.0
S1
Mode 0
Pch=0.0 and Pdis>0.0
S3 or S2
Mode 1
Pch>0.0 and Pdis=0.0
S2
Mode 2
Pch>=0.0 and Pdis=0.0
S3
Mode 3 Figure 5. Function declaration of the CHARGE and DISCHARGE
processes. Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy Figure 5.
Function declaration of the CHARGE and DISCHARGE
processes. In mode 3 the
battery SOC is constant. The second part selects operating modes of the power
station. Each mode is represented by a single place: Mode0,
Mode1, Mode2 and Mode3. Communication between operating
modes is carried out by the transition SELECTED_MODE. The
latter is triggered when it receives information from the first part,
and the next node when the aforementioned mode is selected. Although transition SELECTED_MODE is enabled for all modes, it
can drive only one mode for each hour. This situation is called a
conflict (because the binding elements are enabled individually,
but not synchronously), and it is said that the transition
SELECTED_MODE is in conflict with itself. The switching between
the modes is determined by evaluating the corresponding
arc expression, associated to the output arcs from the places
Mode0, Mode1, Mode2, Mode3, according to the rules described Figure 6. Mode switches in function of time. Figure 6. Mode switches in function of time. TRANSACTIONS ON MARITIME SCIENCE Trans. marit. sci. 2018; 01: 23-32 27 Figure 7. Simulation results. 3. OPTIMIZATION METHODOLOGY where R is the useful lifetime of the project, ir is the real interest
rate, which is a function of the nominal interest rate irnominal and
the annual inflation rate fr , defined by following equation (Yang
et al., 2008): (4)
ir =
irnominal - fr
1 + fr (4) CF ($) are fuel consumption costs for 1 h of diesel generator
operation (Belfkira et al, 2011): (5)
CF = PrF ∙ ( A ∙ PD + B ∙ PRD ) (5) 3. OPTIMIZATION METHODOLOGY where PrF is fuel price ($/l), A=0.246 l/kWh and B=0.0845 l/kWh
fuel curve coefficients. This research proposes a HOGA based-optimal design
of PV-Diesel-Battery stand-alone hybrid energy system for a
specific vessel. The system should be properly designed in
terms of economic and environmental aspects that are affected
by physical and operational constraints and strategies. HOGA
software uses Genetic Algorithms (GA) that may produce
adequate solutions when applied to highly complex problems
(Dufo-Lopez, 2006; Dufo-Lopez and Bernal-Agustin, 2005; Dufo-
Lopez et al. 2007; Gudelj and Krčum, 2013). They optimize system
components (main genetic algorithm) and the control strategy
(secondary genetic algorithm (HOGA, 2017). The program
permits mono or multi objective optimization (Dufo-Lopez and
Bernal-Agustin, 2005). In this research, the focus of the analysis
was on the multi-objective design of the hybrid PV–diesel system
with battery storage, intended to minimize both the Net Present
Cost (NPC) of the system and the life cycle of CO2 emissions (LCE),
taking into account only emissions from fuel consumption. The
NPC represents investment costs plus the discounted present
values of all future costs during the system’s lifetime. It can be
defined as follows: The model of PV-Diesel-Battery stand-alone hybrid energy
system for a specific vessel is a multi-objective problem where
two objects are to be minimized (the sum of the net present cost
and life cycle CO2 emissions) and is expressed as follows: (6)
min F = min [ NPC(x), LCE(x) ]
(7)
x = { NPV , a, NBAT , b, NG , c } (6)
min F = min [ NPC(x), LCE(x) ] (6) (7) where NPV , NBAT , and NG are respectively the total number of PV
panels, batteries and AC generators. a, b and c are the type of PV
panel, the type of battery, the type of AC generator, respectively. Additional constraints to be imposed are: (8)
PPV (t) + PBAT (t) + PG (t) ≥ Pload (t) (8)
PPV (t) + PBAT (t) + PG (t) ≥ Pload (t)
(9)
SOCmin ≤ SOC(t) ≤ SOCmax
(10)
0 ≤ NPV ≤ NPVmax
0 ≤ NBAT ≤ NBATmax } (8) (9)
SOCmin ≤ SOC(t) ≤ SOCmax SOCmin ≤ SOC(t) ≤ SOCmax SOCmin ≤ SOC(t) ≤ SOCmax (9) (2)
NPC = ∑k ( Ck + CREP +CO&M ∙ + CF )
1
CFR ( ir, R )
k
k (10)
0 ≤ NPV ≤ NPVmax
0 ≤ NBAT ≤ NBATmax } (10)
0 ≤ NPV ≤ NPVmax
0 ≤ NBAT ≤ NBATmax } (10) where Ck ($) represents capital costs of each component k (PV
generator, battery, inverter, battery charge controller and diesel
generator). C k
REP ($) indicates the cost of replacement of each
component k during the system’s lifetime. C k
Q&M ($) are the annual
operating and maintenance costs for component k throughout
the system’s lifetime. CRF is capital recovery factor (Yang et al.,
2008; RSoSPS, 2017) which is defined as follows: where Ck ($) represents capital costs of each component k (PV
generator, battery, inverter, battery charge controller and diesel
generator). C k
REP ($) indicates the cost of replacement of each
component k during the system’s lifetime. C k
Q&M ($) are the annual
operating and maintenance costs for component k throughout
the system’s lifetime. CRF is capital recovery factor (Yang et al.,
2008; RSoSPS, 2017) which is defined as follows: Constraint (8) ensures that for any given period t, the total
power supply from the hybrid generation system is sufficient to
supply total demand. The relation (9) determines the maximum
depth of battery discharging and the minimum depth of battery
charging. The relation (10) is the constraint referring to the
number of PV modules and batteries. 4. EXAMPLE OF APPLICATION HOGA was used as a test tool for the optimization of the
hybrid system analyzed in this research. As mentioned above, the
PV-Diesel-Battery energy system on the special-purpose vessel
serving along the eastern Adriatic coast is used as case study. The
system has the DC voltage of 48V and AC voltage of 230V. The
typical daily load profiles of the ship are shown in Figure 8. Trojan’s deep-cycle flooded batteries were chosen. Trojan’s technology has proven to be suitable for use in marine
applications (The Marine battery…, 2015). Three models of
12V batteries with the capacity of 97/106/225 Ah, having the
acquisition cost of 150/195/211.6 $/battery, respectively, are
considered. As the DC voltage of the system is 48 V, there are four
batteries in series. The number of parallel groups allowed ranges
between 1 and 15. The O&M cost amounts to 1.5/1.95/1.6 $/year. The number of possible AC generators in parallel can range
from 1 to 3. The lifetime of an AC generator is 10000 h, and its
minimum AC generator output power is 30 %. CO2 emission is
3.5 kg CO2. The effective interest rate considered is 6 %. The fuel
price is 0.8 €/l. The efficiencies are 80 % for the batteries, 90 % for
the inverter and 90 % for the battery charger. The lifetime of the
entire system is 25 years. Trojan’s deep-cycle flooded batteries were chosen. Trojan’s technology has proven to be suitable for use in marine
applications (The Marine battery…, 2015). Three models of
12V batteries with the capacity of 97/106/225 Ah, having the
acquisition cost of 150/195/211.6 $/battery, respectively, are
considered. As the DC voltage of the system is 48 V, there are four
batteries in series. The number of parallel groups allowed ranges
between 1 and 15. The O&M cost amounts to 1.5/1.95/1.6 $/year. The selection of appropriate solar panels requires data
on solar radiation by month in the given area. An average
monthly solar irradiation energy throughout the year for the
eastern Adriatic Coast is between 1.62 (kWh/m2) in December
and 8.07 (kWh/m2) in July. In this area, the value of average daily
irradiation on horizontal surface is 4.76 (kWh/m2/day). Therefore,
the potential for the utilization of this type of energy is clearly
rather high. The number of possible AC generators in parallel can range
from 1 to 3. (6)
min F = min [ NPC(x), LCE(x) ] The number of batteries to be connected in a series is
not subject to optimization but is a straightforward calculation,
whereas the number of parallel battery strings NBAT,P , each
consisting of NBAT,S batteries connected in series, is a design (3)
CFR (ir, R) =
ir ∙ ( 1 + ir )R
( 1 + ir )R - 1 CFR (ir, R) =
ir ∙ ( 1 + ir )R
( 1 + ir )R - 1 (3) 28 variable that needs optimization (Trazouei and Trazouei, 2013). The total number of batteries is NBAT = NBAT,P * NBAT,S. PV panels are designed for use in residential applications and
will not survive being installed on a vessel or seawater exposure
which will cause them to delaminate, corrode or deteriorate. KYOCERA Solar panels (Kyocera, 2017) have demonstrated
successful and reliable performance in the marine environment
over the years. This is the reason why three commercial models
of multi-crystalline silicon KCM solar panels of 140/255/320 Wp,
featuring 12/12/24 V nominal voltage, having the acquisition
cost of 293/317/432 $/per panel and the annual O&M cost of
2.93/3.17/4.32 $/year, respectively, are considered. As the DC
voltage of the system is 48 V, the application of four or two
panels in series is possible, depending on the nominal voltage
(48/nominal voltage). The number of parallel groups allowed
ranges between 0 and 20. The estimated lifetime of PV arrays is
25 years and emissions are 600/600/800 kgCO2, respectively, in
the manufacturing. ,
,
The number of panels to be connected in series NPV,S
depends on the selected DC bus voltage (bus V) and is not
subject to optimization. The number of parallel strings NPV,P is the
design variable that needs optimization. The total number of PV
panels is NPV = NPV,P * NPV,S. Inputs required for system optimization include capital
expenses, replacement, operating and maintenance costs of
all components, as well as efficiency, components and project
lifetime, component specifications, hourly load demand and
hourly meteorological data over a one year period. 5. OPTIMIZATION RESULTS Table 2. Multi-objective GA Parameters. Parameter
Values
Parameters
Values
Population
Size
15
Selection
function
Elitism
Population
Type
vector
Crossover
function
Single-point
Initial
Population
random
Crossover
rate
0.75
Max
generation
20
Mutation
function
Uniform
Mutation rate
0.01 This section is an assessment of the realistic operating
scenario for PLOVPUT’s working boat. The behavior of the
energy storage and production system was simulated using the
simulator presented in the preceding section. Three load profiles
were tested: profile #1: full AC/DC load was simulated; profile #2:
10 % of AC load and full DC load were simulated; profile #3: only
DC load was simulated. The goal of optimization is to find an optimal configuration
of the system by simultaneously minimizing net present cost and
CO2 emissions in terms of the decision variables of the problem
(Eq. 7). This task was achieved using HOGA, utilizing a multi-
objective genetic algorithm. The applied genetic algorithm GA can search for the
configuration of PV panels, batteries and AC generators that
minimizes the two objectives expressed in Equation (6). The
genetic algorithm GA simulates the survival of the fittest
among individuals over consecutive generations throughout
the solution of a problem (Goldberg, 1989). Each generation
consists of a population analogous to a set of chromosomes. In
this paper, GA uses an integer representation of chromosomes. Each chromosome is a vector in the form [NPV a NBAT b NG c]
that consists of six positions which, respectively, correspond to
six decision variables: number of PV panels, the type of PV panel,
the number of batteries, the type of battery, the number of AC
generators and the type of AC generator (Eq. 7). The individuals
in the population are then exposed to the process of evolution. The elitist mechanism is applied which keeps individuals with
high degree of adaptability depending on their fitness. Crossover
operator is applied to the group, and individuals are selected by
crossover and mutation probability to generate new individuals. Thus, genes from good individuals propagate throughout the
population and each subsequent generation achieves better
fitness values. The obtained optimal configuration for profile #1 is
unacceptable because it includes a large number of PV modules
which cover an area of 120 m2. The obtained optimal configuration for profiles #2 and
#3 has the lowest system total cost and the lowest emissions. 4. EXAMPLE OF APPLICATION The lifetime of an AC generator is 10000 h, and its
minimum AC generator output power is 30 %. CO2 emission is
3.5 kg CO2. The effective interest rate considered is 6 %. The fuel
price is 0.8 €/l. The efficiencies are 80 % for the batteries, 90 % for
the inverter and 90 % for the battery charger. The lifetime of the
entire system is 25 years. In optimizations, commercially available components are
considered and prices are all unfeigned. Most low budget solar Figure 8. Average hourly distribution of AC and DC loads. 37.55
37.55
80.225
80.2
69.075
80.225
80.225
37.55
37.55
1.15
1.15
1.55
1.6
1.5
1.15
1.15
0.2
0.6
1
1.4
1.8
12345678
91
01 11 21 31 41 51 61 71 81 92 02 12 22 32 4
30
70
110
DC_load (kW)
Hours
AC_load (KW)
AC_load
DC_load Figure 8
37.55
37.55
80.225
80.2
69.075
80.225
80.225
37.55
37.55
1.15
1.15
1.55
1.6
1.5
1.15
1.15
0.2
0.6
1
1.4
1.8
12345678
91
01 11 21 31 41 51 61 71 81 92 02 12 22 32 4
30
70
110
DC_load (kW)
Hours
AC_load (KW)
AC_load
DC_load g
Average hourly distribution of AC and DC loads. TRANSACTIONS ON MARITIME SCIENCE Trans. marit. sci. 2018; 01: 23-32 29 5. OPTIMIZATION RESULTS Daily average energy to comply with the operational profiles and excess energy, profile #3. Figure 10. Daily average energy to comply with the operational profiles and excess energy, profile #3. Trans. marit. sci. 2018; 01: 23-32 5. OPTIMIZATION RESULTS According to the results, the lowest NPC over 25 years is obtained
when PV-diesel hybrid generation is combined with battery
storage. In addition, this configuration is capable of meeting the
load demand without any unmet load during simulation time. Hybrid solutions for renewable and AC generation can reduce
costs in the long term, although the initial investment is much
higher. The use of AC generator is substantially reduced, resulting
in fuel economy and emission savings (see Table 2). Figure 9 and
Figure 10 show optimal configurations for load profiles #2 and
#3, total energy production for each component and hourly
simulation throughout the year. During the year, for load profile #2, AC generators produce
about 77.7 % and renewable resources only 22.3 % of the overall
energy. For profile #3, owing to lower load (DC load only), a viable
solution is an AC generator operating only for a couple of hours
each day. The AC generator produces only 0.01 % of the energy, The parameters for the Genetic Algorithm (GA) have been
taken from Table 2. Table 3. Multi-objective GA Parameters. Load
profile
Only Diesel
Optimal results
NPC
($)
AC operation
(h/yr)
CO2
(t/yr)
AC_CO2
(t /yr)
NPC
($)
PV power
(W)
Battery capac. (Ah)
AC Pgen_min
(kVA)
AC operation
(h/yr)
#1
-
-
622.56
595.52
3809600.0
450x255
270x225
57
5127
#2
272261
6852.4
56.32
54.12
699016.88
45x255
72 x 225
3
4818
#3
63034
4376.3
0.774
10.00
49809.00
28 x 320
24 x 225
3
2 Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy Maja Krčum et al.: Optimal Design of Ship’s Hybrid Power System for Efficient Energy 30 30 while renewable resources produce the remaining 99.9 %. CO2
emissions from fuel combustion are avoided, leaving only those
relating to the life cycle of the facility (manufacturing, transport and scrapping). However, the AC generator remains an important
source of energy meeting the AC load demand although its O&M
cost is high. Figure 9. Energy during one year, load profiles #2 and #3. Figure 10. Daily average energy to comply with the operational profiles and excess energy, profile #3. Figure 9. Energy during one year, load profiles #2 and #3. Figure 9. Energy during one year, load profiles #2 and #3. Figure 10. Daily average energy to comply with the operational profiles and excess energy, profile #3. Figure 10. 6. CONCLUSION consideration of a number of factors such as required loads and
the availability of solar energy. Using a simulation model that
only considered PV systems which can actually be mounted on
the deck of Plovput’s vessel, the consumption loads in certain
modes of vessel operation were monitored, and the information
flow followed to manage the distribution of load power. The
optimal design, allowing energy management, operational cost
function minimization and the reduction of CO2 emission, was
implemented using the HOGA software. The goal of this research was to prove that a specific
vessel, a workboat built in 2016 and operated by Plovput, may
generate renewable energy in compliance with the rules of the
International Maritime Organization (IMO), which are becoming
mandatory as of 2025. The use of photovoltaic (PV) solar systems
to supply various onboard users with power (e.g. instruments,
lights, winches, propulsion…) reduces fossil fuel consumption
and consequently the harmful exhaust gas emissions. However,
the efficient application of solar energy onboard ships depends
on investment costs of any given solar system and the careful This
paper
focuses
on
information
management
coordination and energy distribution that contribute to the study
and represent a contribution to meeting IMO recommendations. TRANSACTIONS ON MARITIME SCIENCE Trans. marit. sci. 2018; 01: 23-32 31 It is a part of the authors’ ongoing study and can be used for
further research that can be applied to similar vessels. The study
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35., available at: Yang, H., Zhou, W., and Fang, Z., (2008), Optimal sizing method for stand-alone
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October 2017.]. 32
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Official Tenure, Fiscal Capacity, and PPP Withdrawal of Local Governments: Evidence from China’s PPP Project Platform
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Sustainability
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Official tenure, fiscal capacity, and PPP
withdrawal of local governments: evidence from
China’s PPP project platform Wang, Yingying; Song, Wenjuan; Zhang, Bo; Tiong, Robert Lee Kong © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution (CC
BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 2021 Wang, Y., Song, W., Zhang, B. & Tiong, R. L. K. (2021). Official tenure, fiscal capacity, and
PPP withdrawal of local governments: evidence from China’s PPP project platform. Sustainability, 13(24), 14012‑. https://dx.doi.org/10.3390/su132414012 Wang, Y., Song, W., Zhang, B. & Tiong, R. L. K. (2021). Official tenure, fiscal capacity, and
PPP withdrawal of local governments: evidence from China’s PPP project platform. Sustainability, 13(24), 14012‑. https://dx.doi.org/10.3390/su132414012 Wang, Y., Song, W., Zhang, B. & Tiong, R. L. K. (2021). Official tenure, fiscal capacity, and
PPP withdrawal of local governments: evidence from China’s PPP project platform. Sustainability, 13(24), 14012‑. https://dx.doi.org/10.3390/su132414012 Yingying Wang 1
, Wenjuan Song 1,*, Bo Zhang 2
and Robert L. K. Tiong 3 Yingying Wang 1 1
School of Public Policy and Management, Tsinghua University, Beijing 100084, China;
wangyy2017@tsinghua.org.cn
2
Hang Lung Center for Real Estate, Department of Construction Management, Tsinghua University,
Beijing 100084, China; zhangb_abc@163.com
3
School of Civil and Environmental Engineering, Nanyang Technological University,
Singapore 639798, Singapore; CLKTIONG@ntu.edu.sg
*
Correspondence: songwj18@mails.tsinghua.edu.cn 1
School of Public Policy and Management, Tsinghua University, Beijing 100084, China;
wangyy2017@tsinghua.org.cn 1
School of Public Policy and Management, Tsinghua University, Beijing 100084, China; 1
School of Public Policy and Management, Tsinghua University, Beijing 100084, China;
wangyy2017@tsinghua.org.cn
2
Hang Lung Center for Real Estate, Department of Construction Management, Tsinghua University,
Beijing 100084, China; zhangb_abc@163.com
3
School of Civil and Environmental Engineering, Nanyang Technological University,
Singapore 639798, Singapore; CLKTIONG@ntu.edu.sg
*
Correspondence: songwj18@mails.tsinghua.edu.cn g
g
p
g
g
Beijing 100084, China; zhangb_abc@163.com
3
School of Civil and Environmental Engineering, Nanyang Technological University,
Singapore 639798, Singapore; CLKTIONG@ntu.edu.sg
*
Correspondence: songwj18@mails.tsinghua.edu.cn Beijing 100084, China; zhangb_abc@163.com
3
School of Civil and Environmental Engineering, Nanyang Technological University,
Singapore 639798, Singapore; CLKTIONG@ntu.edu.sg
*
C
d
j18@
il t i
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d j
g
,
;
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3
School of Civil and Environmental Engineering, Nanyang Technological University,
Singapore 639798, Singapore; CLKTIONG@ntu.edu.sg *
Correspondence: songwj18@mails.tsinghua.edu.cn Abstract: PPP withdrawal policy is helpful to reduce over-investment in PPPs leading to sustainable
development. However, little is known about the role of local governments on over-investment in
PPPs. Using the PPP Project Platform Data, a unique dataset, this article is able to quantify over-
investment in PPPs by coding PPP withdrawal for the first time. This research tests the influencing
factors of PPP withdrawal at the municipal level, according to the centralized withdrawal policy
in late 2017 as an exogenous treatment. Based on the theory of over-investment to rapid economic
growth, this study develops a two-pillar framework under the combination of political man and
economic man assumptions to explain the PPP withdrawal of local governments. The results
show that both official tenure and fiscal capacity are significant factors. In addition, debt partially
mediates the mayor tenure on PPP withdrawal, and the land revenue growth can hinder the negative
relationship between mayor tenure and PPP withdrawal. It implies that over-investment in PPPs is
strongly influenced by official leaders’ personal promotion incentive and official group members’
collective benefit. Thus, our findings indicate that the centralized withdrawal policy is an effective
instrument to prevent over-investment in PPPs. https://hdl.handle.net/10356/163401 © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution (CC
BY) license (https:// creativecommons.org/licenses/by/ 4.0/). © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution (CC
BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Downloaded on 24 Oct 2024 12:06:22 SGT sustainability sustainability sustainability Article
Citation: Wang, Y.; Song, W.; Zhang,
B.; Tiong, R.L.K. Official Tenure,
Fiscal Capacity, and PPP Withdrawal
of Local Governments: Evidence from
China’s PPP Project Platform. Sustainability 2021, 13, 14012. https://
doi.org/10.3390/su132414012 Keywords: PPP withdrawal; PPP Project Platform (PPP-PP); over-investment; official tenure; fiscal
capacity Yingying Wang 1
, Wenjuan Song 1,*, Bo Zhang 2
and Robert L. K. Tiong 3 Moreover, a match should be formed between local
development planning and investment plans to promote sustainable of PPP investment.
Citation: Wang, Y.; Song, W.; Zhang,
B.; Tiong, R.L.K. Official Tenure,
Fiscal Capacity, and PPP Withdrawal
of Local Governments: Evidence from
China’s PPP Project Platform. Sustainability 2021, 13, 14012. https://
doi.org/10.3390/su132414012
Academic Editor: Donato Morea
Received: 26 November 2021
Accepted: 14 December 2021
Published: 19 December 2021
Citation: Wang, Y.; Song, W.; Zhang,
B.; Tiong, R.L.K. Official Tenure,
Fiscal Capacity, and PPP Withdrawal
of Local Governments: Evidence from
China’s PPP Project Platform. Sustainability 2021, 13, 14012. https://
doi.org/10.3390/su132414012
Academic Editor: Donato Morea
Received: 26 November 2021
Accepted: 14 December 2021
Published: 19 December 2021 Keywords: PPP withdrawal; PPP Project Platform (PPP-PP); over-investment; official tenure; fiscal
capacity Article
Official Tenure, Fiscal Capacity, and PPP Withdrawal of Local
Governments: Evidence from China’s PPP Project Platform Yingying Wang 1
, Wenjuan Song 1,*, Bo Zhang 2
and Robert L. K. Tiong 3 1. Introduction PPP (Public–Private Partnership) investment has boomed in China since 2014. Ac-
cording to the Ministry of Finance (MOF), local governments have initiated more than
10,000 projects with an investment of RMB 15.1 trillion (about USD 2.3 trillion) by June
2021. Large investment in PPPs aroused much controversy, which may lead to unnecessary
public supplement, hidden debt, and budget burden [1–3]. However, little is known about
local governments’ role in the over-investment in PPPs. The centralized supervisory policy
in China offers a unique opportunity to observe it. This study aims to investigate the
influencing factors of over-investment in PPPs. Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations. g
The central government established the PPP Project Platform (PPP-PP) in 2015. It reflects
that the promotion of PPP investment in China via a top-down strategy [4]. The PPP-PP is
characterized as dynamic management, such as approving entering PPP projects, supervising
the implementation process, and withdrawing unqualified PPP projects. It is helpful to trace
regional investment in PPPs. Once a PPP project behaves irregularly, it will be identified
and suffered withdrawal. If a PPP project is withdrawn from the PPP-PP, it implies that
the project is not in line with the regional investment plan. The summary statistics for local
governments’ PPP withdrawal can reflect regional over-investment in PPPs. Its advantage is Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
distributed
under
the
terms
and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/). https://www.mdpi.com/journal/sustainability Sustainability 2021, 13, 14012. https://doi.org/10.3390/su132414012 Sustainability 2021, 13, 14012 2 of 16 to offer an exogenous treatment rather than the initiation stage of PPP investment launched,
which may suffer the endogenous problem. We choose the first centralized withdrawal
policy occurred in late 2017 involving 1160 projects (about RMB 1.2 trillion). to offer an exogenous treatment rather than the initiation stage of PPP investment launched,
which may suffer the endogenous problem. We choose the first centralized withdrawal
policy occurred in late 2017 involving 1160 projects (about RMB 1.2 trillion). Scholars argue that China’s fast economic growth includes lots of over-investment in
infrastructure construction. The explanation of local governments’ role on over-investment
is under two assumptions, including personal political promotion [5] and regional group
benefit [6,7]. Local official leaders often use their power to pursue political goals [8]. 1. Introduction While
local official groups are keen to launch speed and over-investment for collective benefits [9]. The requirements of PPP-PP highlight that “local governments are not encouraged to
initiate a PPP project if it bears demand risk, provided non-core services, or reimbursed the
project’s investment at a fixed rate of return”. The motivations of over-investment in PPPs
are inherently consistent with local governments’ other investments in infrastructure and
public service. p
However, little attention has been paid to local governments’ role in over-investment
in PPPs. This research codes local governments’ PPP withdrawal as a dependent variable
of over-investment in PPPs for the first time, then offers a Large-N quantitative study to
examine the key factors of PPP withdrawal at the municipal level. The data used in this
research include 280 cities involving an over-investment of RMB 1.2 trillion initiated from
2012 to 2017. This study contributes to the existing PPP investment literature by taking the
lens of PPP withdrawal as over-investment in PPPs. The findings shed additional light on
local governments’ role on over-investment in PPPs. g
The remainder of this study is organized as follows. Section 2 reviews the literature
on PPP investment. Section 3 presents the development of PPP-PP in China. Section 4
presents the framework and hypotheses. Section 5 reports the data and method used in the
study, and the empirical results. The conclusions and discussions are provided in Section 6. 2. Literature Review PPPs are characterized as long-term contractual relationships between government
and enterprise, which does not indicate the government’s diminishing role in PPPs [10,11]. The government’s role is one of the most focal topics in the PPP investment [12], especially
local governments’ motivations of initiating PPP investment by passing barriers of limited
budgetary constraints [13,14] and efficiency gains by providing better Value for Money
(VfM) [15]. The collaborations of PPPs in China are quite different. The Chinese government
collaborates not only with the private sector but also with state-owned enterprises (SOEs),
which play an important role in China’s market economy [16]. This phenomenon has
spurred heated debates about China’s incentives for investing in PPPs. p
g
One stream of the literature on PPP investment plays close attention to key factors
attracting market investment. Macro system quality helps to enhance PPP investment from
the market [4]. Good governance, such as abiding by rules, clear enforcement mechanisms,
and normalized organizations, is very important to conduct PPPs [17]. The difference of
macro system in PPPs across different countries and jurisdictions has produced wildly
diverse PPP market investment [18–20]. It indicates that system change is path-dependent
and is a function of a variety of context-specific variables, implying no one-size-fits-all
system instrument is universally applicable for PPPs [21]. Recent research examined how
institutional, political, and governmental support structures effect PPP development of
PPP-enabling fields [22,23]. Contract management is a typical instrument to help to ensure
the supervision goals regarding PPPs in the context of competitive markets, involving
rewards, persuasion, and deterrence in PPP contract management [24–26]. The other stream the literature on PPP investment focuses on local governments’
motivation. Several studies have identified the key drivers of PPP adoption, which are
broadening financing channels, enhancing supply capacity, and improving infrastructure
supplement efficiency [27–33]. Scholars have proved that political opportunism and trans-
action costs are significant factors for investment in PPPs [2]. Others have discussed that
local governments are manifesting political opportunism and administrative capacity in Sustainability 2021, 13, 14012 3 of 16 3 of 16 PPPs [34]. In recent years, PPP investment has played a supplementary role in infrastruc-
ture investment in China as a response to the pressures of fiscal shortfalls and government
debts [16]. A large amount of the literature has discussed local governments’ motivation to
PPP investment. For instance, Wang et al. 3. Development of PPP-PP in China According to the MOF’s guidebook, local governments are required to submit infor-
mation about all their PPP projects to the PPP-PP. The PPP-PP is the largest one around the
world, which have attracted many scholars’ attention [1–3]. The PPP-PP in China charac-
terizes as a supervisory instrument for normalization of local governments’ investment in
PPPs. By comparison, the World Bank’s Private Participation in Infrastructure (PPI) project
platform is a global recognized database, which supervises PPP projects according to four
situations including concluded, active, cancelled, and distressed. Compared with the
World Bank’s PPI project platform, China’s PPP-PP not only has a statistical function but
also has a dynamic supervisory function. It helps the central government to control local
governments’ investment in PPPs in a rational range, which operates through step-by-step
declaration and dynamic supervision in a whole project life cycle. First, the PPP-PP adopts PPP withdrawal management as a supervisory instrument. According to the MOF’s guidebook, those infrastructure projects with large investment
scale, long-term stable demand, flexible price adjustment mechanism, and a high degree
of marketization are suitable for PPPs. Furthermore, PPP projects should meet four re-
quirements: (1) the period of contract is at least 10 years; (2) the cooperation of contract
includes investment, construction, and operation; (3) the enterprise has a reasonable profit
not exorbitant profit; and (4) the government does not provide a commitment to burden
risks within the project. These four conditions are necessary for PPP projects to be not
withdrawn in the platform. If a project no longer meets at any stage, it will be noticed
to rectified, otherwise, it will be removed from the platform and be noticed to terminate,
which is called PPP withdrawal from the PPP-PP. Second, the PPP-PP adopts a phased dynamic management. According to the MOF’s
guidebook, the whole lifecycle of a PPP project is divided into five stages: identification,
preparation, procurement, implementation, and transfer (See Figure 1). In the identification
stage, a PPP project is initiated by a local governmental sector as the project executor
approved by the local government. The finance department of the jurisdiction then as-
sesses the feasibility of the proposal through a Value of Money (VfM) test and a fiscal
sustainability test (called two tests). In the preparation stage, the local government sector
prepares a detailed project implementation programme involving two tests for the approval
application of the PPP-PP. 2. Literature Review has provided the mechanisms of promotion pres-
sure and financial burden in relation to investments in PPP infrastructure projects. They
suggest that a match should be formed between local economic infrastructure planning
and investment plans to avoid over- or under-investment [35]. Moreover, Zhang et al. has
found that local governments tended to initiate more PPP projects if they have great finan-
cial pressure, higher off-budgetary debts, or lower budgetary deficits [36]. PPP projects
initiated under off-budgetary burdens were more likely to be inappropriate, which indi-
cates over-investment in PPPs. However, little is known about local governments’ role
in over-investment in PPPs. Similar to Keynesianism, the involvement of the Chinese
government may spur economic development but may also lead to hazards if it involves
too much investment. Over-investment in infrastructure construction during China’s rapid
economic development has aroused great attention. Much of the literature has studied the
influence factors of over-investment [37]. Several studies have investigated the factors of
local governments’ over-investment, involving pursuit of political promotion through GDP
assessment [38,39], and pursuit of fiscal capacity [6,7,40]. The over-investment in PPPs
is also involved to enhance infrastructure in the context of rapid economic development
driven by local officials, but there is no evidence to support it. This study attempts to focus
on local governments’ role on over-investment in PPPs. 3. Development of PPP-PP in China The PPP project platform in Chin
Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in China. The PPP project platform plays an important role of supervising loca
investment in PPPs. According to the PPP project platform, the number a
in PPP projects initiated by local governments doubled approximately eve
the end of 2016. The expansion slowed down significantly in late 2017 a
government issuing the central PPP withdrawal policy. A series of policies
and 2018 to mitigate the financial risks, most notably through a PPP clamp
investment’ in PPPs. In early 2018, the PPP project platform withdrew 111
h
f
h
d
l d ff
f
h
The PPP project platform plays an important role of supervising local govern
investment in PPPs. According to the PPP project platform, the number and inve
in PPP projects initiated by local governments doubled approximately every half y
the end of 2016. The expansion slowed down significantly in late 2017 after the
government issuing the central PPP withdrawal policy. A series of policies iss
2017 and 2018 to mitigate the financial risks, most notably through a PPP clamp
of ‘overinvestment’ in PPPs. In early 2018, the PPP project platform withdrew 11
projects. The vast territory of China caused severe spatial difference of PPP withd
i i
liti
(S
Fi
2)
The PPP project platform plays an important role of supervising local governm
investment in PPPs. According to the PPP project platform, the number and inves
in PPP projects initiated by local governments doubled approximately every half y
the end of 2016. The expansion slowed down significantly in late 2017 after the c
government issuing the central PPP withdrawal policy. A series of policies issued i
and 2018 to mitigate the financial risks, most notably through a PPP clampdown of
investment’ in PPPs. In early 2018, the PPP project platform withdrew 1116 PPP pr
The vast territory of China caused severe spatial difference of PPP withdrawal a
municipalities (See Figure 2)
The PPP project platform plays an important role of supervising local governments’
investment in PPPs. According to the PPP project platform, the number and investment
in PPP projects initiated by local governments doubled approximately every half year by
the end of 2016. The expansion slowed down significantly in late 2017 after the central
government issuing the central PPP withdrawal policy. 3. Development of PPP-PP in China It illustrates the PPP withdrawal of local governments. The total investment of
PPP withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment of PPP
withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. 3. Development of PPP-PP in China If the process goes well, the
government signs a contract with the winner for partnership. Finally, the PPP project
moves into the implementation stage and then the transfer stage until the contract expires. At any time in the whole life cycle of a project, a PPP project may be withdrawn from the
platform once it fails to meet the requirements, such as unqualified conditions, irregular
operation, or imperfect information. procurement and selects a winner among multiple bidders. If the process goes w
government signs a contract with the winner for partnership. Finally, the PPP
moves into the implementation stage and then the transfer stage until the contract e
At any time in the whole life cycle of a project, a PPP project may be withdrawn fr
platform once it fails to meet the requirements, such as unqualified conditions, irr
operation, or imperfect information. well, the government signs a contract with the winner for partnership. F
project moves into the implementation stage and then the transfer stage un
expires. At any time in the whole life cycle of a project, a PPP project may
from the platform once it fails to meet the requirements, such as unqualif
irregular operation, or imperfect information. well, the government signs a contract with the winner for partnership. Finally, th
project moves into the implementation stage and then the transfer stage until the co
expires. At any time in the whole life cycle of a project, a PPP project may be with
from the platform once it fails to meet the requirements, such as unqualified cond
irregular operation, or imperfect information. conducts procurement and selects a winner among multiple bidders. If the process goes
well, the government signs a contract with the winner for partnership. Finally, the PPP
project moves into the implementation stage and then the transfer stage until the contract
expires. At any time in the whole life cycle of a project, a PPP project may be withdrawn
from the platform once it fails to meet the requirements, such as unqualified conditions,
irregular operation, or imperfect information. Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in China. Figure 1. The PPP project platform in
Figure 1. The PPP project platform in Chi
Figure 1. 3. Development of PPP-PP in China In the procurement stage, the local government sector conducts Sustainability 2021, 13, 14012
y
,
, 4 of 16
two te
al gov
ts for t
nment
sector procurement and selects a winner among multiple bidders. If the process goes well, the
government signs a contract with the winner for partnership. Finally, the PPP project
moves into the implementation stage and then the transfer stage until the contract expires. At any time in the whole life cycle of a project, a PPP project may be withdrawn from the
platform once it fails to meet the requirements, such as unqualified conditions, irregular
operation, or imperfect information. procurement and selects a winner among multiple bidders. If the process goes w
government signs a contract with the winner for partnership. Finally, the PPP
moves into the implementation stage and then the transfer stage until the contract e
At any time in the whole life cycle of a project, a PPP project may be withdrawn fr
platform once it fails to meet the requirements, such as unqualified conditions, irr
operation, or imperfect information. well, the government signs a contract with the winner for partnership. F
project moves into the implementation stage and then the transfer stage un
expires. At any time in the whole life cycle of a project, a PPP project may
from the platform once it fails to meet the requirements, such as unqualif
irregular operation, or imperfect information. well, the government signs a contract with the winner for partnership. Finally, th
project moves into the implementation stage and then the transfer stage until the co
expires. At any time in the whole life cycle of a project, a PPP project may be with
from the platform once it fails to meet the requirements, such as unqualified cond
irregular operation, or imperfect information. conducts procurement and selects a winner among multiple bidders. If the process goes
well, the government signs a contract with the winner for partnership. Finally, the PPP
project moves into the implementation stage and then the transfer stage until the contract
expires. At any time in the whole life cycle of a project, a PPP project may be withdrawn
from the platform once it fails to meet the requirements, such as unqualified conditions,
irregular operation, or imperfect information. procurement and selects a winner among multiple bidders. 3. Development of PPP-PP in China A series of policies issued in
2017 and 2018 to mitigate the financial risks, most notably through a PPP clampdown
of ‘overinvestment’ in PPPs. In early 2018, the PPP project platform withdrew 1116 PPP
projects. The vast territory of China caused severe spatial difference of PPP withdrawal
among municipalities (See Figure 2). The PPP project platform plays an important role of supervising local governments’
investment in PPPs. According to the PPP project platform, the number and investment
in PPP projects initiated by local governments doubled approximately every half year by
the end of 2016. The expansion slowed down significantly in late 2017 after the central
government issuing the central PPP withdrawal policy. A series of policies issued in 2017
and 2018 to mitigate the financial risks, most notably through a PPP clampdown of ‘over-
investment’ in PPPs. In early 2018, the PPP project platform withdrew 1116 PPP projects. The vast territory of China caused severe spatial difference of PPP withdrawal among
municipalities (See Figure 2). The vast territory of China caused severe spatial difference of PPP withd
municipalities (See Figure 2). g
p
(
g
)
Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment of
PPP withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment of PPP
withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. y
municipalities (See Figure 2). g
p
(
g
) Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment of
PPP withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment of PPP
withdrawal is marked with different shades. The more PPP withdrawal, the darker the color. Figure 2. China’s PPP withdrawal of local governments in 2014–2017. Note: The figure is made by
ArcGIS software. 4.1. Local Governments’ PPP Withdrawal
4.1. Local Governments’ PPP Withdrawal Based on the tenure system of official leaders and fiscal capacity of official
groups, this study develops a two-pillar framework including official tenure and fiscal
capacity to explain PPP withdrawal of local governments (See Figure 3). “Promotion Championship” and “Financial Federation” are two classical theories to
explain local economic development. Local official management by the central govern-
ment often relies on political promotion to promote economic development [43]. They
correspond to two hypotheses, including official leaders as political man and official
groups as economic man, respectively. Official leaders pay more attention to personal
promotion probability, while official groups pay more attention to fiscal revenue. A local
official leader’s tenure in office as the most institutionalized and universal model in offi-
cial management is an important factor affecting official leaders’ ruling behaviors. Mean-
while, local fiscal capacity reflecting collective goals is another important factor affecting
official groups’ efforts. Based on the tenure system of official leaders and fiscal capacity
of official groups, this study develops a two-pillar framework including official tenure
and fiscal capacity to explain PPP withdrawal of local governments (See Figure 3). Figure 3. Theoretical framework of official tenure, fiscal capacity, and PPP withdrawal
Figure 3. Theoretical framework of official tenure, fiscal capacity, and PPP withdrawal. Figure 3. Theoretical framework of official tenure, fiscal capacity, and PPP withdrawa
Figure 3. Theoretical framework of official tenure, fiscal capacity, and PPP withdrawal. 4.2. Official Tenure and Over-Investment in PPPs
4.2. Official Tenure and Over-Investment in PPPs Local official leaders will try their best to create the most satisfactory achievements
of the higher-level government during the term to raise the promotion probability [44]. However, the relationship between tenure and economic development is still controver-
sial. Some research proves official tenure affects GDP growth negatively through a de-
crease in public capital productivity [45]. Others have proved the opposite influence,
which means that official tenure created an incentive structure for local leaders to increase
government expenditures in strategy plans to enhance promotion probability [37,46]. Local official leaders will try their best to create the most satisfactory achievements
of the higher-level government during the term to raise the promotion probability [44]. However, the relationship between tenure and economic development is still controversial. Some research proves official tenure affects GDP growth negatively through a decrease in
public capital productivity [45]. 4.1. Local Governments’ PPP Withdrawal
4.1. Local Governments’ PPP Withdrawal The local governments’ PPP withdrawal from the PPP-PP as discussed, offers a
unique opportunity to observe whether local governments over-invested in PPPs or not. When initiating a PPP project, local officials in China do not have to favor voters but
do have to impress their superiors and gain regional development. PPP projects have
the characteristics of short construction period and long operation period, so that if local
governments are eager to promote the construction of PPP projects, they may over-invest
in PPPs through approving enterprises. It may have great risks during the operation
phase but stimulate short-term economic growth, leading to over-investment in PPPs and
real debt burdens for local governments. These PPP projects face the risk of withdrawal
from the PPP-PP, which is called local governments’ PPP withdrawal. In a word, PPP
withdrawal can be used to measure over-investment in PPPs. The local governments’ PPP withdrawal from the PPP-PP as discussed, offers a
unique opportunity to observe whether local governments over-invested in PPPs or not
When initiating a PPP project, local officials in China do not have to favor voters but do
have to impress their superiors and gain regional development. PPP projects have the
characteristics of short construction period and long operation period, so that if local gov-
ernments are eager to promote the construction of PPP projects, they may over-invest in
PPPs through approving enterprises. It may have great risks during the operation phase
but stimulate short-term economic growth, leading to over-investment in PPPs and real
debt burdens for local governments. These PPP projects face the risk of withdrawal from
the PPP-PP, which is called local governments’ PPP withdrawal. In a word, PPP with-
drawal can be used to measure over-investment in PPPs. “Promotion Championship” and “Financial Federation” are two classical theories to
explain local economic development. Local official management by the central government
often relies on political promotion to promote economic development [43]. They corre-
spond to two hypotheses, including official leaders as political man and official groups
as economic man, respectively. Official leaders pay more attention to personal promotion
probability, while official groups pay more attention to fiscal revenue. A local official
leader’s tenure in office as the most institutionalized and universal model in official man-
agement is an important factor affecting official leaders’ ruling behaviors. Meanwhile,
local fiscal capacity reflecting collective goals is another important factor affecting official
groups’ efforts. Figure 2. China’s PPP withdrawal of local gov
Figure 2. China’s PPP withdrawal of local gov
A
GIS
ft
It ill
t
t
th PPP
ithd
4. Theoretical Framework and Hypotheses g
g
g
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investm
PPP withdrawal is marked with different shades. The more PPP withdrawal, the darker the
ArcGIS software. It illustrates the PPP withdrawal of local governments. The total investment
withdrawal is marked with different shades. The more PPP withdrawal, the darker the color
Local governments’ over-investment is an important issue in the infrastructure con-
struction of various countries. As mentioned, an explanation of political promotion and Sustainability 2021, 13, 14012 5 of 16 fiscal capacity are from centralization theory and decentralization theory, respectively. Increasing literature believes that the combination of economic financial decentralization
and political centralization can better explain China’s economic growth [41,42]. This ar-
ticle aims to examine the factors affecting over-investment in PPPs by taking the lens of
over-investment to rapid economic growth theory. fiscal capacity are from centralization theory and decentralization theory, respectively. Increasing literature believes that the combination of economic financial decentralization
and political centralization can better explain China’s economic growth [41,42]. This arti-
cle aims to examine the factors affecting over-investment in PPPs by taking the lens of
over-investment to rapid economic growth theory. 4.3. Fiscal Capacity and Over-Investment in PPPs Fiscal capacity has a negative impact on PPP withdrawal. Hypothesis 2a. Budget growth has a negative impact on PPP withdrawal. Hypothesis 2a. Budget growth has a negative impact on PPP withdrawal. Hypothesis 2b. Debt has a positive impact on PPP withdrawal. Hypothesis 2b. Debt has a positive impact on PPP withdrawal. Hypothesis 2c. Land revenue growth has a negative impact on PPP withdrawal. 4.1. Local Governments’ PPP Withdrawal
4.1. Local Governments’ PPP Withdrawal Others have proved the opposite influence, which means
that official tenure created an incentive structure for local leaders to increase government
expenditures in strategy plans to enhance promotion probability [37,46]. There are also
studies which show that the relationship between official tenure and economic growth is
an inverted U-shape in China [47]. When an official leader is in the earlier time in office, he/she may have a strong
incentive to save government expenditure but expand adopting PPPs to attract market Sustainability 2021, 13, 14012 6 of 16 investment. What is more, mayors and secretaries, as local official leaders, are both
important in local development. Therefore, we expect the following: investment. What is more, mayors and secretaries, as local official leaders, are both
important in local development. Therefore, we expect the following: Hypothesis 1. Official tenure has a negative impact on PPP withdrawal. Hypothesis 1a. Mayor tenure has a negative impact on PPP withdrawal. Hypothesis 1a. Mayor tenure has a negative impact on PPP withdrawal. Hypothesis 1b. Secretary tenure has a negative impact on PPP withdrawal. Hypothesis 1b. Secretary tenure has a negative impact on PPP withdrawal. 4.3. Fiscal Capacity and Over-Investment in PPPs Another motive is to make profits for regional collective interests. Local group mem-
bers, who have limited promotion probability, are more concerned about their own benefits. The welfare of government members mainly comes from local fiscal capacity. The ex-
penditure of budgetary income needs the approval of local people’s congresses, while
off-budgetary income, as self-supporting income of local governments, is not included in
budget constrain management [48]. Under financial pressure, local group members are
eager to attract market investment and may excessively enter certain industries in search
of high profits [9]. g
p
Several studies have tested the relationship between fiscal capacity and PPP invest-
ment. Some scholars mentioned that fiscal capacity is negatively correlated with investment
in PPPs [16,49,50]. For example, if local governments absorb more tax revenue of burden
to lower debt, investment in PPPs will decrease [34,51]. In the opposite, some scholars
put forward that governments with insufficient fiscal capacity are difficult to promote
PPP projects [1]. Moreover, some scholars have proposed that, based on the interaction of
“resistance” and “pull”, the relationship between fiscal capacity and investment in PPPs
may be an inverted U-shape [52]. Local governments facing huge fiscal pressure may seek
to alleviate the pressure with the help of PPPs to attract investment from enterprises and re-
alize debt deferment [53]. In turn, successful investment in PPPs makes local governments
fiscal illusion, which drives them to initiate PPP investment exceeding local development
planning. Local governments with less budget growth will have stronger incentive to
initiate large amount of PPP projects, which may lead to over-investment in PPPs. Fiscal capacity and investment in PPPs may be mutually causal through different
mechanisms. There are two ways to enhance fiscal capacity including budget and off-
budget. While local governments have more discretion in off-budget income, which is
mainly related to the financing through debt and land exchange revenue. Local govern-
ments with more debt burden will have stronger incentive to initiate large amounts of PPP
projects, while local governments with less land revenue growth will also have stronger
incentive to implement irregular PPP projects. Thus, debt and PPP investment have a posi-
tive relationship, and land revenue and PPP investment have a substitution relationship. Based on the literature review, we can preliminarily assume that there is a clear correlation
between fiscal capacity and PPP overinvestment. Thus, the second hypothesis is as follows: Hypothesis 2. 4.4. Mediate and Moderate Effects Scholars have mentioned the casual relationships between official tenure and fiscal
capacity. For instance, even though local leaders are eager to initiate PPP investment, they
are unable to search for partners due to insufficient fiscal capacity [54]. Although official
leaders are at the top of the pyramid of official management, government intervention Sustainability 2021, 13, 14012 7 of 16 in infrastructure construction needs other government group members. While official
leaders pay more attention to political promotion, government group members pay more
attention to regional collective benefits. As there are some officials with two attributes at
the same time (such as associate official leaders), official leaders control the lower-level
official groups through the personnel system. Thus, official leaders can influence official
group members through fiscal benefits to modify the motivation of official groups on
PPP investment. It means that the effect of official tenure on PPP withdrawal may differ
depending on fiscal capacity. p
g
p
y
However, the composition of government groups is relatively complicated. Official
leaders can make relevant policies through the adoption system to directly influence the
investment in PPPs. Official leaders as political man can also adjust the financial pressure of
official groups by transferring and intervening the off-budgetary income. Thus, we do not
deny the direct influence of official leaders on the investment in PPPs, while official leaders
indirectly influence the investment in PPPs by influencing fiscal capacity. Official groups
actively intervene in the investment in PPPs to achieve the supplement of public goods. It
makes the collective goals of official groups the same as personal goals, which may not all
be through their collective benefits. Other financing vehicles will affect PPP investment. Fox example, in the situation of high debt or low revenue (mainly from land revenue),
investment in PPPs may be out of expectations. This has also become an important mediate
and moderate effects to restrain official leaders from over-investing in PPPs. Thus, the
third and fourth hypothesis are as follows: Hypothesis 3. Debt mediates the relationship between official tenure and PPP withdrawal. Hypothesis 4. Land revenue moderates the relationship between official tenure and PPP withdrawal. 5. Data, Method, and Results This section introduces the data, methods, and results. The hypotheses are tested using
the data mainly collected from the PPP-PP, China City Statistical Yearbook, Wind Database,
China Land and Resources Statistical Yearbook, and Chinese Political Elite Database. We
summarize the investment and number of PPP withdrawals at municipal level from the
PPP-PP and merge it with the municipal data and the official data. Then, we build a panel
data of 280 cities and 6 years from 2012 to 2017. At last, we test the hypotheses by using a
multiple linear regression. Variables and results are discussed as follows. 5.1. Dependent Variable: Local Government’s PPP Withdrawal According to the MOF report, the PPP withdrawal are the expected investment in PPPs,
which were initiated and approved into the PPP-PP at first, resulting to be withdrawal
because of irregular behaviors after initiation. Any PPP project even initiated in a different
time of one year is treated the same. The dependent variables wd_invest and wd_num are the
investments and number of PPP withdrawals in one city, respectively. As shown in Table 1,
the average investment of PPP withdrawal is RMB 170,800, and the average number of
PPP withdrawals is 1.51. 5.2.2. Fiscal Capacity Fiscal capacity is divided into three variables, including budget revenue growth (bud-
get_gr), debt (debt), and land revenue growth (land_gr). The budget revenue directly affects
over-investment in PPPs, the data of which come from China Urban Statistical Yearbook. The off-budget revenue has interaction effect involving mediating variable of debt
(debt) and moderating variable of land revenue growth (land_gr). The mediating variable of
debt is composed of the debt balance of Local Financing Vehicles (LGV) [2]. Specifically,
the debts of LGV are the sum of short-term liabilities, notes payable, non-current liabilities,
and so on. The data are drawn from Wind Database. The moderating variable is land
revenue. The phenomenon of land exchange finance is widespread in China. The data is
from the China Land and Resources Statistical Yearbook. 5.2.1. Official Tenure In China, the mayor and secretary represent the de facto top power of the administra-
tion, which are popular variables to measure China’s political system [2,37,46]. Due to the
large scale and long period of PPP investment, officials will schedule investment according
to their political tenure. We assess the official tenure hypothesis through two indicator
variables, mayor tenure (mayor) and secretary tenure (secretary), which measure the time in
office of the local mayor and Communist Party secretary. Sustainability 2021, 13, 14012 8 of 16 Table 1. Statistics for all variables used in this study. Definition
Variable
Measurement
Mean
SD
Min
Max
Over-investment of PPP
wd_invest
Investment of PPP withdrawal in a year
17.08
73.94
0
1898.19
wd_num
Number of PPP withdrawal in a year
1.51
5.46
0
127
Official tenure
mayor
Mayor’s tenure
2.31
1.42
1
11
secretary
Secretary’s tenure
2.68
1.63
1
9
Fiscal capacity
budget_gr
(Budget revenue t/budget revenue t−1) −1
0.127
0.375
−0.78
4.13
debt
Log (bonds investment in a year)
1.23
1.64
0
5.54
land_gr
(Land revenue t/Land revenue t−1) −1
0.95
5.82
−0.99
99.76
Control variables
PPP_invest
Log (total investment of PPP)
8.27
6.32
0
16.78
PPP_num
Total number of PPP
6.28
12.99
0
172
fixinvest
Log (fixed assets investment in a year)
16.21
0.82
12.79
18.24
loan
Log (bank loans in a year)
16.76
0.962
14.58
20.29
indus
Gross industrial output value t/GDP t
8.27
6.32
0
16.78
gdp
Log (GDP in a year)
16.37
0.932
12.76
19.23
pop
Log (population in a year)
6.28
12.99
0
172 Table 1. Statistics for all variables used in this study. 5.3. Control Variables In order to control the influence of total investment and quantity of PPP on the with-
drawal, we add PPP_invest and PPP_num in the models. Local government characteristics
are also controlled, including the GDP, population, investment, and loans. They are munic-
ipal fixed assets investment (fixinvest), bank loans (loan), gross industrial output value to
GDP (indus), GDP (gdp), and population (pop) in a year. All control variables are one-year
lagged in all models. gg
Table 1 reports the descriptive statistics for all variables in this study. 5.4. Results 5.4.1. Main Effects 5.4.1. Main Effects Table 2 shows the baseline results, which regress when official tenure and fiscal
capacity affect PPP withdrawal. Model 1 reports the OLS regression between official
tenure (mayor and secretary) and PPP withdrawal (wd_invest). The term of mayor has a
negative impact on PPP withdrawal (β = −4.460, p < 0.01), while the effect of secretary
is insignificant. It implies the mayor plays a more direct role than the secretary in the
over-investment in PPPs. Thus, H1a is supported, but H1b is not supported. Therefore, H1
is partially supported. 9 of 16 Sustainability 2021, 13, 14012 Table 2. Impact of official tenure and fiscal capacity on PPP withdrawal. Y = Investment in PPP withdrawal
Variables
(1) Official Tenure
(2) Fiscal Capacity
(3) Total
1a
2b
2a
2b
2c
3
mayor
−4.460 **
−4.695 **
(−2.50)
(−1.99)
secretary
0.892
3.160
(0.47)
(1.17)
budget_gr
−13.661 ***
−14.190 ***
(−3.06)
(−3.12)
debt
0.797
0.894
(0.40)
(0.36)
land_gr
−0.707 **
−0.703 **
(−2.15)
(−2.13)
PPP_invest
1.129 ***
1.234 ***
1.911 ***
1.201 ***
2.093 ***
2.085 ***
(3.35)
(3.56)
(2.93)
(3.43)
(2.93)
(3.09)
PPP_num
2.120 ***
2.143 ***
2.196 ***
2.135 ***
2.154 ***
2.129 ***
(5.42)
(5.30)
(5.15)
(5.36)
(4.94)
(5.04)
fixinvest
1.820
−0.686
7.180
−0.657
4.918
5.661
(0.19)
(−0.08)
(0.37)
(−0.07)
(0.24)
(0.28)
loan
0.861
1.994
66.626
2.326
75.003
73.912
(0.03)
(0.08)
(1.26)
(0.10)
(1.22)
(1.22)
gdp
2.352
−1.932
0.497
−1.331
−0.802
0.471
(0.07)
(−0.06)
(0.01)
(−0.04)
(−0.01)
(0.01)
pop
10.320
8.147
−12.818
8.298
−5.232
3.348
(0.20)
(0.16)
(−0.21)
(0.16)
(−0.08)
(0.05)
indus
−0.521
−0.479
−0.775
−0.475
−0.760
−0.924
(−0.48)
(−0.45)
(−0.44)
(−0.44)
(−0.41)
(−0.51)
Time fixed effect
yes
yes
yes
yes
yes
yes
Municipal fixed effect
yes
yes
yes
yes
yes
yes
Observations
1394
1394
1115
1394
1067
1067
R-squared
0.185
0.181
0.182
0.180
0.177
0.186
Number
280
280
280
280
279
279
Notes: T-statistics are in parenthesis below the coefficient.** and *** denotes 10%, 5% and 1% level of significance, respectively. Table 2. Impact of official tenure and fiscal capacity on PPP withdrawal. In model 2, the independent variable is fiscal capacity (budget_gr, debt, and land_gr). In
model 2a, the growth of the budget has a negative impact on PPP withdrawal (β = −13.661,
p < 0.01). Thus, H2a is supported. In models 2b and 2c, the independent variable is replaced
by debt (debt) and land revenue growth (land_gr), respectively. 5.4.1. Main Effects Similarly, the land revenue
growth has a negative effect on PPP withdrawal (β = −0.707, p < 0.05). Thus, H2b is
supported. However, the coefficient of debt is insignificant. It is possibly because that
debt reflects the financing capacity of the government but also implies debt repayment
burden. As a result, its impact on PPP over-investment may go two ways. It implies
that a local government has greater motivation to implement more irregular PPP projects
when burdening overloaded debt, which reflects the over-investment in PPPs by a local
government. Thus, H2c is supported, but different from H2a and H2b. Therefore, H2 is
partially supported. In Model 3, when all variables are added, the results remain consistent. Our empirical
analysis validates that the PPP withdrawal of local governments is influenced by both
fiscal capacity and official tenure. 10 of 16 10 of 16 Sustainability 2021, 13, 14012 5.4.2. Mediating Effect Table 3 reports the mediating effect of fiscal capacity for official tenure in PPP with-
drawal. The mediating effect can indicate the influence mechanism of official tenure on PPP
withdrawal. Models 1–3 show that debt financing (debt) has a partially intermediary effect
of mayor tenure (mayor) on PPP withdrawal. In model 1, the mayor tenure can increase
debt financing (β = 0.045, p < 0.1). In models 2 and 3, both mayor tenure (β = −0.388,
p < 0.05; β = −0.285, p < 0.05) and debt financing (β = 0.343, p < 0.05; β = 0.216, p < 0.05)
have a significant impact on PPP withdrawal. The conclusion is robust either with control
variables or not. According to the three models, we can infer that debt financing plays a
mediating role between mayor tenure and PPP withdrawal. Therefore, H3 is supported. Table 3. Mediating effect of fiscal capacity for official tenure in PPP withdrawal. (1)
(2)
(3)
Variables
Debt Financing
Number of PPP Withdrawals
Number of PPP Withdrawals
mayor
0.045 *
−0.388 **
−0.285 **
(1.82)
(−2.12)
(−2.07)
debt
0.343 **
0.216 **
(2.24)
(2.13)
budget_gr
−0.715 **
(−2.26)
PPP_num
0.294 ***
(3.45)
fixinvest
−0.664
(−0.53)
loan
−2.829
(−1.07)
gdp
2.784
(0.68)
pop
1.320
(0.65)
indus
−0.034
(−0.48)
Time fixed effect
yes
yes
yes
Municipal fixed effect
yes
yes
yes
Observations
1678
1398
1115
R-squared
0.032
0.121
0.464
Number
280
280
280
Notes: T-statistics are in parenthesis below the coefficient. *, ** and *** denotes 10%, 5% and 1% level of signifi-
cance, respectively. Table 3. Mediating effect of fiscal capacity for official tenure in PPP withdrawal. 5.4.3. Moderating Effect Table 4 shows the moderating effect of fiscal capacity for official tenure on PPP
withdrawal. The moderating effects show that land revenue (land_gr) enhances or hinders
the negative relationships between mayor tenure (mayor) and PPP withdrawal. In model
1, the land revenue growth can hinder the negative relationship between mayor tenure
and PPP withdrawal (β = −0.186, p < 0.05). Furthermore, model 2, including control
variables, shows that the negative moderating is still significant (β = −0.214, p < 0.05),
and the coefficients do not change much, which demonstrates the conclusion is robust. Therefore, H4 is supported. In Figure 4, we present graphic demonstrations of the marginal effects of mayor tenure
on the withdrawal of PPP investment on the condition of land revenue growth, centered
within 95% confidence intervals. The solid line indicates the average change in probability
of the PPP withdrawal upon the change in land revenue growth of the local government. When the land revenue growth is lower than 0, mayor tenure has a significantly negative Sustainability 2021, 13, 14012 11 of 16
(−3.12
2 932 * 11 of 16
(−3.12
2 932 effect on city-level withdrawal of PPP investment with 95% confidence. The fitting lines
of the high, medium and low estimators basically coincide with the linear model, which
verifies that the interaction is linear. fixinvest
7.243
(0.32
loan
65.15 Table 4. Moderating effect of fiscal capacity for official tenure on PPP withdrawal. (1)
(2)
Variables
Investment in PPP Withdrawal
Investment in PPP Withdrawal
mayor
−5.418 **
−4.716 *
(−2.01)
(−1.77)
land_gr
−0.895 *
−0.876
(−1.71)
(−1.47)
mayor * land_gr
−0.186 **
−0.214 **
(−2.11)
(−2.26)
budget_gr
−14.465 ***
(−3.12)
PPP_invest
2.932 ***
(3.79)
fixinvest
7.243
(0.32)
loan
65.153
(0.99)
gdp
−0.539
(−0.01)
pop
−3.772
(−0.06)
indus
−0.543
(−0.29)
Time fixed effect
yes
yes
Municipal fixed effect
yes
yes
Observations
1042
1039
R-squared
0.080
0.103
Number
279
279
Notes: T-statistics are in parenthesis below the coefficient. *, ** and *** denotes 10%, 5% and 1% level of signifi-
(0.99)
gdp
−0.539
(−0.01
pop
−3.772
(−0.06
indus
−0.543
(−0.29
Time fixed effect
yes
yes
Municipal fixed
effect
yes
yes
Observations
1042
1039
R-squared
0.080
0.103
Number
279
279
Notes: T-statistics are in parenthesis below the coefficient. *, ** and *** denotes 10%
level of significance, respectively. 5.4.3. Moderating Effect In Figure 4, we present graphic demonstrations of the marginal effects
ure on the withdrawal of PPP investment on the condition of land revenu
tered within 95% confidence intervals. The solid line indicates the average c
ability of the PPP withdrawal upon the change in land revenue growth of
ernment. When the land revenue growth is lower than 0, mayor tenure has
negative effect on city-level withdrawal of PPP investment with 95% confi
ting lines of the high, medium and low estimators basically coincide with th
hi h
ifi
th t th i t
ti
i li Table 4. Moderating effect of fiscal capacity for official tenure on PPP withdrawal. (−2.11)
(−2.26)
budget_gr
−14.465 ***
(−3.12)
PPP_invest
2.932 ***
(3.79)
fixinvest
7.243
(0.32)
loan
65.153
(0.99)
gdp
−0.539
(−0.01)
pop
−3.772
(−0.06)
indus
−0.543
(−0.29)
Time fixed effect
yes
yes
Municipal fixed effect
yes
yes
Observations
1042
1039
R-squared
0.080
0.103
Number
279
279
Notes: T-statistics are in parenthesis below the coefficient. *, ** and *** denotes 10%, 5% and 1% level of signifi-
cance, respectively. Time fixed effect
yes
yes
Municipal fixed
effect
yes
yes
Observations
1042
1039
R-squared
0.080
0.103
Number
279
279
Notes: T-statistics are in parenthesis below the coefficient. *, ** and *** denotes 10%
level of significance, respectively. In Figure 4, we present graphic demonstrations of the marginal effects
ure on the withdrawal of PPP investment on the condition of land revenu
tered within 95% confidence intervals. The solid line indicates the average c
ability of the PPP withdrawal upon the change in land revenue growth of
ernment. When the land revenue growth is lower than 0, mayor tenure has
negative effect on city-level withdrawal of PPP investment with 95% confi
ting lines of the high, medium and low estimators basically coincide with the
which verifies that the interaction is linear. Figure 4. Moderating effect of results of land revenue growth for official tenure. Notes: According to
the land revenue growth, the sample is divided into three groups: high, middle and low. H stands
for high, M stands for middle, and L stands for low. p
y
Figure 4. Moderating effect of results of land revenue growth for official tenure. Notes: According to
the land revenue growth, the sample is divided into three groups: high, middle and low. H stands
for high, M stands for middle, and L stands for low. Figure 4. 5.4.4. Robust Tests The results for the relationship of official tenure, fiscal capacity, and PPP withdrawal
of local governments need to be assessed for consistency. We tested robustness in two ways. First, we replaced variables. In Table 5, the dependent variable is replaced by the
number of PPP withdrawals (wd_num). In model 1, the term of mayor (mayor) still has a
negative effect on the number of PPP withdrawals (β = −0.259, p < 0.05), even though we
have controlled the total number of PPPs (PPP_num), and so do the interactive effects of
the robust results with control variables or not. In model 2a, the growth of the budget still
has a negative impact on PPP withdrawals (β = −0.726, p < 0.05). The debt has a positive
effect on the number of PPP withdrawals (β = 0.170, p < 0.05). When a local government
has too many debts, they will be initiated to implement more irregular PPP projects. In
Model 3, when all variables are added, the results remain consistent, thus, the robustness
of the conclusion is proved. Second, we change the method. We examine the heterogeneity test, whose results are
not obvious in regions, fields, or payment methods. This further proves that the personal
promotion interest and group fiscal benefits are the key factors driving over-investment
in PPPs. Table 5. Robust test results. 5.4.3. Moderating Effect Moderating effect of results of land revenue growth for official tenure. Notes: According to
the land revenue growth, the sample is divided into three groups: high, middle and low. H stands
for high, M stands for middle, and L stands for low. Figure 4. Moderating effect of results of land revenue growth for official tenure. Notes: According to
the land revenue growth, the sample is divided into three groups: high, middle and low. H stands
for high, M stands for middle, and L stands for low. 12 of 16 12 of 16 Sustainability 2021, 13, 14012 6. Conclusions and Discussion The PPP withdrawal policy is helpful to reduce over-investment in PPPs. More
importantly, it is significant for sustainable development. This research pays attention to
over-investment in PPPs through the centralized policy of PPP withdrawal in late 2017. We
use OLS models of panel data to test key factors of local governments’ PPP withdrawals. The results reveal that both official tenure and fiscal capacity are significant factors. (1) In
the early years of the mayors’ tenure, they implement more irregular PPP projects, which
implies a higher probability of over-investment in PPPs, resulting in withdrawal after
initiation. The result may fulfill “a new broom sweeps clean” to expand market investment
for local development. (2) As fiscal capacity decreases, local governments implement more
irregular PPP projects, which also imply over-investment in PPPs. (3) The intermediary
effect suggests that debt partially mediates the mayor tenure on PPP withdrawal. (4) The
moderate effect suggests that land revenue growth can hinder the negative relationship
between mayor tenure and PPP withdrawal. (5) The robustness test shows that the effect on
the number PPP withdrawals is also significant, and the heterogeneity test is not obvious. g
g
y
The findings and implications might be beneficial to many transitional economies
involving over-investment in PPPs by local governments. First, this research offers a new perspective on PPP investment. Over-investment in
PPPs is very likely to waste public funding on inefficient and costly projects, even expand
the long-term debt of local governments [55,56]. We take a new dependent variable to
measure over-investment in PPPs. The variable summarizes the PPP withdrawal at the
municipal level from the PPP-PP. In China’s vertical-control system, PPP withdrawal by
the central government is a typical supervisory instrument to ensure that local investment
in PPPs is controllable. The result is similar with Wang et al. [35] and Zhang et al. [36] and
deepens the explanation of the over-investment in PPPs. It contributes to offering a unique
opportunity to observe local governments’ role in PPP investment through the centralized
withdrawal policy as an exogenous treatment. p
y
g
Second, this research bridges the gap between over-investment and PPPs in the lit-
erature. We provide evidence that China’s PPP booms are not all economically driven,
but a result of political-economic means [3]. 5.4.4. Robust Tests Y = Number of PPP Withdrawals
Variables
(1) Official Tenure
(2) Fiscal Capacity Constraints
(3) Total
1
2a
2b
2c
3
mayor
−0.259 **
−0.289 **
(−2.28)
(−2.05)
secretary
−0.031
0.043
(−0.33)
(0.39)
budget_gr
−0.726 **
−0.727 **
(−2.24)
(−2.26)
debt
0.170 **
0.206 **
(2.10)
(2.01)
land_gr
−0.019
−0.018
(−1.27)
(−1.20)
PPP_num
0.294 ***
0.295 ***
0.298 ***
0.294 ***
0.296 ***
0.293 ***
(3.51)
(3.50)
(3.43)
(3.50)
(3.29)
(3.31)
fixinvest
−0.512
−0.615
−0.678
−0.698
−0.718
−0.658
(−0.60)
(−0.71)
(−0.54)
(−0.80)
(−0.54)
(−0.49)
loan
−1.921
−1.704
−2.118
−2.015
−2.112
−2.246
(−0.83)
(−0.76)
(−0.82)
(−0.87)
(−0.69)
(−0.74)
gdp
−1.217
−1.503
2.437
−1.325
2.289
2.349
(−0.46)
(−0.56)
(0.60)
(−0.50)
(0.53)
(0.54)
pop
1.962
1.847
0.762
1.814
0.726
1.449
(1.09)
(1.04)
(0.38)
(1.04)
(0.36)
(0.70)
indus
0.024
0.028
−0.032
0.025
−0.031
−0.034
(0.43)
(0.50)
(−0.46)
(0.45)
(−0.43)
(−0.46)
Time fixed effect
yes
yes
yes
yes
yes
yes
Municipal fixed effect
yes
yes
yes
yes
yes
yes
Observations
1394
1394
1115
1394
1067
1067
R-squared
0.466
0.462
0.459
0.464
0.451
0.458
Number
280
280
280
280
279
279
Notes: T-statistics are in parenthesis below the coefficient. ** and *** denotes 10%, 5% and 1% level of signifi-
cance, respectively. 13 of 16 13 of 16 Sustainability 2021, 13, 14012 6. Conclusions and Discussion This is consistent with the existing research
such as Xiong et al.’s [2] and Bertelli’s studies [34], who argued that PPPs are far from
merely a public management issue but a complex political issue. Our results suggest that
official leaders may have higher risk appetite in the earlier year in office, which leads to
high probability of over-investment in PPPs. Meanwhile, group members may have higher
incentive to enhance regional benefits when suffering a large fiscal burden, which also
leads to high probability of over-investment in PPPs. Interestingly, secretaries’ tenures
do not have significant impact on over-investment in PPPs, while mayors’ tenures do. It
shows public goods provision may be the mayor’s performance. However, the coefficient
is in the opposite direction to Xiong et al.’s findings [2]. This research shows that mayors in
earlier years are more likely to initiate over-investing in PPPs. The initiated PPP invest-
ment usually takes several years to be fully implemented, so that PPPs is different with
general investment affecting economic development, which should be initiated in earlier
years during mayors’ tenure cycles. Hence, PPP withdrawal provides micro evidence for
over-investment. Third, our results also shed light on extent understand of government’s role on PPPs. Local governments’ incentives to expand budgets have been considered as one of the main
drivers of PPP adoption [56,57]. This research adds evidence that official tenure and fiscal
capacity are the main factors of over-investment in PPPs. Mayors in earlier years intend to
manipulate the adoption process and initiate more investment in PPPs beyond the needs
in a municipality. Our results suggest that local governments’ fiscal capacity not only effect
PPP withdrawal directly but also drive mayors to increase the decision making of PPP
investment. Government capacity considerations, including budget constraints and debt
payment burdens, work similarly in contracting-out decisions across different countries [58]. Sustainability 2021, 13, 14012 14 of 16 14 of 16 Thus, empirical research on other countries may use this theoretical framework to test the
existence of irregular PPP behavior in different political systems. Thus, empirical research on other countries may use this theoretical framework to test the
existence of irregular PPP behavior in different political systems. g
p
y
The implications for China and other transitional economies are as follows. (1) Local
governments’ initiation of investment in PPPs should be managed by supervisory instru-
ments to prevent irregular PPP projects. 6. Conclusions and Discussion (2) To strengthen the training of PPP project
implementation capacity and to improve the understanding of investment in PPPs, it will
make official leaders invest in PPPs rationally. (3) Improve the information management
of PPP projects. Along with the informatization process of the construction industry, it
is a wise choice to advocate for the application of Building Information Modeling (BIM)
technology in PPP projects. As a result, it will improve the visualization level of perfor-
mance supervision. (4) Improve the market mechanism of PPP projects. For this purpose,
we can provide applicable classification, guidance, and management of PPP investment
according to different industries and regions. (5) Standardize the public finance system
and rationally match the local development planning and investment plans to promote
sustainable PPP investment. Our research opens the black box of local governments’ role on over-investment in
PPPs. However, there are several limitations due to the measurement difficulties. (1) Official
tenure is measured in China’s political system, but future research can consider official cycle
and promotion in strong democratic institutions. (2) Fiscal capacity can be expanded to
other government capacity, such as organization capacity and strategic capacity. (3) Many
relational variables, such as project investment, contract types, and service character, can
influence PPP withdrawal at different level. (4) Other provisional approaches to public
goods, such as collaboration with other governments, and contracts out for nonprofit
organizations, are not involved. Future research can advance the research topic of over-
investment in PPPs in the abovementioned perspectives. Author Contributions: Conceptualization, Y.W., W.S. and R.L.K.T.; methodology, W.S. and Y.W.;
software, W.S. and B.Z.; validation, Y.W. and W.S.; formal analysis, Y.W. and W.S.; investigation, Y.W. and W.S.; resources, Y.W. and W.S.; data curation, B.Z. and W.S.; writing—original draft preparation,
Y.W., R.L.K.T. and W.S.; writing—review and editing, Y.W. and W.S. All authors have read and agreed
to the published version of the manuscript. Funding: This research received no external funding. Funding: This research received no external funding. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Informed Consent Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. p
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https://openalex.org/W3141206018
|
https://hal.archives-ouvertes.fr/hal-03436366/file/2021_traiffort_morisset_international_journal_of_molecular_sciences.pdf
|
English
| null |
Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis
|
International journal of molecular sciences
| 2,021
|
cc-by
| 21,585
|
Defective Oligodendroglial Lineage and Demyelination
in Amyotrophic Lateral Sclerosis Elisabeth Traiffort, Séverine Morisset-Lopez, Mireille Moussaed, Amina Zahaf To cite this version: Elisabeth Traiffort, Séverine Morisset-Lopez, Mireille Moussaed, Amina Zahaf. Defective Oligoden-
droglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis. International Journal of Molec-
ular Sciences, 2021, 22 (7), pp.3426. 10.3390/ijms22073426. hal-03436366
Citation: Traiffort, E.;
Morisset-Lopez, S.; Moussaed, M.;
Zahaf, A. Defective Oligodendroglial
Lineage and Demyelination in
Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2021, 22, 3426. https://
doi.org/10.3390/ijms22073426 Citation: Traiffort, E.;
Morisset-Lopez, S.; Moussaed, M.;
Zahaf, A. Defective Oligodendroglial
Lineage and Demyelination in
Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2021, 22, 3426. https://
doi.org/10.3390/ijms22073426 Citation: Traiffort, E.;
Morisset-Lopez, S.; Moussaed, M.;
Zahaf, A. Defective Oligodendroglial
Lineage and Demyelination in
Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2021, 22, 3426. https://
doi.org/10.3390/ijms22073426 Keywords: oligodendrocyte; demyelination; axonal degeneration Academic Editor: William Camu Review
Defective Oligodendroglial Lineage and Demyelination in
Amyotrophic Lateral Sclerosis verine Morisset-Lopez 2
, Mireille Moussaed 2 and Amina Zahaf 1 Elisabeth Traiffort 1,*, Séverine Morisset-Lopez 2
, Mireille Moussaed 2 and Amina Zahaf 1 1
Diseases and Hormones of the Nervous System U1195 INSERM, Paris Saclay University,
80 Rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France; amina.zahaf@inserm.fr 80 Rue du Général Leclerc, 94276 Le Kremlin Bicêtre, France; amina.zahaf@inserm.fr
2
Centre de Biophysique Moléculaire, UPR 4301 CNRS, Orléans University, INSERM, rue Charles Sadron,
CEDEX 02, 45071 Orleans, France; severine.morisset-lopez@cnrs-orleans.fr (S.M.-L.);
mireille.moussaed@cnrs-orleans.fr (M.M.) ,
,
;
2
Centre de Biophysique Moléculaire, UPR 4301 CNRS, Orléans University, INSERM, rue Charles Sadron,
CEDEX 02, 45071 Orleans, France; severine.morisset-lopez@cnrs-orleans.fr (S.M.-L.);
mireille.moussaed@cnrs-orleans.fr (M.M.) *
Correspondence: elisabeth.traiffort@inserm.fr Abstract: Motor neurons and their axons reaching the skeletal muscle have long been considered as
the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis
(ALS). However, the involvement of glial cells was also more recently reported. Although oligoden-
drocytes have been underestimated for a longer time than other cells, they are presently considered
as critically involved in axonal injury and also conversely constitute a target for the toxic effects of
the degenerative neurons. In the present review, we highlight the recent advances regarding oligo-
dendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells,
the process of myelination, and the tight relationship between axons and myelin. The histological
abnormalities observed in ALS and animal models of the disease are described, including myelin
defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present
data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain
of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms
supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support
of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the
therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.
HAL Id: hal-03436366
https://hal.science/hal-03436366v1
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teaching and research institutions in France or
abroad, or from public or private research centers. International Journal of
Molecular Sciences International Journal of
Molecular Sciences Citation: Traiffort, E.;
Morisset-Lopez, S.; Moussaed, M.;
Zahaf, A. Defective Oligodendroglial
Lineage and Demyelination in
Amyotrophic Lateral Sclerosis. Int. J.
Mol. Sci. 2021, 22, 3426. https://
doi.org/10.3390/ijms22073426 1. Introduction Received: 29 January 2021
Accepted: 24 March 2021
Published: 26 March 2021 Received: 29 January 2021
Accepted: 24 March 2021
Published: 26 March 2021 Amyotrophic lateral sclerosis (ALS), also known as Charcot’s disease, is a progressive
and late-onset neurodegenerative disease that primarily targets motor neurons leading to
fatal paralysis [1]. The first steps include muscular weakness in the arms or legs, which
evolves to muscular atrophy, eventually leading to respiratory muscle failure and death. A
cognitive decline also progressively occurs. In 1869, the description reported by Charcot
in the lateral part of the spinal cord reflected the axonal loss of upper motor neurons
descending from the brain and contacting in a direct or indirect manner the lower motor
neurons located in the spinal cord. Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations. With an incidence of about 2 per 100,000 people per year, the disease comprises 95%
of sporadic cases (sALS) and only 5% of familial forms (fALS) [2,3]. Molecular genetic
approaches have been widely applied to ALS research. Genome-wide association studies
and “next-generation” sequencing have contributed to delineate that around 40–55% of the
genetic causes of fALS can be accounted for by variants in known ALS-linked genes [4]. More than 50 potentially causative or disease-modifying genes have been identified. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
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conditions of the Creative Commons
Attribution (CC BY) license (https://
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4.0/). p
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However, pathogenic variants in superoxide dismutase 1 (SOD1), hexanucleotide
repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), fused in sar-
coma/translocated in liposarcoma (FUS), and transactive response DNA binding protein https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3426. https://doi.org/10.3390/ijms22073426 Int. J. Mol. Sci. 2021, 22, 3426 2 of 27 2 of 27 43 (TDBP43) have been the most widely studied [5]. In sALS cases, diagnostic advance-
ments have only contributed to explain a small part of cases, while the etiology remains
unexplained in more than 90% of patients [6]. ALS is characterized by a sexual dimor-
phism, namely a higher prevalence in males than in females [7] although the ratio of men
to women has tended to decrease for the last decades [8,9]. 1. Introduction Even though alpha motor neurons and their axons in skeletal muscles are the best-
characterized target of the degenerative process, other cells are also affected such as
Renshaw cells [17], corticospinal neurons [18], parvalbumin-expressing neurons [19], pro-
prioceptive sensory neurons [20], and also glial cells including astrocytes and microglia. The involvement of glial cells in the pathogenesis of ALS was reported about 20 years
ago via the study of the transgenic mouse model overexpressing the human mutant of
SOD1 [21]. Although mutant SOD1 mice recapitulate the human pathology until the fatal
motor neuron degeneration, the latter was found to be non-cell autonomous. Indeed, the
expression of the mutant SOD1 in non-neuronal cells contributed to neuronal death [22]
and the conditional deletion of mutant SOD1 in astrocytes or microglial cells significantly
reduced the progression of the disease [23,24]. In parallel, pathological alterations have
been reported in the white matter at a higher level than abnormalities observed in mo-
tor neurons [25]. These alterations occur at early stages of ALS before the first clinical
symptoms [26] and they are also detected in various rodent models of the disease [27–30]. In the present review, we propose to highlight the recent advances regarding the
involvement of oligodendroglial cells in the pathogenesis of ALS. We will present the
oligodendroglial cells, the process of myelination, and the tight relationship between axons
and myelin. Oligodendroglial and white matter abnormalities as well as the chain of
deleterious events and molecular mechanisms associated with these abnormalities will be
described. Finally, we will discuss the therapeutic perspectives provided by the current
data involving the oligodendrocyte in the pathogenesis of ALS. 1. Introduction A viral etiology has also been
suggested via the detection of human endogenous retrovirus-K detected in neurons of a
subpopulation of ALS patients [10,11]. The dramatic and fatal evolution of the disease cannot be halted by any therapeutic
approach as shown by the inability of most molecules to alleviate the symptoms, with the
exception of Riluzole that slightly increases the lifespan of patients [1,12,13] and whose
mechanisms of action have been mostly attributed to the inhibition of glutamatergic
transmission and modulation of sodium channel function [14,15]. On the other hand,
Edavarone, only approved in 2017, is a free radical scavenger that is believed to act as a
neuroprotective agent by reducing oxidative stress and modulate ALS progression during
the early stages [16]. y
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Even though alpha motor neurons and their axons in skeletal muscles are the best-
characterized target of the degenerative process, other cells are also affected such as
Renshaw cells [17], corticospinal neurons [18], parvalbumin-expressing neurons [19], pro-
prioceptive sensory neurons [20], and also glial cells including astrocytes and microglia. The involvement of glial cells in the pathogenesis of ALS was reported about 20 years
ago via the study of the transgenic mouse model overexpressing the human mutant of
SOD1 [21]. Although mutant SOD1 mice recapitulate the human pathology until the fatal
motor neuron degeneration, the latter was found to be non-cell autonomous. Indeed, the
expression of the mutant SOD1 in non-neuronal cells contributed to neuronal death [22]
and the conditional deletion of mutant SOD1 in astrocytes or microglial cells significantly
reduced the progression of the disease [23,24]. In parallel, pathological alterations have
been reported in the white matter at a higher level than abnormalities observed in mo-
tor neurons [25]. These alterations occur at early stages of ALS before the first clinical
symptoms [26] and they are also detected in various rodent models of the disease [27–30]. In the present review, we propose to highlight the recent advances regarding the
involvement of oligodendroglial cells in the pathogenesis of ALS. We will present the
oligodendroglial cells, the process of myelination, and the tight relationship between axons
and myelin. Oligodendroglial and white matter abnormalities as well as the chain of
deleterious events and molecular mechanisms associated with these abnormalities will be
described. Finally, we will discuss the therapeutic perspectives provided by the current
data involving the oligodendrocyte in the pathogenesis of ALS. 2. The Oligodendroglial Cells and Myelination Process
2.1. Oligodendrocyte Generation Responsible for axon myelination in the central nervous system (CNS) and indis-
pensable for its normal function, oligodendrocytes are generated in the developing mouse
forebrain from oligodendrocyte precursor cells (OPCs) produced in three waves occurring
from the embryonic day 12.5 (E12.5) until a last perinatal wave. The last wave arises
from Emx1+ progenitors located in the dorsal subependymal area bordering the lateral
ventricles and gives rise to the bulk of myelinating oligodendrocytes leading to active
myelination of the forebrain during the first three postnatal weeks [31]. In the developing
spinal cord, OPCs arise as two embryonic waves. The first one at E12.5 gives rise to ventral
OPCs, which emerge from the same progenitor domain (called pMN) as motor neurons
(for review, [32]). The second one at E15.5 is called the dorsal wave. Although only few
data are available in the human brain, OPCs were reported to first appear approximately at
9 weeks of gestation, to proliferate until 18 weeks, and to start their differentiation around
27 weeks [33–35]. In the murine brain, early oligodendroglial differentiation is mediated by the down-
regulation of Sox2 and the up-regulation of Sox 10, Olig1, and Olig 2. At early stages, Int. J. Mol. Sci. 2021, 22, 3426 3 of 27 3 of 27 human and murine cells also express platelet derived growth factor receptor α (PDGFRα)
and NG2 (Figure 1A). The transition of OPCs to post-mitotic oligodendrocytes is character-
ized by chromatin condensation with heterochromatin formation, upregulation of selected
microRNAs, and silencing of genes involved in cell proliferation. Loss of PDGFRα/NG2,
and increased expression of 2’,3’-Cyclic nucleotide 3’-phosphodiesterase (CNP) and ade-
nomatous polyposis coli (APC), together with Olig 1 and Olig 2, are characteristic of
pre-myelinating oligodendrocytes. Finally, myelination triggered by myelin regulatory
factor (MYRF) expressed in post-mitotic oligodendrocytes, is accompanied by increased ex-
pression of myelin basic protein (MBP), myelin-associated glycoprotein (MAG), proteolipid
protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) [36,37]. The oligoden-
droglial cells can establish synaptic-like structures with neurons and communicate via
many receptors and ion channels specifically expressed in OPCs or at different stages of
oligodendroglial differentiation and maturation [38]. Although myelinating oligodendrocytes are generated rapidly during the early post-
natal period, a small proportion of NG2-expressing OPCs remain thereafter present in both
gray and white matter in the adult CNS. 2. The Oligodendroglial Cells and Myelination Process
2.1. Oligodendrocyte Generation OPCs constitute an abundant and widely dis-
tributed population of cells that retain the capacity to divide and mature into myelinating
cells under physiological and pathological conditions throughout the whole life [39–41]. According to their region of origin and their expression profile, OPCs can respond to
various insults [42,43]. In agreement with the diversity of oligodendrocytes, transcriptomic
profiles using high-throughput methods and single-cell RNA sequencing revealed differ-
ent subpopulations of oligodendrocytes from several brain regions of juvenile and adult
mouse brain [44] and in response to spinal cord injury [45]. Gene expression studies have
also identified subpopulations of oligodendroglial cells in human adult white matter and
fetal brain [35,36,46]. Altogether, these studies support the existence of highly complex
functional and physiological states of oligodendroglial cells. 2.2. Axonal Myelination Myelination of axons essential for rapid impulse propagation in CNS vertebrates
occurs during the late embryonic and early postnatal development successively in the
spinal cord and in the brain. White matter is predominantly composed of myelinated
and unmyelinated neuronal axons organized into specific tracts with surrounding glial
cells. Myelin is composed of lipids (70–85%) and proteins (15–30%) among which the
most abundant are MBP and PLP while minor proteins include MOG, CNP, and MAG [47]. In white matter tracts that comprise around 50% of the human brain, oligodendrocytes
enwrap segments of axons with their plasma membranes [48]. MBP is not translated in the
cell body of the oligodendrocyte, where it would cause a fatal compaction of the organelle
membranes. Instead, MBP mRNA is silenced and transported to the myelin compartment
by the RNA transport granule, a complex of proteins, and RNA molecules. For transport
to occur, MBP mRNA must be appropriately spliced and contain the so-called A2 response
element (A2RE) in the 3’UTR. The A2RE binds hnRNPA2/B1, which triggers the assembly
of the mRNA-transport granule. Translation then occurs in the myelin compartment [49]. The initial contact between oligodendrocytes and axons triggers myelin sheath synthesis
from the oligodendrocyte processes in position adjacent to the axon. Each segment, called
an internode (for its location between unmyelinated gaps called the nodes of Ranvier),
expands longitudinally and simultaneously with axon elongation that progressively occurs
during body growth. The last step comprises myelin sheath compaction that starts from
the outermost layer [50,51]. The whole process that takes several decades in humans [52]
leads to the distribution of myelin segments according to diversified profiles along single
axons depending on the neuronal identity [53]. p
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Electrical activity derived from the axon is a major regulator of the myelination pro-
cess. Indeed, activity-dependent release of ATP has been reported to bind the astrocyte
purinergic P2 receptor and to induce the release of LIF cytokine, which ultimately stimu-
lates myelination [54]. Moreover, despite their characterization as the myelinating cells of Int. J. Mol. Sci. 2021, 22, 3426 4 of 27 the CNS, the oligodendrocytes are not the only cells implicated in the myelination process. Indeed, astrocytes provide a substantial fraction of the lipids required for myelin synthesis
as suggested by the inability for oligodendrocytes to finalize myelination when a critical
co-activator of the transcription factor Sterol Regulatory Element-Binding Protein was
inactivated in astrocytes [55]. 2.3. Oligodendroglial Metabolic Support to the Axon In the recent years, it has become evident that myelinating cells maintain the long-
term integrity and survival of the axons independently of the presence or absence of
myelin [61–63]. Indeed, besides electrical insulation of axons, the myelin sheath plays
an important role in providing trophic and metabolic supports to the latter [64,65]. As
compacted myelin limits supply from the extracellular space, oligodendrocyte support
to the axons is essential specifically to allow mitochondrial respiration. This support is
based on aerobic glycolysis, where pyruvate and lactate are transferred by diffusion into
the myelinated axon [66,67]. Diffusion of metabolites through the myelin sheath occurs
through a system of cytoplasmic nanochannels via a mechanism involving CNP that orga-
nizes the actin cytoskeleton and prevents complete membrane compaction promoted by
MBP, which acts as a zipper for compacting myelin [51]. In agreement with this observation,
CNP knockout mice display axonal degeneration in myelinated fibers despite the presence
of functional myelin whereas MBP knockout mice exhibit no axonal loss despite absence of
myelination [61,63]. Moreover, glycolytic support of fast-spiking axons has been reported
to be controlled by activity-dependent glutamate release [68] since released glutamate
activates N-methyl-D-aspartate (NMDA) receptors expressed by oligodendrocytes, which
in turn up-regulate the expression of oligodendroglial cell surface glucose transporter 1
(GLUT1). Subsequently, lactate is released towards the axon via monocarboxylate trans-
porter 1 (MCT1) and captured from the peri-axonal environment by MCT2 transporter
expressed by the axon. Together with reminding the astrocyte-neuron lactate shuttle,
metabolic support provided by oligodendrocytes is critical since the depletion of MCT1 in
oligodendrocytes was found to lead to motor neuron death [66–68]. As each oligodendrocyte has the capacity to produce between 20 and 60 myelinating
processes and each of the latter displays an internodal length from 20 to 200 µm [69,70], the
oligodendrocyte is one of the cell types with the largest surface membrane and therefore an
extensive metabolic demand. Thus, though oligodendrocyte turnover is low as indicated
by the replacement of 1 out of 300 cells per year in humans [71], the production of myelin
is much more dynamic since one cell is able to produce three times its own weight in
myelin per day [72,73]. Both the metabolic supply to axons and the metabolic demand
for myelination make oligodendrocyte a major player in CNS homeostasis. 2.2. Axonal Myelination Physical interactions involving connexins present in both
astrocytes and oligodendrocytes were reported to be required for myelination (Figure 1B). In addition, astrocytes contacting the nodes of Ranvier are endowed with the capacity to
remodel myelin at the level of its thickness or the internodal length in order to optimize
the electrical conduction [56]. Besides astrocytes, microglia or at least a specific subset of
these cells uniquely found in the neonatal CNS are endowed with myelinogenic activities
via the secretion of various molecules such as IGF-1 [57,58] (Figure 1B). How OPCs suc-
ceed in integrating signals from the other glial cells starts to be uncovered. For instance,
microglia-derived transglutaminase 2 (TG2), found to bind its OPC receptor GPR56 by
using the extracellular matrix protein laminin, is required for regular developmental oligo-
dendrogenesis and subsequent myelination [59]. The critical activity of the extracellular
matrix in myelination is also supported by the demonstration that extracellular matrix
prepared from decellularized human brain tissue promotes the differentiation of induced
pluripotent stem cells (iPSCs) into myelinating oligodendrocytes [60]. 3.1. TDP-43 Inclusions Besides astrocytes and microglia now known to be deeply involved in the progres-
sion of ALS [76,77], oligodendrocytes also contribute to motor neuron death in ALS. The
aberrant localization of TDP-43 to the cytoplasm rather than the nucleus of neurons has
been identified as a morphological hallmark of patients with sALS [78] while mutations
in the TARDBP gene identified in fALS patients [79] strengthened the hypothesis that
this protein may be involved in the development of the disease. Remarkably, among the
first data reporting oligodendrocyte contribution to ALS neuropathology, numerous cyto-
plasmic inclusions immunoreactive for ubiquitin, p62, and TDP-43 have been visualized
in oligodendrocytes in various CNS regions of ALS patients [28,30]. Analysis of a brain
bank for neurodegenerative disorders including ALS showed that all samples displaying
features of a TDP-43 pathology had morphological features similar to typical sALS. All
samples exhibited oligodendroglial cytoplasmic inclusions [80]. Similarly, another study
revealed TDP-43+ cytoplasmic inclusions in small cells displaying the characteristics of
oligodendroglia that were present in the lower motor nuclei and adjacent white matter,
in 97% of sALS cases and all SOD1-negative fALS samples [81]. The severity of gray and
white matter oligodendroglial TDP-43+ inclusions was reported to correlate closely with
neuronal loss [82]. Moreover, a specific MRI sequence (mcDESPOT) sensitive to water pools
within myelin led to showing that the reduction in global cognitive scores and executive
function was linked to myelin changes with a frontal lobe predominance in ALS patients. The approach also led to distinguishing the more classical ALS forms from the primary
lateral sclerosis, a rare and extreme form of ALS, in which widespread cerebral myelin
water fraction is decreased independently of disease duration and clinical upper motor
neuron alteration [83]. In the same line, the analysis of myelin in the spinal cord from SOD1G93A transgenic
rats revealed ultrastructural disorganization of myelin occurring already in the symptom-
free period (60 and 93 days of life) and subsequently worsening in paralyzed animals
(120 days of life). These anomalies were associated with decrease of both lipids (phos-
pholipids, cholesterol, cerebrosides) and proteins (PLP, MBP) [29]. They were consistent
with SAGE analysis of the whole spinal cord and lower brainstem from pre-symptomatic
SODG93A mice indicating altered expression of genes involved in different biological pro-
cesses including apoptosis, oxidative stress, ATP biosynthesis, myelination, and axonal
transport [84]. 2.3. Oligodendroglial Metabolic Support to the Axon In addition,
the unique mutually dependent unit formed by the oligodendrocyte and the axon can
be considered as a major contributor to the physiological function of axonal connectivity. Consequently, oligodendrocytes and myelin are highly vulnerable to energy metabolism
deficiencies even though mature oligodendrocytes are equipped with metabolic mecha- Int. J. Mol. Sci. 2021, 22, 3426 5 of 27 5 of 27 nisms that can overcome metabolic insults including axon–myelin interactions, which are
mutually supportive [66,74,75]. 3. Pathological Inclusions in Oligodendrocytes from ALS Patients and Animal Models As of 2003, Clement and collaborators revealed that the expression of mutant SOD1 in
motor neurons at levels that classically causes disease is not sufficient to trigger all aspects
of ALS pathology. Most importantly, non-neuronal cells that do not express mutant SOD1
delay degeneration and extend survival of motor neurons [22]. The use of mice carrying a
mutant SOD1 gene that can be deleted from motor neurons led to the conclusion that these
cells are essential for disease onset and its early progression. On the other side, decrease of
the mutant levels in microglia significantly slowed disease progression [76] while reducing
mutant expression in astrocytes delayed microglia activation and consequently also slowed
disease progression [24]. 3.1. TDP-43 Inclusions Proteomic profiling performed on brain-derived exosomes from SOD1G93A
transgenic mice demonstrated a loss of MOG compared with exosomes derived from non-
transgenic animals [85]. Demyelination as well as decreased expression of genes related to
myelin including MBP, Olig1, and Olig2 were similarly observed in a canine model of ALS
expressing mutated SOD1 [86]. Besides the detection of TDP-43 cytoplasmic inclusions within oligodendrocytes in
the motor cortex and spinal cord of ALS patients [80,87–90], similar inclusions of this
protein normally involved in various aspects of RNA processing and thus present in the Int. J. Mol. Sci. 2021, 22, 3426 6 of 27 cell nucleus have been observed in different animal models of the disease including the
mutant SOD1 mice. Detailed analysis of TDP-43 distribution in the spinal cord at different
stages of SOD1G93A animals revealed decreasing amounts of TDP-43 cells from cervical
to thoracic spinal cord segments, mostly detected in the ventral compared to the dorsal
horn, exclusively in neurons and oligodendrocytes. The amount of TDP-43 positive cells
significantly increased at the onset and progression stages of the disease concurrently with
the increase of neuron death in the ventral part of the cervical spinal cord [91]. A high level
of TDP-43 glial inclusions can also be detected in the C9orf72 mutant, which displays the
classical pathology of motor neuron loss, but is nevertheless devoid of the oligodendroglial
phenotype [92]. The molecular machinery responsible for cytosolic accumulation of misfolded TDP-
43 starts to be uncovered. Indeed, the von Hippel Lindau (VHL)/cullin-2 (CUL2) E3
complex is able to recognize and ubiquitinate misfolded TDP-43 and to promote clearance
of the fragmented forms of the protein. However, overexpressed VHL preferentially
recognizes misfolded TDP-43 and augments aggregate formation at the juxtanuclear protein
quality control center (JUNQ) in agreement with the visualization of cytoplasmic inclusions
comprising misfolded TDP-43 and VHL especially in oligodendrocytes in ALS spinal cords. Therefore, the imbalance of VHL/CUL2 may affect oligodendrocytes in ALS by inducing
the accumulation of pathogenic proteins, including not only TDP-43, but also mutant
SOD1 [93]. Furthermore, the formation of TDP-43 cytoplasmic aggregates examined by
time-lapse imaging of rat neural stem cell lines specifically differentiated into neuronal
or glial cells including oligodendrocytes revealed growing cytoplasmic aggregates in
the transduced cells, that were non-membrane bound, composed of electron-dense fine
granular materials of 20–30 nm in diameter, and intermingled with mitochondria and
lysosomal vesicles. 3.1. TDP-43 Inclusions Aggregate formation was followed by collapse of the cell and the
subsequent release of the aggregate as insoluble material in culture media before being
incorporated into neighboring neuronal cells, suggesting cell-to-cell spreading [94]. Recently, TDP-43 was found to be required for oligodendroglial physiological func-
tions. Its selective deletion in mature oligodendrocytes in mice revealed the development
of progressive neurological symptoms leading to early lethality associated with reduction
in myelination. This reduction was proposed to be related to both cell autonomous RIPK1-
mediated necroptosis of mature oligodendrocytes and TDP-43–dependent decrease in
myelin gene expression. In addition, increased proliferation of OPCs was able to replenish
the loss of mature oligodendrocytes, specifically in the white matter. However, degenera-
tion of spinal cord motor neurons was remarkably absent, thus excluding apparent toxicity
of oligodendrocyte TDP-43 loss on motor neurons [95]. 3.2. FUS Inclusions FUS-containing oligodendroglial cytoplasmic inclusions have been also detected in
the CNS of ALS patients exhibiting mutations in the FUS gene. The amount of such in-
clusions was correlated with disease onset [27]. Analysis of the different forms of the
mutant protein in ALS-FUS cases allowed the identification of two distinct clinical and
neuropathological patterns with neuronal cytoplasmic inclusions found in early-onset cases
in contrast to glial (mainly oligodendroglial) cytoplasmic inclusions detected in late-onset
cases [96]. A FUS mouse model expressing cytosol-localized FUS generated by deleting its
nuclear-localization signal displayed a notable reduced expression of myelin-related genes
in the spinal cord [97] while a mouse model expressing wild-type human FUS mimicking
its endogenous expression pattern and level within the CNS developed a progressive albeit
mild motor phenotype, but no apparent FUS aggregates. Transcriptomic analysis never-
theless identified expression changes in a small set of genes with preferential expression
in neurons and OPCs further suggesting that dysfunctions in the oligodendrocyte lineage
cells may also contribute to the observed phenotypes [98]. In the same line, the generation
of a novel conditional knockout in which FUS is selectively depleted in oligodendrocytes
revealed increased novelty-induced motor activity and enhanced exploratory behavior, Int. J. Mol. Sci. 2021, 22, 3426 7 of 27 7 of 27 both reminiscent of some manifestations of frontotemporal lobe degeneration known to
be associated, like fALS, with FUS mutations in humans. Most importantly, the work
discovered a novel role of FUS in controlling myelin deposition across all myelinated axons
and the selective increase in myelination of small caliber axons suggesting that both myelin
ensheathment and axon wrapping are increased in the absence of oligodendroglial FUS. The phenotype was not associated with changes in oligodendrocyte lineage progression,
since the densities of OPCs and oligodendrocytes were not modified. From a molecular
point of view, the phenotype appeared to be associated with activation of the PI3K/Akt
pathway and to a greater expression of the rate-limiting enzyme for cholesterol biosynthe-
sis, the 3-hydroxy-3-méthyl-glutaryl-coenzyme A reductase (HMGCR), via transcriptional
activation mediated by Fus direct binding to HMGCR transcript [99]. 3.3. SOD1 Inclusions SOD1-containing cytoplasmic inclusions have been also observed in the periaxonal
oligodendroglial cytoplasm of SOD1G93A mutant mice analyzed by immunoelectron mi-
croscopy [100]. Misfolded SOD1 in the form of granular aggregates was regularly detected
in the nuclei of ventral horn glial cells including oligodendrocytes in ALS patients carrying
or lacking SOD1 mutations [101] as well as in oligodendrocyte cultures derived from fALS
or sALS patients presenting mutations in the SOD1 or TDP-43 genes [102]. 3.4. ErBB4 Inclusions Another identified causative gene for autosomal dominant, late-onset fALS, des-
ignated as ALS19 and encoding ErBB4, is also at the origin of oligodendroglial inclu-
sions [103]. Like TDP-43, ErBB4 is an important regulator of oligodendrocyte development
and maturation controlling myelin formation by oligodendrocytes in the CNS [104,105]. Patients with pathogenic mutations showed typical clinical features of ALS, clinically undis-
tinguishable from those observed in patients with sALS. Functional analysis of mutations
at the ALS19 locus revealed reduced autophosphorylation capacity of the ErBB4 protein
upon stimulation with NRG-1, suggesting that the disruption of the NRG–ErBB4 pathway
may cause motor neuron degeneration. The loss of ErBB4 cytoplasmic immunoreactivity
in motor neurons in the anterior horns of the spinal cord was correlated with the severity
of motor neuron loss, or with alteration of subcellular localization towards a nucleolar
or nuclear localization. An ectopic oligodendroglial ErBB4 immunoreactivity could also
be detected. Interestingly, the expression of ErBB4 and TDP-43 appeared to be mutually
exclusive in oligodendrocytes [106]. 4. Degenerating and Dysfunctional Oligodendrocytes in ALS Patients and Animal
Models After the first descriptions of the existence of aberrant protein aggregates in oligoden-
drocytes, independent groups successively reported complementary data that accurately
described oligodendrocyte dysfunction, progressive gray-matter demyelination, and reac-
tive changes in OPCs observed in the motor cortex and spinal cord of both sALS and fALS
patients as well as in SOD1G93A mutant mice [67,89,107] (Figure 1C,D). 8 of 27
hat oli- Int. J. Mol. Sci. 2021, 22, 3426 g
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[
]
Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor
cells (OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each pheno-
typic step are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oli-
godendrocytes takes place in the presence of microglial and astroglial cells, which are known to participate namely in the
differentiation of OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in
channel forming proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendro-
genesis is characterized by the increase of OPC proliferation, which gives rise to a higher number of differentiated oli-
godendrocytes. The latter are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43
Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor cells
(OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each phenotypic step
are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oligodendrocytes
takes place in the presence of microglial and astroglial cells, which are known to participate namely in the differentiation of
OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in channel forming
proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendrogenesis is characterized
by the increase of OPC proliferation, which gives rise to a higher number of differentiated oligodendrocytes. The latter
are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43 or ErBB4, SOD1, FUS) or
accumulate abnormal dipeptide repeat proteins (C9orf72) in their nucleus. These abnormal oligodendrocytes are unable to
mature into myelinating cells and ultimately die. 4. Degenerating and Dysfunctional Oligodendrocytes in ALS Patients and Animal
Models In response to cell death, OPC proliferation is highly increased (red arrow). (D) Cellular and molecular mechanisms involved in ALS pathology include axon demyelination and degeneration that may
occur as the primary or secondary event compared to the death of oligodendrocytes. Both glutamate excitotoxicity (orange
broken arrow) from the degenerating neurons and the dysregulation of protein folding leading to abnormal aggregates (blue
and orange ellipses) lead to endoplasmic reticulum stress resulting into the increase of the ER stress apoptotic mediator
CHOP and into the activation of the unfolded protein response (UPR) associated with the specific expression of select UPR
target genes, such as PDI (protein disulfide isomerase). At the level of oligodendrocyte processes, the most abundant myelin
protein MBP and the monocarboxylate transporter 1 (MCT1) required for lactate release to the axon are both decreased. The
altered communication between the oligodendrocyte and the neighboring astrocytes (green) related to changes in connexin
(Cx) expression as well as the pro-inflammatory microglia (blue) namely secreting the cytokine TNFα and triggering the
RIPK1/RIPK3/MLKL signaling pathway, both participate in oligodendrocyte dysfunction and degeneration, respectively. Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor
cells (OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each pheno-
typic step are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oli-
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Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor cells
(OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each phenotypic step
are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oligodendrocytes Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS
h
l h
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(CNS)
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Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor
cells (OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. 4. Degenerating and Dysfunctional Oligodendrocytes in ALS Patients and Animal
Models Specific markers of each pheno-
typic step are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oli-
godendrocytes takes place in the presence of microglial and astroglial cells, which are known to participate namely in the
differentiation of OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in
channel forming proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendro-
genesis is characterized by the increase of OPC proliferation, which gives rise to a higher number of differentiated oli-
godendrocytes. The latter are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43
Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor cells
(OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each phenotypic step
are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oligodendrocytes
takes place in the presence of microglial and astroglial cells, which are known to participate namely in the differentiation of
OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in channel forming
proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendrogenesis is characterized
by the increase of OPC proliferation, which gives rise to a higher number of differentiated oligodendrocytes. The latter
are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43 or ErBB4, SOD1, FUS) or
accumulate abnormal dipeptide repeat proteins (C9orf72) in their nucleus. These abnormal oligodendrocytes are unable to
mature into myelinating cells and ultimately die. In response to cell death, OPC proliferation is highly increased (red arrow). (D) Cellular and molecular mechanisms involved in ALS pathology include axon demyelination and degeneration that may
occur as the primary or secondary event compared to the death of oligodendrocytes. Both glutamate excitotoxicity (orange
broken arrow) from the degenerating neurons and the dysregulation of protein folding leading to abnormal aggregates (blue
and orange ellipses) lead to endoplasmic reticulum stress resulting into the increase of the ER stress apoptotic mediator
CHOP and into the activation of the unfolded protein response (UPR) associated with the specific expression of select UPR
target genes, such as PDI (protein disulfide isomerase). 4. Degenerating and Dysfunctional Oligodendrocytes in ALS Patients and Animal
Models At the level of oligodendrocyte processes, the most abundant myelin
protein MBP and the monocarboxylate transporter 1 (MCT1) required for lactate release to the axon are both decreased. The
altered communication between the oligodendrocyte and the neighboring astrocytes (green) related to changes in connexin
(Cx) expression as well as the pro-inflammatory microglia (blue) namely secreting the cytokine TNFα and triggering the
RIPK1/RIPK3/MLKL signaling pathway, both participate in oligodendrocyte dysfunction and degeneration, respectively. Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor
cells (OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each pheno-
typic step are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oli-
godendrocytes takes place in the presence of microglial and astroglial cells, which are known to participate namely in the
differentiation of OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in
channel forming proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendro-
genesis is characterized by the increase of OPC proliferation, which gives rise to a higher number of differentiated oli-
godendrocytes. The latter are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43
Figure 1. Pathological oligodendrogenesis and myelination in amyotrophic lateral sclerosis (ALS) disease. (A) In the
healthy central nervous system (CNS), oligodendrogenesis comprises the differentiation of oligodendrocyte progenitor cells
(OPC) into pre-myelinating oligodendrocytes, which mature into myelinating cells. Specific markers of each phenotypic step
are indicated. The blue arrow indicates the proliferation of OPCs. (B) Myelination of neuronal axons by oligodendrocytes
takes place in the presence of microglial and astroglial cells, which are known to participate namely in the differentiation of
OPCs (via the secretion of IGF-1) and the supply of metabolic nutrients (via gap junctions enriched in channel forming
proteins connexin, Cx) and lipids for myelin sheath production. (C) During ALS disease, oligodendrogenesis is characterized
by the increase of OPC proliferation, which gives rise to a higher number of differentiated oligodendrocytes. The latter
are dysmorphic and display various protein aggregates in their cytoplasm including (TDP-43 or ErBB4, SOD1, FUS) or
accumulate abnormal dipeptide repeat proteins (C9orf72) in their nucleus. These abnormal oligodendrocytes are unable to
mature into myelinating cells and ultimately die. 4.2. Degeneration and Accelerated Turnover of Oligodendroglial Cells In parallel, further investigations revealed that oligodendrocyte lineage cells are
targets of the disease in both human patients with ALS and mutant SOD1 mice. In the
transgenic SOD1G93A animals, oligodendrocytes clearly degenerate and die, even before
motor neuron loss is evident as shown via immunostaining approaches and genetic fate
tracing of oligodendrocytes using the inducible Cre recombination under the PLP promoter. The process that clearly intensified with disease progression was mostly observed in the
ventral gray matter and at a lower extent in the central white matter. g
y
Oligodendrocyte degeneration was associated with abnormal morphology including
enlarged cytoplasm and elongated reactive processes, cleaved caspase-3 immunoreactivity,
chromatin condensation, and the existence of clusters of microglial cells surrounding them. However, the oligodendrocyte number remained unexpectedly constant during disease
progression. Therefore, it was proposed the existence of a compensatory production of
new cells arising from NG2-expressing OPCs scattered throughout the whole CNS and
comprising the main source of new myelinating oligodendrocytes upon a demyelinating
event. An increase in proliferating NG2+ cells was observed during the symptomatic phase
of the disease in the SOD1G93A mice. The genetic tracing of OPCs using the PDGFRα
promoter allowed the detection of a higher proportion of OPCs differentiating into oligo-
dendrocytes [89] while the genetic tracing of differentiated oligodendrocytes using the
PLP promoter indicated no difference in the total number of oligodendrocytes in the
control or mutant SOD1 mice, but a higher production of new oligodendrocytes in the mu-
tant [108,109]. The increased proliferation and differentiation of OPCs, which themselves
exhibited some hypertrophy, reflected their activation selectively in brain regions where
motor neurons degenerated [89,107]. 4. Degenerating and Dysfunctional Oligodendrocytes in ALS Patients and Animal
Models In response to cell death, OPC proliferation is highly increased (red arrow). (D) Cellular and molecular mechanisms involved in ALS pathology include axon demyelination and degeneration that may
occur as the primary or secondary event compared to the death of oligodendrocytes. Both glutamate excitotoxicity (orange
broken arrow) from the degenerating neurons and the dysregulation of protein folding leading to abnormal aggregates (blue
and orange ellipses) lead to endoplasmic reticulum stress resulting into the increase of the ER stress apoptotic mediator
CHOP and into the activation of the unfolded protein response (UPR) associated with the specific expression of select UPR
target genes, such as PDI (protein disulfide isomerase). At the level of oligodendrocyte processes, the most abundant myelin
protein MBP and the monocarboxylate transporter 1 (MCT1) required for lactate release to the axon are both decreased. The
altered communication between the oligodendrocyte and the neighboring astrocytes (green) related to changes in connexin
(Cx) expression as well as the pro-inflammatory microglia (blue) namely secreting the cytokine TNFα and triggering the
RIPK1/RIPK3/MLKL signaling pathway, both participate in oligodendrocyte dysfunction and degeneration, respectively. Int. J. Mol. Sci. 2021, 22, 3426 9 of 27 4.1. Reduction of MCT1 Expression 4.1. Reduction of MCT1 Expression In agreement with the hypothesis that the aggregates may disrupt the active transport
and/or the free diffusion of metabolites such as lactate, from the oligodendrocyte to
the axon by potentially impairing myelin channel functioning, a first work reported the
selective reduction of MCT transporters in the motor cortex of ALS patients [67]. MCT1
decrease was also observed in rodent and canine models of the disease [67,86]. In mouse
SOD1 mutants, MCT1 transcripts were downregulated in the ventral horn gray matter of
the spinal cord derived from early symptomatic and end-stage animals. The reduced MCT1
reporter expression was not related to a lower number of oligodendroglial cells, since
mature oligodendrocytes were unchanged. Moreover, Sh-RNA-mediated downregulation
of MCT1 specifically in oligodendrocytes in the optic nerve and corpus callosum induced a
dramatic increase in the number of degenerating axons indicating that oligodendrocyte
MCT1 was critical for axon survival [67]. 4.3. Regeneration of Dysfunctional Oligodendrocytes Besides the abnormal morphology of the newly generated oligodendrocytes, myelin
sheaths presented altered lipid and protein composition even before symptom onset. Moreover, the new oligodendrocytes were notably observed close to the degenerating
axons suggesting that the abnormal behavior of NG2-expressing cells was a response to
degeneration of oligodendrocytes following motor neuron loss [29,89,107]. The newly
generated oligodendrocytes were proposed to exist in a differentiated, but non-myelinating
state, possibly related to the lack of appropriate targets, perhaps promoting cell death. Such
a continuous cycle of proliferation, differentiation, and death of oligodendrocytes in ALS
might consequently accelerate the death of neurons already stressed and lacking metabolic
support [107]. Various candidates likely to account for the impairment of OPC maturation have
been evaluated in ALS models. Notch1 signaling is one of the mechanisms that regulate
OPC differentiation during remyelination by promoting OPC expansion but inhibiting
differentiation and myelin formation. However, the conditional deletion of Notch1 in Int. J. Mol. Sci. 2021, 22, 3426 10 of 27 10 of 27 OPCs fails to alleviate oligodendrocyte dysfunction or ameliorate disease outcomes in ALS
mice [109]. These data are consistent with the recent revisit of Notch signaling in ALS
models indicating that the expression patterns of the activated Notch intracellular domain
(NICD) and Notch ligands did not much vary in the oligodendroglial lineage in the spinal
cord of symptomatic SOD1G93A mice. Thus, the Notch signaling pathway does not appear
to contribute much to oligodendroglial dysfunction [110]. OPCs fails to alleviate oligodendrocyte dysfunction or ameliorate disease outcomes in ALS
mice [109]. These data are consistent with the recent revisit of Notch signaling in ALS
models indicating that the expression patterns of the activated Notch intracellular domain
(NICD) and Notch ligands did not much vary in the oligodendroglial lineage in the spinal
cord of symptomatic SOD1G93A mice. Thus, the Notch signaling pathway does not appear
to contribute much to oligodendroglial dysfunction [110]. A second candidate was the extracellular matrix protein, connective tissue growth fac-
tor (CTGF/CCN2), which displays an increased level in the spinal cord from ALS patients
and SOD1G93A mice. An in vitro study using Schwann cells as a source of CTFG/CCN2
showed that this molecule inhibits oligodendrocyte myelination and promotes astrocyte
reactivity supporting the hypothesis that CTGF/CCN2 may specifically impair oligoden-
drocyte maturation and inhibit axon myelination in ALS disease [111]. 4.3. Regeneration of Dysfunctional Oligodendrocytes Another study
performed in mice expressing a moderate level of the fALS-causing mutation SOD1G37R
provided evidence for the possible involvement of other signaling pathways known to
regulate oligodendrocyte maturation and myelination. Alterations in RNAs encoding
components of these pathways including phosphatidylinositol signaling, FcγR-mediated
phagocytosis, and a calcium signaling pathway nevertheless remain to be further investi-
gated [112]. g
Future works should delineate whether a pro-inflammatory OPC phenotype is present
in ALS tissues. This phenotype has been shown to occur in response to inflammatory cues,
to promote tissue damage and to block remyelination [113,114]. Thus, this might account
for the apparent dysfunction of the newly generated oligodendrocytes. In the same line,
the recent finding that alteration of oligodendrocyte heterogeneity in multiple sclerosis,
the most common CNS demyelinating disease, may be related to the progression of the
disease [113] suggests the requirement for more accurately delineating the phenotype of
oligodendrocytes present in ALS tissues. 4.4. Abnormal Myelination The clear reduction of myelination in ALS corticospinal tracts and ventral horn gray
matter of the spinal cord was obviously consistent with the finding that the newly gen-
erated oligodendrocytes were dysfunctional and failed both in terms of myelin synthesis
and trophic support as suggested by the lower expression of MBP and MCT1, respec-
tively [89,107]. Electron microscopy analysis of the ventral gray matter revealed a high
percentage of ultrastructurally normal axons exhibiting immature myelin, i.e., a thick layer
of oligodendrocyte cytoplasm between the axon and the initial myelin wrap in end stage
SOD1G93A mice, suggesting that viable and uninjured axons were remyelinated. Ultra-
structural anomalies typical of Wallerian degeneration were also observed together with
MBP immunoreactivity more diffuse in the end stage mutant than in the control. Axons
with mature myelin displayed a thicker sheath than controls possibly reflecting axonal
shrinkage. Myelin debris and immature myelin sheaths could also be detected [107]. 4.5. Motor Neuron Death Induced by ALS Gene Expression in Oligodendrocytes Importantly, the genetic deletion of mutant human SOD1G37R from OPCs and their
progeny delayed disease onset and prolonged survival, confirming the direct relationship
with motor neuron degeneration. SOD1 removal helped to preserve MCT1 expression in
some mice at early stages of the disease indicating that expression of mutant SOD1 in NG2+
cells and their oligodendrocyte progeny has a deleterious effect on motor neuron survival. Thus, the progressive loss of gray matter oligodendrocytes as well as the failure to restore
these critical cells were proposed to accelerate disease progression in ALS by depriving
motor neurons of essential metabolic support [107]. In vitro models of motor neuron and oligodendrocyte cocultures led to consistent
results indicating that mouse SOD1G93A oligodendrocytes or human ALS oligodendrocytes
derived from multiple genetic and sporadic forms of the disease induce motor neuron death
via soluble and insoluble factors that require cell-to-cell contact or very close proximity. Int. J. Mol. Sci. 2021, 22, 3426 11 of 27 11 of 27 Interestingly, the toxic effects can be rescued by reducing SOD1 in OPCs (but not in
differentiated oligodendrocytes) except for OPCs derived from cells carrying the C9ORF72
mutations, which seem to be SOD1 independent and thus define a discrete subgroup of ALS
patients [102]. In agreement with this observation, oligodendrocytes derived from human
pluripotent stem cells obtained from two ALS patients harboring mutations in the C9ORF72
gene did not exhibit impairment of OPC proliferation, maturation, or viability. However,
RNA foci could be detected as expected from the expanding RNA repeats present in the
mutant. Thus, the presence of the C9ORF72 mutation, the most common manifestation of
familial ALS, contributing to 10% of sporadic- and 37% of familial cases, did not confer
detrimental effects on maturation or survival of oligodendrocytes. Although the data could
not exclude possible impairment of myelination associated with such mutations, they
suggested that the different genetic causes of ALS could be heterogeneous with respect
to the properties of oligodendrocytes [115]. However, intriguingly, the distribution of
C9ORF72 promoter activity was recently found to be enriched in cell types and brain
regions that undergo degeneration in ALS suggesting that cell autonomous effects in the
altered populations of neurons and oligodendrocytes may nevertheless account for their
loss [116]. g
5.1. Glutamate Excitotoxicity Induced by Motor Neuron Death 5.1. Glutamate Excitotoxicity Induced by Motor Neuron Death Since motor neuron degeneration in both spinal cord and motor cortex is an essen-
tial and furthermore necessary component of the disease to confirm diagnosis of ALS,
glutamate excitotoxicity was among the first mechanisms implicated in oligodendrocyte
pathogenesis in ALS. Indeed, when motor neurons start to degenerate, they release high
levels of glutamate [118]. Oligodendrocytes express Ca2+ permeable NMDA receptors,
which thus promote an abundant Ca2+ accumulation in the cells leading to their degenera-
tion [119]. However, a series of other mechanisms have been progressively proposed to
contribute to oligodendrocyte dysfunction (Figure 1D). 4.5. Motor Neuron Death Induced by ALS Gene Expression in Oligodendrocytes Still in regard to disease heterogeneity, a yet higher level of complexity was recently
provided by transcriptome arrays performed in anterior horn of the spinal cord and frontal
cortex from sALS cases that revealed striking regional differences. In the spinal cord,
up- and down-regulated clusters were related to inflammation/apoptosis and axoneme
structures/protein synthesis, respectively. In the frontal cortex, up-regulated gene clusters
involved neurotransmission, synaptic proteins, and vesicle trafficking, whereas down-
regulated genes clustered into oligodendrocyte function and myelin-related proteins even
though patients were at stages with no apparent impairment [117]. 5.2. Abnormalities in Protein Homeostasis Oxidative stress induced by an imbalance of free radicals is also a major contributor
to ALS neurodegeneration. It exacerbates homeostatic dysregulation of mitochondria, pro-
teins, genes, and other cellular processes, which are the subject of continuous investigations. The subsequent alteration of protein folding is consistent with the formation of protein
aggregates promoted by mutations in ALS-related genes including SOD1, FUS, TDP-43,
and ErBB4 as described above. These aggregates cause further endoplasmic reticulum (ER)
stress and cell apoptosis as namely suggested for the SOD1 mutant [107]. In agreement with
this observation, the analysis of the ER-stress apoptotic mediator CHOP (CCAAT/enhancer
binding protein (C/EBP) homologous protein) revealed a marked expression increase in
the spinal cords from both sALS patients and ALS transgenic mice (Figure 1D). In the
latter, CHOP expression increase could be detected at 14 (symptomatic stage) and 18 to 20
(end stage) weeks. Furthermore, localizations of CHOP were detected in motor neurons
and glial cells, such as oligodendrocytes, astrocytes, and microglia, suggesting that the
up-regulation of CHOP in various cell types including oligodendrocytes may play pivotal
roles in the pathogenesis of ALS [120]. Int. J. Mol. Sci. 2021, 22, 3426 12 of 27 12 of 27 To resolve ER stress and defect in protein homeostasis, cells trigger intrinsic mecha-
nisms called unfolded protein response (UPR) and heat shock response (HSR), two of the
major signaling pathways implicated in the restoration of protein homeostasis. In ALS
human post-mortem tissues, UPR is activated in both the motor cortex and spinal cord
with specific expression of select UPR target genes, such as PDIs (protein disulfide iso-
merase) observed in motor cortex of sALS cases where these genes strongly correlate with
oligodendrocyte markers. In contrast, the ER-associated degradation (ERAD) and HSR
genes mostly activated in spinal cord, correlate with the expression of neuronal markers
evidencing cell-type-specific contributions. Interestingly, an increase in PDI expression has
been reported to occur during active myelination in cortical regions of rats. In line with
this observation, a strong PDI expression in oligodendrocytes was observed in SOD1 mice
in agreement with abnormalities in plasma and membrane lipid signaling, especially in the
early symptomatic stages of ALS [121]. Despite the increased expression of the systems
involved in protein homeostasis restauration, a recent metadata analysis of oxidative stress
etiology in pre-clinical ALS patients has proposed an insufficient compensatory response
to oxidative stress [122]. 5.3. Oxidative Damage to mRNAs Involved in Myelination In ALS models, oxidative damage to mRNA has been reported in oligodendrocytes
before the symptomatic stage when microgliosis is not yet detected. Among the most
vulnerable mRNAs are those involved in mitochondrial electron transport and myelination. Thus, oxidative damage to MBP mRNA likely accounts for reduced MBP expression
(Figure 1D) consistent with the myelin defects observed in ALS [123]. The hypothesis that
the loss of critical functions in the aggregation-prone genes is involved in myelination
defect is in agreement with the rescue of white matter degeneration upon removal of
disease causal mutation SOD1 from oligodendrocytes [107] and with the requirement of
the normal function of TDP-43 for oligodendrocyte survival and myelination [95]. Of note,
many critical mRNAs required for normal oligodendroglial function are locally translated
at the myelin sheath. This is true for MBP, MOBP, CAII as well as for several RNA-binding
proteins that have been all characterized to be binding partners of proteins involved in ALS
pathology and, therefore, might contribute to cellular dysfunction. In agreement with this
hypothesis, hnRNP A1 and hnRNP A2/B1, involved in MBP mRNA trafficking, are both
binding partners of C9ORF72 (G4C2) repeat RNA foci and TDP-43 [124]. In addition, they
display intrinsically disordered domains at their C-terminal end supporting the idea that
they are prone to misfolding. Moreover, TDP-43 depletion upregulates specific isoforms of
hnRNP A1 specifically susceptible to aggregation [125]. Finally, post-mortem tissues from
ALS patients displaying C9ORF72 RNA foci were found to sequester hnRNP H/F required
for PLP/DM20 alternative splicing [126] via a mechanism involving their interaction with
Quaking in Myelination (QKI) proteins [127]. 5.4. Deleterious Effects Involving Astrocytes A growing literature is currently providing evidence for the involvement of extrinsic
mechanisms originating in neighboring glial cells and related to the existence of a dual activ-
ity for both reactive astrocytes and microglia in inflammatory diseases of the CNS, namely
demyelinating diseases (for review [128]). Reactive astrocytes secrete pro-inflammatory
molecules promoting the neuroinflammatory process as well as extracellular matrix dele-
terious for remyelination namely via the formation of aggregates known to prevent OPC
differentiation as recently described in several reviews [128–130]. Moreover, changes in
oligodendrocyte and astrocyte connexin expression have been found to affect oligodendro-
cyte and neuronal metabolic support in both ALS patients and disease models. Connexins
form homotypic or heterotypic gap junctions, namely between astrocytes and oligoden-
drocytes, through which intercellular communication occurs as attested by exchanges of
small molecules namely including lactate and glucose transferred by astrocytes to oligo-
dendrocytes. In mutant SOD1 animals, astrocyte Cx43 is significantly upregulated with Int. J. Mol. Sci. 2021, 22, 3426 13 of 27 13 of 27 disease progression, whereas oligodendrocyte Cx32 and Cx47 are downregulated [131,132]
(Figure 1D). The decrease of Cx32 observed earlier as the disease-progressive stage was
suggested to be due to enhanced degradation of the protein since Cx32 transcription only
started to decrease at the end stage of the disease. Cx47 expression also started to decrease
at the disease-progressive stage. However, the decrease was attributed to both decreased
transcription and defective transport from the cytosol to the surface membrane and/or
increased internalization from the membrane to the cytosol. y
All these modifications were particularly evident in the dysmorphic oligodendrocytes
accumulating at the anterior horns suggesting a causative relationship between mutant
SOD1 and connexin pathology. They were also consistent with the stage-dependent
progression of astrogliosis and microglial activation in the anterior horns of the same model. In normal conditions, oligodendrocytes can import glucose through GLUT1 and connexin
junctions for glycolysis. The latter can yield sufficient ATP to support oligodendrocyte
survival while the aerobic glycolysis product, lactate, can be transferred to axons via
MCT1 and used as an energy source for axonal activity. Therefore, loss of membranous
Cx47 and Cx32 in oligodendrocytes in mSOD1 ALS model mice may lead to insufficient
glucose supply both contributing to oligodendrocyte damage and motor neuron death
through energy failure [132]. These finding were supported by the severe demyelination,
oligodendrocyte death, and axonal loss in mice lacking Cx32 and Cx47 [133]. 5.4. Deleterious Effects Involving Astrocytes The changes
in glial network activity through connexin hemichannels likely contribute to the failure
of remyelination and eventual death of motor neurons, although further works based
on knockout or overexpression models for astrocyte/oligodendrocyte connexins should
elucidate the importance of these pathways in the pathogenesis of motor neuron disease. 5.5. Deleterious Effects Involving Microglia Like astrocytes, microglia may be endowed with detrimental effects on oligodendro-
cytes and myelin via the synthesis of cytokines, chemokines, cell adhesion glycoproteins,
or reactive oxygen radicals able to damage axons, myelin, oligodendrocytes, and thus
implicated in the initiation and propagation of the inflammatory cascade contributing to
demyelination. Several recent publications have addressed the topic [128,134]. However, a
specific link between microglia and oligodendrocyte degeneration has been established in
ALS via data reporting that the lack of optineurin function in microglia activates an intrinsic
cascade that triggers these cells to adopt a RIPK1-dependent pro-inflammatory phenotype
(including TNFα secretion) assumed to kill neighboring oligodendrocytes by promoting
their necroptosis [93]. Optineurin is a gene for which loss-of-function mutations have
been linked to ALS, not for motor neuron death or paralysis, but for other features namely
including lower number of axons, abnormally large caliber axons, and signs of thicker,
less compact myelin sheaths in the spinal ventrolateral white matter and to a lesser extent
in the anterior roots from the age of three weeks [135]. The silencing of optineurin was
found to sensitize cultured fibroblasts to necroptosis upon exposure to the caspase inhibitor
zVAD-fmk, by involving RIPK1, RIPK3, and the phosphorylated form of the mixed lineage
kinase domain-like protein (MLKL), which are all increased in the spinal cord of optineurin
knockout mice. In addition, targeting RIPK1/RIPK3 in optineurin and SOD1 mutant mice
mitigated the axon-myelin phenotype in both mutants and in addition, delayed onset of
motor defects in the SOD1 mutant. Whether the assumed death of oligodendrocytes or a
preceding dysfunction of these cells cause the axonopathy still remained unclear [93]. 6. Oligodendrocyte Degeneration as a Primary or Secondary Event in ALS Pathogenesis
6.1. Oligodendrocyte Degeneration as a Primary Event The observation that oligodendrocyte degeneration occurs earlier than motor neuron
loss [89,107] has been the first strong argument for considering oligodendrocyte as the
primary event in ALS pathology. In agreement with this hypothesis, alterations in the
white matter were found to be more pronounced compared with those in motor neurons Int. J. Mol. Sci. 2021, 22, 3426 14 of 27 14 of 27 and they were detected during the early stages of ALS, prior to the appearance of clinical
symptoms [25,26]. and they were detected during the early stages of ALS, prior to the appearance of clinical
symptoms [25,26]. y
p
A recent work also supported the idea that oligodendrocyte and myelin pathology
outstrip neuronal degeneration in some regions by analyzing the extent of inclusion pathol-
ogy in post-mortem tissues from human sALS and mutant C9ORF72-related ALS (C9ALS)
cases [136]. Data revealed a high load of p62 and TDP43 glial inclusions in the prefrontal
cortex, precentral gyrus, and spinal cord, which was greater in C9ALS than in sALS cases. Double staining demonstrated that the majority of these inclusions were in oligodendro-
cytes and the use of immunoblotting led to showing reduced MBP protein levels relative to
PLP (a myelin component that relies on protein not mRNA transport) and to neurofilament
protein used as an axonal marker in the spinal cord. Such a disproportionate loss of MBP
compared to the level of PLP and axonal loss, was in agreement with the likely disruption of
MBP mRNA transport. The observation also fully supported that myelin alteration was not
secondary to axonal loss however without completely excluding that part of myelin degra-
dation might be secondary to axonal loss [136]. Similarly, although the severity of gray and
white matter oligodendroglial TDP-43 inclusions has been reported to mostly correlate with
neuronal loss [82], the detection of some gray matter oligodendroglial TDP-43 inclusions
in areas without evident neuronal TDP-43 aggregates, neuronal loss, or white matter oligo-
dendroglial TDP-43 pathology suggested that gray matter oligodendroglial involvement
could be an early event in the disease process that announced subsequent involvement of
neuronal cells. The location of gray matter oligodendrocytes in close proximity to axonal
connections of motor neurons was also in support of this hypothesis [82]. 6. Oligodendrocyte Degeneration as a Primary or Secondary Event in ALS Pathogenesis
6.1. Oligodendrocyte Degeneration as a Primary Event Other arguments supporting the primary involvement of oligodendrocytes were pro-
vided by the selective deletion of mutant SOD1 protein from the oligodendroglial cells that
was found to delay disease onset and improve mouse survival, probably suggesting a key
role for oligodendroglial cells in accelerating injury to vulnerable motor neurons. However,
the time between symptom onset and death remained unmodified, suggesting that the
longer survival time was only related to the delay in disease onset. Furthermore, the role of
oligodendrocytes in supporting axonal energy metabolism is also obviously consistent with
a major role of oligodendrocytes in the deterioration of motor neurons. In a consistent man-
ner, SOD1 removal from oligodendrocytes led to MCT1 levels comparable to those found in
the wild-type mice as well as to a lower level of reactive astrocytes and microglia that may
also possibly participate in the delay in disease onset since alterations in astrocytes and
microglia are critical for determining disease onset [23,24]. In addition, the generation of
transgenic zebrafish selectively expressing G93A mutant SOD1 in mature oligodendrocytes
revealed that mutant SOD1 directly induced oligodendrocyte degeneration by disrupting
the myelin sheath and downregulating MCT1 subsequently causing spinal motor neuron
degeneration. Since in vivo treatment of the mutant zebrafish using potassium channel
inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, myelin
disruption was nevertheless proposed to induce behavioral abnormalities independently
of MCT1 [137]. 6.2. Oligodendrocyte Degeneration as a Secondary Event On the contrary, a few other works question the primary involvement of oligodendro-
cytes in the pathological propagation of the disease. First, the neuronal expression of mutant SOD1 was found to cause motor neuron
degeneration and paralysis in transgenic mice displaying cytosolic dendritic ubiquitinated
SOD1 aggregates as a dominant pathological feature. Moreover, the crossing of neuron-
specific mutant SOD1 mice with ubiquitously wild-type SOD1-expressing mice led to high
wild-type SOD1 aggregation in oligodendrocytes after the onset of neuronal degenera-
tion. The chronologic steps were thus that mutant SOD1 in neurons triggers neuronal
degeneration, which subsequently may facilitate aggregate formation in surrounding glial
cells [138]. Int. J. Mol. Sci. 2021, 22, 3426 15 of 27 15 of 27 Second, the spread of the pathology into four stages has been initially proposed to
occur through corticofugal axonal transmission consistent with the detection of oligo-
dendroglial TDP-43 aggregates along with neuronal inclusions. However, while TDP-43
immunoreactive oligodendrocytes were frequently observed in the white matter under
the motor and sensory cortices, no TDP-43 pathology was detected, namely in the white
matter along the corticospinal tract of the same tissue samples, [139]. g
p
p
Third, high-throughput RNA sequencing together with translating ribosome affinity
purification (TRAP) provided evidence that pathogenesis involves a temporal cascade of
cell type-selective damage starting in motor neurons, with subsequent damage within
glia that might subsequently drive disease propagation. The data were obtained in mice
expressing a moderate level of the fALS-causing mutation SOD1G37R. Motor neuron dam-
ages included synapse and metabolic abnormalities as well as endoplasmic reticulum
stress. Glia-related changes occurred early in astrocytes in genes involved in inflamma-
tion/metabolism or standing as targets of the lipid-activated transcription factors PPAR
and LXR. Dysregulation of myelination and lipid signaling pathways together with activa-
tion of ETS transcription factors appeared in oligodendrocytes only after disease initiation. Gene expression changes were most dramatic in motor neurons (260 significant changes),
compared to astrocytes (108) and oligodendrocytes (23 including 14 up-regulated and
9 down-regulated RNAs). Notably, ER chaperones PDI and FKBP9 mRNA levels were
much more highly up-regulated in astrocytes and oligodendrocytes compared with motor
neurons, suggesting that motor neurons could be intrinsically more vulnerable to unfolded
protein accumulation. 6.2. Oligodendrocyte Degeneration as a Secondary Event Unexpectedly, MCT1 decrease previously shown in SOD1G93A
mice [67] was not observed in these other SOD1 mutants suggesting that altered levels of
MCT1 could not constitute an early damaging factor able to drive initiation of non–cell-
autonomous toxicity from oligodendrocytes to motor neurons [112]. y
g
y
Fourth, the transfer of fluorescent wild-type or mutant SOD1 cytosolic proteins occur-
ring first in motor neurons and then in neighboring oligodendrocytes in the gray matter of
the ventral spinal cord is still in support of the primary involvement of motor neurons and
not oligodendrocytes [140]. The demonstration was based on a retrograde transduction
experiment using injection of a recombinant AAV6 expressing wild-type SOD1-CFP into
the tibialis anterior muscle in early postnatal mice. Data revealed the appearance of CFP
fluorescence first in motor neurons, as early as 11 days post-injection, followed 17–31 days
later in oligodendrocytes, consistent with time-dependent transfer from motor neurons
to oligodendrocytes. However, since the increase of transferred fluorescent proteins in
recipient motor neurons paralleled the development of fluorescence in neighboring mature
oligodendrocytes and their morphological changes, it was proposed that oligodendrocytes
may serve as a vehicle for subsequent transfer between motor neurons. The precise mech-
anism of cell–cell transfer was proposed to involve a contact between oligodendrocyte
processes and motor neuron cell bodies. However, the exact mechanism of the transfer
remains to be investigated [140]. 6.3. Primary or Secondary Event: A Yet Unanswered Question It is quite clear that our current knowledge does not allow to conclude on the primary
or secondary involvement of oligodendrocytes or motor neurons in ALS. However, a few
arguments quite inconsistent with the hypothesis that neurons are primarily involved can
be pointed out. Indeed, the increase in oligodendrogenesis reported in the ALS models
does not support this hypothesis. First, the production of new oligodendrocytes without
target axons to myelinate would be inadequate. Second, as motor axons comprise only a
minor proportion of myelinated fibers in the spinal cord and as a single oligodendrocyte
can synthesise numerous internodal segments on different axons, healthy non-motor axons
should allow oligodendrocyte survival. Third, the observation of ultrastructurally normal
axons with immature myelin sheaths in the ventral gray matter of symptomatic SOD1
mutant mice is in favor of the attempt of oligodendrocytes to remyelinate viable axons,
rather than to degenerate due to axon loss [107]. For all these reasons, the above data Int. J. Mol. Sci. 2021, 22, 3426 16 of 27 support the idea that oligodendrocyte dysfunction prevents proper axonal support, which
may trigger neuron degeneration. Since demyelination is by itself insufficient to induce
axon degeneration and has to be associated with oligodendrocyte dysfunction [141,142], the
down-regulation of MCT1 is likely one of the associated mechanisms required for neuron
degeneration. However, it appears strikingly evident that in the alternative where motor
neuron degeneration does not contribute to the initiation of oligodendrocyte pathology, it
likely contributes to make surrounding oligodendrocytes more vulnerable namely because
of their high energy requirement and damaging oxidative reactions [143]. Further work is
needed to better understand the existing discrepancies. 6.4. The Hypothesis of the Putative Aberrant Regulation of Olig2 Function In the spinal cord, an additional hypothesis might be the involvement of an aberrant
regulation of Olig2 function, the transcription factor expressed by the progenitor cells
that give rise successively to both the motor neurons and the oligodendrocytes in the
pMN domain during the embryonic development. In support of this hypothesis, the
characterization of ChIP-Seq-based Olig2 target genes in this domain was found to be
relevant to the pathogenesis of ALS. Indeed, 740 Olig2 target genes overlapping between
the newly generated motor neurons and OPCs have been characterized to be closely
related to “alternative splicing” in agreement with increasing evidence indicating that RNA
metabolism, including the regulation of transcription and alternative splicing, is profoundly
disturbed in ALS. Molecular network analysis also suggested that Olig2 down-regulates a
wide range of target genes involved in diverse neuronal and glial functions [144]. Further
work should deal with this hypothesis in depth. yp
p
Still in the context of embryonic development, the increase in OPC proliferation
observed in ALS was found to remind the phenotype observed upon the partial ablation
of Sonic Hedgehog (Shh) signaling in the Olig2-expressing progenitors. Shh signaling
pathway is well characterized for its contribution to the generation of progenitor cells,
which give rise to both motor neurons and OPCs during the embryonic development
of the spinal cord. In ShhOlig2−/−transgenic mice, the decrease of OPC production
in the ventral spinal cord led dorsal OPCs to populate the entire spinal cord and to
take on an altered morphology proposed to be similar to the one found in the vicinity
of motor neurons in the SOD1G93A mice. In addition, in the ShhOlig2−/−mice, the
morphologically abnormal OPCs failed to participate in the synaptic remodeling of motor
neurons in response to motor neuron injury. Therefore, the common characteristic between
OPCs in SOD1G93A and ShhOlig2−/−animals is that OPCs are forced to over-proliferate to
compensate for either OPC degeneration or reduced ventral OPC production, respectively. Thus, a proposed hypothesis is that OPCs in the ALS models might become progressively
unable to contribute to synaptic remodeling of distressed motor neurons [145]. However,
the hypothesis again remains to be further investigated. 7. Therapeutic Perspectives Provided by Oligodendrocyte Implication in the
Pathogenesis of ALS Oligodendrocytes as Targets for Future Treatments in ALS 7. Therapeutic Perspectives Provided by Oligodendrocyte Implication in the
Pathogenesis of ALS g
7.1. Available Treatments and Antisense Oligonucleotides Over the past 20 years, clinical trials in ALS patients have reached limited success likely
due to the complex nature of this disease. Various compounds with different mechanisms
of action have been studied including Riluzole and Edaravone that constitute the only
current treatments for ALS, nevertheless with mild benefits if one considers survival
and quality of life (Table 1). Riluzole was approved in 1995 [146] and is endowed with
an anti-glutamatergic effect, although the precise mechanism of its action was never
fully understood. Edavarone is a novel anti-oxidative agent, believed to be a free-radical
scavenger, although again the precise mechanism of its action is not fully elucidated [147]. Masitinib started in the early stages of the disease has been shown to slow down its
progression and may likely be approved by the Food and Drug Administration in the near
future. This highly specific tyrosine kinase inhibitor blocks the CSF1R and c-Kit pathways, Int. J. Mol. Sci. 2021, 22, 3426 17 of 27 17 of 27 which means the activation of immune cells including mast cells and macrophages, also
involved in motor neuron degeneration in SOD1G93A. The molecule is currently in Phase
III trial [148,149]. Moreover, the most recent therapeutic perspective came from antisense oligonu-
cleotides, which are the first approved drugs to treat spinal muscular atrophy and are
currently proposed to be potentially interesting in ALS treatment [150,151]. These short,
single-stranded nucleic acids binding to RNA able to alter gene expression are chemically
modified to make them able to cross the cell membrane and avoid rapid degradation
by nucleases. They are delivered to target cells by using nanoparticles or through con-
jugation to bioactive ligands or cell penetrating peptides via intrathecal injection, which
allows achievement of effective concentrations and capturing by neurons and glia. The
first antisense oligonucleotide that reached phase 1 clinical trials targets the SOD1 tran-
script [152] whereas antisense oligonucleotide targeted to C9ORF72 transcripts have been
used in pre-clinical studies [151,153–155] (Table 1). In addition, antisense oligonucleotides
targeting ataxin-2 have been tested in TDP-43 transgenic mouse models wherein the drug
is thought to reduce the propensity of TDP-43 to form pathologic inclusions [156]. Simi-
larly, several pre-clinical investigations on the use of short interfering RNA (siRNA) have
been conducted to target ALS genes. However, none have yet reached clinical trials (for
review, [157]). 7.2. 7.2.1. Therapeutic Approaches Requiring Improvements 7.2.1. Therapeutic Approaches Requiring Improvements The dysfunction of oligodendrocytes and the cytoplasmic deposits of ALS proteins
in these cells (that may be or not one of the causes of the disease) led to propose cell
transplantation in order to replenish the lost and/or defective oligodendrocytes. Recently,
the transplantation of human glial restricted progenitor cells (hGRPs; Q-Cells®) into the
lumbar/cervical spinal cord of ALS patients has been proposed. These cells represent
one of the earliest precursors within the oligodendroglial and astroglial cell lineage and
their usage in ALS therapy might be a beneficial approach resulting in the enrichment
of nervous system by healthy donor-derived cells [147]. However, the first trials have
not yet provided as promising results as expected, which will require both the accurate
optimization of the transplanted cells and the determination of the most appropriate mode
of delivery [167]. Moreover, oligodendrocyte replacement should have only restricted
effects if it is used alone and will need to concomitantly counteract the deleterious features
of the host environment. The compensation of MCT1 expression decrease and connexin expression dysreg-
ulation is currently targeted by molecules able to promote ATP synthesis [163,164]. In
the same line, the increase of glucose uptake by the oligodendrocyte might be induced
by using pharmacological modulators of NMDA receptors. However, such an approach
requires further work in order to improve our current knowledge of the accurate molecular
mechanisms involved in the oligodendrocyte metabolic support to the axon [168,169]. g
y
pp
Finally, although neither directly linked to oligodendrocyte involvement in ALS
pathogenesis nor usable as a possible therapeutic perspective, an amazing observation has
reported that myelin antigen-mediated immunization of the SOD1G93A mutant allowed
choroid plexus activation and the subsequent recruitment of immunoregulatory cells
(including IL-10-producing macrophages and Foxp3 regulatory T cells) in the spinal cord,
likely responsible for mitigating disease progression and increasing animal survival [170]. 7.2. Oligodendrocytes as Targets for Future Treatments in ALS None of the molecules mentioned above specifically targets the oligodendrocytes. However, several therapeutic avenues are currently investigated in this purpose. They can
be divided into a series of approaches requiring further technical or conceptual improve-
ments on one side and the use of promyelinating molecules, which likely stand as the most
promising approach in not too a distant future, on the other side. The most important out
of these approaches are listed in Table 1. Table 1. Potential therapies targeting oligodendrocyte defects in ALS. Abbreviation: ASO, antisense oligonucleotide; CSF,
cerebro-spinal fluid; OL, oligodendrocyte; OPC, oligodendrocyte progenitor cell; Tg, transgenic. Oligodendrocyte Defect. Potential Therapy
ALS Patients
Animal Models
TDP-43 inclusions
-ASO for Ataxin-2
TDP-43 Tg: extends lifespan and
reduces pathology [156]
SOD1 inclusions
-ASO
-Phase 1–2: decreases SOD1
concentration in CSF [158]
RNA foci C9orf72
-ASO
C9orf72 Tg: protects against ALS [155]
ErBB4 inclusions
-ASO
-
-
Myelin degeneration
Promyelinating molecules
-Clemastine (Anti-Histamine H1)
-Montelukast (Anti-GPR17)
-Bexarotene (RXR-γ agonist)
-Tamoxifen
-Mitigates progression [159]
-Prolongs survival in SODG93A [160]
-Rescues SODG93A OPC differentiation
in vitro [161]
-Prolongs survival in SODG93A [162]
Altered trophic support to
the axon
Rescue of nutrient flow
-Co-factor of carboxylases to
produce ATP (Biotin)
-Mitochondrial ATP synthesis
(RNS60)
-Pilot study: safe and well
tolerated [163]
-Pilot study: safe and well
tolerated [164]
-Prolongs survival in SODG93A [165] Table 1. Potential therapies targeting oligodendrocyte defects in ALS. Abbreviation: ASO, antisense oligo pies targeting oligodendrocyte defects in ALS. Abbreviation: ASO, antisense oligonucleotide; CSF, -Prolongs survival in SODG93A [165] 18 of 27 Int. J. Mol. Sci. 2021, 22, 3426 Table 1. Cont. Oligodendrocyte Defect. Potential Therapy
ALS Patients
Animal Models
OL degeneration via:
-Glutamate excitotoxicity
-Oxidative stress
-Neuroinflammation
OL replacement
-Anti-glutamatergic (Riluzole)
-Anti-oxidative agents
(Edavarone)
-Modulators of reactive gliosis
(Masitinib)
(Clemastine)
(Cannabinoid receptor 2
antagonist)
-Several Phases 1: delayed disease
progression
-Approved
-Approved
-Phase 3 [148,149]
-Prolongs survival in SODG93A [160]
-Limits progression in TDP-43 Tg [166] -Prolongs survival in SODG93A [160]
-Limits progression in TDP-43 Tg [166] (Cannabinoid receptor 2
antagonist) 7.2.2. Promyelinating Molecules Since oligodendrocyte degeneration and death stand as major features of ALS im-
pairing both axonal conductance and metabolic support to neurons, molecules endowed
with remyelinating properties might thus restore both defects. The development of such
molecules constitutes the current challenge in the therapeutic approach of multiple scle-
rosis, the most common demyelinating disease of the CNS. In this regard, several targets
have been identified during the last years for promoting myelin regeneration in the brain
and spinal cord. They include modulators of sphingosine-1-phosphate receptor, mus-
carinic M1 receptor, histamine H1 receptors, retinoid X receptor γ, or opioid κ-receptors;
inhibitors of γ-secretase blocking Notch, leukotriene, or Lingo pathways; modulators of
hormone signaling such as androgens, estrogens, tri-iodothyronine, and thyroxine; an-
tipsychotics (quetiapine); antifungals (miconazole); and steroids (clobetasol). Only a few
have reached clinical trials of myelin regeneration, which have mostly recruited patients
suffering from optic neuritis, a common symptom of multiple sclerosis, often occurring Int. J. Mol. Sci. 2021, 22, 3426 19 of 27 19 of 27 during the early stage of the pathology. The first results indicate some promising outcomes
in these patients [171]. Whether outcomes in the optic nerve can be extrapolated to other CNS areas remains
unknown. However, targets that are currently considered for multiple sclerosis may be
obviously worth exploring in ALS. A few molecules are currently evaluated in the latter
(Table 1). For instance, Clemastine, a first-generation histamine H1 antagonist endowed
with remyelinating properties in a randomized, controlled, double-blind, cross-over trial in
multiple sclerosis patients [172], was tested in SOD1G93A mice and was found to reduce
microgliosis, modulate microglia-related inflammatory genes, and enhance motor neuron
survival [169] further inciting to consider this molecule in pre-clinical trials as able to target
both remyelination and neuroinflammation. y
Moreover, the P2Y—like G protein-coupled receptor 17 (GPR17), which has been
previously characterized as a good pharmacological target to implement repair and re-
myelination under several neurodegenerative conditions including multiple sclerosis, was
reported to be expressed at a much higher level in the spinal cord from SOD1G93A mice
compared to healthy animals. This increase started at the pre-symptomatic stage and was
exacerbated at the late symptomatic phase suggesting an altered timing of GPR17 expres-
sion. Indeed, GPR17 expression is known to be the result of the complex integration of
intrinsic determinants regulating oligodendroglial differentiation with extracellular stimuli
acting on the Gpr17 gene. 7.2.2. Promyelinating Molecules 2021, 22, 3426 20 of 27 20 of 27 8. Conclusions The critical role of oligodendrocytes in ALS is presently indisputable. The degen-
eration of oligodendrocytes during disease progression together with the increased pro-
liferation of OPCs without full differentiation into mature oligodendrocytes obviously
participate in the whole spectrum of damages contributing to neurodegeneration. The
failure of metabolic support provided to axons and the high level of demyelination directly
related to the defective oligodendroglial lineage should both precipitate the degeneration
of axons and death of neurons. Conversely, motor neuron degeneration may also con-
tribute to make surrounding oligodendrocytes more vulnerable due to the high energy
requirement and damaging oxidative reactions. The key players of the signaling pathways
up to now identified as being implicated in oligodendroglial cell alterations during ALS
disease already provide a valuable source of molecular targets to develop new cell type
selective therapeutic approaches. In addition, since our current knowledge regarding
both glial heterogeneity and cellular communication is conspicuously facilitated by highly
performant ’OMIC’ approaches as shown in several other neurodegenerative diseases, one
may consider that specific transcriptomic changes in cells displaying toxic ALS-related
protein aggregates and in closely neighboring cells should undoubtedly improve our under-
standing of the oligodendrocyte communication with other glial or neuronal cells as well
as their impact on disease progression. Similarly, the emergence of human iPSC models
for ALS together with gene editing technology will allow investigation of the intricate
crosstalk between the various cell types including oligodendrocytes in the human disease. Funding: The review received financial support from the French Amyotrophic Lateral Sclerosis
Association to E.T. (RAK19097LLP). Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References 1. Morris, J. Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Diseases: An Overview. Neurodiagn. J. 2015, 55,
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to impede proper differentiation of OPCs. Interestingly, the defective differentiation of
OPCs isolated from the spinal cord of the SOD1G93A mutant mice was rescued by treatment
with the GPR17 antagonist montelukast (a leukotrien receptor antagonist authorized for
the management of asthma). This already-marketed, orally available drug may represent a
multi-target drug with high translational potential for repurposing strategies namely for
ALS management [161]. This work also provided evidence for a discrepancy regarding
abnormal differentiation of OPCs isolated from the mouse mutant spinal cord compared to
the absence of altered differentiation observed in another work, which analyzed OPCs iso-
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pointed out the heterogeneity of spinal cord and cortical OPCs, which seems to be strictly
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the consideration of oligodendrocyte heterogeneity in the high-throughput screening of
potential promyelinating candidate molecules in the context of ALS. Although remyelinating molecules seem able to reach pre-clinical and clinical de-
velopment before the other approaches listed above, they will preferentially have to be
endowed with multi-target activities if we consider for instance the involvement of mi-
croglia and astrocytes in the inflammatory process contributing to oligodendrocyte degen-
eration [128,130,174]. A few small molecules endowed with such multi-target properties
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approaches different from remyelination are still far from a putative clinical application, it
seems that their combination with promyelinating molecules would be suitable for both
coping with degeneration and neuroinflammation and, promoting regeneration. Most
importantly, patient-derived iPSCs will be undoubtedly critical in the identification of the
therapeutic approach that should be the most suitable for the ALS phenotype displayed
by the patient. Indeed, the generation of oligodendrocytes and other cell types (including
motor neurons, astrocytes, and microglia) from iPSCs derived from patients with ALS will
be critical as a means to provide a microenvironment that closely resembles the one where
the degenerative effects take place. Such a technological approach has been already carried
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biotin (MD1003) in amyotrophic lateral sclerosis: A pilot study. EClinicalMedicine 2020, 19, 100254. [CrossR 003) in amyotrophic lateral sclerosis: A pilot study. EClinicalMedicine 2020, 19, 100254. References CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes. Curr. Biol. 2015, 25, 2411–2416. [CrossRef] 174. Lloyd, A.F.; Miron, V.E. The pro-remyelination properties of microglia in the central nervous system. Nat. Rev. Neurol. 2019. [CrossRef] [PubMed] 175. Laouarem, Y.; Kassoussi, A.; Zahaf, A.; Hutteau-Hamel, T.; Mellouk, A.; Bobe, P.; Mattern, C.; Schumacher, M.; Traiffort, E. Functional cooperation of the hedgehog and androgen signaling pathways during developmental and repairing myelination. Glia 2021. [CrossRef] [PubMed] 176. Mei, F.; Fancy, S.P.; Shen, Y.A.; Niu, J.; Zhao, C.; Presley, B.; Miao, E.; Lee, S.; Mayoral, S.R.; Redmond, S.A.; et al. Micropillar
arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 2014, 20, 954–960. [CrossRef] 177. Garcia-Leon, J.A.; Kumar, M.; Boon, R.; Chau, D.; One, J.; Wolfs, E.; Eggermont, K.; Berckmans, P.; Gunhanlar, N.; de Vrij, F.; et al. SOX10 Single Transcription Factor-Based Fast and Efficient Generation of Oligodendrocytes from Human Pluripotent Stem Cells. Stem. Cell Rep. 2018, 10, 655–672. [CrossRef] [PubMed]
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Does Erasmus Mobility Increase Employability? Using Register Data to Investigate the Labour Market Outcomes of University Graduates
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Does Erasmus Mobility Increase
Employability? Using Register Data to
Investigate the Labour Market Outcomes
of University Graduates Daniela Cr˘aciun, Kata Orosz, and Viorel Proteasa D. Cr˘aciun (B)
University of Twente, Twente, The Netherlands
e-mail: d.craciun@utwente.nl D. Cr˘aciun (B)
University of Twente, Twente, The Netherlands
e-mail: d.craciun@utwente.nl
K. Orosz
Central European University, Vienna, Austria
e-mail: oroszk@ceu.edu
V. Proteasa
West University of Timisoara, Timisoara, Romania
e-mail: viorel.proteasa@e-uvt.ro
© The Author(s) 2020
A. Curaj et al. (eds.), European Higher Education Area: Challenges for a New Decade,
https://doi.org/10.1007/978-3-030-56316-5_8 © The Author(s) 2020
A. Curaj et al. (eds.), European Higher Education Area: Challenges for a New Decade,
https://doi.org/10.1007/978-3-030-56316-5_8 1
Introduction 1 Participation in Erasmus outgoing mobilities: national trends for Romania and institutional
trends for the West University of Timisoara Source: Compiled by authors from data from The
National Agency for Community Programmes in the Field of Education and Vocational Training
(ANPCDEFP)—Erasmus programme data, The National Council for Financing Higher Education
(CNFIS)—student cohorts country level data, The West University of Timisoara—student cohorts
institutional data y = 0.0012x + 0.0013
R² = 0.969
y = 0.0015x + 0.0021
R² = 0.8973
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
% OUTGOING ERASMUS STUDENT MOBILITY
Romania
UVT
Linear (Romania)
Linear (UVT) y = 0.0012x + 0.0013
R² = 0.969
y = 0.0015x + 0.0021
R² = 0.8973
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
% OUTGOING ERASMUS STUDENT MOBILITY
Romania
UVT
Linear (Romania)
Linear (UVT) % OUTGOING ERASMUS STUDENT MOBILITY y = 0.0012x + 0.0013
R² = 0.969 00%
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018 Fig. 1 Participation in Erasmus outgoing mobilities: national trends for Romania and institutional
trends for the West University of Timisoara Source: Compiled by authors from data from The
National Agency for Community Programmes in the Field of Education and Vocational Training
(ANPCDEFP)—Erasmus programme data, The National Council for Financing Higher Education
(CNFIS)—student cohorts country level data, The West University of Timisoara—student cohorts
institutional data Fig. 1 Participation in Erasmus outgoing mobilities: national trends for Romania and institutional
trends for the West University of Timisoara Source: Compiled by authors from data from The
National Agency for Community Programmes in the Field of Education and Vocational Training
(ANPCDEFP)—Erasmus programme data, The National Council for Financing Higher Education
(CNFIS)—student cohorts country level data, The West University of Timisoara—student cohorts
institutional data Fig. 1 Participation in Erasmus outgoing mobilities: national trends for Romania and institutional
trends for the West University of Timisoara Source: Compiled by authors from data from The
National Agency for Community Programmes in the Field of Education and Vocational Training
(ANPCDEFP)—Erasmus programme data, The National Council for Financing Higher Education
(CNFIS)—student cohorts country level data, The West University of Timisoara—student cohorts
institutional data Notwithstanding the increasing popularity of and investment in international stu-
dent mobility, the actual labour market benefits for individuals are still widely debated
(Di Pietro 2019). 1The net effect of student mobility on top of other predictors that are associated with both propensity
to be internationally mobile as a student and employable as a graduate, e.g. individual ability (Kucel
and Vilalta-Bufi2016 Mallik and Shankar 2016) or family background (Akhmedjonov 2011 Kucel
and Vilalta-Bufi2016 Mourifie, Henry, and Meango 2018). 1
Introduction International student mobility is not a new phenomenon (Altbach 2005; Guruz 2008). However, there has been a significant growth in scale in the last few decades. The
Organization for Economic Cooperation and Development (OECD) estimates that
the number of international students across the world has increased from 0.6 million
in 1975 to 2.4 million in 2004 (OECD 2006) and a staggering 4.6 million in 2015
(OECD 2017). In Europe, international student mobility is regarded as one of the
most important drivers for synchronizing the continent’s disparate higher education
systems to the same heartbeat. In this context, the Erasmus program is considered the “flagship of European co-
operation” (Barblan 2002) in higher education. Approximately 4.4 million higher
education students have participated in the Erasmus+ program in the three decades
since the program was set up in 1987, and the program continues to steadily increase
in popularity (European Commission 2017). This year, the European Commission
has pledged “to triple the Erasmus+ budget (going beyond the Junker Commission’s
proposal to almost double the envelope)” (Rubio 2019, (1) for the 2021–2027 pro-
gramming period. The policy decisions at the European level are mirrored by national
and institutional trends of students’ participation in Erasmus outgoing mobilities (see
Fig.1): D. Cr˘aciun (B)
University of Twente, Twente, The Netherlands
e-mail: d.craciun@utwente.nl
K. Orosz
Central European University, Vienna, Austria
e-mail: oroszk@ceu.edu
V. Proteasa
West University of Timisoara, Timisoara, Romania
e-mail: viorel.proteasa@e-uvt.ro
© The Author(s) 2020
A. Curaj et al. (eds.), European Higher Education Area: Challenges for a New Decade,
https://doi.org/10.1007/978-3-030-56316-5_8
105 D. Cr˘aciun (B)
University of Twente, Twente, The Netherlands
e-mail: d.craciun@utwente.nl V. Proteasa
West University of Timisoara, Timisoara, Romania
e-mail: viorel.proteasa@e-uvt.ro © The Author(s) 2020
A. Curaj et al. (eds.), European Higher Education Area: Challenges for a New Decade,
https://doi.org/10.1007/978-3-030-56316-5_8 105 D. Cr˘aciun et al. 106 y = 0.0012x + 0.0013
R² = 0.969
y = 0.0015x + 0.0021
R² = 0.8973
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
% OUTGOING ERASMUS STUDENT MOBILITY
Romania
UVT
Linear (Romania)
Linear (UVT)
Fig. 1
Introduction One of the major claims has been that individuals who study
abroad enjoy better labour market outcomes than their non-mobile peers (Wiers-
Jenssen and Try 2005, Wiers-Jenssen 2008, 2011). Specifically, both credit and
degree mobility are said to lead to a better insertion into the labour market (and
thus to decreased unemployment), above-average earnings, a more prestigious occu-
pation, and a higher likelihood that graduates will work outside their country of
permanent residence/citizenship. However, the actual impact of student mobility on labour market outcomes is less
clear, as research is scarce, the evidence used is often “qualitative and anecdotal” or is
prone to bias (Di Pietro 2019). Traditionally, the effect of mobility on employability
has been measured using interview or survey data collected from (1) students who
participated in mobility programs, (2) university administrators in charge of study
abroad programs, and (3) employers (Di Pietro 2015, 2019). While these types of
studies provide important insights about the benefits associated with international
student mobility they can be affected by social desirability bias (Bowman and Hill
2011)andtheyrarelyaccountforcausality.1 Thus,linkingmobilityandemployability Does Erasmus Mobility Increase Employability? Using Register Data …
107 Does Erasmus Mobility Increase Employability? Using Register Data … 107 in a causal relationship is challenging due to selection and self-selection effects, i.e. “[s]tudents who study abroad may differ from students who do not in unobserved
characteristics that are likely to affect labor market outcomes” (Di Pietro 2019),
and omitted variable bias which can lead to over-estimating or under-estimating the
impact of international mobility on employability. Various econometric techniques can be used to mitigate the selection problems
inherent to observational data, including the use of fixed effects, instrumental vari-
ables, various propensity score matching techniques, and regression discontinuity
designs (Schneider et al. 2007). While such techniques are invaluable in reducing
bias that results from omitted variables and various forms of selection, no analytic
technique can provide valid estimates if the data on which the analysis is performed
is of questionable quality. Obtaining high-quality data by means of surveys is highly
resource-intensive. In this chapter, we take an alternative approach, that of using
register data to answer questions about the benefits of international student credit
mobility. 1
Introduction According to Andersson and Nilsson (2016, 4), in national (or institutional) con-
texts in which “there is access to national registers that cover the entire population”,
register data on income, occupation, unemployment (Nilsson 2017, 79) enable more
“penetrating” (Andersson and Nilsson 2016, 4) and more cost-efficient analyses. Using register data offers the possibility to use already existing population-level data
and compare the actual employment outcomes of mobile and non-mobile students. In this chapter, we present an analysis based on register data from university records
and national employment and baccalaureate exam records of 8 cohorts of graduates
between 2007 and 2014 from the West University of Timisoara (UVT), a leading
comprehensive university in Romania. By demonstrating the utility of pre-existing
data sources in answering policy-relevant research questions through the case of this
single institution, we want to send a broader message to ministers of education and
higher education leaders: to release existing register data to the research community. In this way, the linkages between education and labour market outcomes can be
rigorously and efficiently tested, descriptions of population parameters from which
samples are drawn can be more robust, and policy-makers and institutional leaders
can have access to the evidence needed to make informed decisions. In order to illustrate the utility of combining data from pre-existing registers,
the chapter analyses the impact of credit mobility on labour market outcomes using
institutional- and national-level data. In our analyses, we sought to answer the follow-
ing question: Does credit mobility have a positive impact on graduate employability? To answer this overarching question, we establish the predictors of international stu-
dent mobility and test whether credit mobility is significantly positively associated
with labour market insertion, income levels and occupational prestige. Specifically,
we address the following research questions: (1) What are the predictors of partici-
pation in Erasmus mobility among the specific population of graduates we analyse? (2) Does participation in the Erasmus student mobility program predict insertion on
the labour market within that population? Among those graduates who had an active
work contract, is participation in the Erasmus student mobility program predictive of
(3) an above-average salary or (4) having a more prestigious occupational category? 108 D. Cr˘aciun et al. To answer these questions, the chapter proceeds as follows. First, an overview
of existing studies exploring the relationship between international student mobility
and employment outcomes is provided. 1
Introduction Second, the methodology employed and the
analytic sample are described. Third, the results of the data analysis are presented and
discussed. Finally, the concluding section highlights avenues for further research and
makes an argument for the benefits of using existing register data to test theoretical
claims in higher education research. 2
Literature Review There is a plethora of theoretical arguments linking international student mobility
with individual benefits that are expected to translate into better employment out-
comes for graduates, but relatively few empirical studies have tested these causal
claims (Di Pietro 2015, 2019; Wiers-Jenssen and Try 2005). This section explores
the theoretical expectations and empirical evidence brought forward by previous
research on the relationship between study abroad and labour market outcomes. The theoretical expectation linking mobility and employability is that individuals
who study abroad will accrue non-economic benefits (i.e., skills, mobility capital)
that will ultimately transform into economic benefits (i.e., favourable labour market
outcomes such as domestic or international employment, higher wages, higher occu-
pational prestige) (Cr˘aciun and Orosz 2018). This is expected on the premise that the
skills acquired by individuals through studying abroad are marketable (i.e., valued
by employers) (Di Pietro 2015) and because mobility widens the job search area
of graduates beyond the domestic labour market (i.e., more and better employment
opportunities) (Di Pietro 2019). Internationalstudentmobilityisperceivedandexpectedbyparticipants,university
administrators, and employers to have a positive effect on all aspects of a worker’s
skill set. First, mobility has been shown to have a positive impact on individuals’
cognitiveskills,particularlyforeignlanguageproficiency(Cantoetal.2013;Llaneset
al. 2016), problem-solving, and decision-making skills (Bikson et al. 2003). Second,
studying abroad exposes students to foreign cultures which is expected by employers
to have a positive impact on their non-cognitive skills, especially inter-personal and
inter-cultural skills, confidence and self-reliance (Bikson et al. 2003; Bracht et al. 2006; King et al. 2010; Matherly 2005). Third, mobility can improve job-specific
skills for jobs that have an international component or give students the skills and
experience to pursue an international career (Di Pietro 2019). Cognitive, non-cognitive and job-specific skills are all valued in the workplace,
so the expectation is that they will be rewarded by employers through hiring, higher
wages and more prestigious jobs. Table1 provides an overview of research findings
from existing studies on the relationship between mobility and these employability
indicators. Several studies have shown that there is a positive relationship between mobility
and various labour market outcomes (European Commission 2014, 2016; Di Pietro Does Erasmus Mobility Increase Employability? Using Register Data … Does Erasmus Mobility Increase Employability? 2
Literature Review Using Register Data … 109 Table 1 The relationship between international student mobility and labour market outcomes
Indicator
Benefits for internationally mobile students
Labour market insertion
(+) Less likely to face long term unemployment (European Commission
2014, 2016)
(+) Lower unemployment rates 3 to 10years after graduation (European
Commission 2014, 2016; Di Pietro 2019; Schnepf and Hombres 2018)
(+) Mobility useful in securing (first) job (Bracht et al. 2006; King et al. 2010; Teichler and Janson 2007)
(+) Mobility experience contributes to making job interviews more
successful (King et al. 2010)
(=) No difference in unemployment rates of mobile individuals compared to
non-mobile individuals immediately after graduation (Wiers-Jenssen 2011)
(=) No difference in probability of employment 1month after graduation
(Koda and Yuki 2013)
(=) No difference in holding a graduate level job (Koda and Yuki 2013)
(-) Takes a longer time to find a job (Rodrigues 2013)
Earnings
(+) Higher wages (Rodrigues 2013; Varghese 2008)
(=) No difference in (starting) wages compared to non-mobile individuals
(Koda and Yuki 2013; Messer and Wolter 2007; Wiers-Jenssen 2011)
Occupational category
(+) Likely to have jobs with high professional responsibility (Bracht et al. 2006)
(+) More likely to occupy managerial positions 6months after graduation
(Schnepf and Hombres2018)
(+) More likely to hold a management position 5 to 10years after
graduation (European Commission 2016)
International career
(+) More likely to work abroad after graduation (Parey and Waldinger 2011;
Di Pietro 2012; Rodrigues 2013; Teichler and Janson 2007; Varghese 2008)
(=) No difference in likelihood to have an international job compared to
non-mobile individuals (Wiers-Jenssen 2011)
Source Compiled by authors 2019; Schnepf and D’Hombres 2018) “though they provide mixed results about the
magnitude of this effect” (Di Pietro 2013, 6). Others find no difference between
mobile and non-mobile students in terms of employment outcomes (Koda and Yuki
2013; Messer and Wolter 2007;Wiers-Jenssen 2011). 3
Data and Methodology In order to test whether there is a statistically significant relationship between inter-
national credit mobility and employment outcomes, the chapter relies on an original
dataset constructed from institutional and national register data. We linked three
sources of register data to create the analytic data set: (1) university register data of
individuals who completed a bachelor’s and/or master’s degree at UVT, and national
register data on (2) baccalaureate exam scores and (3) labour market outcomes. The
data comes from an institutional, ICT intensive, tracer study (Proteasa et al. 2018). 110 D. Cr˘aciun et al. The initial dataset was based on university register data of individuals who com-
pleted a bachelor’s and/or master’s degree at UVT. This data set contains, among
other things, information on UVT graduates’ age, gender, the start year of their bach-
elor’s and/or master’s degree, the field of study, whether they received social and/or
merit-based scholarships during their studies, and whether they participated in Eras-
mus mobility during their time at UVT. This dataset was then matched with publicly
available data on the graduates’ baccalaureate exam scores launched in 2004 (Minis-
terul Educatiei Nationale 2019) and with information about UVT graduates’ labour
market outcomes. Information about UVT graduates’ labour market outcomes was
requested and received from ReviSal, a mandatory national register for all employees
in Romania that was launched in 2011 (Guvernul României 2011). Matching ReviSal data with university records allowed us to capture informa-
tion on whether UVT graduates had an active working contract with an employer
operating in Romania, as well as information on the highest salary and highest occu-
pational category associated with each individual’s working contract(s) during the
period 2011–2018. This meant that we were able to test whether mobile students actu-
ally enjoyed better insertion into the labour market, above-average earnings and/or
a more prestigious occupation as compared to non-mobile students. The raw dataset included information on individuals who completed at least a
bachelor’s degree at UVT (n = 20,707). From this dataset, a number of observations
were excluded for various theoretical and practical reasons that are discussed next. First, UVT graduates who could not be matched with ReviSal data were excluded
from the analytic dataset, as a lack of match to ReviSal records meant that no conclu-
sions could be drawn about their labour market outcomes. 2According to the birth year analysis, some people in the analytic sample who started their BA in
2007 or later were born as early as 1947. 3
Data and Methodology Second, UVT graduates
who started their bachelor’s degree program in or before 2007 were also excluded
from analysis, as the UVT Erasmus mobility records we had access to only start
from the academic year 2007/2008. Third, UVT graduates who started their bache-
lor’s degree program in or after 2015 were also excluded from analysis, because they
could not have completed their studies by January 2018, the date when the ReviSal
export was received. Finally, UVT graduates whose baccalaureate exam score was
missing were also excluded from the analysis, as we used their performance on this
national exam as a proxy for academic ability. As a result of delimitating the raw
dataset in this way, we ended up with an analytic dataset of n = 16,565, which
includes information on the labour market outcomes of both mobile (n = 719) and
non-mobile (n = 15,846) UVT graduates. Table2 provides summary statistics for the variables used in our data analysis. The majority of the individuals (88.5)2 in our analytic sample were born between
1988 and 1995. They started their bachelor’s degree program at UVT between 2007
and 2014. The average baccalaureate score among UVT graduates who participated
in Erasmus credit mobility was 8.95, which is statistically significantly higher (t
= −8.7507; p = 0.000) than the average baccalaureate score of UVT graduates
who did not participate in Erasmus credit mobility (8.63). Moreover, the average Does Erasmus Mobility Increase Employability? 3We calculated relative income by comparing all working contracts to the average basic gross salary
of the year in which they ended. Income information associated with working contracts still active
in December 2017 were compared to the 2017 average basic gross salary. The average gross salary
for each year was calculated based on data from national statistics. 3
Data and Methodology b The analytic sample for the analyses on insertion and occupational category was smaller than the
analytic sample for labour market insertion since all observations that did not have an active work
contract had to be excluded. We also excluded all observations that had missing data on income
and occupational category. Thus, the analytic sample size in these analyses is n = 11,540. The
proportion of mobile UVT graduates is 3.9% (n = 451), which is higher than the 1.8% average
credit mobility rate of graduates from Romanian universities (European Commission 2018a). To
compare, the average EU credit mobility rate of university graduates is 8% (European Commission
2018a). c Only refers to enrollment at UVT graduates in the analytic sample who have a bachelor degree
from UVT may have enrolled in master degree program at other universities in Romania, or abroad. d Some UVT graduates had no record of a working contract in ReviSal for the period 2011–2017. This could happen either because these graduates were inactive, unemployed, self-employed or
working in a so-called “liberal profession” (e.g., lawyers), or employed outside of Romania in the
entire period of 2011–2017. Those who participate in Erasmus credit mobility may be more likely
to work abroad after graduation (see Wiers-Jenssen 2011), and those who work abroad would not
show up in the ReviSal database. e Refers to having at least one working contract recorded in ReviSal for the period 2011–2017. a The receipt of social scholarship is based on financial need. b b The analytic sample for the analyses on insertion and occupational category was smaller than the
analytic sample for labour market insertion since all observations that did not have an active work
contract had to be excluded. We also excluded all observations that had missing data on income
and occupational category. Thus, the analytic sample size in these analyses is n = 11,540. The
proportion of mobile UVT graduates is 3.9% (n = 451), which is higher than the 1.8% average
credit mobility rate of graduates from Romanian universities (European Commission 2018a). To
compare, the average EU credit mobility rate of university graduates is 8% (European Commission
2018a). c Only refers to enrollment at UVT graduates in the analytic sample who have a bachelor degree
from UVT may have enrolled in master degree program at other universities in Romania, or abroad. 3
Data and Methodology Using Register Data … 111 Table 2 Descriptive statistics of UVT graduates in the analytic sample
All UVT
graduates (n =
16,565), %
Mobile UVT
graduates (n =
719), %
Non-mobile
UVT graduates
(n = 15,846),
%
Pearson χ2 (p)
Gender
100
100
100
16.1
Women
71.7
78.4
71.4
(0.000)
Men
28.3
21.6
28.6
Baccalaureate exam performance
100
100
100
111.1
Lowest quartile
25.2
16.0
25.7
(0.000)
Low-middle quartile
24.9
17.9
25.2
High-middle quartile
25.0
25.9
25.0
Highest quartile
24.9
40.2
24.2
Field of study (BA)
100
100
100
186.6
Social sciences
61.3
44.5
62.0
(0.000)
Humanities and arts
22.0
42.1
21.1
Math, natural sci., biology & biomed
13.1
12.1
13.1
Physical education and sport
3.7
1.3
3.8
Receipt of merit-based scholarshipa
100
100
100
378.5
Did not receive
59.0
24.1
60.6
(0.000)
Received
41.0
75.9
39.5
Receipt of social scholarship
100
100
100
8.1
Did not receive
89.9
86.8
90.1
(0.004)
Received
10.1
13.2
9.9
Master degree statusb
100
100
100
124.8
Never enrolled in a master program
40.4
21.1
41.3
(0.000)
Enrolled but didn’t graduate
17.3
18.9
17.2
Completed a master program
42.4
59.9
41.6
Labour market insertion in Romania
100
100
100
4.3
Had a working contractc
76.2
73.0
76.4
(0.038)
No record of a working contractd
23.8
27.0
23.6
Occupational category
100
100
100
32.8
Managers
3.9
2.5
4.0
(0.000)
Professionals
34.3
39.9
34.1
Technicians & associate professionals
15.0
15.2
15.0
Clerical support, service & sales workers 20.5
13.6
20.8
Elementary occupations
2.6
1.8
2.6
Missing
23.8
27.0
23.6
Income relative to average salarye
100
100
100
49.4
Below-average salary
46.0
35.7
46.4
(0.000)
(continued) Table 2 Descriptive statistics of UVT graduates in the analytic sample 112 D. Cr˘aciun et al. Table 2 (continued) Table 2 (continued)
All UVT
graduates (n =
16,565), %
Mobile UVT
graduates (n =
719), %
Non-mobile
UVT graduates
(n = 15,846),
%
Pearson χ2 (p)
Similar to average salary
8.4
6.7
8.5
Above-average salary
21.9
30.6
21.5
Missing
23.8
27.0
23.6
l
l
d b
h graduates (n =
16,565), %
graduates (n =
719), %
UVT graduates
(n = 15,846),
%
χ (p)
Similar to average salary
8.4
6.7
8.5
Above-average salary
21.9
30.6
21.5
Missing
23.8
27.0
23.6
Source Calculated by authors
a The receipt of social scholarship is based on financial need. 4“When subjects are not randomly assigned to treatment and non-treatment groups, as is the case
with observational studies, other methods are needed to avoid the possibility of selection bias. Bias
can arise when apparent differences in outcome between treatment and non-treatment groups can
be attributed to characteristics that affected whether a subject received a given treatment rather than
simply to the effect of the treatment itself. Propensity score matching adjusts for such potential
bias by creating a sample group of subjects who received the treatment that is comparable on all
observed characteristics to a sample of subjects that did not receive the treatment” (Di Pietro 2019).
5ThelogoddsofparticipatinginErasmusmobilitywasmodelledasafunctionoftheUVTgraduates’
gender, the field of BA study, the year in which they started their BA, their age at graduation from BA,
their performance in the baccalaureate exam (in quartiles), their receipt of a merit-based scholarship
or social scholarship during their BA, and whether they enrolled in or completed an MA at UVT. 3
Data and Methodology d Some UVT graduates had no record of a working contract in ReviSal for the period 2011–2017. This could happen either because these graduates were inactive, unemployed, self-employed or
working in a so-called “liberal profession” (e.g., lawyers), or employed outside of Romania in the
entire period of 2011–2017. Those who participate in Erasmus credit mobility may be more likely
to work abroad after graduation (see Wiers-Jenssen 2011), and those who work abroad would not
show up in the ReviSal database. p
e Refers to having at least one working contract recorded in ReviSal for the period 2011–2017. age at which UVT graduates completed their bachelor’s degree was 22.7, which is
statistically significantly lower (t = 4.4199, p = 0.000) than the average age at which
UVT graduates who did not participate in Erasmus credit mobility completed their
bachelor’s degree (23.4). age at which UVT graduates completed their bachelor’s degree was 22.7, which is
statistically significantly lower (t = 4.4199, p = 0.000) than the average age at which
UVT graduates who did not participate in Erasmus credit mobility completed their
bachelor’s degree (23.4). To test what predicts labour market outcomes, the log odds of (1) having an active
contract in Romania in the period 2011–2017 (insertion), (2) having an active con-
tract that is associated with an above-average salary (earnings), and (3) having an
active contract that is associated with a managerial or professional job (occupational
category) were modelled as a function of UVT graduates’ gender, field of BA study,
year in which they started their BA, their age at graduation from BA (22 or below
versus above 22), their performance in the baccalaureate exam (in quartiles), their
receipt of a merit-based scholarship or social scholarship during their BA, whether
they enrolled in or completed an MA degree at UVT, and whether they participated
in Erasmus mobility during their studies at UVT.3 Does Erasmus Mobility Increase Employability? Using Register Data … 113 For more robust results, we also estimated the relationship between Erasmus credit
mobility, labour market insertion, earnings and occupational category with the help
of propensity score matching4 models, using the same set of co-variates as the logistic
regression models discussed above. Detailed results from the logistic and propensity-
score matched models are discussed in the next section, and the regression tables are
available from the authors upon request. (1) What Are the Predictors of Participation in Erasmus Mobility Among UVT
Graduates? Comparing mobile and non-mobile students,5 the profile of Erasmus participants
becomes apparent. Even though 78% of the mobile students are women, all other
things being equal, gender is not predictive of participation in Erasmus mobility
among the UVT graduates in our analytic sample. Over the years, higher mobility
rates in the Erasmus program have been observed for women, at around 60% (Brooks
and Waters 2011; Souto-Otero 2008; Teichler et al. 2011). Previous research has
shown that for Romania, the gender gap is even bigger, with females representing
70% of mobile students at the national level (Souto-Otero and McCoshan 2006, 4). However, “[t]he feminisation of higher education is apparent at all levels of study”
in national student populations (Orr et al. 2011, 59). Therefore, the tilted balance
towards higher female participation rates can be in part accounted for by the general
structure of national student populations. Notwithstanding, other factors are predictive of participation in mobility. First,
the year in which students began their BA studies is a positive predictor of mobility:
with each year, the likelihood of participating in the Erasmus program was 12%
higher. This finding is consistent with the growth in popularity, accessibility and
funding of the Erasmus program over the years (European Commission 2017, 2018b),
and reflected in the national and institutional trends—see Fig.1 in the introductory
section. Second, age at the time of BA graduation is a significant negative predictor of
credit mobility: each additional year in age is associated with a 28% lower likelihood 114 D. Cr˘aciun et al. of participating in the Erasmus program. This finding is in line with the predictions
of empirical studies on migration which “overwhelmingly conclude that the relation
with age is negative, i.e., that the likelihood of migration decreases with age” (Zaiceva
2014, 4). Third, academic ability is a predictor of Erasmus mobility. Students’ performance
at the baccalaureate exam (our proxy for academic ability) is a significant positive
predictor of mobility. A one-unit increase in the baccalaureate exam score is asso-
ciated with a 47% higher likelihood of participating in the Erasmus program. The
receipt of a merit-based scholarship is also significantly positively related to mobility. Those students who received a merit-based scholarship were 3.2 times more likely
to participate in Erasmus than those who did not receive such a scholarship. (1) What Are the Predictors of Participation in Erasmus Mobility Among UVT
Graduates? The fact
that Erasmus grants are awarded on academic merit and that “Erasmus appears to
be much more selective in Eastern Europe (where 20% of applicants are rejected)”6
(European Commission 2016) could explain the magnitude of the relationship. There
is no evidence of a link between the receipt of a social (i.e., need-based) scholarship
and credit mobility in the analytic sample. Fourth, degree level is significantly positively associated with Erasmus mobility. Compared to those who never enrolled in a master degree program at UVT, those who
enrolled but did not complete were 91% more likely to participate in mobility, while
those who completed a master degree were 97% more likely to participate in mobil-
ity. This makes intuitive sense, as those who remain affiliated with a higher education
institution longer have more opportunities to apply for an Erasmus scholarship. All
in all, the typical Erasmus mobility participant at UVT is young, academically able
and more likely to pursue graduate education. 7The negative association between Erasmus participation and labor market insertion is significant
in the logistic regression model and in propensity score matching (PSM) model. The association is
negative but not significant in the PSM model if standard errors are clustered by bachelor cohorts.
The inconsistency in results may be due to measurement error on our labour market insertion
variable. 6By way of comparison, the rates of Erasmus application rejection in other European regions
are: 19% for Southern Europe, 9% for Western Europe and 7% for Northern Europe (European
Commission 2016). 6By way of comparison, the rates of Erasmus application rejection in other European regions
are: 19% for Southern Europe, 9% for Western Europe and 7% for Northern Europe (European
Commission 2016).
7The negative association between Erasmus participation and labor market insertion is significant
in the logistic regression model and in propensity score matching (PSM) model. The association is
negative but not significant in the PSM model if standard errors are clustered by bachelor cohorts.
The inconsistency in results may be due to measurement error on our labour market insertion
variable. (2) Does participation in Erasmus mobility predict insertion into the labour
market? Participation in Erasmus mobility is significantly negatively associated with insertion
in the domestic (i.e., Romanian) labour market in our analytic sample.7 Graduates
who were mobile during their studies at UVT (either during bachelor or master degree
programs) were 40% less likely to have an active work contract with an employer
operating in Romania, compared to non-mobile graduates. Rather than implying that
mobile graduates are less likely to be employed, this finding is consistent with the
body of evidence that suggests that mobile students are more likely to work abroad
after graduating (Parey and Waldinger 2011; Di Pietro 2012; Rodrigues 2013; Teich-
ler and Janson 2007; Varghese 2008) and, thus, less likely to appear in the national Does Erasmus Mobility Increase Employability? Using Register Data … 115 employment database with an active contract. As migration research has shown, peo-
ple with a migratory experience have an increased propensity for re-taking this step. “Once someone has migrated, therefore he or she is very likely to migrate again,
and the odds of taking an additional trip rise with the number of trips already taken”
(Massey et al. 1993, 453). Through the experience of mobility, students acquire
‘mobility capital’ and are likely to look for and take up jobs outside the domestic
labour market (Rodrigues 2013; Wiers-Jenssen 2008). All other things being equal, gender, baccalaureate exam results, the year when
the bachelor degree program started, and the receipt of social scholarship (our proxy
for socio-economic status) were not predictive of labour market insertion in our ana-
lytic sample of UVT graduates. As previous studies have also shown, field of study
is predictive of employment status in our analytic sample. Compared to social scien-
tists, humanities and arts graduates and physical education and sports graduates are
significantly less likely to have an active work contract, while graduates from natu-
ral sciences, mathematics, biology and biomedicine are significantly more likely to
have an active work contract. Also, having a master degree is significantly positively
associated with labour market insertion. Compared to those who never enrolled in a
master degree program, master graduates are twice as likely to have an active work
contract in our analytic sample. This finding is in line with human capital theory
predictions. 8Please refer to Table2 for details on how we operationalized higher-than-average monthly salary. (3) Among those who have an active work contract, does participation in Eras-
mus mobility predict an above-average salary? Erasmus mobility is significantly positively associated with earnings. All other things
being equal, those who participated in Erasmus mobility during their studies at UVT
were 75% more likely to have a higher-than-average monthly salary8 associated with
their active work contract. Results from the propensity score matching model (with
the same specification as the logistic regression model discussed above) also suggest
that participation in Erasmus mobility is positively associated with an above-average
monthly salary among those UVT graduates who had an active contract. y
y
g
g
Comparing mobile UVT graduates, the duration of study abroad is not predic-
tive of differences in earnings. In other words, there was no statistically signifi-
cant difference in the likelihood of having an above-average salary, regardless of
whether the mobile student experienced a short-term mobility period (operational-
ized as 5months or less), or a long-term Erasmus mobility period (operationalized
as more than 5months). The year in which students participated in Erasmus credit
mobility is predictive of earning differences. The year of mobility is negatively asso-
ciated with earnings, that is, among mobile UVT graduates, the likelihood of having
an above-average salary decreases with every academic year. This finding is consis-
tent with the expectation that, over time, as Erasmus mobility became more and more
common, it became less valuable in accessing higher-paid positions. Alternatively,
the negative relationship could be explained by the fact that students who went on 116 D. Cr˘aciun et al. D. Cr˘aciun et al. Erasmus earlier have had more time on the labour market, and their longer work
experience explains their higher likelihood of having higher-paid positions. (4) Among those who have an active working contract, does participation in
Erasmus mobility predict having a managerial or professional occupation? Prior research found that “five to ten years after graduation, significantly more Eras-
mus alumni (64%) than non-mobile alumni (55%) hold a management position. The
difference is especially large in Eastern Europe (70% compared to 41%)” (European
Commission 2016). Contrary to the expectation of higher occupational prestige, in
our analytic sample, Erasmus mobility is not predictive of a more prestigious occu-
pational category. All other things being equal, those who participated in Erasmus
mobility during their studies at UVT were not more likely to have an active work
contract with a managerial or professional occupation. (3) Among those who have an active work contract, does participation in Eras-
mus mobility predict an above-average salary? The results from the propen-
sity score matching model (with the same specification as the logistic regression
model discussed above) also suggest that participation in Erasmus mobility is not
associated with managerial or professional occupations among UVT graduates with
an active work contract. Our result might be explained by the fact that higher educa-
tion attainment in Romania is the lowest in the European Union and, as such, having
a tertiary degree per se is highly valued by employers when they are looking to fill
managerial or professional positions. Nevertheless, the mechanisms of obtaining a
higher status job may be underspecified in our model. Further research should look
into the micro-causalities at play on the local labour market as they might provide
an explanation for these findings. Within the sub-group of mobile UVT graduates, the duration of study abroad is
not predictive of occupational category either. In other words, both short- and long-
term Erasmus mobility periods are associated with a similar likelihood of holding
a managerial or professional job. The year of mobility is not associated with the
occupational category either: the likelihood to have a managerial or professional
position is the same irrespective of the academic year in which the Erasmus mobility
took place. 5
Conclusion: Benefits and Limitations of Register Data In this chapter, we analysed a unique dataset from Romania to illustrate how register
data can be used to answer questions about the benefits of Erasmus credit mobility. We found that the typical UVT graduate who participated in Erasmus mobility and
then got employed in Romania after graduation is a woman who has a bachelor
degree in social sciences or in humanities, who did not receive a social scholarship
but received a merit-based scholarship, who enrolled at one point in time in a master
degree program at UVT, and who has a managerial or professional occupation. In terms of labour market outcomes, our analyses indicate that, all else being
equal, participation in Erasmus mobility is (1) significantly negatively associated
with insertion in the domestic labour market; (2) significantly positively associated oes Erasmus Mobility Increase Employability? Using Register Data … 117 with above-average income among those who do work for an employer operating
in Romania, and (3) not predictive of a managerial or professional occupational
category. Working with register data is resource-efficient, but it has its own limitations. Findings presented in this chapter are limited to graduates of a single university
in Romania, as a spin-off from an institutional, ITC intensive, tracer study (Pro-
teasa et al. 2018). The limitations of the Romanian employee register are reflected
into our findings: as the national registry includes only labour contracts, the results
may be less relevant for fields in which self-employment is common, such as law,
psychology and even computer sciences. A further limitation of using data from a
single national register is that we had no employment information about graduates
who were employed outside of Romania. The tracer study used interval measures
of graduates’ salaries (Proteasa et al. 2018), which makes the measurement of our
earnings data less precise. And while working with data from ReviSal allowed us to
observe the labour market outcomes of more UVT graduates than would have been
possible with the use of an alumni survey, our analytic dataset still misses informa-
tion about theoretically important characteristics of the UVT graduates, such as their
marital status, number of children, and the educational background of their parents. Nevertheless, register data shows promising avenues for research and encourages
the efficient use of resources by using data that is already collected for administrative
purposes both at the national and institutional level. 5
Conclusion: Benefits and Limitations of Register Data The availability of register data
enables researchers to test linkages between higher education and a wide range of
individual institutional and societal outcomes. At the very least, register data can
provide researchers with good descriptive population parameters from which sam-
ples can be drawn for further research. Ministries and higher education institutions
should consider these benefits when evaluating requests for data release for research
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Young, yet with Population Aging, Mobility of Elderly and Specialized Workers May Increase. Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0
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Maternal serum uric acid concentration and pregnancy outcomes in women with pre‐eclampsia/eclampsia
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International journal of gynaecology and obstetrics
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cc-by
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K E Y W O R D S Eclampsia; Intrauterine growth restriction; Neonatal complications; Pre-eclampsia; Preterm
birth; Uric acid Tam M. Le1,* | Long H. Nguyen1 | Nam L. Phan1 | Duong D. Le2 | Huy V.Q. Nguyen1 |
Vinh Q. Truong1 | Thanh N. Cao1 1Department of Obstetrics and Gynecology,
Hue University of Medicine and Pharmacy,
Hue University, Hue, Vietnam
2Department of Public Health, Hue University
of Medicine and Pharmacy, Hue University,
Hue, Vietnam | Revised: 14 July 2018 | Accepted: 22 October 2018 | First published online: 8 November 2018 | Revised: 14 July 2018 | Accepted: 22 October 2018 | First published online: 8 November 2018 Received: 9 March 2018 | Revised: 14 July 2018 | Accepted: 22 October 2018 | First published online: 8 November 2018
DOI: 10.1002/ijgo.12697 Abstract Objectives: To determine the relationship between maternal serum uric acid levels
and fetal/neonatal complications in women with pre-eclampsia/eclampsia, and to
establish a predictive threshold value. 2Department of Public Health, Hue University
of Medicine and Pharmacy, Hue University,
Hue, Vietnam Methods: A diagnostic test and historical cohort study conducted by prospective
cross-sectional data collection on pregnant women with pre-eclampsia/eclampsia at
Hue University Hospital, Vietnam, between March 2015 and July 2017. Pre-eclampsia
was diagnosed based on ACOG criteria. Serum uric acid levels were measured by
enzymatic colorimetric testing using a Cobas c 501 analyzer (Roche Diagnostics,
Mannheim, Germany). Fetal complications included intrauterine growth restriction,
preterm delivery, fetal death, and neonatal death. *Correspondence
Tam M. Le, Department of Obstetrics and
Gynecology, Hue University of Medicine and
Pharmacy, Hue University, Hue, Vietnam. Email: leminhtam@huemed-univ.edu.vn Results: There were 205 women enrolled. Serum uric acid at a cutoff of 393 μmol/L is
a good predictor of fetal/neonatal complications (AUC 0.752), with 64.4% sensitivity
and 79.5% specificity. High uric acid level (≥393 μmol/L) resulted in increased risk of
preterm birth (OR 6.367, 95% CI 3.009–13.084), low Apgar scores (OR 5.514, 95% CI
1.877–16.198), intrauterine growth restriction (OR 7.188, 95% CI 3.592–14.382), and
neonatal death (OR 7.818, 95% CI 1.614–37.867). There was no relationship between
uric acid level and fetal death (OR 1.803, 95% CI 0.355–9.168). Conclusions: Maternal serum uric acid concentration is a good predictor of fetal/neo-
natal outcomes in women with pre-eclampsia/eclampsia. Int J Gynecol Obstet 2019; 144: 21–26 Maternal serum uric acid concentration and pregnancy
outcomes in women with pre-eclampsia/eclampsia Tam M. Le1,* | Long H. Nguyen1 | Nam L. Phan1 | Duong D. Le2 | Huy V.Q. Nguyen1 |
Vinh Q. Truong1 | Thanh N. Cao1 Tam M. Le1,* | Long H. Nguyen1 | Nam L. Phan1 | Duong D. Le2 | Huy V.Q. Nguyen1 |
Vinh Q. Truong1 | Thanh N. Cao1 wileyonlinelibrary.com/journal/ijgo was defined as the occurrence of seizures with stages according to
diagnostic criteria.10 levels play an important role in the prognosis of pre-eclampsia,4–6
a unified threshold value has not been determined. Threshold
values of 6 mg/dL (530.4 μmol/L) and 5.6 mg/dL for 38 weeks of
gestation (521.4 μmol/L) have been reported5,7; while Parrish et al.8
reported a mean uric acid level of 363.4 μmol/L in pregnancies with
adverse outcomes. Fetal complications included IUGR, preterm delivery, fetal death,
and neonatal death. Neonatal death was defined as death occurring
during the first 4 weeks after birth, while fetal death was defined as
intrauterine death before delivery (stillbirth).11 Each patient was measured for height and weight. Body mass
index (BMI) was calculated as body weight in kilograms divided by
the square of height in meters. Serum uric acid levels were drawn
intravenously at the hospital after each patient had rested for
30 minutes. The sterilization principle and compliance preserva-
tion regime were ensured during testing by use of the compari-
son color method (enzymatic colorimetric test) using a Coba c 501
analyzer (Roche Diagnostics, Mannheim, Germany) with UA2 ACN
700 (serum/plasma). The peroxide reacts in the presence of perox-
idase,
N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline,
and
4-aminophenazone to form a quinonediimine dye. The intensity of
the red color formed is proportional to the uric acid concentration
and is determined photometrically; the methods used followed the
manufacturer’s instructions. In Vietnam, although there have been many studies on pre-
eclampsia in terms of prevention, early diagnosis, and pregnancy
outcomes, there are limited studies that have investigated uric acid
concentration and its role in predicting severe fetal complications in
pre-eclamptic patients. The aim of the present study was to determine
the relationship between maternal serum uric acid levels and fetal/
neonatal complications in women with pre-eclampsia/eclampsia, and
to establish a predictive value for these complications. 2 | MATERIALS AND METHODS A diagnostic test and historical cohort study conducted by prospec-
tive cross-sectional data collection on singleton pregnant women with
pre-eclampsia/eclampsia admitted to the Department of Obstetrics
and Gynecology, Hue University Hospital, Vietnam, between March
2015 and July 2017. The study excluded chronic hypertensive women,
patients with metabolic disorders, and those with diseases that
adversely affect serum uric acid levels in pregnancy, such as chronic
kidney disease, acute and chronic nephritis, nephrotic syndrome, and
kidney failure. Patients with cellular damage as a result of cancer and
hemolytic diseases were also excluded. The study was approved by
the Hue University of Medicine and Pharmacy Ethics Committee. Because uric acid sampling is indicated routinely for pregnant women
with pre-eclampsia in our clinical practice, informed consent was not
required to obtain samples. All analyses were performed using SPSS version 2.0 (IBM, Armonk,
NY, USA). Receiver operating characteristic (ROC) curves were con-
structed to examine the diagnostic test performance of uric acid for
the prognosis of each fetal/neonatal outcome, and general compli-
cations defined as at least one of five events occurring, including:
preterm birth, APGAR score less than 7 in the first minute, fetal death,
IUGR, or neonatal death. Groups were compared using the t test for
independent samples. Values are given as mean and standard devia-
tion (SD) or absolute number and percentage. Results are expressed as
odds ratio (OR) with 95% confidence interval (CI) or two-sided P value. P<0.05 was considered statistically significant. To estimate the sample size required for this study, we used
the equation n=Zα/2
2 × P × (1 − P)/Δ2, where α=0.05, Δ=0.05, and
Zα/2=1.96. Based on the complication rate of intrauterine fetal death,
neonatal death, small for gestational age or prematurity from the study
by Livingston et al.9 the expected prevalence taken from small for ges-
tational age, which was the most common complication, was 46/125
(P=11%). The minimum sample size required to identify the fetal/neo-
natal outcomes for women with pre-eclampsia attending our hospital
was 150 patients. 1 | INTRODUCTION fetal deaths in pre-eclamptic patients (10%–15% and 5.9%, respec-
tively) is controversial and the subject of ongoing study.3 Int J Gynecol Obstet 2019; 144: 21–26
wileyonlinelibrary.com/journal/ijgo
| 21
1 | INTRODUCTION
Uric acid is the final substance in the process of purine metabolism.1,2
Elevated levels are considered to be an early biomarker of kidney dam-
age in women with pre-eclampsia and also a factor in predicting fetal
death.1,3 The role of uric acid as the possible cause of maternal and
fetal deaths in pre-eclamptic patients (10%–15% and 5.9%, respec-
tively) is controversial and the subject of ongoing study.3
In addition to complications for the mother, pre-eclampsia can
also result in serious consequences for the fetus, including fetal dis-
tress, intrauterine growth restriction (IUGR), and preterm or perina-
tal death. Although most studies have shown that maternal uric acid
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited. © 2018 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley &Sons Ltd on behalf of International Federation of Gynecology and
Obstetrics Uric acid is the final substance in the process of purine metabolism.1,2
Elevated levels are considered to be an early biomarker of kidney dam-
age in women with pre-eclampsia and also a factor in predicting fetal
death.1,3 The role of uric acid as the possible cause of maternal and In addition to complications for the mother, pre-eclampsia can
also result in serious consequences for the fetus, including fetal dis-
tress, intrauterine growth restriction (IUGR), and preterm or perina-
tal death. Although most studies have shown that maternal uric acid
License, which permits use, distribution and reproduction in any medium, | 21 | 21 Int J Gynecol Obstet 2019; 144: 21–26 22 Le ET AL. Le ET AL. | 23 | 23 Le ET AL. 23 TABLE 1 General characteristics of the study population and fetal/neonatal outcomes.a
Characteristics
Group 1: Pre-eclampsia
(n=112)
Group 2: Severe pre-eclampsia/
eclampsia (n=93)
Total (n=205)
P value
Maternal age, y
30.45 ± 6.99
30.88 ± 6.27
30.6 ± 6.7
0.675
<35
78 (69.6)
63 (67.7)
141 (68.8)
0.888
≥35
34 (30.4)
30 (32.3)
64 (31.2)
Parity
0.421
Nulliparous
54 (48.2)
42 (45.2)
105 (51.2)
Multiparous
58 (51.8)
51 (54.8)
100 (48.8)
BMI
27.68 ± 3.95
26.41 ± 3.45
27.23 ± 3.82
0.577
Uric acid, μmol/L
328.99 ± 88.49
427.60 ± 113.54
364.11 ± 108.72
<0.001
Preterm birth
7 (6.3)
39 (41.9)
46 (22.4)
<0.001
Apgar score <7
0
18 (20.7)b
18 (9.0)b
<0.001
Fetal death
0
6 (6.5)
6 (2.9)
0.008
IUGR
15 (13.4)
38 (40.9)
53 (25.9)
<0.001
Neonatal death
0
10 (10.8)
10 (4.9)
<0.001
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); IUGR, intrauterine growth restriction. aValues are given as mean ± SD or number (percentage) unless otherwise indicated. bFetal deaths were not included for the purpose of calculating percentages. TABLE 1 General characteristics of the study population and fetal/neonatal outcomes.a Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); IUGR, intrauterine growth restriction. aValues are given as mean ± SD or number (percentage) unless otherwise indicated. bFetal deaths were not included for the purpose of calculating percentages. Once adjusted for maternal age, grade of pre-eclampsia and parity,
uric acid at a threshold of 393 μmol/L was a good prognostic marker
for IUGR (OR 5.510, 95% CI 2.611–11.628); preterm birth (OR 3.910,
95% CI 1.696–9.011); neonatal death (OR 3.249, 95% CI 0.475–
22.231); low Apgar score (OR 1.716, 95% CI 0.474–6.220); and for
general fetal/neonatal complications (OR 4.399, 95% CI 2.137–9.052). Once adjusted for maternal age, grade of pre-eclampsia and parity,
uric acid at a threshold of 393 μmol/L was a good prognostic marker
for IUGR (OR 5.510, 95% CI 2.611–11.628); preterm birth (OR 3.910,
95% CI 1.696–9.011); neonatal death (OR 3.249, 95% CI 0.475–
22.231); low Apgar score (OR 1.716, 95% CI 0.474–6.220); and for
general fetal/neonatal complications (OR 4.399, 95% CI 2.137–9.052). | 23 For general fetal/neonatal complications (occurrence of at least
one of the other five events), the AUC was 0.752 and the threshold
uric acid level was 393 μmol/L, with 64.4% sensitivity and 79.5%
specificity (Fig. 1). The relationship between fetal outcomes and uric acid threshold
of 393 μmol/L is shown in Table 3. High uric acid level (≥393 μmol/L)
resulted in increased risk of preterm birth (OR 6.367, 95% CI 3.009–
13.084; P<0.001); low Apgar score (OR 5.514, 95% CI 1.877–16.198;
P=0.002); IUGR (OR 7.188, 95% CI 3.592–14.382; P<0.001); and
neonatal death (OR 7.818, 95% CI 1.614–37.867; P=0.009). The only
complication for which the difference was not significant was fetal
death (P=0.773). 3 | RESULTS During the study period, 205 pregnant women with pre-eclampsia/
eclampsia met the eligibility criteria and were recruited consecutively. The general characteristics of the study population and the fetal/neo-
natal complications are shown in Table 1. The mean age of the study
participants was 30.6 ± 6.7 years, and there was no significant differ-
ence in age between group 1 (pre-eclampsia) and group 2 (severe pre-
eclampsia/eclampsia). Differences in parity and BMI were also not
significant between the groups. Recruited patients were divided into two groups: pre-eclampsia
(group 1) or severe pre-eclampsia and eclampsia (group 2), based
on the criteria from the American College of Obstetricians and
Gynecologists (ACOG).10 Pre-eclampsia was defined as the onset of
hypertension and proteinuria from 20 weeks of pregnancy onward.10
Severe pre-eclampsia was defined as pre-eclampsia and at least one
of the following symptoms: systolic blood pressure greater than or
equal to 160 mm Hg or diastolic blood pressure greater than or equal
to 110 mm Hg, pulmonary edema, cerebral or visual disorder, throm-
bocytopenia, liver dysfunction, epigastric or right upper quadrant pain,
nonresponse to treatment, serum creatinine concentration greater
than 1.1 mg/dL, or double serum creatinine concentration. Eclampsia Uric acid concentration was significantly higher in group 2 com-
pared with group 1 (427.60 ± 113.54 vs 328.99 ± 88.49; P<0.001). IUGR was the most common fetal/neonatal complication, accounting
for 25.9% (n=53), followed by preterm birth at 22.4% (n=46). Apgar
score of less than 7 was established for 199 live neonates owing to 6
cases of fetal death. For individual fetal/neonatal complications, the AUC of uric acid
was highest for prognosis of neonatal death (AUC 0.759, P<0.004),
followed by preterm birth (AUC 0.753, P<0.001), Apgar score <7
(AUC 0.752, P<0.001), and IUGR (AUC 0.723, P<0.001) (Table 2). 4 | DISCUSSION This cross-sectional study of 205 pregnant women with pre-
eclampsia/eclampsia aimed to assess the role of maternal serum uric
acid levels in predicting pregnancy outcomes. The study was also
designed to establish a predictive threshold value of maternal uric acid
levels and occurrence of fetal complications. The association of bio-
markers, including uric acid, with adverse outcomes in pre-eclamptic
pregnant women is discussed in ACOG guidelines10; however, its util-
ity as a diagnostic marker is still debated. There was no association between uric acid level and maternal
factors such as age, parity, or delivery method (Table 4). The only asso-
ciated factor was severe pre-eclampsia/eclampsia (OR 5.188, 95% CI
2.790–9.649; P<0.001). Table 5 shows multivariable logistic regression results for predicted
fetal/neonatal outcomes based on a uric acid threshold of 393 μmol/L. TABLE 2 Criterion values, sensitivity, and specificity of serum uric acid concentration as markers for prognosis of fetal/neonatal complication. TABLE 2 Criterion values, sensitivity, and specificity of serum uric acid concentration as markers for prognosis of fetal/neonatal complication. Complications
Criterion of acid
uric, μmol/L
Sensitivity
Specificity
AUC
P value
Preterm birth
>410
65.2
78.6
0.753
<0.001
Apgar <7 (n=199)
>376
83.3
61.3
0.752
<0.001
Fetal death
>376
83.3
57.3
0.634
0.169
IUGR
>393
69.8
75.7
0.723
<0.001
Neonatal death
>378
90.0
60.5
0.759
<0.004
General fetal/neonatal complications (occurrence of at least
one of other five complications)
>393
64.4
79.5
0.752
<0.001
Abbreviations: AUC, area under the curve; IUGR, intrauterine growth restriction. TABLE 2 Criterion values, sensitivity, and specificity of serum uric acid concentration as markers for prognosi sitivity, and specificity of serum uric acid concentration as markers for prognosis of fetal/neonatal complication. 24 |
FIGURE 1 Receiver operating characteristic curve of serum uric
acid concentration in cases of fetal/neonatal complications among
women with pre-eclampsia/eclampsia. Le ET AL. Le ET AL. 24 The occurrence of pregnancy outcomes in the present study were:
preterm birth rate (22.4%), IUGR (25.9%), Apgar score less than 7 (9.0%),
fetal death (2.9%), and neonatal death (4.9%). Other studies have
reported similarly, with preterm birth ranging from 15% to 67%, IUGR
ranging from 10% to 25%, and fetal mortality ranging from 1% to 2%.2 Concerning individual fetal/neonatal complications, the AUC
of uric acid was highest for the prognosis of neonatal death, fol-
lowed by preterm birth, Apgar score less than 7, and IUGR. REFERENCES In the present study, a threshold of 393 μmol/lL was not a
predictive factor for fetal death (OR 1.803, 95% CI 0.355–9.168). However, high uric acid concentration increased the risk of neona-
tal mortality by over sevenfold (OR 7.818, 95% CI 1.614–37.867). This result is controversial owing to the wide confidence interval. In another study, maternal serum uric acid levels were increased
in 86.4% of cases of perinatal.6 Our results are similar to Tejal and
Astha (OR 20.0, 95% CI 1.13–360.29)5 and Yassaee13 who reported
that high serum uric acid concentrations increased the risk of peri-
natal mortality by 30.4 times (OR 30.4, 95% CI 1.7–529) compared
with normal uric acid levels. 1. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role
for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41:1183–1190. 2. Bainbridge AS, Roberts JM. Uric acid as a pathogenic factor in pre-
eclampsia. Placenta. 2008;29(Suppl.A):S67–S72. 3. Duley L. The global impact of preeclampsia and eclampsia. Semin
Perinatol. 2009;33:130–137. 4. Essiben F, Itembe O, Foumane P, Nguefack MT, Eko FE. Blood uric
acid level as a marker of increased risk of eclampsia in severe pre-
eclamptic patients: A cross-sectional study in two tertiary hospitals of
Yaoundé, Cameroon. Health Sci Dis. 2016;17:7–11.i 5. Tejal P, Astha D. Relationship of serum uric acid level to maternal and
perinatal outcome in patients with hypertensive disorders of preg-
nancy. Gujarat Med J. 2014;69:45–47. 5. Tejal P, Astha D. Relationship of serum uric acid level to maternal and
perinatal outcome in patients with hypertensive disorders of preg-
nancy. Gujarat Med J. 2014;69:45–47. The uric acid threshold in the present study was a good predictor
of severity of pre-eclampsia/eclampsia (OR 5.188, 95% CI 2.790–
9.649). These findings were much higher than those of Hawkins
et al.,7 who reported that hyperuricemia indicated an increased risk
of severe hypertension (OR 1.4, 95% CI 1.0–1.9). However, there
was no association between our threshold value and cesarean or
vaginal delivery. 6. Rajalaxmi K, Radhakrishna N, Manjula S. Serum uric acid level in
preeclampsia and its correlation to maternal and fetal outcome. Int J
Biomed Res. 2014;5:22–24. 7. Hawkins AT, Roberts JM, Mangos GJ, Davis GK, Roberts LM,
Brown MA. Plasma uric acid remains a marker of poor outcome
in hypertensive pregnancy: A retrospective cohort study. BJOG. 2012;119:484–492. 8. Parrish M, Griffin M, Morris R, Darby M, Owens MY, Martin JN. ACKNOWLEDGMENTS We thank Armity Simons from Health Volunteers Overseas (HVOUSA),
Scottsdale, AZ, USA, for her translation skills. The authors have no conflicts of interest. The authors have no conflicts of interest. AUTHOR CONTRIBUTIONS Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction;
OR, odds ratio. aSerum uric acid was adjusted for maternal age, grade of pre-eclampsia,
and parity. LMT contributed to study design, data analysis, manuscript drafting,
and critical discussion. NHL, PLN, and NVQH contributed to data
collection, analysis, manuscript drafting, and critical discussion. LDD
contributed to data analysis, manuscript drafting, and critical discus-
sion. TQV and CNT contributed to data interpretation, manuscript
drafting, and critical discussion. All authors were involved in drafting
the work or revising it critically. than that of Bellomo et al.,12 who reported a predictive threshold for
small-for-gestational-age infants of 309 μmol/L (AUC 0.784, 83.7%
sensitivity, 71.7%). Based on our threshold of 393 μmol/L, the risk of preterm birth
was increased 6.367 times (95% CI 3.009–13.084), which was similar
to Tejal’s study (OR 6.0, 95% Cl, 1.24–28.98),5 but higher than results
reported by Hawkins et al. (OR 3.8, 95% CI 2.6–5.6).7 Uric acid level
was also a good predictive factor for Apgar score less than 7 in the first
minute (OR 5.514, 95% CI 1.877–16.198). Similarly, another study of
103 pre-eclamptic women found that maternal serum uric acid con-
centration was associated with Apgar score less than 7 (OR 11.9, 95%
CI 4.4–31.8).13 In our study, the risk of IUGR was increased 7.188
times in women with high uric acid levels (95% CI 3.592–14.382). These results were higher than those of Hawkins (OR 1.8, 95% CI
1.2–2.7)7 and Tejal and Astha (OR 4.04, 95% CI 1.21–13.43).5 TABLE 5 Multivariable logistic regression for predicted fetal/
neonatal outcomes based on uric acid threshold of 393 μmol/L. Outcomes
Crude OR (95% CI)
Adjusted OR (95% CI)a
Preterm birth
6.367 (3.009–13.084)
3.910 (1.696–9.011)
Lower Apgar
score <7
5.514 (1.877–16.198)
1.716 (0.474–6.220)
Fetal death
1.803 (0.355–9.168)
0.456 (0.058–3.593)
IUGR
7.188 (3.592–14.382)
5.510 (2.611–11.628)
Neonatal death
7.818 (1.614–37.867)
3.249 (0.475–22.231)
General
complications
(yes/no)
7.030 (3.710–13.319)
4.399 (2.137–9.052)
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction;
OR, odds ratio. aSerum uric acid was adjusted for maternal age, grade of pre-eclampsia,
and parity. TABLE 5 Multivariable logistic regression for predicted fetal/
neonatal outcomes based on uric acid threshold of 393 μmol/L. fetal/neonatal complications (OR 4.399, 95% CI 2.137–9.052). For
each individual outcome, serum uric acid was a good prognostic
marker for IUGR, preterm birth, neonatal death, and low Apgar score. The present study had some limitations, such as missing maternal
data for preconception and prenatal care, which made the assessment
of maternal risks more difficult. In conclusion, maternal serum uric acid concentration was a good
prognostic factor for monitoring and prognosis of fetal/neonatal out-
comes in women with pre-eclampsia/eclampsia. There was a relation-
ship between high uric acid level and the risk of preterm birth, low
Apgar index, IUGR, and neonatal death, but not fetal death. 4 | DISCUSSION For
each individual outcome, serum uric acid was a good prognostic
marker for IUGR, preterm birth, neonatal death, and low Apgar score. 25 | 25
fetal/neonatal complications (OR 4.399, 95% CI 2.137–9.052). For
each individual outcome, serum uric acid was a good prognostic
marker for IUGR, preterm birth, neonatal death, and low Apgar score. 4 | DISCUSSION ROC
analysis showed that a serum uric acid threshold of 393 μmol/L
was a good predictor of general fetal/neonatal complications (AUC
0.752), with 64.4% sensitivity and 79.5% specificity, in women with
pre-eclampsia/eclampsia. The results of our study are similar to those of Livingston et al.,9
who included 1505 pre-eclamptic pregnant women and reported
that the Z-index of uric acid was associated with adverse perinatal
outcomes (OR 1.5, 95% CI 1.4–1.7); their AUC was 0.72 (95% CI
0.69–0.74).9 Our threshold value of 393 μmol/L is slightly higher
than normal uric acid levels in the third trimester of pregnancy (184–
375 μmol/L).9 Similarly, Tejal and Astha5 selected a uric acid level
of 360 μmol/L to classify risk factors for maternal and fetal compli-
cations. The cutoff threshold in the present study was also higher FIGURE 1 Receiver operating characteristic curve of serum uric
acid concentration in cases of fetal/neonatal complications among
women with pre-eclampsia/eclampsia. TABLE 3 Relationship between fetal outcomes and uric acid threshold of 393 μmol/L. Outcomes
Uric acid ≥393 μmol/L (n=74)
Uric acid <393 (n=131)
P value
OR (95% CI)
Preterm birth
32 (43.2)
14 (10.7)
<0.001
6.367 (3.009–13.084)
Apgar <7 (n=199)
13 (18.3)a
5 (3.8)
0.002
5.514 (1.877–16.198)
Fetal death
3 (4.1)
3 (2.3)
0.773
1.803 (0.355–9.168)
IUGR
37 (50.0)
16 (12.2)
<0.001
7.188 (3.592–14.382)
Neonatal death
8 (10.8)
2 (1.5)
0.009
7.818 (1.614–37.867)
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; OR, odds ratio. aFetal deaths were not included for the purpose of calculating this percentage. TABLE 3 Relationship between fetal outcomes and uric acid threshold of 393 μmol/L. TABLE 4 Relationship between uric acid levels and maternal factors. TABLE 4 Relationship between uric acid levels and maternal factors. Maternal factors
Uric acid ≥393 μmol/L
Acid uric <393 μmol/L
P value
OR (95% CI)
Maternal age, y
0.615
0.811 (0.435–1.512)
≥35 (n=64)
43 (67.2)
21 (32.8)
<35 (n=141)
88 (62.4)
53 (37.6)
Parity
0.642
0.807 (0.473–1.482)
Multiparous (n=100)
66 (66.0)
34 (34.0)
Nulliparous (n=105)
65 (61.9)
40 (38.1)
Pre-eclampsia/eclampsia grade
<0.001
5.188 (2.790–9.649)
Severe pre-eclampsia/eclampsia (n=93)
52 (55.9)
41 (44.1)
Mild (n=112)
22 (19.6)
90 (80.4)
Delivery method
0.280
1.602 (0.766–3.350)
Cesarean delivery (n=162)
100 (61.7)
62 (38.3)
Vaginal delivery (n=43)
31 (72.1)
12 (27.9)
Total (n=205)
131 (63.9)
74 (36.1)
Abbreviations: CI, confidence interval; OR, odds ratio. Le ET AL. | 25
fetal/neonatal complications (OR 4.399, 95% CI 2.137–9.052). REFERENCES Hyperuricemia facilitates the prediction of maternal and perinatal
adverse outcome in patients with severe/superimposed preeclamp-
sia. J Matern Fetal Neonatal Med. 2010;23:1451–1455. In multivariable logistic regression analysis adjusted for mater-
nal age, grade of pre-eclampsia, and parity, serum uric acid was a
good prognostic marker at the threshold of 393 μmol/L for general int/iris/bitstream/handle/10665/43444/9241563206_eng.pdf.
Accessed February 22, 2018. 26 | 26 Le ET AL. int/iris/bitstream/handle/10665/43444/9241563206_eng.pdf. Accessed February 22, 2018. int/iris/bitstream/handle/10665/43444/9241563206_eng.pdf. Accessed February 22, 2018.i 9. Livingston JR, Payne B, Brown M, et al. Uric acid as a predictor of
adverse maternal and perinatal outcomes in women hospitalized with
preeclampsia. J Obstet Gynaecol Can. 2014;36:870–877. 12. Bellomo G, Venanzi S, Saronio P, Verdura C, Narducci PL. Prognostic
significance of serum uric acid in women with gestational hyperten-
sion. Hypertension. 2011;58:704–708. 10. American College of Obstetricians and Gynecologists; Task Force
on Hypertension in Pregnancy. Hypertension in pregnancy. Obstet
Gynecol. 2013;122:1122–1131. 13. Yassaee F. Hyperuricemia and perinatal outcomes in patients with
severe preeclampsia. Iran J Med Sci. 2003;28:198–199. 11. World Health Organization. Neonatal and Perinatal Mortality – Country,
Regional and Global Estimates. Geneva: WHO; 2006. http://www.who.
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English
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Multiple micronutrient supplementation improves vitamin B12and folate concentrations of HIV infected children in Uganda: a randomized controlled trial
|
Nutrition journal
| 2,011
|
cc-by
| 7,855
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* Correspondence: gracendeezi@yahoo.com
1Department of Paediatrics and Child Health, School of Medicine, College of
Health Sciences, Makerere University, Kampala, Uganda
Full list of author information is available at the end of the article RESEARCH Open Access © 2011 Ndeezi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited. Multiple micronutrient supplementation improves
vitamin B12 and folate concentrations of HIV
infected children in Uganda: a randomized
controlled trial Grace Ndeezi1,2*, James K Tumwine1, Christopher M Ndugwa1, Bjørn J Bolann3 and Thorkild Tylleskär2 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 * Correspondence: gracendeezi@yahoo.com
1Department of Paediatrics and Child Health, School of Medicine, College of
Health Sciences, Makerere University, Kampala, Uganda
Full list of author information is available at the end of the article
© 2011 Ndeezi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited. Background Vitamin B12 and folate deficiency are relatively common
in low income countries compared to high income
countries, particularly in communities where the diet is
predominantly vegetarian [1-4], where major sources of
vitamin B12 such as meat, fish, poultry, milk and forti-
fied breakfast cereals [5] are consumed in small amounts
or are not readily available. Dietary sources of folate, on
the other hand, are more prevalent as they include
green leafy vegetables, fruits and dried beans and peas
[6]. During infancy and childhood folate and vitamin
B12 deficiency have been associated with failure to
thrive, reduced physical activity and cognitive function
and megaloblastic anaemia [7,8]. However many of the
symptoms are non-specific and may result from a vari-
ety of medical conditions. The study sites have been previously described [15]. Three sites were located in the capital city of Uganda
(Kampala) and these were Mulago (the national referral
hospital), Mildmay Centre and Nsambya hospital. The
other sites were situated in the regional hospitals in the
east, south-west, central and north of the country. For
logistical reasons, transport and storage, it was not pos-
sible to collect samples for biochemical tests from all
the sites. Therefore blood samples for biochemical tests
were only collected from the three Kampala sites. The
samples were subsequently shipped to the clinical chem-
istry laboratory at Haukeland University Hospital, Ber-
gen (Norway), where vitamin B12 and folate were
analysed. A significant number of HIV-infected children in low-
income countries remain at risk of increased morbidity
due to immunodeficiency related to HIV infection in
addition to micronutrient deficiencies. Low vitamin B12
status has been associated with poor immunological sta-
tus and HIV disease progression in adults [9]. In follow
up studies of HIV infected pregnant women micronutri-
ent supplementation resulted in improved child growth,
haematological indices and vitamin B12 levels [10]. The trial enrolled 847 children at all the seven study
sites. Out of 705 children from whom blood samples
could be stored for micronutrient tests, 261 had no suf-
ficient samples, 230 had other micronutrient tests done
or had either baseline but no result at the second sam-
pling. Because of multiple analyses 214 children had
both baseline and 6 months results for vitamin B12 and
folate concentrations. Methods
Design Cotrimoxazole prophylaxis, initiation of ART, manage-
ment of common illnesses and opportunistic infections
was offered using the national guidelines for Paediatric
HIV care. The study was a randomised controlled trial conducted
between 2005 and 2008 at 7 paediatric HIV clinics in
Uganda. Participants were allocated to the intervention
or ‘standard of care’ supplement in a 1:1 ratio. Abstract Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 supplementation studies going on at the time so the
exclusion for those who were participating in other stu-
dies was done to avoid participant fatigue and interfer-
ence with procedures. Multivitamin supplementation
was routinely practiced at the study clinics but this was
not an exclusion criteria. Eligible participants were con-
secutively enrolled, assigned to the study intervention or
‘standard of care’ supplement and followed for one year. Background There were no significant differ-
ences in demographic and clinical characteristics such
as age, sex, anthropometric measurements and other
laboratory measurements like CD4 + cell count among
those who had results for vitamin B12 and folate com-
pared to those who did not. Food supplementation and multiple micronutrient for-
tification of foods and beverages in children with
unknown HIV status living in low income countries
have shown improved haemoglobin levels and concen-
trations of deficient micronutrients [2,11-14]. We hypothesised that supplementation with two
recommended dietary allowances (RDA) of 14 multiple
micronutrients (MMS) would increase serum vitamin
B12 and folate concentrations compared to a 1 RDA of 6
multivitamin (MV) ‘standard of care’ supplement. We
here report the baseline vitamin B12 and folate status in
Ugandan HIV infected children aged 1-5 years and the
effect of multiple micronutrient supplementation on
serum concentrations of vitamin B12 and folate. The study was approved by the College of Health
Sciences Research and Ethics Committee, Makerere
University, Kampala, Uganda; the Uganda National
Council for Science and Technology, and the Regional
Committee for Medical Research Ethics, Western
Norway. Abstract Background: The effect of multiple micronutrient supplementation on vitamin B12 and folate has hither to not
been reported in African HIV infected children. This paper describes vitamin B12 and folate status of Ugandan HIV
infected children aged 1-5 years and reports the effect of multiple micronutrient supplementation on serum
vitamin B12 and folate concentrations. Methods: Of 847 children who participated in a multiple micronutrient supplementation trial, 214 were assessed
for vitamin B12 and folate concentrations pre and post supplementation. One hundred and four children were
randomised to two times the recommended dietary allowance (RDA) of a 14 multiple micronutrient supplement
(MMS) and 114 to a ‘standard of care’ supplement of 6 multivitamins (MV). Serum vitamin B12 was measured by an
electrochemiluminescence immunoassay and folate by a competitive protein-binding assay using Modular E
(Roche) automatic analyzer. Vitamin B12 concentrations were considered low if less than 221picomoles per litre
(pmol/L) and folate if < 13.4 nanomoles per litre (nmol/L). The Wilcoxon Signed Ranks test was used to measure
the difference between pre and post supplementation concentrations. Results: Vitamin B12 was low in 60/214 (28%) and folate in 62/214 (29.0%) children. In the MMS group, the median
concentration (IQR) of vitamin B12 at 6 months was 401.5 (264.3 - 518.8) pmol/L compared to the baseline of 285.5
(216.5 - 371.8) pmol/L, p < 0.001. The median (IQR) folate concentrations increased from 17.3 (13.5 - 26.6) nmol/L
to 27.7 (21.1 - 33.4) nmol/L, p < 0.001. In the ‘standard of care’ MV supplemented group, the median concentration
(IQR) of vitamin B12 at 6 months was 288.5 (198.8 - 391.0) pmol/L compared to the baseline of 280.0 (211.5 - 386.3)
pmol/L while the median (IQR) folate concentrations at 6 months were 16.5 (11.7 - 22.1) nmol/L compared to 15.7
(11.9 - 22.1) nmol/L at baseline. There was a significant difference in the MMS group in both vitamin B12 and folate
concentrations but no difference in the MV group. Conclusions: Almost a third of the HIV infected Ugandan children aged 1-5 years had low serum concentrations
of vitamin B12 and folate. Multiple micronutrient supplementation compared to the ‘standard of care’ supplement
of 6 multivitamins improved the vitamin B12 and folate status of HIV infected children in Uganda. Trial registration: http://ClinicalTrials.govNCT00122941) Page 2 of 9 Page 2 of 9 Page 2 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Outcomes previous studies of HIV infected adults had indicated
that HIV infected persons may require multiples of
RDA in order to achieve normal serum concentrations
of micronutrients. Thirdly, looking at the tables of the
nutritional requirements for children [6] we noted that
there are 2 age bands where our participants belonged,
1-3 and 4-8 years of age. We noticed that there were
minor variations in dosages of some micronutrients
while others like iodine and vitamin D did not vary. We
therefore decided to use the 4 year old category for our
study. In addition it was easier to administer a uniform
intervention. There were no similar studies in the region
and there was no literature to guide us on the micronu-
trient status of Ugandan HIV infected children. Also
there were no food composition tables based on the
local foods so we could not estimate how much micro-
nutrients children get from the usual diet. The MMS
comprised of 800 mcg vitamin A, 1.2 mg vitamin B1, 1.2
mg vitamin B2, 16 mg niacin, 1.2 mg vitamin B6, 2.4
mcg vitamin B12, 50 mg vitamin C, 400 IU vitamin D,
14 mg vitamin E, 40 mcg folate, 60 mcg selenium, 10
mg zinc, 800 mcg copper and 180 mcg iodine. The mul-
tivitamin ‘standard of care’ supplement contained 400
mcg vitamin A, 0.6 mg vitamin B1, 0.6 mg vitamin B2, 8
mg niacin, 25 mg vitamin C and 200 IU vitamin D. The
contents and formula for the MV supplement was based
on the regular multivitamins supplied at the study
clinics as routine care of HIV infected children. The
daily dose was 4 g and this was equivalent to a levelled
scoop supplied by the manufacturer. The powder was
mixed with 10 to 20 ml of milk or water. The first dose
of the supplement was administered at the study clinic
following a demonstration and under observation by the
study nurse. At the time of administering the first dose
we counselled the mother on the importance of com-
pleting the dose and ensuring that the daily dose was
given. Whenever the child vomited during or within 30
minutes of administering the dose a repeat dose was
given. Mothers were given calendar charts and
instructed to tick on the appropriate date whenever a
dose was given. Outcomes They would return to the clinic with
the container/remaining supplement together with the
calendar charts on routine follow up visits. The remain-
ing amount of supplement was measured using a light
weight scale and the level of compliance determined
using the proportion of the supplement consumed
against the expected. The supply for one month was
140 grams and the expected dose for 30 days was 120
grams. The remaining 20 grams was to cater for vom-
ited doses or in case there was spillage. The mothers
administered the subsequent doses from home and it
was not possible to observe them. The supplements
were given for a period of 6 months when the second The outcome measures were serum vitamin B12 and
folate concentrations pre and post supplementation and
factors associated with low concentrations at baseline. These were secondary objectives of the trial. Survival
was assessed as the primary objective whose findings
have been previously reported [15]. Clinical and laboratory measurements Clinical and laboratory measurements
At enrolment demographic information, history of the
child’s illness and findings on physical examination
were recorded. Non fasting blood samples were drawn
for CD4+ cell count and micronutrient analysis using
procedures previously described in the same cohort
[15]. Vitamin B12 was measured by electrochemilumi-
nescence immunoassay, and folate by a competitive pro-
tein-binding assay on Modular E (Roche) automatic
analyzer. The coefficient of variation for the assays was
less than 5%. To determine cut off values for low vita-
min B12 and folate, we considered what other research-
ers have used since there were no reference values for
Ugandan children. Vitamin B12 concentrations were
considered low if less than 221 picomoles per litre
(pmol/L), combining both very low (<148 pmol/L) and
marginal (148 - 221 pmol/L) status. Concentrations
equal or > 221 pmol/L was considered to be normal. Folate concentrations were low if < 13.4 nanomoles per
litre (nmol/L), similarly combining both very low (<6.8
nmol/L) and marginal (6.8 - 13.4 nmol/L) status. Con-
centrations ≥13.4 nmol/L were regarded as being nor-
mal [16,17]. Participants The trial supplements were manufactured in powder
form and packaged by NUTRISET, France using a for-
mula that was determined by the investigators based on
twice the recommended dietary intake for a 4 year old
category [6]. We decided to use 2 RDA based on the
fact that many children were malnourished despite rou-
tine supplementation with multivitamins. Secondly some HIV infected children aged 1- 5 years presenting at the
study clinics for follow up visits were eligible for the
trial. Children who had enrolled in other studies or
were unable to adhere to a regular follow up schedule
and those whose mothers or guardians declined consent
were excluded. There were no other micronutrient Page 3 of 9 Page 3 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Randomisation and blinding The randomisation sequence was generated using the
stata soft ware in variable blocks of 4 to 20. The supple-
ments were manufactured and packaged in 140 g plastic
containers which were sequentially numbered. RB gen-
erated the randomisation sequence at Geneva and sent
it to the manufacturers in France. The randomisation
code was kept at Geneva and by the manufacturers. The
treatment assignment was revealed upon completion of
the study. Participants were enrolled by the principal investigator
and the other study doctors. The trial nurse at the study
sites dispensed the supplement in serial order. The col-
our, consistency and odour of the intervention and
‘standard of care’ supplement were similar. The princi-
pal investigator, study personnel including doctors and
nurses and the caretakers/participants were all blinded
to treatment assignment. Comparisons between baseline and 6 months’ vitamin
B12 and folate concentrations Baseline median serum vitamin B12 and folate concen-
trations were similar in the two groups. Following sup-
plementation with multiple micronutrients (MMS)
vitamin B12 concentrations increased from a median
(IQR) of 285.5 (216.5 - 371.8) to 401.5 (264.3 - 518.8)
pmol/L at 6 months. This difference was statistically sig-
nificant (p < 0.001). Similarly folate concentrations
increased from 17.3 (13.5 - 26.6) to 27.7 (21.1 - 33.4)
nmol/L and this difference was also significant, p <
0.001 (Table 2). There was no significant difference in
the MV ‘standard of care’ group. Statistical analysis Change in micronutrient concentrations of each partici-
pant was computed in SPSS as follows: concentration at Page 4 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 very low and 47 (22.0%) marginal concentrations (148 -
221 pmol/L). Of the 62 children with low folate status,
3 (1.4%) had very low (<6.8 nmol/L) and 59 (27.6%) had
marginal concentrations (6.8 - 13.4 nmol/L). 6 months minus concentration at baseline. Medians and
their interquartile ranges were used for summarising the
data. Because vitamin B12 and folate concentrations
were not normally distributed the Wilcoxon Signed
Ranks test was used to measure the difference between
baseline and 6 months in each group. Differences in
categorical variables were tested with the Pearson chi-
square or Fischer’s exact test. Differences were consid-
ered significant if a two-sided p-value was less than
0.05. Multiple regression analysis was performed to
examine factors associated with low vitamin B12 or
folate concentrations at baseline assessment. Baseline characteristics of participants Table 1 Characteristics of 214 Ugandan HIV infected children analysed for vitamin B12 and folate by intervention
group
Number (N)
MMS n (%)
’Standard of care’ MV n (%)
p-value
Sex: Male
100
49 (49.0)
51 (51.0)
>0.99
Age less than 24 months
70
33 (47.1)
37 (52.9)
0.77
Mother as carer
146
73 (50.0)
73 (50.0)
0.56
On HAART
44
19 (43.2)
25 (56.8)
0.50
Routine CTX
193
93 (48.2)
100 (51.8)
0.82
Routine MV
144
68 (47.2)
76 (52.8)
0.66
WHZ < -2
28
14 (50.0)
14 (50.0)
>0.99
HAZ < -2
113
56 (49.6)
57 (50.4)
0.89
WHO stage 3 or 4
56
26 (46.4)
30 (53.6)
0.76
CD4+ T cells < 25%
114
50 (43.9)
64 (56.1)
0.20
Elevated CRP (> 6 g/dl)
67
33 (49.3)
34 (50.7)
0.42
Low haemoglobin (< 11 g/dl)
127
61 (48.0)
66 (52.0)
0.89
Low vitamin B12 (< 221 pmol/L)
60
29 (48.3)
31 (51.7)
0.96
Low folate (< 13.4 nmol/L)
62
25 (40.3)
37 (59.7)
0.13
MMS = multiple micronutrient supplementation
HAART = Highly active anti-retroviral therapy
CTX = Cotrimoxazole
MV = ‘standard of care’ multivitamins
WHZ = Weight for height z-score
HAZ = Height for age z-score
WHO = World Health Organisation
CD4+ = Cluster of differentiation 4
CRP = C-reactive protein
Table 2 Biochemical and haematological measurements at baseline and at 6 months of supplementation by
intervention group
Multiple Micronutrient Supplementation
group (n = 104)
Comparative ‘standard of care’ multivitamins
group (n = 110)
Measurement
Median (IQR)
P-value
Median (IQR)
p-value
Vitamin B12 (pmol/L)
Baseline
285.5 (216.5 - 371.8)
<0.001
280.0 (211.5 - 386.3)
0.78
6 months
401.5 (264.3 - 518.8)
288.5 (198.8 - 391.0)
Change
90.5 (-0.8 - 203.5)
10.0 (-73.8 - 83.8)
Folate (nmol/L)
Baseline
17.3 (13.5 - 26.6)
<0.001
15.7 (11.9 - 22.1)
0.44
6 months
27.7 (21.1 - 33.4)
16.5 (11.7 - 22.1)
Change
8.0 (-0.3 - 17.1)
-0.6 (-3.5 - 5.8)
Haemoglobin (g/dl)
Baseline
10.0 (8.7 - 11.2)
0.04
9.8 (8.8 - 11.2)
<0.001
6 months
10.9 (9.4 - 11.7)
10.6 (9.6 - 11.7)
Change
0.3 (-0.4 - 0.9)
0.6 (-0.2 - 1.4)
CD4+ count (cells/μL)
Baseline
1201 (822 - 1556)
0.16
1033 (728 - 1406)
0.52
6 months
1039 (725 - 1358)
1043 (704 - 1484) aracteristics of 214 Ugandan HIV infected children analysed for vitamin B12 and folate by intervention Table 1 Characteristics of 214 Ugandan HIV infected children analysed for vitamin B12 and folate by intervention
group
Number (N)
MMS n (%)
’Standard of care’ MV n (%)
p-value
Sex: Male
100
49 (49.0)
51 (51.0)
>0.99
Age less than 24 months
70
33 (47.1)
37 (52.9)
0.77
Mother as carer
146
73 (50.0)
73 (50.0)
0.56
On HAART
44
19 (43.2)
25 (56.8)
0.50
Routine CTX
193
93 (48.2)
100 (51.8)
0.82
Routine MV
144
68 (47.2)
76 (52.8)
0.66
WHZ < -2
28
14 (50.0)
14 (50.0)
>0.99
HAZ < -2
113
56 (49.6)
57 (50.4)
0.89
WHO stage 3 or 4
56
26 (46.4)
30 (53.6)
0.76
CD4+ T cells < 25%
114
50 (43.9)
64 (56.1)
0.20
Elevated CRP (> 6 g/dl)
67
33 (49.3)
34 (50.7)
0.42
Low haemoglobin (< 11 g/dl)
127
61 (48.0)
66 (52.0)
0.89
Low vitamin B12 (< 221 pmol/L)
60
29 (48.3)
31 (51.7)
0.96
Low folate (< 13.4 nmol/L)
62
25 (40.3)
37 (59.7)
0.13
MMS = multiple micronutrient supplementation gandan HIV infected children analysed for vitamin B12 and folate by intervention out of 40 children (32.5%) who were on HAART had
CD4+ cell percent < 25 compared to 100/159 (63.5%)
who were HAART naïve, p = 0.001 (Fisher’s exact test). Wilcoxon Signed Ranks test was used to measure the difference between baseline and 6 months. Baseline characteristics of participants Of the 214 children with both baseline and 6 months
results for vitamin B12 and folate, 104 (48.6%) received
MMS while the rest received the ‘standard of care’ MV
supplement. The distribution of children by arm and
strata is presented in figure 1. Males and females were
equally represented. The median age (IQR) was 33.2
months (19.6 - 44.4) in the MMS and 30.3 (19.8 - 45.5)
in the MV group. Baseline characteristics are described
in table 1. There were no significant differences between
the two treatment groups. Of the 44 children who were on HAART, 19 received
MMS while 25 received MV. In this stratum the median
(IQR) concentration of vitamin B12 in the MMS arm at
baseline was 262.0 (215.0 - 342.0) compared to 453.0
(261.0 - 594.0) pmol/L at 6 months, p = 0.002. The
median (IQR) folate concentrations increased from 18.6
(13.8 - 23.9) to 25.0 (21.3 - 32.9) nmol/L, p = 0.040. Although the numbers were small these were significant
differences. There was no significant difference in the
MV group. Median (IQR) baseline vitamin B12 concen-
trations were higher in the HAART stratum [306.5 Overall, 60 children (28.0%) had low vitamin B12 con-
centrations less than 221.0 pmol/L, and 62 (29.0%) had
low folate concentrations less than 13.4 nmol/L. Among
the children with low vitamin B12 status, 13 (6.0%) had 847 children enrolled
110 in the
‘standard of care’ arm
104 in the
multiple micronutrient arm
85 HAART
naïve
19 HAART
stratum
214 paired samples
for vitamin B12 and folate
142 at rural sites
261no/minimal samples
230 0ther micronutrient
tests
25 HAART
stratum
85 HAART
naïve
Figure 1 Study profile. 847 children enrolled 142 at rural sites
261no/minimal samples
230 0ther micronutrient
tests 214 paired samples
for vitamin B12 and folate Page 5 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Page 5 of 9 (209.3 - 372.8) pmol/L] compared to the non-HAART
stratum [280.0 (218.0 - 386.3) pmol/L], but not signifi-
cantly so. Folate concentrations were almost the same
[16.1 (13.5 - 22.0) nmol/L] in the HAART and [16.0
(12.1 - 24.9) nmol/L] non-HAART stratum. Thirteen
out of 40 children (32.5%) who were on HAART had
CD4+ cell percent < 25 compared to 100/159 (63.5%)
who were HAART naïve, p = 0.001 (Fisher’s exact test). Median (IQR) duration of anti-retroviral therapy was 9
(6.0 - 14.3) months. Vitamin B12 and folate status at 6 months of
supplementation There was no
significant change in the CD4 cell counts in either the
MMS or MV group. HAART strata and initiation of HAART during the study
Of the 44 children on HAART at enrolment, 15 (34.1%)
and 10 (22.7%) had low vitamin B12 and low folate con-
centrations, respectively. The prevalence of low micro-
nutrient status of these two was not significantly
different between the HAART and non-HAART treated
children. Of the 170 HAART naïve children, 21 started
HAART during the study; 13 in MMS and 8 in MV
group. This difference was not significant, p = 0.35. Seven of the 21 children who initiated HAART during
the study had low vitamin B12 concentrations at
enrolment. Twice the recommended dietary allowance of multiple
micronutrients improved vitamin B12 and folate status
compared to the ‘standard of care’. This is not surpris-
ing since the standard of care supplement did not con-
tain vitamin B12 and folate. This implies that the
standard of care multivitamin is not enough and many
more micronutrients may be required to correct micro-
nutrient deficiencies. A significant number of children
still had low concentrations of vitamin B12 and folate at
the end of 6 months, implying that the duration of sup-
plementation needed to be extended. Vitamin B12 and folate status at 6 months of
supplementation vitamin B12 and folate. Almost a third of the children
had low vitamin B12 and low folate concentrations at
baseline. Very low serum concentrations were uncom-
mon. MMS containing vitamin B12 and folate improved
both vitamin B12 and folate concentrations compared to
the ‘standard of care’ multivitamins. Overall, 42 (19.6%) children had low concentrations of
vitamin B12 at 6 months, 9 (4.2%) with very low and 33
(15.4%) with marginal concentrations. Nine children
(1.4%) were in the MMS and 33 (78.6%) in the MV
group. This was a statistically significant difference. The
odds ratio was 4.5 (95% CI; 2.0 - 10.0). Folate concen-
trations were low in 44/214 (20.6%) children at 6
months of follow up; almost all of them had marginal
concentrations. Five children (11.4%) were supplemen-
ted with MMS and 39 (88.6%) MV; Odds ratio 10.8
(95% CI; 4.1 - 28.9). Low vitamin B12 and folate concen-
trations were more frequent in the MV supplemented
group. Vitamin B12 and folate concentrations in our study are
comparable or slightly lower than what has been
reported in children living in other low-income coun-
tries [1,2,4,17]. Our findings are also comparable to
what other studies in HIV infected adults reported
before the HAART era. These studies showed that low
vitamin B12 concentrations were relatively common with
a prevalence ranging between 10 and 35% [18-22]. There are few studies that have examined vitamin B12
and folate in HIV infected children in Africa. The preva-
lence of low vitamin B12 concentrations in our study was
much higher than the prevalence of 5% reported in South
African HIV infected children [23]. Contrary to our find-
ings a study of HIV infected children in New York showed
elevated vitamin B12 and folate status [24]. Our study
included younger children, the majority of whom were
symptomatic and not on HAART compared to the New
York study. In our study the lack of differences between
the HAART and non-HAART stratum in baseline vitamin
B12 or folate concentrations could be explained by the
short duration of HAART compared to other studies. Other clinical and haematological findings
Eight of the 214 children had signs of neurological dis-
ease, 6 with delayed or loss of developmental milestones,
3 of whom had low or marginal vitamin B12 status. There was a significant increase in the haemoglobin sta-
tus in both groups as shown in table 2. Baseline characteristics of participants Median (IQR) duration of anti-retroviral therapy was 9
(6.0 - 14.3) months. (209.3 - 372.8) pmol/L] compared to the non-HAART
stratum [280.0 (218.0 - 386.3) pmol/L], but not signifi-
cantly so. Folate concentrations were almost the same
[16.1 (13.5 - 22.0) nmol/L] in the HAART and [16.0
(12.1 - 24.9) nmol/L] non-HAART stratum. Thirteen Table 2 Biochemical and haematological measurements at baseline and at 6 months of supplementation by
intervention group
Multiple Micronutrient Supplementation
group (n = 104)
Comparative ‘standard of care’ multivitamins
group (n = 110)
Measurement
Median (IQR)
P-value
Median (IQR)
p-value
Vitamin B12 (pmol/L)
Baseline
285.5 (216.5 - 371.8)
<0.001
280.0 (211.5 - 386.3)
0.78
6 months
401.5 (264.3 - 518.8)
288.5 (198.8 - 391.0)
Change
90.5 (-0.8 - 203.5)
10.0 (-73.8 - 83.8)
Folate (nmol/L)
Baseline
17.3 (13.5 - 26.6)
<0.001
15.7 (11.9 - 22.1)
0.44
6 months
27.7 (21.1 - 33.4)
16.5 (11.7 - 22.1)
Change
8.0 (-0.3 - 17.1)
-0.6 (-3.5 - 5.8)
Haemoglobin (g/dl)
Baseline
10.0 (8.7 - 11.2)
0.04
9.8 (8.8 - 11.2)
<0.001
6 months
10.9 (9.4 - 11.7)
10.6 (9.6 - 11.7)
Change
0.3 (-0.4 - 0.9)
0.6 (-0.2 - 1.4)
CD4+ count (cells/μL)
Baseline
1201 (822 - 1556)
0.16
1033 (728 - 1406)
0.52
6 months
1039 (725 - 1358)
1043 (704 - 1484)
Change
-137 (-348 - 254)
35 (-278 - 352)
Wilcoxon Signed Ranks test was used to measure the difference between baseline and 6 months. Table 2 Biochemical and haematological measurements at baseline and at 6 months of supplementation by
intervention group al and haematological measurements at baseline and at 6 months of supplementation by Page 6 of 9 Page 6 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Factors associated with low vitamin B12 or folate
concentrations Low vitamin B12 could be related to folate deficiency
or to low vitamin B12 binding proteins. Although we did
not find an association between low vitamin B12 and
white blood cell count this does exclude the possibility
that low vitamin B12 concentrations could be related to
neutropenia. Vitamin B12 status was not closely associated with most
of the baseline characteristics (Table 3). However being
male, age less than 24 months and a haemoglobin < 11
g/dl were associated with low folate concentrations. At
multivariate analysis only age and the male sex
remained significantly associated with low serum folate
concentrations. We observed that there was an association between
low folate concentrations and low haemoglobin which
indicates that the anaemia could partly be attributed to
low folate concentrations. In both treatment groups the
haemoglobin improved compared to baseline levels. We
could not conclusively attribute the anaemia to low
folate concentrations since we did not measure red
blood cell folate concentrations. Measuring both serum
folate and Red cell folate would have yielded more diag-
nostic information of folate deficiency. However sub- Discussion This was contrary
to findings of a trial in HAART treated HIV infected
adults living in the USA where multiple micronutrient
supplementation was associated with improved CD4+
cell count compared to a placebo [27]. The lack of effect
on CD4+ cell count in our study could be explained by
the natural immunological deterioration or it may be
apparent due to the small numbers in the HAART
group. It is also possible that the supplementation was
not long enough to show an impact on CD4+ cell count
since one in five children still had low vitamin B12 and
folate concentrations at 6 months of follow up. there was a slight deterioration in the CD4+ cell counts
among the HAART naïve MMS group. This was contrary
to findings of a trial in HAART treated HIV infected
adults living in the USA where multiple micronutrient
supplementation was associated with improved CD4+
cell count compared to a placebo [27]. The lack of effect
on CD4+ cell count in our study could be explained by
the natural immunological deterioration or it may be
apparent due to the small numbers in the HAART
group. It is also possible that the supplementation was
not long enough to show an impact on CD4+ cell count
since one in five children still had low vitamin B12 and
folate concentrations at 6 months of follow up. normal serum folate is a useful indicator of folate status
that warrants reporting. In a landscape of multiple defi-
ciencies, such as HIV-infected children in a low-income
country, there is always the potential for other deficien-
cies to alter the response, for instance, iron deficiency
(the supplement did not contain iron). Folate deficiency
has been reported in almost one in two anaemic HIV
infected patients [25]. Other authors have reported asso-
ciations between anaemia, gender and folate deficiency
in children whose HIV infection status was not known
[26]. normal serum folate is a useful indicator of folate status
that warrants reporting. In a landscape of multiple defi-
ciencies, such as HIV-infected children in a low-income
country, there is always the potential for other deficien-
cies to alter the response, for instance, iron deficiency
(the supplement did not contain iron). Folate deficiency
has been reported in almost one in two anaemic HIV
infected patients [25]. Discussion This paper describes the vitamin B12 and folate concen-
trations of HIV-infected Ugandan children aged 1-5
years and the effect of 2RDA of 14 multiple micronutri-
ents that contained vitamin B12 and folate versus the
‘standard of care’ multivitamins in 1RDA without Page 7 of 9 Page 7 of 9 Ndeezi et al. Discussion Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Table 3 Factors associated with low vitamin B12 and folate among HIV infected children in Uganda
Baseline characteristics
Number N
Low vitamin B12 statusa n (%) Un adjusted OR (95% CI)
Adjusted OR (95%CI)
Vitamin B12 status
Age < 24 months
70
19 (27.1) 0.9 (0.6 - 1.5)
Age ≥24 months
144
41 (28.5)
Male
100
33 (33.0) 1.4 (0.9 - 2.1)
1.6 (0.8 - 3.1)
Female
114
27 (23.7)
Weight for height z score < -2
28
7 (25.0) 0.9 (0.4 - 1.7)
Weight for height z score ≥-2
182
52 (28.6)
Haemoglobin < 11 g/dl
127
37 (29.1) 1.1 (0.7 - 1.7)
Haemoglobin ≥11 g/dl
87
23 (26.4)
CD4+ < 25%
114
33 (28.9) 1.1 (0.6 - 2.1)
CD4+ ≥25%
85
23 (27.1)
On HAART
44
15 (34.1) 1.3 (0.8 - 2.1)
HAART naïve
170
45 (26.5)
Routine CTX prophylaxis
193
56 (29.0) 1.5 (0.6 - 3.8)
No routine CTX prophylaxis
21
4 (19.0)
Previous routine multivitamins
144
40 (27.8) 1.0 (0.6 - 1.5)
No routine multivitamins
70
20 (28.6)
Folate status
Low folate
Age < 24 months
70
27 (38.6) 1.6 (1.1 - 2.4)
2.2 (1.1 - 4.5)
Age ≥24 months
144
35 (24.3)
Male
100
36 (36.0) 1.6 (1.0 - 2.4)
2.1 (1.1 - 4.0)
Female
114
26 (22.8)
Weight for height z score < -2
28
7 (25.0) 0.8 (0.4 - 1.7)
Weight for height z score ≥-2
182
54 (29.7)
Haemoglobin < 11 g/dl
127
45 (35.4) 1.8 (1.1 - 2.9)
1.9 (0.9 - 4.6)
Haemoglobin ≥11 g/dl
87
17 (19.5)
CD4+ < 25%
114
36 (31.6) 1.2 (0.7 - 1.9)
CD4+ ≥25%
85
22 (25.9)
On HAART
44
10 (22.7) 0.7 (0.4 - 1.3)
HAART naïve
170
52 (30.6)
Routine CTX prophylaxis
193
58 (30.1) 1.6 (0.6 - 3.9)
No routine CTX prophylaxis
21
4 (19.0)
Previous routine multivitamins
144
44 (30.6) 1.2 (0.7 - 1.9)
No routine multivitamins
70
18 (25.7)
aLow vitamin B12 < 221 pmol/L, ated with low vitamin B12 and folate among HIV infected children in Uganda
Number N
Low vitamin B12 statusa n (%) Un adjusted OR (95% CI)
Adju there was a slight deterioration in the CD4+ cell counts
among the HAART naïve MMS group. References Allen LH, Rosado JL, Casterline JE, Martinez H, Lopez P, Munoz E, Black AK:
Vitamin B-12 deficiency and malabsorption are highly prevalent in rural
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133(11 Suppl 2):3972S-3980S. We were unable to measure serum homocysteine and
methyl malonic acid concentrations which are more reli-
able indicators of vitamin B12 deficiency because of the
limited amount of blood that we could draw from the
children as we had multiple micronutrients to test for. We also did not conduct absorption studies to examine
the impact of malabsorption on baseline micronutrient
and post-supplementation status. This paper does not
describe the dietary habits of the study children and
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ciations between anaemia, gender and folate deficiency
in children whose HIV infection status was not known
[26]. Neither MMS nor the ‘standard of care’ MV improved
the immunological status of the study children. In fact Page 8 of 9 Page 8 of 9 Page 8 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 University of Bergen, and Laboratory of Clinical Biochemistry, Haukeland
University Hospital, Bergen, Norway. University of Bergen, and Laboratory of Clinical Biochemistry, Haukeland
University Hospital, Bergen, Norway. In our setting it is possible that low concentrations of
vitamin B12 and folate may be related to consumption
of marginal or low levels of vitamin B12 and folate since
twice the recommended dietary intakes increased serum
concentrations as opposed to the multivitamin supple-
ment which did not contain vitamin B12 or folate. Some
authors have shown that Vitamin B12 deficiency is rare
in HIV infected persons consuming vitamin B12 well
above the recommended nutrient intakes [28]. In
Uganda one third of children aged between 6 and 24
months are likely to be getting diary products in their
diet and very few are likely to be getting other animal
source foods [29]. Competing interests The authors declare that they have no competing interests. Received: 19 January 2011 Accepted: 21 May 2011
Published: 21 May 2011 We are not certain whether our findings are similar to
children in the general population since we had no con-
trol group of HIV uninfected children. A study of both
HIV-infected and exposed uninfected children in Brazil
showed no differences in micronutrient status [30]. However another study indicated that HIV infected chil-
dren had significantly lower folate levels than the refer-
ence children while vitamin B12 was similar [31]. Authors’ contributions GN participated in the conception, design and implementation of the study,
statistical analysis, interpretation and writing of the manuscript. JKT
participated in the conception, design and implementation of the study,
statistical analysis, interpretation and drafting of the manuscript. CMN
participated in the design and implementation of the study. BJB participated
in the design, supervised the laboratory work and drafting of the
manuscript. TT participated in the conception, design and implementation
of the study, statistical analysis, interpretation and drafting of the manuscript. All the authors read and approved the final manuscript. Acknowledgements and funding
We thank the children and their mot Acknowledgements and funding
We thank the children and their mothers/caretakers without whose
participation the study would have been impossible to carry out. We are
very grateful to all the participating hospitals and HIV care institutions, the
paediatricians and other study personnel for making this study a success. The study was carried out as part of the ‘Essential Child Health and Nutrition
Project in Uganda’, a collaboration between the Department of Paediatrics
and Child Health, School of Medicine, Makerere University College of Health
Sciences and the Centre for International Health, University of Bergen. The
Norwegian Council for Higher Education’s Programme for Development
Research and Education (NUFU) funded the study. 13.
Varma JL, Das S, Sankar R, Mannar MG, Levinson FJ, Hamer DH:
Community-level micronutrient fortification of a food supplement in
India: a controlled trial in preschool children aged 36-66 mo. Am J Clin
Nutr 2007, 85(4):1127-1133. 14.
Chatterjee A, Bosch RJ, Hunter DJ, Manji K, Msamanga GI, Fawzi WW:
Vitamin A and vitamin B-12 concentrations in relation to mortality and
morbidity among children born to HIV-infected women. J Trop Pediatr
2010, 56(1):27-35. Author details
1Department of Paediatrics and Child Health, School of Medicine, College of
Health Sciences, Makerere University, Kampala, Uganda. 2Centre for
International Health, University of Bergen, Norway. 3Institute of Medicine, Conclusion Low vitamin B12 and folate concentrations are common
in Ugandan HIV infected children aged 1-5 years. Twice
the recommended dietary allowance of 14 multiple
micronutrients as opposed to the 6 multivitamin ‘stan-
dard of care’ supplement improved the vitamin B12 and
folate status of HIV-infected children in Uganda. 15.
Ndeezi G, Tumwine JK, Bolann BJ, Ndugwa CM, Tylleskar T: Zinc status in
HIV infected Ugandan children aged 1-5 years: a cross sectional baseline
survey. BMC Pediatr 2010, 10(1):68. Acknowledgements and funding
We thank the children and their mothers/caretakers without whose
participation the study would have been impossible to carry out. We are
very grateful to all the participating hospitals and HIV care institutions, the
paediatricians and other study personnel for making this study a success.
The study was carried out as part of the ‘Essential Child Health and Nutrition
Project in Uganda’, a collaboration between the Department of Paediatrics
and Child Health, School of Medicine, Makerere University College of Health
Sciences and the Centre for International Health, University of Bergen. The
Norwegian Council for Higher Education’s Programme for Development
Research and Education (NUFU) funded the study. Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 9.
Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA,
Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH: Micronutrients and
HIV-1 disease progression. AIDS 1995, 9(9):1051-1056.
10.
Baylin A, Villamor E, Rifai N, Msamanga G, Fawzi WW: Effect of vitamin
supplementation to HIV-infected pregnant women on the micronutrient
status of their infants. Eur J Clin Nutr 2005, 59(8):960-968.
11.
Ash DM, Tatala SR, Frongillo EA Jr, Ndossi GD, Latham MC: Randomized
efficacy trial of a micronutrient-fortified beverage in primary school
children in Tanzania. Am J Clin Nutr 2003, 77(4):891-898.
12.
Osei AK, Rosenberg IH, Houser RF, Bulusu S, Mathews M, Hamer DH:
Community-level micronutrient fortification of school lunch meals
improved vitamin A, folate, and iron status of schoolchildren in
Himalayan villages of India. J Nutr 140(6):1146-1154.
13.
Varma JL, Das S, Sankar R, Mannar MG, Levinson FJ, Hamer DH:
Community-level micronutrient fortification of a food supplement in
India: a controlled trial in preschool children aged 36-66 mo. Am J Clin
Nutr 2007, 85(4):1127-1133.
14.
Chatterjee A, Bosch RJ, Hunter DJ, Manji K, Msamanga GI, Fawzi WW:
Vitamin A and vitamin B-12 concentrations in relation to mortality and
morbidity among children born to HIV-infected women. J Trop Pediatr
2010, 56(1):27-35.
15.
Ndeezi G, Tumwine JK, Bolann BJ, Ndugwa CM, Tylleskar T: Zinc status in
HIV infected Ugandan children aged 1-5 years: a cross sectional baseline
survey. BMC Pediatr 2010, 10(1):68. doi:10.1186/1475-2891-10-56
Cite this article as: Ndeezi et al.: Multiple micronutrient
supplementation improves vitamin B12 and folate concentrations of HIV
infected children in Uganda: a randomized controlled trial. Nutrition
Journal 2011 10:56. Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 16. Carmel R, Green R, Rosenblatt DS, Watkins D: Update on cobalamin, folate,
and homocysteine. Hematology Am Soc Hematol Educ Program 2003,
62-81. 17. Rogers LM, Boy E, Miller JW, Green R, Sabel JC, Allen LH: High prevalence
of cobalamin deficiency in Guatemalan schoolchildren: associations with
low plasma holotranscobalamin II and elevated serum methylmalonic
acid and plasma homocysteine concentrations. Am J Clin Nutr 2003,
77(2):433-440. 18. Harriman GR, Smith PD, Horne MK, Fox CH, Koenig S, Lack EE, Lane HC,
Fauci AS: Vitamin B12 malabsorption in patients with acquired
immunodeficiency syndrome. Arch Intern Med 1989, 149(9):2039-2041. 19. Rule SA, Hooker M, Costello C, Luck W, Hoffbrand AV: Serum vitamin B12
and transcobalamin levels in early HIV disease. Am J Hematol 1994,
47(3):167-171. 20. Remacha AF, Cadafalch J: Cobalamin deficiency in patients infected with
the human immunodeficiency virus. Semin Hematol 1999, 36(1):75-87. 21. Tang AM, Graham NM, Chandra RK, Saah AJ: Low serum vitamin B-12
concentrations are associated with faster human immunodeficiency
virus type 1 (HIV-1) disease progression. J Nutr 1997, 127(2):345-351. 21. Tang AM, Graham NM, Chandra RK, Saah AJ: Low serum vitamin B-12
concentrations are associated with faster human immunodeficiency
virus type 1 (HIV-1) disease progression. J Nutr 1997, 127(2):345-351. 22. Hepburn MJ, Dyal K, Runser LA, Barfield RL, Hepburn LM, Fraser SL: Low
serum vitamin B12 levels in an outpatient HIV-infected population. Int J
STD AIDS 2004, 15(2):127-133. 22. Hepburn MJ, Dyal K, Runser LA, Barfield RL, Hepburn LM, Fraser SL: Low
serum vitamin B12 levels in an outpatient HIV-infected population. Int J
STD AIDS 2004, 15(2):127-133. 23. Eley BS, Sive AA, Abelse L, Kossew G, Cooper M, Hussey GD: Growth and
micronutrient disturbances in stable, HIV-infected children in Cape
Town. Ann Trop Paediatr 2002, 22(1):19-23. 23. Eley BS, Sive AA, Abelse L, Kossew G, Cooper M, Hussey GD: Growth and
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Cite this article as: Ndeezi et al.: Multiple micronutrient
supplementation improves vitamin B12 and folate concentrations of HIV
infected children in Uganda: a randomized controlled trial. Nutrition
Journal 2011 10:56. Author details
1D
t
t
f Author details
1Department of Paediatrics and Child Health, School of Medicine, College of
Health Sciences, Makerere University, Kampala, Uganda. 2Centre for
International Health, University of Bergen, Norway. 3Institute of Medicine, 15. Ndeezi G, Tumwine JK, Bolann BJ, Ndugwa CM, Tylleskar T: Zinc status in
HIV infected Ugandan children aged 1-5 years: a cross sectional baseline
survey. BMC Pediatr 2010, 10(1):68. Page 9 of 9 Page 9 of 9 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Ndeezi et al. Nutrition Journal 2011, 10:56
http://www.nutritionj.com/content/10/1/56 Submit your next manuscript to BioMed Central
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English
| null |
Retrospective comparison study of warfarinised trauma patients and an age-matched control group of nonwarfarinised patients
|
Critical care
| 2,012
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cc-by
| 261,109
|
P1
Impaired innate and adaptive immunity of accelerated-aged Klotho
mice in sepsis p
Methods We tested for genetic association of IL-17A SNPs with
susceptibility to infection and clinical outcome of severe sepsis using
two cohorts of European ancestry (St Paul’s Hospital (SPH) derivation
cohort, n = 679; Vasopressin and Septic Shock Trial (VASST) validation
cohort n = 517). The primary outcome variable was susceptibility to
Gram-positive bacterial infection. The secondary outcome variable was
28-day mortality. p
S Inoue, K Suzuki-Utsunomiya, K Suzuki-Utsunomiya, T Sato, T Chiba,
K Hozumi
Tokai University, Kanagawa, Japan
Critical Care 2012, 16(Suppl 1):P1 (doi: 10.1186/cc10608) Introduction Sepsis is primarily a disease of the aged and 60% of
sepsis occurs in patients older than 65 years, 80% of deaths due to
sepsis occur in this age group. Klotho knockout mice (Klotho mice)
develop a syndrome resembling human aging, and exhibit shortened
life spans (8 weeks); however, details regarding the immunity of and
immunological changes in Klotho mice after sepsis are still unclear. The
purpose of the study is to elucidate the immunological changes that
occur in Klotho mice after sepsis in order to identify therapeutic targets
for sepsis that occurs in aged individuals. y
y
Results Of four tested tag SNPs (rs4711998, rs8193036, rs2275913,
rs1974226) in the IL-17A gene, rs1974226 SNP was associated with
altered susceptibility to Gram-positive bacterial infection in the
derivation cohort (corrected P = 0.014). Patients who have the GG
genotype of the rs1974226 SNP were more susceptible to Gram-
positive bacterial infection, compared to the AG/AA genotype in the
two cohorts of severe sepsis (SPH, P = 0.0036; VASST, P = 0.011) and
in the subgroup having lung infection (P = 0.017). Furthermore, the G
allele of the IL-17A rs1974226 SNP was associated with increased 28-
day mortality in two cohorts (SPH, adjusted OR 1.44, 95% CI 1.04 to
2.02, P = 0.029; VASST, adjusted OR 1.67, 95% CI 1.17 to 2.40, P = 0.0052). Conclusion IL-17A genetic variation is associated with altered suscepti-
bility to Gram-positive infection and 28-day mortality of severe sepsis. References p
g
Methods (1) Survival study: cecum ligation puncture (CLP) was
performed to Klotho and wild-type (WT) mice and 4-day survivals were
compared. (2) Cell analysis study: mice were sacrifi ced at 8 hours post
CLP or sham surgery. Spleens, thymus, and serum were harvested for
FACS analysis using caspase 3 as a marker for apoptosis, and blood for
serum cytokine assay. MEETING ABSTRACTS MEETING ABSTRACTS P1
Impaired innate and adaptive immunity of accelerated-aged Klotho
mice in sepsis
S Inoue, K Suzuki-Utsunomiya, K Suzuki-Utsunomiya, T Sato, T Chiba,
K Hozumi
Tokai University, Kanagawa, Japan
Critical Care 2012, 16(Suppl 1):P1 (doi: 10.1186/cc10608) P1
Impaired innate and adaptive immunity of accelerated-aged Klotho
mice in sepsis
S Inoue, K Suzuki-Utsunomiya, K Suzuki-Utsunomiya, T Sato, T Chiba,
K Hozumi
Tokai University, Kanagawa, Japan
Critical Care 2012, 16(Suppl 1):P1 (doi: 10.1186/cc10608) P3 Prevalence of TLR4 single nucleotide polymorphisms (ASP299GLY,
THR399ILE) in healthy subjects and septic patients, and association
with outcome
T Mohovic1, R Salomao2, E Nogueira2
1Albert Einstein Hospital, São Paulo, Brazil; 2UNIFESP, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P3 (doi: 10.1186/cc10610) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 32nd International Symposium on Intensive Care
and Emergency Medicine Brussels, Belgium, 20-23 March 2012 Published: 20 March 2012 to the host defense. Whether genetic variation of IL-17A is associated
with altered clinical outcome of severe sepsis is unknown. P1
Impaired innate and adaptive immunity of accelerated-aged Klotho
mice in sepsis
S Inoue, K Suzuki-Utsunomiya, K Suzuki-Utsunomiya, T Sato, T Chiba,
K Hozumi
Tokai University, Kanagawa, Japan
Critical Care 2012, 16(Suppl 1):P1 (doi: 10.1186/cc10608) bility to Gram
References 1. Puel A, et al.: Chronic mucocutaneous candidiasis in humans with inborn
errors of interleukin-17 immunity. Science 2011, 332:65-68. Results (1) Klotho septic mice started to die from 8 to 12 hours after
CLP, and fi nal survival of Klotho mice with CLP was signifi cantly
lower than that of WT with CLP (0% vs. 100%, P <0.01). (2) Increased
bacterial count in peritoneal cavity and decreased recruitment of
neutrophils and macrophages to the peripheral cavity were observed
in Klotho-CLP mice. Serum concentration of IL-6, TNF, and IL-10 were
signifi cantly higher in Klotho-CLP mice than those in the WT-CLP mice. A dramatically increased caspase 3 positive proportion in Klotho-CLP
mice was observed in both fl ow cytometric and immunohistological
analysis (P <0.01). 2. Cho JS, et al.: IL-17 is essential for host defense against cutaneous
Staphylococcus aureus infection in mice. J Clin Invest 2010, 120:1762-1773. 2. Cho JS, et al.: IL-17 is essential for host defense against cutaneous
Staphylococcus aureus infection in mice. J Clin Invest 2010, 120:1762-1773. P1
Impaired innate and adaptive immunity of accelerated-aged Klotho
mice in sepsis Bacterial colony count in peritoneal lavage was
also analyzed. Prevalence of TLR4 single nucleotide polymorphisms (ASP299GLY,
THR399ILE) in healthy subjects and septic patients, and association
with outcome T Mohovic1, R Salomao2, E Nogueira2
1Albert Einstein Hospital, São Paulo, Brazil; 2UNIFESP, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P3 (doi: 10.1186/cc10610) T Mohovic1, R Salomao2, E Nogueira2 Conclusion Poor survival in Klotho-septic mice may be associated
with impaired bacterial clearance with decreased recruitment of
neutrophils/macrophages in peritoneal cavity, elevated cytokines in
serum, and increased apoptosis in thymus and spleen, following to
impaired innate and adaptive immunity. Introduction Our study aimed to determine the prevalence of
functional SNPs (Asp299Gly, Thr399Ile) of TLR4 receptors, in healthy
volunteers and septic patients in a Brazilian population and to correlate
the presence of these polymorphisms in septic patients with clinical
outcome.i P2 P2
IL-17A rs1974226 GG genotype is associated with increased
susceptibility to Gram-positive infection and mortality of severe
sepsis
T Nakada, J Russell, J Boyd, K Walley
University of British Columbia, Vancouver, Canada
Critical Care 2012, 16(Suppl 1):P2 (doi: 10.1186/cc10609) Methods We verifi ed the presence of polymorphisms ASP299GLY,
THR399 ILE by PCR-restriction fragment length polymorphism followed
by digestion with enzymes NcoI for SNP 299 and HinfI for SNP399
followed by electrophoresis for identifi cation of alleles.if yi
Results We observed a statistically signifi cant diff erence between the
genotypes of the Thr399Ile polymorphism and respiratory dysfunction,
indicating a higher frequency than wild-type genotype in subjects with
respiratory dysfunction than those without this condition (P = 0.001). We also observed a statistically signifi cant diff erence between genotype
groups formed by the Asp299Gly and Thr399Ile polymorphisms and
respiratory dysfunction more often featuring group 299Selv/399Selv
grupo299Het/399Het and less frequently in individuals with respiratory
dysfunction than those without this condition (P = 0.003). Critical Care 2012, 16(Suppl 1):P2 (doi: 10.1186/cc10609) Introduction IL-17A plays a key role in host defense against microbial
infection including Gram-positive bacteria. Genetic factors contribute © 2010 BioMed Central Ltd
© 2012 BioMed Central Ltd © 2010 BioMed Central Ltd
© 2012 BioMed Central Ltd S2 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion Our study shows for the fi rst time an assessment of the
prevalence of polymorphisms of TLR4 Asp299Gly and Thr399Ile con-
sidering its cosegregation in healthy individuals and septic patients. References 1. O’Dwyer et al.: The occurrence of severe sepsis and septic shock are related
to distinct patterns of cytokine gene expression. Shock 2006, 26:544-550. Methods We used diff erent wild-type mice strains (BALB/c,
C57BL/6,129SV), and KO mice lacking diff erent leukocytes subset
rag2–/–, rag2gc–/–, cd3e–/–, μ–/–, il-15–/– and Ja18–/–. We used an ex vivo
model consisting of intravenous injection of LPS 20 hours prior to an in
vitro stimulation of AM, peritoneal macrophages and monocytes with
LPS. We pretreated the wild-type mice with anti-cytokines antibodies,
and KO mice with B cells and NK cells adoptive transfer.i 1. O’Dwyer et al.: The occurrence of severe sepsis and septic shock are related
to distinct patterns of cytokine gene expression. Shock 2006, 26:544-550. 2. O’Dwyer et al.: The human response to infection is associated with distinct
patterns of interleukin 23 and interleukin 27 expression. Intensive Care Med
2008, 34:683-691. 2. O’Dwyer et al.: The human response to infection is associated with distinct
patterns of interleukin 23 and interleukin 27 expression. Intensive Care Med
2008, 34:683-691. Results We confi rmed the absence of AM tolerance to endotoxin in all
the strain of wild-type mice. Inhibiting either GM-CSF or INFγ in vivo
at homeostasis led to a decrease in TNF production by AM during
the in vitro stimulation by LPS, suggesting the involvement of these
cytokines in the prevention of tolerance within the lungs. The fact that
AM from rag2–/–, rag2gc–/–, μ–/– could be tolerated, the fact that adoptive
transfer of B lymphocytes in these defi cient mice restores the wild-type
response, and the presence of INFγ mRNA in the lungs at homeostasis
in wild-type mice and before and after adoptive B-lymphocyte transfer Prevalence of TLR4 single nucleotide polymorphisms (ASP299GLY,
THR399ILE) in healthy subjects and septic patients, and association
with outcome And that septic patients who develop respiratory dysfunction have
more presence and genotypes 399Selv 299Selv/399Selv and less the
presence of genotype 299Het/399Het, featuring a protective eff ect of
the polymorphism Thr399Ile. changes in aged sepsis is still unclear. The purpose of this study was to
clarify the immunological changes in sepsis of aged patients. Conclusion Our study shows for the fi rst time an assessment of the
prevalence of polymorphisms of TLR4 Asp299Gly and Thr399Ile con-
sidering its cosegregation in healthy individuals and septic patients. Methods Forty-four septic patients and 48 gender-matched healthy
volunteers were prospectively enrolled in the study, which included
the following investigations: (1) The SOFA score and clinical outcome
were compared between adult sepsis (<65 years of age) and older adult
sepsis (≥65 years of age). (2) Blood samples were collected from septic
and control volunteers. Separated peripheral blood mononuclear cells
were stained with CD4, CD8, programmed death-1 (PD-1), CD28, and
CD62L antibodies and analyzed by fl ow cytometry, and serum was used
to measure cytokine concentrations by using multiplex bead assay. Values were compared among four groups: normal adult (<65 years of
age), normal older adult (≥65 years of age), adult sepsis (<65 years of
age), and older adult sepsis (≥65 years of age) groups. g
g
g
y
p
p
And that septic patients who develop respiratory dysfunction have
more presence and genotypes 399Selv 299Selv/399Selv and less the
presence of genotype 299Het/399Het, featuring a protective eff ect of
the polymorphism Thr399Ile. p y
p
References 1. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA: A novel
polymorphism in the toll-like receptor 2 gene and its potential association
with staphylococcal infection. Infect Immun 2000, 68:6398-6401. 1. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA: A novel
polymorphism in the toll-like receptor 2 gene and its potential association
with staphylococcal infection. Infect Immun 2000, 68:6398-6401. p y
2. Janeway CA, Jr, Medzhitov R: Introduction: the role of innate immunity in
the adaptive immune response. Semin Immunol 1998, 10:349-350. 2. Janeway CA, Jr, Medzhitov R: Introduction: the role of innate immunity in
the adaptive immune response. Semin Immunol 1998, 10:349-350. g
y
g
g
Results (1) No diff erences in SOFA scores were observed between
adult sepsis (n = 19, 39 years) and older adult sepsis (n = 25, 78 years),
but 3-month survival in older adult sepsis was signifi cantly decreased
compared with that in adult sepsis (36% vs. 4%, P <0.05). (2) Population
of CD8+ T cells in normal older adults was signifi cantly less than that
in normal adults (1.5×105 vs. 5.7×104/ml, P <0.01), and percentage
of PD-1+CD8+ T cells in the older adult sepsis group was signifi cantly
greater than that in the normal older adult group (40% vs. 29%,
P <0.01). Population of CD4+, CD62L+CD4+, and CD28+CD4+ T cells in the
older adult sepsis group was signifi cantly less than that in the normal
older adult group (n = 26, 80 years) (1.8×105 vs. 5.9 ×104/ml, 1.6×105 vs. 5.4×104/ml, and 1.6×105 vs. 4.4×104/ml, respectively; P <0.01); however,
these values did not diff er between the adult sepsis and normal adult
(n = 22, 39 years) groups. Serum IL-12 level in older adult sepsis was
increased when compared with that in the other three groups (P <0.01). Conclusion Poor prognosis in older adult sepsis may be related to both
preexisting decrease of CD8+ T cells with aging and loss of CD4+ T cells
with sepsis. Modelling immune responses in sepsis R Grealy1, M White2, M O’Dwyer2, P Stordeur3, DG Doherty1, R McManus1,
T Ryan2 R Grealy1, M White2, M O’Dwyer2, P Stordeur3, DG Doherty1, R McManus1,
T Ryan2 R Grealy1, M White2, M O’Dwyer2, P Stordeur3, DG Doherty1, R McManus1,
T Ryan2 y
1Trinity College Dublin, Ireland; 2St James’s Hospital, Dublin, Ireland; 3Hopital
d’Erasme, Bruxelles, Belgium y
1Trinity College Dublin, Ireland; 2St James’s Hospital, Dublin, Ireland; 3Hopital
d’Erasme, Bruxelles, Belgium Critical Care 2012, 16(Suppl 1):P4 (doi: 10.1186/cc10611) Critical Care 2012, 16(Suppl 1):P4 (doi: 10.1186/cc10611) Introduction The onset and evolution of the sepsis syndrome in
humans is modulated by an underlying immune suppressive state [1,2]. Signalling between immune eff ector cells plays an important part in
this response. The objective of this study was to investigate peripheral
blood cytokine gene expression patterns and serum protein analysis
in an attempt to model immune responses in patients with sepsis of
varying severity. We hypothesised that such immunologic profi ling
could be of use in modelling and prediction of outcomes in sepsis in
addition to the evaluation of future novel sepsis therapies. Methods A prospective observational study in a mixed medical/
surgical ICU and general wards of a large academic teaching hospital
was undertaken. Eighty ICU patients with a diagnosis of severe sepsis,
50 patients with mild sepsis (bacteraemia not requiring ICU admission)
and 20 healthy controls were recruited. Gene expression analysis by
qPCR for INFγ, TNFα, IL-2, IL-7, IL-10, IL-23, IL-27 on peripheral blood
mononuclear cells (PBMCs) and serum protein analysis for IL-6 was
performed. Multivariate analysis was used to construct a model of gene
expression based on cytokine copy numbers alone and in combination
with serum IL-6 levels. Homeostatic pulmonary microenvironment is responsible for
alveolar macrophages resistance to endotoxin tolerance
F Philippart1, C Fitting2, B Misset1, J Cavaillon2
1Groupe Hospitalier Paris Saint Joseph, Paris, France; 2Institut Pasteur de Paris,
Paris, France
Critical Care 2012, 16(Suppl 1):P6 (doi: 10.1186/cc10613) Homeostatic pulmonary microenvironment is responsible for
alveolar macrophages resistance to endotoxin tolerance
F Philippart1, C Fitting2, B Misset1, J Cavaillon2 Homeostatic pulmonary microenvironment is responsible for
alveolar macrophages resistance to endotoxin tolerance
F Philippart1, C Fitting2, B Misset1, J Cavaillon2 pp
g
1Groupe Hospitalier Paris Saint Joseph, Paris, France; 2Institut Pasteur de Paris,
Paris, France
Critical Care 2012, 16(Suppl 1):P6 (doi: 10 1186/cc10613) Critical Care 2012, 16(Suppl 1):P6 (doi: 10.1186/cc10613 Introduction Endotoxin tolerance (ET) is a modifi cation of immune
response to a second challenge with lipopolysaccharide (LPS), which
results in a decreased production of proinfl ammatory cytokines, and
is considered partly responsible for the susceptibility to infectious
processes in hospitalized patients [1]. We previously observed an
absence of ET of alveolar macrophages (AM) to LPS in an ex vivo
murine model of endotoxin tolerance [2]. We hypothesized that this
singularity could be mediated by granulocyte–macrophage colony-
stimulating factor (GM-CSF) (known to be predominantly produced
by type II pneumocytes) and interferon-gamma (INFγ), two cytokines
known to prevent the occurrence of ET [3]. The objectives were to
confi rm the absence of tolerance of AM to LPS and to assess the
respective roles of GM-CSF and INFγ in this phenomenon and the
cellular origin of INFγ.f Results Sepsis was characterised by decreased IL-2, IL-7, IL-23, INFγ
and greater TNFα, IL-10 and IL-27 gene expression levels compared
to controls. Severe sepsis diff ered from mild sepsis by a decreased
INFγ and increased IL-10 gene expression (P <0.0001). A composite
cytokine gene expression score diff erentiated controls from mild sepsis
and mild sepsis from severe sepsis (P <0.0001). A model combining
these cytokine gene expression levels and serum IL-6 protein levels
distinguished sepsis from severe sepsis with an ROC value of 0.89. Conclusion Accurate modelling of patient response to infection is
possible using peripheral blood mononuclear cell gene expression
and serum protein analysis. Molecular biological techniques provide
a robust method of such profi ling. This approach may be used to
evaluate novel sepsis therapies. References P7
In vivo natural killer and natural killer T-cell depletion aff ects
mortality in a murine pneumococcal pneumonia sepsis model
E Ch i t ki1 E Di
1 SM O
l2 A Pi tiki3 DI D
iti3 DP C
3 p
gg
M Georgitsi3, N Malisiovas1, P Nikolaidis1, EJ Giamarellos-Bourboulis3
1Aristotle University of Thessaloniki, Greece; 2Memorial Hospital of RI, Alpert
School of Medicine of Brown University, Providence, RI, USA; 3University of
Athens, Medical School, Athens, Greece Figure 2 (abstract P7). Kaplan–Meier survival curve of groups B and C. Critical Care 2012, 16(Suppl 1):P7 (doi: 10.1186/cc10614) Critical Care 2012, 16(Suppl 1):P7 (doi: 10.1186/cc10614) Conclusion Our study has shown that NK cells appear to contribute
to mortality in pneumococcal pneumonia. More research is needed to
explore their role in host response to bacterial infection and sepsis. Introduction Apart from macrophages and neutrophils, natural killer
(NK) and natural killer T (NKT) cells have been found to play a role in
the early stages of bacterial infection. In this study, we investigated
the role of NK and NKT cells in host defense against Streptococcus
pneumoniae, using a murine pneumococcal pneumonia sepsis model. Our hypothesis was that NK and NKT cells play an immune-regulatory
role during sepsis and thus in vivo depletion of those cell populations
may aff ect mortality. P8
Mobilization of hematopoietic and nonhematopoietic stem cell
subpopulations in sepsis: a preliminary report. T Skirecki1, U Zielińska-Borkowska1, M Złotorowicz1, M Złotorowicz1,
J Kawiak2, G Hoser1
1Medical Center of Postgraduate Education, Warsaw, Poland; 2Polish Academy
of Science, Warsaw, Poland
Critical Care 2012, 16(Suppl 1):P8 (doi: 10.1186/cc10615) f
Methods We used four groups of C57BL/6 mice (A, B, C and D, n = 10
mice/group). Animals were infected intratracheally with 50 μl of
S. pneumoniae suspension (106 cfu). Twenty-four hours prior to bacterial
inoculation, Group A received 50 μl of anti-asialoGM1 rabbit polyclonal
antibody (Wako Chemicals GmbH, Neuss, Germany) intravenously (i.v.)
to achieve in vivo NK cell inactivation; in Group B, NKT cell depletion
was performed by targeting the CD1d receptor using 2 mg/kg of the
monoclonal antibody anti-CD1d, clone 1B1 (BD Pharmingen, San
Diego, CA, USA) i.v.; Group C (control) received an equivalent amount
of isotype antibody control (nonspecifi c Ig). Group D received sham
intratracheal installation of normal saline. Animals were observed daily
for 7 days and deaths were recorded. The survival analysis was plotted
using the Kaplan–Meier method and diff erences in survival between
groups were compared with the log-rank test. Introduction Sepsis and septic shock lead to the multiorgan damage
by extensive release of infl ammatory mediators. Regenerative
mechanisms include such regimens as stem cells which diff erentiate
towards specifi c tissues. Ratajczak MZ, et al.: Leukemia 2010, 24:1667-1675. 5
Decreased peripheral CD4+/CD8+ lymphocytes and poor prognosis
in aged sepsis g
p
S Inoue, K Utsunomiya-Suzuki, S Morita, T Yamagiwa, S Inokuchi
Tokai University, Kanagawa, Japan g
S Inoue, K Utsunomiya-Suzuki, S Morita, T Yamagiwa, S Inokuchi
Tokai University, Kanagawa, Japan y
g
p
Critical Care 2012, 16(Suppl 1):P5 (doi: 10.1186/cc10612) Introduction Aging is a signifi cant factor and is associated with a
poor prognosis in sepsis; however, the mechanism of immunological Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S3 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Figure 2 (abstract P7). Kaplan–Meier survival curve of groups B and C. in KO mice demonstrated the involvement of these cells in the wild-
type phenotype.i Conclusion We confi rm the resistance of AM to endotoxin tolerance. Both GM-CSF and INFγ within the lung microenvironment at
homeostasis are involved in this phenomenon. B lymphocytes play a
key role in the local expression of INFγ. f g
3. Adib-Conquy M, et al.: J Biol Chem 2002, 277:27927-27934. g
3. Adib-Conquy M, et al.: J Biol Chem 2002, 277:27927-27934. g
3. Adib-Conquy M, et al.: J Biol Chem 2002, 277:27927-27934. P7
In vivo natural killer and natural killer T-cell depletion aff ects
mortality in a murine pneumococcal pneumonia sepsis model
E Ch i t ki1 E Di
1 SM O
l2 A Pi tiki3 DI D
iti3 DP C
3 Also, in the course of the systemic infl ammation
the disruption of various regulatory axes occurs, including chemokines
(VEGF, HGF) and complement proteins (C5a,C3a). Among other
functions these axes maintain stem cell circulation and recruitment
[1]. The aim of the study was to evaluate circulating stem cells in the
peripheral blood of septic patients.i Results We found that in vivo NK cell depletion improved survival after
pneumococcal pneumonia and sepsis in the group of mice that received
the anti-asialoGM1 antibody when compared with animals that
received nonspecifi c IgG antibody (P = 0.041) (Figure 1). Nevertheless,
when NKT cell depletion was attempted, survival worsened compared
to the control group; however, that diff erence did not reach statistical
signifi cance (P = 0.08) (Figure 2). Methods Blood samples were obtained from fi ve patients with sepsis
or septic shock on the second day after diagnosis. Blood from fi ve
healthy volunteers served as control. Samples were stained with the
panel of antibodies against: CD45, lineage markers (Lin), CD34, CD133,
VEGFR2 and isotypic controls. Cells were analyzed by fl ow cytometry
and the total cell count per milliliter was calculated. Results On the basis of cell surface phenotype the following stem
cell subpopulations were distinguished: hematopoietic stem cells
(HSCs) CD34+CD133+CD45+Lin–, endothelial progenitor cells (EPCs)
CD34+CD133+VEGFR2+; and primitive nonhematopoietic stem cells. In the blood of septic patients we found: HSCs (5/5), median level
96/ml; EPCs (5/5), median 48/ml; and nonhematopoietic stem cells
(4/5), median 48/ml. Whereas in the control group the results were as
follow: HSCs (5/5), median level 644/ml; EPCs (5/5), median 70/ml; and
nonhematopoietic stem cells (0/5). Two of fi ve patients died of septic
shock. A trend to lower number of HSCs in nonsurvivors was observed. Conclusion Stem cells can be identifi ed phenotypically in the blood
of septic patients and healthy volunteers. However, the circulating
primitive nonhematopoietic stem cells could not be detected under
physiological conditions. Furthermore, we suggest that stem cells
analysis may have serve as prognostic tool in the future. Figure 1 (abstract P7). Kaplan–Meier survival curve of groups A and C. Acknowledgements Supported by EU Structural Funds, ‘Innovative
Methods of Stem Cells Applications in Medicine’, Innovative Economy
Operational Programme, POIG 01.02-00-109/09. Reference Figure 1 (abstract P7). Kaplan–Meier survival curve of groups A and C. Ratajczak MZ, et al.: Leukemia 2010, 24:1667-1675. P7
In vivo natural killer and natural killer T-cell depletion aff ects
mortality in a murine pneumococcal pneumonia sepsis model
E Ch i t ki1 E Di
1 SM O
l2 A Pi tiki3 DI D
iti3 DP C
3 S4 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results Mean respective apoptosis of groups 0, A, B, C, D and E at
24 hours were 37.9%, 77.6%, 81.9%, 73.8%, 83.6% and 75.4%; and at
48 hours 78.5%, 79.4%, 77.7%, 78.2%, 81% and 84.9% (P <0.05 group 0
vs. others). Mean respective MFI of TREM-1 of groups 0, A, B, C, D and E
at 24 hours were 2.4, 4.4, 3.4, 3, 3.2 and 3; and at 48 hours 2.7, 2.8, 2.8,
2.6, 2.8 and 2.7 (P <0.05 group 0 vs. others). Tissue cultures were sterile. Release of IL-17 was greater by splenocytes of group D (Figure 1). Conclusion Increased neutrophil apoptosis and TREM-1 expression
and modulated IL-17 responses are found within burn injury. Figure 1 (abstract P10). Release of IL-17 by mice splenocytes in relation
to the type of thermal injury. P9
Blunted IL-17 responses early after advent of multiple injuries
M Paraschos1, M Patrani1, A Pistiki2, J Van der Meer3, M Netea3,
E Giamarellos-Bourboulis2, K Mandragos1
1Korgialeneion Benakeion Hospital, Athens, Greece; 2University of Athens,
Medical School, Athens, Greece; 3UMC St Radboud, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P9 (doi: 10.1186/cc10616) Figure 1 (abstract P10). Release of IL-17 by mice splenocytes in relation
to the type of thermal injury. Introduction To defi ne the impact of multiple injuries without the
presence of sepsis in IL-17 responses. Methods A total of 32 patients and 17 healthy volunteers were
enrolled. All patients were bearing: multiple injuries necessitating ICU
admission with an injury severity score more than 16; and systemic
infl ammatory response syndrome. Patients with infections upon ICU
admission were excluded from the study. Heparinized venous blood
was sampled within the fi rst 24 hours after ICU admission. Peripheral
blood mononuclear cells (PBMCs) were isolated after gradient
centrifugation of whole blood over Ficoll. They were incubated for
5 days in RPMI 1640 supplemented with 2 mM glutamine and 10% FBS
in the presence of 10 ng/ml lipopolysaccharide (LPS) of Escherichia coli
O55:B5; of 5 μg/ml phytohemmaglutin (PHA); of 5×105 cfu/ml of heat-
killed Candida albicans (HKCA), of Pseudomonas aeruginosa (HKPA) or of
Staphylococcus aureus (HKSA). IL-17 was measured in supernatants by
an enzyme immnunoassay. P7
In vivo natural killer and natural killer T-cell depletion aff ects
mortality in a murine pneumococcal pneumonia sepsis model
E Ch i t ki1 E Di
1 SM O
l2 A Pi tiki3 DI D
iti3 DP C
3 Results Mean respective apoptosis of groups 0, A, B, C, D and E at
24 hours were 37.9%, 77.6%, 81.9%, 73.8%, 83.6% and 75.4%; and at
48 hours 78.5%, 79.4%, 77.7%, 78.2%, 81% and 84.9% (P <0.05 group 0
vs. others). Mean respective MFI of TREM-1 of groups 0, A, B, C, D and E
at 24 hours were 2.4, 4.4, 3.4, 3, 3.2 and 3; and at 48 hours 2.7, 2.8, 2.8,
2.6, 2.8 and 2.7 (P <0.05 group 0 vs. others). Tissue cultures were sterile. Release of IL-17 was greater by splenocytes of group D (Figure 1). Conclusion Increased neutrophil apoptosis and TREM-1 expression
and modulated IL-17 responses are found within burn injury. y
y
Results Mean APACHE II score of patients was 14. Release of IL-17 by
PBMCs of patients was signifi cantly lower compared to controls, as
shown in Figure 1. P values refer to comparisons between controls and
patients. p
Conclusion The presented fi ndings show that early upon advent of
multiple injuries IL-17 responses are blunted. This may corroborate
with the susceptibility of patients for superinfections. P11
Insuffi cient autophagy relates to mitochondrial dysfunction, organ
failure and adverse outcome in an animal model of critical illness
J Gunst, I Derese, A Aertgeerts, EJ Ververs, A Wauters, G Van den Berghe,
I Vanhorebeek
Katholieke Universiteit Leuven, Belgium
Critical Care 2012, 16(Suppl 1):P11 (doi: 10.1186/cc10618) Insuffi cient autophagy relates to mitochondrial dysfunction, organ
failure and adverse outcome in an animal model of critical illness
J Gunst, I Derese, A Aertgeerts, EJ Ververs, A Wauters, G Van den Berghe,
I Vanhorebeek Figure 1 (abstract P9). Release of IL-17 by PBMCs of controls and of
patients. Introduction Increasing evidence implicates mitochondrial dysfunction
in the pathogenesis of critical illness-induced multiple organ failure. We previously demonstrated that prevention of hyperglycemia limits
mitochondrial damage in vital organs [1,2], thereby reducing morbidity
and mortality [3]. We now hypothesize that inadequate activation of
mitochondrial repair processes (mitochondrial clearance by autophagy,
mitochondrial fusion and fi ssion, and biogenesis) may contribute to
accumulation of mitochondrial damage, persistence of organ failure
and adverse outcome of critical illness. Methods We addressed this hypothesis in a rabbit model of critical
illness. First, we studied whether vital organ mitochondrial repair
pathways are diff erentially aff ected in surviving and nonsurviving
hyperglycemic animals, in relation to mitochondrial and organ function. Next, we investigated whether preventing hyperglycemia with insulin
aff ects mitochondrial repair over time. We quantifi ed mRNA/protein
levels of key players of these processes. Activities of respiratory chain
complexes I to V were measured spectrophotometrically. Plasma
transaminases and creatinine were measured as markers of liver,
respectively kidney, dysfunction. P12
Modulation of mediators derived from whole blood or monocytic
cells stimulated with lipopolysaccharide reduces endothelial cell
activation A Schildberger, T Stoifl , D Falkenhagen, V Weber
Danube University Krems, Austria
Critical Care 2012, 16(Suppl 1):P12 (doi: 10.1186/cc10619) Introduction Modulation of infl ammatory mediators with specifi c or
selective adsorbents may represent a promising supportive therapy
for septic patients. The aims of this study were to modulate mediator
concentrations from lipopolysaccharide (LPS)-stimulated whole blood
or monocytic THP-1 cells with specifi c or selective adsorbents and to
compare the infl uence on endothelial cell activation. Conclusion Our small sample of intensive care patients with a
confi rmed A/H1N1 infection supports the scarce published data about
the early immunological profi le of these patients. All our patients had
a prominent lymphopenia with a most signifi cant decrease in CD4 and
CD8 cells. Due to the number of patients in the season 2010/11 and
the survival of all patients we could not analyse the relation of survival
and the change in time of immunological profi le in this unique and
probably already extinct group of patients. pl
Methods Whole blood or THP-1 cells (1×106 cells per ml medium
containing 10% human plasma) [1] were stimulated with 10 ng/ml LPS
from Escherichia coli for 4 hours. Mediator modulation was performed
with either a specifi c adsorbent for TNFα which was based on sepharose
particles functionalized with anti-TNFα antibodies, or with a selective
albumin-coated polystyrene divinylbenzene copolymer (PS-DVB)
[2]. Human umbilical vein endothelial cell (HUVEC) activation was
monitored for 15 hours by measuring secretion of IL-6 and IL-8, as well
as surface expression of the adhesion molecules ICAM-1 and E-selectin. Results Conditioned media derived from whole blood (CMB) or THP-
1 cells (CMT) both contained approximately 1,300 pg/ml TNFα which
is known to be an important stimulator for HUVEC [1,2]. However,
CMB led to a signifi cantly higher HUVEC activation as compared to
CMT, as indicated by increased secretion of IL-6 and IL-8 (IL-6: 52,000
vs. 2,000 pg/ml; IL-8: 295,000 vs. 43,000 pg/ml), as well as signifi cantly
increased E-selectin surface expression (50 vs. 12 mean fl uorescence
intensity for CMP and CMT, respectively). P12 P12
Modulation of mediators derived from whole blood or monocytic
cells stimulated with lipopolysaccharide reduces endothelial cell
activation
A Schildberger, T Stoifl , D Falkenhagen, V Weber
Danube University Krems, Austria
Critical Care 2012, 16(Suppl 1):P12 (doi: 10.1186/cc10619) P13 P13
A/H1N1 infection: immunological parameters in ICU patients
I Zykova, P Sedlák, T Zajíc, A Vitouš, F Stejskal
Regional Hospital Liberec, Czech Republic
Critical Care 2012, 16(Suppl 1):P13 (doi: 10.1186/cc10620) P10 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S5 Time of course CD64, a leukocyte activation marker, during
extracorporeal circulation S Djebara, P Biston, F Emmanuel, A Daper, M Joris, P Cauchie,
M Piagnerelli CHU Charleroi, Belgium Introduction CD64 is a high-affi nity leukocyte receptor for the Fc
portion of IgG [1]. As CD64 expression on neutrophil cells (PMNs) is
upregulated specifi cally after bacterial stimulation, it could be used
to discriminate infl ammatory states from bacterial infections [1-3]. The
objective was a comparison of the time course of CD64 expression
on PMN cells between patients undergoing cardiac surgery with
extracorporeal circulation (ECC) with septic patients. f
g
Conclusion Infl ammatory mediator modulation with specifi c or
selective adsorbents reduces endothelial cell activation and thus may
support the development of new therapies for sepsis. References Methods Prospective study realized in the ICU of CHU Charleroi (Belgium). Thirty-nine patients scheduled for a cardiac surgery with ECC (coronary,
valvular or mixed surgery) (ECC group) and 11 patients with severe sepsis
or septic shock (septic group) were included. The CD64 expression on
PMNs was quantifi ed by the hematologic Cell Dyn Sapphire method
(Abotte US) before T0, at ICU admission (T1) and postoperatively on day
1 (T2) and day 5 (T3) for the ECC group and on days 0, 1 and 5 for the
septic group. Values are expressed as median (25th to 75th) percentiles
Results Fifty patients were included among which 39 in the ECC
group (nine valvular, 20 coronary artery bypass grafting and 10 mixed
surgery). As expected, the infl ammatory parameters were signifi cantly
increased in septic patients compared to the ECC group except on day 1. Schildberger et al.: Innate Immun 2010, 16:278-287. 2. Schildberger et al.: Blood Purif 2011, 32:286-295. 1. Schildberger et al.: Innate Immun 2010, 16:278-287. 2. Schildberger et al.: Blood Purif 2011, 32:286-295. P10 P10
Apoptosis of neutrophils, expression of TREM-1 on neutrophils and
IL-17 responses in experimental burn in injury are related to the
type and time of burn exposure
A Alexis1, D Carrer1, A Pistiki1, K Louis1, D Droggiti1, J Van der Meer2,
M Netea2, E Giamarellos-Bourboulis1
1University of Athens, Medical School, Athens, Greece; 2UMC St Radboud,
Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P10 (doi: 10.1186/cc10617) P10
Apoptosis of neutrophils, expression of TREM-1 on neutrophils and
IL-17 responses in experimental burn in injury are related to the
type and time of burn exposure p
y
y
y
Results In the liver and kidney of nonsurviving hyperglycemic
rabbits, molecular markers of insuffi cient autophagy were evident,
including accumulation of p62 protein (but no increase of p62 mRNA)
and decreases in the autophagosome-associated protein LC3-II
(microtubule-associated protein light chain 3). These changes were
less prominent in surviving animals and correlated with impaired
mitochondrial and organ function. In contrast, key players in
mitochondrial fusion, fi ssion or biogenesis were not aff ected by survival
status. Therefore, we focused on autophagy to study the impact of
preventing hyperglycemia. Both after 3 and 7 days of illness, autophagy
was better preserved in normoglycemic than in hyperglycemic rabbits,
which correlated strongly with improved mitochondrial and organ
function. Introduction To defi ne infl ammatory responses in experimental burn
injury in relation with the type and time of burn exposure. j
y
yp
p
Methods Burn injury was induced in 110 C57/B6 male mice after
time exposure of their back as follows: group 0, sham; group A, 60°C
for 60 seconds; group B, 60°C for 45 seconds and 4°C for 45 seconds;
group C, 75°C for 60 seconds; group D, 90°C for 5 seconds; and group E,
4°C for 45 seconds and 60°C for 45 seconds. Mice were sacrifi ced at 24
and 48 hours. Tissues were cultured and splenocytes were isolated and
stimulated with heat-killed Staphylococcus aureus and Candida albicans
for 5 days for release of IL-17. Neutrophil apoptosis and expression of
TREM-1 were determined after staining for ANNEXIN-V, PI and anti-
TREM-1-PE and fl ow cytometry analysis. Conclusion These fi ndings put forward insuffi cient autophagy as
a potentially important contributor to mitochondrial and organ
dysfunction in critical illness, and open perspectives for therapies that
activate autophagy during critical illness. References Results In season 2010/11 only six patients with a confi rmed A/H1N1
infection required admission to intensive care (47% of all patients with
a confi rmed A/H1N1 infection admitted to our hospital). All patients
required ventilation. Median APACHE II score was 18.2. Median ICU stay
was 18.5 days. Median number of ventilator days was 14. No patient
died, both 28-day and 3-month mortality was 0%. Total leukocyte
count was without substantial diff erences, but there was a prominent
lymphopenia at the time of admission (0.05 to 0.22% of total leukocyte
count) as has been described in similar studies. All lymphocyte
populations were decreased but a most prominent decrease was in
CD4 (T-helpers) and CD8 (T-suppressors), CD19 (B-lymphocytes) and
NK cells were less decreased. Comparison of the admission sample and
the second sample taken 21 days after admission: both CD4 and CD8
were most decreased at admission, immunoregulatory index had a
shift to positive values in the admission sample. References
1. Vanhorebeek I, et al.: Lancet 2005, 365:53-59. 2. Vanhorebeek I, et al.: Kidney Int 2009, 76:512-520. 3. Van den Berghe G, et al.: N Engl J Med 2001, 345:1359-1367. 1.
Schildberger et al.: Innate Immun 2010, 16:278-287.
2.
Schildberger et al.: Blood Purif 2011, 32:286-295. i
References 1. Shapovalov KG, et al.: Immunological and bacteriological monitoring of
patients with pneumonia and infl uenza A/H1N1 infection. Zh Mikrobiol
Epidemiol Immunobiol 2011, 1:79-82. 2. Kim JE, et al.: CD4+/CD8+ T lymphocytes imbalance in children with severe
2009 pandemic infl uenzaA/H1N1 pneumonia. Korean J Pediatr 2011,
54:207-211. P12
Modulation of mediators derived from whole blood or monocytic
cells stimulated with lipopolysaccharide reduces endothelial cell
activation Adsorption of infl ammatory
mediators from the conditioned medium of whole blood or THP-1 cells
either with the specifi c TNFα adsorbent or with the selective PS-DVB
beads resulted in decreased endothelial cell activation, as shown by
statistically signifi cant reduction of IL-6 and IL-8 secretion from HUVEC,
as well as statistically signifi cant reduction of surface expression
of the adhesion molecules ICAM-1 and E-selectin. The reduction of
HUVEC activation was more pronounced when applying the selective
adsorbent showing that the modulation of more than one cytokine is
more eff ective than removing TNFα alone. fl
fi Acknowledgements Our study was supported by a grant from
Scientifi c Board of Regional Hospital Liberec. Acknowledgements Our study was supported by a grant from
Scientifi c Board of Regional Hospital Liberec. References Scientifi c Board of Regional Hospital Liberec. References
f Oral neutrophil quantitation in patients undergoing elective
cardiopulmonary bypass Results Red blood cells preferentially metabolized pyruvate (ninefold
increase) compared to heart (1.2-fold increase) or liver (–2.1-fold
decrease), and were a net lactate source (2.1-fold increase). Glycolytic
intermediates increased in the heart, but decreased in red blood cells,
while TCA intermediates decreased in the heart and amino acids
increased in the liver. Under the hypoglycemic conditions of the animal
model, red blood cells were found to accumulate glycerol-3-phosphate
(red cell glycerol fl ux remained normal) and 2,3BPG following C13-
pyruvate injection. ATP was stable in the heart, but decreased in
the liver and red blood cells. Echocardiography revealed a transient
recovery of left ventricular function that correlated with shifts in red
blood cell metabolism. cardiopulmonary bypass
ME Wilcox1, P Perez2, C DosSantos3, M Glogauer1, E Charbonney3,
A Duggal2, S Sutherland2, G Rubenfeld2
1University of Toronto, Canada; 2Sunnybrook Health Sciences Centre, Toronto,
Canada; 3St Michael’s Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P15 (doi: 10.1186/cc10622) ME Wilcox1, P Perez2, C DosSantos3, M Glogauer1, E Charbonney3,
A Duggal2, S Sutherland2, G Rubenfeld2
1University of Toronto, Canada; 2Sunnybrook Health Sciences Centre, Toronto,
Canada; 3St Michael’s Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P15 (doi: 10.1186/cc10622) Introduction Recent research suggests that the oral cavity may provide
an early opportunity to monitor the innate immune system; an oral rinse
assay was found to be a reliable predictor of bone marrow engraftment
and neutrophil recovery in patients undergoing bone marrow
transplantation [1]. Multiorgan failure may be mediated by neutrophil
extravasation and aggregation [2] in highly infl ammatory states, such
as cardiopulmonary bypass (CPB). The objective of this novel pilot study
was to determine whether the kinetics of oral neutrophil recovery post-
CPB surgery refl ect systemic immune activation. Conclusion Metabolic investigation of diff erent septic tissues revealed
shifts in metabolism between organs, suggesting that sepsis induces
complex metabolic shifts in response to changing nutrient availability
and cell function; moreover, enhancing red blood cell metabolism
may be benefi cial to depressed organ function during the onset of
endotoxemia. yl
y
Methods Samples [3] from four-quadrant mucosal swabs and oral cavity
rinses were obtained from 41 patients undergoing on-CPB elective
cardiac surgery preoperatively (t–1) and postoperatively upon arrival to
the CVICU (t0), at 12 to 18 hours (t1), and on day 3 (t2). Oral neutrophil
counts (/ml) were determined by hemacytometry and validated by an
electronic cell counter. P13
A/H1N1 infection: immunological parameters in ICU patients
I Zykova, P Sedlák, T Zajíc, A Vitouš, F Stejskal
Regional Hospital Liberec, Czech Republic
Critical Care 2012, 16(Suppl 1):P13 (doi: 10.1186/cc10620) Introduction The outbreak of infl uenza A/H1N1 2009 had infl uenced
ICUs all over the world. In the season 2009/10 we admitted to intensive
care 13 patients with A/H1N1 infection in our regional hospital. In
the next season 2010/11 another outbreak of A/H1N1 infection was
predicted. We decided to study the immunological profi les of these
patients and its development in time. Table 1 (abstract P14)
ECC
Sepsis
P value
T0
0.8 (0.6 to 1.08)
3.24 (1.9 to 7.8)
<0.001
T1
0.9 (0.6 to 1.14)†
Not available
T2
1.3 (0.77 to 1.8)*,**
4.4 (2.63 to 6.7)*
<0.001
T3
1.1 (0.74 to 1.4)‡
1.3 (0.74 to 1.4)
0.16
*P <0.05 T2 vs. T3, **T2 vs. T0, †T2 vs. T1, ‡T3 vs. T0. ANOVA tests. Methods We conducted a prospective study on patients admitted to our
hospital with A/H1N1 infection in the season 2010/11. The diagnosis was
confi rmed by RT-PCT from nasopharyngeal smear or bronchoalveolar
lavage in all patients. Immunological parameters (leukocyte count,
lymphocyte count, CD19, CD4, CD8, immunoregulatory index, NK cells)
were analysed on admission and 3 weeks after admission. *P <0.05 T2 vs. T3, **T2 vs. T0, †T2 vs. T1, ‡T3 vs. T0. ANOVA tests. S6 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 5 (for example, CRP: 0.2 (0.1 to 0.6) vs. 12.5 (5.7 to 26.9) mg/dl; WBC 6.5
(5.2 to 8.7) vs. 19.5 (12 to 20.5) 103/mm3; for respectively ECC and septic
group at T0, P <0.001). The CD64 expression increased signifi cantly in
both groups but index values were lower in the ECC compared to the
septic group except on T3 (Table 1). changes in metabolism and the metabolic interaction between tissues
and red blood cells are not well understood. The objective of this study
was to assess changes in intermediary metabolism during the onset
of an animal model of sepsis by determining glycolytic, TCA and PPP
metabolites, amino acids and ATP levels in heart, liver and red blood
cells. p
g
p
p
Conclusion ECC modifi es the infl ammatory parameters, including
the expression of the CD64 on PMNs but this one presents the best
specifi city to diagnose an infection. Thus, CD64 expression could be
proposed as a promising marker in the early diagnosis of the infection. References Methods C57BL/6 mice (30 to 35 g) were injected intraperitoneally
with lipopolysaccharide (LPS, 40 mg/kg) to induce endotoxemia. Oral neutrophil quantitation in patients undergoing elective
cardiopulmonary bypass Concurrent blood samples were collected for
measurement of IFNα, interleukins (IL-1β, IL-6, IL-8 and IL-10), chemokine
C-C motif ligand 4 (CCL-4) and Th1 and Th2 cytokines using a 10-plex
human cytokine mediator panel. Continuous variables were summarized
with means (standard deviation). Preoperative and postoperative oral
neutrophil counts were compared using paired t tests.i Acknowledgements Supported by the Ministry of Education, Culture,
Sports, Science and Technology, Japan, Global COE Program. AMP-activated protein kinase controls liposaccharide-induced
hyperpermeability P13
A/H1N1 infection: immunological parameters in ICU patients
I Zykova, P Sedlák, T Zajíc, A Vitouš, F Stejskal
Regional Hospital Liberec, Czech Republic
Critical Care 2012, 16(Suppl 1):P13 (doi: 10.1186/cc10620) Six hours post LPS, C13-pyruvate (a key intermediate metabolite) was
administered subcutaneously for fl uxome analysis of intermediate
metabolites. At 20, 40 and 60 minutes, heart, liver and red blood cells
were collected and stored at –80°C. Labeled metabolites were measured
using capillary electrophoresis–mass spectrometry, quantifi ed by
calculating the AUC/t0–60 and expressed relative to control. Heart
function was monitored by echocardiography. 1. Ioan-Fascinay A, et al.: Immunity 2002, 16:391-402. 1. Ioan-Fascinay A, et al.: Immunity 2002, 16:391-402. 1. Ioan-Fascinay A, et al.: Immunity 2002, 16:391-402. 2. Nuutila J, et al.: J Immunol Methods 2007, 328:189-200. 3. Qureshi SS, et al.: Clin Exp Immunol 2001, 125:258-265. 2. Nuutila J, et al.: J Immunol Methods 2007, 328:189-200. 3. Qureshi SS, et al.: Clin Exp Immunol 2001, 125:258-265. p
References 1. Cheretakis C, et al.: Bone Marrow Transplant 2005, 36:227-232. 2. Fung YL, et al.: J Crit Care 2008, 23:542-549. 3. Wright DG, et al.: Blood 1986, 67:1023-1030. y p
y
Methods Sepsis was induced by intraperitoneal injection of
liposaccharide, 10 mg/kg (LPS). Alpha-1 AMPK knockout mice (α1KO)
were compared with wild-type. Vascular permeability was characterized
by Evans blue extravasation. Infl ammatory cytokine mRNA expression
was determined by qPCR analysis. Left ventricular mass was assessed
by echocardiography. In addition, to emphasize the benefi cial role of
AMPK on heart vascular permeability, AMPK activator (acadesine) was
administered to C57Bl6 mice before LPS injection. The ANOVA test with
Bonferroni’s post hoc test and the log-rank test were used. P <0.05 was
considered as signifi cant. AMP-activated protein kinase controls liposaccharide-induced
hyperpermeability D Castanares-Zapatero1, M Overtus2, D Communi3, M Horckmans3,
L Bertrand2, C Oury4, C Lecut4, P Laterre1, S De man2, C Sommereyns2,
S Horman2, C Beauloye2 Results Patients were 65 (10.6) years old; 78% male; 51% had signifi cant
co-morbidities (25% diabetes); 54% took a statin; APACHE II score was
22 (4.4); and multiorgan dysfunction score (MODS) was highest on
hospital day 1 (6.2; 2.2). Mean delta oral neutrophil count by oral swab
(between t–1 and t0) was 1.7×106 (2.0×106). A signifi cant diff erence was
seen in the absolute neutrophil counts (oral swab) between t–1 (1.7×106
(1.3×106)) and t0 (3.4×106 (2.7×106); P <0.001), but not between t–1 and
t1 (2.0×106 (1.7×106); P = 0.14) or t2 (6.6×105 (1.1×106); P = 0.14). Similar
results were obtained by oral cavity rinse. 1Université catholique de Louvain, Cliniques universitaires Saint Luc,
Brussels, Belgium; 2Université catholique de Louvain, Institut de Recherche
Expérimentale et Clinique, Brussels, Belgium; 3Université libre de Bruxelles,
Institut de Recherche Interdisciplinaire en Biologie humaine et moléculaire,
Brussels, Belgium; 4Université de Liège, Groupe Interdisciplinaire de
Génoprotéomique Appliquée, Liège, Belgium
Critical Care 2012, 16(Suppl 1):P17 (doi: 10.1186/cc10624) Introduction Organ dysfunction determines the severity of sepsis and
is correlated to mortality. Endothelial increased permeability contri-
butes to the development of organ failure. AMP-activated protein
kinase (AMPK) has been shown to modulate cytoskeleton and could
mediate endothelial permeability. Our hypothesis is that AMPK controls
sepsis-induced hyperpermeability in the heart and is involved in septic
cardiomyopathy. y
y
Conclusion An oral swab assay has the potential to provide rapid, risk-
free, and early data on neutrophil activation and chemotactic defects in
response to CPB, obviating the need for invasive sampling. This method
could provide a new perspective on the systemic infl ammatory
response in surgery, traumatic injury, burns, and sepsis. References P16 Keio University, Tokyo, Japan Keio University, Tokyo, Japan y
y
p
Critical Care 2012, 16(Suppl 1):P16 (doi: 10.1186/cc10623) i
Results Increased cardiac vascular permeability was observed in the
LPS group in comparison to untreated animals (2.5% vs. 16%; P <0.05). The α1KO mice exhibited an increase vascular permeability after LPS
injection in comparison to wild-type mice (41.5% vs. 16%; P <0.05). Introduction The systemic infl ammatory response to bacterial infection,
or sepsis, results in a hypermetabolic state; yet, systemic metabolic S7 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 tremendous fi nancial costs. Recently, the primary metabolite of
sevofl urane, hexafl uoro-2-propanol (HFIP), has been found to exert
immunomodulatory properties attenuating infl ammatory response
to lipopolysaccharides (LPS) in vitro [1]. We investigated whether HFIP
attenuates plasma and tissue infl ammatory mediator expression in a
rat model of endotoxic shock. α1KO animals had a signifi cant mortality increase after LPS injection
(70% vs. 10%; P <0.05). LPS markedly induced the production of
proinfl ammatory cytokines (TNFα, IL-1β, IL-6) that were signifi cantly
higher in the α1KO animals. More importantly, LPS treatment leads to
an increased left ventricular mass in the α1KO mice within 24 hours,
suggesting the onset of edema. Finally LPS-induced vascular
hyperpermeability was greatly reduced after AMPK activation by
acadesine (13.2% vs. 40%; P <0.05). α1KO animals had a signifi cant mortality increase after LPS injection
(70% vs. 10%; P <0.05). LPS markedly induced the production of
proinfl ammatory cytokines (TNFα, IL-1β, IL-6) that were signifi cantly
higher in the α1KO animals. More importantly, LPS treatment leads to
an increased left ventricular mass in the α1KO mice within 24 hours,
suggesting the onset of edema. Finally LPS-induced vascular
hyperpermeability was greatly reduced after AMPK activation by
acadesine (13.2% vs. 40%; P <0.05). Methods Thirty-two male Wistar rats were anesthetized, tracheoto-
mized, and mechanically ventilated. The animals were randomly
assigned to one of the following groups: (I) LPS group (n = 8), which
received intravenous Escherichia coli endotoxin (1 mg/kg); (II) LPS/
HFIP group (n = 8), which was treated identically to the LPS group with
the additional administration of HFIP (67 μg/kg over 30 minutes) after
LPS injection. Control groups received Ringer’s lactate instead of LPS. General anesthesia was maintained with propofol. P18 Reduced expression of PPAR-β/δ limits the potential benefi cial
eff ects of GW0742 during septic shock in atherosclerotic swine
H Bracht1, F Simon1, J Matallo1, M Gröger1, O McCook1, A Seifritz1,
M Georgieff 1, E Calzia1, P Radermacher1, A Kapoor2, C Thiemermann2
1University Clinic Ulm, Germany; 2William Harvey Research Institute, London, UK
Critical Care 2012, 16(Suppl 1):P18 (doi: 10.1186/cc10625) ll
y
Results Plasma MCP-1 protein levels assessed 6 hours after LPS injection
were increased by +5,192 ng/ml compared to baseline (R2 = 0.661,
P <0.001). This increase in MCP-1 protein was attenuated by –48% in
the LPS/HFIP group (+2,706 ng/ml to baseline, R2 = 0.661; P = 0.004). Similar results were found in BALF, in which HFIP decreased the LPS-
induced raise in MCP-1 protein concentration by –62% (diff erence of
54 ng/ml, P = 0.034). LPS-stimulated animals had a +12% higher mean
arterial blood pressure after 6 hours when treated with HFIP (78 mmHg
vs. 67 mmHg, R2 = 0.684, P = 0.035). No signifi cant diff erences in lactate
levels were observed. HFIP attenuated base defi cit in LPS-stimulated
animals by 1 mmol/l (R2 = 0.522, P = 0.034). Introduction The PPAR-β/δ agonist GW0742 was shown to attenuate
cardiac dysfunction in murine septic shock [1] and renal ischemia/
reperfusion injury in diabetic rats [2]. Since these data originate from
unresuscitated models, we investigated the eff ects of GW0742 during
long-term, resuscitated porcine septic shock. In order to assess the role
of pre-existing cardiovascular morbidity we used animals with familial
hypercholesteremia (11.1 (7.4; 12.3) vs. 1.4 (1.3; 1.5) mmol/l in a healthy
strain; P <0.001) and consecutive, diet-induced ubiquitous atherosclerosis
resulting in coronary artery disease [3], reduced glomerular fi ltration rate
(76 (60; 83) vs. 103 (79; 120) ml/minute in healthy swine; P = 0.004) and
presence of chronic histological kidney injury. y
Conclusion Hexafl uoro-2-propanol attenuated LPS-induced infl amma-
tory mediator secretion, the decrease in mean arterial blood pressure,
and base defi cit. These results suggest that hexafl uoro-2-propanol
may partly inhibit infl ammatory response, hypotension and the
development of metabolic acidosis during endotoxic shock. Reference Methods Anesthetized and instrumented animals randomly received
vehicle (n = 9) or GW0742 (n = 10; 0.03 mg/kg) at 6, 12, 18 hours after
induction of fecal peritonitis [4]. Hydroxyethyl starch and noradrenaline
were infused to maintain normotensive, hyperdynamic hemodynamics. P20f Eff ects of noradrenaline and lipopolysaccharide exposure on
mitochondrial respiration in alveolar macrophages
M Gröger, M Widman, J Matallo, P Radermacher, M Georgieff
University of Ulm, Germany
Critical Care 2012, 16(Suppl 1):P20 (doi: 10.1186/cc10627) y
Conclusion Even early post-treatment with the PPAR-β/δ agonist
GW0742 did not benefi cially infl uence acute kidney injury during long-
term, resuscitated fecal peritonitis-induced septic shock in swine with
pre-existing impairment of kidney function and histological damage. The lacking benefi cial eff ect of GW0742 was most likely due to the
reduced expression of the PPAR-β/δ receptor. Introduction Mitochondrial respiratory capacity of immune cells seems
to be impaired in septic patients [1]. On the other hand, the eff ects of
catecholamines on mitochondrial function are still controversial [2] and
may confound the genuine mitochondrial response to the septic event. In order to test if catecholamine therapy may infl uence the impairment
of mitochondrial function in immune cells during sepsis, we measured
mitochondrial respiration in cultured murine alveolar macrophages
(AMJ2-C11) after 24 hours of incubation with noradrenaline and
lipopolysaccharide (LPS). Acknowledgements Supported by the Else-Kröner-Fresenius-Stiftung. References 1. Kapoor et al.: Am J Respir Crit Care Med 2010, 182:1506-1515. 2. Collino et al.: Free Radic Biol Med 2011, 50:345-353. 3. Thim D: Med Bull 2010, 57:B4161. 4. Simon F, et al.: Crit Care 2009, 13:R113. Methods Three states of mitochondrial respiratory activity were
quantifi ed in terms of O2-fl ux (JO2) in intact cells at 37°C by means of
an O2K (Oroboros® Instruments Corp., Innsbruck, Austria) according
to a previously published protocol [3] yielding routine respiration (R)
as the standard respiratory level of the cells without any intervention,
proton leak compensation (L) after blocking ATP synthesis by 2.5 μM
oligomycine, and maximum capacity of the electron transport system
(E) after uncoupling by 1 μM FCCP. The cells were studied after fi ve
diff erent exposure conditions: control (C), 15 μmol/ml noradrenaline
(high NoA), 5 nmol/ml noradrenaline (medium NoA), LPS, and LPS +
high NoA. All data are presented in pmol/(s*million cells) as medians
and 25 to 75% quartiles. Statistical signifi cance was tested by means of
the Kruskal–Wallis one-way ANOVA followed by Dunn’s method. P16 All animals received
additional 30 ml/kg Ringer’s lactate after injection of LPS over a time
period of 1 hour. Arterial blood gases were measured every hour. Animals were euthanized 6 hours after endotoxin injection. The
concentrations of monocyte chemoattractant protein-1, key player in
the recruitment of monocytes during endotoxemia, was analyzed in
bronchoalveolar lavage fl uid and in plasma. Linear regression was used
to evaluate infl uence of HFIP on infl ammatory mediator expression. Conclusion AMPK importantly regulates cardiac vascular permeability
and could control the sepsis-induced cardiomyopathy. AMPK could
represent a new pharmacological target of sepsis. 1. Gustot T: Curr Opin Crit Care 2011, 17:153-159. 1. Gustot T: Curr Opin Crit Care 2011, 17:153-159. P18 Creatinine clearance was measured from 0 to 12 hours and from 12 to
24 hours of sepsis, respectively. Data are median (quartiles).f 1. Urner et al.: Am J Respir Cell Mol Biol 2011, 45:617-624. 1. Urner et al.: Am J Respir Cell Mol Biol 2011, 45:617-624. Results GW0742 did not aff ect the noradrenaline infusion rate required
to achieve target hemodynamics (0.57 (0.30; 3.83) vs. 0.56 (0.41; 0.91)
μg/kg/minute; P = 0.775) nor the fall in creatinine clearance (GW0742:
from 129 (114; 140) to 78 (55; 95) ml/minute, P = 0.002; vehicle: from
130 (91; 142) to 41(31; 84) ml/minute, P = 0.004; P = 0.967 and P = 0.191
between groups). Immune histochemistry analysis of kidney biopsies
in sham-operated swine showed markedly reduced tissue expression
of the PPAR-β/δ receptor in atherosclerotic swine (281 (277; 404) vs. 57
(53; 77)×103 densitometric units in healthy swine; P = 0.008). P19f P19
Eff ects of hexafl uoro-2-propanol on infl ammatory and
hemodynamic responses in a rat model of endotoxic shock
M Urner, IK Herrmann, M Hasler, C Booy, B Beck-Schimmer
University Hospital Zurich, Institute of Anesthesiology, Zurich, Switzerland
Critical Care 2012, 16(Suppl 1):P19 (doi: 10.1186/cc10626) P21f P21
Eff ects of the anti-diabetic imeglimin in hyperglycemic mice with
septic shock
F Wagner1, J Vogt1, U Wachter1, S Weber1, B Stahl1, M Groeger1, O McCook1,
M Georgieff 1, P Fouqueray2, T Kuhn2, E Calzia1, P Radermacher1,
E Fontaine3, K Wagner1
1University Medical School Ulm, Anesthesia, Ulm, Germany, 2Poxel, Lyon,
France, 3Université Joseph Fourier, LBFA, Grenoble, France
Critical Care 2012, 16(Suppl 1):P21 (doi: 10.1186/cc10628) References References
1. Wu R, et al.: Mol Med 2009, 15:28-33. 2. Ertmer C, et al.: Br J Anaesth 2007, 99:830-836. 3. Guignant C, et al.: Intensive Care Med 2009, 35:1859-1867. 4. Mazzocchi G, et al.: Life Sci 2000, 66:1445-1450. 5. Hyvelin JM, et al.: J Card Surg 2002, 17:328-335. 6. Wagner F, et al.: Shock 2011, 35:396-402. 7. Wagner F, et al.: J Trauma 2011. [Epub ahead of print] References
1. Wu R, et al.: Mol Med 2009, 15:28-33. 2. Ertmer C, et al.: Br J Anaesth 2007, 99:830-836. 3. Guignant C, et al.: Intensive Care Med 2009, 35:1859-1867. 4. Mazzocchi G, et al.: Life Sci 2000, 66:1445-1450. 5. Hyvelin JM, et al.: J Card Surg 2002, 17:328-335. 6. Wagner F, et al.: Shock 2011, 35:396-402. 7. Wagner F, et al.: J Trauma 2011. [Epub ahead of print] 1. Wu R, et al.: Mol Med 2009, 15:28-33. q
Results Imeglimin decreased blood glucose levels (165 (153; 180) vs. 192 (184; 221) mg/dl, P = 0.007) by increasing whole body glucose
oxidation (55 (52; 57) vs. 51 (49; 55)% of infused isotope, P = 0.085), which
coincided with partial restoration of gluconeogenesis (0.38 (0.34; 0.41)
vs. 0.31 (0.27; 0.33) mg/g/hour, P = 0.032), liver mitochondrial activity
(oxidative phosphorylation (136 (134; 160) vs. 116 (97; 122) pmol O2/
second/mg tissue, P = 0.003); maximal oxidative capacity (166 (154;
174) vs. 147 (130; 159) pmol O2/second/mg tissue, P = 0.064). Imeglimin
increased liver HO-1, reduced liver Bax expression and attenuated NF-
κB activation (all P <0.001). P22
Adrenomedullin blockade improves catecholamine responsiveness
and kidney function in resuscitated murine septic shock
K Wagner1, U Wachter1, J Vogt1, S Weber1, M Groeger1, O McCook1,
M Georgieff 1, A Bergmann2, H Luettgen2, E Calzia1, P Radermacher1,
F Wagner1
1University Medical School Ulm, Germany; 2AdrenoMed AG, Henningsdorf,
Germany
Critical Care 2012, 16(Suppl 1):P22 (doi: 10.1186/cc10629) Adrenomedullin blockade improves catecholamine responsiveness
and kidney function in resuscitated murine septic shock
K Wagner1, U Wachter1, J Vogt1, S Weber1, M Groeger1, O McCook1,
M Georgieff 1, A Bergmann2, H Luettgen2, E Calzia1, P Radermacher1,
F Wagner1
1University Medical School Ulm, Germany; 2AdrenoMed AG, Henningsdorf,
Germany
Critical Care 2012, 16(Suppl 1):P22 (doi: 10.1186/cc10629) Conclusion High but not moderate doses of noradrenaline reduced
mitochondrial respiration in alveolar macrophages in vitro. Surprisingly,
LPS increased routine respiration regardless of simultaneous
noradrenaline exposure. Introduction The eff ects of adrenomedullin in circulatory shock states
are controversially discussed: while its exogenous supplementation
improved organ function and survival [1] in experimental models due
to maintenance of hyperdynamic hemodynamics [2] in otherwise
hypo dynamic conditions, high blood levels were associated with
increased mortality in patients with septic shock [3], most likely as a
result of excessive vasodilatation [4] and/or impaired systolic heart
function [5]. P21
Eff ects of the anti-diabetic imeglimin in hyperglycemic mice with
septic shock P21
Eff ects of the anti-diabetic imeglimin in hyperglycemic mice with
septic shock
F Wagner1, J Vogt1, U Wachter1, S Weber1, B Stahl1, M Groeger1, O McCook1,
M Georgieff 1, P Fouqueray2, T Kuhn2, E Calzia1, P Radermacher1,
E Fontaine3, K Wagner1
1University Medical School Ulm, Anesthesia, Ulm, Germany, 2Poxel, Lyon,
France, 3Université Joseph Fourier, LBFA, Grenoble, France
Critical Care 2012, 16(Suppl 1):P21 (doi: 10.1186/cc10628) i
Results Adrenomedullin antagonism decreased the noradrenaline
requirements needed to achieve target hemodynamics (0.009 (0.009;
0.012) vs. 0.02 (0.015; 0.044) μg/g/hour, P <0.001), increased total
diuresis (2.6 (2.3; 3.9) vs. 0.6 (0.5; 2.7) ml, P = 0.028) resulting in improved
fl uid balance (0.18 (0.14; 0.2) vs. 0.26 (0.19; 0.27), P = 0.011) and kidney
function (creatinine levels at the end of the experiment: 1.3 (1.2; 1.5) vs. 2.0 (1.5; 2.9) μg/ml, P = 0.006; creatinine clearance: 400 (316; 509) vs. 197 (110; 301) μl/minute, P = 0.006). Introduction Shock-related hyperglycemia impairs mitochondrial
function and integrity [1], ultimately leading to apoptosis and
organ failure [1,2]. Imeglimin is a new anti-diabetic drug with anti-
hyperglycemic and anti-apoptotic properties [3]. Therefore we
investigated its eff ects in hyperglycemic mice with septic shock. Conclusion In resuscitated murine septic shock, early modulation
of excess adrenomedullin activity via antibody HAM1101 improves
cardiovascular catecholamine responsiveness, ultimately associated
with attenuation of acute kidney injury. f
Methods Immediately after cecal ligation and puncture, mice
randomly received s.c. vehicle (n = 9) or imeglimin (n = 10; 100 μg/g). Fifteen hours later animals were anesthetized, mechanically ventilated
and instrumented for a consecutive 6-hour observation period. After
a second imeglimin bolus, colloid fl uid resuscitation and continuous
i.v. noradrenaline were titrated to maintain normotensive and
hyperdynamic hemodynamics. Then 2 mg/g/hour glucose was infused
to induce hyperglycemia. Glucose oxidation and gluconeogenesis
were derived from blood 13C6-glucose and mixed expiratory 13CO2/12CO2
isotope enrichment during continuous isotope infusion. Liver mito-
chondrial activity was assessed using high-resolution respirometry
[4,5], Bax, HO-1 and NF-κB expression by immunoblotting and EMSA. All data are median (quartiles). Acknowledgements Supported by an unrestricted grant from
AdrenoMed AG. Eff ects of hexafl uoro-2-propanol on infl ammatory and
hemodynamic responses in a rat model of endotoxic shoc
l
k
h University Hospital Zurich, Institute of Anesthesiology, Zurich, Switzerland
Critical Care 2012, 16(Suppl 1):P19 (doi: 10.1186/cc10626) Introduction Sepsis with multiple organ failure remains a leading
cause of hospital morbidity and mortality on ICUs imparting S8 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 References 1. Japiassú AM, et al.: Crit Care Med 2011, 39:1056-1063.l 1. Japiassú AM, et al.: Crit Care Med 2011, 39:1056-1063.l 2. Porta F, et al.: Infl ammation 2009, 32:315-321. l
3. Renner K, et al.: Biochim Biophys Acta 2003, 1642:115-123. 3. Renner K, et al.: Biochim Biophys Acta 2003, 1642:115-123. Methods Immediately after cecal ligation and puncture to induce
peritonitis, mice randomly received vehicle (n = 11) or the adreno-
medullin antibody HAM1101 (n = 9; 2 μg/g to achieve antibody
concentrations >4 ng/ml). Fifteen hours later animals were anesthetized,
mechanically ventilated and instrumented for a consecutive 6-hour
observation period. Colloid fl uid resuscitation and continuous i.v. noradrenaline were titrated to maintain normotensive (mean blood
pressure >60 mmHg) and hyperdynamic hemodynamics. Creatinine
blood levels and clearance were assessed as surrogate for glomerular
fi ltration [6,7]. All data are median (quartiles). P22 Results After exposure with high but not with medium NoA we
observed a statistically signifi cant decrease in maximum mitochondrial
respiratory capacity (E-state, C 133 (118; 148) vs. high NoA 111 (106;
113), and medium NoA 129 (123; 140), P <0.05 C vs. high NoA). Both
LPS and LPS + high NoA did not aff ect E-state respiration (LPS: 152
(136; 179), and LPS + NoA 129 (125; 137)), but increased routine (R)
respiration when compared to control (C 45 (40; 55) vs. LPS 66 (51; 72)
and LPS + NoA 65 (55; 68), P <0.05; high NoA 41 (37; 47), and medium
NoA 52 (51; 57), NS). P24
Soluble usokinase plasminogen activator receptor as a useful
biomarker to defi ne advent of sepsis in patients with multiple
injuries Role of serum biomarkers in the diagnosis of infection in patients
undergoing extracorporeal membrane oxygenation
M Pieri1, T Greco1, AM Scandroglio1, M De Bonis1, G Maj1, L Fumagalli2,
A Zangrillo1, F Pappalardo1
1Istituto Scientifi co San Raff aele, Milan, Italy; 2Istituto Scientifi co San Raff aele
Turro, Milan, Italy
Critical Care 2012, 16(Suppl 1):P26 (doi: 10.1186/cc10633) Introduction Although rates and causal organisms of infections occur ring
in patients on extracorporeal membrane oxygenation (ECMO) have already
been described [1], diagnosis of infection itself is challenging in clinical
practice. In addition, a signifi cant heterogeneity in infection surveillance
practice patterns among ELSO centers has recently been reported [2]. The
aim of the study was to analyze the role of C-reactive protein (CRP) and
procalcitonin (PCT) in the diagnosis of bacterial and fungal infection in
critically ill patients requiring ECMO, and to assess the diff erence between
venovenous (VV) and venoarterial (VA) ECMO setting. Introduction Soluble usokinase plasminogen activator receptor
(suPAR) has been considered a useful biomarker to defi ne prognosis in
patients with sepsis [1]. The present study aimed to defi ne the kinetics
of suPAR during the physical course of patients with multiple injuries. Introduction Soluble usokinase plasminogen activator receptor
(suPAR) has been considered a useful biomarker to defi ne prognosis in
patients with sepsis [1]. The present study aimed to defi ne the kinetics
of suPAR during the physical course of patients with multiple injuries. Methods A total of 62 patients were enrolled. All patients were
bearing: multiple injuries necessitating ICU admission with an injury
severity score (ISS) more than 8; and systemic infl ammatory response
syndrome. Patients with infections upon ICU admission were excluded
from the study. Peripheral venous blood was sampled within the fi rst
24 hours after ICU admission. Blood sampling was repeated within the
fi rst 24 hours upon advent of sepsis. suPAR was measured in serum by
an enzyme immnunoassay. Methods A total of 62 patients were enrolled. All patients were
bearing: multiple injuries necessitating ICU admission with an injury
severity score (ISS) more than 8; and systemic infl ammatory response
syndrome. Patients with infections upon ICU admission were excluded
from the study. Peripheral venous blood was sampled within the fi rst
24 hours after ICU admission. Blood sampling was repeated within the
fi rst 24 hours upon advent of sepsis. suPAR was measured in serum by
an enzyme immnunoassay. P25 comparative statistical analysis was performed using SPSS version 15.0
(SPSS Inc., Chicago, IL, USA). Role of mannose-binding lectin on pneumococcal infections
J Solé Violán1, I García-Laorden1, F Rodríguez de Castro1, A Payeras2,
J Ferrer Agüero1, M Briones3, L Borderías4, J Aspa5, J Blanquer3, O Rajas5,
M García-Bello1, J Noda1, J Rello6, C Rodríguez Gallego1
1Hospital Dr Negrín, Las Palmas de Gran Canaria, Spain; 2Hospital Son Llatzer,
Palma de Mallorca, Spain; 3Hospital Clínico y Universitario, Valencia, Spain;
4Hospital San Jorge, Huesca, Spain; 5Hospital de La Princesa, Madrid, Spain;
6Hospital Universitario Vall d´Hebró, Barcelona, Spain
Critical Care 2012, 16(Suppl 1):P25 (doi: 10.1186/cc10632) Role of mannose-binding lectin on pneumococcal infections
J Solé Violán1, I García-Laorden1, F Rodríguez de Castro1, A Payeras2,
J Ferrer Agüero1, M Briones3, L Borderías4, J Aspa5, J Blanquer3, O Rajas5,
M García-Bello1, J Noda1, J Rello6, C Rodríguez Gallego1
1Hospital Dr Negrín, Las Palmas de Gran Canaria, Spain; 2Hospital Son Llatzer,
Palma de Mallorca, Spain; 3Hospital Clínico y Universitario, Valencia, Spain;
4Hospital San Jorge, Huesca, Spain; 5Hospital de La Princesa, Madrid, Spain;
6Hospital Universitario Vall d´Hebró, Barcelona, Spain
Critical Care 2012, 16(Suppl 1):P25 (doi: 10.1186/cc10632) Results We analyzed 150 consecutive episodes of severe sepsis
(16%) or septic shock (84%) admitted to the ICU. The median age was
64 years old (interquartile range, 48.7 to 71); male: 60%. The beginning
of severe sepsis took place in the emergency area in 46% of cases. The main sources of infection were respiratory tract 38% and intra-
abdomen 45%; 70.7% had medical pathology. The 28-day mortality
was 22.7%. The profi le of death patients were men (64.7%, n = 22),
with signifi cantly higher average age (63 vs. 57 years; P = 0.049), as
well as clinical severity scores, APACHE II (29.8 vs. 24.1; P <0.001) and
SOFA (12.1 vs. 8.9; P <0.001) and major dysfunction organs (4.6 vs. 3.6;
P <0,001); we observed signifi cantly major consumption of PC (55.2 vs. 70.1, P = 0.011). Lower levels of PC were found in surgery septic shock
patients, neurological focus or catheter-related infection and Gram-
negative pathogens from blood cultures. The ROC analysis showed
superior risk prediction of SOFA score for 28-day mortality, AUC 0.81
(95% CI: 0.73 to 0.88, sensitivity: 73.5%; specifi city: 76.7%, P = 0.001),
that improves by combining with PC, AUC 0.83 (95% CI: 0.75 to 0.90,
sensitivity: 77%; specifi city: 83%, P = 0.001). P25 Introduction The role of mannose-binding lectin (MBL) defi ciency
(MBL2 XA/O + O/O genotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, SP-A2 and SP-D, and other collectins
whose genes are located near MBL2, are part of the fi rst-line lung
defence against infection. We analyzed the role of MBL on susceptibility
to pneumococcal infection and the existence of linkage disequilibrium
(LD) among the four genes. g
g
Methods We studied 348 patients with pneumococcal community-
acquired pneumonia (P-CAP) and 1,591 controls. A meta-analysis of
MBL2 genotypes in susceptibility to P-CAP and to invasive pneumo-
coccal disease (IPD) was also performed. The extent of LD of MBL2 with
SFTPA1, SFTPA2 and SFTPD was analyzed. i
Conclusion This cohort study showed an improvement in the survival
in septic patients under a lower consumption of PC. Low levels of PC are
associated with more severity in Sepsis, dysfunction organ and poor
outcome. Results MBL2 genotypes did not associate with either P-CAP or
bacteraemic P-CAP in the case–control study. The MBL-defi cient O/O
genotype was signifi cantly associated with higher risk of IPD in a meta-
analysis, whereas the other MBL-defi cient genotype (XA/O) showed
a trend towards a protective role. We evidenced the existence of LD
between MBL2 and SPs genes. References 1. Brunkhorst F, et al.: Protein C concentrations correlate with organ
dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology 2007, 107:15-23. g
dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology 2007, 107:15-23. 2. Yan SB, et al.: Low levels of protein C are associated with poor outcome in
severe sepsis. Chest 2001, 120:915-922. 2. Yan SB, et al.: Low levels of protein C are associated with poor outcome in
severe sepsis. Chest 2001, 120:915-922. g
Conclusion The data do not support a role of MBL defi ciency on
susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must
be considered in studies on the role of MBL in infectious diseases. 1.
Savva A, et al.: J Infect 2011, 63:344-350. P24 P24 P24
Soluble usokinase plasminogen activator receptor as a useful
biomarker to defi ne advent of sepsis in patients with multiple
injuries
M Patrani1, M Paraschos1, M Georgitsi2, E Giamarellos-Bourboulis2,
K Mandragos1
1Korgialeneion Benakeion Hospital, Athens, Greece; 2University of Athens,
Medical School, Athens, Greece
Critical Care 2012, 16(Suppl 1):P24 (doi: 10.1186/cc10631) P24
Soluble usokinase plasminogen activator receptor as a useful
biomarker to defi ne advent of sepsis in patients with multiple
injuries
M Patrani1, M Paraschos1, M Georgitsi2, E Giamarellos-Bourboulis2,
K Mandragos1
1Korgialeneion Benakeion Hospital, Athens, Greece; 2University of Athens,
Medical School, Athens, Greece
Critical Care 2012, 16(Suppl 1):P24 (doi: 10.1186/cc10631) P24
Soluble usokinase plasminogen activator receptor as a useful
biomarker to defi ne advent of sepsis in patients with multiple
injuries
M Patrani1, M Paraschos1, M Georgitsi2, E Giamarellos-Bourboulis2,
K Mandragos1
1Korgialeneion Benakeion Hospital, Athens, Greece; 2University of Athens,
Medical School, Athens, Greece
Critical Care 2012, 16(Suppl 1):P24 (doi: 10.1186/cc10631) P24
Soluble usokinase plasminogen activator receptor as a useful
biomarker to defi ne advent of sepsis in patients with multiple
injuries Methods A case–control study on 27 patients. We analyzed serum
values of PCT and CRP according to the presence of infection. Results Forty-eight percent of patients had infection. Gram-negative
bacteria were the predominant pathogens (54%), and Candida was
the most frequent isolated microorganism overall (15%). PCT had an
AUC of 0.681 (P = 0.0062), for the diagnosis of infection in patients on
VA ECMO, but failed to discriminate infection in the VV ECMO group
(P = 0.14). The AUC of CRP was 0.707 (P ≤0.001) in all ECMO patients. In
patients receiving VA ECMO, PCT had good accuracy with 1.89 ng/ml
as the cut-off (SE = 87.8%, SP = 50%) and CRP as well with 97.70 mg/l
as the cut-off (SE = 85.3%, SP = 41.6%). PCT and CRP tests in parallel
had SE = 87.2%, and SP = 25.9%. Four variables were identifi ed as
statistically signifi cant predictors of infection: PCT and CRP tests in
parallel (OR = 1.184; P = 0.0008), age (OR = 0.980; P ≤0.001), presence
of infection before ECMO implantation (OR = 1.782; P ≤0.001), and the
duration of ECMO support (OR = 1.056; P ≤0.001).l y
y
Results Mean ISS of patients was 14.6. Median suPAR upon ICU
admission was 3.74 ng/ml (range: 1.57 to 16.77 ng/ml). No correlation
was found between ISS and suPAR. Sepsis was presented in 27 patients. Median suPAR upon sepsis diagnosis was 7.05 ng/ml (range: 2.18 to
32.51 ng/ml) (P <0.0001 compared with ICU admission). This change
corresponded to median increase of 57.81%.i p
Conclusion The presented fi ndings show that measurement of serum
suPAR may help diagnosis of sepsis presenting in patients with multiple
injuries. P23 Activated protein C, severe sepsis and 28-day mortality
M De La Torre-Prados, A García-de la Torre, M Nieto-González,
I Lucena-González, R Escobar-Conesa, A García-Alcántara,
A Enguix-Armada
Hospital Virgen de la Victoria, Málaga, Spain
Critical Care 2012, 16(Suppl 1):P23 (doi: 10.1186/cc10630) Activated protein C, severe sepsis and 28-day mortality
M De La Torre-Prados, A García-de la Torre, M Nieto-González,
I Lucena-González, R Escobar-Conesa, A García-Alcántara,
A Enguix-Armada
Hospital Virgen de la Victoria, Málaga, Spain
Critical Care 2012, 16(Suppl 1):P23 (doi: 10.1186/cc10630) Conclusion Imeglimin improved whole body glucose utilization and
gluconeogenesis, a well-established marker of liver metabolic capacity
[4,5], and attenuated organ injury, at least in part due to inhibition of
the mitochondrial apoptosis pathway. Introduction Protein C (PC) defi ciency is prevalent in severe sepsis,
studies showing that more than 80% of patients with severe sepsis
have a baseline PC level below the lower limit of normal [1,2]. The aim
of the study was to relate the anticoagulation activity evaluated by PC,
with clinical parameters and 28-day mortality. Acknowledgements In memoriam of Xavier Leverve who initiated this
project; supported by an unrestricted grant from Poxel. References Acknowledgements In memoriam of Xavier Leverve who initiated this
project; supported by an unrestricted grant from Poxel. References 1. Vanhorebeek I, et al.: Crit Care Med 2009, 37:1355-1364. Methods A cohort study of 150 patients >18 years with severe sepsis
according to the Surviving Sepsis Campaign, in an ICU of a university
hospital. Demographic, clinical parameters and coagulation markers
during the fi rst 24 hours were studied. PC activity was analysed using
a haemostasis laboratory analyser (BCS® XP; Siemens). Descriptive and 2. Devos P, et al.: Curr Opin Clin Nutr Metab Care 2006, 9:131-139. 3. Fouqueray, et al.: J Diabetes Metab 2011, 2:4. 4. Albuszies G, et al.: Intensive Care Med 2007, 33:1094-1101. 5. Baumgart K, et al.: Crit Care Med 2010, 38:588-595. S9 Critical Care 2012, Volume 16 Suppl 1
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Correlation of VAP diagnosis with parameters of critically ill patients
in a general ICU Introduction We aimed to describe various parameters of critically ill
patients who developed VAP and correlate them with its outcome. Introduction We aimed to describe various parameters of critically ill
patients who developed VAP and correlate them with its outcome. Introduction We aimed to describe various parameters of critically ill
patients who developed VAP and correlate them with its outcome. Methods Twenty-three VAP cases out of 338 ICU patients were studied
retrospectively. Data regarding age, sex, etiology, scores (APACHE II,
SOFA, CPIS), CRP, miniBAL cultures, comorbidities, antibiotic exposure,
duration of mechanical ventilation, length of ICU and total stay, VAP
and patient outcome were recorded. Chi-square and Mann–Whitney U
tests were used for statistical analyses. y
Results VAP incidence was 23/338 (6.8%). Fourteen of 23(60.9%)
were males, and 9/23(39.1%) were surgical patients. Their age was
63.5 ± 16.6 years. APACHE II was 20.5 ± 6.7, initial SOFA was 8.8 ± 3.7,
SOFA at VAP was 9.4 ± 3.1, CPIS 2 days before VAP was 4.6 ± 2, CPIS the
day before VAP was 6 ± 1.2, and CPIS at VAP was 7.6 ± 1.3. Length of
stay was 25.5 ± 13.1 days, ICU stay was 24.8 ± 13.4 days, and duration
of mechanical ventilation was 22.5 ± 12.1 days. Previous antibiotic
exposure included: linezolid 10/23 (43.5%), vancomycin 2/23 (8.7%),
antipseudomonadic penicillins 14/23 (60.9%), β-lactams ± β-lactamase
inhibitor 7/23 (30.4%), quinolones 14/23 (60.9%), aminoglycosides
6/23 (26.1%), antifungals 4/23 (17.4%), carbapenems 1/23 (4.3%),
tigecycline 3/23 (13%), and colistin 8/23 (34.8%). Antibiotic therapy
after the positive miniBAL was modifi ed according to antibiograms. The
isolated microorganisms in miniBAL were A. baumannii 10/23 (43.5%),
P. aeruginosa 5/23 (21.7%), K. pneumoniae 4/23 (17.4%), Candida spp. 2/23 (8.7%), and other 4/23 (17.4%); one infection was polymicrobial. In 20/23 cases (87%) VAP was of late onset (>4 days) (9.7 ± 6.8 days). VAP was improved in 17/23 cases (73.9%), but 15/23 patients (65.2%)
died. High overall mortality may be attributed to grave condition. Most
patients were admitted to the ICU hours after they were admitted
to the hospital. Increased SOFA scores during admission (12 ± 2 vs. 7.7 ± 3.4, P = 0.009) and on the day of VAP diagnosis (11.5 ± 2.1 vs. 8.6 ± 3, P = 0.016) were associated with VAP deterioration. Increased
CPIS on the last 2 days before VAP was also associated with worse VAP
outcomes (6.2 ± 1.7 vs. j
Reference Reference Conclusion Both traditional and emerging infl ammatory biomarkers
can help in the diagnosis of infection in patients receiving ECMO. Indeed, we demonstrated for the fi rst time that PCT is a reliable
infection marker in patients undergoing VA ECMO. We suggest routine S10 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 concomitant PCT and CRP assay with defi nite cut-off values as a new
test to identify infection in patients undergoing VA ECMO. References 12th day. C-reactive protein (CRP) and PCT were measured daily. We
compared infected and noninfected patients. concomitant PCT and CRP assay with defi nite cut-off values as a new
test to identify infection in patients undergoing VA ECMO. References 12th day. C-reactive protein (CRP) and PCT were measured daily. We
compared infected and noninfected patients. p
p
Results A total of 50 patients were included during a 12-month
period (age 70.5 ± 9.4 years, 50% male). The 21 patients (42%) that
subsequently developed infection (16 surgical wound infections) had
age, Charlson comorbidity score, primary diagnosis, surgical procedure,
intestinal preparation and antibiotic prophylaxis similar to those who
had an uneventful recovery. Infection was less frequent in men (28%
vs. 72%, P = 0.042). Moreover PCT and CRP before surgery were equally
low in patients with or without postoperative infection (0.10 ± 0.06 vs. 0.07 ± 0.04 ng/ml; 1.81 ± 2.83 vs. 0.72 ± 1.12 mg/dl, respectively). After
surgery, both PCT and CRP increased markedly: PCT increased around
10× the basal level and peaked at 24 to 48 hours; CRP increased more
than 15× and peaked at 48 hours. Infection was diagnosed a median
of 7 days after surgery. The CRP time-course from the day of surgery
onwards was signifi cantly diff erent in infected and noninfected patients
(P = 0.001). In opposition, the PCT time-course was almost parallel in
both groups (P = 0.866). To assess the diagnostic performance of each
biomarker, we performed multiple comparisons between infected and
noninfected patients between day 5 and day 9. The CRP concentration
was signifi cantly diff erent (P < 0.01, Bonferroni correction) on days 6, 7
and 8. The area under the ROC curve of CRP of days 6, 7 and 8 were 0.74,
0.73 and 0.75, respectively. Procalcitonin as a predictive marker for PCR test and blood culture
results in suspected invasive candidemia A Cortegiani, SM Raineri, F Montalto, MT Strano, A Giarratano
University Hospital Policlinico P. Giaccone, Palermo, Italy
Critical Care 2012, 16(Suppl 1):P29 (doi: 10.1186/cc10636) A Cortegiani, SM Raineri, F Montalto, MT Strano, A Giarratano
University Hospital Policlinico P. Giaccone, Palermo, Italy
Critical Care 2012, 16(Suppl 1):P29 (doi: 10.1186/cc10636) Introduction Procalcitonin (PTC) seems to have potential to predict
the result of blood culture (BC) supporting the diagnosis of invasive
candidemia. Although blood culture is still the gold standard, PCR
assays are able to quickly and reliably detect fungi in blood in suspected
invasive candidemia. Our aim is to verify the potential of PTC values to
predict the result of PCR assay in suspected invasive candidemia. y
Methods We retrospectively analyzed 78 patients with suspected
invasive candidemia from whom we obtained PCT value, BC and
PCR assay. All tests have been obtained on the day in which patients
reached a Candida score ≥4. We calculated PTC mean values according
to BC and PCR results and compared data using the Mann–Whitney U
test. We performed the ROC analysis to test the diagnostic performance
of PTC with regards to BC and PCR result. Conclusion Our fi ndings support the prognostic value of SOFA score. CPIS values of 6, although not diagnostic, may need increased alertness
on behalf of the clinician. R f Results PCR tests and BC were both negative in 48 patients and the
PTC mean value in this group was 21.5 ng/ml while 19 patients were
PCR-positive and BC-positive with a PTC mean value of 2.07 ng/ml. The
diff erence between these PCT mean values was signifi cant (P = 0.0001). In eight cases BC were negative whereas PCR tests were positive with
the PCT mean level in this group being 1.82 ng/ml. No patient resulted
PCR-negative and BC-positive. According to PCR results only, there
was a signifi cant diff erence between PTC mean values in positives and
negatives (P = 0.0001). The ROC analysis showed that the best PTC cut-
off value for prediction of BC result was 4.57 with AUC of 0.91 (CI 0.83 to
0.96, sensitivity 99%, specifi city 80.39%). Concerning the PCR result, the
calculated cut-off was 4.31 with AUC of 0.96 (CI 0.948 to 1, sensitivity
96.6%, specifi city 97.9%; positive predictive value 94.51%; negative
predictive value 97.83%). References
1. Vincent JL, et al.: Intensive Care Med 1996, 22:707-710. 2. P27
Correlation of VAP diagnosis with parameters of critically ill patients
in a general ICU 4.1 ± 1.8 and 6.8 ± 1.2 vs. 5.7 ± 1.1, P = 0.03 and
P = 0.03, respectively).i Conclusion After a major elective surgical insult both CRP and PCT
serum levels increased independently of the presence of infection. The CRP time-course showed to be useful in the early detection of an
infectious complication whereas PCT was unhelpful. Procalcitonin as a predictive marker for PCR test and blood culture
results in suspected invasive candidemia
A Cortegiani, SM Raineri, F Montalto, MT Strano, A Giarratano
University Hospital Policlinico P. Giaccone, Palermo, Italy
Critical Care 2012, 16(Suppl 1):P29 (doi: 10.1186/cc10636) Procalcitonin as a predictive marker for PCR test and blood culture
results in suspected invasive candidemia Papazian L, et al.: Am J Respir Crit Care Med 1995, 152:1982-1991. 1. Vincent JL, et al.: Intensive Care Med 1996, 22:707-710. 2. Papazian L, et al.: Am J Respir Crit Care Med 1995, 152:1982-1991. P27 P27
Correlation of VAP diagnosis with parameters of critically ill patients
in a general ICU
DK Matthaiou, A Ioannidis, G Gounti, D Lathyris, A Vathis, S Vasiliagkou,
K Kontopoulou, K Mandraveli, E Antoniadou
‘G. Gennimatas’ General Hospital, Thessaloniki, Greece
Critical Care 2012, 16(Suppl 1):P27 (doi: 10.1186/cc10634) j
Reference A CRP concentration >5.0 mg/dl at day 6
was predictive of infection with a sensitivity of 85% and a specifi city of
62% (positive likelihood ratio 2.2, negative likelihood ratio 0.2). 1. Bizzarro MJ, et al.: Pediatr Crit Care Med 2011, 12:277-281. 2. Kao LS, et al.: ASAIO J 2011, 57:231-238. P30 P30
Would procalcitonin measurement aid antimicrobial stewardship in
a UK district general hospital mixed adult critical care population? J Clayton, J White, L Wilson, M Leonard, J Cuniff e
Wirral University Teaching Hospital NHS Foundation Trust, Wirral, UK
Critical Care 2012, 16(Suppl 1):P30 (doi: 10.1186/cc10637) Introduction We sought to establish what impact knowledge of
procalcitonin (PCT) levels could have on antimicrobial prescribing
and stewardship within our 18-bed mixed critical care unit. Assicot
and colleagues demonstrated that PCT levels are raised during sepsis
and can correlate with the severity [1]. The PCT level peaks after 6 to
12 hours and has a half-life of approximately 25 to 36 hours in critically
ill patients [2], declining with adequate treatment. A recent multicentre
trial demonstrated reduced duration of antibiotic therapy by using
PCT-guided treatment strategy; however, only 10% of the cohort was
surgical patients and therefore this fi nding cannot be extrapolated to a
general critical care population [3]. Conclusion The late-onset candidemia are more likely to be associated
with death than earlier episodes. Unresolved organ failure as assessed
through SOFA score despite eff ective antifungal treatment was
associated with death, while PCT failed to predict the outcome. References Methods The question was posed: would knowledge of PCT levels
have altered real-time clinical management of patients on established
antimicrobial therapy? Over a 2-month period patients were treated
in a conventional manner based on clinical fi ndings and standard
investigations. Plasma samples from days 0 (respective to antimicrobial
therapy) 1, 3, 5 and 7 were analysed for PCT. Nonparametric statistical
analysis of PCT levels was available for a retrospective multidisciplinary
team review of case notes. This was performed within the context of a
local service review and the chair of the local ethics committee gave
approval for analysis of plasma samples and case-note reviewi 1. Charles PE, et al.: Intensive Care Med 2006, 32:1577-1583. 2. Charles PE, et al.: Intensive Care Med 2009, 35:2146-2150. 3. Martini A, et al.: J Infect 2010, 60:425-430. Usefulness of daily monitoring of procalcitonin and C-reactive
protein in the early diagnosis of infection after elective colonic
surgery g
y
J Rebanda, P Povoa p
,
,
,
g
Critical Care 2012, 16(Suppl 1):P28 (doi: 10.1186/cc10635) Introduction The diagnosis of infectious complications after elective
colonic surgery is frequently misleading, delaying its resolution. Recently several biomarkers, namely procalcitonin (PCT), have been
described as more specifi c in infection diagnosis. Conclusion According to our data, PTC seems to be characterized by
a remarkable diagnostic performance and predictive value for both
BC and PCR assay in suspected invasive candidemia. PCT could be
considered as the fi rst step of the diagnostic process for suspected
invasive candidemia in order to spare as much time as possible before
starting a pre-emptive antifungal therapy. This may lead to less useless
therapies in negative patients and quicker and more reliable start of i
Methods We conducted a prospective observational study segregating
patients submitted to elective colonic surgery. Patients were assessed
before surgery, and then from the day of surgery until discharge or the Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S11 follow-up data including PCT measurement were collected. The SOFA
score was calculated daily during the fi rst week of antifungal treatment. Survivors at discharge from the ICU were compared to nonsurvivors by
univariate followed by a Cox regression analysis. follow-up data including PCT measurement were collected. The SOFA
score was calculated daily during the fi rst week of antifungal treatment. Survivors at discharge from the ICU were compared to nonsurvivors by
univariate followed by a Cox regression analysis. treatment in positive patients while waiting for the BC and antibiogram
results. R f Assessment of the usefulness of presepsin (soluble CD14 subtype)
in septic patients Assessment of the usefulness of presepsin (soluble CD14 subtype)
in septic patients
T Nishida1, H Ishikura1, A Murai1, Y Irie1, R Yuge1, T Kamitani1, S Endo2
1Fukuoka University Hospital, Fukuoka City, Japan; 2Iwate Medical University,
Iwate, Japan
Critical Care 2012, 16(Suppl 1):P32 (doi: 10.1186/cc10639) Results Twenty-seven patients were identifi ed. Antimicrobial cessation
was deemed possible in seven of these cases at day 5. Nonescalation
of treatment was supported in six further cases. In one case treatment
had been escalated and PCT supported this decision. This would have
resulted in 19 fewer days of antibiotic therapy. T Nishida1, H Ishikura1, A Murai1, Y Irie1, R Yuge1, T Kamitani1, S Endo2
1Fukuoka University Hospital, Fukuoka City, Japan; 2Iwate Medical University
Iwate, Japan T Nishida1, H Ishikura1, A Murai1, Y Irie1, R Yuge1, T Kamitani1, S Endo2
1Fukuoka University Hospital, Fukuoka City, Japan; 2Iwate Medical University,
Iwate, Japan Critical Care 2012, 16(Suppl 1):P32 (doi: 10.1186/cc10639) Critical Care 2012, 16(Suppl 1):P32 (doi: 10.1186/cc10639) Introduction Sepsis is a life-threatening condition that is characterized
by a whole-body infl ammatory state. The early diagnosis and
treatments of sepsis will improve the outcome of the patients. The aims
of this study were to investigate the most useful biomarkers which are
serum levels of soluble CD14 subtype (sCD14-ST) named presepsin,
procalcitonin (PCT), IL-6, and C-reactive protein (CRP) as markers for
early diagnosis of sepsis. Conclusion Our experience suggests the availability of the PCT
response between days 0 and 5 would have been a useful adjunct in
monitoring treatment of sepsis on our unit and would have facilitated
timely de-escalation and hence exposure to antimicrobial therapy. We hypothesise such a reduction could help to prevent antimicrobial
resistance, lead to decreased pharmacy and consumable costs and
reduce the incidence of adverse antimicrobial-related events. Reference 1. Charles PE, Castro C, Ruiz-Santana S, et al.: Serum procalcitonin levels in
critically ill patients colonized with Candida spp: new clues for the early
recognition of invasive candidiasis? Intensive Care Med 2009, 35:2146-2150. y
g
y
Results Fifty patients were included among whom 28 (56%) died
in the ICU. Candida albicans was the most common isolated yeast
(58%), regardless of the outcome. Nonsurvivors were elder and had
a greater SAPS II score value on admission than survivors (55.8 ± 21.7
vs. 42.5 ± 14.9 points, P = 0.01). The time elapsed between the ICU
admission and the onset of invasive candidiasis was signifi cantly longer
in the nonsurvivors than in the survivors (8.3 ± 12.8 vs. 1.2 ± 2.8 days,
P = 0.01). At the onset of candidemia, the nonsurvivors were more
severely ill as assessed through SOFA score calculation (10.4 ± 4.4 vs. 7.8 ± 3.9 points, P = 0.04). Antifungal treatment was given within the
fi rst 24 hours following the onset of candidemia in 60% of the whole
patients and was always appropriate, regardless of the survival. During
therapy, the SOFA score remained greater in the nonsurvivors than
in the survivors. In contrast, PCT failed to diff erentiate the survivors
from the nonsurvivors the day antifungals were started (8.7 ± 13.1
vs. 4.5 ± 4.1 ng/ml, P = 0.21), as well as the following days. The SAPS
II, the SOFA score and the time elapsed between ICU admission and
candidemia onset were the sole independent predictors of death in our
study population. References Methods A single-center, prospective, observational study. Patients
who had one or more systemic infl ammatory response syndrome (SIRS)
criteria were included in this study. The blood samples for measuring
the markers were collected and the severity of sepsis was evaluated
at the time of admission and every other day for a week. Eighty-four
patients were enrolled for this prospective study from June 2010 to
June 2011. 1. Assicot M, et al.: Lancet 1993, 341:515-518. 2. Meisner M, et al.: Intensive Care Med 2000, 26:1193-1200. 3. Bouadma L, et al.: Lancet. 2010, 375:463-474. P33 Circulating cell-free DNA levels measured by a novel simple
fl uorescent assay are predictive for outcome of severe sepsis
A Douvdevani, A Avriel, M Paryente Wiessman, V Novack, Y Almog
Soroka University Medical Center and Ben-Gurion University of the Negev,
Beer-Sheva, Israel
Critical Care 2012, 16(Suppl 1):P33 (doi: 10.1186/cc10640) Results We enrolled 49 subjects. There was no signifi cant correlation
between EA levels and endotoxin concentration measured by LAL
assay. There were no signifi cant diff erence in the EA levels of the Gram-
negative infection patients and the others. The diagnostic value of EA
levels was investigated using ROC curve analysis. For the diagnosis of
sepsis, area under the curve of EA levels, PCT, presepsin, IL-6 and CRP
were calculated as 0.76, 0.83, 0.89, 0.88 and 0.72, respectively. Both the
EA levels and ICU mortalities of the patients who met the criteria for
severe sepsis were signifi cantly higher than those of the patients who
did not have sepsis (0.44 ± 0.21 vs. 0.22 ± 0.17, P = 0.0004; EA levels,
33% vs. 5%, P = 0.022; ICU mortalities). There was a positive relationship
between EA levels and thrombomodulin (r = 0.30, P = 0.049), EA
levels and lactate (r = 0.31, P = 0.028), and EA levels and SOFA score
(r = 0.34, P = 0.02). There was a negative relationship between EA levels
and platelet counts (r = –0.34, P = 0.018), EA levels and antithrombin
(r = – 0.41, P = 0.004), and EA levels and protein C (r = –0.38, P = 0.010). Conclusion EA levels in the patients on ICU admission correlated
with disease severity. Moreover, we strongly suggested that EAA may
have the potential to assess organ dysfunction with sepsis, especially
coagulopathy. Introduction Circulating cell-free DNA (CFD) was found to be a predic-
tor of outcome in severe sepsis and septic shock [1]. The standard
CFD assays are work-intensive and not practical for routine clinical
laboratory use. We have recently developed a new simple, fast and
reliable assay for CFD measurement. The aim was to evaluate the
association between admission levels of CFD and severe sepsis
outcome in patients hospitalized in intensive care utilizing the new
assay. y
Methods Seventy-six patients diagnosed with severe sepsis hospitalized
in the ICU were enrolled in the study. Prognostic value of serum galactomannan in mixed ICU patients:
a retrospective observational study Prognostic value of serum galactomannan in mixed ICU patients:
a retrospective observational study
S Teering, A Verreth, W Verlinden, J Jacobs, S Pilate, M Peetermans,
A Verrijcken, N Van Regenmortel, I De laet, K Schoonheydt, H Dits,
M Van De Vyvere, M Malbrain
ZNA Stuivenberg, Antwerp, Belgium
Critical Care 2012, 16(Suppl 1):P35 (doi: 10.1186/cc10642) Conclusion By using a simple fl uorometric assay, we were able to
measure CFD levels in severe septic patients. CFD levels were found
to be an independent predictors for 28-day mortality. We believe that
CFD is an objective, reliable and integrative prognostic marker that will
allow fast evaluation of intensive care patients and predicting mortality. References Introduction Little is known about galactomannan (GM) testing in
mixed ICU patients that are often not neutropenic. The aim of this study
was to look for the incidence and outcome of invasive aspergillosis (IA)
in critically ill patients, to validate previous reported GM thresholds and
to evaluate the prognostic value of GM. g
Methods A retrospective study of 474 GM samples in 160 patients from
1 January 2003 to 1 February 2004. GM tests were ordered because of
clinical suspicion of IA or on a regular basis in immune compromised
patients. The number of samples per patient was 3 ± 2.6. Similarly to
the EORTC criteria we defi ned ‘proven IA’ as those patients with positive
tissue specimen, ‘probable IA’ as those with positive cultures, and
‘possible IA’ as those treated with antifungals (high clinical index of
suspicion). The number of positive samples (GM >0.5 ng/ml) was 230
(48.5%). Patient characteristics: M/F ratio 1/1, age 64.5 ± 15.9, SAPS
45.5 ± 16.8, APACHE II 19.3 ± 8, SOFA 5.8 ± 3.5, mean days on ventilation
12.9 ± 8.7, mean CRP 10.4 ± 11.2 mg/dl. 1. Saukkonen K, et al.: Clin Chem 2008, 54:1000-1007. 2. Goldshtein H, et al.: Ann Clin Biochem 2009, 46:488-494. 1. Saukkonen K, et al.: Clin Chem 2008, 54:1000-1007. 1. Saukkonen K, et al.: Clin Chem 2008, 54:1000-1007. 2. Goldshtein H, et al.: Ann Clin Biochem 2009, 46:488-494. ,
,
2. Goldshtein H, et al.: Ann Clin Biochem 2009, 46:488-494. Procalcitonin has a poor prognosis value in critically ill patients with
candidemia Procalcitonin has a poor prognosis value in critically ill patients with
candidemia
PE Charles, R Bruyère, H Roche, JP Quenot, S Prin, A Pavon, F Dalle
University Hospital, Dijon, France
Critical Care 2012, 16(Suppl 1):P31 (doi: 10.1186/cc10638) Results Eighteen were SIRS and 42 were sepsis at the time of
registration. In the receiver operating characteristics (ROC) analysis,
the area under the curve (AUC) to distinguish sepsis was the highest
for presepsin (0.92) followed by IL-6 (0.89), PCT (0.88), and CRP (0.83). The ROC analysis showed that at a cut-off value 647 pg/ml, presepsin
may be able to discriminate between patients with and without sepsis
with a sensitivity and a specifi city of 92.9% and 83.3% respectively with
95% confi dence intervals of 0.929 (0.805 to 0.985). And the presepsin
values were signifi cantly higher in the patients with the more severe
septic condition (for example, sepsis, severe sepsis, septic shock). In
addition, a signifi cant correlation was found between the SOFA scores
and the presepsin values (r2 = 0.258; P <0.01). But there was only
weak correlation between APACHE II scores and the presepsin values
(r2 = 0.053). PE Charles, R Bruyère, H Roche, JP Quenot, S Prin, A Pavon, F Dalle
University Hospital, Dijon, France
Critical Care 2012, 16(Suppl 1):P31 (doi: 10.1186/cc10638) Introduction Candidemia is an infrequent but serious infection in the
critically ill patients. Although eff ective antifungal drugs are available,
mortality rates remain high so far. Procalcitonin (PCT) repeated
measurements have proven useful for assessing the prognosis and the
antimicrobial treatment responsiveness in the patients with systemic
bacterial infection. Little is known about it in the setting of candidemia. The PCT predictive value regarding the outcome of such patients was
therefore addressed. Conclusion In this study, presepsin is the most valuable predictor
about sepsis compared with PCT, IL-6, and CRP. Moreover, these results
suggest that presepsin values can serve as a parameter that closely Methods A retrospective single-centre observational study. All
patients with ICU-acquired pure candidemia between 2005 and 2011
were included. Baseline characteristics and both clinical and biological S12 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 who had suspected infection in the emergency room and ICU, but
the clinical usefulness of measuring EAA in the diagnosis of sepsis in
critically ill patients is not yet clear. P33 Serum CFD levels were measured
upon admission and after 72 hours using the SYBR-Gold rapid direct
fl uorescent assay [2]. Primary outcome was 28-day mortality. Logistic
regression analysis of CFD quintiles adjusted for baseline comorbidities
and severity of the disease was utilized. y
Results Out of those diagnosed with severe sepsis, 28 (36.8%) have died
either during hospitalization or within 28 days of admission to the ICU. Decedents had higher APACHE II score on admission (median 24.5 vs. 17.5, P = 0.140). Similarly their admission CFD levels were higher than
in survivors (median 3,712 vs. 1,974, P = 0.001). Spearman’s correlation
analysis showed signifi cant correlation between APACHE II score and
CFD level on admission (ρ = 0.315, P = 0.007). ROC curve for APACHE
II score and CFD level on admission for prediction of 28-day mortality
showed area under the curve of 0.59, 95% CI 0.44 to 0.74 (P = 0.208),
for APACHE II score; and area under the curve of 0.73, 95% CI 0.60
to 0.86 (P = 0.001), for CFD level on admission. The study group was
divided into quintiles by CFD levels of admission. The 28-day mortality
rate was 12.5% in the CFD lowest quintile and 60.9% in the highest
quintile. Logistic regression analysis showed that adjusted for age,
sex and APACHE II score CFD divided into quintiles was signifi cantly
associated with death at 28 days, OR = 1.83 per quintile (95% CI 1.12
to 2.98, P = 0.015). g
Reference Reference Methods We performed an observational cohort study in critically
ill patients in the ICU of a tertiary care hospital. We investigated the
correlation between EA levels and blood concentration of endotoxin
measured by the chromogenic limulus amoebocyte lysate (LAL) assay,
causative microorganism identifi ed in laboratory culture, procalcitonin
(PCT), soluble CD14 subtype (named presepsin), IL-6, antithrombin,
protein C, thrombomodulin, lactate, disseminated intravascular
coagulation scores in both the Japanese Ministry of Health and Welfare
and the Japanese Association for Acute Medicine, and severity of illness
at ICU admission.i 1. Endo S, Yaegashi Y, Sato N, et al.: Comparative study of soluble CD14 and
soluble CD14-subtype in sepsis. Med Postgrad 2006, 44:381-385. Reference 1. Marshall JC, et al.: J Infect Dis 2004, 190:527-534. Procalcitonin has a poor prognosis value in critically ill patients with
candidemia refl ects the pathology. So we strongly suggest that presepsin will be
not only a very useful new biomarker for a diagnosis of the sepsis, but
also useful for monitoring the severity of the disease in the near future. Reference P34 Clinical usefulness of measuring endotoxin activity on ICU
admission
A Murai, H Ishikura, T Nishida, Y Irie, T Kamitani, R Yuge, T Kitamura,
T Umemura
Fukuoka University Hospital, Fukuoka City, Japan
Critical Care 2012, 16(Suppl 1):P34 (doi: 10.1186/cc10641) g
Results In our study population 5% had proven IA, 5% probable
IA, 17.5% possible IA and 72.5% had no IA. We could not identify a
GM threshold for IA. The best threshold was GM >1.1 for identifying
patients with IA (proven + probable + possible) with a specifi city of
70.7% and negative predictive value of 76.6%. The ICU mortality was
41.9% and the hospital mortality was 58.1%. Patients who died in the
ICU had higher APACHE, SAPS and SOFA scores (P <0.0001), and had a
signifi cant increase in GM during their stay (0.27 ± 1.26 vs.–0.43 ± 1.7,
P = 0.004). We observed higher mean GM values in nonsurvivors but Introduction According to the Surviving Sepsis Campaign, diagnosis
of sepsis and infection is urgent, therefore rapid diagnostic tools play
a major role in the management of septic patients. The endotoxin
activity (EA) assay (EAA) is one of those tools based on the ability of
antigen–antibody complexes to prime neutrophils for an augmented
respiratory burst response [1]. EAA has been used widely in patients Introduction According to the Surviving Sepsis Campaign, diagnosis
of sepsis and infection is urgent, therefore rapid diagnostic tools play
a major role in the management of septic patients. The endotoxin
activity (EA) assay (EAA) is one of those tools based on the ability of
antigen–antibody complexes to prime neutrophils for an augmented
respiratory burst response [1]. EAA has been used widely in patients S13 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 this was not statistically signifi cant. Patients who died in the hospital
also showed a signifi cant increase in GM during their stay (0.11 ± 1.55
vs. –0.48 ± 1.51, P = 0.017). There was a trend towards higher GM values
in patients treated with piperacillin/tazobactam (n = 34) but this was
not statistically signifi cant. Neutropenic patients (n = 31) showed an
increase in GM during their stay (0.32 ± 1.3 vs. –0.43 ± 1.7, P = 0.07). Patients on total parenteral nutrition (n = 125) had higher maximal
GM levels (1.55 ± 1.94 vs. P34 0.88 ± 1.25, P = 0.058). Patients that were
mechanically ventilated had signifi cantly higher mean (P = 0.038) and
maximal (P = 0.007) GM levels. The presence of IA was associated with
100% hospital mortality. admission. Heart rate variability (HRV) is decreased in severe sepsis. The objective was to determine the ability of a panel of HRV indices
to identify physiologically stable ED sepsis patients who will develop
worsening organ failure. We hypothesized that patients meeting the
outcome of progressive organ failure will have decreased HRV on initial
presentation. Methods We performed a prospective observational study of adult
ED patients admitted to the hospital for infection and treated with
i.v. antibiotics. Patients in overt shock (vasopressor requirement or
mechanical ventilation) at enrollment or with the inability to provide
written informed consent were excluded. A panel of HRV indices
was assessed over a 2-hour ED period using CIMVA (continuous
individualized multiorgan variability analysis) software including
standard deviation (SD), LF/HF ratio, Poincare SD, sample entropy,
wavelet AUC, detrended fl uctuation analysis (DFA), correlation
dimension, and the Lyapunov exponent. Patients were followed to
assess the occurrence of the primary outcome of increased organ failure
(SOFA score increase greater than 1 point at 24 hours), mechanical
ventilation, vasopressor use, or in-hospital mortality. p
y
Conclusion The current GM threshold of 0.5 ng/ml does not allow one
to discriminate between patients with and without IA. A threshold of
1.1 ng/ml had the best specifi city and negative predictive value for IA. There seems to be a correlation between GM levels and total parenteral
nutrition due to interference with the ELISA test. p
p
y
Results We enrolled 105 ED sepsis patients. Twenty patients were
removed due to nonsinus cardiac rhythm or poor data quality of the
telemetry signal. Complete HRV assessment was performed on 81
subjects with 17 patients removed who developed shock in the ED. The primary outcome was met in 44% (28/64) of the cohort. On HRV
assessment, outcome patients had a lower LF/HF ratio (1.47 vs. 3.11,
P = 0.009) and DFA (0.65 vs. 0.94, P = 0.04) compared with stable
patients with no diff erences in other HRV indices. The overall mortality
rate was 15%. Compared to stable patients, outcome patients had no
diff erence in age, initial heart rate, systolic blood pressure, or serum
lactate with similar initial SOFA scores that were higher at 24 hours (1.0
vs. P38 P38
Severe community-acquired pneumonia: risk factors for in-hospital
mortality
JM Pereira1, JA Paiva1, JP Baptista2, F Froes3, J Gonçalves-Pereira4
1Centro Hospitalar S. João, Porto, Portugal; 2Hospitais Universidade Coimbra,
Portugal; 3Hospital Pulido Valente – CHLN, Lisbon, Portugal; 4Hospital S. Francisco Xavier, Lisbon, Portugal
Critical Care 2012, 16(Suppl 1):P38 (doi: 10.1186/cc10645) Severe community-acquired pneumonia: risk factors for in-hospital
mortality JM Pereira1, JA Paiva1, JP Baptista2, F Froes3, J Gonçalves-Pereira4
1Centro Hospitalar S. João, Porto, Portugal; 2Hospitais Universidade Coimbra,
Portugal; 3Hospital Pulido Valente – CHLN, Lisbon, Portugal; 4Hospital S. Francisco Xavier, Lisbon, Portugal
Critical Care 2012, 16(Suppl 1):P38 (doi: 10.1186/cc10645) f
Conclusion The BDG profi le in ICU patients is similar to that of other
inpatients. It can be useful in clinical practice if implemented in the
proper setting and interpreted after consideration of the patient’s
clinical status. Introduction Severe community-acquired pneumonia (SCAP) is an
important cause of hospital mortality. The goal of this study was to
identify variables associated with increased risk of in-hospital mortality
at ICU admission. Introduction Severe community-acquired pneumonia (SCAP) is an
important cause of hospital mortality. The goal of this study was to
identify variables associated with increased risk of in-hospital mortality
at ICU admission. P34 3.0), a higher ICU transfer rate (62 vs. 20%, P <0.001) and increased
ICU length of stay. P36
Analysis of (13)β-D-glucan as a diagnostic adjunct for invasive
fungal infections in the ICU setting
N Yamada, K Shirai, T Doi, K Kumada, M Nakano, S Yoshida, I Toyoda,
S Ogura
Gifu University Hospital, Gifu, Japan
Critical Care 2012, 16(Suppl 1):P36 (doi: 10.1186/cc10643) References 1. Committee for Guideline for Management of Deep-seated Mycoses 2007: 1. Committee for Guideline for Management of Deep-seated Mycoses 2007:
Guideline for Management of Deep-seated Mycoses 2007. Tokyo: Kyowa kikaku;
2007. 1. Committee for Guideline for Management of Deep-seated Mycoses 2007:
Guideline for Management of Deep-seated Mycoses 2007. Tokyo: Kyowa kikaku; 1. Committee for Guideline for Management of Deep-seated Mycoses 2007:
G id li
f
M
f D
d M
2007 T k
K
kik k g
p
y
Guideline for Management of Deep-seated Mycoses 2007. Tokyo: Kyowa kikaku;
2007. Guideline for Management of Deep-seated Mycoses 2007. Tokyo: Kyowa kikaku;
2007. Methods A prospective, multicentre, observational cohort study of
all patients with SCAP consecutively admitted to 15 Portuguese ICUs
during a 12-month period. Demographic characteristics, co-morbidities,
general severity scores (SAPS II, SAPS3, total SOFA), microbiological data
and initial empirical antibiotherapy were recorded. Logistic regression
analysis was performed to identify predictors of in-hospital mortality. Results A total of 505 (14%) of the 3,572 enrolled patients had SCAP,
mostly male (66%) with a median age 58 (29 to 82). Median general
severity scores were: SAPS II 44 (21 to 80), SAPS3 65 (41 to 98) and
total SOFA 8 (3 to 17). Comorbidities were present in 74% of the
patients and the most frequent were: diabetes mellitus (22%), chronic
respiratory failure (18%) and alcoholism (15%). Median Charlson’s
comorbidity index was 4 (0 to 13). At ICU admission, 44% of SCAP
patients had septic shock. Thirty-seven per cent of the cases were
microbiologically documented (St. pneumoniae – 24%; infl uenza A 2. Drosos EK, et al.: β-D-glucan assay for the diagnosis of invasive fungal
infections: a meta analysis. Clin Infect Dis 2011, 52:750–770. 2. Drosos EK, et al.: β-D-glucan assay for the diagnosis of invasive fungal
infections: a meta analysis. Clin Infect Dis 2011, 52:750–770. Analysis of (13)β-D-glucan as a diagnostic adjunct for invasive
fungal infections in the ICU setting Introduction Since invasive fungal infections are associated with
high morbidity and increased mortality in the ICU, early diagnosis
and treatment are essential. This study assesses the performance of
an assay of serum (13)-D-glucan (BDG) concentration in patients
admitted to the ICU. Conclusion While standard physiologic parameters in the ED were
unable to diff erentiate sepsis patients who developed increased organ
failure, a decreased LF/HF ratio and DFA, measurements of variability
representing physiologic reserve, was associated with impending
deterioration. The ability of decreased HRV to predict clinical outcomes
in a high-risk yet physiologically identical population at presentation
supports the need for continued studies into the predictive role of HRV
assessment in the ED to supplement clinical decision-making in sepsis
patients. Methods Patients admitted to our advanced critical care center from
April 2007 to March 2011 with measurements of BDG were enrolled
in this retrospective study. BDG was measured when invasive fungal
infection was suspected based on the Japanese guidelines for
diagnosis and treatment of invasive fungal infections. BDG levels were
measured using the WAKO method. A BDG level greater than 11 pg/ml
was considered to be positive. No gray zone was considered. Results Of the 872 patients enrolled in this study, there were 580 males
and 292 females. The mean age was 60.7 years (range: 48 to 87). The
mortality rate was 16.3%. We make a clinical diagnosis of invasive
fungal infections according to Japanese guidelines for diagnosis and
treatment of invasive fungal infections. The sensitivity of the BDG
assay was 71.9% and the specifi city was 91.0%. There were signifi cant
diff erences in sensitivity, specifi city, and optimal cut-off points among
patients with diff erent clinical conditions (that is, trauma, burn,
postoperative, and medical conditions).The area under the summary
receiver operating characteristic curve was 0.82, but there were also
diff erences across clinical categories. Characteristics of leptospirosis patients admitted to a tropical
university hospital during the 2000 to 2010 period
H Mehdaoui, E Caffi ot, R Theodose, R Valentino, D Resiere, C Chabartier,
M Jonas
Fort de France University Hospital, Fort De France, Martinique
Critical Care 2012, 16(Suppl 1):P40 (doi: 10.1186/cc10647) Characteristics of leptospirosis patients admitted to a tropical
university hospital during the 2000 to 2010 period
H Mehdaoui, E Caffi ot, R Theodose, R Valentino, D Resiere, C Chabartier,
M Jonas
Fort de France University Hospital, Fort De France, Martinique
Critical Care 2012, 16(Suppl 1):P40 (doi: 10.1186/cc10647) Introduction Leptospirosis is an endemic disease in the intertropical
area. Most of the patients present with mild to moderate clinical forms,
but leptospirosis may lead to multiple organ failure and death. Methods We retrospectively analyzed the characteristics of 113
patients with leptospirosis admitted to our emergency department. Results PCR and/or immunological investigations confirmed the Introduction Leptospirosis is an endemic disease in the intertropical
area. Most of the patients present with mild to moderate clinical forms,
but leptospirosis may lead to multiple organ failure and death. Introduction Leptospirosis is an endemic disease in the intertropical
area. Most of the patients present with mild to moderate clinical forms,
but leptospirosis may lead to multiple organ failure and death. Methods We retrospectively analyzed the characteristics of 113
patients with leptospirosis admitted to our emergency department. Results PCR and/or immunological investigations confi rmed the
diagnosis for 88 patients. We compared the periods before and after
PCR diagnosis implementation (2006), and determined the pattern of
the most severe forms. Thirty-two patients were admitted to our ICU. Eight of the ICU patients died including four with confi rmed diagnosis. Nineteen patients were diagnosed before 2006, and 69 during the
period to 2010. Patients were less frequently admitted to the ICU during
the second period (29% vs 63% P = 0 013) ICU patients had a higher p
p
y
p
g
Methods We retrospectively analyzed the characteristics of 113
patients with leptospirosis admitted to our emergency department.i Conclusion Disease severity evaluated by SAPS II and sepsis staging
score and inappropriate initial antibiotherapy were independent
risk factors for in-hospital mortality. The use of a macrolide was
independently associated with a reduced risk of death. Results PCR and/or immunological investigations confi rmed the
diagnosis for 88 patients. We compared the periods before and after
PCR diagnosis implementation (2006), and determined the pattern of
the most severe forms. Thirty-two patients were admitted to our ICU. Eight of the ICU patients died including four with confi rmed diagnosis. Nineteen patients were diagnosed before 2006, and 69 during the
period to 2010. P40 (H1N1) virus – 20%; Enterobacteriaceae – 18%) and 12% had secondary
bacteremia. Antibiotics were administered in the fi rst 3 hours after
hospital admission in 71% of the patients and 76% of them received
combination therapy. Antibiotherapy was appropriate in 80% with a
median duration of 8 days. Median ICU and hospital lengths of stay
were 10 and 19 days respectively. Median ICU and hospital mortalities
were 25% and 34% respectively. Variables independently associated
with hospital mortality were: SAPS II score (OR 1.06; 95% CI 1.037 to
1.086), severe sepsis (OR 3.61; 95% CI 1.334 to 9.791), septic shock (OR
4.25; 95% CI 1.61 to 11.194), inappropriate antibiotherapy (OR 5.06;
95% CI 1.766 to 14.516) and the use of a macrolide (OR 0.40; 95% CI
0.203 to 0.809). Systemic corticosteroids for community-acquired pneumonia in
adults RJ Pugh, N Roy Glan Clwyd Hospital, Rhyl, UK Introduction We aimed to evaluate evidence from randomised
controlled trials (RCTs) investigating the eff ect of systemic
corticosteroids in adults with community-acquired pneumonia
(CAP). Observational data suggest that corticosteroids may decrease
mortality in severe CAP [1], and several large RCTs have been published
since the recent Cochrane review [2]. Conclusion The use of PCR dramatically improved the diagnosis of mild
to moderate forms of leptospirosis and led to an apparent increase its
incidence. Severe forms were less easy to assess as they occur later and
we should have a more aggressive policy to improve the immunological
diagnosis which was sometimes neglected since the implementation
of PCR diagnosis. Severe forms have a more pronounced infl ammatory
syndrome and diff use organ failure. Aggressive fl uid loading as
recommended in septic states may have worsened hemodynamic
and respiratory conditions in the ICU group. This is suggested by the
hemodilution pattern found in this group. The association of renal,
myocardial and respiratory failures in leptospirosis should lead to a
careful monitoring of fl uid loading and myocardial status. Methods A systematic review of the literature: Cochrane Central
Register for Controlled Clinical Trials, MEDLINE, EMBASE and SCOPUS,
and reference lists of original studies and reviews. Data were collated
and analysed using Review Manager v5.1. y
g
g
Results A total of 254 RCTs were identifi ed. Seven met inclusion
criteria, totalling 806 patients. Studies varied in methodology,
participants, interventions, and outcome measures. Where meta-
analysis was possible, data are presented in Table 1 (outcomes: hospital
mortality, 30-day mortality, hospital length of stay, superinfection,
hyperglycaemia). Excepting hyperglycaemia, eff ect estimates were
not statistically signifi cant. Two small studies (n = 46 and n = 30)
concentrated on severe CAP (using ATS and BTS criteria); one study
found a statistically signifi cant reduction in mortality, lengths of stay
and duration of mechanical ventilation in the steroid group, but similar
improvements in the other study, and in a large subgroup of patients
with severe CAP in another study (n = 93) were not found. Signifi cant
reductions in infl ammatory markers in the week following initiation of
steroid treatment were found in six studies. Characteristics of leptospirosis patients admitted to a tropical
university hospital during the 2000 to 2010 period
H Mehdaoui, E Caffi ot, R Theodose, R Valentino, D Resiere, C Chabartier,
M Jonas
Fort de France University Hospital, Fort De France, Martinique
Critical Care 2012, 16(Suppl 1):P40 (doi: 10.1186/cc10647) Patients were less frequently admitted to the ICU during
the second period (29% vs. 63%, P = 0.013). ICU patients had a higher
heart rate (111 ± 28 vs. 93 ± 21, P = 0.001), and had more frequently
jaundice (94% vs. 64%, P = 0.002) and oliguria (81% vs. 23%, P <0.001). Glycemia (8.7 ± 3.3 vs. 7.1 ± 3.4, P = 0.04), creatinin (530 ± 299 vs. 142 ± 113, P <0.0001), bilirubin (423 ± 251 vs. 69 ± 103, P <0.0001), CRP
(325 ± 135 vs. 210 ± 127, P <0.0001), and WBCC (21.7 ± 9.5 vs. 9.7 ± 5.3,
P <0.0001) were higher and protidemia (58 ± 15 vs. 68 ± 13, P = 0.002),
hematocrit (24 ± 6 vs. 34 ± 6, P <0.0001), and P/F ratio (271 ± 127
vs. 352 ± 84, P = 0.036) were lower in the ICU group. Troponin was
increased more frequently in the ICU group (44% vs. 9%, P = 0.0003)
and ECG anomalies (78% vs. 52%, P = 0.02) were more frequent. Among
the 22 early cardiac echographies performed in the ICU, 11 patients
had LVEF <50%. P37
Impaired heart rate variability predicts clinical deterioration and
progressive organ failure in emergency department sepsis patients
R Arnold, G Green, A Bravi, S Hollenberg, A Seely P37
Impaired heart rate variability predicts clinical deterioration and
progressive organ failure in emergency department sepsis patients
R Arnold, G Green, A Bravi, S Hollenberg, A Seely
Cooper University Hospital, Camden, NJ, USA
Critical Care 2012, 16(Suppl 1):P37 (doi: 10.1186/cc10644) g
Cooper University Hospital, Camden, NJ, USA g
Cooper University Hospital, Camden, NJ, USA p
y
p
,
,
,
Critical Care 2012, 16(Suppl 1):P37 (doi: 10.1186/cc10644) p
y
p
,
,
,
Critical Care 2012, 16(Suppl 1):P37 (doi: 10.1186/cc10644) Introduction Emergency department (ED) sepsis patients without
overt shock have a high incidence of clinical deterioration after S14 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P41 Prognostic impact of imported and newly-isolated
methicillin-resistant Staphylococcus aureus in the ICU
S Ohshimo, K Ota, T Tamura, Y Kida, J Itai, K Suzuki, K Kanao, Y Torikoshi,
K Koyama, T Otani, T Sadamori, K Une, R Tsumura, Y Iwasaki, N Hirohashi,
K Tanigawa
Hiroshima University, Hiroshima, Japan
Critical Care 2012, 16(Suppl 1):P41 (doi: 10.1186/cc10648) Prognostic impact of imported and newly-isolated
methicillin-resistant Staphylococcus aureus in the ICU
S Ohshimo, K Ota, T Tamura, Y Kida, J Itai, K Suzuki, K Kanao, Y Torikoshi,
K Koyama, T Otani, T Sadamori, K Une, R Tsumura, Y Iwasaki, N Hirohashi,
K Tanigawa Table 1 (abstract P39). Meta-analysis of clinical outcomes
Outcome
Number of studies
Population
Eff ect
Hospital mortality
5
537
OR 0.65
30-day mortality
3
562
OR 0.90
Hospital LOS
2
244
MD –1.52
Superinfection
3
563
OR 1.24
Hyperglycaemia
2
517
OR 2.69*
LOS, length of stay. *P <0.0001. Table 1 (abstract P39). Meta-analysis of clinical outcomes Table 1 (abstract P39). Meta-analysis of clinical outcomes Introduction Methicillin-resistant Staphylococcus aureus (MRSA) is a
leading pathogen of hospital-acquired pneumonia. The diff erence in
outcome between patients with imported and newly-isolated MRSA
in the ICU has not been well investigated. The aim of our study was
to explore the incidence, risk factors and outcome in patients with
imported and newly-isolated MRSA. Methods Patients admitted to the ICU in our university between
April 2009 and May 2010 were prospectively studied. Nasal swabs
were collected from all patients on admission and subsequently
collected weekly during the ICU stay. When patients were intubated,
intratracheal aspirates were concurrently collected. The correlations of
positive culture of MRSA with clinical variables were analysed. Conclusion Systemic corticosteroid administration as adjunctive
treatment for CAP does not appear to improve relevant clinical
outcomes, regardless of severity, and is associated with signifi cantly
increased incidence of hyperglycaemia. R f P43 467 females. Median age was 63 (1 to 97). Of these, imported MRSA
was found in 124 (10%) patients, and newly-isolated MRSA in 57 (4%)
patients. The incidence of imported MRSA was associated with the
comorbidity of cardiovascular disease or malignancy and long hospital
stay before admission to the ICU, whereas the incidence of newly-
isolated MRSA was associated with the positive culture in intratracheal
aspirates or blood/intravenous catheter, the comorbidity of shock,
pneumonia or trauma, increased number of isolated sites, higher
APACHE II score, prolonged ICU stay and higher mortality during the ICU
stay. Although no statistical signifi cance was found in total patients, the
subset analysis of the male patients demonstrated that the outcome
of newly-isolated patients was signifi cantly poor compared with those
of imported MRSA (P = 0.005). Multivariate analysis revealed that new
isolation of MRSA in the ICU (P = 0.03; hazard ratio (HR), 2.62), negative
culture of MRSA in nasal swab (P = 0.02; HR, 4.18), ≥2 isolated sites
(P = 0.01; HR, 4.59) and comorbidity of ARDS (P = 0.002; HR, 4.63) were
the independent poor prognostic factors. Predicting methicillin-resistant Staphylococcus aureus in critically ill
patients with pneumonia presenting to the hospital
AF Shorr1, DE Myers2, DB Huang3, BH Nathanson4, MF Emmons5
1Washington Hospital Centre, Washington, DC, USA; 2Pfi zer, Inc., Collegeville,
PA, USA; 3VA NJ Healthcare System, East Orange, NJ, USA; 4OptiStatim, LLC,
Longmeadow, MA, USA; 5Cerner LifeSciences, Beverly Hills, CA, USA
Critical Care 2012, 16(Suppl 1):P43 (doi: 10.1186/cc10650) Introduction Methicillin-resistant Staphylococcus aureus (MRSA)
represents an important pathogen in those presenting to the hospital
with pneumonia and requiring ICU admission. However, empiric
treatment against MRSA in those admitted to the ICU with severe non-
nosocomial pneumonia could lead to overuse of anti-MRSA therapy. To address this concern, we sought to develop a simple clinical score
for identifying ICU patients presenting to the hospital with pneumonia
unlikely to be caused by MRSA. y
y
Methods We retrospectively identifi ed patients admitted to the ICU
with community-acquired pneumonia (CAP) or healthcare-associated
pneumonia (HCAP) between April 2007 and March 2009 at 62 hospitals
in the USA. The diagnosis of pneumonia was based on ICD-9 codes. We
only included patients with laboratory evidence of bacterial infection
(for example, positive sputum, blood, pleural cultures or urinary
antigen testing). P42 P42
Necrotizing pneumonia due to methicillin-sensitive Staphylococcus
aureus secreting Panton-Valentine leukocidin: a review of case
reports
L Kreienbuehl1, E Charbonney2, P Eggimann3
1HUG, Geneva, Switzerland; 2Li Ka Shing Knowledge Institute, St Michael’s
Hospital, Toronto, Canada; 3CHUV, Lausanne, Switzerland
Critical Care 2012, 16(Suppl 1):P42 (doi: 10.1186/cc10649) Necrotizing pneumonia due to methicillin-sensitive Staphylococcus
aureus secreting Panton-Valentine leukocidin: a review of case
reports p
L Kreienbuehl1, E Charbonney2, P Eggimann3
1HUG, Geneva, Switzerland; 2Li Ka Shing Knowledge Institute, St Michael’s
Hospital, Toronto, Canada; 3CHUV, Lausanne, Switzerland
Critical Care 2012, 16(Suppl 1):P42 (doi: 10.1186/cc10649) Introduction Community-acquired necrotizing pneumonia caused
by Panton-Valentine leukocidin (PVL)-secreting Staphylococcus aureus
is a highly lethal infection, which mainly aff ects healthy children and
young adults [1,2]. This study focuses on necrotizing pneumonia due
to methicillin-sensitive S. aureus strains, with the purpose to determine
factors associated with outcome. pi
y
Conclusion The prevalence of MRSA in patients with CAP or HCAP
requiring ICU care was high. A score to assess the risk for MRSA in these
patients performed poorly but requires external validation. Given the
high risk of MRSA in this setting along with the limited discriminatory
power of our risk score, empiric therapy for MRSA in these patients
seems appropriate. Methods We performed a systematic review of case reports on
PVL-secreting MSSA necrotizing pneumonia and analyzed factors
associated with outcome. Results A total of 32 patient descriptions were retained for analysis. Septic shock, infl uenza-like prodrome and the absence of a previous
skin and soft tissue infection were associated with fatal outcome. In multivariate analysis, infl uenza-like prodrome (OR 7.44; 95% CI:
1.24 to 44.76; P = 0.028) and absence of previous skin and soft tissue
infection (OR 0.09; 95% CI: 0.010 to 0.86; P = 0.036) remained signifi cant
predictors of death. See Table 1. P44 P44 Predictors of multidrug-resistant Acinetobacter baumannii
infections: a retrospective analysis in surgical ICU patients
A Camkiran, A Kundakci, C Araz, A Pirat, P Zeyneloglu, H Arslan, G Arslan
Baskent University, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P44 (doi: 10.1186/cc10651) Table 1 (abstract P42). Univariate analysis of mortality risk factors
Univariate
Died
Survived
analysis
(n = 13)
(n = 19)
OR (95% CI)
P value
Flu-like prodrome
9/12 (75%)
4/16 (25%)
9.00 (1.60 to 50.7)
0.020
SSTI
1/13 (8%)
9/19 (47%)
0.09 (0.01 to 0.86)
0.024
Septic shock
11/11
7/15 (47%)
26.0 (1.30 to 522)
0.007
Leukocytopenia
9/11 (82%)
8/17 (47%)
5.06 (0.83 to 30.8)
0.115
Conclusion Infl uenza-like prodrome may be predictive of adverse
outcome and previous skin and soft tissue infection may be associated
with improved prognosis. References
1. Gillet Y, et al.: Lancet 2002, 359:753-759. 2. Gillet Y, et al.: Clin Infect Dis 2007, 45:315-321. Table 1 (abstract P42). Univariate analysis of mortality risk factors
Univariate
Died
Survived
analysis
(n = 13)
(n = 19)
OR (95% CI)
P value
Flu-like prodrome
9/12 (75%)
4/16 (25%)
9.00 (1.60 to 50.7)
0.020
SSTI
1/13 (8%)
9/19 (47%)
0.09 (0.01 to 0.86)
0.024
Septic shock
11/11
7/15 (47%)
26.0 (1.30 to 522)
0.007
Leukocytopenia
9/11 (82%)
8/17 (47%)
5.06 (0.83 to 30.8)
0.115 Table 1 (abstract P42). Univariate analysis of mortality risk factors Introduction Multidrug-resistant Acinetobacter baumannii (MRAB)
is an important cause of hospital-acquired infection and leads to an
increasing morbidity and mortality in ICUs. The aim of this study was
to investigate the predictors of MRAB infection in surgical ICU patients. Methods The charts of the patients who were admitted to the ICU
between January 2008 and August 2010 were reviewed to identify
patients with MRAB infection. Recorded data were as follows: age,
sex, medical history, underlying surgical pathology, APACHE II score
on ICU admission, days in hospital before ICU, presence of invasive
procedures (intubation, tracheostomy, arterial, central venous lines,
urinary and nasogastric catheters, enteral or parenteral nutrition and
renal replacement therapy), days in the ICU and white blood cell (WBC)
count on infection day, infection site, complications (such as organ/
system failure), length of stay (LOS) in the ICU and hospital, and fi nal
outcome. P43 We determined, via logistic regression, variables
independently associated with the presence of MRSA (two-thirds of
cohort) and developed a risk score based on this. We then internally
validated (one-third of cohort) the score. p
p
p
g
Conclusion The new isolation of MRSA during the ICU stay was
associated with poor outcome compared with the imported MRSA. Clinicians should be aware of the high-risk group of MRSA infection. Strict hand hygiene plus a careful assessment of the patient, applying
aggressive procedures such as patient isolation, staff cohorting, and
active surveillance cultures should be indicated. Results The cohort included 957 patients (mean age 65.8 ± 16.4
years, 50.2% male, 43.7% HCAP). MRSA was identifi ed in 20.1%. The
risk score assigned points as follows: 1 point – age <30 or >79 years,
recent immunosuppression other than corticosteroids, shock; 2
points – admission from a skilled nursing facility, history of diabetes
without coronary artery disease (CAD) or heart failure without CAD. The prevalence of MRSA increased with escalating score (P <0.001). We
collapsed the score into three strata based on risk for MRSA (score of
0 to 1 (low), 2 to 4 (moderate), ≥5 (high)). The respective MRSA rates
by strata equaled 15.2%, 24.7%, and 31.9%, (P <0.001). A score ≤1 as a
screening test to exclude MRSA performed poorly (sensitivity 58.3%,
specifi city of 53.3%). 1.
Gillet Y, et al.: Lancet 2002, 359:753-759. References positive culture of MRSA with clinical variables were analysed. Results A total of 1,270 consecutive patients were enrolled. Median
follow-up period was 404 (187 to 609) days. There were 803 males and 1. Garcia-Vidal et al.: Eur Respir J 2007, 30:951-956. 2. Chen et al.: Cochrane Database of Systematic Reviews 2011, 3. S15 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 2.
Gillet Y, et al.: Clin Infect Dis 2007, 45:315-321. P45 P45
Risk factors for bronchial acquisition of resistant Gram-negative
bacteria in critically ill patients and outcome
I Papakonstantinou1, E Perivolioti1, C Vrettou2, I Baraboutis1, E Magira2,
E Balioti1, D Panopoulou1, T Pitsolis1, C Routsi2, S Nanas2
1Evaggelismos Hospital, Athens, Greece; 2National and Kapodistrian University
of Athens, Greece
Critical Care 2012, 16(Suppl 1):P45 (doi: 10.1186/cc10652) Figure 1 (abstract P46). Introduction It has been advocated that resistant Gram-negative
bacteria (RGNB) colonization of ICU patients is to some extent a result
of increased use of antibiotics. The aim of our study was to investigate,
in adjustment with patients’ characteristics, the impact of colonization
status and antibiotic use during ICU stay on the impending acquisition
of RGNB in the bronchial tree of newly intubated patients and to
estimate the outcome. Methods Bronchial and pharyngeal surveillance cultures were
obtained up to day 7 (d7) of ICU admission. RGNB considered for
analysis on d7 were A. baumannii (RAB) and K. pneumoniae (RKP). Polymicrobial colonization with ≥2 RGNB (PMC) was also evaluated. To assess dependence between diff erent explanatory variables,
multivariable logistic regression was used. Variables included in the
model were: SOFA score, department prior to ICU admission, medical
cause of admission, emergency surgery, CRF, prior aminoglycosides
and tigecycline use during ICU stay and concurrent RAB or RKP
pharyngeal colonization, respectively. To estimate outcome (death),
variables included in multivariate model were: APACHE, SOFA score,
department prior to ICU admission, medical cause of admission,
emergency surgery, CRF and d7 RAB, RKP.i Figure 1 (abstract P46). Conclusion The need for a complex strategy to manage and eradicate
an MRA outbreak in the ICU led to a clinically signifi cant decrease in
antibiotic use and prescribing cost saving following eradication of
MRA. Improved antibiotic stewardship is achievable through better
infection control strategies. g
y
g
y
Results Ninety-fi ve eligible patients with bronchial colonization data on
d7 were included for further analysis. In the case of RAB in multivariate
model (R2 = 0.538), pharyngeal d7 RAB was the only predictor of d7
RAB bronchial colonization (OR 0.042, 95% CI 0.012 to 0.148, P <0.001). In the case of RKP in multivariate model (R2 =0.648), pharyngeal d7 RKP
(OR 0.037, 95% CI 0.004 to 0.031, P = 0.004), aminoglycoside use (OR
0.094, 95% CI 0.015 to 0.573, P = 0.01) and SOFA score (OR 1.66, 95%
CI 1.07 to 2.58, P = 0.023) characterized bronchial d7 RKP colonization. P45 Multivariate model for PMC (R2 = 0.49) revealed only d7 pharyngeal
PMC as predictor of bronchial PMC (OR 0.12, 95% CI 0.026 to 0.50,
P = 0.004). Department prior to ICU, medical cause of admission, CRF,
and emergency surgery were not found to infl uence RGNB bronchial
colonization. Outcome death increased with APACHE score (OR 0.84,
95% CI 0.76 to 0.94, P = 0.002) and bronchial d7 RKP colonization (OR
9.14, 95% CI 1.3 to 64.4, P = 0.026). Acknowledgements Thanks to Chelsea and Westminster Healthcare
Charity, and ICU and microbiology staff . References Results During the study period 25 patients with MRAB infection were
identifi ed. When compared with their matched control group (n = 25), 1. Gillet Y, et al.: Lancet 2002, 359:753-759. 2. Gillet Y, et al.: Clin Infect Dis 2007, 45:315-321. S16 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 patients with MRAB infection had a signifi cantly higher mean APACHE
II score (P <0.001) and more frequently had an open wound (P = 0.002)
or required mechanical ventilation (P = 0.005), arterial catheterization
(P = 0.006), and central venous catheterization (P = 0.004). Multivariate
logistic regression revealed that APACHE II score (OR, 1.19; 95% CI,
1.005 to 1.315; P = 0.043) and open wound (OR, 0.45; 95% CI, 0.003 to
0.587; P = 0.18) were predictors of MRAB infection in these patients. Compared to their controls, patients with MRAB infection had a longer
LOS in the ICU (36.44 ± 30.44 days vs. 7.80 ± 8.13 days, P <0.001) and
hospital (55.12 ± 40.81 days vs. 19.04 ± 13.44 days, P <0.001). In-hospital
mortality rates for patients with MRAB infection and their controls were
56% and 32%, respectively (P = 0.154). Reference 1. Kollef M, et al.: Ann Internal Med 2001, 134:298-314. Improved antibiotic stewardship resulting from a multifaceted
strategy implemented after an outbreak of multiresistant
Acinetobacter baumannii in a university ICU
M Beach, M Cohen, V Grover, J Ho, N Soni, B Azadian, S Singh
Chelsea & Westminster Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P46 (doi: 10.1186/cc10653) Improved antibiotic stewardship resulting from a multifaceted
strategy implemented after an outbreak of multiresistant
Acinetobacter baumannii in a university ICU
M Beach, M Cohen, V Grover, J Ho, N Soni, B Azadian, S Singh
Chelsea & Westminster Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P46 (doi: 10.1186/cc10653) Introduction A 12-bed ICU experienced an outbreak of multiresistant
Acinetobacter baumannii (MRA) from October 2009 to May 2010. A
multifaceted strategy involving segregation, enhanced infection
control procedures, and microbiological surveillance was implemented. We evaluated its impact on antibiotic stewardship. p
y
Conclusion Our results indicate that higher APACHE II scores and
presence of an open wound are predictors of MRAB in ICU surgical
patients. Patients with MRAB infection tended to have a higher
mortality and had a longer LOS in the ICU and hospital than their
controls. Methods A retrospective review of patient notes and results using
AcuBase® was conducted: 90 consecutive patients before the outbreak
(January to June 2008) and 91 thereafter (October 2010 to May
2011). Data included patient profi les, admission criteria, ICU survival,
antimicrobials used, antibiotic days, number of patients on antibiotics,
prescribing cost and the demographic of microbes isolated. Results Following the outbreak, enhanced infection control measures
were implemented alongside the Matching Michigan protocols. Daily
operational critical care and elective planning meetings and a staff
education programme were undertaken. ICU mortality (31 (14%) vs. 43
(16%)) was unchanged. Microbiological isolates were overall similar, with
a reduction in coagulase-negative Staphylococcus and Klebsiella and an
increase in Enterobacter. The use of cefuroxime (3.2 vs. 2.3 antibiotic days/
patient) and quinolones (6 vs. 2) decreased. There was a reduction in
average antibiotic days per patient episode (5.1 vs. 4.2) (P = 0.0291) and
the prescribing cost savings were £13,558 (47%). See Figure 1. Predictive and prognostic factors of septic shock of nosocomial
origin JP Quenot1, A Pavon1, C Binquet1, F Kara2, O Martinet3, F Ganster3,
JC Navellou4, V Castelain5, D Barraud6, J Cousson4, JF Poussel7, P Perez8,
K Kuteifan9, A Noirot2 y
g
y
Results Fifty-one patients were included (30 with suspected IC and
21 with proven IC). At the onset of antifungal therapy, the Candida
score was greater in the patients with suspected IC than in those with
proven infection (3.7 ± 0.7 vs. 3.0 ± 0.8, P = 0.001) since multifocal
colonization was more frequent in the former. In addition, the patients
with suspected but unproven IC looked more seriously ill according to
the SOFA score (8.3 ± 3.0 vs. 6.6 ± 3.5, P = 0.07). This mainly resulted
from a greater level of hypotension as assessed through the SOFA score
(2.8 ± 1.5 vs. 1.2 ± 1.5 points, P = 0.0006). Obviously, the clinical response
to antifungal therapy was signifi cantly more consistent in the patients
with unproven IC than in those with proven infection (P = 0.032). In
addition, there was a trend toward an improved survival in the former
patients (53 vs. 47%, P = 0.42). The only independent protective factor
was echinocandin therapy duration (HR = 0.84 (95% CI 0.75 to 0.94),
P = 0.0034).i 1University Hospital Bocage, Dijon, France; 2Centre Hospitalier, Haguenau,
France; 3Nouvel Hopital Civil, Strasbourg, France; 4University Hospital,
Besancon, France; 5Hopital Hautepierre, Strasbourg, France; 6Hopital Central,
Nancy, France; 7Regional Hospital, Metz-Thionville, France; 8Hopital Brabois,
Nancy, France; 9CHG, Mulhouse, France
C iti
l C
2012 16(S
l 1) P49 (d i 10 1186/
10656) Introduction The incidence of septic shock in intensive care in France is
around 8 to 10%, with in-hospital mortality ranging from 55 to 60% [1]. Mortality increases by 10% when the infection causing septic shock is
acquired in-hospital or in the ICU [1]. We aimed to determine predictive
and prognostic factors for septic shock caused by a nosocomial
infection (NI). Methods Subgroup analysis of a prospective, multicentre, observa-
tional study performed between November 2009 and March 2011 in
14 ICUs from 10 university and community (nonacademic) hospitals
in the northeast of France. This study was supported by the Collège
Interrégional des Réanimateurs du Nord-Est. Patients were included
if they were aged >18 years and had septic shock plus at least one
criterion of hypoperfusion. Infection was classed as nosocomial if
acquired in-hospital more than 48 hours after admission. References Methods A retrospective single-centre observational study including
every patient with highly suspected but unproven IC (that is, Candida
score >3, multifocal Candida sp. colonization, unresolved sepsis
despite >2-day broad-spectrum antibiotics, negative blood culture)
who received at least two doses of one echinocandin between 2008
and 2011. Patients with proven IC (that is, candidemia) over the same
period were used as controls. These two groups of patients were
compared regarding baseline characteristics and both clinical and
biological follow-up data while receiving antifungal therapy. The
clinical response to antifungal therapy was assessed through the SOFA
score daily decrease from day 0 to day 3 in both groups and compared
by repeated-measures ANOVA. Then, independent predictors of death
in the ICU were determined by Cox regression analysis. 1. Gonçalves e Silva CR, Melo KE, Leão MV, Ruis R, Jorge AO: Relationship
between Candida in vaginal and oral mucosae and salivary IgA. Rev Bras
Ginecol Obstet 2008, 30:300-305. 2. Bai XD, Liu XH, Tong QY: Intestinal colonization with Candida albicans and
mucosal immunity. World J Gastroenterol 2004, 10:2124-2126. 2. Bai XD, Liu XH, Tong QY: Intestinal colonization with Candida albicans and
mucosal immunity. World J Gastroenterol 2004, 10:2124-2126. Empirical antifungal treatment in the critically ill patients: how does
it impact on the outcome? R Bruyère, C Vigneron, J Quenot, M Hamet, F Dalle, S Prin, PE Charles
University Hospital, Dijon, France R Bruyère, C Vigneron, J Quenot, M Hamet, F Dalle, S Prin, PE Charles
University Hospital, Dijon, France Conclusion Of the parameters included in our model, concurrent d7
pharyngeal RAB and RKP, respectively, resulted eventually in bronchial
colonization with the same pathogens. Of the overall antibiotics
used only aminoglycosides had signifi cant correlation only for RKP
colonization. y
p
j
ical Care 2012, 16(Suppl 1):P47 (doi: 10.1186/cc10654) Introduction Given the high mortality attributable to invasive
candidiasis (IC) and the lack of reliable diagnosis tool, antifungals S17 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Conclusion The above data show a slight reduction of Candida spp. colonization in septic shock patients treated with IgGAM therapy. Further studies are needed to confi rm this fi nding. are often started in high-risk patients with severe sepsis despite
the absence of proven disease. According to current guidelines,
echinocandins are the drugs of choice in this setting. However, the level
of evidence supporting this statement is low. Conclusion The above data show a slight reduction of Candida spp. colonization in septic shock patients treated with IgGAM therapy. Further studies are needed to confi rm this fi nding. References Predictive and prognostic factors of septic shock of nosocomial
origin Data control
and statistical analysis were performed by the CIC-EC of Dijon University
Hospital (INSERM Unit CIE1). Conclusion A signifi cant clinical improvement is achieved in patients
with suspected but not proven IC receiving empirical antifungal
therapy with an echinocandin. In contrast, the patients with proven IC
are less responsive to therapy and are more likely to die in the ICU. Our
data support the use of an echinocandin as empirical therapy in very
high-risk patients. Reference Reference 1. Annane D: Am J Respir Crit Care Med 2003, 168:165. g
References References 1. Pappas PG, et al.: Clin Infect Dis 2009, 48:503-535. 2. Leon C, et al.: Crit Care Med 2009, 37:1624-1633. 1. Pappas PG, et al.: Clin Infect Dis 2009, 48:503-535. 2
Leon C et al : Crit Care Med 2009 37:1624-1633 Results In total, 1,147 patients were included in the cohort, of whom
409 (35.6%) presented a NI (345/409 (84%) acquired in-hospital and
64/409 (16%) acquired in the ICU). The factors signifi cantly associated
with NI (in-hospital or in-ICU) were: immunodepression, a Knaus score
C to D, SAPS II score, and SOFA score. Other variables such as age, sex,
type of admission and type of infection were not signifi cantly related to
the nosocomial origin of infection. In-hospital mortality for community-
acquired versus NIs was 40.8% vs. 53.5% respectively (P <0.01), and
46.9% vs. 62% respectively at 28 days (P <0.01). Relationship between polyclonal immunoglobulin therapy and
colonization by Candida spp.i G Serafi ni, I Cavazzuti, C Venturelli, M Girardis University Hospital, Modena, Italy Critical Care 2012, 16(Suppl 1):P48 (doi: 10.1186/cc10655 Critical Care 2012, 16(Suppl 1):P48 (doi: 10.1186/cc10655) Conclusion Mortality of patients with septic shock of nosocomial origin
is particularly high. Scores evaluating gravity of disease are also higher
in patients with NI versus those with community-acquired infection. This could be explained by delayed presentation or diffi culties with
management, but also by immunodepression and a poor state of
prior health. It is likely that appropriate measures, particularly aimed
at prevention, could help to reduce mortality in patients with septic
shock caused by NI. Introduction Low IgA levels in blood serum and in saliva have been
associated with an increased risk for Candida colonization and infec-
tion [1,2]. In this retrospective cohort study, we aimed to evaluate the
eff ects of an intravenous immunoglobulin preparation containing
polyclonal IgG, IgM and IgA (IgGAM) on the prevention of Candida spp. colonization in patients with septic shock. p
p
Methods In this study we analyzed 69 patients with septic shock and
without Candida spp. colonization before shock appearance admitted
to the ICU of a university hospital from January 2008 to November
2011. All of the patients were treated in according to the Surviving
Sepsis Campaign guidelines. In addition to standard therapy, 44 (64%)
patients received IgGAM therapy (Pentaglobin® 38 g/l IgG, 6 g/l IgM,
and 6 g/l IgA) within 24 hours from the diagnosis of septic shock at the
dose of 250 mg/kg/day for 3 days. The colonization by Candida spp. was
evaluated by analyzing the results of the microbiological surveillance
cultures (two times per week) of pharyngeal swab, tracheal aspirate,
urine and surgical drains between 48 hours and 21 days after the
diagnosis of septic shock. P50 P50
Catheter-related bloodstream infection: factors aff ecting incidence
K Boner1, M McGovern2, J Bourke1, C Walshe3, D Phelan1
1Mater Misericordiae University Hospital, Dublin, Ireland; 2Harvard University,
Cambridge, MA, USA; 3Beaumont Hospital, Dublin, Ireland
Critical Care 2012, 16(Suppl 1):P50 (doi: 10.1186/cc10657) Introduction Catheter-related bloodstream infection (CRBSI), its
associated morbidity, mortality and expense are the most important
adverse eff ect of central venous catheters (CVCs) [1]. The objective of
this study of a population in whom the rate of CRBSI fell signifi cantly g
p
Results In the IgGAM group, 11 patients (25%) developed Candida spp. colonization compared to nine patients (36%) of the control group. The
Candida colonization index was similar in the two groups: 0.42 ± 0.16 in
the IgGAM group and 0.45 in the control group. S18 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P <0.01); Knaus score C–D (OR 2.16, 95% CI 1.64 to 2.84, P <0.01); SOFA
score (OR for an increase of 1 point 1.32, 95% CI 1.26 to 1.38, P <0.01);
and infection acquired in the ICU (OR 1.86, 95% CI 1.03 to 3.37, P = 0.03). Protective factors were surgical admission (OR 0.61, 95% CI 0.41 to
0.89, P = 0.01) and urinary tract infection (OR 0.55, 95% CI 0.37 to 0.82,
P <0.01). over 12 years [2] was to evaluate the infl uence of both patient and CVC
factors on CRBSI rates in patients receiving total parenteral nutrition
(TPN) in this time. Methods Set in a 525-bed university hospital providing acute and
tertiary services. A prospective database was established in 1997,
recording data on all patients with CVCs inserted for TPN administration. This database was examined up to 2009 to ascertain the eff ects of
patient and CVC factors on CRBSI. Conclusion Our fi ndings are coherent with the literature. Multivariate
analysis found nonmodifi able risk factors such as age, but also
modifi able risk factors that warrant further investigation, such as
infections acquired in-hospital or in the ICU. Future clinical studies in
septic shock should take these fi ndings into account when selecting
patients. p
Results During the 12-year study period, 2,573 CVCs were inserted into
1,343 patients and 15,385 CVC days were accumulated. Overall, 13.8%
of patients developed CRBSI throughout the study. Severe sepsis in the United Sates: a 5-year analysis
J Knittel, S Quraishi Massachusetts General Hospital, Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P52 (doi: 10.1186/cc10659) Massachusetts General Hospital, Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P52 (doi: 10.1186/cc10659) Introduction We describe patient-level healthcare data related to
severe sepsis over a 5-year period (2004 to 2008) in the United States. Methods We queried the largest all-payer inpatient care database in
the United States to identify cases of hospital admissions between 2004
and 2008 with a primary diagnosis of severe sepsis (ICD 9: 995.92). This
retrospective analysis was performed with data from the Healthcare
Cost and Utilization Project National Inpatient Sample (NIS) repository. Data related to length of stay, in-hospital mortality, and hospital
charge was extracted. The 2004 and 2008 data for these variables
were compared and further analyzed by age and sex in SPSS v.19 (IBM
Corporation, Amonk, NY, USA). Results are reported with ± standard
error where applicable, and P <0.05 represented statistical signifi cance. Results Our query of the NIS data revealed a similar number of hospital
admissions with a primary diagnosis of severe sepsis in 2004 versus
2008. Sex (male vs. female) and age group composition (18 to 44 vs. 45 to 64 vs. 65 to 85 vs. 85+) within these cohorts were similar. No
signifi cant change in overall length of stay or in-hospital mortality rate
was appreciated. However, a signifi cant increase in overall cost was
appreciated ($67,670 ± 5,742 vs. $100,973 ± 10,525; P = 0.006), which
outpaced healthcare-specifi c and general infl ation during this period. Sex did not infl uence length of stay or in-hospital mortality rate. Cost
of care was higher for males versus females (2004: $78,361 ± 8,982
vs. $57,040 ± 5,959; P = 0.048 and 2008: $111,298 ± 13,835 vs. $90,730 ± 11,380; P <0.001). Age had a signifi cant infl uence on in-
hospital mortality in 2004 and in 2008, with the highest percentage
of in-hospital deaths in the 85+ category. Age also had a signifi cant
infl uence on cost/day. Whereas in 2004 patients in the 85+ category
represented the age subset with the lowest cost/day, in 2008 this age
group witnessed a threefold increase in daily costs (P <0.001) and
represented the highest cost/day subset. Conclusion CRBSI occurs commonly in TPN populations, but there are
very limited published data as regards incidence or factors aff ecting
incidence in this population. References 1. O’Grady NP, Alexander M, Dellinger EP, et al.; Healthcare Infection Control
Practices Advisory Committee: Guidelines for the prevention of
intravascular catheter-related infections. Infect Control Hosp Epidemiol 2002,
23:759-769. 2. Walshe CM, Boner K, Bourke J, et al.: Catheter related blood stream infection
(CRBSI) in TPN patients. Benefi t of an educational programme using
multimodal CRBSI expression. Clin Govern Int J 2010, 15:292-301. 2. Walshe CM, Boner K, Bourke J, et al.: Catheter related blood stream infection
(CRBSI) in TPN patients. Benefi t of an educational programme using
multimodal CRBSI expression. Clin Govern Int J 2010, 15:292-301. Severe sepsis in the United Sates: a 5-year analysis
J Knittel, S Quraishi This large study of TPN patients provides
prospective analysis of both patient and CVC factors infl uencing the
development of CRBSI for the fi rst time. P50 In terms of patient
factors aff ecting CRBSI rates, CRBSI was increased in patients with
longer duration of TPN administration (where each additional day was
associated with a relative risk ratio of 1.02, P <0.01), increased numbers
of CVCs inserted (where each additional line was associated with a
relative risk ratio of 1.21, P <0.01), and use of lipid formulation of TPN
(58.9 vs. 49% use was associated with a relative risk ratio of 1.56, P <0.01). Overall 8.6% of CVCs inserted became infected. Hospital location of
CVC insertion was an important risk factor for CRBSI. The most common
site for insertion was the ICU (almost 40% of CVCs); however, compared
to ICU insertion, insertion in the HDU was associated with an increased
risk of CRBSI (a relative risk ratio of 1.75, P <0.01), as was insertion in the
operating theatre for ward patients (a relative risk ratio of 2.08, P <0.01). CVC maintenance at ward level was associated with increased CRBSI
rates, with a relative risk ratio of 2.06 (P <0.01). Reference Reference 1. Annane D: Am J Respir Crit Care Med 2003, 168:165. Prognostic factors of septic shock
1
1
2 JP Quenot1, A Pavon1, C Binquet2, F Kara3, O Martinet4, F Ganste JC Navellou5, V Castelain6, D Barraud7, J Cousson3, JF Poussel8, P Perez9,
K Kuteifan3 JC Navellou5, V Castelain6, D Barraud7, J Cousson3, JF Poussel8, P Perez9,
K Kuteifan3 1University Hospital Bocage, Dijon, France; 2CIC EC, Dijon, France; 3Centre
Hospitalier, Haguenau, France; 4Nouvel Hopital Civil, Strasbourg, France;
5University Hospital, Besancon, France; 6Hopital Hautepierre, Strasbourg,
France; 7Hopital Central, Nancy, France; 8Regional Hospitalier, Metz-Thionville,
France; 9Hopital Brabois, Nancy, France p
y
Critical Care 2012, 16(Suppl 1):P51 (doi: 10.1186/cc10658) Conclusion Our data suggest that despite signifi cant increases in
healthcare costs attributable to severe sepsis, survival and length of
stay has not improved signifi cantly between 2004 and 2008. Dramatic
increases in cost are particularly notable in males versus females and in
patients who are 85 years old and over. Policies to control healthcare
costs in the United States should focus on the root causes that lead to
such signifi cant increases in cost without appreciable societal returns
on investment. Introduction The incidence of septic shock in intensive care (ICU) in
France is around 8 to 10%, with in-hospital mortality ranging from
55 to 60% [1]. The identifi cation of prognostic factors is essential to
guarantee optimal management. Methods A prospective, multicentre, observational study was per-
formed between November 2009 and March 2011 in 14 ICUs from 10
university and community (nonacademic) hospitals in the northeast
of France. This study was supported by the Collège Interrégional
des Réanimateurs du Nord-Est. Patients were included if they were
aged >18 years and had septic shock plus at least one criterion of
hypoperfusion. Data control and statistical analysis was performed by
the CIC-EC of Dijon University Hospital (INSERM Unit CIE1). Univariate
and multivariate logistic regression analysis was used to identify
predictors of mortality at 28 days. P54 p
Results Over a 24-month period we have a database with 1,571
patients. The results demonstrate that the median time to antibiotic
administration is consistently near our target of 1 hour for all septic
patients included in this pathway. Through continued refi nement and
staged introduction the proforma and the process has demonstrated
consistency from medical to surgical wards; introduction in new areas
has rapidly improved results. See Figure 1 overleaf. Compliance with the sepsis resuscitation bundle in patients with
severe sepsis and septic shock admitted to Scottish ICUs
JA Davidson1, K Dunne2i Compliance with the sepsis resuscitation bundle in patients with
severe sepsis and septic shock admitted to Scottish ICUs
JA Davidson1, K Dunne2
1Victoria Infi rmary, Glasgow, UK; 2Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P54 (doi: 10.1186/cc10661) 1Victoria Infi rmary, Glasgow, UK; 2Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P54 (doi: 10.1186/cc10661) Introduction Severe sepsis is the second leading cause for admission
to critical care and in spite of advanced care remains associated with
a high mortality. When implemented the sepsis resuscitation bundle
has been associated with a 20% reduction in mortality and is therefore
recommended as standard care for all patients with severe sepsis [1]. Conclusion Our pathway has undergone a successful and dynamic
development process guided by a multidisciplinary team. Compared
with the usual audit process this has allowed rapid changes and
improvements to take place and be tested. Further analysis of our
database is ongoing, determining our impact on length of stay,
mortality and intensive care admissions with a matched cohort. p
p
Methods All new admissions to seven west of Scotland ICUs were
screened during a 12-week period for evidence of severe sepsis
or septic shock. Those meeting the criteria were then assessed for
sepsis bundle compliance. The Institute for Healthcare Improvement
sepsis resuscitation bundle was taken as standard of care. This has a
6-hour time frame and includes measurement of serum lactate, blood
cultures taken prior to antibiotics, antibiotics administered within
3 hours, fl uids of 20 ml/kg if hypotensive or hyperlatataemia and use
of early goal-directed therapy in the event of persistent hypotension/
hyperlatataemia in spite of fl uid resuscitation.i P56 P56
Source-directed antimicrobials: a shot in the dark? Improving early administration of antibiotics: a ‘Plan Do Study Act’
approach Improving early administration of antibiotics: a ‘Plan Do Study Act’
approach
A Revill1, N Wennicke2, J Tipping2, R Matull2
1Derriford Hospital, Plymouth, UK; 2Taunton Musgrove Park Hospital, Taunton,
UK
Critical Care 2012, 16(Suppl 1):P55 (doi: 10.1186/cc10662) Introduction Delayed administration of antibiotics is associated with
an increased mortality in severe sepsis. The Surviving Sepsis Campaign
advocates administering antibiotics to severely septic patients within
1 hour. Predicting the patients that will become severely septic is
diffi cult, and therefore we have introduced a pathway via a unique care
bundle to identify and treat all patients with suspected sepsis, prior to
signifi cant organ dysfunction, and maintain a 1-hour target. Conclusion H1N1 pneumonia was associated with signifi cant morbidity
and mortality requiring advanced multiorgan support in the majority
of patients. Although the incidence of organ dysfunction in our cohort
mirrored that found in the Swift study [1], in keeping with advances
in management of H1N1-associated critical illness the mortality was
lower in the current study. i
y
Methods In September 2009, we introduced an audit proforma and
management tool into the medical admissions unit of our hospital. This
was accompanied by an extensive education programme of all medical
and nursing staff . The proforma consists of two parts, a recognition and
intervention section. The process is triggered when the patient satisfi es
two of the SIRS criteria and has symptoms consistent with an infection. All six management processes, including antibiotic administration,
must then be completed within 1 hour of the trigger time. By using the
‘Plan Do Study Act’ cycle, we refi ned the proforma and streamlined the
process and introduced it into emergency department and the surgical
admissions unit. A dedicated multidisciplinary team was assigned to
review and improve performance every 2 weeks by amending the form
and processes. Methods In September 2009, we introduced an audit proforma and
management tool into the medical admissions unit of our hospital. This
was accompanied by an extensive education programme of all medical
and nursing staff . The proforma consists of two parts, a recognition and
intervention section. The process is triggered when the patient satisfi es
two of the SIRS criteria and has symptoms consistent with an infection. Reference 1. Rowan KM, et al.: The Swine Flu Triage (SwiFT) study: development and
ongoing refi nement of a triage tool to provide regular information to
guide immediate policy and practice for the use of critical care services
during the H1N1 swine infl uenza pandemic. Health Technol Assess 2010,
14:335-492. District hospital experience of organ support requirements for
H1N1-associated pneumonia Results In total, out of 7,833 patients admitted to intensive care during
the study period, 1,147 (14.6%) had septic shock. Factors signifi cantly
associated with mortality at 28 days by logistic regression were: age
>70 (OR 1.98, 95% CI 1.5 to 2.6, P <0.01); transfer (OR 1.42, 95% CI 1.04
to 1.95, P = 0.02); immunodepression (OR 1.91, 95% CI 1.41 to 2.57, Introduction The objective of our study was to describe the disease
pattern, outcomes and organ support required in treating H1N1-
associated pneumonia in a single-centre, district hospital ICU. S19 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods All of the patients with confi rmed H1N1 infection admitted to
our ICU during the months of December 2010 and January 2011 were
studied. The outcome measures were incidence, severity and support
for organ dysfunction, length of stay in ICU and mortality. still a large proportion of patients not receiving aspects of the bundle
in spite of being in a critical care environment. Reference still a large proportion of patients not receiving aspects of the bundle
in spite of being in a critical care environment. Reference 1. Dellinger RP, Levy MM, et al.: Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock. Intensive
Care Med 2007, 34:17-60. Results During the study period 27 patients were admitted. The mean
age was 46.6 years (SD 13.6) with 20 (74%) patients being female, of
whom two were pregnant. The mean APACHE scores were similar
between survivors and nonsurvivors, 14.1 and 13.7 respectively. Twenty
patients (74%) required invasive mechanical ventilation with median
duration of 9 days (range 2 to 54 days). Advanced techniques like prone
position ventilation and high-frequency oscillatory ventilation were
required in 20% and 10% of these patients respectively. Two patients
were referred for ECMO. Ventilator-associated pneumonia (VAP)
ensued in 25% of invasively ventilated patients resulting in an increase
in ventilator days (median) from 9 to 19 and ICU stay (median) from 15
to 23 days. Four (15%) required advanced cardiovascular support, 14
(52%) developed acute kidney injury (AKI) of which nine (33%) patients
required renal replacement therapy. The ICU mortality was 11.1% and
hospital mortality was 14.8%. The cohort who developed AKI had 21%
mortality. The median ICU stay (range) was 15 days (2 to 68 days). P54 L Richardson1, GB McNeill2, S Gupta1
1University Hospital Southampton NHS Foundation Trust, Southampton, UK;
2Sheffi eld Teaching Hospitals NHS Foundation Trust, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P56 (doi: 10.1186/cc10663) l
Results Of the 652 patients screened, 115 met the defi nition of
severe sepsis or septic shock (17.6%). We collected full data from 108
patients, of which 69 patients (63.8%) had severe sepsis and 39 patients
(36.1%) had septic shock. Full bundle compliance was 5.6%. Early ICU
admission (within 6 hours) was associated with improved compliance
with measured lactate (87.3% vs. 60.4%, P <0.01), and where indicated,
vasopressor use (94.4% vs. 61.3%, P <0.01), CVP measurement (77.5%
vs. 44.4%, P <0.01), and ScvO2 measurement (25.6% vs. 2.8%, P <0.01). ICU mortality was 12/64 patients (18.8%) with severe sepsis and 18/38
patients (47.4%) for those with septic shock. Full bundle compliance
and mortality was not diff erent for those reaching ICU early compared
with those who were admitted after 6 hours. Introduction The Surviving Sepsis Campaign advocates giving early
empirical antibiotics directed against all likely pathogens [1]. The
failure to instigate antimicrobials against a later confi rmed pathogen
impacts negatively on mortality [2]. Many hospitals advise source-
directed therapy from the beginning. Our project aims to elicit the
proportion where the source of sepsis is initially predicted incorrectly
thereby putting patients at risk. Methods A prospective cohort study was performed in two UK
teaching hospitals of patients presenting with sepsis to critical care
between May 2010 and March 2011. Hospital computer systems and
patient notes were used to extract the initial suspected source of sepsis,
and later verifi ed with true microbiology data. Overall mortality was
measured and compared between correctly and incorrectly suspected
source of sepsis patients. Conclusion At present the sepsis resuscitation bundle is not uniformly
implemented. Although compliance with early goal-directed therapy
and lactate measurement is better in those reaching ICU early, there is S20 Critical Care 2012, Volume 16 Suppl 1 Critical Care 2012, Volume 16 Suppl 1
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pp
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P55). Median time to antibiotics. Figure 1 (abstract P55). Median time to antibiotics. We advise that in patients with severe sepsis or septic shock fi rst-line
antibiotics should remain broad spectrum with rigorous follow up to
de-escalate as early as possible. P54 References Results Of the 128 patients, the source of sepsis was wrongly identifi ed
in 30% (38/128) (Southampton 28% 15/53, Sheffi eld 31% 23/75 respect-
ively) (Figure 1). The most common source was the bowel, which was
initially suspected as a respiratory source in most cases. Interestingly,
the mortality was higher in the correctly identifi ed group (13%, 16/128
vs. 5%, 7/128). This probably refl ects the severity of illness where the
diagnosis is sometimes more obvious. 1. Dellinger RP, et al.: Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock. Crit Care Med 2008,
36:296-327. 2. Kumar A, et al.: Initiation of inappropriate antimicrobial therapy results in
fi vefold reduction of survival in human septic shock. Chest 2009,
136:1237-1248. 2. Kumar A, et al.: Initiation of inappropriate antimicrobial therapy results in
fi vefold reduction of survival in human septic shock. Chest 2009,
136:1237-1248. 2. Kumar A, et al.: Initiation of inappropriate antimicrobial therapy results in
fi vefold reduction of survival in human septic shock. Chest 2009,
136:1237-1248. Conclusion Good antimicrobial governance requires early adminis-
tration of narrow-spectrum antibiotics as best guess source-directed
therapy from the outset, because de-escalation is often not practical. Our data reveal that in 30% of cases we incorrectly guess the source. Figure 1 (abstract P56). Proportion of correctly and incorrectly identifi ed
sources. P57 Relation between temperature in the initial 24 hours in patients
with severe sepsis or septic shock with mortality and length of stay
in the ICU Relation between temperature in the initial 24 hours in patients
with severe sepsis or septic shock with mortality and length of stay
in the ICU
R Sanga, S Zanotti, C Schorr, B Milcareck, K Hunter, P Dellinger, J Parrilo
Cooper University Hospital, Camden, NJ, USA
Critical Care 2012, 16(Suppl 1):P57 (doi: 10.1186/cc10664) Relation between temperature in the initial 24 hours in patients
with severe sepsis or septic shock with mortality and length of stay
in the ICU P59 P59
Impact of antifungal treatment in ICU patients with Candida
colonization: analysis of the EPIC II study population
D Kett1, G Dimopoulus2, E Azoulay3, P Echeverria1, C De La Cuesta1,
JL Vincent4
1University of Miami Miller School of Medicine, Miami, FL, USA; 2University
Hospital ATTIKO Medical School, University of Athens, Greece; 3St-Louis
Hospital and Paris VII University, Paris, France; 4Erasme University Hospital,
Université Libre de Bruxelles, Belgium
Critical Care 2012, 16(Suppl 1):P59 (doi: 10.1186/cc10666) in the ICU R Sanga, S Zanotti, C Schorr, B Milcareck, K Hunter, P Dellinger, J Parrilo
Cooper University Hospital, Camden, NJ, USA
Critical Care 2012, 16(Suppl 1):P57 (doi: 10.1186/cc10664) p
y
p
Critical Care 2012, 16(Suppl 1):P57 (doi: 10.1186/cc10664) Introduction Fever is a common event (ranges from 25 to 70%) in
patients admitted to the ICU. The usual clinical approach in most
units is to treat the fever either with medications (acetaminophen,
nonsteroid anti-infl ammatory drugs) or external measures, like cooling
blankets. No studies assessed clinical evidence for these interventions. There is otherwise evidence that fever may be benefi cial, inducing heat
shock proteins and decreasing NK-κB activation. Also treating fever can
mask an important clinical sign and avoid early treatment in patients
with severe sepsis. p
Methods We did a case–control study using two available databases
and collected 750 patients with the diagnosis of severe sepsis and
septic shock. We collected age, sex, days on mechanical ventilation,
APACHE II score, vasopressor use and correlated with the presence of
hyperthermia (>101.3°F), hypothermia (<96.8°F) and normothermia Figure 1 (abstract P56). Proportion of correctly and incorrectly identifi ed
sources. S21 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 in the initial 24 hours. We used a mean of the available temperature
data. Then we used logistic regression (univariate and multivariate) to
compare these temperatures with mortality and length of stay in the
ICU. in the initial 24 hours. We used a mean of the available temperature
data. Then we used logistic regression (univariate and multivariate) to
compare these temperatures with mortality and length of stay in the
ICU. Figure 2 (abstract P58). Indication for paracetamol administration
(n = 152). Results Compared to patients with normal temperature the
hyperthermic patients had a lower mortality (22.58% vs. 39.1%) in
the univariate analysis (P <0.01). The patients with hypothermia had a
mortality of 32.67% (NS). Length of stay was not signifi cantly diff erent
between the groups. In the multivariate logistic regression the factors
that were associated independently with mortality were age, APACHE
II score, use of vasopressors, mechanical ventilation and temperature. Patients with T >101.3°F were 59% less likely to die when compared
with patients with normal temperature. Conclusion The results of this study highlight the importance of
investigating the real eff ects of fever in severe sepsis or septic shock. Is it necessary to treat when they are not causing harm to the patients? Are we delaying diagnosis of severe sepsis because of the lack of this
important clinical sign? The next step should be a prospective trial of
treatment versus no treatment of fever in the ICU. Figure 2 (abstract P58). Indication for paracetamol administration
(n = 152). P58 y
p
Conclusion Pharmacological antipyretics are used regularly for pain
management rather than fever management, with paracetamol the
most common antipyretic therapy. The use of NSAIDS and physical
cooling was rare. Noncore temperature measurements were common. g
y
y
Critical Care 2012, 16(Suppl 1):P58 (doi: 10.1186/cc10665) Introduction Our primary aim was to determine the frequency of use
of pharmacological and physical cooling strategies in ICU patients in
current Australian and New Zealand (ANZ) practice. These patients
had sepsis and infl ammation but did not have neurological injury or
recent surgery. We also aimed to establish current indications for use of
antipyretics in these patients, as well as information on the prevalence
of fever and the methods to measure temperature. References 38°C. Paracetamol was used in 152/311 (48.8%), nonsteroidal anti-
infl ammatory drugs (NSAIDS) in 2/311 (0.6%) and physical cooling
in 3/311 (1.0%) (Figure 1). Paracetamol was administered for pain
in 92/152 (60.5%) for both pain and fever in 26/152 (17.1%); and for
fever alone in 14/152 (10%) (Figure 2). For the 40 patients who received
paracetamol for an indication of fever, the peak recorded temperature
was 38.3°C (SD 0.8°C). The peak temperature for patients receiving
physical cooling was 39.2°C (SD 0.9°C). Temperature measurement
were mainly noncore (n = 251/311) with axillary (37%; n = 116/311) and
tympanic (35%; n = 110/311) the most common sites. 1. Marik P: Fever in the ICU. Chest 2000, 117:885-869. 1. Marik P: Fever in the ICU. Chest 2000, 117:885-869. 2. Levy M: Clinical review of fever in intensive care unit patients. Crit Care
2003, 7:221-225. 3. Dellinger P: Surviving Sepsis Campaign Guidelines. Crit Care Med 2008,
36:296-327. Cases of tetanus after the Japan crisis 2011 Cases of tetanus after the Japan crisis 2011
K Morino1, M Kobayashi2, Y Yamada3, S Yamanouchi4, Y Tsujimoto1,
K Takeda1, S Sato1, S Kimura1, N Mita1, M Sato1, S Kushimoto4, S Endo3
1Yamagata Prefectural Medical Center for Emergency, Yamagata, Japan;
2Ishinomaki Red Cross Hospital, Ishinomaki, Japan; 3Iwate Medical University,
Morioka, Japan; 4Tohoku University, Sendai, Japan
Critical Care 2012, 16(Suppl 1):P62 (doi: 10.1186/cc10669) Cases of tetanus after the Japan crisis 2011
K Morino1, M Kobayashi2, Y Yamada3, S Yamanouchi4, Y Tsujimoto1,
K Takeda1, S Sato1, S Kimura1, N Mita1, M Sato1, S Kushimoto4, S Endo3
1Yamagata Prefectural Medical Center for Emergency, Yamagata, Japan;
2Ishinomaki Red Cross Hospital, Ishinomaki, Japan; 3Iwate Medical University,
Morioka, Japan; 4Tohoku University, Sendai, Japan
Critical Care 2012, 16(Suppl 1):P62 (doi: 10.1186/cc10669) Methods Eight severe burn patients within 14 days after injuries
(M:F = 5:3, 19 to 85 years old, 35 to 85% total body surface area) were
treated with MCFG (200 to 300 mg, 3.45 to 4.49 mg/kg) once daily
by intravenous infusion over 1 hour. The MCFG concentrations in the
plasma at the end of the initial administration of MCFG (P1), just before
the second dosing (T1), at the end of the fourth dosing (P4), and just
before the fi fth dosing (T4) were determined, and were compared with
the reported values in health volunteers [2]. MCFG concentrations in
the burn eschar at T1 and T4 were also measured. Introduction Tetanus is an infectious disease caused by tetanus
neurotoxin produced by Clostridium tetani [1]. This bacterium resides
in the soil extensively and about 100 people contract this disease
annually in Japan. Tetanus is prevented by vaccines. A 1968 law
required universal DPT vaccination against diphtheria, pertussis and
tetanus in Japan. The survival rate with intensive care has reached more
than 90% in recent years. Tetanus is said to have been found to increase
in natural disasters [2]. So we will describe cases in the aftermath of the
2011 Tohoku earthquake and tsunami. Results The plasma concentrations of MCFG per dose normalized with
body weight (C/D) at P1, T1, P4, and T4 were 1.37 to 6.28, 0.51 to 1.38,
3.20 to 6.46, and 0.65 to 2.18 (μg/ml)/(mg/kg), respectively, indicating
marked interindividual diff erences. These values were comparable
with or slightly lower than the reported values in healthy volunteers
(P1: 5.7, T1: 1.3, T4: 2.1). Pharmacokinetics of micafungin in patients with severe burn
injuries j
J Sasaki1, S Kishino2, N Aikawa1, S Hori1
1Keio University School of Medicine, Tokyo, Japan; 2Meiji Pharmaceutical
University, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P60 (doi: 10.1186/cc10667) Conclusion The presence of bacteremia relates to the severity and the
mortality of septic patients with high serum PCT in the ICU. Introduction Micafungin (MCFG), an echinocandin antifungal agent,
exhibits more potent antifungal activity against a broad spectrum of
clinically important Candida and Aspergillus species [1]. Few studies
have reported the pharmacokinetics (PK) of antifungal agents in
patients with burn injuries. A purpose of this study is to characterize
the PK of MCFG in severe burn patients. References 1. Aikawa N, et al.: J Infect Chemother 2009, 15:219-227. 1. Aikawa N, et al.: J Infect Chemother 2009, 15:219-227. 2. Azuma J, et al.: Jpn J Chemother 2002, 50(Suppl 1):155-184. 2. Azuma J, et al.: Jpn J Chemother 2002, 50(Suppl 1):155-184. 2. Azuma J, et al.: Jpn J Chemother 2002, 50(Suppl 1):155-184. Cases of tetanus after the Japan crisis 2011 The MCFG concentrations in the burn eschar
of three patients at T1 and T4 were <0.1 to 3.98 and 1.10 to 14.81 μg/
ml, respectively. Most of MCFG concentrations in the plasma and burn
eschar were higher than the reported MIC90 of MCFG against clinically
important Candida and Aspergillus species. There was no correlation
between the laboratory parameters of liver/kidney function and the
plasma C/D of MCFG. Methods We researched the case reports in a national database and
a hospital database which could access patients’ exact data. We made
and analysed these case profi les. Results We had nine tetanus cases in this crisis. This number was high
compared with previous data. All patients lived in the Pacifi c coast of
Tohoku districts and suff ered from the tsunami. Geographically, seven
patients were in Miyagi prefecture, and Iwate Prefecture had two cases. Of the nine cases, we could examine seven cases in detail. Mean age
was 67 years, two were male cases and fi ve women were injured on
the day. Time to onset of symptoms such as trismus was an average
of 12 days. The average was 3 days from symptom onset to medical
consultation. All seven cases had some wounds, including minimal. Three had obvious wound infection. All patients had tetanus vaccine
and tetanus immunoglobulin during their therapy but the time of
injection was inconsistent because of the chaotic state. Four people
were supported by mechanical ventilation with sedation and three out
of four had tracheostomy. Three out of four with mechanical ventilation
were treated with intravenous magnesium therapy to reduce spasticity. The average mechanical ventilation period was 23 days. We have no
intravenous metronidazole preparation in Japan. No one had a reliable
history of tetanus vaccine. No deaths were reported. Conclusion The plasma concentrations of MCFG in patients with severe
burn injuries were comparable with or slightly lower than the reported
values in healthy volunteers. In addition, MCFG seems to be capable of
penetrating burn eschar. Bacteremia aff ects the mortality of septic patients with high serum
procalcitonin level in the ICU M Kamochi, K Nagata, Y Isa, S Nihei, N Harayama, K Aibara, T Sata
University Hospital of Occupational and Environmental Health, Kitakyush
Japan M Kamochi, K Nagata, Y Isa, S Nihei, N Harayama, K Aibara, T Sata
University Hospital of Occupational and Environmental Health, Kitakyushu,
Japan Conclusion We reported nine tetanus patients and investigated seven
cases in detail. Older people had developed an unknown vaccination
history. So we should have more opportunity to give vaccinations to
older people and be careful with tetanus in disasters. References p
Critical Care 2012, 16(Suppl 1):P61 (doi: 10.1186/cc10668) p
Critical Care 2012, 16(Suppl 1):P61 (doi: 10.1186/cc10668) Impact of antifungal treatment in ICU patients with Candida
colonization: analysis of the EPIC II study population p
Methods This point prevalence study was conducted on 17 November
and 15 December 2010 in 38 ICUs in ANZ. We identifi ed a cohort of
patients with sepsis and infl ammation without neurological injury or
recent surgery. g
y
Results Of 506 patients surveyed on the point prevalence days, 311
were identifi ed to have sepsis in the absence of neurological injury
or recent surgery. These patients had peak temperature of 37.3°C
(SD 0.8°C). In 32.2% (n = 100/311) the peak temperature was above Introduction We wished to evaluate the impact of receiving antifungal
therapy in ICU patients with Candida colonization. py
p
Methods EPIC II recruited 1,265 ICUs in 76 countries. Patient charac-
teristics were collected on the study day. Outcome data were assessed
at ICU and hospital discharge. Patients colonized with Candida
spp. were classifi ed as having received antifungal treatment or not
(*P <0.05 compared between groups). Numerical values are reported
as mean ± SD and length of stay (LOS) data as median (IQR). Figure 1 (abstract P58). Type of antipyretic and physical cooling used on
the study day (n = 311). g
y
Results A total of 13,796 adult patients were in participating ICUs on
the study day. Of these, 371 were classifi ed as colonized. Diff erences Table 1 (abstract P59). Patients with Candida colonization: characteristics
and outcomes
Therapy (n = 184)
No therapy (n = 175)
SAPS II
39 ± 15
41 ± 18
SOFA
7.6 ± 4.1
7.4 ± 4.4
MV
76%
63%
Pressor
36%
32%
ICU mortality
35%
22%
Hospital mortality
41%
28% Table 1 (abstract P59). Patients with Candida colonization: characteristics
and outcomes Figure 1 (abstract P58). Type of antipyretic and physical cooling used on
the study day (n = 311). S22 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 in patient characteristics and outcomes are reported (Table 1). Baseline characteristics were similar in colonized patients treated with
antifungal therapy compared to those that were untreated. Only a
modest diff erence in the length of stay in the ICU prior to study day (25
(14, 40) vs. 21 (8, 43)) and utilization of mechanical ventilatory support
(76% vs. 63%) was noted in the treated compared to the untreated
patients with Candida colonization (P <0.05). Impact of antifungal treatment in ICU patients with Candida
colonization: analysis of the EPIC II study population Despite the relatively
similar baseline characteristics and equivalent severity of illness scores,
treated patients had an increased ICU (35.3 vs. 22.3%) and hospital
(41.0 vs. 27.7%) mortality (P <0.05). in patient characteristics and outcomes are reported (Table 1). Baseline characteristics were similar in colonized patients treated with
antifungal therapy compared to those that were untreated. Only a
modest diff erence in the length of stay in the ICU prior to study day (25
(14, 40) vs. 21 (8, 43)) and utilization of mechanical ventilatory support
(76% vs. 63%) was noted in the treated compared to the untreated
patients with Candida colonization (P <0.05). Despite the relatively
similar baseline characteristics and equivalent severity of illness scores,
treated patients had an increased ICU (35.3 vs. 22.3%) and hospital
(41.0 vs. 27.7%) mortality (P <0.05). rapid diagnosis and immediate treatment are necessary to improve the
survival of septic patients. However, the presence of bacteremia seems
to relate to the severity and mortality of septic shock patients in the
ICU. Methods The patients clinically suspected with sepsis were tested for
serum procalcitonin level using a procalcitonin kit (BRAHMUS PCT Kit). The PCT test was performed 334 times from March 2008 to August 2010. Sixty-three adult patients showed high PCT level (>10 ng/ml). Thirty
of 62 (48%) patients showed bacteremia. Sixteen of these bacteremic
patients were Gram-negative bacteremia and 14 patients were Gram-
positive bacteremia. The hemodynamic parameter, APACHE II score,
SOFA score, serum lactate, some other laboratory data and mortality
rate were compared between the patients with bacteremia and those
without bacteremia. Statistical analyses were performed by chi-square
test and Mann–Whitney U test. Conclusion As colonized patients receiving antifungal treatment had
signifi cantly higher mortality, our data do not support the routine use
of antifungal therapy in ICU patients based solely on colonization. Reference 1. Vincent JL, et al.: JAMA 2009, 302:2323-2329. 1. Vincent JL, et al.: JAMA 2009, 302:2323-2329. y
Results The bacteremic patients with high serum PCT level showed
signifi cant higher APACHE II score, SOFA score and serum lactate
concentration than nonbacteremic patients. The mortality rate of
bacteremic patients was signifi cantly higher than that of nonbacteremic
patients (66% vs. 28.1%, P <0.01). There were no diff erences in the
severity and the mortality between Gram-negative and Gram-positive
bacteremia. P60 Pharmacokinetics of micafungin in patients with severe burn
injuries
J Sasaki1, S Kishino2, N Aikawa1, S Hori1
1Keio University School of Medicine, Tokyo, Japan; 2Meiji Pharmaceutical
University, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P60 (doi: 10.1186/cc10667) p
p
References Introduction It is still controversial whether bacteremia aff ects the
severity and the mortality of septic shock. Recent diagnostic criteria
of septic shock do not include the presence of bacteremia, because Farrar JJ, et al.: J Neurol Neurosurg Psychiatry 2000, 69:292-301
Aceh Epidemiology Group: Glob Public Health 2006, 1:173-177. Farrar JJ, et al.: J Neurol Neurosurg Psychiatry 2000, 69:292-301
Aceh Epidemiology Group: Glob Public Health 2006, 1:173-177. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S23 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P63
Does the day of the week predict the presence of microbiologically
confi rmed ventilator-associated pneumonia? C Linssen, H Van Dessel, W Van Mook
Maastricht University Medical Centre, Maastricht, the Netherlands
Critical Care 2012, 16(Suppl 1):P63 (doi: 10.1186/cc10670) Methods This study was a retrospective analysis of patients confi rmed
as appendicitis pathologically from November 2009 to September
2010 at two hospitals. The delta neutrophil index was automatically
calculated as a subset of routine complete blood count test. The
diagnostic performance of the delta neutrophil index for perforated
appendicitis was evaluated. Results During the study period, 308 patients were enrolled. Among
them, 32 patients (10.4%) were confi rmed as perforated appendicitis. The delta neutrophil index was signifi cantly higher in the perforated
group than the nonperforated group (4.8 ± 7.1% vs. 2.0 ± 2.0%,
P <0.05). The sensitivity and specifi city of the delta neutrophil index for
predicting perforated appendicitis was 25.0% and 96.7% respectively
at a cutoff level of 5% with an area under the curve of 0.78 on the ROC
curve. Introduction At our hospital, ventilator-associated pneumonia
(VAP) is diagnosed by microbiological and cytological analysis of
bronchoalveolar lavage fl uid (BALF). Opening hours of the in-house
microbiological laboratory are between 8:00 am and 5:00 pm. During
off -hours a laboratory technician is on call for urgent samples including
BALF. The total laboratory work-up of the BALF takes 2 hours. The aim
of the present study was to detect patterns in the submission time of
BALF samples. Conclusion This study suggested that the delta neutrophil index is
associated with perforated appendicitis. However, the sensitivity was
not high enough to use as a clinical guidance. p
Methods During a 60-month period (January 2006 to December
2010), the day and hour of submission of all consecutive BALF samples
obtained from patients suspected of VAP were recorded. References 1. Nahm CH, Choi JW, Lee J: Delta neutrophil index in automated immature
granulocyte counts for assessing disease severity of patients with sepsis. Ann Clin Lab Sci 2008, 38:241-246. Results A total of 376 BALF samples were included. On weekdays, on
average a total of 59.8 ± 11.4 were submitted, compared to 34 and
43 samples on Saturdays and Sundays. For more than one-half (203,
54%) of the samples, the on-duty laboratory technician was required:
86 (23%) samples arrived within 1 hour before closing time, and an
additional 117 (31%) were submitted thereafter. VAP was diagnosed
in 149 (39.6%) samples, of which 79 (53%) after closing hours. BALF
samples were obtained more frequently on Thursdays and Fridays (51
and 47 samples respectively) compared to Mondays and Tuesdays (64
and 76 samples). Interestingly, VAP was confi rmed proportionally more
frequently on Mondays and Tuesdays (26/51 (51%) and 23/47 (49%))
compared to Thursdays and Fridays (20/64 (31%) and 26/76 (34%)). 2. Andersson RE: Meta-analysis of the clinical and laboratory diagnosis of
appendicitis. Br J Surg 2004, 91:28-37. 3. Oliak D, Yamini D, Udani VM, et al.: Can perforated appendicitis be
diagnosed preoperatively based on admission factors? J Gastrointest Surg
2000, 4:470-474. 4. Ansari-Lari MA, Kickler TS, Borowitz MJ: Immature granulocyte
measurement using the Sysmex XE-2100. Relationship to infection and
sepsis. Am J Clin Pathol 2003, 120:795-799. Conclusion The high number of BALFs processed after laboratory
opening hours is of concern because of the suboptimal working
conditions (fatigue, lack of supervision and experience). Technicians’
time spent on these samples puts a strain on the laboratory in terms
of costs and absence of the technicians because of legal recuperation. A higher number of confi rmed episodes of VAP early in the week
compared to just before the beginning of the weekend, combined with
a larger number of BALF samples obtained on Thursdays and Fridays,
may suggest that clinicians want to exclude VAP before the weekend
resulting in a lower threshold for requesting a BALF. p
p
References VAP was
microbiologically confi rmed if quantitative cultures were ≥104 cfu/ml
and/or presence of ≥2% infected cells. P64
Assessing perforation of acute appendicitis using the delta
neutrophil index refl ecting the peripheral immature granulocyte
count Introduction The delta neutrophil index corresponds to the calculated
immature granulocyte counts and the severity of sepsis. This study
investigated the diagnostic value of the delta neutrophil index as a
preoperative laboratory marker for appendiceal perforation in patients
with acute appendicitis. Table 1 (abstract P65)
Month
Outcome
June
July
August
September
Odds ratio (95% CI)
P value
ICU death, n (%)
100 (36.0%)
122 (38.5%)
137 (34.9%)
82 (24.9%)
0.83 (0.75; 0.93)
0.001
In-hospital death, n (%)
108 (38.6%)
125 (43.0%)
151 (38.5%)
96 (29.2%)
0.85 (0.76; 0.94)
0.002
Mean diff erence (95% CI)
SMR, mean (SD)
1.25 (0.37)
1.63 (0.95)
1.31 (0.62)
0.89 (0.51)
–0.15 (–0.28; –0.01)
0.04
CRBSI, mean (SD)
11.8 (19.7)
4.3 (11.9)
4.4 (5.4)
3.3 (6.0)
–2.11 (–4.68; 0.45)
0.10 Eff ects of a multifaceted quality improvement intervention in
reducing mortality and bloodstream infection in ICUs: insights from
the QUALITI initiative AB Cavalcanti, JC Othero, JC Mouro, KN Silva, ES Victor, AA Kodama,
O Berwanger, B Weber, LH Mota Research Institute – Hospital do Coração, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P65 (doi: 10.1186/cc10672) Introduction Our objective was to evaluate if the implementation of
a multifaceted intervention program for quality improvement in ICUs
of nonacademic hospitals would decrease mortality and the catheter-
related bloodstream infection rate (CRBSI). Methods A clinical practice improvement program involving 17
Brazilian ICUs of nonacademic public hospitals located far from major
economic centers under coordination of a not-for-profi t private hospital
with the support of Brazilian Ministry of Health. We implemented the
following interventions: (1) hospital visits to assess the facilities, human
resources and processes; (2) workshop with hospital directors and ICU
coordinators to elaborate improvement proposals based on the initial
visit fi ndings; (3) multidisciplinary videoconference lectures every
3 weeks about critical care medicine assistance and quality issues; (4)
website containing project educational material, videoconference
recordings, and an evidence-based practice course; (5) subscription of
an electronic clinical information resource for all participating hospitals
(UpToDate®); (6) 3-day workshop to share the coordinating institution
quality improvement practices with directors and ICU coordinators Ceftazidime dosage regimen recommendations in burn patients
based on a Monolix population pharmacokinetic study Introduction The aim of our present work was to predict in burn
patients the best adapted ceftazidime dosage regimen to obtain a
serum target of 40 to 100 mg/l taking into account the infl uence of
patients’ characteristics on ceftazidime pharmacokinetics (PK). Methods In a retrospective study we compared three groups
of patients: patients with intermittent vancomycin (Intermittent
group, n = 27) with target trough level of 5 to 10 mg/l, patients with
continuous vancomycin (CV1 group, n = 24) with target trough level of
20 to 25 mg/l and patients with continuous vancomycin (CV2 group,
n = 20) with target trough level of 15 to 20 mg/l. The demographic data,
total and average vancomycin doses, target level achievement and side
eff ects were analyzed. Methods A Monolix population PK model was developed and
validated in 70 burn patients with Pseudomonas aeruginosa infection. Monte Carlo simulations (n = 1,000) were performed to explore the
appropriateness of diff erent dosage regimens in burn patients. Target
concentrations to achieve were defi ned as a 40 to 100 mg/l steady–
state concentration interval. The recommended dosage was chosen as
the minimum dose providing the maximum of patients in this interval. Results A two-compartment model described ceftazidime disposition. Serum creatinine and age were identifi ed as covariates of ceftazidime
clearance. Age also infl uences the volume of distribution. The
simulations showed that the common dosage regimens of 6 g/day did
not allow achieving the desired target interval. This was achieved with
continuous administration dosage regimens varying between 8 and
16 g/day in the youngest patients. Whatever the dosage regimen, the
age and the serum creatinine, the mean highest percentage of patients
reaching the 40 to 100 mg/l target interval was 76.43 ± 2.13% (range:
65.1 to 80.1%) (Table 1). f
Results There was no diff erence in age, weight, surgical complexity
and mortality between the groups. The average vancomycin daily
dose (mg/kg) was the same in the Intermittent and CV2 groups, the
dose was twofold higher in CV1 group (P <0.001) (Table 1). The CV2
group has less trough samples per day of treatment than the CV1 and
intermittent groups (P = 0.015). Target levels were reached in 42.4%,
30.9%, and 42.9% samples in Intermittent, CV1 and CV2 groups,
respectively (P <0.001). Below target were 9.8%, 38.5% and 16.7%
samples in Intermittent, CV1 and CV2 groups, respectively. Ceftazidime dosage regimen recommendations in burn patients
based on a Monolix population pharmacokinetic study There was
no deep sternal infection in any patient. There was similar incidence of
peritoneal dialysis in all three groups. No case of renal insuffi ciency was
directly related to increased trough vancomycin level. Table 1 (abstract P67)
Intermittent group
CV1 group
CV2 group
TLC (n)
272
250
233
TLC per day (n)
1 (0.6 to 2.3)
0.92 (0.5 to 1.5)
0.81 (0.62 to 1.8)
Daily dose
15 (7.6 to 45)
26.2 (7.6 to 54.3)
15.7 (5.9 to 37.3)
CV, continuous vancomycin; TLC, trough level count. Table 1 (abstract P66). Recommended ceftazidime dosage regimen
Target = 40 mg/l
Creatinine
20
30
40
50
60
70
80
90
(μmol/l)
years
years
years
years
years
years
years
years
30
16 g
16 g
16 g
16 g
14 g
12 g
12 g
10 g
40
16 g
16 g
16 g
14 g
12 g
12 g
10 g
10 g
50
16 g
16 g
16 g
12 g
12 g
10 g
10 g
8 g
60
16 g
16 g
14 g
12 g
12 g
10 g
8 g
8 g
70
16 g
14 g
12 g
12 g
10 g
10 g
8 g
8 g
80
14 g
14 g
12 g
10 g
10 g
8 g
8 g
8 g
90
14 g
14 g
12 g
10 g
10 g
8 g
8 g
6 g
100
14 g
12 g
10 g
10 g
8 g
8 g
8 g
6 g
120
12 g
10 g
10 g
8 g
8 g
6 g
6 g
6 g
140
10 g
10 g
8 g
8 g
6 g
6 g
6 g
4 g
160
10 g
8 g
8 g
6 g
6 g
6 g
4 g
4 g
Recommended ceftazidime dosage regimen after a 2 g loading dose required
to reach a steady-state concentration between 40 and 100 mg/l in the highest
percentage of typical burn patients in function of serum creatinine and age. Conclusion This study highlights the peculiarities of ceftazidime Table 1 (abstract P66). Recommended ceftazidime dosage regimen CV, continuous vancomycin; TLC, trough level count. Continuous versus intermittent vancomycin in children after cardiac
surgery with delayed sternal closure Continuous versus intermittent vancomycin in children after cardiac
surgery with delayed sternal closure
P Skrak, L Hlinkova, L Kovacikova
National Institute of Cardiovascular Diseases, Bratislava, Slovakia
Critical Care 2012, 16(Suppl 1):P67 (doi: 10.1186/cc10674) Conclusion A multifaceted intervention program applied to a network
of ICUs in nonacademic public hospitals reduced mortality. P Skrak, L Hlinkova, L Kovacikova
National Institute of Cardiovascular Diseases, Bratislava, Slovakia
Critical Care 2012, 16(Suppl 1):P67 (doi: 10.1186/cc10674) P66 Introduction Delayed sternal closure (DSC) is a technique used in
patients with hemodynamic instability, lung dysfunction, edema or
prolonged bleeding after cardiac surgery. This group of patients has
signifi cant morbidity and mortality with fl uid overload and changes
in renal function. Adequate antibiotic coverage is of great importance
and vancomycin is used as a part of antibiotic prophylaxis in our
department. The objective of our study was to compare the effi cacy
and effi ciency of intermittent and continuous vancomycin in pediatric
cardiac patients with DSC. P66
Ceftazidime dosage regimen recommendations in burn patients
based on a Monolix population pharmacokinetic study
S Ruiz1, JM Conil1, B Georges1, F Ravat2, T Seguin1, P Letocart1, O Fourcade1,
S Saivin3
1Hôpital Rangueil CHU Toulouse, France; 2Centre hospitalier St Joseph et St
Luc, Lyon, France; 3Institut Fédératif de Biologie CHU Toulouse, France
Critical Care 2012, 16(Suppl 1):P66 (doi: 10.1186/cc10673) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Age and serum creatinine signifi cantly infl uence the ceftazidime
disposition. These covariates must be used to propose the fi rst doses of
ceftazidime. The required dosage regimens are higher than in other ICU
patients and doses between 4 and 16 g/day are proposed. Age and serum creatinine signifi cantly infl uence the ceftazidime
disposition. These covariates must be used to propose the fi rst doses of
ceftazidime. The required dosage regimens are higher than in other ICU
patients and doses between 4 and 16 g/day are proposed. from the 17 participant institutions; (7) 3-day nursing visits from the
coordinating hospital to perform advice on care practice; (8) basic life
support courses, 56 vacancies per hospital, and fundamentals of critical
care support, 30 vacancies; and (9) implementation of a web-based
system to collect ICU and hospital mortality, SAPS3, standardized-
mortality ratio (SMR) and CRBSI after June 2011. We assessed variation
of SMR and CRBSI on time using weighted linear regression, and
variation of mortality on time using generalized-estimating equations. Results The results are presented in Table 1. Ceftazidime dosage regimen recommendations in burn patients
based on a Monolix population pharmacokinetic study Conclusion In children after cardiac surgery with DSC both intermittent
vancomycin with trough level of 5 to 10 mg/l and continuous vanco-
mycin with trough level of 15 to 20 mg/l were comparable with regard
to administered dose and target values achievement. There was
signifi cantly higher daily dose and trough sample count below target
values in patients with continuous vancomycin and target of 20 to
25 mg/l. Table 1 (abstract P65) S24 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 A post-authorisation survey to analyse the perioperative
teicoplanin plasma concentrations in adult patients with chronic
bone sepsis, who received loading doses of 12 mg/kg 12-hourly for
48 hours followed by 12 mg/kg once daily AJ Brink1, G Richards2, C Lautenbach1, N Rapeport1, V Schillack3, J Roberts4,
J Lipman4 AJ Brink1, G Richards2, C Lautenbach1, N Rapeport1, V Schillack3, J Roberts4,
J Lipman4 Results Our study population included fi ve patients (three female) with
mean age 60.6 years. Median (range) colistin concentrations in ELF
were 6.9 (6.2 to 13.9), 3.7 (2.7 to 11.6) and 2.1 (1.2 to 8.7) g/ml at 1, 4,
and 8 hours, respectively, after nebulization. Colistin concentrations in
serum were substantially lower than those observed in ELF with peak
median (range) values 1.56 (1.19 to 2) g/ml. The estimated colistin
mean half-life was 3.4 hours. p
1Milpark Hospital, Johannesburg, South Africa; 2University of Witwatersrand,
Johannesburg, South Africa; 3Ampath National Referral Laboratory, Pretoria,
South Africa; 4University of Queensland, Brisbane, Australia
Critical Care 2012, 16(Suppl 1):P69 (doi: 10.1186/cc10676) Introduction To rapidly achieve teicoplanin trough (Cmin) concentrations
≥20 mg/l suggested for sternal sepsis, loading doses higher than 6 mg/
kg 12-hourly might be warranted [1]. Conclusion Administration of 1 million units of inhaled CMS resulted in
high colistin concentrations in the ELF; moreover, concentrations were
maintained for up to 8 hours in the majority of patients. This fi nding
might support the use of inhaled CMS for the treatment of patients
with VAP due to multidrug-resistant Gram-negative bacteria. Moreover,
the low serum concentrations and the short half-life suggest that
administration of inhaled colistin may be associated with less systemic
toxicity. Methods Patients (n = 10) with deep-seated Gram-positive infections
were enrolled perioperatively. During the fi rst 4 days of therapy
teicoplanin loading doses of 12 mg/kg 12-hourly were administered for
48 hours and 12 mg/kg once daily thereafter. Surgical debridement was
performed on D3. Samples were collected 15 minutes before and 30
minutes and 120 minutes after each teicoplanin administration. Total
and unbound teicoplanin levels were determined using HPLC. P70 P70
Pharmacokinetics of inhaled colistin in critically ill patients with
ventilator-associated tracheobronchitis
Z Athanassa1, M Fousteri2, S Markantonis2, P Myrianthefs3, E Boutzouka3,
E Tsigou3, A Tsakris4, G Baltopoulos3
1Hygeia Hospital, Marousi, Greece; 2Faculty of Pharmacy, University of Athens,
Greece; 3Faculty of Nursing, University of Athens, Greece; 4Faculty of Medicine,
University of Athens, Greece
Critical Care 2012, 16(Suppl 1):P70 (doi: 10.1186/cc10677) 0
Pharmacokinetics of inhaled colistin in critically ill patients with
ventilator-associated tracheobronchitis Introduction Although inhaled colistin is frequently used in ventilator-
associated pneumonia (VAP), data regarding its pharmacokinetic
properties are scarce [1-3]. The aim of this study was to describe colistin
pharmacokinetics in critically ill patients after administration of a single
dose of 1 million units of colistimethate sodium (CMS) via nebulization. Methods Patients with ventilator-associated tracheobronchitis dye
to polymyxin-only susceptible Gram-negative bacteria were included
in the study; patients receiving intravenous and/or nebulized colistin
were excluded. CMS was administered at a dose of 1 million units every
8 hours for 7 days, via a vibrating-mesh nebulizer. Mini bronchoalveolar
lavage was collected before and at 1, 4 and 8 hours post nebulization,
while blood samples were collected before and at 0.16, 0.5, 1, 2, 4, and
8 hours post nebulization. Colistin concentrations in epithelial lining
fl uid (ELF) and plasma were determined by high-performance liquid
chromatography.i Conclusion Clearance of LZD in patients undergoing CVVHDF was
signifi cantly lower than in patients with normal renal function. Pharmacokinetic data from CVVHDF patients demonstrated that
fl ow rates signifi cantly infl uenced the effi ciency of LZD removal. The maintenance dose of LZD may need to be reduced in patients
undergoing CVVHDF under reduced fl ow conditions. Reference 1. Meyer B, et al.: J Antimicrob Chemother 2005, 56:172-179. References 1. Ratjen F, et al.: J Antimicrob Chemother 2006, 57:306-311. 2. Marchand S, et al.: Antimicrob Agents Chemother 2010, 54:3702-3707. 3. Lu Q, et al.: Intensive Care Med 2010, 36:1147-1155. Results All patients had hypoalbuminemia (mean 20.2 g/l). The SS
PK parameters of teicoplanin are described in Table 1. On D3 the
median total and free Cmin were 14.66 (8.93 to 19.66) and 3.09 (0.0 to
6.4) mg/l, respectively. In a multivariate logistic regression model,
total teicoplanin concentrations (P = 0.174) and serum creatinine
concentration (P = 0.034) did not impact signifi cantly on free
teicoplanin levels whereas, in contrast, albumin concentration did (OR
0.120, 95% CI 0.078 to 0.161, P <0.001). References i
yp
yil
Results Fourteen CVVHDF patients and nine NRF patients were
included into the study. CVVHDF was performed using polysulfone
and triacetate membranes. Mean blood, dialysate and fi ltration fl ow
rates were 79.3 ± 2.7 ml/minute, 8.7 ± 5.1 ml/minute and 5.5 ± 2.5
ml/minute, respectively. Sc was 0.86 ± 0.03. T–1/2 data (8.78 ± 3.74 vs. 5.54 ± 3.27 hours, P = 0.05) were signifi cantly longer in the CVVHDF
compared with the NRF group, AUC data (247.9 ± 107.8 vs. 136.0 ± 84.9
g hour/ml, P = 0.02) were signifi cantly higher and CL (2.94 ± 1.38 vs. 5.92 ± 2.97 l/hour, P = 0.004) and Vd (31.0 ± 3.8 vs. 35.8 ± 3.3 l, P = 0.01)
data were signifi cantly lower. LZD clearance was not correlated with
the type of membrane used (polysulfone vs. triacetate: 2.8 ± 1.5 vs. 3.6 ± 1.2 l/hour, P = 0.39). P70 P68
Elimination of linezolid in patients undergoing low-fl ow continuous
venovenous haemodiafi ltration teicoplanin
Total
Free
Cmax
20.1
2.6
Cmin
6.7
2.3
AUC
137.9
28.6
CL
7.0
33.5
Vz
174.1
196.6 Methods LZD (600 mg) was administered intravenously every 12 hours
in ICU patients on CVVHDF and NRF patients (creatinine clearance
50 ml/minute). Blood and fi ltrate samples were collected at 0, 1, 1.5,
2, 3 and 5 hours after infusion from both groups. The elimination half-
life (T–1/2), maximum concentration, concentration time curve (AUC),
volume distribution (Vd), clearance (CL) and sieving coeffi cient (Sc) were
evaluated. Patient characteristics and CVVHDF parameters including
the fi lter type, dialysate and fi ltration fl ow rates were recorded. P68
Elimination of linezolid in patients undergoing low-fl ow continuous
venovenous haemodiafi ltration Recommended ceftazidime dosage regimen after a 2 g loading dose required
to reach a steady-state concentration between 40 and 100 mg/l in the highest
percentage of typical burn patients in function of serum creatinine and age. Introduction It has been reported that linezolid (LZD) is highly
removed in patients undergoing high-fl ow continuous venovenous
haemofi ltration (CVVH: blood fl ow and fi ltration rates were 186 ± 15
and 40 ± 8 ml/minute) compared with patients with normal renal Conclusion This study highlights the peculiarities of ceftazidime
pharmacokinetics in burn patients with high interindividual variability. S25 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 References
1. Brink et al.: Int J Antimicrob Agents 2008, 32:455-458. 2. Mimoz et al.: Intensive Care Med 2006, 32:775-779. P70
Pharmacokinetics of inhaled colistin in critically ill patients with
ventilator-associated tracheobronchitis
Z Athanassa1, M Fousteri2, S Markantonis2, P Myrianthefs3, E Boutzouka3,
E Tsigou3, A Tsakris4, G Baltopoulos3
1Hygeia Hospital, Marousi, Greece; 2Faculty of Pharmacy, University of Athens,
Greece; 3Faculty of Nursing, University of Athens, Greece; 4Faculty of Medicine,
University of Athens, Greece
Critical Care 2012, 16(Suppl 1):P70 (doi: 10.1186/cc10677)
d
i
l h
h
h l d
l
f
l
d
l
Table 1 (abstract P69). Steady-state pharmacokinetic parameters of
teicoplanin
Total
Free
Cmax
20.1
2.6
Cmin
6.7
2.3
AUC
137.9
28.6
CL
7.0
33.5
Vz
174.1
196.6 Table 1 (abstract P69). Steady-state pharmacokinetic parameters of
teicoplanin function (NRF). It is generally considered that no adjustment of LZD
dosage is needed in subjects undergoing CVVH. In Japan, continuous
venovenous haemodiafi ltration (CVVHDF) has preferentially been
administered under low fl ow rate. Investigating the eff ects of fl ow
rate on LZD removal during continuous renal replacement therapy is
essential to regulate therapeutic dosages. We aimed to investigate the
pharmacokinetics of LZD in CVVHDF patients in this setting. function (NRF). It is generally considered that no adjustment of LZD
dosage is needed in subjects undergoing CVVH. In Japan, continuous
venovenous haemodiafi ltration (CVVHDF) has preferentially been
administered under low fl ow rate. Investigating the eff ects of fl ow
rate on LZD removal during continuous renal replacement therapy is
essential to regulate therapeutic dosages. We aimed to investigate the
pharmacokinetics of LZD in CVVHDF patients in this setting. Effi cacy of inhaled tobramycin in severe nosocomial pneumonia Both sampling methods
demonstrated a gradation of cytokine level, with burns and ALI/ARDS
having signifi cantly higher levels than patients with stable chronic lung
disease or healthy controls. to estimate the effi cacy of inhaled tobramycin (IT) as an adjunct to
systemic antibiotics in the treatment of severe NP. y
Methods Twenty ICU patients with NP were enrolled in the study (all
male, 49 ± 7.3 years old); primary reason for ICU stay – intraabdominal
infections (60%), mediastinitis (10%), others (30%). Diagnosis of NP
was made according to standard clinical and CPIS criteria. Associa-
tions of multiresistant Gram-negative bacteria were detected in
bronchoalveolar lavage (BAL) of all patients. Eighty percent of bacteria
were sensitive to tobramycin. Patients were randomized into two
groups – ‘IT’ (group 1, n = 10) + systemic antibiotics (carbapenems,
amino glycosides, protected penicillins); ‘no IT’ (group 2, n = 10), only
systemic antibiotics, same as in group 1. Groups were comparable in
APACHE II and CPIS scores. IT (Bramitob) was administered 300 mg BID
via nebulizer. y
Conclusion The BMS probe was well tolerated and provided cytokine
data comparable to that obtained by BAL in acute and chronic
respiratory diseases. The BMS probe may have utility as a biomarker
sampling modality in patients where clinicians have concerns over
conventional BAL. Acknowledgements The BMS probes were provided by Olympus
(Tokyo, Japan). Results Duration of IT use in group1 was 7.5 ± 2.5 days. There were no
statistically reliable diff erences between groups detected due to the
small number of patients enrolled. But it was clinically detected that
treatment with IT in group1 was associated with a decrease of SIRS
signs and CPIS scores and an increase of oxygenation index in 70% of
patients. Positive dynamics in chest X-ray and computed tomography
was detected in two patients of group 1 (20%; no dynamics in group
2). The titre of microbes in BAL decreased (100%) and their sensitivity
to other groups of antibiotics, which they were previously resistant to,
increased (40%) in group 1 patients after IT administration. Effi cacy of
IT in patients with a registered resistance of microbes to tobramycin
can be explained by a high local concentrations of tobramycin in
lungs. The mortality in groups was similar (40% and 40%) and not
related to a progression of NP. P72 Comparison of a bronchoscopic microsample probe with
bronchoalveolar lavage to measure cytokine levels in critically ill
patients
V Grover, LE Christie, P Charles, P Kelleher, P Shah, S Singh
Chelsea and Westminster Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P72 (doi: 10.1186/cc10679) Introduction The use of bronchoalveolar lavage (BAL) to investigate
infl ammatory lung disease in the critically ill may not be tolerated in
hypoxic patients. Furthermore, soluble protein analysis of BAL fl uid
suff ers from inaccuracies related to saline dilution. The bronchoscopic
microsample (BMS) probe allows absolute cytokine levels in epithelial
lining fl uid (ELF) to be measured directly without lavage [1]. We
compared cytokine levels from ELF obtained by the BMS probe with
those from BAL, to verify its utility in critical illness. Table 1 (abstract P73)
P value
OR (95% CI)
NIV success
0.005
0.1(0.01 to 0.4)
SOFA score*
0.01
1.2(1 to 1.3)
Male gender
<0.001
14(5 to 39.4)
Immunosuppressive status
0.001
4(1.7 to 9.6)
*Mean value. y
y
Methods We recruited 45 patients into fi ve groups in whom BMS and
BAL were conducted sequentially: two ventilated with ALI/ARDS, six
with burns inhalational injury (fi ve ventilated), 15 with COPD, 18 with
interstitial lung disease and four healthy patients. The BMS probe
was bronchoscopically inserted to the subsegmental level in order to
contact the mucosa for 5 to 7 seconds, collecting approximately 20 μl
ELF [1]. BAL was performed with 150 ml of 0.9% saline, discarding the
fi rst 20 ml (bronchiolar fraction). We assayed IL-1, IL-6, IL-8, TNFα and
G-CSF. Comparisons between paired cytokine ELF concentrations in
BMS and BAL were analysed using the nonparametric Wilcoxon’s test
and Spearman’s correlation coeffi cient. Conclusion VAP occurrence seems to be associated with increased
morbidity and ICU mortality. NIV use, avoiding endotracheal
intubation and invasive mechanical ventilation, has appeared to be
eff ective in reducing the rate of VAP episodes, particularly in high-risk
patients (severe immunosuppressed). The application of behavioural
intervention bundles might represent the suitable preventive measure
in settings where high rates of MDR pathogens limit the extensive use
of pharmacological ones. fi
Results The critically ill patients were aged 18 to 84 years (APACHE
II 12 to 21). One patient had ARDS due to urinary tract infection and
another related to pneumonia. No adverse incidents noted were
noted. Overall, cytokine levels were all higher in the BMS group than Effi cacy of inhaled tobramycin in severe nosocomial pneumonia A Kuzovlev1, S Polovnikov2, V Stec2, V Varvarin2
1V.A. Negovsky Scientifi c Research Institute of General Reanimatology RAMS,
Moscow, Russia; 2N.N. Burdenko Main Clinical Military Hospital, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P71 (doi: 10.1186/cc10678) A Kuzovlev1, S Polovnikov2, V Stec2, V Varvarin2
1V.A. Negovsky Scientifi c Research Institute of General Reanimatology RAMS,
Moscow, Russia; 2N.N. Burdenko Main Clinical Military Hospital, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P71 (doi: 10.1186/cc10678) Conclusion The levels achieved on D3 in this study are similar to those
achieved by Mimoz and colleagues using the same dosing schedule
in ICU patients with VAP [2]. Only hypoalbuminemia impacted on the
free levels of teicoplanin in this setting. High teicoplanin loading doses
of 12 mg/kg 12-hourly should probably be extended beyond 48 hours,
before major elective surgery for chronic bone sepsis. Introduction Nosocomial pneumonia (NP) is one of the most prevalent
complications in ICUs. The effi cacy of inhaled antibiotics in treatment
of NP was shown in several research works. The aim of this study was Introduction Nosocomial pneumonia (NP) is one of the most prevalent
complications in ICUs. The effi cacy of inhaled antibiotics in treatment
of NP was shown in several research works. The aim of this study was S26 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 BAL (P <0.0001), consistent with ELF dilution by saline lavage. The
ratio of BMS-derived cytokine to BAL for each patient group did not
diff er signifi cantly. Spearman coeffi cients (r) for IL-1, IL-6, IL-8, TNFα
and G-CSF were 0.38, 0.52, 0.25, 0.38 and 0.40. All correlations were
signifi cant (P <0.01) except for IL-8 (P = 0.05). Both sampling methods
demonstrated a gradation of cytokine level, with burns and ALI/ARDS
having signifi cantly higher levels than patients with stable chronic lung
disease or healthy controls. to estimate the effi cacy of inhaled tobramycin (IT) as an adjunct to
systemic antibiotics in the treatment of severe NP. BAL (P <0.0001), consistent with ELF dilution by saline lavage. The
ratio of BMS-derived cytokine to BAL for each patient group did not
diff er signifi cantly. Spearman coeffi cients (r) for IL-1, IL-6, IL-8, TNFα
and G-CSF were 0.38, 0.52, 0.25, 0.38 and 0.40. All correlations were
signifi cant (P <0.01) except for IL-8 (P = 0.05). Reference 1. Polovnikov SG, Kuzovlev AN, Iliychev AN: Case report of a successful
treatment of severe nosocomial pneumonia with inhaled tobramycin. Pulmonologia 2011, 2:109-112. 1. Polovnikov SG, Kuzovlev AN, Iliychev AN: Case report of a successful
treatment of severe nosocomial pneumonia with inhaled tobramycin. Pulmonologia 2011, 2:109-112. 1. Polovnikov SG, Kuzovlev AN, Iliychev AN: Case report of a successful
treatment of severe nosocomial pneumonia with inhaled tobramycin. Pulmonologia 2011, 2:109-112. .
Vincent JL, et al.: Drugs 2010, 70:1927-1944. Clinical and epidemiological risk factors for ventilator-associated
pneumonia in a cohort of critically ill patients
G D P
l
MA P
i i V R
i E Pi
i
i V B
i i A O
hi G De Pascale, MA Pennisi, V Raggi, E Piervincenzi, V Bernini, A Occhionero,
P De Santis, A Moccaldo, S Cicconi, R Maviglia, M Tumbarello, M Antonelli
Sacro Cuore Catholic University, Rome, Italy
Critical Care 2012, 16(Suppl 1):P73 (doi: 10.1186/cc10680) Introduction Ventilator-associated pneumonia (VAP) represents a
major infectious complication in the ICU. The aim of this study is to
identify risk factors for VAP acquisition. y
Methods All patients admitted to the 18-bed ICU of our university
hospital between 1 October 2009 and 31 December 2010 were
enrolled on the day of VAP diagnosis. Controls were selected by our
computerized database. Statistical analyses were performed using the
StataICl l program. fi
y
Conclusion Administration of IT as an adjunct to systemic antibiotics
is effi cient and safe in treatment of severe nosocomial pneumonias
caused by multiresistant Gram-negative bacteria. Profound randomized
clinical trials on IT are required. p
g
Results Over the study period, among 902 admissions, 100 VAP occurred. The rate of multidrug resistance (MDR) was 23%. Development of VAP
was associated with a signifi cantly longer duration of ICU stay (24
days (17 to 30) vs. 7 days (5 to 9); P <0.001) and mechanical ventilation
(19 days (13 to 20) vs. 4 days (3 to 6); P <0.001). Overall ICU mortality
was higher in the VAP population (41% vs. 29%; P = 0.09). Comparing
patients aff ected by VAP with controls (100 matched patients), the
former group was signifi cantly more likely to be male (P <0.001) and
to be immunosuppressed (P = 0.004). In addition, VAP development
was associated with higher rate of central venous catheter placements
(P <0.001), higher mean SOFA score value (P <0.001) and previous
exposure to antimicrobials (P = 0.004). Successful use of noninvasive
ventilation, and trauma admission appeared as protective factors
(P <0.001). Table 1 shows independent risk factors associated with VAP
acquisition in multivariate analysis. Reference Effi cacy of inhaled tobramycin in severe nosocomial pneumonia Two patients of group 1 (20%) presented
with hearing loss and tinnitus which revealed 3 months after the last
IT administration. There were no cases of bronchospasm or renal
insuffi ciency in group 1. y
p
Reference y
p
Reference 1. Ishizaka A, et al.: Crit Care Med 2001, 29:896-898. 1. Ishizaka A, et al.: Crit Care Med 2001, 29:896-898. 1. Ishizaka A, et al.: Crit Care Med 2001, 29:896-898. P73 Use of a ventilator-associated pneumonia (VAP) bundle to decrease
the VAP rate in Syria Use of a ventilator-associated pneumonia (VAP) bundle to decrease
the VAP rate in Syria
R Alsadat1, M Mazloum2, A Alshamaa3, A Dakkak4, H Al-Bardan1, M Eltayeb2,
A Marie2, F Esber1, O Naes3, M Shama5, I Betelmal5, M Kherallah6
1Al-Mouassat Hospital, Damascus, Syria; 2General Assembly of Damascus
Hospital, Damascus, Syria; 3Al-Bassel Heart Institute, Damascus, Syria; 4Ibn
Alnafees Hospital, Damascus, Syria; 5World Health Organization, Damascus,
Syria; 6King Faisal Specialist Hospital and Research Center, Riyadh, Saudi
Arabia
Critical Care 2012, 16(Suppl 1):P74 (doi: 10.1186/cc10681) R Alsadat1, M Mazloum2, A Alshamaa3, A Dakkak4, H Al-Bardan1, M Eltayeb2,
A Marie2, F Esber1, O Naes3, M Shama5, I Betelmal5, M Kherallah6
1Al-Mouassat Hospital, Damascus, Syria; 2General Assembly of Damascus
Hospital, Damascus, Syria; 3Al-Bassel Heart Institute, Damascus, Syria; 4Ibn
Alnafees Hospital, Damascus, Syria; 5World Health Organization, Damascus,
Syria; 6King Faisal Specialist Hospital and Research Center, Riyadh, Saudi
Arabia p
Results A total of 619 patients were enrolled in the study. During
the baseline period (Phase 1), 238 patients with 2,456 catheter days
were assessed, 30 patients developed a CRBSI. The CRBSI rate during
this period was 12.2 per 1,000 catheter days. All nurses and principle
doctors in the seven ICUs received training on the standard of care
for catheter maintenance along with the introduction of Q-Syte™ and
Posifl ush™. In Phase 2, following introduction of the interventions,
12 of 381 patients developed a CRBSI. Total catheter days during this
period were 3,562. The CRBSI rate decreased to 3.4 per 1,000 catheter
days. This was signifi cantly lower than during the baseline period
(Wilcoxon nonparametric test, u = 4.36, P = 0.0003). Additional analyses
demonstrated that patients were at higher risk for developing a CRBSI
if associated with: a prolonged catheter dwell time, a higher number
of insertion attempts, a blood infusion or an increased frequency
of catheter connector changes. We also found that the patients who
developed a CRBSI had prolonged hospital stay and signifi cantly added
to the cost of treatment. Critical Care 2012, 16(Suppl 1):P74 (doi: 10.1186/cc10681) Introduction Implementation of a ventilator-associated pneumonia
(VAP) bundle as a performance improvement project in the critical
care units for all mechanically ventilated patients aiming to decrease
the VAP rates over the study period at four major teaching hospitals in
Damascus. Methods CDC criteria were used to defi ne VAP. Reference Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S27 maintenance standards in the baseline period (Phase 1). The bundle
was introduced in Phase 2. CRBSI was determined according to US CDC
diagnostic criteria. The rates of CRBSI before and after the introduction
of the bundle of interventions were compared. Use of a ventilator-associated pneumonia (VAP) bundle to decrease
the VAP rate in Syria VAP rates were
calculated based on occurrences per 1,000 ventilator days, VAP rates
were monitored on a monthly basis throughout the project period. VAP
bundle elements included elevation of the head of the bed to between
30 and 45°, daily sedation vacation, daily assessment of readiness to
wean, peptic ulcer disease prophylaxis and deep venous thrombosis
prophylaxis if not contraindicated. Each hospital formed a task force
with a team leader, one or two physicians and one or two nurses. Education took place at an initial conference and a follow-up meeting
for the implementation process and frequent staff education session
in individual units. Compliance with the VAP bundle was considered
based on the implementation of all elements of the bundle. Statistical
Control Chart (SPC) was used to monitor the compliance with the
individual bundle elements as well the bundle as a whole. Conclusion Introduction of Q-Syte™ and Posifl ush™ and improved stan-
d ards of practice for catheter maintenance can signifi cantly decrease
CRBSI in the ICU. Reference Reference 1. O’Grady NP, Alexander M, Burns LA, et al.: Guidelines for the Prevention of
Intravascular Catheter-Related Infections 2011 [www.cdc.gov/hicpac/bsi/
bsi-guidelines-2011.html] 1. O’Grady NP, Alexander M, Burns LA, et al.: Guidelines for the Prevention of
Intravascular Catheter-Related Infections 2011 [www.cdc.gov/hicpac/bsi/
bsi-guidelines-2011.html] 1. O’Grady NP, Alexander M, Burns LA, et al.: Guidelines for the Prevention of
Intravascular Catheter-Related Infections 2011 [www.cdc.gov/hicpac/bsi/
bsi-guidelines-2011.html] Results VAP bundle compliance rates were steadily increasing from 33
to 80% in Hospital 1, from 33 to 86% in Hospital 2 and from 83 to 100%
in Hospital 3 during the study period. The VAP bundle was not applied
in Hospital 4 and therefore no data were available. This correlated with a
decrease in VAP rates from 30 to 6.4 per 1,000 ventilator days in Hospital
1, from 12 to 4.9 per 1,000 ventilator days in Hospital 3, whereas the VAP
rate failed to decrease in Hospital 2 (despite better compliance) and it
remained high around 33 per 1,000 ventilator days in Hospital 4 where
the VAP bundle was not implemented or monitored.f P76 Wash your hands: simple measures save lives
S Macedo, GV Bispo, LA Ferreira, TO Cavalcanti, PF Rosa, C Paiva,
DR De Melo, LG Rezende
São Jose do Avai Hospital, Itaperuna, Brazil
Critical Care 2012, 16(Suppl 1):P76 (doi: 10.1186/cc10683) Introduction Sepsis is a challenge for the intensive therapy unit, being
the principal cause of death during hospitalization. p
Conclusion The VAP bundle is known to be an eff ective way to
decrease VAP but has performed diff erently in diff erent hospitals in
our study. Prevention of VAP requires concerted eff orts on the part of
hospital administration, physicians, and ICU personnel. The program
must be evidence-based, maintained, and accepted by ICU personnel. Monitoring and collection of data should be strict and objective. Continued education and feedback are crucial to maintain a low VAP
rate. Other factors of healthcare infection prevention should also be
taken into consideration. p
p
g
p
Methods We realized a longitudinal and individuated intervention
authorized by the HSJA ethics committee applying the campaign
‘Simple Measures Save Lives’ in which 105 educational adhesives
served as a guide for washing hands and fl ags for high-contaminated
locations. A decontamination routine of monitors, control panels, fans
and infusion bombs was established at each 12 hours; and continued
education for the health team was intensifi ed during the intervention. Was separated two groups, patient enrollments in periods of 45 days
before and after the intervention, with more than 24 hours of
hospitalization: group A with 18 patients and group B with 15 patients. Results The hospital infection incidence decreased by 40% and VAP by
39.6%. Urine culture was positive in 33.3% of those patients (n = 5) in
group A and in 16.7% (n = 1) in group B (a 50.1% decrease). The cultures
of catheter tip were positive in 68.8% (n = 22) of catheters in group A,
which used 32 catheters in total, and none in group B, which used 13
catheters. The sepsis incidence decreased by 39.6%. Septic shock was
detected in 16.6% (n = 3) of patients in group A. There was a drop of
the costs between groups (R4,479.28, 10.5%). The cost of campaign
material was R$50.00. P76 Results Total number of patient consultations during morning ward
round n = 99; total number of occasions a keyboard used n = 40; total
number of times a keyboard used and keyboard required cleaning
n = 37; keyboard used and cleaned when required prior to use n = 5. In total, a rate of compliance at 14% for cleaning keyboards when
appropriate. Further observations over the same time period showed
that keyboards were indicating they required cleaning on 96% of
occasions observed. Introduction In a previous study we showed that cross-contamination
with resistant bacteria occurred less frequently in a single-room (SR)
ICU when compared to an open-plan (OP) ICU. We attempted to identify
whether this was mediated by a change in human behavior; that is,
whether hand hygiene (HH) practices were similar in the OP versus SR ICU. Methods The SR ICU comprises eight single-patient rooms. The OP
ICU includes four beds in a common area. Covert HH observations
were made of physicians and nurses in both ICU areas. Defi ned HH
opportunities occurred before and after contact with the patient
or their environment. Each observation session lasted 20 minutes. Compliance was defi ned as use of alcohol hand rub or chlorhexidine
wash. Qualitative records were made of tasks preceding missed HH
opportunities (patient contact, computer use, obtaining additional
supplies or other). Conclusion The rate of compliance for cleaning bedside keyboards
was 14%, below the standard set of 100%. This may be due to several
factors, including lack of education and resistance to changes in
behaviour which have previously been described in various models of
human behaviour such as the theory for planned behaviour. This may
refl ect compliance with other areas of infection control and have a
detrimental eff ect on patient safety and health. This may also become a
signifi cant issue in the future if compliance rates remain low as more IT
and touchscreen equipment is employed in ICUs. The ICU has adjusted
the induction programme for new medical staff to include education
on infection control measures with bedside IT equipment. pp
Results Observations sessions were completed on 34 and 35 occasions
in the SR and OP ICUs respectively including 277 and 418 HH
opportunities. The number of staff observed per session was 2.6 ± 0.7 in
the SR ICU versus 2.1 ± 0.5 in the OP ICU (P = 0.01). P76 g
Methods We realized a longitudinal and individuated intervention
authorized by the HSJA ethics committee applying the campaign
‘Simple Measures Save Lives’ in which 105 educational adhesives
served as a guide for washing hands and fl ags for high-contaminated
locations. A decontamination routine of monitors, control panels, fans
and infusion bombs was established at each 12 hours; and continued
education for the health team was intensifi ed during the intervention. P75
A strategy for prevention and control of catheter-related
bloodstream infection of ICU patients in China (Prevent CRBSI):
a prospective, multicenter, controlled study
G Cai, J Yan
Zhejiang Hospital, Hangzhou, China
Critical Care 2012, 16(Suppl 1):P75 (doi: 10.1186/cc10682) Introduction Catheter-related bloodstream infection (CRBSI) continues
to be a key issue in ICUs despite recent improvements in the clinical
technique, standardization of the CVC insertion protocol and hand
hygiene. The impact of catheter maintenance on CRBSI rates in China
needs to be further investigated. The objective of study is to evaluate a
bundle of interventions for reducing CRBSI in ICUs. The bundle includes
new technology (BD Q-Syte™ and BD Posifl ush™) in addition to updated
standards of practice for catheter maintenance. Conclusion This intervention was a simple form to decrease the related
number of infections in the neurovascular ICU, having spent irrelevant
values when compared with treatment of these clinical tables. R f 1. Zanon F, Caovilla JJ, Michel RS, et al.: Sepsis in the intensive care unit:
etiologies, prognostic factors and mortality. Rev Bras Terapia Intensiva 2008
20:128-134. 2. Silva E, Pedro MA, Sogaya ACB, et al.: Brazilian Sepsis Epidemiological Study. Crit Care 2004, 8:R251-R260. Methods This is a prospective, multicenter, controlled study. Patients
receiving CVCs in the ICUs were eligible for inclusion. The study was
performed in seven general and teaching hospitals from June 2010
to June 2011 in China. The clinicians conducted their original catheter 3. Chesley R: Getting to zero: an emerging policy framework for the
elimination of hospital-associated infections. Infect Control Hosp Epidemiol
2008, 30:71-73. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S28 P77
Comparison of hand hygiene in single-room versus open-plan ICUs
I Gork, S Benenson, M Brezis, CL Sprung, PD Levin
Hadassah Hebrew University Medical Center, Jerusalem, Israel
Critical Care 2012, 16(Suppl 1):P77 (doi: 10.1186/cc10684) equipment. A standard of 100% compliance for cleaning the keyboard
appropriately when required was set for audit purposes. P76 There were fewer HH
opportunities per session in the SR ICU (8.4 ± 3.3 vs. OP ICU 11.9 ± 5.2,
P <0.001). HH compliance before patient contact was higher in the SR
ICU than the OP ICU (1.8 ± 1.4 vs. 0.8 ± 1.1 episodes/session, P = 0.001),
but similar after patient contact (2.6 ± 1.4 vs. 2.2 ± 1.5 episodes/
session, P = 0.29). Causes of missed HH opportunities were recorded
on 98 and 140 occasions in the SR and OP ICUs. Comparing the SR to
OP ICU: patient contact accounted for 21/98 (21%) versus 50/140 (36%,
P = 0.02) missed HH opportunities respectively; use of the bedside
computer 1/98 (1%) versus 14/140 (10%, P = 0.005); additional supplies
(drugs, cleaning, dressing, and so forth) 9/98 (9%) versus 20/140 (14%,
P = 0.24); and other 4/98 (6%) versus 15/140 (10%, P = 0.06). P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU
A De Nicola, MJ Sucre
San Leonardo Hospital, Castellammare di Stabia, Italy
Critical Care 2012, 16(Suppl 1):P80 (doi: 10.1186/cc10687) P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU
A De Nicola, MJ Sucre
San Leonardo Hospital, Castellammare di Stabia, Italy
Critical Care 2012, 16(Suppl 1):P80 (doi: 10.1186/cc10687) P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU
A De Nicola, MJ Sucre
San Leonardo Hospital, Castellammare di Stabia, Italy
Critical Care 2012, 16(Suppl 1):P80 (doi: 10.1186/cc10687) Reduced air contamination in an ICU environment with a portable
air purifi cation system air purifi cation system
J Papaparaskevas1, V Papas2, M Pratikaki2, A Tsakris1, C Routsi2
1Medical School, University of Athens, Greece; 2Evangelismos Hospital, Athens,
Greece
Critical Care 2012, 16(Suppl 1):P79 (doi: 10.1186/cc10686) J Papaparaskevas1, V Papas2, M Pratikaki2, A Tsakris1, C Routsi2
1Medical School, University of Athens, Greece; 2Evangelismos Hospital, Athens,
Greece Introduction Indoor air contamination has been implicated in hospital-
acquiring infections, especially in immunocompromised patients. This
implies that, along with other preventing measures, maintenance
of good air quality in critical areas in hospitals is helpful to reduce
the incidence of these infections. The objectives of this study were
to evaluate the quality of an ICU air environment regarding total
and fungal fl ora and the ability of a mobile air purifi cation system
(Hegoa; ANEMO, Oullins, France). This device uses UVc technology
(photocatalysis) to destroy a wide range of microorganisms, including
fungi. Conclusion There were more HH opportunities in the OP ICU and
HH compliance there was lower. The main diff erence in compliance
occurred before patient care, with compliance after patient care being
similar. This may refl ect ease of access from patient to patient in the
OP ICU where turning around brings you easily from one patient to
the next. In the SR ICU movement from patient to patient requires
exiting one room and entering another with a clear end to patient
care in one room and a beginning in the next. Patient contact and
use of the bedside computer accounted for the majority of missed HH
opportunities and present possibilities for interventions to improve HH
compliance. Methods Air samples were obtained before and after the Hegoa air
purifi cation system was started in seven ICU rooms, including a total
of 10 beds, during a 24-hour period and at 3-hour intervals. From each
room and time point, 200 l air samples were collected using a calibrated
biocollector (Air Ideal; bioMerieux, Marcy L’Etoile, France). Cultures were
performed on Triptycase Soy Agar and Sabouraud chloramphenicol
agar plates, for the total and the fungal fl ora, respectively. Plates were
incubated at 36°C and room temperature for a period of 7 days. P78
Compliance for decontamination of bedside computer keyboards
on an ICU Results A total of 112 air samples from sampling sites in the ICU rooms
were collected during the 24-hour study period. Before starting the
air purifi cation unit, total fl ora ranged from 175 to 70 cfu/m3 and
fungal fl ora from 30 to 35 cfu/m3. Total fl ora values were continuously
decreasing and at 24 hours after air purifi cation onset were signifi cantly
reduced to 30 to 50 cfu/m3 (72% reduction). Similarly, environment
fungal levels were continuously decreased and at 24 hours after the
start were undetectable. Introduction An audit to assess the compliance of decontamination
of bedside computer keyboards by medical staff on an ICU. The topic
was used for audit as previously identifi ed by the hospital infection
control department as the worst-performing area on ‘clean trace’
scoring, and had been a regular topic of discussion between members
of the medical team. Bedside keyboards automatically emit an alarm
sound and small fl ashing LED light if cleaning is required prior to use. Discussion and hypothesis on reasons for rates of compliance follow
this, including social/human factors that are barriers to compliance
with infection control measures.f Conclusion The Hegoa mobile air purifi cation system shown a rapid
lowering of contaminates with eventual elimination of fungal fl ora. Therefore, that equipment may provide an effi cient method of reducing
air contamination into the ICU. Whether equipping ICU rooms with
such devices could protect immunocompromised patients admitted to
the ICU against fungal and microbial risk has to be examined. P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU CFU of sample sites before and after sanitation
Sample sites
Before UFC/cm2
After UFC/cm2
Mattress
104
<0.5
Vital parameters monitor
5,000
<0.5
Wall
2,000
<0.5
Bed rail
<0.5
<0.5
Bed remote control
<0.5
<0.5
Ventilator screen
5,000
<0.5
Ventilator chassis
104
<0.5
Infusion pump
<0.5
<0.5 Table 1 (abstract P80). CFU of sample sites before and after sanitation Conclusion All-cause mortality in massive hemoptysis at our center
was 18.8%. Lung cancer, necrotizing pneumonia and bronchiectasis
carried signifi cantly higher mortality. BAE showed low mortality but
required multiple interventions in nearly two-thirds of cases. Hence,
surgery remains the intervention of choice in massive hemoptysis at
our setup with acceptable mortality and outcome. p
g
p y
C Wallace, S Cole, B McGuire
Ninewells Hospital, Dundee, UK
Critical Care 2012, 16(Suppl 1):P82 (doi: 10.1186/cc10689) Conclusion The destruction of the bacteria has practically taken place
in all the points tested. The system has resulted to be compatible
with the electronic equipment and a few minutes after the end of
the procedure it is possible to use the area. The catalytic action of the
silver atoms produces the tyndallisation of the surfaces, increasing
the eff ectiveness of the sanitizer. Eight minutes after the end of the
treatment, 98% of the OH – radicals have been destroyed and 95% of the
dry cloud has been deposited, inhibiting the possibility of regeneration
of any resistant microorganism. Introduction Almost 20% of adverse airway events reported to the
Royal College of Anaesthetists 4th National Audit Project (NAP4)
occurred in the ICU [1]. NAP4 commented that the failure to use
capnography probably contributed to 77% of the ICU airway mortality. NAP4 subsequently made a number of recommendations pertaining
to capnography use. We designed a survey to describe practice with
regards to these. Methods A survey was sent to an intensivist at each of the 23 adult
ICUs in Scotland. Results There was a 100% response rate. Nineteen (83%) units used
capnography for all tracheal intubations on the unit, two (9%) in over
three-quarters, one (4%) in under one-half and one (4%) unit reported
never using it. For tracheal intubations prior to unit admission, the
corresponding usage was three (13%) always, seven (30%) in over
three-quarters, seven (34%) in over one-half and six (26%) in less than
one-half of all intubations. Continuous capnography monitoring was
in use on 54% of the intubated patients and 63% of the ventilator-
dependent patients. P81 P81
Massive hemoptysis in a respiratory ICU: causes, interventions and
outcomes – Indian study
D Talwar, J Chudiwal, R Jain, S Kumar
Metro Center for Respiratory Diseases, Noida, India
Critical Care 2012, 16(Suppl 1):P81 (doi: 10.1186/cc10688) Introduction Massive hemoptysis carries high mortality and morbidity,
requiring multidisciplinary management. In India, tuberculosis is a
very common cause of severe hemoptysis and is being treated in
tuberculosis hospitals where such an approach is not available. We
evaluated the profi le of patients admitted with massive hemoptysis in
a well-equipped Indian tertiary-care respiratory center. Conclusion UK Intensive Care Society (ICS) guidelines make strong
recommendations for the use of capnography in all critically ill patients
during intubation [2]. We show a reassuring compliance with those
guidelines during tracheal intubations performed on ICUs. Compliance
was much poorer with the guidelines for those intubations performed
outside units. An AAGBI safety statement recommended that
continuous capnography should be used in all patients with intubated
tracheas, regardless of location [3]. This was not echoed in the 2009 ICS
guidelines (although in the light of NAP4, these have been updated to
support this). Despite the majority of units in Scotland having facilities
to monitor patients using capnography, just over one-half were doing
so routinely. Capnography monitoring will surely increase in the advent
of NAP4 and because of the change to the ICS guidelines. References q pp
y
p
y
Methods Retrospective analysis of 376 patients admitted with
hemoptysis to the respiratory ICU of the Metro Center for Respiratory
Diseases, India was done. We identifi ed 90 patients with massive
hemoptysis (>600 ml in 24 hours) between 2005 and 2011 and the
results were analyzed. As per our protocol all patients had active
medical management and those suitable for surgery underwent
elective or emergent surgery. Unsuitable candidates underwent
bronchial artery embolisation (BAE) or bronchoscopic interventions
(BI) and if suitable were taken for surgery later. Results The mean age of patients was 49.5 ± 16.53 years with 73.33%
(n = 66) being male. Mortality in male patients was signifi cantly higher
than females (64.7 vs. 35.3%, P = 0.02). The mean length of stay in
hospital was 10.44 ± 6.9 days and signifi cantly less (7.06 ± 4.8, P = 0.01)
in the mortality group. Massive hemoptysis was due to tuberculosis
(active and old) in 61%, pneumonia in 25.5%, bronchiectasis in 21.1%,
aspergillus-releated disease in 11.1%. P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU Methods Observations and recording of medical staff and their
compliance of cleaning bedside keyboards when required during a
morning consultant-led ward round over a 10-day period. Further
observations were taken at two other points in time during each day
over the same time period. Observations were conducted by the
author. Medical staff were informed at the beginning of the audit
that this behaviour was being observed and staff were reminded of
the principles of infection control, specifi cally maintaining clean IT f
of the ICU of the ICU
A De Nicola, MJ Sucre
San Leonardo Hospital, Castellammare di Stabia, Italy
Critical Care 2012, 16(Suppl 1):P80 (doi: 10.1186/cc1068 A De Nicola, MJ Sucre Introduction The ICU contains a large quantity of sensitive electrical
equipment which must not be aff ected by any bio-decontamination S29 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P81). Types of management versus mortality in massive
hemoptysis Table 1 (abstract P81). Types of management versus mortality in massive
hemoptysis process. To disinfect the ICU environment we have used the original
device, Medisize 99.99®, which releases a synergistic formulation of
hydrogen peroxide with silver ions. The machine launches a dry cloud
of 0.5 to 2 m particles which penetrates everywhere, without humidity
or corrosive activity. process. To disinfect the ICU environment we have used the original
device, Medisize 99.99®, which releases a synergistic formulation of
hydrogen peroxide with silver ions. The machine launches a dry cloud
of 0.5 to 2 m particles which penetrates everywhere, without humidity
or corrosive activity. hemoptysis
Management
Total
Mortality
Percentage
Medical
6
5
83.3
BI
35
7
20
BAE
19
1
5.2
Surgery
30
4
13.3
Multiple
21
2
9.5 y
Methods The study has been conducted in the ICU area, just after the
patients have been discharged, before and after the use of the Medisize
99.99® device. The overall number of samples taken has been 54 on
three diff erent days. The sampling has been taken with Petri contact
plates and incubated at 35°C for 48 hours, counting afterwards the
CFU/plate. p
Results We found the annulment of the contamination at all sites
tested after sanitation (Table 1). CT chest in 65.5% and in 64.4% by fi ber optic bronchoscopy (FOB). However, combined FOB and CT scan could localize bleeding in 87.8%. See Table 1. Table 1 (abstract P80). 1.
Cook TM, et al.: Br J Anaesth 2011, 106:617-631 and 632-642.
2.
Thomas AN, et al.: Standards for Capnography in Critical Care. London:
Intensive Care Society Standards and Guidelines; 2009.
3.
The Association of Anaesthetists of Great Britain and Ireland: Safety Statement
on Capnography Outside The Operating Theatre. London: AAGBI; 2009 [http://
www.aagbi.org/sites/default/fi les/AAGBI%20SAFETY%20STATEMENT_0] P80
Eff ectiveness of an innovative system for the bio-decontamination
of the ICU Twelve (52%) units reported using capnography
in all the intubated and ventilated patients. Of the units not using
continuous capnography routinely, two (18%) had no equipment for
continuous monitoring. P81 Lung cancer in 6.6% cases but
this carried highest mortality. The bleeding site was identifi ed on 1. Cook TM, et al.: Br J Anaesth 2011, 106:617-631 and 632-642. 2. Thomas AN, et al.: Standards for Capnography in Critical Care. London:
Intensive Care Society Standards and Guidelines; 2009. 3. The Association of Anaesthetists of Great Britain and Ireland: Safety Statement
on Capnography Outside The Operating Theatre. London: AAGBI; 2009 [http://
www.aagbi.org/sites/default/fi les/AAGBI%20SAFETY%20STATEMENT_0] 1. Cook TM, et al.: Br J Anaesth 2011, 106:617-631 and 632-642. 2. Thomas AN, et al.: Standards for Capnography in Critical Care. London:
Intensive Care Society Standards and Guidelines; 2009. 3. The Association of Anaesthetists of Great Britain and Ireland: Safety Statement
on Capnography Outside The Operating Theatre. London: AAGBI; 2009 [http://
www.aagbi.org/sites/default/fi les/AAGBI%20SAFETY%20STATEMENT_0] 3. The Association of Anaesthetists of Great Britain and Ireland: Safety Statement
on Capnography Outside The Operating Theatre. London: AAGBI; 2009 [http://
www.aagbi.org/sites/default/fi les/AAGBI%20SAFETY%20STATEMENT_0] S30 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 pressure support ventilation (PSV). This can be reduced with the
application of an external positive end-expiratory pressure (PEEPe) [1]. However, an accurate measurement of PEEPi during PSV is challenging
[2]. The aim of the present study is to investigate if the use of the
electrical activity of diaphragm (EAdi) may yield the detection of PEEPi
in patients undergoing PSV. We reasoned that if PEEPi was present
the inspiratory airfl ow would start after EAdi had reached a given
value (EAdi-threshold) necessary to generate the muscle pressure
overcoming PEEPi. P83
Digitalized acoustic monitoring of lung congestion
S Lev1, L Wolloch2, I Kagan1, M Grienv1, P Singer1
1Rabin Medical Center, Petah Tikva, Israel; 2Deep Breeze Ltd, Or-Akiva, Israel
Critical Care 2012, 16(Suppl 1):P83 (doi: 10.1186/cc10690) Introduction Changes in lung water are known to change breath sound
acoustics [1]. Using two pig models, we observed that continuous
elevation of lung sound amplitude may indicate an increase in total
lung water content [2]. Here we report three cases of ventilated
patients in whom continuous acoustic monitoring was done during
extravascular lung water (EVLW) measurements. Methods Ten patients with a clinical suspicion of PEEPi undergoing PSV
were enrolled. Exclusion criteria were: age <18 years, hemodynamic
instability, fever and PaO2/FiO2 <100 mmHg. All patients were tested
during PSV for seven steps of 3 minutes each with increasing PEEPe (2,
4, 6, 8, 10, 12, 14 cmH2O). P81 At the end of each step, PEEPi was estimated
with an end-expiratory occlusion maneuver. During the study, we
continuously recorded airway pressure, fl ow, volume and EAdi wave-
forms for off -line analysis. Data were analysed by linear regression and
t test. P <0.05 was considered statistically signifi cant. Methods We retrospectively analyzed cases in which EVLWi (PiCCO) and
other clinical parameters were measured, during continuous acoustic
monitoring (VRI), using eight small sensors adhered to the anterior
chest. A transmission factor (TF) was calculated, using the sound transfer
function between diff erent sensors. The TF changes in correspondence
to changes in tissue density [1]. The diff erence in TF was calculated
between recordings when pulmonary edema was observed (>7 ml/kg
threshold accompanied with an increase of 2 ml/kg in the EVLWi) and
when absent. Statistical analysis was made using a t test. yi
Results If PEEPi is present, EAdi-threshold is supposed to gradually
decrease together with the raise of PEEPe; thus we divided patients
into fi ve responders for whom EAdi-threshold was signifi cantly
correlated with PEEPe, as opposed to fi ve nonresponders. In the
group of responders we observed signifi cant correlations between the
reduction of PEEPi and the increase of PEEPe (r2 = 0.86, P <0.01), and
between EAdi-threshold and PEEPi at diff erent PEEPe levels (r2 =0.96,
P <0.001). In the same group, respiratory rate (RR) decreased (r2 = 0.76,
P = 0.01), tidal volume increased (r2 = 0.71, P = 0.02) and the peak of
EAdi decreased (r2 = 0.94, P <0.001) at increasing levels of PEEPe. On
the contrary, in the nonresponder group the increase of PEEPe was
associated only with an increase of RR (r2 = 0.75, P = 0.01). Results A total of 336 continuous acoustic recordings in three patients
(acoustic monitoring was applied together with EVLWi measurements)
were analyzed (146 recordings when lung edema was present; 190
with no edema). In all patients, the acoustic profi le corresponded
to changes in the clinical picture. In two of the cases, changes in
acoustic profi le were similar to the ones in the EVLWi and other
clinical parameters (Figure 1). In one case, where there was stability in
lung sound acoustics, EVLWi and other clinical parameters were also
stable. Signifi cant diff erences existed between recordings with edema
(–3.61 ± 0.39) and without edema (–5.71 ± 0.15) (P <0.001). References 1. Donnerberg: Br J Dis Chest 1980, 74:23. 2. Lev: Crit Care 2011, 15:P174. P85
Adequate lung sliding identifi cation is not infl uenced by the level of
academic or ultrasound training P85
Adequate lung sliding identifi cation is not infl uenced by the level of
academic or ultrasound training
E Piette1, R Daoust1, J Lambert2, A Denault3
1Hôpital du Sacré-Coeur de Montréal, Canada; 2Université de Montréal,
Canada; 3Institut de Cardiologie de Montréal, Canada
Critical Care 2012, 16(Suppl 1):P85 (doi: 10.1186/cc10692) Introduction Rapid confi rmation of the adequacy of endotracheal
intubation is critical in the fi eld of emergency medicine (EM). Methods
confi rming endotracheal tube (ET) position should have accuracy
near 100%. Studies confi rming ET position using lung sliding (LS)
identifi cation were done by physicians with extensive ultrasound (US)
training using sometimes lengthy examination. These conditions are
not easily reproduced in the emergency department. Our primary
objective was to compare the accuracy of EM physicians with diff erent
levels of academic and US training to correctly identify presence or
absence of LS on random short sequences of lung US. Our secondary
objective was to determine if results were better when participants had
the choice to abstain themselves in uncertain cases. Conclusion Changes in lung water tend to result in changes in the
sound TF, due to changes in the tissue’s density. These preliminary
results indicate that monitoring lung sounds has the potential to
monitor changes in lung water. Conclusion Changes in lung water tend to result in changes in the
sound TF, due to changes in the tissue’s density. These preliminary
results indicate that monitoring lung sounds has the potential to
monitor changes in lung water. Methods We recorded in the operating room 280 short lung US
sequences (one respiratory cycle), of present and absent LS of intubated
patients and randomly presented them to two groups of EM physicians. Accuracy was calculated for diff erent academic and US training: none,
basic Focused Assessment with Sonography in Trauma (FAST), FAST and
advanced cardiac US, fellowship in EM US. We compared them using an
ANOVA test. Only participants in the second group where instructed to
abstain from answering in uncertain cases and accuracy was compared
to the fi rst group using a Student’s t test. The project was approved by
the research and ethics committees. References e e e ces
1. Mancebo J, et al.: Anesthesiology 2000, 93:81-90. 2. Marini JJ: Am J Respir Crit Care Med 2011, 184:756-762. 1. Mancebo J, et al.: Anesthesiology 2000, 93:81-90. 2. Marini JJ: Am J Respir Crit Care Med 2011, 184:756-762. P81 Conclusion In fi ve of 10 patients with clinical suspicion of PEEPi, when
the PEEPe was increased we observed a decrease of EAdi-threshold,
associated with improved respiratory mechanics, suggesting that EAdi-
threshold could be a useful indicator for the presence of PEEPi. References Figure 1 (abstract P83). VRI (average ± SE) versus PiCCO and CXR. Figure 1 (abstract P83). VRI (average ± SE) versus PiCCO and CXR. P84 Usefulness of electrical activity of the diaphragm to detect intrinsic
positive end-expiratory pressure during pressure support ventilation
S Arrigoni, T Mauri, G Bellani, A Pradella, M Turella, V Sala, E Rezoagli, A Pesenti
University of Milano-Bicocca, Monza, Italy 1.
Donnerberg: Br J Dis Chest 1980, 74:23. Usefulness of electrical activity of the diaphragm to detect intrinsic
positive end-expiratory pressure during pressure support ventilation positive end-expiratory pressure during pressure support ventilation
S Arrigoni, T Mauri, G Bellani, A Pradella, M Turella, V Sala, E Rezoagli, A Pesenti
University of Milano-Bicocca, Monza, Italy y
,
,
y
Critical Care 2012, 16(Suppl 1):P84 (doi: 10.1186/cc10691) Results Two medical students, 42 EM residents and 31 EM attendings
participated. No diff erence in accuracy was shown between the
subgroups of academic training with mean accuracies of 66.3% (medical Introduction Intrinsic positive end-expiratory pressure (PEEPi) may add
a substantial workload on respiratory muscles of patients undergoing S31 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 students), 70.9% (residents) and 69.0% (attendings) (P = 0.361). No diff erence was shown between the subgroups of US training
with means of 63.9% (no formation), 70.2% (FAST), 70.9% (FAST +
advanced cardiac US), and 74.2% (fellowship) (P = 0.119). Accuracy was
signifi cantly better when participants could abstain from answering in
uncertain cases with means of 67.5% (95% CI: 65.7 to 69.4) in the fi rst
group and 73.1% (95% CI: 70.7 to 75.5) in the second (P <0.001). students), 70.9% (residents) and 69.0% (attendings) (P = 0.361). No diff erence was shown between the subgroups of US training
with means of 63.9% (no formation), 70.2% (FAST), 70.9% (FAST +
advanced cardiac US), and 74.2% (fellowship) (P = 0.119). Accuracy was
signifi cantly better when participants could abstain from answering in
uncertain cases with means of 67.5% (95% CI: 65.7 to 69.4) in the fi rst
group and 73.1% (95% CI: 70.7 to 75.5) in the second (P <0.001). medicine (EM) to diagnose pneumothorax as well as to evaluate the
adequacy of endotracheal intubation. Presence of the Lung Pulse
artefact (back and forth pleural motion induced by the heartbeat)
as well as the underlying heart may aff ect correct identifi cation of
LS in the left hemithorax, but this has never been studied. Our main
objective was to evaluate the rate of correct identifi cation (accuracy) of
the presence or absence of LS in the right and left hemithorax. p
g
Methods A total of 280 short lung US sequences (one respiratory
cycle), recorded in the operating room, of presence and absence of
LS in intubated patients were randomly presented to two groups of
physicians (in total: two medical students, 42 EM residents and 31 EM
attendings). Trans-thoracic echo evaluation before and during noninvasive
ventilation y
p
g
p
g
Results We included 21 patients (age (median) 38 years; male 71%). Most (80%) patients were admitted because of acute respiratory
insuffi ciency by pneumonia. Seventeen (81%) had CD4 cell counts
lower than 200/mm3. The SAPS 2 score was 47 points and the SOFA
score on day 1 of admission was 6 points. Hospital mortality was
43%. All radiographic pneumonia images were viewed on lung US
examinations. Possible and probable pneumonia by P. jiroveci was
diagnosed in six patients; all of these patients presented diff use thin
and/or gross B lines on both lungs. Bacterial (n = 7), mycobacterial
(tuberculosis (n = 6) and Mycobacterium kansasii (n = 1)), and fungal
(Aspergillus sp. (n = 1)) were diagnosed in other patients. Peripheral
microabscesses were viewed on one patient with PCP and four patients
with other etiologies (P = NS); pleural eff usions were present on US
of seven patients with diverse etiologies (no PCP patient had pleural
eff usions; P = 0.06); no pneumothorax was diagnosed in the study. Consolidation was present in one patient with PCP and 11 patients
with bacterial, mycobacterial and fungal pneumonia (P = 0.05). There
was a high degree of symmetry on lung US examinations of PCP
patients, while there was always diff erences between the right and left
hemithorax among other etiologic pneumonia (P <0.001).f ventilation
L Vetrugno, M Costa, C Centonze, N Langiano, M Rojatti, G Della Rocca
University Hospital of Udine, Italy
Critical Care 2012, 16(Suppl 1):P88 (doi: 10.1186/cc10695) Introduction Over the last decade noninvasive ventilation (NIV) gained
the dignity of fi rst-line intervention for acute lung injury (ALI) and acute
respiratory distress syndrome (ARDS) in the ICU. Its great interest is
based on a lower complications rate compared with traditional invasive
ventilation. However, the NIV application, although less invasive, cannot
ignore its hemodynamic eff ect over the patient. This study evaluates
the NIV eff ects on the left ventricle in terms of systolic and diastolic
function through trans-thoracic echocardiography (TTE). We also try to
obtain a preload value index equivalent of fl ow time corrected (FTc). p
ql
Methods Thirteen patients admitted to our ICU with ALI/ARDS
underwent TTE before and during NIV. NIV was set as a 1 hour cycle with
5 to 7 cmH2O of PEEP and 5 to 7 cmH2O of pressure support ventilation. During NIV for a better patient compliance a continuous i.v. Usefulness of electrical activity of the diaphragm to detect intrinsic
positive end-expiratory pressure during pressure support ventilation Sequences were divided equally between the right and left
hemithorax. Each participant’s knowledge of the Lung Pulse artefact
was noted. Only the second group was instructed not to answer in case
of uncertainty. A Kolmogorov–Smirnov test showed the rate of correct
LS identifi cation did not follow a normal distribution. Median rates are
reported with interquartile range (IQR) and compared using a Mann–
Whitney test. Conclusion Correct LS identifi cation on short lung US sequences is not
infl uenced by the level of academic or US training. Accuracy is better
when the possibility to abstain oneself from answering is given. LS
identifi cation using one respiratory US sequences should be used with
caution to confi rm adequacy of endotracheal intubation. P86
Lung ultrasound can diff erentiate Pneumocystis jiroveci versus other
etiologies among critically ill AIDS patients with pneumonia
A Japiassu, F Bozza
IPEC-FIOCRUZ, Rio de Janeiro, Brazil
Critical Care 2012, 16(Suppl 1):P86 (doi: 10.1186/cc10693) Trans-thoracic echo evaluation before and during noninvasive
ventilation infusion of
remifentanil was used (range 0.03 to 0.05 μg/kg/minute). At baseline
(T0 = before NIV) and after 30 minutes of NIV (T1), the following data
were recorded: respiratory – RR, SaO2%, PaO2, PaCO2, pH, BE, and HCO3
–;
and cardiac – heart rate (HR), arterial blood pressure (systolic, diastolic
and media), diastolic and systolic volume (EDV, ESV), ejection fraction
(EF), stroke volume (SV), velocity time integral (VTI), FTc, E wave,
deceleration time (Dt), A wave, ventricular fl ow propagation velocity
(Vp). Conclusion We suggest that high-degree symmetric and diff use B
lines, without pleural eff usions, are compatible with P. jiroveci as the
etiology of recent diagnosed pneumonia in critically ill AIDS patients. P87
Diff erence in accuracy of lung sliding identifi cation between the
right and left hemithorax
R Daoust1, E Piette1, J Lambert2, A Denault3
1Hôpital du Sacré-Coeur de Montréal, Canada; 2Université de Montréal,
Canada; 3Institut de Cardiologie de Montréal, Canada
Critical Care 2012, 16(Suppl 1):P87 (doi: 10.1186/cc10694) Lung ultrasound can diff erentiate Pneumocystis jiroveci versus other
etiologies among critically ill AIDS patients with pneumonia
A Japiassu, F Bozza Results Knowledge of Lung Pulse was higher in the second group
(55% vs. 21%, P <0.05). Globally, median accuracy of identifi cation of LS
presence or absence was 74.0% (IQR: 48.0 to 90.0) in the fi rst group and
83.7% (IQR: 53.3 to 96.2) in the second (P = 0.006). For the fi rst group,
median accuracy was 80.0% (IQR: 57.0 to 95.0) in the right hemithorax
and 67.0% (IQR: 43.0 to 83.0) in the left (P <0.001). For the second group,
median accuracy was 88.7% (IQR: 63.1 to 96.9) in the right hemithorax
and 76.3% (IQR: 42.9 to 90.9) in the left (P <0.001). Introduction Lung ultrasound (US) can be applied as a point-of-care
approach for diagnosis of pneumonia in AIDS patients. We compare
US examinations of Pneumocystis jiroveci versus other etiologies of
pneumonia in critically ill patients. p
y
p
Methods Every HIV/AIDS patients admitted to the ICU with pneumonia
was included. The fi rst US examination was performed until 72 hours
after admission. Pneumonia was defi ned by clinical examination,
laboratorial parameters and chest X-rays. Etiologic agents were defi ned
according to appropriate cultures and serology. US was applied to
four fi elds (apex, lateral middle third, anterior basal and posterior
basal regions) for each hemithorax, with 2.5 MHz curved transducer. Three pneumonia patterns were defi ned: interstitial pneumonia,
bronchopneumonia
and
pneumonia
with
consolidation. The
presence of B lines, peripheral microabscesses (bronchopneumonia),
consolidations and pleural eff usions were compared between the
Pneumocystis pneumonia group (PCP) versus other etiologies. Conclusion Accuracy of identifi cation of LS presence or absence
is higher in the right hemithorax. Our study is the fi rst to report this
fi nding. Presence of the Lung Pulse artefact, as well as the underlying
heart, probably explains the worse accuracy found in the left
hemithorax. Caution should be taken in using LS identifi cation as a
diagnostic tool in the left hemithorax and knowledge of the Lung Pulse
artefact should be emphasized in chest US curriculum. P88 P89 P89
Listen to PaO2/FiO2 ratios: they tell us about length of stay
V Inal, B Comert, L Yamanel
GATA, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P89 (doi: 10.1186/cc10696) P89
Listen to PaO2/FiO2 ratios: they tell us about length of stay
V Inal, B Comert, L Yamanel
GATA, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P89 (doi: 10.1186/cc10696) Introduction Classifi cation of respiratory distress has been dependent
on PaO2/FiO2; that is, <300 acute lung injury (ALI) and <200 acute
respiratory distress syndrome (ARDS). In this study, PaO2/FiO2 was
analyzed for predicting ICU patients’ length of stay (LOS). References References
1. Antonelli M, Pennisi MA, Montini L: Clinical review: Noninvasive ventilation
in the clinical setting – experience from the past 10 years. Crit Care 2005,
9:98-103. References
1. Antonelli M, Pennisi MA, Montini L: Clinical review: Noninvasive ventilation
in the clinical setting – experience from the past 10 years. Crit Care 2005,
9:98-103. 2. Shekerdemian L, Bohn D: Cardiovascular eff ects of mechanical ventilation. Arch Dis Child 1999, 80:475-480. 2. Shekerdemian L, Bohn D: Cardiovascular eff ects of mechanical ventilation. Arch Dis Child 1999, 80:475-480. Conclusion We concluded that the PaO2/FiO2 ratio was a powerful
indicator for predicting ICU LOS in patients with RI. In addition there
was no need to classify patients according to PaO2/FiO2 to predict
LOS; any decreased ratio meant a longer LOS. However, this study
was weak in power; it had a small sample, did not include comorbid
conditions, did not account for accepted scoring systems, and did not
include daily ABGA for prediction. On the other hand, these results are
promising for future observations that ABGA taken in the ED would be
a supplemental tool for the physician’s approach in the ICU. Diff erence in accuracy of lung sliding identifi cation between the
right and left hemithorax On the other hand, these results are
promising for future observations that ABGA taken in the ED would be
a supplemental tool for the physician’s approach in the ICU. Age
>300 (n)
ALI (n)
ARDS (n)
(n)
(years)
LOS (days)
LOS (days)
LOS (days)
Male 165
65 ± 8.2
47 8 ± 2.1
65 12 ± 3.4
53 16 ± 4.2
Female 108
69 ± 7.6
33 7 ± 2.9
43 11 ± 3.7
32 17 ± 3.8 Diff erence in accuracy of lung sliding identifi cation between the
right and left hemithorax Results From T0 to T1 the following changes with Wilcoxon matched pairs
test were statistically signifi cant (P <0.05*). PaO2 (94 to 123 mmHg*), SaO2
(87 to 97%*) and PaO2/FiO2, RR (37 to 28/minute*). At T0, EF was >55%
in seven patients and <55% in six patients. In the group with EF <55%
(T0) the EF increased at T1 (42 to 52%*). Dt signifi cantly increased
from T0 to T1 (182 to 198 cm/second*). No signifi cant changes were
observed in VTI, E/A ratio, Vp, and E/Vp ratio, from T0 to T1. g
R Daoust1, E Piette1, J Lambert2, A Denault3
1Hôpital du Sacré-Coeur de Montréal, Canada; 2Université de Montréal,
Canada; 3Institut de Cardiologie de Montréal, Canada
Critical Care 2012, 16(Suppl 1):P87 (doi: 10.1186/cc10694) Introduction The fi eld of lung ultrasound (US) in critical care is in rapid
expansion. Lung sliding (LS) identifi cation has been used in emergency Introduction The fi eld of lung ultrasound (US) in critical care is in rapid
expansion. Lung sliding (LS) identifi cation has been used in emergency Conclusion Our study suggests that NIV improves cardiac function in
patients with reduced EF, positioning the patients to a more favorable S32 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P89). Patient data Table 1 (abstract P89). Patient data point of the Frank Starling curve. In these patients we also showed an
increase in FTc that seems to be aff ected by either preload or afterload
reduction. (
)
Age
>300 (n)
ALI (n)
ARDS (n)
(n)
(years)
LOS (days)
LOS (days)
LOS (days)
Male 165
65 ± 8.2
47 8 ± 2.1
65 12 ± 3.4
53 16 ± 4.2
Female 108
69 ± 7.6
33 7 ± 2.9
43 11 ± 3.7
32 17 ± 3.8
Conclusion We concluded that the PaO2/FiO2 ratio was a powerful
indicator for predicting ICU LOS in patients with RI. In addition there
was no need to classify patients according to PaO2/FiO2 to predict
LOS; any decreased ratio meant a longer LOS. However, this study
was weak in power; it had a small sample, did not include comorbid
conditions, did not account for accepted scoring systems, and did not
include daily ABGA for prediction. Reference 1. Ventilation with lower tidal volumes as compared with traditional tidal
volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000,
342:1301-1308. 1. Ventilation with lower tidal volumes as compared with traditional tidal
volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000,
342:1301-1308. 1. Pediatr Crit Care Med 2010, 11:12-17. Figure 1 (abstract P91). Oxygenation Index versus P/F ratio. The Oxygenation Index compared with the P/F ratio in ALI/ARDS
M Van Haperen1, PH Van der Voort2, RJ Bosman2 1AMC, Amsterdam, the Netherlands; 2Olvg, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P91 (doi: 10.1186/cc10698) 1AMC, Amsterdam, the Netherlands; 2Olvg, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P91 (doi: 10.1186/cc10698) Introduction The usual way to describe the severity of pulmonary
dysfunction in ventilated ICU patients is by using the PaO2/FiO2 ratio
(PF). The PF may be adjusted by the ventilator pressure settings in order
to reduce inspiratory oxygen fraction but the PF does not take the
mean airway pressure (MAP) into account. In contrast, the Oxygenation
Index (OI) is defi ned as the reciprocal of PF times MAP: OI = (FiO2×mean
airway pressure) / PaO2. As such, the OI is a better representative of
oxygenation dysfunction. The objective was to study the correlation
between and the impact of the MAP on the PF and OI. p
Results Seventeen patients with mean age of 70.2 years (SD 14.1)
and median APACHE IV expected mortality of 31% (IQR 14 to 70),
10 admitted for medical reasons and seven for surgical reasons, and
ventilated for 4 days median (IQR 3 to 6) fulfi lled inclusion criteria and
were included in the study. Results of tidal volume measurements are
shown in Table 1. Table 1 (abstract P92). Tidal volume measurements Table 1 (abstract P92). Tidal volume measurements Table 1 (abstract P92). Tidal volume measurements Table 1 (abstract P92). Tidal volume measurements
Total number of aVt measurements
286
Number of aVt measurements per patient (IQR)
12 (4 to 20)
aVt <6 ml/kg PBW
25 (9%)
aVt 6 to 8 ml/kg PBW
156 (58%)
aVt 8 to 10 ml/kg PBW
82 (29%)
aVt >10 ml/kg PBW
23 (8%)
Mean aVt per kg PBW (SD)
7.85 (1.23)
aVt, actual tidal volume; PBW, predicted body weight. Methods We performed a retrospective analysis of 27 consecutive
mechanically ventilated patients admitted to our ICU with bilateral
interstitial/alveolar lung disease, defi ned as ALI or ARDS. The data of
these patients were collected during a time period of maximum 30
consecutive days. Demographic data were recorded and the PF, OI
and MAP were assessed daily at 6:00 am during the fi rst 30 days of
admission. OI >8.1 is usually regarded as ARDS and >5.3 as ALI [1]. y
g
[ ]
Results We included 27 patients, 25 were male, the mean APACHE II
score was 22, the median length of stay on the ICU 11 days and the ICU
mortality was 11/16 (69%). The mean PF was 165 (SD 83), the mean OI
was 8.2 (SD 5) and the mean MAP was 16 cmH2O (SD 5). The 27 patients
resulted in 364 measurements. Of these measurements 158 had OI
>8.1, of which 157 had PF <200 and a mean MAP of 19.3 cmH2O. In
one patient PF was >200 while OI was >8.1 with MAP 18 cmH2O. Of the
100 measurements with OI 5.3 to 8.1, 14 had PF 200 to 300 and 85 had
PF <200. The MAP in these measurements was 17, 64 and 24 cmH2O
respectively. Figure 1 shows the nonlinear relation between OI and PF. Conclusion In patients with ARDS, OI >8.1 is usually in agreement with
PF <200. However, patients with ALI based on OI 5.3 to 8.1 frequently
had PF <200. More studies are needed to determine the optimal level
of OI for the diagnosis of ALI/ARDS. Reference Conclusion In this small single-centre study, the mean aVt is between
6 and 8 ml/kg PBW as prescribed, but only 58% of measured tidal
volumes are indeed between 6 and 8 ml/kg PBW. P92 P92 Results Data were available for 815 patients (see Figure 1). Increasing
OI was associated with increasing mortality (P <0.0001 chi-squared test
for trend). Each step increase in OI was associated with approximately
a 6% absolute increase in mortality. The OI was also associated with
increasing Standardised Mortality Ratio (ICNARC model).i Do actual tidal volumes diff er from prescribed tidal volumes? R Kleijn, B Kalkman, N Verburg, H Oudijk, B Van Vondelen, M Luttmer,
I Slagers, M Ruijters, I Meynaar
Reinier de Graaf Groep, Delft, the Netherlands
Critical Care 2012, 16(Suppl 1):P92 (doi: 10.1186/cc10699) g
y
Conclusion The highest OI occurring in the fi rst 24 hours of ventilation
is an independent predictor of mortality. Collection of OI data may
allow better prediction of outcome than P/F ratio data alone. References Introduction Studies have shown that the selection of incorrect
tidal volume can cause ventilator-induced lung injury and increased
mortality [1]. This study was done to determine if the actual tidal
volume (aVt) diff ers from the prescribed tidal volume (pVt) based on
predicted body weight (PBW). 1. Winter B, et al.: Management of Severe Refractory Hypoxia in Critical Care
in the UK in 2010 Report from UK Expert Group [http://www.ics.ac.uk/
latest_news/management_of_severe_respiratory_failure_in_critical_care_] 2. Britos M, Smoot E, Liu KD, et al.: The value of positive end-expiratory
pressure and FiO2 criteria in the defi nition of the acute respiratory distress
syndrome. Crit Care Med 2011, 39:2025-2030. y
Methods The ICU is a 10-bed intensivist-led unit in a 500-bed teaching
hospital. All consecutive patients receiving invasive mechanical
ventilation in June 2011 were included. Patients with noninvasive
ventilation or with continuous positive airway pressure only were
excluded. The ICU has a mechanical ventilation protocol that prescribes
tidal volume to be between 6 and 8 ml/kg PBW. A table with prescribed
tidal volumes based on PBW is available at the bedside throughout the
ICU. All patients were ventilated with Drager Evita XL ventilators on
pressure support (ASB) or pressure control mode (BIPAP). During the
study period we compared the aVt with the pVt each day at 0, 6, 10, 14,
18 and 22 hours for all patients. P90
Worst Oxygenation Index during the fi rst 24 hours of ventilation
predicts mortality y
y
Methods Data of 273 patients admitted to the ICU with RI were
retrospectively analyzed for LOS in the ICU. Patients admitted to the
emergency department (ED) with RI, documented arterial blood gas
analysis (ABGA), and hospitalized in the ICU were eligible for this study
within 4 years. The fi rst ABGA in ED PaO2/FiO2 were taken for predicting
ICU LOS. Patients’ comorbid diseases, APACHE II/Glasgow scores, non/
invasive mechanical ventilation supports were not included in the
analysis. Patients were classifi ed into three groups as: (1) >300 not
having RI, (2) <300 ALI, (3) <200 ARDS; they were then compared for
predicting ICU LOS, and also receiver operating curve (ROC) analysis
and area under curve (AUC) were calculated.i RJ Jackson, TH Gould, MJ Thomas
Bristol Royal Infi rmary, Bristol, UK
Critical Care 2012, 16(Suppl 1):P90 (doi: 10.1186/cc10697) Introduction The ratio of PaO2 to FiO2 (P/F ratio) is often used to classify
patients with hypoxic respiratory failure, and is recommended in
guidelines from a UK expert group [1] but does not take airway pressures
into account. A study found that adjusting for PEEP did not aff ect the
predictive ability of the P/F ratio [2]; however, the mean airway pressure
(MAP) may be a better indicator of lung recruitment. The Oxygenation
Index (OI = (FiO2×MAP) / PaO2)) includes an adjustment for MAP. Results Analysis showed statistical signifi cance of P <0.01 for all groups
pointing out that ED ABGA PaO2/FiO2 levels negatively aff ected patients’
LOS in the ICU. ROC analysis of PaO2/FiO2 for LOS showed signifi cant
AUC: 0.917 levels, which was predicted as a powerful indicator. Patients’
data are presented in Table 1. 2
2
Methods We retrospectively assessed a computerised record (from
2008 to 2010) of ventilator parameters and identifi ed the highest OI for
all ventilated patients from a general adult university teaching hospital
ICU, during the fi rst 24 hours of ventilation. Patients were grouped
according to highest OI, and mortality was calculated for subgroups. Figure 1 (abstract P90). Mortality and number of patients by Oxygenation Index. Figure 1 (abstract P90). Mortality and number of patients by Oxygenation Index. Figure 1 (abstract P90). Mortality and number of patients by Oxygenation Index. S33 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P93 P93
Intratracheal administration of siRNA targeting FAS reduces
ischemia–reperfusion-induced lung injury
L Del Sorbo, G Muraca, A Costamagna, G Rotondo, L Laudari, F Civiletti,
E Tonoli, E Martin, V Fanelli, V Ranieri
University of Turin, Italy
Critical Care 2012, 16(Suppl 1):P93 (doi: 10.1186/cc10700) ,
,
,
University of Turin, Italy
Critical Care 2012, 16(Suppl 1):P93 (doi: 10.1186/cc10700) Introduction Ischemia–reperfusion injury is one of the main causes
of primary graft dysfunction after lung transplantation. Fas-mediated
apoptosis plays a major role in the pathogenesis of ischemia–
reperfusion injury. Exogenous administration of small interfering RNA
(siRNA) is an eff ective strategy to specifi cally silence the expression of
proteins through blocking the translation of mRNA. The aim of this
study was to investigate in an ex vivo mouse model of lung ventilation
and perfusion whether a specifi c siRNA targeting Fas is able to reduce
ischemia–reperfusion injury. Figure 1 (abstract P91). Oxygenation Index versus P/F ratio. S34 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods C57BL/6 male mice were randomized to intratracheally
receive a specifi c sequence of siRNA targeting FAS (siRNA-FAS) or
a scrambled siRNA 48 hours before undergoing 6 hours of cold
ischemic time (4°C) followed by 2 hours of ex vivo ventilation (peak
inspiratory pressure = 7 cmH2O, PEEP = 2 cmH2O, respiratory rate = 100
breaths/minute, FiO2 = 100%) and reperfusion (4% bovine serum
albumin RPMI medium with 10% fresh blood at 1 ml/minute fl ow
rate) in a predisposed humidifi ed chamber at 37°C. At the end of the
experiment, lung elastance, assessed through tidal volume, and total
protein concentration in the bronchoalveolar lavage (BAL) fl uid were
measured. A separate set of lungs were analysed by western blot before
undergoing cold ischemia to assess the expression of FAS protein. Conclusion Acute lung injury induced by intratracheal hydrochloric
acid instillation requires the function of TNFα receptor I and associates
with activation of downstream proinfl ammatory signaling pathways
p44/42 and c-Jun N-Terminal kinase. P96 g
Methods Subjects were male and female C57Bl/6 mice, wild-type,
TNFα knockout, TNFα receptor I knockout (n = 135). Hydrochloric acid
was instilled intratracheally to mice, followed by respiratory system
elastance measurement, bronchoalveolar lavage and lung tissue
harvesting 24 hours post injection. The TNFα inhibitor etanercept was
administered as pretreatment to a subset of mice prior to hydrochloric
acid exposure.l A new miniaturized extracorporeal membrane oxygenator with
integrated rotary blood pump (Ilias): fi rst results in a porcine mode
of lung injury
K Pilarczyk1, J Heckmann1, K Lyskawa1, A Strauß2, U Aschenbrenner2,
H Jakob1, M Kamler1, N Pizanis1
1West German Heart Centre Essen, University Hospital, Essen, Germany;
2iliasmedical GmbH, Bochum, Germany
Critical Care 2012, 16(Suppl 1):P96 (doi: 10.1186/cc10703) P93 P95
Retrieval of patients with severe respiratory failure on venovenous
extracorporeal membrane oxygenation: an intensivist-led model
A Burrell1, V Pellegrino1, D Pilcher1, S Bernard1, M Kennedy2
1The Alfred Hospital, Melbourne, Australia; 2Adult Retrieval Victoria,
Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P95 (doi: 10.1186/cc10702) g
g
p
p
Results The intratracheal administration of siRNA-FAS reduced
the expression of FAS in the lung by 44% (siRNA-FAS 0.90 ± 0.11 vs. scrambled siRNA 1.61 ± 0.18 AU). Lung elastance and BAL total protein
concentration were signifi cantly reduced in the siRNA-FAS group as
compared to control in lungs exposed to 6 hours of cold ischemia
followed by 2 hours of reperfusion. See Table 1. Introduction Patients with severe respiratory failure may require veno-
venous extracorporeal membrane oxygenation (vv-ECMO). However,
this treatment is only available in specialized centres. Previous reports
of vv-ECMO cannula insertion and retrieval have included large teams
of surgeons, perfusionists, physicians, retrieval doctors, paramedics
and nurses. We hypothesized that an intensivist-led model for rapid
response to a referring hospital, the insertion of vv-ECMO cannulae and
subsequent retrieval would be safe and feasible. Table 1 (abstract P93)
siRNA-FAS
siRNA scrambled
Elastance (cmH2O/ml)
11.34 ± 0.24*
13.75 ± 0.99
BAL proteins (μg/ml)
529.1 ± 64.8*
928.5 ± 138.2
Data are mean ± SE. Comparison between groups was performed with the
Student’s t test. *P <0.05. Methods The Alfred Hospital ICU is the specialist centre for ECMO
services for the states of Victoria and Tasmania in Australia. The
intensivists in our ICU are trained to insert ECMO cannulae using a
percutaneous femoral approach and manage the ECMO circuit during
transport. A new ECMO retrieval service was set up in 2008 to allow the
cannulation and retrieval of patients from other referring hospitals. The
retrieval team comprises two intensivists to insert femoral cannulae
and manage the ECMO circuit, a third physician to manage the
ventilator and infusion pumps and a paramedic to manage the logistics
of the patient transfer. We reviewed all consecutive patients from 2008
to 2011 with severe respiratory failure who received vv-ECMO and were
retrieved to our specialist center. Conclusion The intratracheal administration of siRNA targeting FAS
prevents the increase of the alveolar membrane permeability during
ischemia–reperfusion injury. p
j
y
cknowledgements Funded by PRIN and Regione Piemonte. P94
Acute lung injury in mice associates with p44/42 and c-Jun
N-terminal kinase activation and requires the function of TNFα
receptor I Critical Care 2012, 16(Suppl 1):P94 (doi: 10.1186/cc10701) Introduction Aspiration of hydrochloric acid-containing gastric juice
leads to acute lung injury and hypoxemic respiratory failure due to an
exuberant infl ammatory response associated with pulmonary edema
from increased endothelial and epithelial permeability. The aim of this
study was to determine the role and signaling mechanisms of TNFα in
experimental acute lung injury from hydrochloric acid aspiration using
a combination of genetic animal models and pharmacologic inhibition
strategies. g
Conclusion An intensivist-led model of vv-ECMO cannulation and
retrieval appears to be a safe and eff ective model for vv-ECMO retrieval. This model may lead to a more rapid and cost-eff ective response and is
the subject of further study. P94 p
Results There were 23 patients from 2008 to 2011. All cannulations
were successfully performed percutaneously at the referring hospital
by the intensivists. The underlying condition was H1N1 in 11 patients,
bacterial pneumonia in six, acute lung injury in four, metastatic
seminoma in one and multiple lung abscesses in one. The average age
was 36 years (range 17 to 60 years). Males were 61%. Transport was by
fi xed-wing aircraft in 35% and road ambulance in 65%. The retrieval
distance averaged 76 km (range 7 to 1,770 km). During transport,
there were two transient pump failures requiring hand cranking and
one monitor failure. These resulted in no adverse clinical eff ects. The
average ICU length of stay was 14 days. Overall survival to hospital
discharge was 17/23 (74%). P94
Acute lung injury in mice associates with p44/42 and c-Jun
N-terminal kinase activation and requires the function of TNFα
receptor I
N Maniatis1, A Sfi ka1, I Nikitopoulou1, A Vassiliou1, C Magkou1, M Kardara1,
A Armaganidis1, C Roussos1, G Kollias2, S Orfanos1, A Kotanidou1
1University of Athens, Greece; 2‘Al. Fleming’ Biomedical Sciences Research
Center, Vari, Greece
Critical Care 2012, 16(Suppl 1):P94 (doi: 10.1186/cc10701) ECMO in nonintubated patients as a bridge to lung transplant:
our experience M Chierichetti, A Santini, F Pagan, S Crotti, A Lissoni, L Gattinoni
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan,
Italy
Critical Care 2012, 16(Suppl 1):P97 (doi: 10.1186/cc10704) Introduction Extracorporeal membrane oxygenation (ECMO) has now
been used by an expanding number of centres for bridging to lung
transplant (LTx) in patients with advanced cardiac and respiratory
failure [1]. ECMO has been used for bridging to LTx almost exclusively
in patients receiving mechanical ventilation. In order to avoid the
drawbacks and complications associated with intubation and
prolonged mechanical ventilation we hypothesized that the use of
venovenous ECMO (VV-ECMO) in awake and spontaneously breathing
patients might be an option for respiratory support in those patients
who are severely deteriorating while waiting for lung transplant. Results A total of 19 trauma patients, 15 males and four females,
underwent the ECLS technique. All of the following data are expressed
as median and 25th and 75th percentiles are enclosed in parenthesis. Median age was 48 (31.8 to 63.8) years. Injury severity score was 59 (41.3
to 73.8). Thirteen patients had polytrauma with brain injury. Fourteen
patients received va ECLS and fi ve patients vv ECLS. Indications to ECLS
placement were: cardiac arrest in nine patients, severe bleeding shock
in fi ve patients and acute respiratory failure in fi ve patients. In four
patients, ECLS was placed in the shock room, two patients received
ECLS in the operating room during damage control surgery and 13
patients in the ICU. Timing to ECLS from the trauma event was within
6 hours for six patients, between 6 and 24 hours for fi ve patients and
over 24 hours for eight patients. Sixteen patients were admitted to the
ICU. Five patients were discharged from the ICU. Brain death diagnosis
as a consequence of traumatic injury was performed in six patients. In
four of these patients organ donation was possible. Methods We performed a retrospective analysis of seven patients (three
female, mean age 31.7 ± 12.1 years) who underwent lung transplant
while on ECMO support between May 2009 and October 2011 and
who had not been ventilated for more than 24 hours before the LTx. All patients were fully awake and they kept on receiving noninvasive
ventilation for a variable amount of time per day after ECMO support
was started, according to clinical evaluation. A new miniaturized extracorporeal membrane oxygenator with
integrated rotary blood pump (Ilias): fi rst results in a porcine model
of lung injury K Pilarczyk1, J Heckmann1, K Lyskawa1, A Strauß2, U Aschenbrenner2,
H Jakob1, M Kamler1, N Pizanis1
1West German Heart Centre Essen, University Hospital, Essen, Germany;
2iliasmedical GmbH, Bochum, Germany
Critical Care 2012, 16(Suppl 1):P96 (doi: 10.1186/cc10703) Results Hydrochloric acid instillation induced an infl ammatory
response in the lungs of wild-type mice, evidenced as increased
bronchoalveolar lavage total cells, neutrophils and total protein,
histologic lung injury score and respiratory system elastance, while
TNFα receptor I mRNA levels were maintained. These alterations could
be prevented by pretreatment with etanercept or genetic deletion
of the 55 kDa TNFα receptor I, but not by deletion of the TNFα gene. Hydrochloric acid induced a sixfold increase in apoptotic, caspase-
3-positive cells in lung sections from wild-type mice, which was
abrogated in mice lacking TNFα receptor I. In immunoblotting and
immunohistochemistry studies, hydrochloric acid stimulated signaling
via p44/42 and c-Jun N-Terminal kinase, which was blocked in TNFα
receptor I knockout mice. Introduction Extracorporeal membrane oxygenation (ECMO) is used
for most severe acute respiratory distress syndrome cases in specialized
centres. However, critically ill patients fulfi lling ECMO criteria are often
not suitable for transportation and currently available ECMO systems
are not designed for emergency use or interhospital transfer. Therefore,
a new miniaturized ECMO (Ilias; Figure 1) with only 5 kg weight was
developed to reduce fi lling volume and simplify management. Introduction Extracorporeal membrane oxygenation (ECMO) is used
for most severe acute respiratory distress syndrome cases in specialized
centres. However, critically ill patients fulfi lling ECMO criteria are often
not suitable for transportation and currently available ECMO systems
are not designed for emergency use or interhospital transfer. Therefore,
a new miniaturized ECMO (Ilias; Figure 1) with only 5 kg weight was
developed to reduce fi lling volume and simplify management. Methods Acute lung injury was induced with repeated pulmonary
saline infusion in 13 pigs until the Horowitz Index was <100 mmHg. Pigs were assigned to the following three groups: group 1 (n = 3), Methods Acute lung injury was induced with repeated pulmonary
saline infusion in 13 pigs until the Horowitz Index was <100 mmHg. Pigs were assigned to the following three groups: group 1 (n = 3), Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum com/supplements/16/S1 S35 ,
pp
http://ccforum.com/supplements/16/S1 Results All patients survived successfully until the transplant. Extracorporeal life support in major trauma: case series from a
tertiary referral trauma 9
ECMO in nonintubated patients as a bridge to lung transplant:
our experience
M Chierichetti, A Santini, F Pagan, S Crotti, A Lissoni, L Gattinoni
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan,
Italy
Critical Care 2012, 16(Suppl 1):P97 (doi: 10.1186/cc10704) Reference Reference 1. Bermudez CA, et al.: Extracorporeal membrane oxygenation as a bridge to
lung transplant: midterm outcomes. Ann Thorac Surg 2011, 92:1226-1232. Figure 1 (abstract P96). The Ilias prototype. Extracorporeal life support in major trauma: case series from a
tertiary referral trauma Extracorporeal life support in major trauma: case series from a
tertiary referral trauma
R Spina, S Biondi, A Circelli, G Cianchi, S Degl’Innocenti, M Bonacchi,
A Peris
Careggi Teaching Hospital, Florence, Italy
Critical Care 2012, 16(Suppl 1):P98 (doi: 10.1186/cc10705) Results No device failed during the observation period. Oxygenation
increased signifi cantly in both ECMO groups compared to baseline and
to control (paO2 from 79 ± 8 before Ilias to 340 ± 108 mmHg and from
61 ± 12 mmHg to 309 ± 59 mmHg in the standard ECMO group). The
CO2 elimination by the Ilias reduced arterial paCO2 from 134 ± 25 mmHg
at baseline to 53 ± 7 mmHg. Hemodynamic instability, signifi cant
activation of the plasmatic coagulation or platelet consumption was
not observed. However, hemolyses were signifi cantly higher in the Ilias
group compared to the Maquet group. Introduction Major trauma (MT) is a leading cause of death and
disability worldwide. Immediate fatal complications are bleeding shock
followed in the post-emergency phase by severe head and spine injury
and post-traumatic respiratory failure. Venoarterial (va) or venovenous
(vv) extracorporeal life support (ECLS) could represent a valid option to
face these life-threatening trauma complications. Moreover, ECLS can
potentially be employed to expand the pool of donors in patients with
brain death diagnosis after trauma event. Conclusion The Ilias prototype provided excellent gas exchange
with hemodynamic stability comparable to a standard ECMO system. Further development and design modifi cations (optimized rotation
speed and surface coating of rotor) are already done and another
experiment is projected to reduce hemolysis for clinical application. Methods Patient data were collected from January 2009 to November
2011. A multidisciplinary algorithm-based protocol was written by
our ECLS Team. The va-ECLS indications were bleeding shock, with
potential controllable bleeding sites, not responding to massive fl uid
and blood resuscitation and to vasopressor support and cardiac arrest
not responding after 10 minutes of cardiopulmonary resuscitation
(CPR). vv-ECLS criteria establishment were severe hypoxia and/or
hypercarbia due to acute lung failure not responding to conventional
ventilatory strategies. The ECLS device is composed of a centrifugal
pump and a hollow fi ber membrane oxygenator (Quadrox-D; Maquet,
Germany). Coagulation status was controlled by the activated partial
thromboplastin time every 4 hours and thromboelastography. P98 control group, conventional ventilation; group 2 (n = 5), standard
venovenous ECMO (Maquet); group 3 (n = 5), Ilias group. Gas exchange,
hemodynamics, hemolysis, and coagulation activation were examined
over a period of 8 hours. A new miniaturized extracorporeal membrane oxygenator with
integrated rotary blood pump (Ilias): fi rst results in a porcine model
of lung injury All
patients underwent BLTx on VV-ECMO support, three were converted
to VA during transplant and then back to VV at the end of the procedure. One patient died after BLTx due to hemorrhagic complications. Mean
ECMO support was BloodFlow 3.1 ± 0.8 l/minute, GasFlow 4.7 ± 2.5 l/
minute, no one needed mechanical ventilation before BLTx. After lung
transplant fi ve patients remained intubated and they were ventilated
for 13.9 ± 16.4 days. Mean duration of ECMO support after LTx was
4.7 ± 5.4 days. Mean ICU LOS after LTx was 18 ± 17.9 days. Among this
population three patients developed hemorrhagic complication, two
primary graft dysfunction, two neuromuscular dysfunction, while only
one chronic renal failure. Results All patients survived successfully until the transplant. All
patients underwent BLTx on VV-ECMO support, three were converted
to VA during transplant and then back to VV at the end of the procedure. Figure 1 (abstract P96). The Ilias prototype. Conclusion Our experience shows that bridge to lung transplant with
VV-ECMO in awake and spontaneously breathing patients is not only
feasible but also successful. Survival to BLTx in our center was 100%,
while survival after BLTx is comparable to that of patients who were not
on ECMO support. ECMO in nonintubated patients as a bridge to lung transplant:
our experience Mean blood gas values
before ECMO support was started were: pH 7.26 ± 0.13, PaCO2
81.7 ± 31.6, PaO2 151.4 ± 164.2, PEEP 9 ± 4, FiO2 83 ± 20, mean time on
ECMO before LTx 11.7 ± 17.7 days. p
g
p
Conclusion ECLS in a multimodal approach in MT represents a
challenging opportunity to face potential fatal complications. Moreover ECLS applied to selected trauma patients could expand the
potential donor pool. Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P99
Two years’ experience with bicaval dual lumen cannula for
venovenous extracorporeal membrane oxygenation in adult
refractory acute respiratory distress syndrome
J Reeb, PE Falcoz, J Pottecher, X Delabranche, N Santelmo, A Steib,
M Hasselmann, G Massard
Hôpitaux universitaires de Strasbourg, France
Critical Care 2012, 16(Suppl 1):P99 (doi: 10.1186/cc10706) trauma in 10 patients, sepsis in three patients, pulmonary hemorrhage in
two patients and others in two patients. The overall hospital mortality rate
was 39% (15/38). Compared with the nonsurvivors group, the survivors
group was younger (33.3 ± 15.1 vs. 52.2 ± 18.1 years old, P = 0.001) and
had lower APACHE II scores (18.7 ± 6.3 vs. 26.7 ± 6.6, P = 0.001) and SOFA
scores (10.4 ± 2.7 vs. 12.7 ± 2.4, P = 0.014). Furthermore, the survivors
group had early signifi cant resolution in the sequential SOFA scores
compared with the nonsurvivors group. trauma in 10 patients, sepsis in three patients, pulmonary hemorrhage in
two patients and others in two patients. The overall hospital mortality rate
was 39% (15/38). Compared with the nonsurvivors group, the survivors
group was younger (33.3 ± 15.1 vs. 52.2 ± 18.1 years old, P = 0.001) and
had lower APACHE II scores (18.7 ± 6.3 vs. 26.7 ± 6.6, P = 0.001) and SOFA
scores (10.4 ± 2.7 vs. 12.7 ± 2.4, P = 0.014). Furthermore, the survivors
group had early signifi cant resolution in the sequential SOFA scores
compared with the nonsurvivors group. g
Conclusion Survivors had early improvements in SOFA scores after
ECMO for severe ARDS patients. SOFA score evolution may be used for
evaluating the eff ect of ECMO. Introduction Venovenous extracorporeal membrane oxygenation
(ECMO) is a respiratory support increasingly used in adult refractory
acute respiratory distress syndrome (ARDS). Corticosteroids for critically ill patients: an international survey of
intensivists F Lamontagne1, N Adhikari2, D Cook3, KK Koo4, F Lauzier5, KE Burns2,
I Douglas6, AF Turgeon5, H Quiroz1, Y Poulin1, K Choong3, N Ferguson2,
ME Kho7, M Duff ett3, C Chant2, O Lesur1, MO Meade3
1Université de Sherbrooke, Canada; 2University of Toronto, Canada; 3McMaster
University, Hamilton, Canada; 4University of Western Ontario, London,
Canada; 5Université Laval, Québec, Canada; 6Denver Health Medical Center,
Denver, CO, USA; 7Johns Hopkins University, Baltimore, MD, USA
Critical Care 2012, 16(Suppl 1):P101 (doi: 10.1186/cc10708) y
Methods A prospective single-center study between November 2009
and November 2011 including all medical and surgical adult patients
receiving ECMO for refractory ARDS. All ECMOs were performed with
DLC implanted percutaneously in the right internal jugular vein. Variables under study were: arterial blood gases, duration of ECMO
support, activated cephalin time (TCA) values, number of blood products
transfused, and patient’s outcome. Statistical test: Student’s t test.i p
Results Twenty-fi ve ECMOs were performed in 24 patients (16 men
and eight women). Mean age of patients was 52.2 years ± 17.5. All
these patients had severe ARDS despite optimal medical therapy. At DLC implantation, mean pH, PaCO2, PaO2, and PaO2/FiO2 ratio
were 7.25 ± 0.11, 60.5 ± 17.5 mmHg, 58.9 ± 13.6 mmHg, and 61 ± 14
respectively. Mean duration of respiratory support with ECMO was
9.5 ± 4.8 days and mean blood fl ow was 3.3 ± 0.6 l/minute. During
ECMO, arterial blood gases were signifi cantly improved (P <0.05):
mean PaCO2, and PaO2 were 39.9 ± 4.8 mmHg, and 92.7 ± 21.1 mmHg
respectively. Concerning haemostasis and provision of blood products,
mean TCA and mean pellets of red blood cells transfused were
53.6 ± 1.2 seconds and 10.7 ± 7 respectively. Eleven patients (46%) died
under ECMO. Causes of death with ECMO support were: fi ve multiorgan
failures, two septic shocks, two withdrawal of care, one hemodynamic
shock, and one refractory hypoxemia. ECMO withdrawal was possible
in 13 patients (twice in one patient) with PaO2/FiO2 ratio 258 ± 24 at
withdrawal. Removal of the endotracheal tube was performed for eight
patients (33%), 18.3 ± 6.2 days after DLC implantation. Eight patients
(33%) were discharged alive from the ICU, 18.3 ± 6.3 days after DLC
implantation. These eight patients were discharged alive from hospital. No adverse event related to the DLC was observed. Introduction We surveyed intensivists to evaluate their stated use of
systemic steroids in the ICU. Resolution of organ functional scores to predict outcomes in
severe acute respiratory distress syndrome patients receiving
extracorporeal membrane oxygenation
L Chiu, Y Chen, H Hu, C Huang, F Tsai, K Kao
Chang Gung Memorial Hospital, Taoyuan, Taiwan
Critical Care 2012, 16(Suppl 1):P100 (doi: 10.1186/cc10707) y
Conclusion Certain clinical conditions may prompt intensivists to
almost always prescribe systemic steroids and reduce equipoise for
future placebo-controlled trials. Moreover, this survey shows that in
selected academic centres a majority of intensivists do not prescribe
corticosteroids for pneumonia, ALI and ARDS. Introduction Extracorporeal membrane oxygenation (ECMO) may be used
as an alternative therapy for severe acute respiratory distress syndrome
(ARDS) patients who have failed conventional mechanical ventilation. We
undertook a study to investigate the determinants of mortality and the
sequential evolution of organ failures in ECMO-treated ARDS patients. Methods This was a prospective observational study of severe ARDS
patients who received venovenous ECMO in the ICU of Chang Gung
Memorial Hospital between March 2006 and December 2010. We
included data on all 38 consecutive patients who receive venovenous
ECMO. Retrospective data included the following: demographics,
primary diagnosis for ARDS, ventilator setting before ECMO,
oxygenation, durations of ECMO, SOFA scores and outcome. l
l f
l
bl Introduction Extracorporeal membrane oxygenation (ECMO) may be used
as an alternative therapy for severe acute respiratory distress syndrome
(ARDS) patients who have failed conventional mechanical ventilation. We
undertook a study to investigate the determinants of mortality and the
sequential evolution of organ failures in ECMO-treated ARDS patients. P102f P102
Eff ects of salbutamol on airway characteristics in mechanically
ventilated adults without COPD
J Van Rosmalen, QL Habes, I Havinga, F Van Beers, A Van Hees,
D Ramnarain, JA Van Oers
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P102 (doi: 10.1186/cc10709) ECMO in nonintubated patients as a bridge to lung transplant:
our experience Technological advances
such as bicaval dual lumen cannula (DLC) allow one to decrease
drawbacks associated with this cardiopulmonary bypass technique and
to implement it in the ICU setting. We report our 2 years’ experience of
using DLC for ECMO in adult refractory ARDS. Corticosteroids for critically ill patients: an international survey of
intensivists The effi cacy of steroids in septic shock
and ARDS remains uncertain and clinicians’ perceptions of competing
indications and contraindications may jeopardize future randomized
controlled trials (RCT). Knowledge of current practice will inform the
design of future RCTs addressing the effi cacy of systemic steroids in
septic shock and ARDS. Introduction We surveyed intensivists to evaluate their stated use of
systemic steroids in the ICU. The effi cacy of steroids in septic shock
and ARDS remains uncertain and clinicians’ perceptions of competing
indications and contraindications may jeopardize future randomized
controlled trials (RCT). Knowledge of current practice will inform the
design of future RCTs addressing the effi cacy of systemic steroids in
septic shock and ARDS. Methods We designed and conducted a self-administered survey of
intensivists practicing in academic settings with expertise in ARDS
clinical research. We generated questionnaire items in focus group
sessions with content experts and refi ned them through a standardized
process of clinical sensibility, pilot and intra-rater reliability testing. Respondents used a four-point scale to grade how frequently they
would administer systemic steroids in a 14 diff erent clinical situations
and reported their opinions of 16 near absolute indications or
contraindications for systemic steroids. Local research staff distributed
the survey to all intensivists practicing in the 11 centres (Canada and
USA) with most patients enrolled in the OSCILLATE trial. Results In total, 103 of 125 potential respondents returned completed
surveys (response rate 82%). A majority of respondents ‘almost
always’ prescribe systemic steroids in the setting of recent systemic
steroid use and low blood pressure (93%), signifi cant bronchospasm
in a mechanically ventilated patient (93%) and vasopressor refractory
septic shock (52%). A majority of respondents would ‘almost never’
prescribe steroids in severe community-acquired pneumonia (81%), ALI
(76%) and ARDS (65%). One-half (50%) would ‘almost never’ prescribe
steroids for severe ARDS (50%). The near absolute indications selected
by a majority of respondents were ‘known adrenal insuffi ciency’ (99%)
and ‘suspicion of cryptogenic organizing pneumonia’ (89%). The only
near absolute contraindication selected by a majority of respondents
was ‘systemic fungal infection’ (52%). Conclusion ECMO with a bicaval DLC is feasible in the ICU. It improves
signifi cantly haemostasis parameters in patients suff ering from
refractory ARDS. DLC also decreases drawbacks associated with the
ECMO respiratory support. P100 Resolution of organ functional scores to predict outcomes in
severe acute respiratory distress syndrome patients receiving
extracorporeal membrane oxygenation
L Chiu, Y Chen, H Hu, C Huang, F Tsai, K Kao
Chang Gung Memorial Hospital, Taoyuan, Taiwan
Critical Care 2012, 16(Suppl 1):P100 (doi: 10.1186/cc10707) P103
Respiratory system elastance monitoring during PEEP titration
h
1
h
1
h
2
3 p
p
Methods In this prospective study, we enrolled 11 critically ill MV
patients without COPD. These intubated patients were on volume-
controlled ventilation (6 ml/kg/PBW). Exclusion criteria were the use
of β-blockers, propofol or neuromuscular blockers. They received fi ve
puff s of salbutamol (100 μg/puff ) delivered by metered dose inhaler
via the adapter on the Y-piece. Ventilator settings and body position
were unchanged during the study. Before and after salbutamol
administration vital signs were recorded and lung mechanics were
measured using the ventilator (Servo-i® or Hamilton-G5®) at –1, +1,
+15, +30, +60, +90 and +240 minutes. Values after administration of
salbutamol (T0) were compared to those before administration. Results
are presented as mean ± SD. Data were evaluated by paired t test and
P <0.05 was taken as statistically signifi cant. Introduction PEEP selection during mechanical ventilation (MV) for
patients with acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS) remains a challenge for clinicians. Clinicians often
rely on experience and intuition in setting MV, resulting in a more
variable treatment and outcome. We hypothesise that monitoring
patient-specifi c respiratory system elastance (Ers) during PEEP change
may provide an insight into the patient’s condition. y p
g
p
Methods Thirteen patients with ALI/ARDS underwent a step-wise
PEEP increase (5 cmH2O) recruitment manoeuvre (RM) until peak
airway pressure reaches 45 cmH2O. Airway pressure and fl ow profi le
were recorded using a pneumotachometer. The change of patient’s
respiratory system elastance (Ers = 1 / compliance) and the end of
expiratory lung volume (EELV) during RM were estimated and studied. The trials were approved by New Zealand South Island Regional Ethics
Committee. y
gi
Results The study group consisted of seven men and four women,
mean age 53 years. Underlying causes for ventilation were diverse. The median time spent on the ventilator before inclusion was 36 hours
(6 to 151). After salbutamol administration inspiratory resistance
and dynamic compliance decreased, but not signifi cantly. Expiratory
resistance, dynamic compliance, elastance, SpO2 and EtCO2 did not
change (Table 1).if g
Conclusion There was no signifi cant eff ect of salbutamol inhalation
on airway characteristics and vital signs in non-COPD patients on MV. Therefore standard salbutamol inhalation in MV patients without COPD
can be aborted. Results The median (IQR) Ers over all patients was 34.0 cmH2O/l (26.1
to 51.0), refl ecting the heterogeneity of the patients and their response
to PEEP. P103
Respiratory system elastance monitoring during PEEP titration
h
1
h
1
h
2
3 This outcome supports the idea that MV/ PEEP should be
individualised. During RM, patients’ Ers decreased with PEEP increase
until a specifi c minimum and increase at higher PEEP. The decreased of
Ers suggest alveolar recruitment whereas an increase of Ers at higher
PEEP shows potential overinfl ation. An example is shown in Figure 1a. A clear infl ection/minimum Ers can be found in Figure 1a, indicating a Eff ects of salbutamol on airway characteristics in mechanically
ventilated adults without COPD q
g
p
Methods This was a prospective observational study of severe ARDS
patients who received venovenous ECMO in the ICU of Chang Gung
Memorial Hospital between March 2006 and December 2010. We
included data on all 38 consecutive patients who receive venovenous
ECMO. Retrospective data included the following: demographics,
primary diagnosis for ARDS, ventilator setting before ECMO,
oxygenation, durations of ECMO, SOFA scores and outcome. J Van Rosmalen, QL Habes, I Havinga, F Van Beers, A Van Hees,
D Ramnarain, JA Van Oers
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P102 (doi: 10.1186/cc10709) Introduction In our ICU, salbutamol inhalation to prevent broncho-
spasm is standard care in mechanically ventilated (MV) patients. In
MV patients without COPD the eff ect of salbutamol remains unclear. Introduction In our ICU, salbutamol inhalation to prevent broncho-
spasm is standard care in mechanically ventilated (MV) patients. In
MV patients without COPD the eff ect of salbutamol remains unclear. Results A total of 38 severe ARDS patients receiving ECMO were eligible. The causes of ARDS in these 38 patients were pneumonia in 21 patients, S37 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Therefore we examined the eff ect of inhaled salbutamol on resistance
and compliance in MV patients without COPD. Methods In this prospective study, we enrolled 11 critically ill MV
patients without COPD. These intubated patients were on volume-
controlled ventilation (6 ml/kg/PBW). Exclusion criteria were the use
of β-blockers, propofol or neuromuscular blockers. They received fi ve
puff s of salbutamol (100 μg/puff ) delivered by metered dose inhaler
via the adapter on the Y-piece. Ventilator settings and body position
were unchanged during the study. Before and after salbutamol
administration vital signs were recorded and lung mechanics were
measured using the ventilator (Servo-i® or Hamilton-G5®) at –1, +1,
+15, +30, +60, +90 and +240 minutes. Values after administration of
salbutamol (T0) were compared to those before administration. Results
are presented as mean ± SD. Data were evaluated by paired t test and
P <0.05 was taken as statistically signifi cant. Results The study group consisted of seven men and four women,
mean age 53 years. Underlying causes for ventilation were diverse. The median time spent on the ventilator before inclusion was 36 hours
(6 to 151). After salbutamol administration inspiratory resistance
and dynamic compliance decreased, but not signifi cantly. Eff ects of salbutamol on airway characteristics in mechanically
ventilated adults without COPD Expiratory
resistance, dynamic compliance, elastance, SpO2 and EtCO2 did not
change (Table 1). Conclusion There was no signifi cant eff ect of salbutamol inhalation
on airway characteristics and vital signs in non-COPD patients on MV. Therefore standard salbutamol inhalation in MV patients without COPD
can be aborted. Reference
1. Malliotakis P, et al.: Infl uence of respiratory eff orts on β2-agonist induced
bronchodilation in mechanically ventilated COPD patients: a prospective
clinical study. Respir Med 2007, 101:300-307. P103
Respiratory system elastance monitoring during PEEP titration
YS Chiew1, JG Chase1, GM Shaw2, T Desaive3
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand; 3University of Liege, Belgium
Critical Care 2012, 16(Suppl 1):P103 (doi: 10.1186/cc10710)
Introduction PEEP selection during mechanical ventilation (MV) for
patients with acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS) remains a challenge for clinicians. Clinicians often
rely on experience and intuition in setting MV, resulting in a more
variable treatment and outcome. We hypothesise that monitoring
patient-specifi c respiratory system elastance (Ers) during PEEP change
may provide an insight into the patient’s condition. Methods Thirteen patients with ALI/ARDS underwent a step-wise
PEEP increase (5 cmH2O) recruitment manoeuvre (RM) until peak
airway pressure reaches 45 cmH2O. Airway pressure and fl ow profi le
were recorded using a pneumotachometer. The change of patient’s
respiratory system elastance (Ers = 1 / compliance) and the end of
expiratory lung volume (EELV) during RM were estimated and studied. The trials were approved by New Zealand South Island Regional Ethics
Committee. Results The median (IQR) Ers over all patients was 34.0 cmH2O/l (26.1
to 51.0), refl ecting the heterogeneity of the patients and their response
to PEEP. This outcome supports the idea that MV/ PEEP should be
individualised. During RM, patients’ Ers decreased with PEEP increase
until a specifi c minimum and increase at higher PEEP. The decreased of
Ers suggest alveolar recruitment whereas an increase of Ers at higher
PEEP shows potential overinfl ation. An example is shown in Figure 1a. Eff ects of salbutamol on airway characteristics in mechanically
ventilated adults without COPD A clear infl ection/minimum Ers can be found in Figure 1a, indicating a
Table 1 (abstract P102)
T–1
T0
T+1
T+15
T+30
T+60
T+90
T+240
Rins (cm H2O/l/second)
14 (6)
Salbutamol
14 (4)
13 (5)
13 (5)
12 (4)
12 (5)
12 (4)
NS
administration
Rexp (cm H2O/l/second)
17 (7)
17 (6)
16 (6)
17 (8)
18 (10)
18 (8)
17 (7)
NS
Cdyn (ml/cm H2O)
44 (12)
42 (11)
42 (11)
37 (10)
36 (9)
38 (9)
38 (8)
NS
Cstat (ml/cm H2O)
49 (13)
49 (12)
47 (13)
43 (11)
44 (12)
45 (12)
43 (12)
NS
Elastance (cm H2O/l)
19 (3)
20 (4)
21 (4)
22 (4)
23 (4)
21 (4)
18 (8)
NS
Heart rate (beats/minute)
81 (22)
84 (24)
85 (23)
87 (22)
85 (22)
82 (18)
84 (20)
NS
SpO2 (%)
98 (1)
98 (2)
98 (2)
98 (1)
98 (2)
98 (2)
97 (2)
NS
EtCO2 (kPa)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.8)
4.7 (0.7)
NS
Figure 1 (abstract P103). Ers and EELV change with PEEP increase. Table 1 (abstract P102)
T–1
T0
T+1
T+15
T+30
T+60
T+90
T+240
Rins (cm H2O/l/second)
14 (6)
Salbutamol
14 (4)
13 (5)
13 (5)
12 (4)
12 (5)
12 (4)
NS
administration
Rexp (cm H2O/l/second)
17 (7)
17 (6)
16 (6)
17 (8)
18 (10)
18 (8)
17 (7)
NS
Cdyn (ml/cm H2O)
44 (12)
42 (11)
42 (11)
37 (10)
36 (9)
38 (9)
38 (8)
NS
Cstat (ml/cm H2O)
49 (13)
49 (12)
47 (13)
43 (11)
44 (12)
45 (12)
43 (12)
NS
Elastance (cm H2O/l)
19 (3)
20 (4)
21 (4)
22 (4)
23 (4)
21 (4)
18 (8)
NS
Heart rate (beats/minute)
81 (22)
84 (24)
85 (23)
87 (22)
85 (22)
82 (18)
84 (20)
NS
SpO2 (%)
98 (1)
98 (2)
98 (2)
98 (1)
98 (2)
98 (2)
97 (2)
NS
EtCO2 (kPa)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.7)
4.7 (0.8)
4.7 (0.7)
NS Therefore we examined the eff ect of inhaled salbutamol on resistance
and compliance in MV patients without COPD. P103
Respiratory system elastance monitoring during PEEP titration
YS Ch
1 JG Ch
1 GM Sh
2 T D
3 05
Flow-controlled expiration discloses PEEP-dependent dynamic
hysteresis of the pressure–volume loop
S Schumann1, L Vimlati2, M Lichtwarck-Aschoff 2, J Guttmann1
1University Medical Center Freiburg, Germany; 2Uppsala University, Uppsala,
Sweden
Critical Care 2012, 16(Suppl 1):P105 (doi: 10.1186/cc10712) The relative hysteresis area was calculated as the quotient
of hysteresis area divided by the rectangular area which is limited by
the minima and maxima of pressure and volume of the respective
pressure–volume loop [2].i P104 P104
Accuracy of the pressure–volume curve method compared to
quantitative lung CT scan to assess the recruitable lung in patients
with acute respiratory failure
D Chiumello1, A Marino2, I Cigada2, F Menga2, M Brioni2, IR Piva2
1Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy;
2Università degli Studi di Milano, Milan, Italy
Critical Care 2012, 16(Suppl 1):P104 (doi: 10.1186/cc10711) Introduction In patients with acute lung injury the knowledge
of recruitable lung is useful for a physiological PEEP setting. The
quantitative lung CT scan analysis remains the reference method [1]. However, it is time consuming and often it is not applicable in clinical
management. The PV curve at two PEEP levels has been proposed as
an alternative method [2]. The aim of this study was to evaluate the
accuracy of these two methods in predicting the lung recruitability. Methods In fi ve Swedish Landrace Hybrid pigs weighing 26 ± 2 kg the
lungs were ventilated in the volume-controlled mode. PEEP was set
to 0, 6, 12 and 15 cmH2O. The fl ow-controlled expiration was realized
by a computer-controlled expiratory resistance which was adjusted
in a fashion that expiratory fl ow was strongly limited in the beginning
and continuously facilitated towards the end of expiration. Using
the gliding-SLICE method [1], intratidal inspiratory and expiratory
compliance profi les were calculated from inspiration data only and
from expiration data only, respectively. The dynamic hysteresis area
was calculated as the area within the dynamic tracheal pressure–
volume loop. The relative hysteresis area was calculated as the quotient
of hysteresis area divided by the rectangular area which is limited by
the minima and maxima of pressure and volume of the respective
pressure–volume loop [2].i Methods Sedated and paralyzed patients underwent a PV curve using
the low-fl ow method and whole-lung CT scan at 5 and 15 cmH2O of
PEEP. The lung recruitability was defi ned as the decrease in the not
aerated tissue by the quantitative lung CT analysis and as the diff erence
between the lung volume computed on the two PV curves for an
airway pressure of 20 cmH2O. 05
Flow-controlled expiration discloses PEEP-dependent dynamic
hysteresis of the pressure–volume loop
S Schumann1, L Vimlati2, M Lichtwarck-Aschoff 2, J Guttmann1
1University Medical Center Freiburg, Germany; 2Uppsala University, Uppsala,
Sweden
Critical Care 2012, 16(Suppl 1):P105 (doi: 10.1186/cc10712) Critical Care 2012, 16(Suppl 1):P105 (doi: 10.1186/cc10712) Introduction Hysteresis of the pressure–volume loop is a measure
for the additional energy that is required during inspiration to recruit
and infl ate additional alveoli. The hysteresis area is usually constructed
using data from a low-fl ow infl ation/defl ation maneuver; that is,
from a quasi-static situation that the lung never sees during ongoing
ventilation. However, during the dynamic conditions of mechanical
ventilation the hysteresis area is biased by resistive pressure portions. Therefore we uncoupled fl ow and volume by linearizing expiratory fl ow
(fl ow-controlled expiration). This enabled calculation of compliance
separately for inspiration and expiration. We hypothesized that the
volume-dependent intratidal compliance profi les diff er between
inspiration and expiration, describing a dynamic hysteresis behavior.i Introduction Hysteresis of the pressure–volume loop is a measure
for the additional energy that is required during inspiration to recruit
and infl ate additional alveoli. The hysteresis area is usually constructed
using data from a low-fl ow infl ation/defl ation maneuver; that is,
from a quasi-static situation that the lung never sees during ongoing
ventilation. However, during the dynamic conditions of mechanical
ventilation the hysteresis area is biased by resistive pressure portions. Therefore we uncoupled fl ow and volume by linearizing expiratory fl ow
(fl ow-controlled expiration). This enabled calculation of compliance
separately for inspiration and expiration. We hypothesized that the
volume-dependent intratidal compliance profi les diff er between
inspiration and expiration, describing a dynamic hysteresis behavior. Methods In fi ve Swedish Landrace Hybrid pigs weighing 26 ± 2 kg the
lungs were ventilated in the volume-controlled mode. PEEP was set
to 0, 6, 12 and 15 cmH2O. The fl ow-controlled expiration was realized
by a computer-controlled expiratory resistance which was adjusted
in a fashion that expiratory fl ow was strongly limited in the beginning
and continuously facilitated towards the end of expiration. Using
the gliding-SLICE method [1], intratidal inspiratory and expiratory
compliance profi les were calculated from inspiration data only and
from expiration data only, respectively. The dynamic hysteresis area
was calculated as the area within the dynamic tracheal pressure–
volume loop. References 1. Gattinoni L, et al.: Lung recruitment in patients with the acute respiratory
distress syndrome. N Engl J Med 2006, 354:1775-1786. 1. Gattinoni L, et al.: Lung recruitment in patients with the acute respiratory
distress syndrome. N Engl J Med 2006, 354:1775-1786. i
g
p
References 2. Ranieri VM, et al.: Volume–pressure curve of the respiratory system predicts
eff ects of PEEP in ARDS: ‘occlusion’ versus ‘constant fl ow’ technique. Am J
Respir Crit Care Med 1994, 149:19-27. 2. Ranieri VM, et al.: Volume–pressure curve of the respiratory system predicts
eff ects of PEEP in ARDS: ‘occlusion’ versus ‘constant fl ow’ technique. Am J
Respir Crit Care Med 1994, 149:19-27. 1. Schumann et al.: Anesthesiology 2011, 114:1111-1117. 2. Bachofen H, Hildebrandt J: J Appl Physiol 1971, 30:493-497. 1. Schumann et al.: Anesthesiology 2011, 114:1111-1117. 2. Bachofen H, Hildebrandt J: J Appl Physiol 1971, 30:493-497. 1. Schumann et al.: Anesthesiology 2011, 114:1111-1117. 2. Bachofen H, Hildebrandt J: J Appl Physiol 1971, 30:493-497. Figure 1 (abstract P104). Linear regression between quantitative CT scan
analysis and PV curve method. 05
Flow-controlled expiration discloses PEEP-dependent dynamic
hysteresis of the pressure–volume loop
S Schumann1, L Vimlati2, M Lichtwarck-Aschoff 2, J Guttmann1
1University Medical Center Freiburg, Germany; 2Uppsala University, Uppsala,
Sweden
Critical Care 2012, 16(Suppl 1):P105 (doi: 10.1186/cc10712) 2
Results Ten patients (mean age 65.4 ± 10.4 years, body mass index
24.0 ± 6.8 kg/m2, PaO2/FiO2 181 ± 37) were enrolled. The mean
recruitable lung was 3.9 ± 6.3% of the total lung weight and 218 ± 266
ml for the quantitative lung CT scan and PV curve. The linear regression
between the two methods (Figure 1) was not signifi cant (P = 0.338 and
R2 = 0.115). Results Intratidal compliance profi les of inspiration and expiration
diff ered strongly in mean value and slope at low PEEP. With increasing
PEEP the inspiratory compliance profi le approximated closer to the
expiratory compliance profi le. This was accompanied by a decreased
relative hysteresis area by 26%. Conclusion The recruitable lung computed as the diff erence in not
aerated tissue was not related to the diff erence in volume estimated by
the PV curve. The role of the PV curve to estimate the lung recruitability
remains to be elucidated. R f y
y
Conclusion Flow-controlled expiration allows for calculation of respira-
tory system compliance separately for inspiration and expiration. This
compliance displays the hysteresis behavior of the respiratory system
during uninterrupted ventilation. Such analysis, which is similar to the
time-honored quasi-static hysteresis area analysis, could be helpful for
fi nding an optimal PEEP. References P105 potential method to optimise PEEP selection for a particular patient. Figure 1b shows the change of patient’s EELV with PEEP increase. As
PEEP increases, the potentially recruitable collapsed lung decreases. Conclusion The change of patient-specifi c Ers and EELV during
minimally invasive PEEP titration provides an insight into the patient’s
lung condition, and thus could potentially be used as a method to
individualise MV treatment and, in particular, PEEP selection. P105
Flow-controlled expiration discloses PEEP-dependent dynamic
hysteresis of the pressure–volume loop
S Schumann1, L Vimlati2, M Lichtwarck-Aschoff 2, J Guttmann1
1University Medical Center Freiburg, Germany; 2Uppsala University, Uppsala,
Sweden
Critical Care 2012, 16(Suppl 1):P105 (doi: 10.1186/cc10712) Reference 1. Malliotakis P, et al.: Infl uence of respiratory eff orts on β2-agonist induced
bronchodilation in mechanically ventilated COPD patients: a prospective
clinical study. Respir Med 2007, 101:300-307. Figure 1 (abstract P103). Ers and EELV change with PEEP increase. Figure 1 (abstract P103). Ers and EELV change with PEEP increase. S38 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 potential method to optimise PEEP selection for a particular patient. Figure 1b shows the change of patient’s EELV with PEEP increase. As
PEEP increases, the potentially recruitable collapsed lung decreases. Conclusion The change of patient-specifi c Ers and EELV during
minimally invasive PEEP titration provides an insight into the patient’s
lung condition, and thus could potentially be used as a method to
individualise MV treatment and, in particular, PEEP selection. P108 Hemodynamics eff ects of recruitment maneuver
k
d
k
h Hemodynamics eff ects of recruitment maneuver
D Protsenko, R Magomedov, O Ignatenko, AI Yaroshetskiy, B Gelfand
Russian National Research Medical University, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P108 (doi: 10.1186/cc10715) Introduction Acute respiratory distress syndrome (ARDS) is a frequent
complication in critically ill patients. Recruitment maneuver (RM) is a
rescue procedure which improves oxygenation [1-3]. However, it is not
clear whether improving oxygen delivery (DO2) exists after RM. The aim
of this study was to evaluate the eff ects of RM on hemodynamics and
DO2. Conclusion APRV settings and the protocol for sedation used in this
trial allowed to reach suffi cient spontaneous breathing for the majority
of the patients without any major complication and with a tidal volume
below 8 ml/kg PBW. For a few patients, spontaneous breathing seems
to be hard to obtain, especially within the fi rst 2 days. R f 2
Methods A prospective, randomized trial in ARDS patients (AECC
criteria). The protocol was approved by the local ethics committee. Fifty-seven patients with extrapulmonary ARDS were randomized
into three groups: group A (n = 17) – 40×40 RM (CPAP 40 cmH2O for
40 seconds), group B (n = 17) – PCV RM (PIP 40 to 50 cmH2O, PEEP 18
to 20 cmH2O for 120 seconds), and group C (n = 17) – stepwise PCV
RM. Gas exchange and systemic hemodynamics by aortal blood fl ow
(transesophageal Doppler; ARROW, USA) were measured before, after,
30 and 120 minutes after RM. 1. Mercat A, Richard JC, Vielle B, et al.; Expiratory Pressure (Express) Study Group:
Positive end-expiratory pressure setting in adults with acute lung injury
and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008, 299:646-655. 1. Mercat A, Richard JC, Vielle B, et al.; Expiratory Pressure (Express) Study Group:
Positive end-expiratory pressure setting in adults with acute lung injury
and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008, 299:646-655. Results In all groups we observed rapid increasing of paO2 (mmHg)
from 65.9 ± 24.9; 77.2 ± 14.0; 87.0 ± 16.7 to 110.3 ± 38.7; 124.5 ± 45.5;
115.2 ± 32.6 (P <0.0001) after RM. We also observed signifi cant
improvement of oxygenation 120 minutes after RM (95.6 ± 25.6;
99.3 ± 25.3; 108.1 ± 26.8). There was no statistical diff erence
between groups. A device for ventilation-analogue mechanostimulation in vitro
K Gamerdinger, M Schneider, E Smudde, J Guttmann, S Schumann
University Medical Center Freiburg, Germany
Critical Care 2012, 16(Suppl 1):P107 (doi: 10.1186/cc10714) y
g,
y
Critical Care 2012, 16(Suppl 1):P107 (doi: 10.1186/cc10714) Introduction
The
mechanical
stress–strain
characteristics
of
most living tissues is nonlinear and frequency dependent. During
spontaneous breathing the mechanical strain on the pulmonary tissue
is akin to a sinusoidal profi le. In contrast, during mechanical ventilation
the stimulation profi le of the lung tissue diff ers considerably from a
sinusoidal pattern. While all in vitro experiments aiming at dynamic
stimulation typically use sinusoidal patterns, we here describe the
establishment of a new device aff ording a ventilation-analogue
stimulation pattern, allowing a better imitation of the situation in
vivo. The new device includes a linear motor connected to four piston
pumps and it allows the identical stimulation of four probes at the
same time. Here we show how we stressed four test samples with
sinusoidal, rectangular and ventilation-analogue mechanostimulation
and how we analyzed them for frequency contents by means of a fast-
Fourier transform. g
g
Conclusion Three diff erent RMs increase oxygenation and decrease CO
equally. But RM does not improve oxygen delivery due to decreasing
CO. Reference 1. Schumann S, et al.: J Biomed Mater Res B Appl Biomater 2008, 86:483-492. Results At inclusion, baseline characteristics of the patients were the
following: fi ve men and fi ve women, 59 years old on average (25 to
85), SAPS II score of 42 (20 to 71), PO2/FiO2 ratio of 107 (74 to 175) and
respiratory system compliance (Cst,rs) of 25 ml/cmH2O (18 to 36). We
did not observe any pneumothorax. Eight of patients had RASS ≥–4
during the 5 days of enrollment. From day 2, the level of spontaneous
breathing ranged between 10 and 50% of total minute ventilation
in eight patients. The tidal volume (spontaneous and mechanical)
measured for 5 days for each patient was mainly distributed around
6 ml/kg PBW (Figure 1). The mean PO2/FiO2 ratio increased from
107 ± 29 at enrollment to 173 ± 91 at day 5 (P <0.05). Feasibility of early spontaneous breathing in acute respirator
distress syndrome
S Mortaza, A Mercat
CHU Angers, France
Critical Care 2012, 16(Suppl 1):P106 (doi: 10.1186/cc10713) Tidal volume distribution (ml/kg PBW) for
5 days for each patient. i
Conclusion With our new mechanostimulation system we are able
to confi gure the frequency content of the applied strain profi le and
furthermore to identify the frequency content of the resulting stress
on the tissue. of 6 ml/kg of predicted body weight (PBW), T high between 0.8 and
1 second, T low set to reach the same respiratory rate as in VAC. Patients
were initially paralyzed. Then sedation was adapted to keep RASS ≥–4
and a level of spontaneous breathing between 10 and 50% of total
minute ventilation. A computer was continuously connected to the
ventilator for 5 days in order to record respiratory variables. 1.
Marini JJ, Amato MB: Lung recruitment during ARDS. In Acute Lung Injury.
Edited by Marini JJ, Evans TW. Berlin: Springer; 1998:236-257.
2.
Odenstedt H, Lindgren S, et al.: Slow moderate pressure recruitment
maneuver minimizes negative circulatory and lung mechanic side eff ects:
evaluation of recruitment maneuvers using electric impedance
tomography. Intensive Care Med 2005, 31:1706-1714.
3.
Medoff BD, Harris RS, Kesselman H, et al.: Use of recruitment maneuvers and
high-positive end-expiratory pressure in a patient with acute respiratory
distress syndrome. Crit Care Med 2000, 28:1210-1216. P108 Contrarily, DO2 (ml/minute/m2) after RM statistically
signifi cantly decreased from 709.5 ± 297.5; 804.9 ± 217.3; 811.7 ± 638.3
to 569.8 ± 211.9; 675.5 ± 244.7; 661.7 ± 421.3 (P = 0.053) and lasted more
than 2 hours. The reason for this alteration was decreasing of cardiac
output (CO) from 5.3 ± 2.5 l/minute to 3.6 ± 1.7 l/minute (P <0.0001)
after RM. We hypothesized that the main reason for decreasing CO is
rapid increasing of intrathoracic pressure during RM. Feasibility of early spontaneous breathing in acute respirator
distress syndrome
S Mortaza, A Mercat
CHU Angers, France
Critical Care 2012, 16(Suppl 1):P106 (doi: 10.1186/cc10713) S Mortaza, A Mercat Introduction Airway pressure release ventilation (APRV) is as a
pressure preset mode that allows unrestricted spontaneous breathing
throughout the entire ventilator cycle. In ARDS, this mode may
decrease the need for sedation, increase alveolar recruitment and
improve hemodynamic tolerance. The aim of this study is to assess
the feasibility of a protocol combining APRV settings and sedation
adaptation in order to obtain levels of spontaneous breathing between
10 and 50% of total minute ventilation. Methods We designed a monocentric study including 10 patients with
early ARDS. We used a Dräger Evita XL ventilator. We initially used the
volume-assist control (VAC) mode to set the PEEP, tidal volume and
respiratory rate according to the increased recruitment strategy of
the ExPress trial [1]. These settings were used to adjust the ventilator’s
parameters in APRV mode: low pressure at the same level as the PEEP
applied in VAC, high pressure (<32 cmH2O) set to reach a tidal volume Figure 1 (abstract P104). Linear regression between quantitative CT scan
analysis and PV curve method. Figure 1 (abstract P104). Linear regression between quantitative CT scan
analysis and PV curve method. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum com/supplements/16/S1 S39 http://ccforum.com/supplements/16/S1 repetition rates ranging from 15/minute to 2,000/minute at amplitude
volumes of 0.5 up to 2.8 ml, corresponding to a surface increase of 5% up
to 100%, were used. The system was driven with sinusoidal, rectangular
and ventilation-analogue profi les simulating the ventilatory pattern
which is associated with the volume-controlled ventilation. Figure 1 (abstract P106). Tidal volume distribution (ml/kg PBW) for
5 days for each patient. Results The drive system allowed us to vary the amplitude from 0 up to
100% surface increase. At amplitudes of 0.5 and 1.0 ml we were able to
apply a frequency range from 0 up to 2,000/minute, and at an amplitude
of 2.0 ml a frequency range from 0 up to 800 sinusoidal defl ections per
minute. We were able to apply the rectangular and the ventilation-
analogue volume patterns to the probes. Close inspection of the
pressure curves revealed that rapid volume increases were followed
by peaks with subsequent relaxation decays when rectangular or
ventilation-analogue stimulation patterns were applied. The frequency
spectra of the pressure variation revealed side frequencies of up to
10 Hz for the rectangular mechanostimulation profi le. Figure 1 (abstract P106). P107 A device for ventilation-analogue mechanostimulation in vitro
K Gamerdinger, M Schneider, E Smudde, J Guttmann, S Schumann
University Medical Center Freiburg, Germany
Critical Care 2012, 16(Suppl 1):P107 (doi: 10.1186/cc10714) References 1. Marini JJ, Amato MB: Lung recruitment during ARDS. In Acute Lung Injury. Edited by Marini JJ, Evans TW. Berlin: Springer; 1998:236-257. 2. Odenstedt H, Lindgren S, et al.: Slow moderate pressure recruitment
maneuver minimizes negative circulatory and lung mechanic side eff ects:
evaluation of recruitment maneuvers using electric impedance
tomography. Intensive Care Med 2005, 31:1706-1714. g p y
3. Medoff BD, Harris RS, Kesselman H, et al.: Use of recruitment maneuvers and
high-positive end-expiratory pressure in a patient with acute respiratory
distress syndrome. Crit Care Med 2000, 28:1210-1216. Methods Silicone membranes serving as substitutes for biological tissue
samples were placed inside a bioreactor [1] either in single-membrane
or in double-membrane confi guration. Cyclic mechanostimulation at S40 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P109f Results The study comprised 20 patients with mean age of 58.9 ± 20.69
years, 11 men versus nine women (P >0.05). NT-proBNP was negatively
correlated with PH on day 2 (P = 0.008, r = –0.53) and day 7 with
(P = 0.02, r = –0.50). NT-proBNP was positively correlated with PEEP
on day 2 (P = 0.05, r = 0.46) and day 7 (P = 0.035, r = 0.48). NT-proBNP
was negatively correlated with the PaO2/FiO2 ratio on day 7 (P = 0.0035,
r = 0.60). However, there was no signifi cant correlation between NT-
proBNP and other respiratory indices including PaCO2, HCO3, PaO2,
SaO2, FiO2, PAO2, P(A-a)O2 and a/A ratio (P >0.05). Neither troponin I
nor troponin T showed any signifi cant correlation with any respiratory
indices PH, PEEP, PaO2/FiO2, PaCO2, HCO3, PaO2, SaO2, FiO2, PAO2, P(A-a)
O2 and a/A ratio on any day (P >0.05). None of the cardiac markers NT-
proBNP, troponin I or troponin T showed any signifi cant correlation with
the lung mechanics parameters Cdyn, Raw, Ceff , PIP, Pplat, and Pmean (P >0.05). Conclusion High NT-proBNP level was correlated with high PEEP, low
PH and low PaO2/FiO2 ratio while troponin T and troponin I did not
show signifi cant correlations with respiratory parameters in ARDS
patients with structurally normal hearts. Early application of high-frequency oscillatory ventilation in H1N1
infl uenza-related severe ARDS is associated with better outcome
S Jog, M Patel, D Patel Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2012, 16(Suppl 1):P111 (doi: 10.1186/cc10718) Results The groups were equal before and at the end of laparotomy. During the endotoxin infusion, PaO2/FiO2 was higher in groups I and
II than in group III, whereas in pulmonary compliance or functional
residual capacity no diff erences were found. In contrast, group I showed
greater negative changes than group III in the circulatory variables;
that is, arterial blood pressure, cardiac index, oxygen delivery and
oxygen consumption. In all measured variables, group II showed an
intermediate response to groups I and III, but no signifi cant diff erences
were found between groups I and II. Groups I and II had slightly higher
mean airway pressure at the end of the experiment than group III. However, this does not explain the circulatory diff erences since they
occurred early in the course, temporally diff erent from the continuous
slow increase of the airway pressures (P ≤0.01 ANOVA group by time
interaction). Introduction High-frequency oscillatory ventilation (HFOV) is a
promising rescue modality for refractory hypoxia and was used
extensively in H1N1 infl uenza-related ARDS in 2009 and 2010. The aim
of this study was to fi nd predictors of successful outcome of HFOV in
H1N1 infl uenza-related severe ARDS [1].l l
Methods Patients with H1N1 infl uenza-related severe ARDS by the
new Berlin defi nition (applied retrospectively) receiving volume-
controlled ventilation (VCV) as per the ARDSnet protocol with PO2/FiO2
≤100 at PEEP ≥12 cmH2O and FiO2 ≥0.7 were connected to HFOV as a
rescue therapy for refractory hypoxia. All patients were followed until
discharge from the hospital (survivors) or death (nonsurvivors). Conclusion Low VT ventilation combined with higher PEEP in healthy
animals exposed to laparotomy and subsequent experimental post-
operative sepsis leads to a less prominent pulmonary dysfunction
but to a more hypodynamic circulatory state compared to animals
ventilated with a medium–high VT and lower PEEP. Reference Results About 80 parameters were evaluated as outcome predictors
of HFOV like demographics, comorbidities, clinical features, laboratory
parameters, X-rays, ventilatory and blood gas parameters and therapy-
related complications. Previously collected data of 19 patients were
analysed applying the new Berlin defi nition. Demographic, clinical,
comorbidity, laboratory and radiological parameters were comparable
in survivors and nonsurvivors. Table 1 shows comparison of survivors
and nonsurvivors with respect mainly to ventilatory and gas exchange
parameters before application of HFOV. References f P109
Diff erential pulmonary and circulatory eff ects of preventive lung
protective ventilation in an experimental postoperative sepsis
model
J Sperber1, M Lipcsey2, A Larsson2, A Larsson2, J Sjölin2, M Castegren1
1Centre for Clinical Research Sörmland, Eskilstuna, Sweden; 2Uppsala
University, Uppsala, Sweden
Critical Care 2012, 16(Suppl 1):P109 (doi: 10.1186/cc10716) Introduction It has been proposed that low tidal volume (VT)
ventilation combined with higher PEEP should be used in patients with
risk of developing postoperative lung injury instead of the commonly
used VT of 10 ml/kg with lower PEEP [1]. Such a ventilatory mode would
in theory reduce postoperative lung and organ dysfunction. However,
this hypothesis has neither been tested clinically nor experimentally. Therefore we developed an experimental endotoxemic postoperative
sepsis model to evaluate the eff ect of diff erent modes of ventilation. Methods Twenty-fi ve healthy pigs were randomized to three ventilation
groups: I: PEEP 10 cmH2O, VT 6 ml/kg; II: PEEP 5 cmH2O, VT 10 ml/kg,
changed to PEEP 10 cmH2O, VT 6 ml/kg at the end of laparotomy; III:
PEEP 5 cmH2O, VT 10 ml/kg. For all groups the plateau pressure was
kept below 28 cmH2O, normocapnia was reached by respiratory rate
and FiO2 was adjusted to reach PaO2 >12 kPa. Laparotomy for 2 hours
was performed to simulate a surgical procedure and then a continuous
endotoxin infusion was started at 0.25 μg/kg/hour for 5 hours. Diff erences between groups were analyzed with ANOVA for repeated
measures. Introduction It has been proposed that low tidal volume (VT)
ventilation combined with higher PEEP should be used in patients with
risk of developing postoperative lung injury instead of the commonly
used VT of 10 ml/kg with lower PEEP [1]. Such a ventilatory mode would
in theory reduce postoperative lung and organ dysfunction. However,
this hypothesis has neither been tested clinically nor experimentally. Therefore we developed an experimental endotoxemic postoperative
sepsis model to evaluate the eff ect of diff erent modes of ventilation.i Methods Twenty-fi ve healthy pigs were randomized to three ventilation
groups: I: PEEP 10 cmH2O, VT 6 ml/kg; II: PEEP 5 cmH2O, VT 10 ml/kg,
changed to PEEP 10 cmH2O, VT 6 ml/kg at the end of laparotomy; III:
PEEP 5 cmH2O, VT 10 ml/kg. For all groups the plateau pressure was
kept below 28 cmH2O, normocapnia was reached by respiratory rate
and FiO2 was adjusted to reach PaO2 >12 kPa. Reference 1. Mitaka C, et al.: Increased plasma concentrations of BNP in patients with
ALI. J Crit Care 1997, 12:66-71. P111 Early application of high-frequency oscillatory ventilation in H1N1
infl uenza-related severe ARDS is associated with better outcome
S Jog, M Patel, D Patel
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2012, 16(Suppl 1):P111 (doi: 10.1186/cc10718) References Laparotomy for 2 hours
was performed to simulate a surgical procedure and then a continuous
endotoxin infusion was started at 0.25 μg/kg/hour for 5 hours. Diff erences between groups were analyzed with ANOVA for repeated
measures. Reference 1.
Mitaka C, et al.: Increased plasma concentrations of BNP in patients with
ALI. J Crit Care 1997, 12:66-71. Early application of high-frequency oscillatory ventilation in H1N1
infl uenza-related severe ARDS is associated with better outcome
S Jog, M Patel, D Patel Duration of conventional
mechanical ventilation before HFOV, 1.4 ± 0.69 versus 3.66 ± 3.53 days
(P = 0.03), was the only discriminating parameter between survivors
and nonsurvivors. 1. Schultz et al.: Anesthesiology 2007, 106:1226-1231. 1. Schultz et al.: Anesthesiology 2007, 106:1226-1231. 1. Schultz et al.: Anesthesiology 2007, 106:1226-1231. P110 P110
High NT-proBNP level is correlated with high PEEP, low PH and low
PaO2/FiO2 in ARDS
Y Nassar, D Monsef, S Abdelshafy, G Hamed
Cairo University, Giza, Egypt
Critical Care 2012, 16(Suppl 1):P110 (doi: 10.1186/cc10717) Mechanical ventilation in intensive and critical care units of Russia:
RuVent national epidemiologic study Results The gestational age more than 25 weeks was in 21 patients
and between 20 and 25 weeks was in two patients. The mean age
of these patients were 31 ± 5.7. The leading causes of ICU admission
were obstetric emergency (26%), cardiovascular disease (26%) and
infectious disease (26%) in these 23 patients. A total of 19 patients were
respiratory failure and ARDS was diagnosed in nine of 19 patients. Of
these nine ARDS patients, tidal volume (mean: 385 ± 31 ml), PaO2/FiO2
ratio (mean: 116 ± 47), positive end-expiratory pressure (PEEP) (mean:
13 ± 1.4 mmHg), peak airway pressure (mean: 34 ± 9.1 mmHg) and FiO2
(mean: 93 ± 7%). The intra-uterine fetal death ratio was 33% (3/9) and
the Apgar score of the other six living births (6/9) was 7.8 ± 0.7. The
hospital mortality rate of these ARDS patients was only 11% (1/9). p
g
y
DN Protsenko1, AI Yaroshetskiy1, SG Suvorov2, AU Lekmanov2, BR Gelfand1
1Russian National Research Medical University, Moscow, Russia; 2Moscow
Research Institute of Pediatrics and Child Surgery, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P114 (doi: 10.1186/cc10721) DN Protsenko1, AI Yaroshetskiy1, SG Suvorov2, AU Lekmanov2, BR Gelfand1
1Russian National Research Medical University, Moscow, Russia; 2Moscow
Research Institute of Pediatrics and Child Surgery, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P114 (doi: 10.1186/cc10721) Introduction Experimental data have shown that mechanical
ventilation can amplify or possibly trigger lung injury [1,2]. The biggest
up-to-date clinical trial by the ARDS Network demonstrates reduction
of mortality in ARDS patients with a protective lung strategy [3]. But we
can see some gaps between international recommendations and real
clinical practice [4,5]. y
y
Conclusion For pregnant ARDS patients, intensivists had a challenge
for fetal and maternal life-threatening distress. In our study, early
delivery combined with a lung-protective ventilation strategy may
provide signifi cantly better fetal and maternal outcomes. References p
Methods The multicenter clinical trial included 470 patients from 101
centers (ICUs) in Russia. Inclusion criteria were all patients without age
restrictions ventilated for more than 12 hours for any reason from 14
to 18 February 2011. Recruitment of centers and data collection were
made online. 1. Oram MP, et al.: Severe acute respiratory distress syndrome in pregnancy. Caesarean section in the second trimester to improve maternal 1. Oram MP, et al.: Severe acute respiratory distress syndrome in pregnancy. Caesarean section in the second trimester to improve maternal
ventilation. P110 P112
Outcomes of early delivery in pregnant patients with acute
respiratory distress syndrome
CY Hung, HC Hu, CH Chang, CC Huang, KC Kao
Chang Gung Memorial Hospital, Taoyuan, Taiwan
Critical Care 2012, 16(Suppl 1):P112 (doi: 10.1186/cc10719) episodes increased by 8% and >15 day episodes decreased by 7% from
1999 to 2009. The overall reintubation rate was 13.8%. Less than 48-hour
reintubation dropped from 14.4% in 1999 to 6.7 in 2009 while more than
48-hour reintubation remained similar (5.6% in 1999 and 6.2% in 2009). NIV use signifi cantly increased over this time – almost quadrupled (from
78 in 1999 to 315 in 2009). The most prominent increase was noted in
the surgical and burn ICUs where, in 1999, NIV use was minimal (burn: 0,
SICU: 6 and 16 and 131 in 2009). Medical and neuro ICUs doubled their
use. A total 52.7% of NIV applications were associated with IV within
48 hours of NIV therapy. The sequence of IV–NIV revealed similar patterns
through the years, overall, 58.4% of NIV application followed extubation,
24.2% preceded intubation and 17% was in between. References 1. Dreyfuss D, Saumon G: Am J Respir Crit Care Med 1998, 157:294-323. 2. Ignatenko O, Protsenko D, Yaroshetskiy A, Gelfand B: Crit Care 2010, 14(Suppl
1):P200. Methods Data were retrospectively collected using the Respiratory
Care Services’ Database. The number of invasive and noninvasive MV
services, their sequence if both were used for a given patient, the
duration of the services, and reintubation episodes for years 1999
to 2009 were extracted. Four ICUs were included; surgical, medical,
neuro and burn ICUs. If a patient was reintubated within 48 hours
of extubation, the case was regarded as a single episode of MV and
the duration was calculated accordingly. For NIV, if restarted within
48 hours, it was counted as a single episode as well.i 3. ARDS Network: N Engl J Med 2000, 342:1301- 3. ARDS Network: N Engl J Med 2000, 342:1301-1308. 4
Esteban A et al : JAMA 2002 287:345 355 5. Esteban A, et al.: Am J Respir Crit Care Med 2008, 177:170-177. Mechanical ventilation demographics between 1999 and 2009
DS Sulemanji, E Burns, R Kacmarek
Massachusetts General Hospital, Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P113 (doi: 10.1186/cc10720) Mechanical ventilation demographi
DS Sulemanji, E Burns, R Kacmarek DS Sulemanji, E Burns, R Kacmarek Massachusetts General Hospital, Boston, MA, USA Conclusion Results of the RuVent study are comparable with
international epidemiologic multicenter studies. Further investigations
are needed for evaluation of the situation in ICUs which are a long
distance from big medical centers. Critical Care 2012, 16(Suppl 1):P113 (doi: 10.1186/cc10720) Introduction Eff orts at many levels are being directed at decreasing
the economic burden of mechanical ventilation (MV), its related
complications and their consequences. Our aim was to determine the
length of MV, reintubation rates and use of noninvasive ventilation
(NIV), over a 10-year period. P112
Outcomes of early delivery in pregnant patients with acute
respiratory distress syndrome p
y
y
CY Hung, HC Hu, CH Chang, CC Huang, KC Kao
Chang Gung Memorial Hospital, Taoyuan, Taiwan
Critical Care 2012, 16(Suppl 1):P112 (doi: 10.1186/cc10719) Introduction Critical illnesses in pregnancy account for 0.11 to 0.89%
of deliveries resulting in ICU admissions. The high rate of perinatal
asphyxia in infants and high mortality rate in gravid patients supported
a strategy of early delivery during the third trimester. The mortality rate
of acute respiratory distress syndrome (ARDS) is high and varied from
15 to 72% among the studies. The present study reports the outcomes
of early delivery within 48 hours after ICU admission in pregnant
patients with ARDS. p
Conclusion We found that the duration of MV decreased, reintubations
within 48 hours decreased and the use of NIV increased over this 10-
year period. The analysis of outcomes from our data has yet to be
completed, but it would not be premature to speculate these results
are related to the incorporation of SBT protocols and awaking trials,
lesser use of neuromuscular blocking agents as well as extensive
application of lung-protective ventilation strategies. p
Methods A total of 23 pregnant patients with gestational age more
than 20 weeks admitted to the ICU was recorded from January 2009
to November 2012. Emergent delivery was performed within 48 hours
after ICU admission. The collected data included etiologies of ICU
admission, patients’ characteristics and ventilator setting, infant and
maternal clinical outcomes. P114 Mechanical ventilation in intensive and critical care units of Russia:
RuVent national epidemiologic study Anaesth Intensive Care 2007, 35:975-978. Oram MP, et al.: Severe acute respiratory distress syndrome in pregn Results Total mortality was 35.1%, mortality in ARDS was 44.9%. Preva-
lence of ARDS was 18.7%. Leading causes for initiation of respiratory
support were pathology of the central nervous system (severe TBI 13.3%,
stroke 15.7%, craniocephal tumors 5%), sepsis (8.3%), community-
acquired pneumonia (8.8%) and ARDS (10.5%). Controlled modes of
mechanical ventilation were predominant in our study (A/C 20.2%, SIMV
45.1%, BIPAP 12.6%), other modes includes pressure support ventilation,
ASB and PAV. Prevalence of noninvasive respiratory support was only
1.1%. Mean tidal volume calculated by ideal body weight was 8.13 (6.84
to 9.35) for boys and men and 9.1 (7.6 to 10.9) for girls and women. Mean
PEEP was 5 (4 to 8) in the whole study and 6 (5 to 9) for ARDS patients. ventilation. Anaesth Intensive Care 2007, 35:975-978. 2. Cole DE, et al.: Acute respiratory distress syndrome in pregnancy. Crit Care
Med 2005, 33:S269-S278. 3. Bandi VD, et al.: Acute lung injury and acute respiratory distress syndrome
in pregnancy. Crit Care Clin 2004, 20:577-607. P114 P114
Mechanical ventilation in intensive and critical care units of Russia:
RuVent national epidemiologic study
DN Protsenko1, AI Yaroshetskiy1, SG Suvorov2, AU Lekmanov2, BR Gelfand1
1Russian National Research Medical University, Moscow, Russia; 2Moscow
Research Institute of Pediatrics and Child Surgery, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P114 (doi: 10.1186/cc10721) P110 Table 1 (abstract P111). Comparison of survivors and nonsurvivors
Variable
Survivors
Nonsurvivors
P value
APACHE
13.3 ± 1.7
13.2 ± 2.2
0.14
Time VCV
1.4 ± 0.69
3.66 ± 3.5
0.03
PIP
35.6 ± 7.1
35.2 ± 5.1
0.44
PEEP
13.4 ± 2.0
13.4 ± 2.8
0.48
P/F
82.6 ± 31
68.8 ± 34
0.37
OI
36.08 ± 24
25.32 ± 7
0.1 Table 1 (abstract P111). Comparison of survivors and nonsurvivors Introduction Cardiac injury may occur in ARDS patients with structurally
normal hearts and may be correlated with respiratory parameters [1]. We aimed at observing NT-proBNP, troponin I and troponin T relations
with diff erent respiratory parameters in ARDS. f
Methods Inclusion criteria were any adult patient diagnosed to have
ARDS according to the criteria of the American–European Consensus
Conference in 1994. Exclusion criteria were any structural heart disease
by echo, pulmonary embolism, atrial fi brillation, renal insuffi ciency,
and age <18. All patients benefi ted from a lung protective ventilation
strategy. Plasma NT-proBNP, troponin I and troponin T were measured
on day 0 and on day 2 and day 7 of ARDS diagnosis. PH, PaCO2, PaO2,
P(A-a)O2 (alveolar–arterial gradient), PaO2/FiO2 ratio, a/A ratio, PEEP, PIP
(peak airway pressure), Pmean, Pplat (plateau pressure) and Ceff (eff ective
compliance), and Raw (airway resistance) were monitored daily. S41 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P112 episodes increased by 8% and >15 day episodes decreased by 7% from
1999 to 2009. The overall reintubation rate was 13.8%. Less than 48-hour
reintubation dropped from 14.4% in 1999 to 6.7 in 2009 while more than
48-hour reintubation remained similar (5.6% in 1999 and 6.2% in 2009). NIV use signifi cantly increased over this time – almost quadrupled (from
78 in 1999 to 315 in 2009). The most prominent increase was noted in
the surgical and burn ICUs where, in 1999, NIV use was minimal (burn: 0,
SICU: 6 and 16 and 131 in 2009). Medical and neuro ICUs doubled their
use. A total 52.7% of NIV applications were associated with IV within
48 hours of NIV therapy. The sequence of IV–NIV revealed similar patterns
through the years, overall, 58.4% of NIV application followed extubation,
24.2% preceded intubation and 17% was in between. Eff ects of low and high tidal volume and pentoxifylline on intestinal
blood fl ow and leukocyte–endothelial interactions in mechanically
ventilated rats Eff ects of low and high tidal volume and pentoxifylline on intestinal
blood fl ow and leukocyte–endothelial interactions in mechanically
ventilated rats
N Nakagawa1, P Aikawa1, HZ Zhang2, C Correia1, R Pazzeti1,
C Valente Barbas1, T Mauad1, E Silva1, P Sannomiya1
1Faculdade de Medicina da Universidade de São Paulo, Brazil; 2University of
Toronto and Saint Michael Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P116 (doi: 10.1186/cc10723) N Nakagawa1, P Aikawa1, HZ Zhang2, C Correia1, R Pazzeti1,
C Valente Barbas1, T Mauad1, E Silva1, P Sannomiya1
1Faculdade de Medicina da Universidade de São Paulo, Brazil; 2University of
Toronto and Saint Michael Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P116 (doi: 10.1186/cc10723) Table 1 (abstract P117)
Male 1
Male 2
R estimated
3.7 ± 0.7
3.2 ± 0.7
R measured
5.2 ± 1.9
2.9 ± 1.2
C estimated
97.7 ± 20.6
85.4 ± 18.7
C measured
100.5 ± 21.9
76.5 ± 18.7
Mean ± SD of R in cmH2O/l/second and C in ml/mbar (measured = MLR,
estimated = O+D). Introduction The combination of high positive end-expiratory pressure
(PEEP) and low tidal volume (VT) decreases some risks of mechanical
ventilation, including pulmonary overdistention, damage due to cyclic
opening and closing of the alveoli, and infl ammatory responses that
can lead to multiple-organ dysfunction. We hypothesized that high VT
and high PEEP induce mesenteric microcirculatory disturbances and
that those disturbances would be attenuated by pentoxifylline, which
is anti-infl ammatory.l Mean ± SD of R in cmH2O/l/second and C in ml/mbar (measured = MLR,
estimated = O+D). l
y
Methods We anesthetized (isofl urane 1.5%), tracheostomized, and
mechanically ventilated 57 male Wistar rats with PEEP of 10 cmH2O and
FIO2 of 0.21 for 2 hours. One group received low VT (7 ml/kg), another
group received high VT (10 ml/kg), and a third group received high VT
(25 mg/kg) plus pentoxifylline. We measured mean arterial pressure,
respiratory mechanics, mesenteric blood fl ow, and leukocyte–
endothelial interactions. Figure 1 (abstract P117). PTPinsp from measured Pdi (APdi) versus
PTPinsp from reconstruction (ArPdi). Results The mean arterial pressure was similar among the groups
at baseline (108 mmHg (IQR 94 to 118 mmHg)) and after 2 hours of
mechanical ventilation (104 mmHg (IQR 90 to 114 mmHg)). P116f Results After validation with simulations, we used data from two
healthy adults breathing at several levels of WOB. The occlusions caused
the expected signals reproducing Pdi as desired with R and C values
typical for healthy men (Table 1). Measured and assessed PTPinsp
correlated well (R2 = 0.93 and 0.89) and had small mean diff erences
(mean ± 2SD = 1.78 ± 3.81 and 0.27 ± 4.80 cmH2O.second) (Figure 1). P115 There were fewer adherent
leukocytes (P = 0.005) and fewer migrated leukocytes (P = 0.002) in the
low-VT group (5 cells/100 μm length (IQR 4 to 7 cells/100 μm length)
and 1 cell/5,000 μm2 (IQR 1 to 2 cells/5,000 μm2), respectively) and
the high-VT/pentoxifylline group (5 cells/100 μm length (IQR 3 to 10
cells/100 μm length) and 1 cell/5,000 μm2 (IQR 1 to 3 cells/5,000 μm2),
respectively) than in the high-VT group (14 cells/100 μm length (IQR 11
to 16 cells/100 μm length) and 9 cells/5,000 μm2 (IQR 8 to 12 cells/5,000
μm2), respectively). and active breathing patients. The minute volume is adjusted according
to end-tidal CO2 (ETCO2) information in passive breathing patients
(and respiratory rate in active breathing patients), and oxygenation
is adjusted according to SpO2 information. This study reports the
ventilation and oxygenation delivered by IntelliVent-ASV® in long-term
ventilated ICU patients. p
Methods This prospective, observational study included 100 patients
invasively ventilated using IntelliVent-ASV® from admission to weaning
or death. The rate and reason for stopping automation were recorded. Settings automatically selected, delivered ventilation, respiratory
mechanics and arterial blood gas results were collected once a day. Patients were categorized in diff erent lung conditions: normal lung,
ALI/ARDS, COPD. Analysis of variance compared the ventilation-days for
each type of lung condition for active and passive breathing patients. Results Patients (age 73 (64 to 79) years; SAPS II 56 (48 to 69)) were
ventilated using IntelliVent-ASV® to weaning or death (31%) for a
median duration of 3.0 (2.0 to 7.0) days without any safety issue. The
ventilation controller was deactivated in two patients because of high
PaCO2–ETCO2 gradient. Oxygenation controller was deactivated in
seven patients for 1 day because of a poor SpO2 signal. In passive and
active ventilation-days, minute volume, VT/PBW, respiratory rate, FiO2,
and PEEP were statistically diff erent based on lung condition. In passive
ALI/ARDS ventilation-days, VT/PBW was signifi cantly lower (7.5 (6.9 to
7.9) ml/kg) than passive normal lung (8.1 (7.3 to 8.9) ml/kg; P <0.05)
and passive COPD patients (9.9 (8.3 to 11.1) ml/kg; P <0.05). In passive
ALI/ARDS ventilation-days, FiO2 and PEEP were statistically higher than
passive normal lung (35 (33 to 47)% vs. 30 (30 to 31)% and 11 (8 to 13)
cmH2O vs. 5 (5 to 6) cmH2O, respectively; P <0.05). P115 In active normal lung
ventilation-days, VT/PBW was not diff erent (8.4 (7.8 to 9.1) ml/kg) than
in active ALI/ARDS (8.1 (7.5 to 9.3) ml/kg), and in active COPD (9.3 (8.6 to
11.6) ml/kg). In active ALI/ARDS and COPD ventilation-days, PEEP was
signifi cantly higher than active normal lung (8 (5 to 10) cmH2O, 7 (5 to
10) cmH2O, and 5 (5 to 5) cm H2O, respectively; P <0.05). Methods This prospective, observational study included 100 patients
invasively ventilated using IntelliVent-ASV® from admission to weaning
or death. The rate and reason for stopping automation were recorded. Settings automatically selected, delivered ventilation, respiratory
mechanics and arterial blood gas results were collected once a day. Patients were categorized in diff erent lung conditions: normal lung,
ALI/ARDS, COPD. Analysis of variance compared the ventilation-days for
each type of lung condition for active and passive breathing patients. Conclusion Low VT with high PEEP was lung-protective, and early
pentoxifylline reduced the infl ammatory response to high VT with
high PEEP (and presumed lung overdistention) during mechanical
ventilation. yp
g
p
g p
Results Patients (age 73 (64 to 79) years; SAPS II 56 (48 to 69)) were
ventilated using IntelliVent-ASV® to weaning or death (31%) for a
median duration of 3.0 (2.0 to 7.0) days without any safety issue. The
ventilation controller was deactivated in two patients because of high
PaCO2–ETCO2 gradient. Oxygenation controller was deactivated in
seven patients for 1 day because of a poor SpO2 signal. In passive and
active ventilation-days, minute volume, VT/PBW, respiratory rate, FiO2,
and PEEP were statistically diff erent based on lung condition. In passive
ALI/ARDS ventilation-days, VT/PBW was signifi cantly lower (7.5 (6.9 to
7.9) ml/kg) than passive normal lung (8.1 (7.3 to 8.9) ml/kg; P <0.05)
and passive COPD patients (9.9 (8.3 to 11.1) ml/kg; P <0.05). In passive
ALI/ARDS ventilation-days, FiO2 and PEEP were statistically higher than
passive normal lung (35 (33 to 47)% vs. 30 (30 to 31)% and 11 (8 to 13)
cmH2O vs. 5 (5 to 6) cmH2O, respectively; P <0.05). In active normal lung
ventilation-days, VT/PBW was not diff erent (8.4 (7.8 to 9.1) ml/kg) than
in active ALI/ARDS (8.1 (7.5 to 9.3) ml/kg), and in active COPD (9.3 (8.6 to
11.6) ml/kg). P115 In active ALI/ARDS and COPD ventilation-days, PEEP was
signifi cantly higher than active normal lung (8 (5 to 10) cmH2O, 7 (5 to
10) cmH2O, and 5 (5 to 5) cm H2O, respectively; P <0.05). P115 P115
Use of a fully closed-loop ventilation mode in long-term ventilated
ICU patients: a prospective study
J Arnal1, A Garnero1, M Wysocki2, D Demory1, G Corno1, A Berric1,
S Donati1, L Ducros1, J Durand-Gasselin1
1Hôpital Ste Musse, Toulon, France; 2Hamilton Medical, Bonaduz, Switzerland
Critical Care 2012, 16(Suppl 1):P115 (doi: 10.1186/cc10722) Use of a fully closed-loop ventilation mode in long-term ventilated
ICU patients: a prospective study
J Arnal1, A Garnero1, M Wysocki2, D Demory1, G Corno1, A Berric1,
S Donati1, L Ducros1, J Durand-Gasselin1
1Hôpital Ste Musse, Toulon, France; 2Hamilton Medical, Bonaduz, Switzerland
Critical Care 2012, 16(Suppl 1):P115 (doi: 10.1186/cc10722) Results A total of 19,734 IV and 2,472 NIV episodes were identifi ed
during this period. The number of MV episodes increased from 1,660 in
1999 to 2,182 in 2009 with an increasing NIV/IV ratio (from 0.05 to 0.17). In the medical and surgical ICUs, median IV days decreased from 4 to 3
and 3 to 2 days respectively. Overall, 76% of IV episodes lasted <7 days,
14% between 8 and 14 days and 10% >15 days. The number of <7 day IV Introduction IntelliVent-ASV® is a closed-loop ventilation mode that
automatically adjusts ventilation and oxygenation settings in passive S42 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 group (12.7 cmH2O (10.7 to 16.0 cmH2O)). There were fewer adherent
leukocytes (P = 0.005) and fewer migrated leukocytes (P = 0.002) in the
low-VT group (5 cells/100 μm length (IQR 4 to 7 cells/100 μm length)
and 1 cell/5,000 μm2 (IQR 1 to 2 cells/5,000 μm2), respectively) and
the high-VT/pentoxifylline group (5 cells/100 μm length (IQR 3 to 10
cells/100 μm length) and 1 cell/5,000 μm2 (IQR 1 to 3 cells/5,000 μm2),
respectively) than in the high-VT group (14 cells/100 μm length (IQR 11
to 16 cells/100 μm length) and 9 cells/5,000 μm2 (IQR 8 to 12 cells/5,000
μm2), respectively). group (12.7 cmH2O (10.7 to 16.0 cmH2O)). A method for continuous noninvasive assessment of respiratory
mechanics during spontaneous breathing K Lopez-Navas1, S Brandt2, H Gehring2, M Strutz1, U Wenkebach1
1Fachhochschule Lübeck, Germany; 2Universitätsklinikum Schleswig-Holstein,
Lübeck, Germany y
Critical Care 2012, 16(Suppl 1):P117 (doi: 10.1186/cc10724) Critical Care 2012, 16(Suppl 1):P117 (doi: 10.1186/cc10724) Introduction The proper assessment of patient’s work of breathing
(WOB) is the key to a better or even automatic setting of ventilation
parameters. We introduce the Occlusion+Delta method (O+D) to
continuously determine resistance (R) and compliance (C), allowing
one to assess noninvasively the inspiratory force. y
p
y
Methods The O+D method uses a short expiratory occlusion producing
immediate changes in airway pressure (Paw), fl ow (V’) and volume
(V) but not in transdiaphragmatic pressure (Pdi). The diff erences
between an occluded and an undisturbed cycle are related by V’R +
V/C = Paw + Pdi. If both cycles are similar Pdi can be neglected, making
its measurement unnecessary. Then R and C are derived from linear
regression (MLR) and used to make a reconstruction of Pdi (rPdi). As control, R and C were calculated by MLR using the objectively
measured (with balloon catheters) Pdi. The inspiratory pressure time
product (PTPinsp) of measured Pdi (APdi) and reconstructed Pdi (ArPdi)
were compared as expression of WOB. 2
2
y
Conclusion IntelliVent-ASV® can be used safely in long-term ventilated
ICU patients and selects automatically diff erent ventilation and
oxygenation settings according to the lung condition, especially for
passive breathing patients. P118l Introduction Severe cutaneous adverse reactions, such as Stevens–
Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug
reaction with eosinophilia and systemic symptoms (DRESS) are
uncommon but potentially critical ills. Pulmonary involvements in these
severe cutaneous reactions patients are rare but are life-threatening
complications. Therefore, we conducted a study to investigate the
outcomes and risk factors of patients with severe cutaneous reactions
with pulmonary complications. P118
Infl uence of catheter diameter, endotracheal tube diameter, suction
pressure, and PEEP on the tracheal pressure and lung volume
during endotracheal suctioning using a lung model
KJ Snijders1, PE Spronk1, TW Fiks1, H Boon1, T Ten Kleij1, AA Becht1,
FH De Jongh2
1Gelre Ziekenhuizen, Apeldoorn, the Netherlands; 2Academic Medical Center,
Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P118 (doi: 10.1186/cc10725) y
Methods This is a retrospective study conducted in a tertiary teaching
hospital in Taiwan. Between September 2002 and June 2011, 23
consecutive patients admitted to our hospital under the diagnosis of
severe cutaneous adverse reactions with pulmonary involvements
were enrolled. The collected demographic data included gender, age
and comorbidity. Laboratory data and possible off ending etiology also
were collected by reviewing the medical records. Introduction Endotracheal suctioning (ETS) is frequently performed in
the ICU for clearing bronchial secretions in intubated and ventilated
patients. However, research shows that subatmospheric pressures in
the trachea and decreases in lung volume are measured during ETS
when unfavourable parameters are chosen, causing complications (for
example, atelectasis) [1,2]. The aim of this study was to investigate the
infl uence of the parameters: area ratio ‘catheter/endotracheal tube’,
suction pressure, type of ventilation, and positive end-expiratory
pressure (PEEP) on tracheal pressure and lung volume during ETS. Results A total of 21 severe cutaneous adverse reactions patients were
eligible. In these 21 patients, 16 (76.2%) patients were SJS/TEN and
fi ve (23.8%) patients were DRESS. Allopurinol was the most common
culprit medicine (n = 9). There were 11 (52.4%) patients progressing to
respiratory failure with mechanical ventilation. Among these 11 patients,
one was upper airway obstruction, two patients were pneumonia, three
patients were acute respiratory distress syndrome and the other fi ve
patients were acute pulmonary edema. The overall hospital mortality
rate was 47.6% (11/21). The survivors group was younger (51.5 ± 25.4
years vs. 70 ± 10.7 years, P = 0.046) and had less chronic kidney disease
(9% vs. 60%, P = 0.021) compared with the nonsurvivors group. P119 Conclusion Our fi rst results demonstrate a great potential in the
proposed method. A study with 30 volunteers is being carried out and
results will be presented in 2012. P120
During spontaneous breathing cardiac output lacks major eff ect on
pulmonary shunting in porcine lungs with partial collapse
L Vimlati, A Larsson, G Hedenstierna, M Lichtwarck-Aschoff
Uppsala University, Uppsala, Sweden
Critical Care 2012, 16(Suppl 1):P120 (doi: 10.1186/cc10727) Introduction Spontaneous breathing (SB) improves oxygenation com-
pared to mechanical ventilation (MV), and does so even without recruit-
ing atelectasis [1,2]. Since it cannot be excluded that cardiac output
(CO) impacts on pulmonary shunt, we investigated whether pulmonary
shunt correlates with CO in a porcine model of lung collapse. 2
Conclusion During endotracheal suctioning the area ratio (between
the catheter and the endotracheal tube) and the applied suction
pressure should be minimal to avoid high pressure and lung volume
losses. g
Methods In 12 anaesthetized and relaxed supine piglets, lung collapse
was induced by negative pressure application to the endotracheal
tube during MV. Six animals resumed SB after 15 minutes; the other six P118l p
(
)
p
g
g
Methods A lung model (two intersurgical balloons of 2 litres each and
an artifi cial trachea with a 25 mm internal diameter) for spontaneous
breathing and pressure-controlled ventilation (PCV) was designed. Spontaneous breathing was simulated by varying the pressure inside
the chamber in which the balloons were mounted by an electronically
controlled syringe. During PCV, a Servo 300 ventilator was added. An
open suction system (VBM, 5 mm suction gap) was used. After insertion
of the catheter, suction (pressures ranged from 20 to 65 kPa) was
applied for 15 seconds during withdrawal, as used in clinical practice. During spontaneous breathing the parameters pressure and area ratio
(79%, 58%, 34%, 25%, 13%) were varied, while during PCV the PEEP was
varied too. Each setting was repeated three times and the mean results
were used for analysis. Conclusion Severe cutaneous adverse reaction with lung involvement
may contribute a high mortality rate. Older age and comorbidity
of chronic kidney disease were the risk factors of mortality in severe
cutaneous adverse reactions patients. y
Results For spontaneous breathing (n = 45) the mean tracheal pressure
and lung volume decreased strongly when the area ratio and/or
suction pressure increased (for example, mean tracheal pressure
–13 ± 1.3 cmH2O compared to atmospheric pressure, and lung volume
–524 ± 37 ml using 20 kPa suction pressure and area ratio 0.58), the fi rst
having the greater infl uence. Similar results (n = 84) were found for PCV
(for example, 22 ± 0.35 cmH2O and –536 ± 137 ml, using 20 kPa suction
pressure, area ratio 0.58 and PEEP 20 cmH2O). P120 P120
During spontaneous breathing cardiac output lacks major eff ect on
pulmonary shunting in porcine lungs with partial collapse
L Vimlati, A Larsson, G Hedenstierna, M Lichtwarck-Aschoff
Uppsala University, Uppsala, Sweden
Critical Care 2012, 16(Suppl 1):P120 (doi: 10.1186/cc10727) Eff ects of low and high tidal volume and pentoxifylline on intestinal
blood fl ow and leukocyte–endothelial interactions in mechanically
ventilated rats Mesenteric
blood fl ow was also similar between the groups: low VT 15.1 ml/
minute (IQR 12.4 to 17.7 ml/minute), high VT 11.3 ml/minute (IQR 8.6
to 13.8 ml/minute), high-VT/pentoxifylline 12.4 ml/minute (10.8 to
13.7 ml/minute). Peak airway pressure was lower (P = 0.03) in the low-
VT group (10.4 cmH2O (IQR 10.2 to 10.4 cmH2O)) than in the high-VT
group (12.6 cmH2O (10.2 to 14.9 cmH2O)) or the high-VT/pentoxifylline Figure 1 (abstract P117). PTPinsp from measured Pdi (APdi) versus
PTPinsp from reconstruction (ArPdi). S43 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Conclusion Our fi rst results demonstrate a great potential in the
proposed method. A study with 30 volunteers is being carried out and
results will be presented in 2012. Risk factors of mortality in severe cutaneous adverse reactions
patients with pulmonary involvement Risk factors of mortality in severe cutaneous adverse reactions
patients with pulmonary involvement P122 were kept on MV at a respiratory rate and tidal volume corresponding
to SB. All animals were followed over 120 minutes, and repeated
measurements were converted to the area under curve and analysed
by Mann–Whitney test and linear regression. were kept on MV at a respiratory rate and tidal volume corresponding
to SB. All animals were followed over 120 minutes, and repeated
measurements were converted to the area under curve and analysed
by Mann–Whitney test and linear regression. Oxygenation correlates with lung aeration during unsupported
spontaneous breathing in porcine lung collapse model
L Vimlati, A Larsson, G Hedenstierna, M Lichtwarck-Aschoff
Uppsala University, Uppsala, Sweden
Critical Care 2012, 16(Suppl 1):P121 (doi: 10.1186/cc10728) pp
y
pp
Critical Care 2012, 16(Suppl 1):P121 (doi: 10.1186/cc10728) y
gi
Results Neither heart rate, mean arterial pressure nor respiratory rate
showed any signifi cant change after IPV. Oxygen saturation improved
immediately after IPV and was also present after 15 minutes. See Table 1. Introduction We investigated whether oxygenation correlates with
lung aeration during unsupported spontaneous breathing (SB) and
mechanical ventilation (MV) in a porcine lung collapse model. Table 1 (abstract P122). Values before, after and 15 minutes after therapy Table 1 (abstract P122). Values before, after and 15 minutes after therapy
Heart
Mean
Respiratory
Oxygen
rate
arterial pressure
rate
saturation
Before
84.5 ± 18.2
86.6 ± 19.0
24.7 ± 5.6
93.9 ± 3.0
After
86.0 ± 17.6
87.4 ± 21.0
24.1 ± 6.7
95.8 ± 2.8*
After 15 minutes
83.1 ± 16.7
85.4 ± 18.9
23.4 ± 6.0
95.5 ± 2.8*
*P <0.01. g
Methods In 14 anesthetized supine piglets, lung collapse was induced
by negative pressure application (NPA) to the endotracheal tube. Eight
animals resumed SB 5 minutes after NPA, six animals were kept on MV
at a respiratory rate and tidal volume corresponding to SB. Thoracic
CTs and arterial blood gases were taken 2.5 and 30 minutes after NPA. Spearman rank correlation was used for testing; values are given as
mean (95% CI). Results Thirty minutes after NPA the amount of lung tissue in collapsed
regions was similar in both groups (MV: 40% (36 to 44), SB: 35% (26 to
43); P = 0.22). Resuming SB, PaO2/FiO2 improved signifi cantly more with
less amount of collapsed lung tissue 2.5 minutes after NPA (r = –0.87,
P = 0.033). During SB a signifi cant negative correlation between PaO2/
FiO2 and the amount of collapsed lung tissue (r = –0.76, P = 0.038)
was observed; no such correlation could be seen during MV (r = –0.3,
P = 0.2) (Figure 1). Conclusion We demonstrated that IPV is a safe therapy, and oxygen
saturation improved after therapy with IPV. P123
Impact of an open lung approach on hemodynamic parameters
after cardiac surgery
A Leme, F Galas, M Volpe, J Fukushima, J Almeida, R Ianotti, L Hajjar,
M Amato
Heart Institute, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P123 (doi: 10.1186/cc10730) Safety and eff ect of intermittent intrapulmonary percussive
ventilation on oxygen saturation and hemodynamic functions
I Blum, R Janssen-Dean, A Van Overdijk, B Speelberg
St Anna Hospital Geldrop, the Netherlands
Critical Care 2012, 16(Suppl 1):P122 (doi: 10.1186/cc10729) Safety and eff ect of intermittent intrapulmonary percussive
ventilation on oxygen saturation and hemodynamic functions
I Blum, R Janssen-Dean, A Van Overdijk, B Speelberg
St Anna Hospital Geldrop, the Netherlands
Critical Care 2012, 16(Suppl 1):P122 (doi: 10.1186/cc10729) Results PaO2/FiO2 was higher and venous admixture (Qva/Qt) was
lower in the SB group. Hemodynamics was stable and CO was similar
in both groups. Qva/Qt correlated with CO (r = 0.83, P = 0.04) in the MV
group, but not in the SB group (r = 0.08, P = 0.88) (Figure 1). Introduction Intrapulmonary percussive ventilation (IPV) is a
ventilatory technique which is used to clear endobronchial secretions
in patients. IPV uses a Phasitron, which delivers rapid, high-fl ow, mini-
bursts of air mixed with oxygen to the patients. We investigated the
safety of IPV on hemodynamic values and the eff ect of IPV on oxygen
saturation and respiratory rate. g
g
g
Conclusion SB achieves higher PaO2/FiO2 and lower Qva/Qt compared
to MV. During SB, Qva/Qt seems to be unaff ected by CO. This lung
collapse model has stable hemodynamics and gas exchange for at least
2 hours irrespective of the mode of ventilation. References Methods From April until August 2011 we investigated 42 consecutive
patients admitted to our eight-bed adult general ICU with respiratory
failure. Variables such as heart rate, mean arterial pressure, respiratory
rate, and oxygen saturation were measured and compared at three
diff erent time points: before starting IPV therapy, directly after and 15
minutes later. All patients received IPV using a Bird Intrapulmonary
Percussionator Ventilator Model IPV-2C for a period of 20 minutes
consisting of two cycles of 10 minutes. After the fi rst 10 minutes of IPV
therapy in combination with chest compressions the frequency rate was
reduced in order to suction the mobilized secretions. This cycle was then
repeated. Statistical analysis was done with SPSS version 17. Student’s t
test was used to compare values before therapy with directly after and
after 15 minutes of therapy. P <0.05 was considered signifi cant. 1. Carvalho AR, Spieth PM, Pelosi P, et al.: Pressure support ventilation and
biphasic positive airway pressure improve oxygenation by redistribution
of pulmonary blood fl ow. Anesth Analg 2009, 109:856-865.f 2. Vimlati L, Kawati R, Hedenstierna G, Larsson A, Lichtwarck-Aschoff M:
Spontaneous breathing improves shunt fraction and oxygenation in
comparison with controlled ventilation at a similar amount of lung
collapse. Anesth Analg 2011, 113:1089-1095. References 1. Wood CJ, et al.: Intensive Crit Care Nurs 1998, 14:124-136. 2
P d
CM
l I
i
C i C
N
2009 25 21 30 1. Wood CJ, et al.: Intensive Crit Care Nurs 1998, 14:124-136. Figure 1 (abstract P120). Venous admixture (Qva/Qt) plotted against CO (pooled data for each group). Solid circles, mechanical ventilation (MV); open
circles, spontaneous breathing (SB). Figure 1 (abstract P120). Venous admixture (Qva/Qt) plotted against CO (pooled data for each group). Solid circles, mechanical ventilation (MV); open
circles, spontaneous breathing (SB). S44 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P125 respiratory parameters. Nevertheless, adverse hemodynamic eff ects
can occur due to the RM technique. The aim of this study is to evaluate
the eff ect of the RM on hemodynamic parameters in the immediate
postoperative period after cardiac surgery. A rule for predicting the new equilibrated carbon dioxide partial
pressure after changes in the ventilation frequency
S Buehler, M Jensen, S Lozano, S Schumann, J Guttmann
Uniklinik Freiburg, Germany
Critical Care 2012, 16(Suppl 1):P125 (doi: 10.1186/cc10732) p
p
p
g
y
Methods A total of 120 patients with PaO2/FiO2 ratio <250 was
randomized to a conventional strategy of mechanical ventilation or
open lung strategy. The open lung strategy was performed using RM
with an inspiratory pressure amplitude of 15 cmH2O and PEEP of 30
cmH2O three times during 1 minute and setting PEEP after RM at 13
cmH2O. The conventional strategy was done using PEEP = 8 cmH2O
and RM with CPAP = 20 cmH2O three times during 30 seconds and
setting PEEP after RM at 8 cmH2O. The heart rate, systolic, diastolic and
mean arterial blood pressures were recorded before, immediately and
5 minutes after RM. Respiratory mechanics and blood gas analysis were
recorded before and after RM. Introduction In mechanical ventilation the arterial carbon dioxide
partial pressure (PCO2) is one of the key parameters to control the
ventilation frequency. Qualitatively, the eff ect of changes in the
ventilation frequency on the arterial PCO2 level is well known. However,
little is known about the time it takes for the PCO2 value to reach a new
equilibrium after a change in the ventilation frequency (the period
of latency), nor in what way the transition between two states of
equilibrium takes place. Results The open lung group presented a higher variability on blood
pressure immediately after RM compared to the conventional group. There were no diff erences in baseline blood pressure or 5 minutes after
RM and heart rate between groups. The open lung group presented
higher lung compliance (60 ± 17 vs. 48 ± 13 ml/cmH2O) and PaO2/FiO2
(431 ± 124 vs. 229 ± 68) ratio compared to the conventional group. Methods We carried out a clinical study on patients without any
history of lung disease or intracranial surgery in order to determine
these relations. Patient–ventilator asynchrony during conventional or automated
pressure support ventilation in diffi cult-to-wean patients Introduction Cardiac surgical procedures are associated with a high
incidence of postoperative complications, increasing costs and
mortality. The aim of this study is to evaluate the eff ect of a strategy
of protective ventilation on pulmonary complications after cardiac
surgery. g
y
Methods We prospectively evaluated 120 patients immediately after
cardiac surgery, presenting hypoxemia and PaO2/FiO2 <250. Patients
were randomized to protective or conventional ventilation strategy. Protective strategy: PEEP = 13 cmH2O, recruitment maneuver (RM) with
inspiratory pressure amplitude of 15 cmH2O and PEEP of 30 cmH2O. Conventional strategy: PEEP = 8 cmH2O and RM with CPAP = 20 cmH2O. Both patients were ventilated in pressure controlled at 6 ml/kg. Pulmonary mechanic and oxygenation parameters were collected
at baseline, 15, 240 and 255 minutes after the start of treatment. Occurrence of respiratory complications was assessed in the fi rst 5 days
according to the severity score 1 to 4. Introduction Patient–ventilator asynchrony, defi ned as a mismatch
between patient’s inspiratory time and the ventilator insuffl ation time,
occurs in nearly 25% of intubated patients. High asynchrony rates are
associated with higher incidence of weaning failure and tracheostomy,
and prolonged mechanical ventilation. The aim of this study was to
compare the asynchrony rate during conventional pressure support
ventilation (PSV) and automated PSV (SmartCare; Draeger) in diffi cult-
to-wean patients. Methods A prospective, crossover study in diffi cult-to-wean patients
(patients who required up to three spontaneous breathing trials
(SBTs) or as long as 7 days to achieve successful weaning). Patients
were ventilated with an Evita XL ventilator for two consecutive 3-hour
periods applied in random order: with conventional PSV managed by
the attending physicians; and with PSV managed by SmartCare. The
periods were administered in the afternoon (3:00 to 9:00 pm) and
in the night (12:00 pm to 6:00 am). In both periods, the starting PS
level with either conventional or automated PSV was the basal level
before enrolment. During every period, airway pressure, fl ow and
volume signals were continuously recorded on a PC connected to the
ventilator using dedicated software (VentView). These signals were
analyzed offl ine by two clinicians. The asynchrony index was defi ned as Results The protective group compared to the conventional group
had better lung compliance (60 ± 17 vs. 48 ± 13 ml/cmH2O, P <0.001)
and higher PaO2/FiO2 (431 ± 124 vs. 229 ± 68, P <0.001) at 15 minutes
after the start. 1.
Amato MB, Barbas CS, Medeiros DM, et al.: Eff ect of a protective-ventilation
strategy on mortality in the acute respiratory distress syndrome. N Engl J
Med 1998, 338:347-354. 1.
Amato MB, Barbas CS, Medeiros DM, et al.: Eff ect of a protective-ventilation
strategy on mortality in the acute respiratory distress syndrome. N Engl J
Med 1998, 338:347-354. P125 We collected data for the arterial PCO2 from blood gas
analyses at discrete points in time as well as continuous end-tidal CO2
(etPCO2) and transcutaneous CO2 (PtcCO2) data and checked for the
accuracy of the latter two. Least-squares fi tting and a statistical analysis
were carried out. Conclusion An open lung approach after cardiac surgery improves
lung compliance and the PaO2/FiO2 ratio with minimum hemodynamic
detrimental eff ect. Results We determined a general rule to estimate the period of latency
after a change in the ventilation frequency. Furthermore, we specifi ed
the relation between a change in the ventilation frequency and the
change in the PCO2 level. Last, the transition between two PCO2 levels
was found to follow an exponential law and the fi tting resulted in a
formula for the prediction of the new PCO2 level. The new equilibrium
can be predicted with high confi dence in all cases after only 3 to
4 minutes using four data points while the period of latency lasts much
longer, usually between 10 and 20 minutes. Reference 1. Amato MB, Barbas CS, Medeiros DM, et al.: Eff ect of a protective-ventilation
strategy on mortality in the acute respiratory distress syndrome. N Engl J
Med 1998, 338:347-354. g
y
Conclusion The general rule for the period of latency allows an
estimation of the amount of time it takes for the PCO2 value to stabilise
again after a disturbance. A quantitative knowledge of the transition
between two PCO2 equilibria allows for the prediction of the new PCO2
level long before the period of latency is over. Thus, with our relation
between the change in ventilation frequency and the change in PCO2
at hand, an optimal PCO2 level can be aimed for at bedside in the
shortest time span possible. A protective-ventilation strategy reduces pulmonary complications
after cardiac surgery A protective-ventilation strategy reduces pulmonary complications
after cardiac surgery g
y
F Galas1, A Leme1, J Almeida1, M Volpe2, R Ianotti1, J Fukushima1, L Hajjar1,
M Amato3 1Heart Institute, São Paulo, Brazil; 2Federal University of Triângulo Mineiro
Minas Gerais, Uberaba, Brazil; 3Hospital das Clinicas, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P124 (doi: 10.1186/cc10731) P126 P123
Impact of an open lung approach on hemodynamic parameters
after cardiac surgery g
Conclusion In porcine lung collapse PaO2/FiO2 correlates with lung
aeration during unsupported SB, but not during MV at a similar
breathing pattern. The less lung collapse the animals have, the more
PaO2/FiO2 improves resuming SB. 2
2
p
g
Reference 1. Cressoni M, Caironi P, Polli F, et al.: Anatomical and functional
intrapulmonary shunt in acute respiratory distress syndrome. Crit Care Med
2008, 36:669-675. 1. Cressoni M, Caironi P, Polli F, et al.: Anatomical and functional
intrapulmonary shunt in acute respiratory distress syndrome. Crit Care Med
2008, 36:669-675. Introduction Lung recruitment maneuver (RM) has been associated
with an increase of arterial oxygen saturation and improvement of Figure 1 (abstract P121). PaO2/FiO2 plotted against the proportion of atelectatic lung tissue. Open circles, SB; solid circles, MV. Figure 1 (abstract P121). PaO2/FiO2 plotted against the proportion of atelectatic lung tissue. Open circles, SB; solid circles, MV. Figure 1 (abstract P121). PaO2/FiO2 plotted against the proportion of atelectatic lung tissue. Open circles, SB; solid circles, MV. S45 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P124 P124
A protective-ventilation strategy reduces pulmonary complications
after cardiac surgery
F Galas1, A Leme1, J Almeida1, M Volpe2, R Ianotti1, J Fukushima1, L Hajjar1,
M Amato3
1Heart Institute, São Paulo, Brazil; 2Federal University of Triângulo Mineiro
Minas Gerais, Uberaba, Brazil; 3Hospital das Clinicas, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P124 (doi: 10.1186/cc10731) P126 Patient–ventilator asynchrony during conventional or automated
pressure support ventilation in diffi cult-to-wean patients
MM Bitondo1, HM Aguirre-Bermeo2, A Moccaldo1, P De Santis1, V Bernini1,
A Tersali1, S Italiano2, DL Grieco1, FA Idone1, J Grandjean2, F Roche-Campo2,
M Antonelli1, J Mancebo Cortes2, SM Maggiore1
1Catholic University of the Sacred Heart, Roma, Italy; 2San Pau University
Hospital, Barcelona, Spain
Critical Care 2012, 16(Suppl 1):P126 (doi: 10.1186/cc10733) Patient–ventilator asynchrony during conventional or automated
pressure support ventilation in diffi cult-to-wean patients Also, the protective group had a lower incidence of
complications after 5 days of follow-up (grade 2 = 47% vs. 55%, grade
3 = 9% vs. 13%, grade 4 = 0% vs. 3%, P = 0.045). Conclusion A protective-ventilation strategy after cardiac surgery
reduces hypoxemia, increases lung compliances and results in less
respiratory complications without adverse eff ects. Reference P127 Methods We performed a retrospective study of prospectively
collected data involving 2,012 consecutive patients undergoing
mechanical ventilation (MV) in a 16-bed university-affi liated hospital
between 1 October 2005 and 31 August 2011. Eighty-fi ve patients with
FE were matched 1:3 with successfully extubated patients (SE) using
diagnostic category, age, Acute Physiology Score (APS) and duration of
ventilation (DOV) before PE as matching criteria. P127
High levels of B-type natriuretic peptide predict weaning failure
from mechanical ventilation in adult patients after cardiac surgery
L Hajjar1, T Lara1, J Almeida1, J Fukushima1, C Barbas1, A Rodrigues1,
E Nozawa1, JL Vincent2, F Jatene1, J Auler Jr1, F Galas1
1Heart Institute, São Paulo, Brazil; 2Erasme Hospital, Université libre de
Bruxelles, Belgium
Critical Care 2012, 16(Suppl 1):P127 (doi: 10.1186/cc10734) g
Results Patients undergoing MV included 1,209 (60.1%) with SE; 224
(11.1%) died during ventilation (without prior FE); 206 (10.2%) were
extubated to withdraw support; 180 (8.9%) were transferred from
the ICU while ventilated; 81 (4.0%) were liberated from MV after
tracheostomy; 85 (6.6%) failed PE. APS scores were higher (53 (42 to
69) vs. 43 (32 to 60), P <0.0001) and DOV before PE longer (1.8 (0.8 to
4.4) vs. 0.9 (0.4 to 2.6), P = 0.0001) in FE than in SE. There was 100%
concordance of diagnostic category and no statistically signifi cant
diff erences between the groups in regards to age, APS and DOV
before PE. Table 1 illustrates the results of the case–control analysis. In
addition, FE had more days in the hospital after ICU discharge than did
SE: 11 (4 to 24) versus 5 (2 to 9), P <0.0001. Introduction Failure to wean from mechanical ventilation is related
to worse outcomes after cardiac surgery. The aim of the study was to
evaluate B-type natriuretic peptide (BNP) as a predictor factor of failure
to wean from mechanical ventilation after cardiac surgery. Methods We conducted a prospective and observational cohort study
of 101 patients that underwent on-pump coronary artery bypass
grafting. BNP was measured postoperatively after ICU admission
and at the end of a spontaneous breathing test (SBT). Demographic
data, hemodynamic and respiratory parameters, fl uid balance, need
for vasopressor or inotropic support, lengths of ICU and hospital stay
were recorded. Weaning failure was considered as either the inability
to sustain spontaneous breathing after 60 minutes or the need for
reintubation within 48 hours.i Table 1 (abstract P128). Case–control study of failed extubation Introduction Failed extubation (FE), defi ned as reintubation within
48 hours of planned extubation (PE), is common. The literature suggests
that FE complicates 10 to 20% of PE. The consequences of FE have not
been well described, nor have its risk factors. Conclusion As compared with conventional PSV, Smartcare may
reduce asynchronies in diffi cult-to-wean patients, possibly because of
greater variability of the PS level. This needs to be further confi rmed. P128
Case–control study of failed extubation
J Krinsley, P Reddy, A Iqbal
Stamford Hospital, Stamford, CT, USA
Critical Care 2012, 16(Suppl 1):P128 (doi: 10.1186/cc10735) Case–control study of failed extubation
J Krinsley, P Reddy, A Iqbal
Stamford Hospital, Stamford, CT, USA
Critical Care 2012, 16(Suppl 1):P128 (doi: 10.1186/cc10735) P127 Case–control analysis of failed extubation: key
outcomes Results BNP levels were signifi cantly higher both at ICU admission and
in the end of breathing test in patients with weaning failure than in
the other patients. A BNP concentration of 299 ng/l at the end of the
SBT identifi ed weaning failure with 92% sensitivity and 87% specifi city,
resulting in an area under the curve value of 0.91 (95% CI (0.86 to 0.97), FE
SE
P value
ICU LOS
11.8 (7.7 to 17.5)
3.8 (2.1 to 7.5)
<0.0001
VAP (%)
7.1
0.8
0.0043
Mortality (%)
23.5
10.2
0.0052 Figure 1 (abstract P127). Area under receiving operating characteristic
curve for BNP-2 (at the end of spontaneous breathing test) to predict
weaning failure. Conclusion FE is associated with increased ICU and hospital LOS,
increased risk of VAP and increased mortality. Eff orts to prospectively
identify patients at risk for FE may reduce its incidence and improve
outcomes. Reference 1. Amato MB, Barbas CS, Medeiros DM, et al.: Eff ect of a protective-ventilation
strategy on mortality in the acute respiratory distress syndrome. N Engl J
Med 1998, 338:347-354. S46 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P <0.001) (Figure 1). In a multivariate model, BNP level at the end of SBT
was the only predictor of weaning failure from mechanical ventilation. Conclusion BNP was an independent predictor factor of failure to wean
from mechanical ventilation after cardiac surgery, which suggests
that optimization of the ventricular function must be a goal prior to
liberation from mechanical ventilation. the number of asynchronies (wasted eff orts, double cycles, premature
cycling off ) divided by the total respiratory rate (ventilator cycles +
asynchrony events), multiplied by 100. the number of asynchronies (wasted eff orts, double cycles, premature
cycling off ) divided by the total respiratory rate (ventilator cycles +
asynchrony events), multiplied by 100. y
y
y
Results Sixteen patients were enrolled (age 64 ± 11 years; SAPS II
66 ± 14; COPD 25%; days of mechanical ventilation before enrollment
9 ± 4, number of SBTs 3 ± 1). The asynchrony index was lower with
Smartcare (10% vs. 14%, P = 0.01), but not diff erent between afternoon
and night. Mean PS level (11 vs. 12 cmH2O) was not diff erent between
conventional and automated PSV, although the coeffi cient of variability
of PS level was greater with Smartcare (20% vs. 0%, P <0.01). No
diff erences were observed in PaCO2 (36 vs. 36 mmHg), PaO2 (106 vs. 102
mmHg), total respiratory rate (22 vs. 23), and P0.1 (1.4 vs. 1.6 cmH2O)
between conventional PSV and Smartcare. P128 Out-of-bed extubation: changing paradigms Out-of-bed extubation: changing paradigms Out o bed e tubat o : c a g
g pa ad g
s
F Dexheimer Neto, R Cremonese, J Maccari, F Carlin, C Rodrigues,
A Raupp, P Vesz, C Leaes, J De Andrade
Hospital Ernesto Dornelles, Porto Alegre, Brazil
Critical Care 2012, 16(Suppl 1):P129 (doi: 10.1186/cc10736) g
g p
g
Dexheimer Neto, R Cremonese, J Maccari, F Carlin, C Rodrigues, p
g
Critical Care 2012, 16(Suppl 1):P129 (doi: 10.1186/cc10736) Introduction The position of the patient at the time of extubation is an
important topic as several studies have shown that early mobilization
is benefi cial for the critically ill patient and, generally, it occurs
simultaneously with the weaning from mechanical ventilation (MV). Extubations are currently performed with the patient in a supine position
(SP) with the head elevated, and there are no data available concerning
the safety of removing the endotracheal tube of a patient seated in
an armchair (SA). The aim of this study was to evaluate the safety of
proceeding extubations in SA patients compared with those in a SP. Introduction The position of the patient at the time of extubation is an
important topic as several studies have shown that early mobilization
is benefi cial for the critically ill patient and, generally, it occurs
simultaneously with the weaning from mechanical ventilation (MV). Extubations are currently performed with the patient in a supine position
(SP) with the head elevated, and there are no data available concerning
the safety of removing the endotracheal tube of a patient seated in
an armchair (SA). The aim of this study was to evaluate the safety of
proceeding extubations in SA patients compared with those in a SP. Methods A retrospective cohort study of a clinical and surgical 23-bed
ICU, in a private hospital in Brazil – Hospital Ernesto Dornelles (Porto
Alegre, RS, Brazil). Extubation success was the primary outcome –
defi ned as tolerating removal of the endotracheal tube for at least g
Methods A retrospective cohort study of a clinical and surgical 23-bed
ICU, in a private hospital in Brazil – Hospital Ernesto Dornelles (Porto
Alegre, RS, Brazil). Extubation success was the primary outcome –
defi ned as tolerating removal of the endotracheal tube for at least Figure 1 (abstract P127). Area under receiving operating characteristic
curve for BNP-2 (at the end of spontaneous breathing test) to predict
weaning failure. Figure 1 (abstract P127). P130
Prediction of post-extubation failure by portable ICU ultrasound
Y Sutherasan, P Theerawit, T Hongpanat, C Kiatboonsri, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P130 (doi: 10.1186/cc10737) Effi cacy of IAPS in each of these
patient groups was studied. Methods We conducted a prospective, observational study from
December 2010 to September 2011 using portable critical care
ultrasound to examine air-column width diff erences of vocal cords
before and after defl ation of a endotracheal cuff balloon. All patients
also underwent cuff leak volume tests and vocal cord examination by
direct video laryngoscopy. Results The average age was 64.3 ± 17.8 years, APACHE II score
21.0 ± 7.7, and SOFA score 8.4 ± 3.1. Six patients were diagnosed
with A, three with B, two with C, and others had multiple diagnoses. Combinations with NPPV or cricothyroidotomy were also successful. Of the patients who required re-intubation, four were re-intubated
for reasons other than aspiration. Two had possibly aspirated. Among
patients receiving IAPS, the rate of re-intubation due to oropharyngeal
aspiration was 8.3%. No major complication was observed. Results We enrolled 101 patients with planned extubation. The overall
prevalence of post-extubation stridor and/or vocal cord oedema was
17%. Age, gender, duration of intubation and BMI were not diff erent
between patients with and without post-extubation complications. The average sizes of endotracheal tubes were similar in both groups
(No. 7.5). The mean diff erence of increasing of air-column width in
patients without complications was considerably higher than those
with complications (1.9 mm vs. 1.1 mm; P <0.001). The sensitivity
and specifi city at air-column width diff erences ≥1.6 mm were 0.706
and 0.702 respectively. The positive predictive value and negative
predictive value were 0.324 and 0.922. The area under the ROC curve of
tracheal ultrasound was 0.823 (95% CI: 0.698 to 0.947) and that of the
cuff leak volume test was 0.840 (95% CI: 0.715 to 0.964). Conclusion IAPS is a potential method for supraglottic airway
management after extubation that may reduce the re-intubation risk. IAPS is a simple method requiring common instruments. Combined
eff ects of IAPS with NPPV or cricothyroidotomy can modify airway
management. IAPS is a temporary method in which the exact timing
for re-intubation should not be missed. To successfully apply IAPS and
reduce aspiration, the suctioning method, duration of application and
position of the suctioning tube should be further optimized. Conclusion Portable ICU ultrasound visualising air-column width
diff erences between pre and post defl ation cuff balloon is a promising
objective tool which aids in prediction of successful extubation. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 48 hours. All statistical analysis were done using SPSS version 16 and
the diff erences between the groups were assessed using Student’s
t test and the chi-square test. Figure 1 (abstract P131). Intermittent aspiration of pharyngeal secretion. Results Ninety-one patients were included in the analysis – from
December 2010 to June 2011. Mean (± SD) age of the population was
71 ± 12 years, mean APACHE II score was 21 ± 7.6, mean duration of
MV was 2.6 ± 2 days and mean number of spontaneous breathing
trials was 1.3 ± 0.6. Extubation was performed in 33 SA patients (36%)
and 58 SP patients (64%), with a similar success rate of 82% and 85%,
respectively (P >0.05). Furthermore, no signifi cant diff erences between
these groups were found in terms of APACHE II score, time of MV and
postextubation distress or complications. Conclusion The outcomes of proceeding extubation in patients seated
in armchairs are similar to those extubated in supine position with the
head elevated. This new practice can be considered safe and allow
extubations to be performed simultaneously with early mobilization. P130
Prediction of post-extubation failure by portable ICU ultrasound
Y Sutherasan, P Theerawit, T Hongpanat, C Kiatboonsri, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P130 (doi: 10.1186/cc10737) 30
Prediction of post-extubation failure by portable ICU ultrasound
Y Sutherasan, P Theerawit, T Hongpanat, C Kiatboonsri, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P130 (doi: 10.1186/cc10737) Prediction of post-extubation failure by portable ICU ultrasound
Y Sutherasan, P Theerawit, T Hongpanat, C Kiatboonsri, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P130 (doi: 10.1186/cc10737) Figure 1 (abstract P131). Intermittent aspiration of pharyngeal secretion. oropharyngeal secretion, we devised a suctioning method: intermittent
aspiration of pharyngeal secretion (IAPS). IAPS is a simple, low-cost
technique utilizing an intermittent suction unit and a common
suction tube (Figure 1), which may reduce the risk of re-intubation on
extubated patients requiring supraglottic airway management. oropharyngeal secretion, we devised a suctioning method: intermittent
aspiration of pharyngeal secretion (IAPS). IAPS is a simple, low-cost
technique utilizing an intermittent suction unit and a common
suction tube (Figure 1), which may reduce the risk of re-intubation on
extubated patients requiring supraglottic airway management. Methods A retrospective study was performed on 24 patients who
received IAPS after extubation from June 2009 to May 2011. A suction
tube was placed in the pharynx after extubation. The same suction unit
used in intermittent subglottic secretion drainage was applied. IAPS is
eff ective for patients with large amounts of oropharyngeal secretion
(A), patients with poor laryngopharyngeal function (B), and patients
unable to expel viscous sputum (C). Effi cacy of IAPS in each of these
patient groups was studied. Introduction Stridor and vocal cord oedema are common in ICU
patients. Currently, the cuff leak volume test is a standard technique to
assess these complications [1,2]; however, wide variations in terms of
its sensitivity and specifi city have been demonstrated in many studies. Recently, ultrasound is a promising noninvasive method widely used in
ICU patients and allows visualization of the vocal cords and larynx [3]. Thus, we would like to determine the diagnostic accuracy of portable
ultrasound for detection of these post-extubation complications. Methods A retrospective study was performed on 24 patients who
received IAPS after extubation from June 2009 to May 2011. A suction
tube was placed in the pharynx after extubation. The same suction unit
used in intermittent subglottic secretion drainage was applied. IAPS is
eff ective for patients with large amounts of oropharyngeal secretion
(A), patients with poor laryngopharyngeal function (B), and patients
unable to expel viscous sputum (C). Effi cacy of biphasic cuirass ventilation in the critical care
department 1. De Bast Y, De Backer D, Moraine JJ, et al.: The cuff leak test to predict failure
of tracheal extubation for laryngeal edema. Intensive Care Med 2002,
28:1267-1272. T Yamashita1, Y Taniwaki2, H Takayama2, Y Sakamoto1
1Saga University, Saga, Japan; 2National Hospital Organization Nagasaki
Medical Center, Omura, Japan
Critical Care 2012, 16(Suppl 1):P132 (doi: 10.1186/cc10739) 2. Chung YH, Chao TY, Chiu CT, et al.: The cuff -leak test is a simple tool to
verify severe laryngeal edema in patients undergoing long-term
mechanical ventilation. Crit Care Med 2006, 34:409. Introduction Biphasic cuirass ventilation (BCV) assists ventilation by
applying intermittent or continuous negative pressure to the thorax. BCV has been reported to improve lung function in various respiratory
failures. However, to determine the therapeutic eff ect of BCV is diffi cult,
because it is too diffi cult to include animal experiments. Therefore it is
important to compile amounts of clinical cases for discussion. We have
tried to fi nd a way of developing BCV in critical care. 3. Ding LW, Wang HC, Wu HD, et al.: Laryngeal ultrasound: a useful method in
predicting post-extubation stridor. A pilot study. Eur Respir J 2006, 27:384. Introduction Biphasic cuirass ventilation (BCV) assists ventilation by
applying intermittent or continuous negative pressure to the thorax. BCV has been reported to improve lung function in various respiratory
failures. However, to determine the therapeutic eff ect of BCV is diffi cult,
because it is too diffi cult to include animal experiments. Therefore it is
important to compile amounts of clinical cases for discussion. We have
tried to fi nd a way of developing BCV in critical care. Methods This is a retrospective, nonrandomized study. Before and after
BCV, we compared pO2, pCO2, tidal volume, P/F ratio, respiratory index,
A-aDO2, shunt ratio, dead space ventilation rate, and chest X-ray. We
also performed a questionnaire study about BCV which focused on
physicians and nurses working in the ICU. P130
Prediction of post-extubation failure by portable ICU ultrasound
Y Sutherasan, P Theerawit, T Hongpanat, C Kiatboonsri, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P130 (doi: 10.1186/cc10737) Conclusion Portable ICU ultrasound visualising air-column width
diff erences between pre and post defl ation cuff balloon is a promising
objective tool which aids in prediction of successful extubation. References Conclusion Portable ICU ultrasound visualising air-column width
diff erences between pre and post defl ation cuff balloon is a promising
objective tool which aids in prediction of successful extubation. Referencesf P132fi Out-of-bed extubation: changing paradigms Area under receiving operating characteristic
curve for BNP-2 (at the end of spontaneous breathing test) to predict
weaning failure. S47 Intermittent aspiration of pharyngeal secretion for re-intubation
prevention T Nakamura, O Nishida, J Shibata, N Kuriyama, Y Hara, M Yumoto
Fujita Health University School of Medicine, Toyoake, Japan
Critical Care 2012, 16(Suppl 1):P131 (doi: 10.1186/cc10738) Methods This is a retrospective, nonrandomized study. Before and after
BCV, we compared pO2, pCO2, tidal volume, P/F ratio, respiratory index,
A-aDO2, shunt ratio, dead space ventilation rate, and chest X-ray. We
also performed a questionnaire study about BCV which focused on
physicians and nurses working in the ICU. Introduction The inability of extubated patients to clear oropharyngeal
secretion increases the risk of re-intubation. To eliminate excessive S48 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results From April 2008 to May 2010, BCV was performed by applying
RTX (Medivent Ltd, London, UK) for 18 patients admitted to the ICU,
National Hospital Organization Nagasaki Medical Center. All of them
had acute respiratory failure, and 15 of them were intubated and
mechanically ventilated. Thirteen were men, and the mean age was 68
years (1 to 82 years). One case could not continue the treatment due to
discomfort of wearing the cuirass. We used the control mode (negative
pressure –21 cmH2O, positive pressure +7 cmH2O, I:E ratio 1:1). It
improved the tidal volume, P/F ratio, shunt ratio in all cases during
BCV (P <0.05). Skin damage caused by the cuirass was observed in one
case. According to the questionnaire survey, they had some problems
about the durability of the urethane of the cuirass, too close to a thin
body or deformation. Some of them had no confi dence because of
unfamiliarity with the machine. Methods We used the Sensewear Armband (Bodymedia Inc., USA) to
measure the Galvanic Skin Response (GSR) in 11 healthy volunteers (36
to 53 years). The 60-second averages of each test condition were made
after 20 minutes of stabilization. Test conditions were pre and post
baseline (no intervention), 10 cmH2O CPAP (Resmed, Sydney, Australia)
and 15 LPM HFT (TNI, Würzburg, Germany) both in room air. Repeated
ANOVA with P <0.05.if Results There were no statistically signifi cant diff erences in GSR
between pre and post baselines. CPAP produced an increase in GSR
compared to both baselines (45%; P <0.05) and to HFT (41%; P <0.05). HFT produced no signifi cant change in GSR compared to baseline. See
Figure 1. P133f Introduction In emergency medicine, noninvasive ventilation (NIV) has
grown up for COPD and acute pulmonary edema through the use of
continuous positive airway pressure (CPAP). Recently, several studies
have reported the use of NIV coupled with nebulized bronchodilators
to optimize the management of acute asthma patients in emergency
departments and ICUs. This has indicated an improvement in gas
exchanges, decreased lung resistances and decreased work of
breathing. The purpose of this study is to assess prehospital practices
in CPAP for these patients, to target patients for its use, and to compare
clinical data before and after achievement of CPAP with nebulization. Introduction In emergency medicine, noninvasive ventilation (NIV) has
grown up for COPD and acute pulmonary edema through the use of
continuous positive airway pressure (CPAP). Recently, several studies
have reported the use of NIV coupled with nebulized bronchodilators
to optimize the management of acute asthma patients in emergency
departments and ICUs. This has indicated an improvement in gas
exchanges, decreased lung resistances and decreased work of
breathing. The purpose of this study is to assess prehospital practices
in CPAP for these patients, to target patients for its use, and to compare
clinical data before and after achievement of CPAP with nebulization. Methods We have conducted a retrospective, descriptive and
observational study, by collecting all fi les (EMA, Dispatching Center)
for each patient receiving CPAP associated with nebulization, for
pulmonary bronchospasm (excluding acute pulmonary edema),
and supported by the emergency medical service. Several data were
analyzed: age, sex, history, severity signs, cardiac and respiratory rate,
blood pressure, pulse oxymetry, need for intubation, nebulization of
β2-agonists, anticholinergics, intravenous corticosteroids, and arterial
blood gases. Intermittent aspiration of pharyngeal secretion for re-intubation
prevention Conclusion GSR is a measurement of the sympathetic component
of the autonomic nervous system. It is commonly referred to as the
‘Fight or Flight’ response, and when elevated indicates a state of
psychological or physiological stress. Our data suggest that CPAP
produces an increase in the GSR compared to rest, whilst TNI therapy
produces no change in GSR compared to rest. This increased stress may
lead to lower patient compliance when using CPAP therapy compared
to TNI therapy, which has very high patient compliance rates. y
Conclusion We conclude that BCV is also useful for respiratory care in
the ICU. Further confi rmation is needed regarding problems such as
the criteria to start and terminate BCV. References 1. Chari S, King J, Rajesh PB, Stuart-Smith K: Resolution of left lower lobe
collapse postesophagectomy using the Medivent RTX respirator, a novel
noninvasive respiratory support system. J Cardiothorac Vasc Anesth 2004,
18:482-485. 2. Dolmage TE, De Rosie JA, Avendano MA, Goldstein RS: Eff ect of external 2. Dolmage TE, De Rosie JA, Avendano MA, Goldstein RS: Eff ect of external
chest wall oscillation on gas exchange in healthy subjects. Chest 1995, 2. Dolmage TE, De Rosie JA, Avendano MA, Goldstein RS: Eff ect of external
chest wall oscillation on gas exchange in healthy subjects. Chest 1995,
107:433-439. 3. Ciesla ND: Chest physical therapy for patients in the intensive care unit. Phys Ther 1996, 76:609-625. Management of acute bronchospasm respiratory distress with
CPAP ventilation associated with nebulization in the prehospital
emergency setting y
4. Rocker GM, Mckenzie MG, Williams B, Logan PM: Noninvasive positive
pressure ventilation:successful outcome in patients with acute lung
injury/ARDS. Chest 1999, 115:173-177. Management of acute bronchospasm respiratory distress with
CPAP ventilation associated with nebulization in the prehospital
emergency setting
J Cuny, C Berteloot, P Goldstein, E Wiel
CHRU de Lille, France
Critical Care 2012, 16(Suppl 1):P134 (doi: 10.1186/cc10741) g
y
g
J Cuny, C Berteloot, P Goldstein, E Wiel
CHRU de Lille, France
Critical Care 2012, 16(Suppl 1):P134 (doi: 10.1186/cc10741) 5. Hill NS: Clinical applications of body ventilators. Chest 1986, 90:897. 5. Hill NS: Clinical applications of body ventilators. Chest 1986, 90:897. P135
Diff erence between continuous positive airway pressure via mask
therapy plus chest physiotherapy (CPT) and incentive spirometry
therapy plus CPT to treat or prevent acute atelectasis after cardiac
surgery
F ALMutairi1, S Fallows1, W Abukhudair2, B Islam2
1University of Chester, Manchester, UK; 2King Fahd Armed Forces Hospital,
Jeddah, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P135 (doi: 10.1186/cc10742) P135
Diff erence between continuous positive airway pressure via mask
therapy plus chest physiotherapy (CPT) and incentive spirometry
therapy plus CPT to treat or prevent acute atelectasis after cardiac
surgery
F ALMutairi1, S Fallows1, W Abukhudair2, B Islam2
1University of Chester, Manchester, UK; 2King Fahd Armed Forces Hospital,
Jeddah, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P135 (doi: 10.1186/cc10742) g
y
F ALMutairi1, S Fallows1, W Abukhudair2, B Islam2
1University of Chester, Manchester, UK; 2King Fahd Armed Forces Hospital,
Jeddah, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P135 (doi: 10.1186/cc10742) Introduction All types of therapy such as an incentive spirometry (IS)
or continuous positive airway pressure (CPAP) have a valuable role to
play in the prevention or the treatment of acute atelectasis. However,
the type of therapy that should be used is not yet completely clear. This study aims to clarify the diff erence in eff ectiveness between CPAP
therapy plus chest physiotherapy (CPT) and IS therapy plus CPT to treat
or prevent acute atelectasis. Results The paO2 was highest under NIV with 129 ± 38 mmHg, followed
by NHFO2 (101 ± 34 mmHg, P <0.01 vs. NIV) and VM (85 ± 21 mmHg,
P <0.001 vs. NIV, P <0.01 vs. NHFO2, ANOVA). All other vital and blood
gas parameters did not show signifi cant diff erences. Dyspnea rating on
a 10-point Borg scale was signifi cantly better under NHFO2 (2.9 ± 2.1)
and VM (3.3 ± 2.3) compared to NIV (5.0 ± 3.3) (P <0.05, vs. NHFO2
or VM). Comfort rating showed similar results: NHFO2 2.7 ± 1.8; VM
3.1 ± 2.8; NIV 5.4 ± 3.1 (P <0.05, NIV vs. NHFO2 or VM). In the fi nal global
rating using German school grades from 1 to 6 NHFO2 also received
the best rating (2.3 ± 1.4), followed by VM (3.2 ± 1.7, P = NS vs. NHFO2)
and NIV (4.5 ± 1.7, P <0.01 vs. NHFO2 and P <0.05 vs. VM). For further
treatment 10 patients chose NHFO2, three VM and one NIV. Methods Seventy-two patients who fi t the inclusive criteria (smoker,
hemodynamically stable, normal lung and above 50 years old)
participated in this study. The participants were divided randomly
into two groups: the control group used IS 15 times per hour plus CPT
4 hours for 3 days, and the trial group used CPAP via mask therapy for
half an hour every 2 hours plus CPT 4 hours. Short-term eff ect of humidifi ed high nasal fl ow oxygen in critically
ill patients p
F Van Beers, A Van Hees, J Van Rosmalen, D Ramnarain
St Elisabeth Hospital Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P137 (doi: 10.1186/cc10744) if
Conclusion Adding chest physiotherapy to CPAP via mask therapy had
better outcomes to treat or prevent acute postoperative atelectasis. P136
Nasal high-fl ow oxygen in patients with hypoxic respiratory
failure: eff ect on functional and subjective respiratory parameters
compared to conventional oxygen therapy and noninvasive
ventilation
R Riessen, N Schwabbauer, B Berg, G Blumenstock, M Haap, J Hetzel
University Hospital Tübingen, Germany
Critical Care 2012, 16(Suppl 1):P136 (doi: 10.1186/cc10743)
Introduction This study compared a nasal high flow oxygen therapy
Figure 1 (abstract P135). Eff ect of adding CPT to CPAP via mask therapy
to treat acute atelectasis. Figure 1 (abstract P135). Eff ect of adding CPT to CPAP via mask therapy
to treat acute atelectasis. Figure 1 (abstract P135). Eff ect of adding CPT to CPAP via mask therapy
to treat acute atelectasis. Introduction Recently, humidifi ed high-fl ow nasal cannula oxygen
(HFNC) has gained popularity in treating patients with acute respiratory
insuffi ciency. Studies have shown that HFNC generates a low level of
positive airway pressure, reduction of airway resistance and fl ushes
nasopharyngeal dead space leading to less work of breathing. However,
in which type of patient HFNC could be of benefi t, the short-term as
well as long-term eff ects, tolerance and outcome are unknown. We used
HFNC in a variety of patients. We evaluated the short-term eff ect of HFNC. Methods We retrospectively studied respiratory, oxygen-derived and
hemodynamic parameters before and 1 hour after start of HFNC in 50
patients during the past 12 months. All patients were treated in a mixed
medical, surgical, neurological ICU of a teaching hospital. The HFNC
used consisted of an air–oxygen blender with adjustable FiO2 (0.21 to
1.0), delivering a modifi able gas fl ow up to 60 l/minute (Optifl ow; Fisher
& Paykel, Auckland, New Zealand). y
Results Fifty patients were included, 29 men and 21 women, mean
age 65 ± 14, mean APACHE II score on admission 19 ± 5.9. The mean
duration of HFNC was 22 ± 21 hours. Diff erences in neurophysiologic eff ects between CPAP and a novel
high-fl ow therapy systemfi fi
Special Care Technologies, Banbury, UK y
Critical Care 2012, 16(Suppl 1):P133 (doi: 10.1186/cc10740) Critical Care 2012, 16(Suppl 1):P133 (doi: 10.1186/cc10740) Introduction CPAP therapy for respiratory insuffi ciency is an established
and accepted mode of therapy; however, patient compliance remains
an issue. Recent studies have shown that high-fl ow therapy (HFT),
which uses high fl ows of warmed and humidifi ed air/O2 mixtures
through a nasal cannula, can also be eff ective in treating respiratory
insuffi ciency. Although a nasal cannula is commonly preferred over a
CPAP mask, patient comfort with HFT and CPAP has not been measured
empirically. We sought to examine the autonomic neurophysiologic
responses as a measure of comfort between these therapies. Methods We have conducted a retrospective, descriptive and
observational study, by collecting all fi les (EMA, Dispatching Center)
for each patient receiving CPAP associated with nebulization, for
pulmonary bronchospasm (excluding acute pulmonary edema),
and supported by the emergency medical service. Several data were
analyzed: age, sex, history, severity signs, cardiac and respiratory rate,
blood pressure, pulse oxymetry, need for intubation, nebulization of
β2-agonists, anticholinergics, intravenous corticosteroids, and arterial
blood gases. Figure 1 (abstract P133). g
Results Over an 18-month period, 21 patients were enrolled: 38% for
severe asthma, and 62% for COPD exacerbation. Regarding the history:
67% were under long-term corticosteroid, 48% smokers, 29% received
antibiotics, and all of them presented a clinical bronchospasm, and
severity criteria for respiratory distress. Sixty percent of patients were
hypoxic (SpO2 <92%). All patients received salbutamol inhalation,
associated with inhaled anticholinergic agent in 71.4%. Intravenous
glucocorticoid drug was dispensed in 71.4% and intravenous
salbutamol in 23.8%. None of the asthma patients was intubated, fi ve
COPD patients (24.8%) were intubated. Twelve patients were admitted
to the ICU (one with asthma and 11 with COPD). Comparison of clinical
parameters between prehospital care and the emergency room shows
a signifi cant diff erence (P <0.05) for respiratory rate (35.9 ± 7.48 vs. 24.95 ± 8.25) and pulse oxymetry (81.8 ± 15.8 vs. 96.4 ± 3.54). Conclusion NIV through CPAP associated with nebulizations appears
to provide benefi t by reducing respiratory work (decreased respiratory
rate) and improving alveolar ventilation (increased SpO2) in patients
with asthma. However, in COPD patients, no improvement of symptoms
has been observed. P135
Diff erence between continuous positive airway pressure via mask
therapy plus chest physiotherapy (CPT) and incentive spirometry
therapy plus CPT to treat or prevent acute atelectasis after cardiac
surgery
F ALMutairi1, S Fallows1, W Abukhudair2, B Islam2
1University of Chester, Manchester, UK; 2King Fahd Armed Forces Hospital,
Jeddah, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P135 (doi: 10.1186/cc10742) The inspiratory capacity
(IC) in liters was used to compare the two groups of therapy and it was
measured by incentive spirometer after the operation as baseline test,
after 12 hours, 24 hours, 48 hours and post therapy. At the same time,
RR, HR and SpO2 were measured for both groups. Failure was defi ned as
a need for advanced therapy. 2
Conclusion NHFO2 is a promising new device for oxygen supply in
respiratory failure, off ering better oxygenation than the VM and better
patient comfort and tolerance than NIV. Results Thirty-six patients participated in each group (57 male and 15
female). IC was increased signifi cantly in the CPAP group (P = 0.005) and
SpO2 was decreased signifi cantly in the control group (P = 0.037). There
were no signifi cant diff erences in RR and HR. See Figure 1. Diff erences in neurophysiologic eff ects between CPAP and a novel
high-fl ow therapy systemfi Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S49 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P135f Methods We included 14 patients with hypoxic respiratory failure
(paO2 <55 mmHg under room air). Exclusion criteria were ventilatory
failure, hemodynamic instability, cardiogenic pulmonary edema, NIV
contraindications and inability to cooperate. Patients were treated
in a randomized order for 30 minutes each with NHFO2 (Optifl ow®;
Fisher-Paykel), VM or NIV, using a FiO2 of 0.6. Every treatment phase was
preceded by a 15-minute baseline phase in which the patients received
oxygen via a standard nasal prong (SaO2 goal >88%). At the end of
each treatment phase vital signs and blood gases were measured and
patients rated their dyspnea and their general comfort on a 10-point
scale. Finally, patients were ask for a global rating of all three devices
ranging from 1 (very good) to 6 (failed) and could choose one device
for further treatment. Short-term eff ect of humidifi ed high nasal fl ow oxygen in critically
ill patients Indications for HFNC could be
divided into fi ve categories: (1) no acceptance of noninvasive positive
pressure ventilation (NPPV) (n = 8), (2) weaning from NPPV, (3) hypoxia
(n = 14), (4) respiratory distress/discomfort (n = 9), and (5) other (n = 5). Despite the use of HFNC, in 15 patients intubation was unavoidable;
group 1, n = 8, group 3, n = 6, group 4, n = 1. Oxygen saturation
increased from 91 ± 7.2 to 97.5 ± 1.7 (P ≤0.05). PaO2/FiO2 ratio increased
from 140 ± 79.1 to 169.8 ± 68 (P ≤0.05). PCO2 decreased from 6.5 ± 3.0
to 6.2 ± 2.9 mmHg (P ≤0.05). No signifi cant diff erences were seen in
heart rate, blood pressure and respiratory rate. Ten patients died, in
eight patients of which the policy was not to reanimate and not to
be intubated due to extensive comorbidity. Two patients died during
treatment in the ICU due to underlying disease. P139 The group that was in need of endotracheal intubation showed
a less prominent response to 1-hour HNF therapy, expressed in PaO2
(13.2 ± 2.6 kPa vs. 16.1 ± 3.4 kPa, P = 0.548), saturation (94.4 ± 1.6%
vs. 96.5 ± 0.8%, P = 0.228) and breathing frequency (25 ± 2.4/minute
vs. 22 ± 2/minute, P = 0.357). The duration of HNF therapy was
26.1 ± 6.3 hours in the nonintubated group and 15.1 ± 9.8 hours for
those who were intubated (P = 0.345). fi
Methods A prospective observational study during a 6-month period
in patients ≥18 years with acute hypoxic respiratory failure when
conservative oxygen therapy (15 l/minute) failed. Arterial blood gas
analysis was done before HNF therapy and after 1 hour on fl ow 50 l/
minute with FiO2 1.0. Breaths per minute and saturation were noted. When patients remained respiratory insuffi cient they were intubated. Methods All intubated patients who were admitted to the Ipswich
Hospital ICU between April and December 2010 were identifi ed and
data relating to basic demographics, airway management and the use
of capnography were collected. An airway was classed as diffi cult if
there were two or more attempts at intubation, a bougie was used, or
it was Cormack–Lehane grade III/IV. Complications arising from airway
intubation were also noted. Results A total of 139 intubations on 118 patients were identifi ed. Fifty-eight (42%) intubations occurred on the ICU, 41 (29%) in the
emergency department (ED) and fi ve (4%) on the ward; 29 (21%)
intubations occurred in theatre for surgery and six (4%) out of hospital. Of the 104 intubations on the ICU, ED or ward, nine (9%) were classed as
diffi cult and there were 21 (20%) documented complications (hypoxia,
hypotension, oesophageal intubation, cardiac arrest and aspiration). Complication rates were similar across junior trainees, senior trainees
and consultants. Only 27% of all intubated patients received continuous
capnography. g
y
Conclusion Our fi ndings are consistent with the NAP4 view that airway
management outside the controlled confi nes of a theatre setting has
the potential to be more diffi cult. Steps should be taken to minimise
the risk associated with this procedure, including a thorough airway
assessment, use of continuous capnography and the presence of
suitably trained operators and assistants. P139 P139
An audit of airway complications in a district general hospital ICU
JW Chan, KJ Turner, R Lloyd, R Howard-Griffi n
Ipswich Hospital NHS Trust, Ipswich, UK
Critical Care 2012, 16(Suppl 1):P139 (doi: 10.1186/cc10746) Good response on high nasal oxygen fl ow reduces the need for
intubation in adult respiratory failure
L Van Wagenberg, IM Hoekstra, GC Admiraal, M Slabbekoorn
Medisch Centrum Haaglanden, Den Haag, the Netherlands
Critical Care 2012, 16(Suppl 1):P138 (doi: 10.1186/cc10745) Good response on high nasal oxygen fl ow reduces the need for
intubation in adult respiratory failure Introduction The 4th National Audit Project of The Royal College of
Anaesthetists and The Diffi cult Airway Society (NAP4) highlighted
the increased incidence of airway-related complications in an ICU
setting [1]. The aim of this audit was to establish our local ICU airway
intubation complication rate as well as our compliance with the NAP4
recommendation that continuous capnography should be used on all
intubated patients. Introduction High nasal fl ow (HNF) therapy has proven its effi ciency
in acute respiratory failure when compared to conservative oxygen
therapy [1]. This study was performed to fi nd a responding and
nonresponding group on HNF therapy in adults with hypoxic respiratory
insuffi ciency measured by oxygenation and work of breathing. fi
y
y
yg
g
Methods A prospective observational study during a 6-month period
in patients ≥18 years with acute hypoxic respiratory failure when
conservative oxygen therapy (15 l/minute) failed. Arterial blood gas
analysis was done before HNF therapy and after 1 hour on fl ow 50 l/
minute with FiO2 1.0. Breaths per minute and saturation were noted. When patients remained respiratory insuffi cient they were intubated. Results A total of 20 patients was included. Mean age 63.95 ± 3 years
and APACHE II score 23 ± 7. Mean PaO2/FiO2 (P/F) ratio on admission was
77.7 ± 4.2. A total of seven out of 20 patients (35%) needed endotracheal
intubation. After 1 hour of HNF therapy PaO2 and saturation measured
in arterial blood gas signifi cantly increased from respectively 8.9 ± 0.3
kPa to 16.1 ± 2.4 kPa (P = 0.023) and from 91.8 ± 1.2% to 96.5 ± 0.8%
(P = 0.001). Work of breathing, measured by the frequency of breathing,
signifi cantly decreased from 35 ± 3 times a minute to 22 ± 2 times a
minute. Multidisciplinary care for patients with tracheostomy shortened
time to decannulation A Van Hees, F Van Beers, J Van Rosmalen, D Ramnarain,
W Van den Wildenberg
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P140 (doi: 10.1186/cc10747) A Van Hees, F Van Beers, J Van Rosmalen, D Ramnarain,
W Van den Wildenberg
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P140 (doi: 10.1186/cc10747) Introduction Care for cannulated patients in our hospital is not uniform
and clear, leading to an unnecessarily long period of cannulation and
even unsafe situations. Therefore our hospital formed a specialized
multidisciplinary cannula team (SMCT) consisting of an intensivist,
three ventilation practitioners and a registered nurse. The aim of this
team was to shorten the period of cannulation and to guarantee
uniform care and safety around cannulated patients in our ICU and on
the ward. Methods The study was conducted in the mixed medical and
neurosurgical ICU of a teaching hospital with a duration of 22
months. Two groups of patients were studied. Group one received
PDT before introduction of a SMCT (n = 49) and group two received
PDT (n = 27) after introduction of a SMCT. During treatment in the ICU
and after discharge, all patients were followed by the cannula team. This team eventually made the decision to decannulate the patients. We evaluated the results of a multidisciplinary cannula team (SMCT)
during a follow-up period of 22 months. Results For patient data see Table 1. Seventy-six patients were included
in this study. The study showed a reduction in time to decannulation
after a mechanical ventilation period of 8.4 days. However clinically
relevant, this was not statistically signifi cant. Methods The study was conducted in the mixed medical and
neurosurgical ICU of a teaching hospital with a duration of 22
months. Two groups of patients were studied. Group one received
PDT before introduction of a SMCT (n = 49) and group two received
PDT (n = 27) after introduction of a SMCT. During treatment in the ICU
and after discharge, all patients were followed by the cannula team. This team eventually made the decision to decannulate the patients. We evaluated the results of a multidisciplinary cannula team (SMCT)
during a follow-up period of 22 months. Figure 1 (abstract P138). PaO2 after 1-hour HNF therapy. Figure 1 (abstract P138). PaO2 after 1-hour HNF therapy. Results For patient data see Table 1. Seventy-six patients were included
in this study. P140 Multidisciplinary care for patients with tracheostomy shortened
time to decannulation
A Van Hees, F Van Beers, J Van Rosmalen, D Ramnarain,
W Van den Wildenberg
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P140 (doi: 10.1186/cc10747) P139 The fi nding that complications
occurred at a similar rate regardless of the seniority could be explained
by more senior staff intubating the most unwell patients. Reference Conclusion All included patients did have a reduced P/F ratio and are
therefore to be considered severely respiratory compromised. PaO2
and saturation increased with the use of HNF therapy, while work
of breathing decreased. These changes were less prominent in the
nonresponding group (Figure 1). The nonresponders, except one, were
intubated within 15 hours after the start of HNF therapy. Reference 1. Cook TM, et al.: Br J Anaesth 2011, 106:632-642. 1. Cook TM, et al.: Br J Anaesth 2011, 106:632-642. 1. Roca et al.: Respir Care 2010, 55:408-413. 1. Roca et al.: Respir Care 2010, 55:408-413. Figure 1 (abstract P138). PaO2 after 1-hour HNF therapy. P136 P136
Nasal high-fl ow oxygen in patients with hypoxic respiratory
failure: eff ect on functional and subjective respiratory parameters
compared to conventional oxygen therapy and noninvasive
ventilation
R Riessen, N Schwabbauer, B Berg, G Blumenstock, M Haap, J Hetzel
University Hospital Tübingen, Germany
Critical Care 2012, 16(Suppl 1):P136 (doi: 10.1186/cc10743) P136
Nasal high-fl ow oxygen in patients with hypoxic respiratory
failure: eff ect on functional and subjective respiratory parameters
compared to conventional oxygen therapy and noninvasive
ventilation R Riessen, N Schwabbauer, B Berg, G Blumenstock, M Haap, J Hetzel
University Hospital Tübingen, Germany
Critical Care 2012, 16(Suppl 1):P136 (doi: 10.1186/cc10743) Conclusion We used HFNC therapy for a variety of indications. In 70% of
our study population HFNC was successful. Oxygen-derived parameters
signifi cantly increased after 1 hour of HFNC. HFNC was successful and
well tolerated in patients weaning from NPPV. After noncompliance of
NPPV in 42% of patients in our population, intubation could be avoided
with the use of HFNC. Introduction This study compared a nasal high-fl ow oxygen therapy
(NHFO2) with conventional oxygen therapy via a Venturi mask (VM)
or noninvasive ventilation (NIV) in patients with hypoxic respiratory
failure. Study endpoints were functional respiratory parameters,
dyspnea, patient comfort and a global rating by the patients. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S50 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P138 Infl uence of percutaneous tracheostomy on gas exchange in
mechanically ventilated patients Introduction The infl uence of percutaneous tracheostomy on patients’
ventilator-dependency and clinical outcomes has been deeply
investigated [1]. However, except for immediate intraprocedural
variations [2], tracheostomy’s impact on gas exchange has scarcely
been explored. The aim of the present study is to investigate the
persisting eff ects of percutaneous tracheostomy on pulmonary
function in a group of ICU-admitted patients. Conclusion PDT is an extremely safe procedure when performed by
an experienced intensivist under bronchoscopic guidance. Our low
complication rate is due to careful screening and selection of patients
and being performed or supervised by an experienced intensivist
under direct vision. Methods Clinical records of 107 patients from San Gerardo Hospital
General and neurosurgical ICUs that underwent a percutaneous
tracheostomy were retrospectively revised to compare ventilator
settings, gas exchange and hemodynamic parameters on the day
before and on the day after the procedure. For each parameter we
averaged the values of three diff erent recordings during the day. A
pre-established subgroup analysis on the hypoxemic (PaO2/FiO2 <300
mmHg) patients (n = 38) was performed. Analyses were performed by
paired t test and linear regression; a level of P <0.05 was considered
statistically signifi cant. P143 1.
Terragni PP, et al.: JAMA 2010, 303:1483-1489. Risk factors for poor outcome in patients with osmotic
demyelination syndrome y
y
MA Peters1, JG Van der Hoeven2, C Hoedemaekers2
1Canisius Wilhemina Hospital, Nijmegen, the Netherlands; 2Radboud
University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P143 (doi: 10.1186/cc10750) y
y
MA Peters1, JG Van der Hoeven2, C Hoedemaekers2
1Canisius Wilhemina Hospital, Nijmegen, the Netherlands; 2Radboud
University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P143 (doi: 10.1186/cc10750) MA Peters1, JG Van der Hoeven2, C Hoedemaekers2
1Canisius Wilhemina Hospital, Nijmegen, the Netherlands; 2Radboud
University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P143 (doi: 10.1186/cc10750) y
gi
Results Among all analyzed patients, we found, after tracheostomy, a
marginal decrease in PaCO2 (43 ± 9 vs. 42 ± 8 mmHg, before vs. after
P <0.01) and increase in pH (7.43 ± 0.04 vs. 7.44 ± 0.03 mmHg, before vs. after P <0.01), with no variation in PaO2/FiO2. Considering the subgroup
of hypoxemic patients, despite unchanged ventilator parameters, after
the tracheostomy a higher PaO2/FiO2 (222 ± 60 mmHg vs. 256 ± 84
mmHg, before vs. after P <0.01) and a lower PaCO2 (46 ± 11 vs. 43 ± 9
mmHg, before vs. after P <0.01) were found. For hypoxemic patients,
a positive correlation was found between PaCO2 on the day before
tracheostomy and the decrease of PaCO2 (r2 = 0.29; P <0.01). Moreover,
taking in account the subgroup of hypoxemic patients under pressure
support ventilation (n = 28), the PaCO2 decrease was loosely but
signifi cantly correlated with the pressure support level on the day
before the procedure (r2 = 0.25; P <0.01). Introduction The osmotic demyelination syndrome (ODS) is a
devastating complication of rapid correction of hyponatremia. The
objective of this study was to identify prognostic factors that determine
outcome in patients with ODS. outcome in patients with ODS. Methods We performed a literature search using MEDLINE and Embase. Case reports or case series were eligible for this study in cases of: (1)
hyponatremia defi ned as a serum sodium ≤130 mEq/l on hospital
admission or thereafter, but preceding the clinical signs of ODS; (2) a
clear diagnosis of ODS, confi rmed by MRI scanning or pathology; and
(3) a description of patient outcome. We defi ned a favourable outcome
as a Glasgow Outcome Score >3 or a Modifi ed Rankin Scale <4. Results A total of 120 manuscripts were identifi ed describing 125 cases:
86/125 (69%) had a favourable outcome. 2.
Benini A, et al.: Intensive Care Med 2002, 28:726-730. P142
Bronchoscope-guided percutaneous dilatational tracheostomy
performed by an experienced intensivist: a 26-month experience at
a tertiary care center in United Arab Emirates y
M Rahman, R Ammar, D Abdullah, F Chedid, S Abuhasna
Tawam Hospital, Al Ain, United Arab Emirates
Critical Care 2012, 16(Suppl 1):P142 (doi: 10.1186/cc10749) Introduction Bedside percutaneous dilatational tracheostomy (PDT)
is a safe procedure with an acute complication rate of 10 to 15%. Our hypothesis was that having an experienced person performing
or supervising the procedure results in extremely low complications
with PDT. We formed a tracheostomy team which always included at
least a consultant or specialist experienced (at least 25 procedures) in
performing the procedure. Methods A retrospective chart review of all patients who had PDT in a
multidisciplinary adult medical surgical ICU during November 2008 to
December 2010. The patients’ demographics, indications for intubation
and PDT, early and late complications, date weaned off the ventilator,
date of decannulation, discharge from ICU and hospital, and outcome
of these patients in the hospital were noted. Conclusion With the introduction of a SMCT a clinically relevant
reduction of cannulation period could be achieved. The group was
small and probably underpowered to show a statistically signifi cant
reduction in the cannulation period. p
p
Results Out of a total of 2,364 admission 57 patients underwent PDT,
all with bronchoscopic guidance by an intensivist experienced in PDT
(>25 procedures); there were 45 (78.9%) males and 12 (21%) females
with the median age of 42 (range 18 to 90) years. The most common
admission diagnosis was cardiac arrest n = 14 (24%) followed by severe
head injury n = 13(23%) and cerebrovascular accident n = 8 (14%). The
commonest indication for tracheostomy was airway protection n = 40
(73%) followed by prolonged mechanical ventilation n = 25 (45%). The
median duration of intubation before PDT was 11 days (IQ 8 to 18). The
median time elapsed between tracheostomy and weaning of ventilator
was 1 day (IQ 1 to 3). However, the median time to decannulation was
37 day (IQ 10 to 136). Acute complication of paratracheal insertion
occurred in n = 1 (1.8%) patient. No deaths were reported related
to the procedure. However, n = 13 (22.8%) patients died during the
hospital stay. No procedure was converted to surgical tracheostomy. The median duration between tracheostomy and discharge from ICU
was 12 days (IQ 5 to 21). Chronic complication of subglottic stenosis
occurred in n = 1 (1.8%) patient. Multidisciplinary care for patients with tracheostomy shortened
time to decannulation The study showed a reduction in time to decannulation
after a mechanical ventilation period of 8.4 days. However clinically
relevant, this was not statistically signifi cant. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S51 Conclusion With the introduction of a SMCT a clinically relevant
reduction of cannulation period could be achieved. The group was
small and probably underpowered to show a statistically signifi cant
reduction in the cannulation period. Table 1 (abstract P140). Results of comparative analysis between patients
before and after the cannula team
Pre-cannula
Post-cannula
team (n = 49)
team (n = 27)
Age (years)
52.2 ± 16.3
56.4 ± 16.8
APACHE II score
20.9 ± 5.2
21.4 ± 5.7
Intubated days before tracheostomy
12.8 ± 7.9
9.9 ± 7.3
Length of stay in ICU
34.1 ± 4.7
36.6 ± 28.9
Cannulation days
22 ± 15.4
20 ± 0.7
Mechanical ventilation after tracheostomy
9.3 ± 7.4
9.1 ± 9
Tracheostomy after mechanical ventilation
18.2 ± 27.7
9.8 ± 9.5 Table 1 (abstract P140). Results of comparative analysis between patients
before and after the cannula team P142
Bronchoscope-guided percutaneous dilatational tracheostomy
performed by an experienced intensivist: a 26-month experience at
a tertiary care center in United Arab Emirates
M Rahman, R Ammar, D Abdullah, F Chedid, S Abuhasna
Tawam Hospital, Al Ain, United Arab Emirates
Critical Care 2012, 16(Suppl 1):P142 (doi: 10.1186/cc10749) P142
Bronchoscope-guided percutaneous dilatational tracheostomy
performed by an experienced intensivist: a 26-month experience at
a tertiary care center in United Arab Emirates P142
Bronchoscope-guided percutaneous dilatational tracheostomy
performed by an experienced intensivist: a 26-month experience at
a tertiary care center in United Arab Emirates P141
Infl uence of percutaneous tracheostomy on gas exchange in
mechanically ventilated patients
A Pradella1, G Bellani1, S Abd El Aziz El Sayed Deab1, T Mauri1, E Rezoagli1,
S Arrigoni1, F Leone1, G Citerio2, A Pesenti1
1University of Milano-Bicocca, Monza, Italy; 2San Gerardo Hospital, Monza,
Italy
Critical Care 2012, 16(Suppl 1):P141 (doi: 10.1186/cc10748) Risk factors for poor outcome in patients with osmotic
demyelination syndrome The highest sodium concentration after correction was
signifi cantly higher in the patients with a poor outcome (139.0 ± 9.3
vs. 134.0 ± 7.3, P = 0.003). Serum osmolality, and concentrations of
potassium, chloride, creatinin and glucose were comparable between
the outcome groups. The development of tetraparesis (55/125 (44%),
P = 0.02) or a decreased level of consciousness (58/125 (46%), P <0.001)
were associated with a poor outcome. In contrast, mutism or dysarthria
(82/125 (66%), P = 0.002), tremors (29/125 (23%), P = 0.001) or ataxia
(58/125 (46%), P <0.001) were associated with a favourable outcome. Conclusion The highest serum sodium concentration during sodium
correction rather than the speed of sodium correction or severity of
the hyponatremia is a determinant of outcome in patients with ODS. The development of tetraparesis and decreased consciousness are
associated with a poor outcome in these patients. patients. We investigated the epidemiology of dysnatremia in a large
cohort of surgical ICU patients and evaluated the possible infl uence
of the time of acquisition of dysnatremia and fl uctuations in serum
sodium concentrations on hospital mortality in these patients. out of 125 (34%) of cases were associated with alcohol abuse, 14/125
(11%) with malnutrition, 26/125 (21%) with use of diuretics and 9/125
(7%) with use of psychoactive medication; none of these characteristics
were signifi cantly related to outcome. The sodium concentration on
admission was 107.3 ± 9.6 in the patients with a favourable outcome
versus 108.4 ± 9.4 in the patients with a poor outcome (P = 0.54). The
speed of sodium correction was 1.12 ± 1.6 mmol/hour versus 1.16 ± 0.9
mmol/hour respectively in the favourable and poor outcome cases
(P = 0.19). The highest sodium concentration after correction was
signifi cantly higher in the patients with a poor outcome (139.0 ± 9.3
vs. 134.0 ± 7.3, P = 0.003). Serum osmolality, and concentrations of
potassium, chloride, creatinin and glucose were comparable between
the outcome groups. The development of tetraparesis (55/125 (44%),
P = 0.02) or a decreased level of consciousness (58/125 (46%), P <0.001)
were associated with a poor outcome. In contrast, mutism or dysarthria
(82/125 (66%), P = 0.002), tremors (29/125 (23%), P = 0.001) or ataxia
(58/125 (46%), P <0.001) were associated with a favourable outcome. sod u
co ce t at o s o
osp ta
o ta ty
t ese pat e ts. Impact of ketogenesis and strong ion diff erence on acid–base in our
CICU The administration
of large volumes of chloride-rich fl uids (as may occur during cardiac
surgery to prime the cardiopulmonary bypass circuit or resuscitate
the patient) is known to induce hyperchloraemic metabolic acidosis
[1]. Using simplifi cations of the original Fencl–Stewart’s equations,
it is possible to partition the base defi cit into its constituent parts,
subsequently determining the relative contribution of chloride,
albumin and unmeasured anions to acidosis [2,3]. Ketone production
may contribute signifi cantly to the unmeasured anion component. Methods A prospective cohort analysis. Fifty postoperative cardiac
patients were recruited. For each we measured urinary ketones three
times per day for the fi rst 48 hours of their CICU admission. Arterial
blood gas (ABG) data were recorded in conjunction each time. For
each blood gas we partitioned the base defi cit into its constituent
components using previously published equations [1-3]. Results A total of 231 ABGs were analysed Urinary ketones were Conclusion We found no evidence that increased ADH secretion would
explain low sodium levels in Legionella patients, or other pneumonia
patients, challenging the common believe of Legionella causing
SIADH. Rather, ADH precursors were upregulated as a response to
severe disease. Future studies continuing to explore the cause of
sodium disturbance in Legionella are warranted. yi
y
Methods A prospective cohort analysis. Fifty postoperative cardiac
patients were recruited. For each we measured urinary ketones three
times per day for the fi rst 48 hours of their CICU admission. Arterial
blood gas (ABG) data were recorded in conjunction each time. For
each blood gas we partitioned the base defi cit into its constituent
components using previously published equations [1-3]. Risk factors for poor outcome in patients with osmotic
demyelination syndrome Mean age in the favourable
outcome group was 44.7 ± 14.4 years versus 52.3 ± 13.6 years in the
poor outcome group (P = 0.006). The ODS was exclusively pontine in
44/125 (35%), extrapontine in 34/125 (37%) and combined pontine
and extrapontine in 47/125 (37%) of cases. The anatomical localisation
of the lesion was not associated with outcome (P = 0.64). Forty-two Methods We performed a literature search using MEDLINE and Embase. Case reports or case series were eligible for this study in cases of: (1)
hyponatremia defi ned as a serum sodium ≤130 mEq/l on hospital
admission or thereafter, but preceding the clinical signs of ODS; (2) a
clear diagnosis of ODS, confi rmed by MRI scanning or pathology; and
(3) a description of patient outcome. We defi ned a favourable outcome
as a Glasgow Outcome Score >3 or a Modifi ed Rankin Scale <4.i gi
Results A total of 120 manuscripts were identifi ed describing 125 cases:
86/125 (69%) had a favourable outcome. Mean age in the favourable
outcome group was 44.7 ± 14.4 years versus 52.3 ± 13.6 years in the
poor outcome group (P = 0.006). The ODS was exclusively pontine in
44/125 (35%), extrapontine in 34/125 (37%) and combined pontine
and extrapontine in 47/125 (37%) of cases. The anatomical localisation
of the lesion was not associated with outcome (P = 0.64). Forty-two p
Conclusion In a relatively large cohort of mechanically ventilated
patients, percutaneous tracheostomy seems to increase the carbon
dioxide elimination. This eff ect was even more pronounced in the
subgroup of hypoxic patients, in whom also oxygenation improved. References S52 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 out of 125 (34%) of cases were associated with alcohol abuse, 14/125
(11%) with malnutrition, 26/125 (21%) with use of diuretics and 9/125
(7%) with use of psychoactive medication; none of these characteristics
were signifi cantly related to outcome. The sodium concentration on
admission was 107.3 ± 9.6 in the patients with a favourable outcome
versus 108.4 ± 9.4 in the patients with a poor outcome (P = 0.54). The
speed of sodium correction was 1.12 ± 1.6 mmol/hour versus 1.16 ± 0.9
mmol/hour respectively in the favourable and poor outcome cases
(P = 0.19). Impact of ketogenesis and strong ion diff erence on acid–base in our
CICU Impact of ketogenesis and strong ion diff erence on acid–base in our
CICU
T Clark, B McGrath, P Murphy, M Jayarajah
Derriford Hospital, Plymouth, UK
Critical Care 2012, 16(Suppl 1):P146 (doi: 10.1186/cc10753) yp
g
p
Methods We measured CT-ProVasopressin and sodium levels in
a prospective cohort of 925 pneumonia patients from a previous
multicenter study with 31 patients having positive antigen tests for
Legionella pneumophilia. We calculated Spearman rank correlations
and multivariate regression models. T Clark, B McGrath, P Murphy, M Jayarajah
Derriford Hospital Plymouth UK Results Legionella patients had higher rates of hyponatremia
(sodium <130 mmol/l) (43% vs. 8%, P <0.01), but similar median CT-
ProVasopressin levels (pmol/l) (20 (12 to 26) vs. 26 (13 to 53), P = 0.89)
compared to pneumonia of other etiology. In Legionella patients, high
CT-ProVasopressin was not associated with low sodium levels, but
showed a positive correlation with sodium levels (r = 0.42, P <0.05). Independent of pneumonia etiology, CT-ProVasopressin were
signifi cantly correlated with the pneumonia severity index (r = 0.56,
P <0.05) and showed an association with risk for ICU admission (odds
ratio per decile, 95% CI) (1.4, 1.2 to 1.6) and 30-day mortality (1.3, 1.2
1.4). Introduction Persistence of a mild metabolic acidosis or base defi cit
was occasionally observed in our otherwise well patients post cardiac
surgery, sometimes delaying discharge. We hypothesised that this
metabolic abnormality may be due to either ketogenesis caused by a
combination of starvation and the surgical stress response, or strong
ion imbalances following fl uid administration. The administration
of large volumes of chloride-rich fl uids (as may occur during cardiac
surgery to prime the cardiopulmonary bypass circuit or resuscitate
the patient) is known to induce hyperchloraemic metabolic acidosis
[1]. Using simplifi cations of the original Fencl–Stewart’s equations,
it is possible to partition the base defi cit into its constituent parts,
subsequently determining the relative contribution of chloride,
albumin and unmeasured anions to acidosis [2,3]. Ketone production
may contribute signifi cantly to the unmeasured anion component. Introduction Persistence of a mild metabolic acidosis or base defi cit
was occasionally observed in our otherwise well patients post cardiac
surgery, sometimes delaying discharge. We hypothesised that this
metabolic abnormality may be due to either ketogenesis caused by a
combination of starvation and the surgical stress response, or strong
ion imbalances following fl uid administration. Is inappropriate secretion of anti-diuretic hormone (SIADH) the
cause of hyponatremia in Legionella pneumonia?
P Schuetz, S Haubitz, B Mueller, for the ProHOSP Study Group
Medical University Clinic, Kantonsspital Aarau, Switzerland
Critical Care 2012, 16(Suppl 1):P144 (doi: 10.1186/cc10751) Is inappropriate secretion of anti-diuretic hormone (SIADH) the
cause of hyponatremia in Legionella pneumonia? P Schuetz, S Haubitz, B Mueller, for the ProHOSP Study Group
Medical University Clinic, Kantonsspital Aarau, Switzerland
Critical Care 2012, 16(Suppl 1):P144 (doi: 10.1186/cc10751) Conclusion Dysnatremia was common in surgical ICU patients and
was independently associated with an increased risk of in-hospital
death in these patients. Dysnatremia at ICU admission was associated
with a higher risk of death compared to ICU-acquired dysnatremia. Fluctuations in serum sodium concentrations were independently
associated with an increased risk of in-hospital death, even in patients
who remained normonatremic during the ICU stay. Introduction Medical textbooks list Legionella as a diff erential
diagnosis for the syndrome of inadequate anti-diuretic hormone (ADH)
secretion (SIADH), but empirical evidence supporting this association
is largely lacking. Partly this is explained by the analytical challenges of
ADH measurement. With the recent availability of an immunoassay that
measures the more stable ADH precursor peptide (CT-ProVasopressin),
we sought to investigate whether increased ADH levels would explain
hyponatremia found in Legionella patients. P146 Risk factors for poor outcome in patients with osmotic
demyelination syndrome Methods All patients admitted to the ICU between January 2004 and
January 2009 were included retrospectively in this study. Hyponatremia
was defi ned as a serum sodium concentration (sNa) <135 mmol/l and
hypernatremia as a sNa >145 mmol/l. Hyponatremia was defi ned as a
sNa less than 135 mmol/l and hypernatremia as a sNa greater than 145
mmol/l. Patients were classifi ed according to the onset of dysnatremia
into those who had abnormal sodium concentrations in the initial
blood sample, analyzed within 2 hours of admission to the ICU, or those
acquiring dysnatremia thereafter. We performed a logistic regression
multivariate analysis with hospital outcome as the dependent factor to
investigate the possible infl uence of dysnatremia on hospital outcome. Results Of the 10,923 surgical ICU patients included in the study, 1,215
(11.2%) had hyponatremia and 277 (2.5%) hypernatremia at admission
to the ICU. Among patients with normonatremia at admission to the
ICU (n = 9,431), the incidence of ICU-acquired dysnatremia was 31.3%. Dysnatremia present at ICU admission (OR = 2.53; 95% CI: 2.06 to
3.12, P <0.001) and ICU-acquired dysnatremia (OR = 2.06; 95% CI: 1.71
to 2.48, P <0.001) were independently associated with an increased
risk of in-hospital death. Dysnatremia at ICU admission (OR = 1.23;
95% CI: 1.01 to 1.50) was associated with a higher risk of in-hospital
death, compared to ICU-acquired dysnatremia. Fluctuation in serum
sodium concentration was also independently associated with an
increased risk of in-hospital mortality; both in patients who remained
normonatremic (>6 mmol/l/ICU stay) and those with dysnatremia
(>12 mmol/l/24 hours or >12 mmol/l/ICU stay). Conclusion The highest serum sodium concentration during sodium
correction rather than the speed of sodium correction or severity of
the hyponatremia is a determinant of outcome in patients with ODS. The development of tetraparesis and decreased consciousness are
associated with a poor outcome in these patients. Metabolic acid–base disturbances in patients in the emergency
department
EM Antonogiannaki, E Lilitsis, D Georgopoulos
University Hospital of Heraklion, Greece
Critical Care 2012, 16(Suppl 1):P149 (doi: 10.1186/cc10756) Metabolic acid–base disturbances in patients in the emergency
department
EM Antonogiannaki, E Lilitsis, D Georgopoulos
University Hospital of Heraklion, Greece
Critical Care 2012, 16(Suppl 1):P149 (doi: 10.1186/cc10756) p
gy
Methods The observational study included 50 children aged 12 months
to 16 years (among them 27 boys) with metabolic acidosis after surgery-
associated hemorrhage: 40% patients lost 58 ± 8.5% of total blood
volume, 26% lost 150 ± 9.5% of total blood volume. Patients received
3.66% THAM infusion. The dose of THAM infusion was calculated as
the dose administered (ml):negative standard BE (mmol/l)×kg body
weight, and did not increase 1.5 ml/kg body weight every 24 hours. The following were analyzed: Na+, K+, ionized calcium, lactate, pH, pCO2,
HCO3 and BE of arterial blood, before therapy, and after receiving a one-
half dose and a full dose of THAM. The signifi cance of diff erences was
assessed by Student’s t test, Mann–Whitney coeffi cient and chi-square
test; P <0.05 was considered statistically valid.f y
p
Critical Care 2012, 16(Suppl 1):P149 (doi: 10.1186/cc1 Introduction The aim of the present study is to determine in
unselected patients that visit the emergency department whether
the physicochemical approach improves the ability to diagnose acid–
base disorders compared with the two commonly used diagnostic
approaches; one relying on the plasma bicarbonate concentration
(HCO3
–) and anion gap (AG), and the other on the base excess (BE). 3
Methods A prospective observational study took place in the
emergency department at a university hospital during the period of
March to September 2011. Three hundred and sixty-fi ve patients were
included. Arterial and venous samples were drawn for blood gases and
a serum biochemical panel, respectively. The decision to collect arterial
samples was made by the attending physician in the emergency
department who was not involved in the study. Results There were no diff erences in the concentrations of electrolytes
and lactate. At the stages of the research the following signifi cant
dynamics have been noted: pH (7.27 ± 0.01; 7.31 ± 0.01; 7.35 ± 0.01;
P <0,01), HCO3 (18.59 ± 0.26; 19.5 ± 0.3; 21.2 ± 0.41 mmol/l; P <0.01)
and BE (–8.34 ± 0.3; –6.58 ± 0.37; –4.47 ± 0.45 mmol/l; P <0.01). PaCO2
tension did not change signifi cantly (38.9 ± 0.83; 37.3 ± 0.94; 37.5 ± 0.95
mmHg; P >0.05). Metabolic acid–base disturbances in patients in the emergency
department
EM Antonogiannaki, E Lilitsis, D Georgopoulos
University Hospital of Heraklion, Greece
Critical Care 2012, 16(Suppl 1):P149 (doi: 10.1186/cc10756) p
y
Results All patients were admitted to the hospital, while 103 of them
(28%) were transferred directly to the ICU. Hypoalbuminemia (serum
albumin ≤35 g/l) was observed in 191 patients (52%). The BE and HCO3
–
were normal in 35% and 38% of the total patients, respectively. The
corresponding values in patients admitted to the ICU were 41% and
28%. In a signifi cant proportion of patients in whom BE and/or HCO3
–
were normal the physicochemical approach detected the presence
of acidifying and/or alkalinizing disturbances. Hypoalbuminemia
(metabolic alkalosis) was identifi ed in 45% of patients with normal
HCO3
– and 48% of patients with normal BE. Strong ion diff erence (SID)
acidosis (SID ≤36 mEq/l) was observed in 49% and 44% of patients
with normal HCO3
– and BE, respectively. A high unmeasured strong
ion concentration ([XA–] ≥8 mEq/l, metabolic acidosis) was observed in
48% of patients with normal HCO3
– and in 52% of patients with normal
BE. Patients in whom hidden acidosis of high unmeasured strong
anion type was observed were identifi ed by the common diagnostic
approach only using the AG adjusted for hypoalbuminemia (AGadj
≥13 mEq/l). Patients who were admitted to clinical wards with acidosis,
other than hyperchloremic, remained signifi cantly more days in the
hospital than those without the disturbance.i Conclusion THAM infusion resulted in metabolic acidosis correction
without the development of hypernatremia and increase of CO2
tension. However, the small number of observations does not allow
one to assess accurately the clinical eff ect of THAM for these patients. References References
1. Taylor et al.: Intensive Care Med 2006, 32:295-301. 2. Story et al.: Br J Anaesth 2004, 92:54-60. 3. O’Dell et al.: Crit Care 2005, 9:R464-R470. References
1. Taylor et al.: Intensive Care Med 2006, 32:295-301. 2. Story et al.: Br J Anaesth 2004, 92:54-60. 3. O’Dell et al.: Crit Care 2005, 9:R464-R470. Conclusion Pyroglutamic acidosis is an uncommon condition, but
should be considered in a high anion gap metabolic acidosis of
unknown cause. The incidence in critical care may be more prevalent
due to lack of screening currently. It is associated with sepsis, hepatic
and renal dysfunction [3], and in patients who are receiving drugs such
as paracetamol and fl ucloxacillin. If known precipitants are stopped,
the condition can be rapidly reversed with full patient recovery. R f Buff er therapy in metabolic acidosis after surgery-associated
hemorrhage in pediatric oncology N Matinyan, A Saltanov, I Letyagin, O Obukhova
N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P147 (doi: 10.1186/cc10754) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods During a 12-month period, three patients on our ICU with
unexplained high anion gap metabolic acidosis had their urine
screened for organic acids. Methods During a 12-month period, three patients on our ICU with
unexplained high anion gap metabolic acidosis had their urine
screened for organic acids. contributed to greater than 75% of the BETOTAL, whilst in 74 (32%) of
these the BECl was greater than the BETOTAL. In 18 ABGs a BECl of less
than –2 caused a metabolic acidosis. contributed to greater than 75% of the BETOTAL, whilst in 74 (32%) of
these the BECl was greater than the BETOTAL. In 18 ABGs a BECl of less
than –2 caused a metabolic acidosis. Conclusion Our observation of persistent metabolic abnormalities
in otherwise well postoperative cardiac patients may be due to
iatrogenic strong ion imbalances caused by hyperchloraemic solutions. Ketogenesis was not a signifi cant contributing factor. The impact of
relative hyperchloraemia on pH was buff ered by other counteracting
metabolic factors (for example, hypoalbuminaemia), as in 74 ABGs the
BECl was greater than the BETOTAL. Results All had chronic methicillin-sensitive Staphylococcus aureus
infections treated with long-term paracetamol and fl ucloxacillin. All
cases presented to intensive care with reduced level of consciousness
after several weeks of treatment. In each case, common causes of high
anion gap metabolic acidosis were excluded and urine specimens
contained grossly elevated levels of pyroglutamic acid. Flucloxacillin
and paracetamol were stopped and N-acetylcysteine commenced,
which led to resolution of the metabolic acidosis within 48 hours. All
three patients made full recoveries. The fi rst case has been previously
described [2]. References References
1. Croal BL, et al.: Clin Chem 1998, 44:336-340. 2. Myall K, et al.: Lancet 2011, 377:526. 3. Peter J, et al.: Med J Aust 2006, 185:223-225. References
1. Croal BL, et al.: Clin Chem 1998, 44:336-340. 2. Myall K, et al.: Lancet 2011, 377:526. 3. Peter J, et al.: Med J Aust 2006, 185:223-225. Introduction Surgery in pediatric oncology is usually massive and
traumatic and often leads to acute blood loss, which can result in
metabolic acidosis. To treat acidosis, sodium bicarbonate is often used;
however, its application has some side eff ects. In this situation tris-
hydroxymethyl aminomethane (THAM) seems to be more eff ective. The objective of this study was to evaluate the eff ect of THAM for
treating metabolic acidosis after surgery-associated hemorrhage in
pediatric oncology. P145 P145
Fluctuations in serum sodium level are associated with an increased
risk of death in surgical ICU patients
Y Sakr, S Rother, AM Ferreira, C Ewald, P Dünich, K Reinhart
Friedrich Schiller University Hospital, Jena, Germany
Critical Care 2012, 16(Suppl 1):P145 (doi: 10.1186/cc10752) P145
Fluctuations in serum sodium level are associated with an increased
risk of death in surgical ICU patients
Y Sakr, S Rother, AM Ferreira, C Ewald, P Dünich, K Reinhart
Friedrich Schiller University Hospital, Jena, Germany
Critical Care 2012, 16(Suppl 1):P145 (doi: 10.1186/cc10752) p
g p
y p
q
Results A total of 231 ABGs were analysed. Urinary ketones were
checked along with 181 of the ABGs. A total of 14 ketonuria checks
were positive (8%) in 11 patients (22%). In nine ABGs ketonuria was
associated with a signifi cant base defi cit, whilst in three it was also
associated with a metabolic acidosis. The average starvation time was
39 hours (SD 11 hours). In 121 (52%) ABGs the chloride component
of the base defi cit (BECl) was below –2. In 104 (45%) ABGs the BECl Introduction Dysnatremia may have an impact on outcomes in critically
ill patients, but this has not been widely investigated in surgical ICU S53 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 An unusual cause of high anion gap metabolic acidosis:
pyroglutamic acidosis
RJ Wardell, LA Burrows, K Myall, A Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P148 (doi: 10.1186/cc10755) An unusual cause of high anion gap metabolic acidosis:
pyroglutamic acidosis
RJ Wardell, LA Burrows, K Myall, A Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P148 (doi: 10.1186/cc10755) Introduction Metabolic acidosis is a common acid–base disturbance in
intensive care. A high anion gap indicates the presence of endogenous
acids, which in critically ill patients are most commonly ketones,
lactate and those accumulated in renal failure. However, excluding
these causes means more rare forms of acid must be considered,
including pyroglutamic acidosis. Pyroglutamic acidosis is caused by the
accumulation of 5-oxoproline [1] due to the depletion of glutathione. This leads to loss of negative feedback and therefore the build-up of
Y-glutamyl cysteine, which is converted to 5-oxoproline. Conclusion Hypoalbuminemia is a common fi nding in patients in
the emergency department and complicates the interpretation of
acid–base data using the common diagnostic approaches. A physico-
chemical approach may better identify metabolic disturbances in this
population. S54 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P150 Pre-admission baseline creatinine was available on all subjects. Logistic
regression examined the RIFLE criteria outcome. Adjusted odds ratios
(ORs) were estimated by multivariable logistic regression models. Estimates were adjusted for age, gender, race (white, nonwhite), Deyo–
Charlson index, sepsis and patient type (surgical vs. medical).i P150
Aberrant bone metabolism in critical illness
I Vanhees, L Solie, SJ Roberts, A Wauters, J Gunst, F Luyten,
S Van Cromphaut, G Van den Berghe, HC Owen
Katholieke Universiteit Leuven, Belgium
Critical Care 2012, 16(Suppl 1):P150 (doi: 10.1186/cc10757) y
g
Results Pre-admission 25(OH)D defi ciency is predictive for acute
kidney injury. Patients with 25(OH)D defi ciency have an OR for acute
kidney injury of 1.73 (95% CI, 1.30 to 2.30; P <0.0001) relative to patients
with 25(OH)D suffi ciency. The 25(OH)D defi ciency remains a signifi cant
predictor of acute kidney injury following multivariable adjustment
(adjusted OR 1.50; 95% CI, 1.42 to 2.24; P <0.0001). Patients with 25(OH)
D insuffi ciency have an OR for acute kidney injury of 1.49 (95% CI, 1.15
to 1.94; P = 0.003) and an adjusted OR of 1.23 (95% CI, 1.12 to 1.72;
P = 0.003) relative to patients with 25(OH)D suffi ciency. The vitamin
D–acute kidney injury association is independent of the time between
25(OH)D draw and hospital admission.i Introduction Critically ill patients present with distinct alterations
in bone metabolism. Concentration of major vitamins in critically ill patients Concentration of major vitamins in critically ill patients
H Hayami, K Mizutani, M Shiota, N Nakayasu, T Masubuchi, M Idei, T Gotoh
Yokohama City University Hospital, Yokohama, Japan
Critical Care 2012, 16(Suppl 1):P152 (doi: 10.1186/cc10759) Introduction Commercially available vitamin solutions have been
improved during the last decade, but there have been a few recent
reports on defi ciency occurring in the ICU setting. In general, daily
delivery of a comprehensive modern vitamin regimen will suffi ce and
TPN solution which contains vitamins and trace elements is now widely
used because of the view of convenience and infection control. But the
dose of vitamins is determined by the American Medical Association
(AMA) recommendation which is based on requirement by healthy
subjects and it is not clear whether the dose is applicable for critically
ill patients. We measured the concentration of major vitamins in 19
critically ill patients who stayed in the ICU and analyzed those treated
for more than 3 weeks. f
Results Circulating mononuclear precursors were increased in patients
compared to healthy controls (99.1% vs. 83.9%; P <0.05). Patient
PBMCs diff erentiated into mature actively resorbing osteoclasts in
the presence or absence of osteoclastogenic factors (3.2-fold increase
vs. healthy cells; P <0.01) and when cultured in PS this spontaneous
osteoclast formation was increased further (2.3-fold; P <0.05). There
were no diff erences in the osteogenic diff erentiation of hPDCs
treated with PS, but there was a twofold (P <0.01) decrease in vascular
endothelial growth factor receptor 1 expression. Scaff olds with
patient serum-treated hPDCs displayed decreased vascularization and
increased osteoclast activity leading to a 28.9% (P <0.001) decrease in
bone formation. Methods Of 19 patients, 10 were treated for more than 3 weeks under
artifi cial ventilation; seven of which received renal replacement therapy
(RRT). Early enteral nutrition was established in six patients who
were assessed to have normal intestinal function. For those patients
who were diagnosed to have malfunction in intestine, nutrition was
supplied via peripheral route for 1 week, and led to total parenteral
nutrition after 1 week. Multivitamin product (Vit B1 3 mg, Vit B6 4 mg,
Vit C 100 mg, Folate 400 mg, and so on) was administered from day 0. We measured the concentration of those vitamins every 7 days. Conclusion Circulating mononuclear precursors from critically ill
patients seem prone to form osteoclasts both in the presence of
osteoclastogenic factors and spontaneously. An unusual cause of high anion gap metabolic acidosis:
pyroglutamic acidosis
RJ Wardell, LA Burrows, K Myall, A Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P148 (doi: 10.1186/cc10755) We have previously reported a decrease in
bone formation markers and a dramatic increase in bone resorption
markers. In a rabbit model of critical illness, we observed signifi cantly
lower bone mineral content in the trabeculae of critically ill rabbits
compared to healthy controls. This suggested uncoupling between
bone formation and degradation during critical illness, and could
increase risk of fracture during rehabilitation or impaired healing of
bone fractures. In this study, we investigated the eff ect of critical illness
on bone metabolism at the tissue and cellular level. Conclusion Defi ciency of 25(OH)D prior to hospital admission is a signi-
fi cant predictor of acute kidney injury in a critically ill patient population. Methods Circulating CD14/CD11b osteoclast precursors in peripheral
blood samples of critically ill patients and healthy controls were
measured by fl ow cytometry. Peripheral blood mononuclear cells
(PBMCs) were isolated and diff erentiated towards osteoclasts in vitro in
10% healthy (HS) or patient serum (PS) for 14 days. When analyzing bone
formation, human periosteal-derived cells (hPDCs) were cultured in vitro
in 10% HS or PS, and analyzed for osteoblast diff erentiation after 14 days. Bone formation was studied using serum-treated hPDCs implanted onto
NuOss™ calcium phosphate scaff olds in a murine in vivo model. Low serum 25-hydroxyvitamin D levels and acute kidney injury in
the critically ill Low serum 25-hydroxyvitamin D levels and acute kidney injury in
the critically ill
AB Braun1, AA Litonjua1, T Moromizato1, FK Gibbons2, E Giovannucci3,
KB Christopher1
1Brigham and Women’s Hospital, Boston, MA, USA; 2Massachusetts General
Hospital, Boston, MA, USA; 3Harvard School of Public Health, Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P151 (doi: 10.1186/cc10758) Introduction Given the importance of infl ammation in acute kidney
injury and the relationship between vitamin D and infl ammation, we
sought to elucidate the eff ect of vitamin D status on acute kidney
injury. We hypothesized that defi ciency in 25-hydroxyvitamin D
(25(OH)D) prior to hospital admission would be associated with acute
kidney injury in the critically ill. g
p
g
y
p
Conclusion In critically ill patients, especially those who received RRT,
the concentration of water-soluble vitamins such as Vit C remained low
even when they received the AMA recommended dose. Measurement
of vitamins and additional administration will be needed as necessary
depending on the disease condition. y
j
y
y
Methods We performed an observational study of patients treated
in medical and surgical ICUs in two teaching hospitals in Boston,
Massachusetts between 1998 and 2009. We studied 2,075 patients,
age ≥18 years, in whom serum 25(OH)D was measured prior to
hospitalization. The exposure of interest was pre-admission serum
25(OH)D and categorized a priori as defi ciency (25(OH)D ≤15 ng/
ml), insuffi ciency (25(OH)D 15 to 30 ng/ml) or suffi ciency (25(OH)D
≥30 ng/ml). The primary outcome was acute kidney injury defi ned as
meeting RIFLE Injury or Failure criteria in the 7 days prior to critical care
initiation and the 7 days following critical care initiation. We applied
the serum creatinine criteria to determine the maximum RIFLE class. P151 y
y
Results Concentrations of Vit B1, Vit 12, and Folate were 37 ± 16 pg/
ml, 1,068 ± 1,702 pg/ml, and 9.9 ± 14.4 ng/ml on day 7, and there was
tendency of increasing to normal range subsequently. On the other
hand, the concentration of Vit C was low (2.5 ± 2.4 g/ml: median 1.75)
on day 7, and it remained low through 3 weeks (median 2.0 g/ml on
day 21). Especially, the concentration of Vit C was extremely low in
seven patients who received RRT (median 1.0 g/ml) on day 7 compared
with those without RRT (median 2.6 g/ml, P = 0.05). We administered a
high dose of Vit C (ascorbic acid 1,000 mg/day) for three patients in this
group but restoration to normal range was seen in only two patients. y
y
Results Concentrations of Vit B1, Vit 12, and Folate were 37 ± 16 pg/
ml, 1,068 ± 1,702 pg/ml, and 9.9 ± 14.4 ng/ml on day 7, and there was
tendency of increasing to normal range subsequently. On the other
hand, the concentration of Vit C was low (2.5 ± 2.4 g/ml: median 1.75)
on day 7, and it remained low through 3 weeks (median 2.0 g/ml on
day 21). Especially, the concentration of Vit C was extremely low in
seven patients who received RRT (median 1.0 g/ml) on day 7 compared
with those without RRT (median 2.6 g/ml, P = 0.05). We administered a
high dose of Vit C (ascorbic acid 1,000 mg/day) for three patients in this
group but restoration to normal range was seen in only two patients. Conclusion In critically ill patients, especially those who received RRT,
the concentration of water-soluble vitamins such as Vit C remained low
even when they received the AMA recommended dose. Measurement
of vitamins and additional administration will be needed as necessary
depending on the disease condition. Concentration of major vitamins in critically ill patients The murine in vivo model
confi rmed an increase in osteoclastic resorption and a decreased
vascularization, leading to decreased bone formation in patient
scaff olds. These fi ndings will help to unravel the mechanisms behind
bone loss during critical illness. Reduced cortisol metabolism drives hypercortisolism in critical
illness E Boonen1, H Vervenne1, P Meersseman2, L Mortier3, YM Vanwijngaerden1,
I Spriet2, L Langouche1, I Vanhorebeek1, G Van den Berghe1
1KU Leuven, Belgium; 2University Hospitals, Leuven, Belgium; 3Virga Jesse
Hospital, Hasselt, Belgium
Critical Care 2012, 16(Suppl 1):P155 (doi: 10.1186/cc10762) Results Vitamin D defi ciency was defi ned as a serum 25-OH vitamin D
concentration <20 ng/ml. The study was conducted between February
and August 2011. A total of 105 patients were included. Dosages were
performed on day 3 (2, 4) (median, interquartiles). The number of
patients with 25-OH vitamin D <10 ng/ml, between 10 and 20 ng/ml,
between 20 and 30 ng/ml and >30 ng/ml was respectively 56, 26, 14
and 9. No diff erences were seen between defi cient and nondefi cient
patients if we compare SAPS III (58 ± 13 vs. 60 ± 15), predicted mortality
(34 ± 21% vs. 40 ± 25%), intra-ICU mortality (8.5 vs. 8.7%), intrahospital
mortality (19.5 vs. 21.7%), mean length of stay in the ICU (10 days ± 8),
and median SOFA score during the fi rst 5 days (5, 4, 4, 3, 3 vs. 4, 4, 3,
3, 4). A higher (but nonsignifi cant) prevalence of sepsis was found at
admission in defi cient patients (42/82 patients vs. 8/23 patients). Eleven
defi cient patients were treated with oral vitamin D (25,000 units/day)
for 5 days. After treatment, 25-OH vitamin D was above 20 ng/ml in
seven patients (31 ± 14 ng/ml). If we adjust groups for vitamin D post
treatment, no diff erences were found if we compare defi cient versus
nondefi cient patients for intra-ICU mortality (9.3% vs. 6.6%) and intra-
hospital mortality (14.6% vs. 23.3%). Introduction Critical illness is hallmarked by elevated cortisol levels,
refl ecting the severity of illness. Paradoxically, previous studies
reported suppressed ACTH, implicating another mechanism driving
elevated cortisol during critical illness. We hypothesized that cortisol
metabolism is reduced in critical illness, in part via elevated bile acids,
which may explain the paradoxical ACTH–cortisol dissociation by
negative feedback inhibition. Methods In a fi rst clinical study (n = 59), we determined the time
course of ACTH and cortisol levels during the fi rst week in the ICU. In a
second study (n = 28), we calculated the plasma half-life of exogenous
cortisol in critically ill patients. P155 The aim of our study was to evaluate the relationship between 25-OH
vitamin D defi ciency at admission and the outcome in a medical ICU. Methods A prospective observational study in a 10-bed medical ICU at
an inner-city hospital in Brussels. Patients with an expected stay in ICU
>48 hours were included. P154 Plasma levels of Coenzyme Q10 are reduced in critically ill patients
as compared to healthy volunteers and correlate with age
A Coppadoro1, L Berra2, A Kumar2, M Yamada2, R Pinciroli2, E Bittner2,
U Schmidt2, M Kaneki2
1University of Milan-Bicocca, Monza, Italy; 2Massachusetts General Hospital,
Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P154 (doi: 10.1186/cc10761) y
Conclusion Reduced expression and activity of cortisol metabolizing
enzymes, possibly driven by elevated bile acids, contributes to the
hypercortisolism in the critically ill, which explains the increased
cortisol plasma half-life and feedback-inhibited ACTH release. Reduced
cortisol metabolism could inferentially suppress the cortisol response
to an ACTH stimulation test, thereby reducing its diagnostic value for
adrenal failure. Introduction The purpose of this study is to investigate Coenzyme
Q10 (Q10) levels in critically ill patients as compared to healthy
volunteers. Q10 is an essential cofactor for the electron transport
chain reactions necessary for the aerobic cellular respiration. Q10
insuffi ciency, therefore, leads to mitochondrial dysfunction. It also acts
as an antioxidant. Oxidative state is prominent in critically ill patients,
favoring the production of oxygen-free radicals. A recent study showed
reduced Q10 levels in septic shock patients [1]. Eff ect of low-dose hydrocortisone on the expression of
glucocorticoid receptor alpha of the septic kidney in rats and its
protective eff ect on kidney injury Eff ect of low-dose hydrocortisone on the expression of
glucocorticoid receptor alpha of the septic kidney in rats and its
protective eff ect on kidney injury
DW Wu, HP Guo
Qilu Hospital of Shandong University, Jinan, Shandong, China
Critical Care 2012, 16(Suppl 1):P156 (doi: 10.1186/cc10763) No association between vitamin D defi ciency at admission and
outcome in a medical ICU No association between vitamin D defi ciency at admission and
outcome in a medical ICU
M Claus, L Schmitz, A Roman, E Stevens, P Dechamps
Hôpital Saint Pierre, Brussels, Belgium
Critical Care 2012, 16(Suppl 1):P153 (doi: 10.1186/cc10760) M Claus, L Schmitz, A Roman, E Stevens, P Dechamps
Hôpital Saint Pierre, Brussels, Belgium
Critical Care 2012, 16(Suppl 1):P153 (doi: 10.1186/cc10760) Introduction Vitamin D defi ciency is associated with chronic illness
and an excess in morbidity and mortality in the general population. Studies have found an even higher prevalence in ICU patients. Introduction Vitamin D defi ciency is associated with chronic illness
and an excess in morbidity and mortality in the general population. Studies have found an even higher prevalence in ICU patients. S55 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 1.
Donnino MW, et al.: Coenzyme Q10 levels are low and may be associated
with the infl ammatory cascade in septic shock. Crit Care 2011, 15:R189. Reduced cortisol metabolism drives hypercortisolism in critical
illness In a third clinical study (n = 51), urinary
cortisol metabolites were quantifi ed to estimate the activity of cortisol
metabolizing enzymes. In a fourth study (n = 64), we quantifi ed the
major cortisol metabolizing enzymes in the liver and adipose tissue
in relation to circulating cortisol and bile acids. We performed every
study in a similar, heterogeneous ICU population, in comparison with a
healthy control group matched for age, gender and BMI. Conclusion Our study confi rmed the high prevalence of vitamin D
defi ciency in ICU patients but not the association with an excess of
mortality. Reference y
g
p
g
g
Results In the presence of elevated total cortisol, ACTH remained much
lower in patients than in healthy controls (P <0.001), confi rming the
ACTH–cortisol dissociation during critical illness. Cortisol half-life was
substantially prolonged in patients compared to controls. Based on
urinary metabolites, the activity of 5α-reductase and 5β-reductase was
signifi cantly lower in patients than controls (P <0.0001). Furthermore,
the calculated activity of 11-hydroxysteroid dehydrogenase type
2 was reduced (P <0.0001). In the liver, gene and protein expression
of 5α-reductase and 5β-reductase was reduced (P <0.0001) and
corre lated inversely with circulating cortisol. Moreover, the enzyme
expression correlated inversely with circulating levels of conjugated
bile acids, which were markedly elevated in patients [1] and which have
been shown capable of suppressing expression and activity of cortisol
metabolizing enzymes [2]. 1. Lee P, et al.: N Engl J Med 2009, 360:1912-1914. P154 References 1. Vanwijngaerden et al.: Hepatology 2011, 54:1741-1752. 2. McNeilly et al.: J Hepatol 2010, 52:705-711. Methods We recruited 18 healthy volunteers and 36 critically ill
patients in the surgical ICU of the Massachusetts General Hospital. Ethical committee approval and written informed consent were
obtained. At the moment of blood sampling, height, weight, and age
as well as clinical data were collected. Plasma total Q10 concentrations
were measured by high-performance liquid chromatography. The
Assessment of Daily Living (ADL) score was obtained after discharge. Results Patients’ age and gender did not diff er as compared to healthy
volunteers (P = NS). Plasma Q10 levels were lower in critically ill patients
as compared to healthy volunteers (0.81 ± 0.22 vs. 0.50 ± 0.36 μg/ml,
P <0.001). In critically ill patients, plasma Q10 levels inversely correlated
with age (R = 0.40, P = 0.015). Lower levels of plasma Q10 (<0.4 μg/
ml, median) were associated with lower ADL score after discharge
(P = 0.005). In our patient population, plasma Q10 levels were not
related to PaO2/FiO2, septic shock, SAPS 2 at ICU admission, SOFA score
or mortality (all P = NS). Methods We recruited 18 healthy volunteers and 36 critically ill
patients in the surgical ICU of the Massachusetts General Hospital. Ethical committee approval and written informed consent were
obtained. At the moment of blood sampling, height, weight, and age
as well as clinical data were collected. Plasma total Q10 concentrations
were measured by high-performance liquid chromatography. The
Assessment of Daily Living (ADL) score was obtained after discharge.f Eff ect of low-dose hydrocortisone on the expression of
glucocorticoid receptor alpha of the septic kidney in rats and its
protective eff ect on kidney injury
DW Wu, HP Guo
Qilu Hospital of Shandong University, Jinan, Shandong, China
Critical Care 2012, 16(Suppl 1):P156 (doi: 10.1186/cc10763) y
Results Patients’ age and gender did not diff er as compared to healthy
volunteers (P = NS). Plasma Q10 levels were lower in critically ill patients
as compared to healthy volunteers (0.81 ± 0.22 vs. 0.50 ± 0.36 μg/ml,
P <0.001). In critically ill patients, plasma Q10 levels inversely correlated
with age (R = 0.40, P = 0.015). Lower levels of plasma Q10 (<0.4 μg/
ml, median) were associated with lower ADL score after discharge
(P = 0.005). In our patient population, plasma Q10 levels were not
related to PaO2/FiO2, septic shock, SAPS 2 at ICU admission, SOFA score
or mortality (all P = NS). Qilu Hospital of Shandong University, Jinan, Shandong, China
Critical Care 2012, 16(Suppl 1):P156 (doi: 10.1186/cc10763) Introduction Infl ammation out of control caused by sepsis can
eventually lead to multiple organ dysfunction, of which the kidney
is one of the most common injured organs. Sepsis-induced acute
kidney injury (SI-AKI) can obviously increase the mortality of sepsis. At
present, there are controversial views about the impact of exogenous
glucocorticoid to SI-AKI on kidney pathological changes and
glucocorticoid receptor (GR) expression. So, we want to investigate
whether low-dose glucocorticoid has a protective eff ect on SI-AKI and
what is the mechanism. y
Conclusion Plasma Q10 levels are reduced in critically ill patients,
suggesting reduced antioxidant capacity. Older patients seem to be
more prone to exhibit low Q10 levels. Oral supplementation might be
considered for those patients. 1.
Vanwijngaerden et al.: Hepatology 2011, 54:1741-1752.
2.
McNeilly et al.: J Hepatol 2010, 52:705-711. P159 Investigating diarrhoea on the ICU: a retrospective study
N Tirlapur, M Kelsey, H Montgomery
Whittington Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P159 (doi: 10.1186/cc10766) Results Hydrocortisone infusion was independently associated with
mild hypoglycemia (APACHE II score <15, OR 2.40, 95% CI 2.01 to 2.85;
APACHE II score 15 to 24, OR 1.53, 95% CI 1.44 to 1.62; APACHE II score
>24, OR 1.10, 95% CI 1.05 to 1.15) and severe hyperglycemia in all
APACHE II groups (APACHE II score <15, OR 3.26, 95% CI 2.59 to 4.10;
APACHE II score 15 to 24 OR 1.45, 95% CI 1.33 to 1.68; and APACHE II
score >24 OR 1.09, 95% CI 1.02 to 1.17). Hydrocortisone infusion was
independently associated with mild hypoglycemia in patients with
APACHE II score 15 to 24 (OR 1.74, 95% CI 1.42 to 2.13) and >24 (OR
1.64, 95% CI 1.42 to 1.90), but not in patients with APACHE II score <15
(OR 1.83, 95% CI 0.94 to 3.55). Introduction Diarrhoea is common in ICU patients, with a reported
prevalence of 15 to 38% [1]. Many factors may cause diarrhoea,
including Clostridium diffi cile, drugs (for example, laxatives, antibiotics),
faecal impaction with overfl ow and enteral feeds. Diarrhoea increases
nursing workload, impacts on patient dignity, increases costs and
exacerbates morbidity through dermal injury, impaired enteral uptake
and subsequent fl uid imbalance. We aimed to identify prevalence, yield
of stool investigations and clinical impact of diarrhoea on our ICU. Introduction Diarrhoea is common in ICU patients, with a reported
prevalence of 15 to 38% [1]. Many factors may cause diarrhoea,
including Clostridium diffi cile, drugs (for example, laxatives, antibiotics),
faecal impaction with overfl ow and enteral feeds. Diarrhoea increases
nursing workload, impacts on patient dignity, increases costs and
exacerbates morbidity through dermal injury, impaired enteral uptake
and subsequent fl uid imbalance. We aimed to identify prevalence, yield
of stool investigations and clinical impact of diarrhoea on our ICU. Methods A retrospective observational study of all ICU patients
treated in a 15-bed district general hospital from 1 January 2010 to 31
December 2010 was performed. ICU patients from whom stool samples
had been sent for microbiological analysis (including microscopy and
C. diffi cile toxin (CDT)) were assumed to have suff ered diarrhoea. Stool
sample results were compiled with patient demographics, ICU length
of stay (LOS) and mortality data. Conclusion Hydrocortisone increases the risk of dysglycemia in
critically ill patients. P158 SI-AKI model was reproduced using the cecum ligation and puncture
method. Pathological changes of the kidney were detected by H & E
staining. The expression of GRα and NF-κB in the kidney was detected
by immunohistochemistry. The levels of IL-1, IL-6, TNFα and IL-10 in the
plasma were detected by ELISA. Reference Referencei 1. Heymsfi eld SB, Baumgartner RN, Pan FS: Nutritional assessment of
malnutrition by anthropometric methods. Treaty of Modern Nutrition in
Health and Disease. Edited by Shils M, Olson JA, Shike M, Ross C. New York:
Manole; 2003. 1. Heymsfi eld SB, Baumgartner RN, Pan FS: Nutritional assessment of
malnutrition by anthropometric methods. Treaty of Modern Nutrition in
Health and Disease. Edited by Shils M, Olson JA, Shike M, Ross C. New York:
Manole; 2003. yp
g y
yp g y
y
p
Methods Blood glucose measurements (n = 73,400) of patients
admitted to the ICU from January 2007 to December 2009 (n = 2,167)
were analyzed. Logistic regression was used to analyze the eff ect of
hydrocortisone infusion on mild (blood glucose level ≥150 mg/dl) and
severe hyperglycemia (≥180 mg/dl) and mild hypoglycemia (≤70 mg/
dl) separately. To adjust for severity of disease, patients were stratifi ed
in APACHE II score groups (<15; 15 to 24; >24). P157 Hydrocortisone increases the risk of dysglycemia in critically ill
patients RT Van Hooijdonk, JM Binnekade, RE Harmsen, MJ Schultz
Academic Medical Center, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P157 (doi: 10.1186/cc10764) y
y
Conclusion The age, length of stay and diagnosis associated with
the level of organ dysfunction are key factors to progress to the state
of malnutrition. The multidisciplinary team has an ongoing role in
controlling the supply of proteins and calories with essential nutrients
in order to improve the provision, preventing complications and
adverse outcomes. Introduction Hyperglycemia and hypoglycemia are independently
associated with mortality and morbidity of critically ill patients [1,2]. Critically ill patients frequently receive hydrocortisone for refractory
shock. While hydrocortisone infusion is associated with hyperglycemia
[3], the eff ect of hydrocortisone on the incidence of hypoglycemia is
uncertain. We hypothesized hydrocortisone infusion to increase the
risk of hyperglycemia and hypoglycemia in critically ill patients. P159 Whether these dysglycemic eff ects diminish the
benefi cial eff ects of hydrocortisone treatment should be investigated
in future studies. References 1. Robter W, et al.: N Engl J Med 2004, 351:159-169. 2. Rittirsch D, et al.: Nat Protoc 2009, 4:31-36. 3. Leelahavanichkul A, et al.: Am J Physiol Renal Physiol 2008, 295:1825-1895. 3. Leelahavanichkul A, et al.: Am J Physiol Renal Physiol 2008, 295:1825-1895. Results The study included 247 patients hospitalized in ICUs, mean
age 63 years and 60% (148 patients) were male. Sepsis was the most
frequent cause of hospitalization at 57% and the average hospital
stay was 16 days. The rate of albumin and mean hemoglobin level
were respectively 2.1 and 9.5 g/dl. For those patients hospitalized over
10 days were observed average levels of 1.5 and 8.9 g/dl. For mechanical
ventilation in patients with septic shock the results were 1.4 and
7.9 g/dl with a mean hospital stay of 14 days. The postoperative group
was the highest level observed at 2.6 and 10.4 g/dl and mean total
time of hospitalization of 5 days. The worst results based on diagnosis
were respectively pulmonary septic shock, ischemic hemispheric brain
stroke and cardiogenic shock. All patients with length of stay over
11 days resulted in a clinically malnourished state. Reference Reference Methods Healthy Wistar male rats were randomly divided into a sham
group, SI-AKI group and SI-AKI hydrocortisone group (HC group). The 1. Donnino MW, et al.: Coenzyme Q10 levels are low and may be associated
with the infl ammatory cascade in septic shock. Crit Care 2011, 15:R189. S56 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 2.
Bagshaw SM, et al.: Crit Care Med 2009, 37:463-470. 3.
Annane D, et al.: JAMA 2009, 301:2362-2375. Nutritional status of patients occupying ICUs in the state of Rio de
Janeiro SO Oliveira1, R Goldwasses2, U Melo3, M Bandeira4, F Dessa5, R Almeida1,
I Kouh6 1Albert Schweitzer State Hospital, Rio de Janeiro, Brazil; 2Healh Provider
State Government, Rio de Janeiro, Brazil; 3Alberto Torres State Hospital, São
Gonçalo, Brazil; 4Real Cordis Hospital, Rio de Janeiro, Brazil; 5Bangu Hospital,
Rio de Janeiro, Brazil; 6UFRJ University Hospital, Rio de Janeiro, Brazil
Critical Care 2012, 16(Suppl 1):P158 (doi: 10.1186/cc10765) p
y
Results The survival rate of the AKI group and HC group showed
no statistical diff erence (P >0.05). H & E stain showed renal tubular
epithelial cells swelling and falling off , and the tubular brush border
disappeared and vacuolated in the AKI group. Pathological changes of
the renal tubular could be alleviated after hydrocortisone treatment. Compared with the AKI group, immunohistochemistry showed that
GRα expression was increased and NF-κB expression was decreased in
the HC group (P <0.01). The level of TNFα, IL-6, and IL-1 were reduced
and the level of IL-10 was increased in the HC group compared with the
AKI group (P <0.01). Introduction Nutritional status and anemia infl uence the clinical
course of hospitalized patients. Anemia appears in the fi rst days of
hospitalization and can sustain itself and grow worse over time and
is caused by a number of factors such as dilution secondary to fl uid
replacement, hemolysis, abnormalities in iron metabolism, blood loss
in the gastrointestinal tract and also due to decreased production of
erythropoietin, a consequence of decreased erythropoiesis caused by
the presence of infl ammatory cytokines. Conclusion Low-dose hydrocortisone can inhibit the NF-κB activity,
possibly in part by increasing the expression of GRα in renal sepsis
rats. Accordingly, it could reduce the production of infl ammatory
factors participating in sepsis, eff ectively inhibit the infl ammation and
extenuate the sepsis-induced renal pathological changes. l
y y
Methods A cross-sectional study on 30 November, patients >18 years. Evaluated characteristics of all patients admitted with age, sex, APACHE
II score, mean length of stay, cause of hospitalization in mechanical
ventilation, organ failure, sedation and analgesia, coma and underuse
of vasoactive drugs. e e e ces
1.
Krinsley JS, et al.: Crit Care Med 2007, 35:2262-2267.
2.
Bagshaw SM, et al.: Crit Care Med 2009, 37:463-470.
3.
Annane D, et al.: JAMA 2009, 301:2362-2375. 1.
Krinsley JS, et al.: Crit Care Med 2007, 35:2262-2267. P160 P160
Preliminary report of surface electrogastrography in critically ill
septic patients after resuscitation
C Mancilla, R Galvez, G Landskron, E Tobar, A Madrid
Hospital Clinico Universidad de Chile, Santiago, Chile
Critical Care 2012, 16(Suppl 1):P160 (doi: 10.1186/cc10767) Table 1 (abstract P161). Nutritional adequacy and clinical endpoints in
tolerant and intolerant EN patients
%
%
Ventilator-
Time to
Calorifi c
Protein
free
60-day
ICU stay discharge
adequacy adequacy
days
mortality
(days)
alive
Tolerant
64.3
63.7
11.2
26.2
11.3
25.2
Intolerant
55.5
55.6
2.5
30.8
14.4
31.1
Conclusion Intolerance is common amongst the EN ICU population
and is associated with poor nutritional and clinical outcomes. Table 1 (abstract P161). Nutritional adequacy and clinical endpoints in
tolerant and intolerant EN patients Introduction Impaired gastrointestinal motility is common in critically ill
patients. Multiple conditions such as shock with diminished splanchnic
perfusion, surgery, fl uid overload, intra-abdominal hypertension, and
drugs are responsible for this phenomena. Assessing gastric motility in
this setting is complex. Surface electrogastrography (sEGG) is a recent
noninvasive technique that determines basal and postprandial gastric
motility [1]. Our aim is to study basal gastric motility in critically ill
septic patients in the post-resuscitative phase, by sEGG. y
Methods Eligible patients were those admitted to the ICU with
diagnosis of septic shock as stated by the Sepsis Conference 2001 [2]. At the moment of the study the patients were in the post-resuscitative
phase, defi ned as normal clinical and laboratory perfusion parameters. sEGG is a noninvasive technique that uses skin abdominal electrodes to
record myoelectrical stomach activity. The basal slow wave originates in
the proximal stomach and propagates to the antrum with a frequency
of approximately 3 cycles per minute (cpm). Basal activity below
2.4 cpm is defi ned as bradygastria and above 3.7 cpm as tachygastria
[1]. Data were correlated with severity scores, lactate levels, and doses
of sedatives. The study was approved by the Ethics Committee of the
Hospital Clínico Universidad de Chile. P162
Gastric emptying assessment in critically ill patients with feed
intolerance; comparison of 13C octanoic acid, paracetamol and
3-O-methylglucose absorption tests
M Chapman1, R Fraser1, N Nguyen1, A Deane1, LS Vasist2, K Hacquoil2,
M Barton2, GE Dukes2
1University of Adelaide, Australia; 2GlaxoSmithKline, Research Triangle Park,
NC, USA
Critical Care 2012, 16(Suppl 1):P162 (doi: 10.1186/cc10769) 1University of Adelaide, Australia; 2GlaxoSmithKline, Research Triangle Park,
NC, USA Results We recruited 16 patients (10 females). 1.
Chang F-Y: J Gastroenterol Hepatol 2005, 20:502-516. Frequency, determinants and impact of feed intolerance amongst
the critically ill Frequency, determinants and impact of feed intolerance amongst
the critically ill y
U Gungabissoon1, K Hacquoil1, C Bains1, G Dukes2, M Irizarry3, D Heyland3
1GlaxoSmithKline, Stockley Park, UK; 2GlaxoSmithKline, Research Triangle Park,
NC, USA; 3CERU, Queen’s University, Kingston, Canada
Critical Care 2012, 16(Suppl 1):P161 (doi: 10.1186/cc10768) y
U Gungabissoon1, K Hacquoil1, C Bains1, G Dukes2, M Irizarry3, D Heyland3
1GlaxoSmithKline, Stockley Park, UK; 2GlaxoSmithKline, Research Triangle Park,
NC, USA; 3CERU, Queen’s University, Kingston, Canada
Critical Care 2012, 16(Suppl 1):P161 (doi: 10.1186/cc10768) Introduction Provision of early and adequate enteral nutrition (EN)
to critically ill patients is associated with improved clinical outcomes;
however, 50 to 60% of prescribed EN is received. We aimed to
characterise the incidence and determinants of intolerance and assess
its infl uence on nutritional and clinical outcomes using the 2009 Critical
Care Nutrition Survey (CCNS). y
Methods The CCNS survey is a prospective observational cohort study
of nutrition practices from over 150 ICUs around the world. Included
patients were those that remained in ICU for ≥72 hours and were
mechanically ventilated ≤48 hours of admission to ICU. We collected
pertinent baseline and outcome data that included nutritional
adequacy, ventilator-free days, 60-day mortality and ICU stay. Intolerance was defi ned as interruption of EN due to gastrointestinal
(GI) reasons (high gastric residuals, increased abdominal girth/
abdominal distension, vomiting/emesis, diarrhoea or subjective
discomfort). In the analysis of intolerance we included each potential
eff ect into a logistic regression analysis to determine its signifi cance. g
y
Conclusion Diarrhoea was common on our ICU, its prevalence (17%)
being consistent with established literature. It was associated with
statistically increased ICU LOS and mortality, although any direction of
causality remains to be established. A low stool investigation yield and
low prevalence of C. diffi cile suggests that other noninfective causes
of diarrhoea need excluding. Further research is required to establish
the prevalence and pathogenesis of diarrhoea on UK ICUs, in order to
develop evidence-based management plans for reducing its incidence,
and its clinical and fi nancial impact. y
Methods The CCNS survey is a prospective observational cohort study
of nutrition practices from over 150 ICUs around the world. Included
patients were those that remained in ICU for ≥72 hours and were
mechanically ventilated ≤48 hours of admission to ICU. We collected
pertinent baseline and outcome data that included nutritional
adequacy, ventilator-free days, 60-day mortality and ICU stay. 1.
Chang F-Y: J Gastroenterol Hepatol 2005, 20:502-516.
2
Levy MM et al : Crit Care Med 2003 31:1250-1256 References S57 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results Of 782 patients (mean age ± 2SD 62.1 ± 37.1, 52.3% female)
treated on our ICU, 334 stool samples were sent from 133 (17.0%)
patients. Two samples (0.6%) yielded abnormal results: one out of
131 (0.8%) patients with CDT samples sent and one out of 108 (0.9%)
patients with stool microscopy samples sent had a positive sample. The
prevalence of C. diffi cile (1/782) and other organisms (1/782) was 0.1%
and 0.1% respectively. In terms of diagnostic yields, positive fi ndings
were found in one out of 191 (0.5%) CDT samples and one out of
141 (0.7%) stool microscopy samples (for Candida). When compared
to patients without diarrhoea, suff erers were older (64.1 ± 33.2 vs. 61.7 ± 37.8 years, P = 0.16) with greater female preponderance (55.6%
vs. 51.6%, P = 0.40). Suff erers experienced longer ICU LOS (16.3 ± 45.6
vs. 4.6 ± 19.4 days, P <0.0001) and greater ICU mortality (19.5% vs. 12.6%, P = 0.035) during the study period. Reference 1. Wiesen P, et al.: Curr Opin Crit Care 2006, 12:149-154. f
g
g
y
gi
Results Data from 1,888 ICU patients receiving EN were analysed. The
incidence of intolerance was 30.5%, and occurred after a median 3 days
from EN initiation. Factors associated with intolerance were: diagnosis
category (P = 0.0009) (GI, cardiovascular and sepsis categories with
the highest risk), pre-emptive motility agent use (P = 0.0125), non-
GI interruptions to feed (P = 0.0086) and global region (P = 0.0006). Intolerance was associated with poor nutritional adequacy, increased
mortality, longer ventilator dependence and increased length of
ICU stay (P <0.05) (Table 1). Poorer clinical outcomes were seen with
increasing number of days of intolerance. 2.
Levy MM, et al.: Crit Care Med 2003, 31:1250-1256. Frequency, determinants and impact of feed intolerance amongst
the critically ill Intolerance was defi ned as interruption of EN due to gastrointestinal
(GI) reasons (high gastric residuals, increased abdominal girth/
abdominal distension, vomiting/emesis, diarrhoea or subjective
discomfort). In the analysis of intolerance we included each potential
eff ect into a logistic regression analysis to determine its signifi cance. Results Data from 1,888 ICU patients receiving EN were analysed. The
incidence of intolerance was 30.5%, and occurred after a median 3 days
from EN initiation. Factors associated with intolerance were: diagnosis
category (P = 0.0009) (GI, cardiovascular and sepsis categories with
the highest risk), pre-emptive motility agent use (P = 0.0125), non-
GI interruptions to feed (P = 0.0086) and global region (P = 0.0006). Intolerance was associated with poor nutritional adequacy, increased
mortality, longer ventilator dependence and increased length of
ICU stay (P <0.05) (Table 1). Poorer clinical outcomes were seen with
increasing number of days of intolerance. Reference 1.
Wiesen P, et al.: Curr Opin Crit Care 2006, 12:149-154. P160 Mean age 62 years (50 to
76) (P = 0.8). APACHE II score 25 (19 to 28) (P = 0.4) and SOFA score 9 (7
to 11) (P = 0.29). Lactate at admission 3.8 mmol/l (1.2 to 6.5) (P = 0.72). Fentanyl total dose 172.7 μg/kg (59 to 256.6) (P = 0.91) and midazolan
total dose 3.4 mg/kg (0.1 to 3.1) (P = 0.07). We obtained a reliable
register in all the patients and found six patients with bradigastria,
three with tachygastria and nine with normal motility. In this small
sample size study there was a trend to bradygastria in relation to high
total doses of midazolam. P164
Preliminary experience with ketone-targeted treatment of diabetic
ketoacidosis F Riccio, T Drake, S Mathieu, J Cranshaw
Royal Bournemouth Hospital, Bournemouth, UK
Critical Care 2012, 16(Suppl 1):P164 (doi: 10.1186/cc10771) Introduction In May 2011 the Joint British Diabetes Societies (JBDS)
published new guidance for managing adult diabetic ketoacidosis. We
developed a JBDS-based protocol that measured and treated capillary
ketonaemia (not blood glucose) hourly with i.v. 0.1 IU insulin/kg/hour
increased by 1 IU/hour if the ketone reduction was <0.5 mM/hour. The
fi nal target was capillary ketonaemia <0.3 mM. To allow this insulin
rate and avoid hypoglycaemia, 125 ml/hour of 10 or 20% dextrose was
started when blood glucose was <14 mM (250 mg/dl). As the eff ects
of this new protocol were unknown, all patients were managed in our
high-dependency unit (HDU). We report our experience of the new
protocol compared to our old ‘sliding scale’ insulin titration to blood
glucose protocol. Table 1 (abstract P162). Correlations between GE parameters
13C GEC
OMG AUC60
0.675*
13C GEC
OMG C60
0.758*
13C GEC
PA AUC60
0.678*
13C GEC
PA C60
0.590*
PA AUC60
OMG AUC60
0.534*
PA C60
OMG C60
0.553*
*P <0.0001. Table 1 (abstract P162). Correlations between GE parameters Table 1 (abstract P162). Correlations between GE parameters Methods We prospectively gathered results of the new protocol over
3 months and performed a chart review of the same results from
patients admitted in the previous year managed on wards and the
HDU. Results are expressed as median (range). Results Patients on the new protocol (n = 7) cleared ketones to <0.3 mM
in 8 (7 to 20) hours. The insulin rate needed was 10 (6 to 17) IU/hour. Potassium during treatment was 4 (3.2 to 5.2) mM and required 35 (12
to 60) mM/hour to maintain the target 3.5 to 5 mM. No episodes of
blood glucose <4 mM were recorded. Time to reach glucose <14 mM
was 7 (1 to 15) hours with a fall rate of 3.7 (2.9 to 6.8) mM/hour. Patients
on the old protocol (n = 39) were treated for 15 (5 to 20) hours with 3
(0.5 to 6) IU/hour. Potassium during treatment was 3.5 (2.8 to 5.5) mM
and required 9 (6 to 16) mM/hour to maintain the target 3.5 to 5 mM. Time to reach glucose <14 mM was 3.5 (1 to 13) hours with a fall rate
of 4.2 (0.3 to 13) mM/hour. Critical Care 2012, 16(Suppl 1):P162 (doi: 10.1186/cc10769) Introduction Delayed gastric emptying (GE) occurs frequently in
critically ill patients and may result in impaired small intestinal delivery
of drugs and nutrients. Use of direct methods of GE assessment
(scintigraphy) in the ICU for clinical monitoring or research is challeng-
ing. Indirect methods that utilize substances which rely on eff ective GE
and rapid absorption from the small intestine off er a feasible estimate
of GE. Three substances with these characteristics are 13C-octanoic
acid (13C), paracetamol (PA) and 3-O-methylglucose (OMG). We have
previously shown signifi cant correlation to scintigraphy for 13C (r = 0.63)
and OMG absorption (r = –0.77 to –0.87). The current study examined
the relationship between three indirect methods of GE assessment: 13C,
PA, OMG. Conclusion sEGG is a feasible technique in critically ill septic patients. In
the post-resuscitative phase 43.8% of patients present normal gastric
motility, and 37% showed bradygastria. Future research is warranted in
order to fi nd risk factors of gastrointestinal dismotility. References 1. Chang F-Y: J Gastroenterol Hepatol 2005, 20:502-516. 2. Levy MM, et al.: Crit Care Med 2003, 31:1250-1256. S58 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods GE was concurrently assessed in mechanically ventilated
patients (n = 33) with enteral feeding intolerance (gastric residual
volume >200 ml) on two occasions 24 hours apart. A test meal of 100
ml Ensure with 100 μl 13C, 1,000 mg PA, 3 g OMG was infused into the
stomach over 5 minutes. Breath samples for 13C and plasma samples
for PA, OMG determination were collected over the subsequent 4-hour
period. Bivariate Pearson correlations were calculated between the
following parameters; 13C (gastric emptying coeffi cient (GEC)), PA
(concentration at 60 minutes (C60), AUC0–60 min), OMG ((C60), AUC0–60 min). See Table 1. Impact of blood glucose on blood lactate levels in a medical ICU:
a retrospective cohort study G Adelsmayr, R Brunner, U Holzinger
Medical University Vienna, Austria
Critical Care 2012, 16(Suppl 1):P165 (doi: 10.1186/cc10772) Results In the 556 study patients, early enteral feeding was started in
379 patients (68.16%). Out of 379 patients, 100% calorie requirements
were met only in 43 patients (7.73%). For the remaining study patients,
more than 40%, 50% and 60% calorie goals were achieved in 115
(30.34%), 128 (33.77) and 93 (24.53%) patients respectively.f Introduction Although blood lactate and glucose both represent
important markers in the intensive care setting, they have been
considered quite independently. Especially, the ideal glucose target
range has been the topic of recent studies with confl icting results [1,2]. Blood lactate is an acknowledged predictor of outcome in critically ill
patients [3]. The aim of this study was to establish a possible correlation
between elevated blood glucose and lactate levels in intensive care
patients. p
p
y
Conclusion The initiation of early enteral feeding is still far off for a
signifi cant proportion of the ICU population despite evidence-based
defi nite recommendations to improve ICU outcome. The calorie
goal achievements were also very suboptimal. This important but
still neglected nutritional therapy must be carefully looked at and
implemented in all ICUs. P164
Preliminary experience with ketone-targeted treatment of diabetic
ketoacidosis A total 0.02 results per hour <4 mM were
recorded in the old protocol. Results Observed GE rates for all parameters were across the spectrum
from fast to delayed (for example, with r range = 0.534 to 0.758,
P <0.0001). )
Conclusion These three practical indirect methods of GE assessment
may provide similar estimates of GE in critically ill patients. P163
Early enteral nutrition in the critically ill: a single-centre study
A Gupta, E Rupert, R Sharma, D Mishra
Rabindranath Tagore Hospital, Kolkata, India
Critical Care 2012, 16(Suppl 1):P163 (doi: 10.1186/cc10770) P163
Early enteral nutrition in the critically ill: a single-centre study
A Gupta, E Rupert, R Sharma, D Mishra
Rabindranath Tagore Hospital, Kolkata, India
Critical Care 2012, 16(Suppl 1):P163 (doi: 10.1186/cc10770) Conclusion The median insulin infusion rate in an individual patient
and the range required to suppress capillary ketonaemia in all patients
with diabetic ketoacidosis using this protocol was more than three
times that in the old protocol and the amount of i.v. potassium required
to maintain near-normal blood potassium during treatment was four
times more. There was a slower correction of initial blood glucose. Blood glucose and potassium maintenance during treatment with
this protocol would appear to require high-intensity nursing care to
maintain patient safety. Introduction Early enteral nutrition in critically ill patients has been
established as a valuable addition to improve overall outcome and
mortality. The recommendation is to initiate feeding within 24 to
48 hours of admission and to meet the calorie goal within the next 48
to 72 hours. The purpose of this study was to fi nd out whether these
guidelines are followed in the ICU as per the new protocol. 2.
Kreyman KG, Berger MM, Deutz NE, et al.: ESPEN guidelines on enteral
nutrition: intensive care. Clin Nutr 2006, 25:210-223. Reference Methods This is a prospective observational study done in a 32-bed
mixed medical and surgical ICU over the period from March 2011 to
August 2011. Consecutively, 575 patients admitted to this ICU were
followed up. Nineteen patients were excluded from the study where
enteral nutrition could not be commenced within 48 hours due to
various reasons. The remaining 556 patients’ data were analyzed. Data were collected by interviewing the doctors and nurses as well as
reviewing medical notes and all ICU charts. 1. Joint British Societies Guideline for the management of diabetic
ketoacidosis. Diabet Med 2011, 28:508-515. Variability of insulin sensitivity during the fi rst 4 days of critical
illness C Pretty1, A Le Compte1, JG Chase1, G Shaw2, JC Preiser3, S Penning4,
T Desaive4 Methods We performed a retrospective study in 2,943 adult patients
admitted to our ICU from 2004 until 2010. Glucose variability was
calculated for all subjects as the LI [3] during the hospital stay on
capillary, arterial and venous blood. The ROC curve was performed to
verify discrimination of the LI towards mortality and ICU infections. 1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand; 3Hospital Erasme, Free University of Brussels,
Belgium; 4University of Liege, Belgium
Critical Care 2012, 16(Suppl 1):P167 (doi: 10.1186/cc10774) 1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand; 3Hospital Erasme, Free University of Brussels,
Belgium; 4University of Liege, Belgium
Critical Care 2012, 16(Suppl 1):P167 (doi: 10.1186/cc10774) y
y
Results There were 709 infections and 447 deaths. There was a
signifi cant interaction between the LI and infections in patients. The
LI had a great ability to predict hospital mortality (area under the
curve = 0.62, 95% CI = 0.59 to 0.65, P <0.5; Figure 1) but moreover
infections (area under the curve = 0.80, 95% CI = 0.78 to 0.82, P <0.5;
Figure 2). Introduction Safe, eff ective tight glycaemic control (TGC) can
improve outcomes in critical care patients, but is diffi cult to achieve
consistently. Insulin sensitivity defi nes the metabolic balance between
insulin concentration and insulin-mediated glucose disposal. Hence,
variability of insulin sensitivity can cause variable glycaemia. This study
investigates the evolution of insulin sensitivity level and variability in
patients receiving TGC during the fi rst 4 days of their ICU stay. g
Conclusion Glucose variability has ability to predict outcome but
moreover infections in patients in the ICU, because it is a predictor
of clinical outcomes in patients with hyperglycemia and diabetes. i
y
y
Methods A retrospective analysis of patient data (n = 164 patients)
from the SPRINT TGC study in the Christchurch Hospital ICU [1]. All
patients commenced TGC within 12 hours of ICU admission and
spent at least 24 hours on the SPRINT protocol. Model-based insulin
sensitivity (SI) was identifi ed using a validated glucose–insulin system
model developed for critical care patients. SI was identifi ed every hour
for each patient using clinical data and the model. Level and hour-to-
hour percentage changes in SI were assessed on cohort and per-patient
bases. p
References p
Methods Blood gas data of 1,170 patients, admitted to the medical
ICU of the Department of Medicine III, Medical University Vienna,
between the years 2001 and 2009, were analysed retrospectively. The
association of circulating blood glucose levels with corresponding
lactate levels was investigated using a linear regression model. The
impact of diff erent blood glucose intervals (<80, 80 to 120, 120 to 160,
160 to 200, >200 mg/dl) on blood lactate levels was analysed using
ANOVA. The infl uence of blood glucose variability, expressed as the 1. McClave SA, Martindale RG, Vanek VW, et al.: Guidelines for the provision
and assessment of nutrition support therapy in the adult critically ill
patient: Society of Critical Care Medicine (SCCM) and Americal Society for
Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr
2009, 33:277-316. 1. McClave SA, Martindale RG, Vanek VW, et al.: Guidelines for the provision
and assessment of nutrition support therapy in the adult critically ill
patient: Society of Critical Care Medicine (SCCM) and Americal Society for
Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr
2009, 33:277-316. 2. Kreyman KG, Berger MM, Deutz NE, et al.: ESPEN guidelines on enteral
nutrition: intensive care. Clin Nutr 2006, 25:210-223. 2. Kreyman KG, Berger MM, Deutz NE, et al.: ESPEN guidelines on enteral
nutrition: intensive care. Clin Nutr 2006, 25:210-223. S59 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Strategies to reduce glucose variability should be studied to improve
the outcomes in ICU patients. References
1. N Engl J Med 2001, 345:1359. 2. Crit Care Med 2008, 36:2316. 3. Diabetes 2004, 53:955. Figure 2 (abstract P166). blood glucose standard deviation, on mean lactate concentrations for
the period of ICU stay was analysed using a linear regression model. To
adjust for the severity of illness, a multivariate regression analysis was
conducted including SAPS II and APACHE II scores. Figure 2 (abstract P166). g
Results Blood glucose and lactate presented a U-shaped curve with a
minimum blood lactate (1.5 mmol/l) between 80 and 120 mg/dl blood
glucose. ANOVA and linear regression demonstrated a signifi cant
infl uence of blood glucose and blood glucose variability on blood
lactate (P = 0.0001). The identifi cation of this relation was supported by
the result of a multivariate regression analysis, adjusting for severity of
illness (P = 0.0001). P167 Introduction Hyperglycemia and glucose variability are important
factors associated with morbidity and mortality in critically ill patients
[1,2]. Our objective was to determine the association between the
glucose Lability Index (LI), infections and outcome in critical illness. Methods We performed a retrospective study in 2,943 adult patients
admitted to our ICU from 2004 until 2010. Glucose variability was
calculated for all subjects as the LI [3] during the hospital stay on
capillary, arterial and venous blood. The ROC curve was performed to
verify discrimination of the LI towards mortality and ICU infections. Results There were 709 infections and 447 deaths. There was a
signifi cant interaction between the LI and infections in patients. The
LI had a great ability to predict hospital mortality (area under the
curve = 0.62, 95% CI = 0.59 to 0.65, P <0.5; Figure 1) but moreover
infections (area under the curve = 0.80, 95% CI = 0.78 to 0.82, P <0.5;
Figure 2). Relationship between glycemic Lability Index, infections and
outcome in critically ill patients Relationship between glycemic Lability Index, infections and
outcome in critically ill patients
A Donati, L Botticelli, R Castagnani, V Gabbanelli, E Damiani, R Domizi,
P Pelaia
Università Politecnica delle Marche, Ancona, Italy
Critical Care 2012, 16(Suppl 1):P166 (doi: 10.1186/cc10773) References
1. N Engl J Med 2001, 345:1359. 2. Crit Care Med 2008, 36:2316. 3. Diabetes 2004, 53:955. Introduction Hyperglycemia and glucose variability are important
factors associated with morbidity and mortality in critically ill patients
[1,2]. Our objective was to determine the association between the
glucose Lability Index (LI), infections and outcome in critical illness. ,
References 1. van den Berghe G, et al.: Intensive insulin therapy in the critically ill
patients. N Engl J Med 2001, 345:1359-1367. 2. Finfer S, et al.: Intensive versus conventional glucose control in critically ill
patients. N Engl J Med 2009, 360:1283-1297. 3. Khosravani H, et al.: Occurrence and adverse eff ect on outcome of
hyperlactatemia in the critically ill. Crit Care 2009, 13:R90. Strategies to reduce glucose variability should be studied to improve
the outcomes in ICU patients. Strategies to reduce glucose variability should be studied to improve
the outcomes in ICU patients. References
1. N Engl J Med 2001, 345:1359. 2. Crit Care Med 2008, 36:2316. 3. Diabetes 2004, 53:955. p
References Conclusion The results demonstrate an infl uence of blood glucose and
blood glucose variability on blood lactate, independent of severity of
illness, in a medical ICU patient population. Variability of insulin sensitivity during the fi rst 4 days of critical
illness Level and variability of SI were compared over time on 24-hour
and 6-hour timescales for the fi rst 4 days of the ICU stay. Figure 1 (abstract P166). i
y
y
Results Cohort and per-patient median SI levels increased by 34% and
33% (P <0.001) between days 1 and 2 of the ICU stay. Concomitantly,
cohort and per-patient SI variability reduced by 32% and 36% (P <0.001). For 72% of the cohort, median SI on day 2 was higher than day 1. The
day 1 and 2 results were the only clear, statistically signifi cant trends
across both analyses. Analysis of the fi rst 24 hours using 6-hour blocks
of SI data showed that most of the improvement in insulin sensitivity
level and variability seen between days 1 and 2 occurred during the
fi rst 12 to 18 hours of day 1. This rapid improvement was probably due
to the decline of counterregulatory hormones as the acute phase of
critical illness progressed.i Conclusion ICU patients have signifi cantly lower and more variable
insulin sensitivity on day 1 than later in their ICU stay and particularly
during the fi rst 12 hours. Clinically, these results suggest that while using Figure 1 (abstract P166). S60 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 TGC protocols with patients during their fi rst few days of ICU stay, extra
care should be aff orded. Increased measurement frequency, higher
target glycaemic bands, conservative insulin dosing and modulation
of carbohydrate nutrition should be considered to safely minimize
outcome glycaemic variability and reduce the risk of hypoglycaemia. Reference Methods We used the Eirus™ system (DipylonMedical, Solna, Sweden)
based on microdialysis for CGM in three mechanically ventilated
patients necessitating continuous intravenous insulin. The CGM
system consists of a dedicated triple-lumen central venous catheter, a
disposable sensor on a reusable sensor holder outside the patient, and
a monitor producing a new measurement each minute. Calibrations
were performed every 8 hours using arterial blood samples and a blood
gas analyzer (Radiometer SAS, Neuilly-Plaisance, France). The attending
nurses also performed intermittent blood glucose measurements with
a point-of-care glucometer in order to set the insulin rate according to
our glucose control method. Evaluation of a continuous blood glucose monitoring system using
a central venous catheter with an integrated microdialysis function
F Möller, J Liska, A Öwall, A Franco-Cereceda Evaluation of a continuous blood glucose monitoring system using
a central venous catheter with an integrated microdialysis function
F Möller, J Liska, A Öwall, A Franco-Cereceda
Karolinska Institutet, Solna, Sweden
Critical Care 2012, 16(Suppl 1):P170 (doi: 10.1186/cc10777) Introduction Glycemic control in critically ill patients has been debated
over the last decade. An accurate glucose monitoring system is
essential to understand and study this concern. We have evaluated the
accuracy and technical feasibility of a continuous glucose monitoring
system using intravascular microdialysis. p
Results The best model for insulin secretion was based on blood
glucose concentration alone. There was clear separation of secretion
levels between normal glucose tolerant (NGT) and impaired glucose
tolerant (IGT) patients. Hence, ISR was modeled as a constrained linear
function of BG (in mmol/l) for NGT and IGT patients separately with
R2 = 0.61 and 0.69 respectively. NGT: ISR = 893×BG – 2,996 (mU/hour). IGT: ISR = 296×BG – 1,644 (mU/hour). The glucose coeffi cients of 893
and 296 mU.l/mmol.hour were comparable to data published in a
number of other studies for healthy and diabetic subjects. Methods Thirty patients undergoing cardiac surgery were monitored
using a triple-lumen central venous catheter (Eirus TLC®; Dipylon
Medical AB, Sweden) with an integrated microdialysis membrane. The catheter was placed with the tip in the superior vena cava, and
functions both as a central venous catheter, enabling blood sampling
and administration of medication, while simultaneously measuring Figure 1 (abstract P170). Clarke error grid analysis. Conclusion This work presents a simple model for pancreatic insulin
secretion in critically ill patients based on clinical data. The model is
a function of blood glucose level and glucose tolerance status and
compares well with published data for healthy and diabetic subjects. This model can be incorporated into glucose–insulin system models
and could potentially improve model-based glycaemic control. References 1. Chase JG, et al.: Crit Care 2008, 12:R49. 2. Van Cauter E, et al.: Diabetes 1992, 41:368-377. 3. Kjems L, et al.: Diabetes 2003, 52:380-386. Variability of insulin sensitivity during the fi rst 4 days of critical
illness GV was assessed by the variability index
defi ned as the mean of the absolute value of the fi rst derivative of the
glucose signal during CGM. In order to simulate sCGM, we extracted
CGM values every 15 minutes for calculating the corresponding
variability index as the mean of the absolute value of the variation rate
between two consecutive measurements. 1. Chase JG, et al.: Crit Care 2008, 12:R49. Endogenous insulin secretion in critically ill patients Endogenous insulin secretion in critically ill patients
C Pretty1, A Le Compte1, J Lin1, G Shaw2, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital
Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P168 (doi: 10.1186/cc10775) y
p
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand y
p
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand Introduction Glucose–insulin system models can be used for improved
glycemic control of critically ill patients. A key component of glucose–
insulin models is pancreatic insulin secretion. There are limited data
in the literature quantifying insulin secretion in critically ill patients at
physiologic levels. This study presents a model of pancreatic insulin
secretion in critically ill patients based on data from a critically ill
population. Results The variability indexes were respectively 1.97, 1.65, 1.55 mmol/l/
hour for CGMS, and 1.07, 0.65, 0.83 mmol/l/hour for sCGMS. Conclusion sCGM in comparison with CGM may considerably under-
estimate a marker of GV during glucose control in critical care patients. Reference 1. Mackenzie et al.: The metrics of glycaemic control in critical care. Intensive
Care Med 2011, 37:435-443. p p
Methods Samples were collected from 19 patients enrolled in a
prospective clinical trial studying sepsis at the Christchurch Hospital
ICU. Fifteen of the patients had confi rmed sepsis and three were
diagnosed type 2 diabetics. All patients were on the SPRINT glycaemic
control protocol [1]. Each patient had arterial blood samples assayed
for insulin and C-peptide. Two sets of four samples were taken from
each patient, with each set collected over 60 minutes. Blood glucose
(BG) data were collected with a bedside glucometer. C-peptide data
were deconvolved using the model and population parameter values
of van Cauter and colleagues [2] to determine pancreatic insulin
secretion rates (ISRs). Data from Kjems and colleagues investigating the
potentiating eff ects of glucagon-like peptide-1 on insulin secretion [3]
suggested a maximum secretion rate of 16 U/hour. A minimum rate of
1 U/hour was also adopted. Pilot trial of STAR in the medical ICU
LM Fi k1 AJ L C
1 GM Sh
2 S P LM Fisk1, AJ Le Compte1, GM Shaw2, S Penning3, T Desaive3, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand; 3Université de Liege, Belgium
Critical Care 2012, 16(Suppl 1):P172 (doi: 10.1186/cc10779) Introduction Medical ICU patients often develop stress-induced
hyperglycemia. Regulating blood glucose (BG) levels in these patients
using insulin can be diffi cult due to varying patient conditions and
therapy, leading to increased risk of hypoglycaemia. This abstract
describes a pilot trial of STAR, a computerised risk-management
accurate glycemic control (AGC) protocol. g y
p
Methods Thirteen hyperglycaemic patients (BG >145 mg/dl) were
consented from Christchurch Hospital ICU. The BG target range was
80 to 145 mg/dl or 108 to 162 mg/dl (chosen clinically). Model-based
insulin sensitivity was calculated for every measurement and its
variability for the next 1 to 3 hours forecast using stochastic models. These data and model were used to calculate new insulin/nutrition
interventions for the next 1 to 3 hours, limiting risk of BG <80 mg/dl to
a maximum of 5%. Nursing staff selected the BG measurement interval
to manage workload. Insulin was delivered as boluses (max 6 U/hour;
max increase +2U/intervention), with infusions up to 3 U/hour for
highly resistant patients. Nutrition was 30 to 100% of clinical goal feed
(max change ±30% per intervention) and constant rates were used
when desired clinically. Limiting insulin/nutrition changes prevents
over-response to erroneous BG measurements and results were
resampled hourly for consistency. Approval was granted by the Upper
South A Regional Ethics Committee (Christchurch, New Zealand). Figure 2 (abstract P170). Bland–Altman analysis. glucose. The patients were monitored for up to 48 hours postoperatively
in the ICU. As reference, arterial blood samples were taken every hour. Results Data were available from all 30 patients. A total of 725 paired
(arterial blood gas–microdialysis) samples were obtained. Glucose
correlation coeffi cient was 0.87. Using Clarke error grid analysis,
100% of the paired samples were in region AB and 97.4% in region A
(Figure 1). Mean glucose level was 8.6 mmol/l, bias –1.3% and mean
absolute relative diff erence was 4.8%. A total 97.5% of the paired
samples were correct according to ISO criteria. Bland–Altman analysis
showed bias ± limits of agreement –0.11 ± 1.3 mmol/l (Figure 2). g
Results Median BG was 109 mg/dl for 80 to 145 mg/dl target patients
and 145 mg/dl for 108 to 162 mg/dl target patients. Impact of the type of glucose monitoring on the assessment of
glycemic variability in critical care patients
P Kalfon, M Chilles
CH Chartres, France
Critical Care 2012, 16(Suppl 1):P169 (doi: 10.1186/cc10776) P Kalfon, M Chilles
CH Chartres, France
Critical Care 2012, 16(Suppl 1):P169 (doi: 10.1186/cc10776) Introduction While minimizing glycemic variability (GV) during glucose
control in critical care patients could become a new therapeutic goal, it
is important to have a reliable assessment of GV. The aim of the study
is to compare a real continuous glucose monitoring (CGM) system
in comparison with a semi-continuous glucose monitoring (sCGM)
system, with respect to the reliability of a marker of GV. Figure 1 (abstract P170). Clarke error grid analysis. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S61 variable and maximum BG levels was considered to link to better
outcome. (3) On the other hand, part of the severe patients seemed
to have the lowest of those variable and maximum BG levels, judging
from two-dimensional or parabolic correlations between those BG
parameters and SOFA scores. Figure 2 (abstract P170). Bland–Altman analysis. P172 P172
Pilot trial of STAR in the medical ICU
LM Fisk1, AJ Le Compte1, GM Shaw2, S Penning3, T Desaive3, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand; 3Université de Liege, Belgium
Critical Care 2012, 16(Suppl 1):P172 (doi: 10.1186/cc10779) Pilot trial of STAR in the medical ICU
LM Fi k1 AJ L C
1 GM Sh
2 S P In total, 85.6% of
time was in the specifi ed target band, with 1.18% of BG <72 mg/dl and
2.41% BG <80 mg/dl. BG measurement frequency was 13.3 measures/
day. Per-patient median carbohydrate intake was 10.7 g/hour (IQR: 4.0
to 11.9 g/hour) and median insulin usage was 2.5 U/hour (IQR: 1.75 to
3.5 U/hour). Requirements varied considerably by patient. Observed
response to insulin varied by a factor of 14× between patients. Accurate
control was maintained over a range of metabolic conditions, and STAR
adapted safely to therapies including high-dose steroids, long-acting
insulin (Glargine) and changing insulin response. Conclusion Central venous microdialysis is an accurate and reliable
method for continuous blood glucose monitoring in critically patients. P171 P171
Variable and maximum blood glucose levels during the fi rst week
after ICU admission are related to the severity of the patients
M Hoshino1, Y Haraguchi2, K Oda1, S Kajiwara1
1Shisei Hospital, Saitama, Japan; 2Geriatric Health Services Facility,
Kokubunnji-shi, Japan
Critical Care 2012, 16(Suppl 1):P171 (doi: 10.1186/cc10778) Conclusion STAR provided AGC in a clinical setting. Tight and accurate
control was able to be extended to patients with a range of metabolic
requirements, and the risk-management approach proved capable of
balancing clinical workload and risks presented by patient variability. Introduction Signifi cance of blood glucose (BG) control in ICU patients,
especially in terms of mortality reduction, has been recognized in
recent years. However, the relationship between BG profi le and the
severity, as well as BG target, is not clearly elucidated. A preliminary
study was performed in order to clarify the relationship between BG
profi le and the severity of ICU patients. Glucometer accuracy and implications for clinical studies
AJ Le Compte1, CG Pretty1, GM Shaw2, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P173 (doi: 10.1186/cc10780) P174 Initial experience with continuous intra-arterial fl uorescent glucose
monitoring in patients in the ICU following cardiac surgery
S Bird1, L Macken1, O Flower1, E Yarad1, F Bass1, N Hammond1, D LaCour2,
P Strasma2, S Finfer1
1Royal North Shore Hospital, St Leonards, NSW, Australia; 2GluMetrics, Inc.,
Irvine, CA, USA
Critical Care 2012, 16(Suppl 1):P174 (doi: 10.1186/cc10781) Introduction A need for continuous blood glucose monitoring has
always been expressed by critical care practitioners. The results from
several iterations of a novel optical fl uorescence-based intravascular
blood glucose sensor were examined for correlation with an accepted
laboratory assay. Ever since Van Den Berghe’s group demonstrated
reductions in hospital mortality and morbidity from the application of
tight glycaemic control [1], many groups have attempted to replicate
those results with limited success. Practitioners have speculated
upon the reasons behind this observation, and have cited manpower
implications and incidence of hypoglycaemic episodes as contributing
factors [2]. Investigators have speculated that a continuous blood
glucose sensor might contribute towards safe eff ective glycaemic
control [3]. Critical Care 2012, 16(Suppl 1):P174 (doi: 10.1186/cc10781) Introduction Continuous glucose monitoring (CGM) in ICUs has
the potential to improve patient safety and outcomes. The GluCath
Intravascular CGM System uses a novel quenched chemical fl uorescence
sensing mechanism to measure glucose concentration (BG) in venous
or arterial blood. This is the fi rst report of its use in cardiac surgery
patients. p
Methods This ongoing clinical study is evaluating the system deployed
via a standard 20G radial artery catheter inserted for routine care in
20 patients undergoing cardiac surgery. Data are presented from
fi ve run-in patients. Outcome measures are qualitative (ease-of-use,
workfl ow fi t) and quantitative (accuracy vs. reference analyzer). Sensors
were inserted shortly after ICU admission with placement confi rmed
by ultrasound and in vivo calibration 30 minutes later. Clinical staff
managed blood glucose according to usual protocols. Glucose values
were recorded each minute for 24 hours; hourly reference samples
from the same arterial catheter were analyzed on a Radiometer ABL
Blood Gas Analyzer.i Methods A series of postoperative and direct admission ICU patients
had an optical fl uorescence-based intravascular glucose sensor
(GlySure Ltd, Abingdon, UK) placed into the left internal jugular vein
on admission to the ICU. The sensor remained in situ throughout the
ICU stay. Periodic blood samples and simultaneous real-time values
of blood glucose measured by the sensor were recorded. Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 patient. The defi ned cut-off for ‘good’ control for a patient was ≥70%
of BG in 72 to 126 mg/dl (cTIB ≥0.7), and ‘poor’ as <70% (cTIB <0.7),
based on original observed clinical BG. The number of true BG profi les
that resulted in misclassifi cation between ‘good’ and ‘poor’ control for a
patient was recorded over all Monte-Carlo runs. The maximum change
in true and observed BG mean and standard deviation were used to
evaluate potential worst-case scenarios. Figure 1 (abstract P174). ISO-modifi ed Bland–Altman plot. Results Good control was clinically measured in 76% of patients (24%
with cTIB <0.7). Of these, 83% of ‘good’ and 64% of ‘poor’ control would
never be misclassifi ed over all 100 runs due to sensor error. A total of
91% (good) and 87.5% (poor) could be misclassifi ed 10% of the time. Patients with cTIB near 0.7 were more likely to be misclassifi ed when
accounting for glucometer error. Hence, a deadband around the cut-off
would reduce this misclassifi cation. If ‘good’ cut-off was cTIB ≥0.5 (95%
of clinical patients) then 100% correct classifi cation was 97% for good
control patients, but fell to 40% of poor control patients. The median
largest diff erence in observed and true mean BG across patients was
–54 mg/dl (90th percentile: –21 mg/dl) and the standard deviation was
3.2 mg/dl (90th percentile: 1.8 mg/dl). g
pi
Patients with cTIB near 0.7 were more likely to be misclassifi ed when
accounting for glucometer error. Hence, a deadband around the cut-off
would reduce this misclassifi cation. If ‘good’ cut-off was cTIB ≥0.5 (95%
of clinical patients) then 100% correct classifi cation was 97% for good
control patients, but fell to 40% of poor control patients. The median
largest diff erence in observed and true mean BG across patients was
–54 mg/dl (90th percentile: –21 mg/dl) and the standard deviation was
3.2 mg/dl (90th percentile: 1.8 mg/dl). Figure 1 (abstract P174). ISO-modifi ed Bland–Altman plot. g
g
Conclusion Glucometers can distinguish between patients that
received good and poor BG control but risk of misclassifi cation
rises for patients nearer cut-off s. P174 The results
were correlated with the results of blood sample analysed by a Yellow
Springs Instrument glucose analyser. The sensor, which has a heparin
coating on its surface, required no further heparinisation; a ‘keep vein
open’ rate of normal saline infusion was maintained throughout the
period of operation.i Results Sixteen patients received the current confi guration blood
glucose sensor; during their combined length of stay, 296 paired values
were obtained for correlation purposes. A total 99.6% of these values
fall within the A+B areas of the Clarke error grid. All sensors continued
to function throughout the length of stay, maximum 92 hours, and
were withdrawn immediately prior to discharge from the ICU. Results The sensor was successfully deployed in all fi ve patients and did
not interfere with clinical care, blood pressure monitoring or sampling. One patient suff ered a cardiopulmonary arrest; the sensor functioned
successfully during resuscitation and urgent return to the operating
room. One hundred and twenty reference samples ranging from 5.9 to
13.4 mmol/l were collected; 107/120 (89.2%) of GluCath measurements
met ISO 15197 criteria (within ±20% of reference when BG >4.2 mmol/l;
Figure 1). In Subject 1 the sensor was inadvertently retracted into the
arterial catheter during the study, leading to measurement error from
arterial fl ush solution contamination. In a sensitivity analysis excluding
this patient, 89/95 (93.7%) of measurements met ISO 15197 with a
mean absolute relative diff erence of 9.4%. Conclusion The pre-production intravascular blood glucose sensors
successfully track blood glucose values, with improved insight into
blood glucose variability in ICU patients. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Reliable classifi cation to associate
with outcomes relies on the control protocol and cut-off choice to
achieve suffi cient separation between groups so that device errors
do not result in signifi cant misclassifi cation confounding the results. A
deadband around cut-off values to eliminate patients at high risk of
misclassifi cation may be required. 5
Preliminary ICU experience of a novel intravascular blood glucose
sensor Preliminary ICU experience of a novel intravascular blood glucose
sensor
KP Mulavisala1, PB Gopal2, B Crane3, A Mackenzie3
1Axon Anaesthesia Associates Care Hospital Nampally, Hyderabad, India;
2Apollo Hospitals, Hyderabad, India; 3Glysure, Abingdon, UK
Critical Care 2012, 16(Suppl 1):P175 (doi: 10.1186/cc10782) KP Mulavisala1, PB Gopal2, B Crane3, A Mackenzie3
1Axon Anaesthesia Associates Care Hospital Nampally, Hyderabad, India;
2Apollo Hospitals, Hyderabad, India; 3Glysure, Abingdon, UK
Critical Care 2012, 16(Suppl 1):P175 (doi: 10.1186/cc10782) 1.
Van den Berghe G, et al.: Intensive insulin therapy in critically ill patients.
N Engl J Med 2001, 345:1359-1367.
2.
Aragon D, et al.: Evaluation of nurse work eff ort and perception about
blood glucose testing in TGC. Am J Crit Care 2006, 15:370-377.
3.
Krinsley J, Preiser JC: Moving beyond TGC to safe eff ective glycemic control
(SEGC). Crit Care 2008, 12:149. Glucometer accuracy and implications for clinical studies
AJ Le Compte1, CG Pretty1, GM Shaw2, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P173 (doi: 10.1186/cc10780) pi
y
p
Methods Forty-seven patients were studied. The following parameters
were calculated during fi rst week after ICU admission. (1) Mean and
maximum value of SOFA scores (SOFAm and SOFAmax, respectively). (2)
Mean, standard deviation, maximum, minimum, and diff erence of BG
levels (BGm, BGsd, BGmax, BGmin, BGd(BGmax – BGmin), respectively). BG levels were measured basically every 6 hours with capillary blood. (3) Correlation coeffi cients (r) between the abovementioned SOFA
scores and BG parameters were calculated using two-dimensional and
linear regression analysis (rt, rl, respectively). AJ Le Compte1, CG Pretty1, GM Shaw2, JG Chase1
1University of Canterbury, Christchurch, New Zealand; 2Christchurch Hospital,
Christchurch, New Zealand
Critical Care 2012 16(Suppl 1):P173 (doi: 10 1186/cc10780) Introduction Elucidating links between glycemic control and clinical
outcome requires reliable discrimination between groups with
diff erent target blood glucose (BG) cut-off s. Point-of-care glucometers
are commonly used, but lower accuracy means BG errors will impact
classifi cation and thus outcome analyses. This study reanalyses a BG
control trial with an error model of a typical glucometer to assess the
impact of sensor errors on interpretation of trial results.i Introduction Elucidating links between glycemic control and clinical
outcome requires reliable discrimination between groups with
diff erent target blood glucose (BG) cut-off s. Point-of-care glucometers
are commonly used, but lower accuracy means BG errors will impact
classifi cation and thus outcome analyses. This study reanalyses a BG
control trial with an error model of a typical glucometer to assess the
impact of sensor errors on interpretation of trial results. t
l
Results (1) rt and rl (rt/rl) between SOFAmax and BG parameters: BGsd
(0.48/0.36), BGmax (0.47/0.33), BGd (0.47/0.35), BGm (0.30/0.22),
BGmin (0.21/0.36). (2) (rt/rl) between SOFAm and BG parameters: BGsd
(0.45/0.33), BGmax (0.45/0.28), BGd (0.45/0.30), BGm (0.28/0.17), BGmin
(0.17/0.29).i Methods BG profi les from 301 patients (stay >24 hours) from the
SPRINT trial with BG measurements (n = 25,000) using the Arkray
SuperGlucocard II GT-1630. A model of sensor bias and variance (CV
2.7 to 3.5%, regression: y = 3.92 + 0.97x) was used to estimate possible
‘true’ BG profi les from measured BG and repeated 100 times for each Conclusion (1) Variable and maximum BG levels during the fi rst week
(BGsd, BGd, BGmax), rather than mean and minimum BG levels (BGm,
BGmin), were related to the severity. (2) Suppression of the higher S62 g
References 1. Van den Berghe G, et al.: Intensive insulin therapy in critically ill patients. N Engl J Med 2001, 345:1359-1367. 2. Aragon D, et al.: Evaluation of nurse work eff ort and perception about
blood glucose testing in TGC. Am J Crit Care 2006, 15:370-377. 3. Krinsley J, Preiser JC: Moving beyond TGC to safe eff ective glycemic control
(SEGC). Crit Care 2008, 12:149. f
Conclusion The GluCath System measured glucose concentration
continuously in a cardiac surgery ICU without compromising arterial
line function or patient care. In all patients the sensor operated without
interruption for 24 hours following a single in vivo calibration. 2. Aragon D, et al.: Evaluation of nurse work eff ort and perception about
blood glucose testing in TGC. Am J Crit Care 2006, 15:370-377. 3. Krinsley J, Preiser JC: Moving beyond TGC to safe eff ective glycemic control
(SEGC). Crit Care 2008, 12:149. S63 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 in ‘tight’ glycaemic control [2]; however, recent negative studies have
dampened this interest [3]. In view of more recent analyses, which off er
possible explanations for equivocal results [4], it is possible there will
be renewed interest in glycaemic control. The purpose of this survey is
to assess the utilisation of tight glycaemic control protocols in a sample
of ICUs in England, as a refl ection of current UK intensive care practice. Methods We identifi ed 171 large acute hospital trusts, of which 87
were randomly selected. Of these, 85 had ICUs, which were contacted
by telephone. The senior nurse in charge at the time was asked whether
their ICU used a protocol for the management of blood glucose, and
what were the upper and lower target limits. P176
Does tight glycemic control positively impact on patient mortality? S Penning1, AJ Le Compte2, M Signal2, P Massion3, JC Preiser4, GM Shaw5,
T Desaive1, JG Chase2
1Université de Liege, Belgium; 2University of Canterbury, Christchurch, New
Zealand; 3CHU de Liège, Belgium; 4Erasme University Hospital, Brussels,
Belgium; 5Christchurch Hospital, Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P176 (doi: 10.1186/cc10783) Introduction High and variable blood glucose (BG) levels have been
associated with increased mortality. Tight glycemic control (TGC) aims
at reducing BG levels to improve patient outcome and mortality. This
research evaluates the impact of TGC on mortality. pp
g
Results A blood glucose protocol was used in 87.1% of ICUs
surveyed. References y
Conclusion Results show that, irrespective of TGC protocols, high cTIB
and thus normoglycemia are associated with higher odds of living. This
suggests that TGC positively infl uences patient outcome. 1. Van den Berghe G, et al.: N Engl J Med 2001, 345:1359-1367. 2. Mackenzie et al.: Intensive Care Med 2005, 31:1136. 2. Mackenzie et al.: Intensive Care Med 2005, 31:1136. 3. NICE-SUGAR Study Investigators: N Engl J Med 2009, 360:1283. 4. Mackenzie et al.: Intensive Care Med 2011, 37:435-443. 3. NICE-SUGAR Study Investigators: N Engl J Med 2009, 360:1283. 4. Mackenzie et al.: Intensive Care Med 2011, 37:435-443. g
References Of these, the median lower limit of allowed blood glucose
concentration was 4.0 mmol/l (range 3.0 to 7.0), with an upper limit of
8.0 mmol/l (range 6.0 to 12.0). Only 22 ICUs (25.9%) had a target range
similar to the Leuven study. A further 34 ICUs used a lower limit similar
to the Leuven study, of 4.0 to 4.5 mmol/l, but had a higher upper limit. This is refl ective of the general opinion from the nurses contacted, that
a tight protocol is diffi cult to achieve, can result in hypoglycaemia, and
has been recently relaxed in many departments. y
Methods This study used glycemic data from 1,488 patients of two
cohorts: Glucontrol (n = 704) and SPRINT (n = 784). TGC glycemic
outcome is measured by cumulative time in the 4 to 7 mmol/l band
(cTIB), defi ned daily for each patient. Each day, patients were divided
into two groups: cTIB <70% and cTIB ≥70%. For each group, odds of
living (OL = #lived / #died) was calculated. g
Results OL for cTIB ≥70% patients tends to increase over time while OL
for cTIB <70% patients decreases (Figure 1). On Day 1, OL for cTIB <70%
patients and cTIB ≥70% patients are similar (OL = 5.1 and OL = 5.5
respectively). The diff erence between the two groups increases over
the ICU stay. On Day 10, OL = 2.8 and OL = 10.5 for cTIB <70% and cTIB
≥70% patients respectively. These results suggest that survival rate is
higher when cTIB ≥70% and thus when BG levels are tightly controlled
around normoglycemia. The longer patients’ ICU stay, the lower survival
rate they have when cTIB <70%. Conclusion Our data suggest that glycaemic control has, to a very
large extent, been accepted as a standard of care in the UK, although
in most ICUs this does not constitute tight glycaemic control. The full
benefi t of tight glycaemic control, achieved by minimisation of mean
glucose, glucose variability and episodes of hypoglycaemia, will not be
achieved until robust techniques for continuous, or semi-continuous,
blood glucose measurement are available. References P179 P179
Perioperative glycemic control with a computerized algorithm
versus conventional glycemic control
M Punke1, S Bruhn1, M Goepfert1, S Kluge1, H Reichenspurner2, A Goetz1,
D Reuter1
1University Medical Center Hamburg–Eppendorf, Hamburg, Germany;
2University Heart Center, Hamburg, Germany
Critical Care 2012, 16(Suppl 1):P179 (doi: 10.1186/cc10786) P179
Perioperative glycemic control with a computerized algorithm
versus conventional glycemic control
M Punke1, S Bruhn1, M Goepfert1, S Kluge1, H Reichenspurner2, A Goetz1,
D Reuter1
1University Medical Center Hamburg–Eppendorf, Hamburg, Germany;
2University Heart Center, Hamburg, Germany
Critical Care 2012, 16(Suppl 1):P179 (doi: 10.1186/cc10786) P179
Perioperative glycemic control with a computerized algorithm
versus conventional glycemic control Introduction In critically ill patients, both hypoglycemia and
hyperglycemia seem to infl uence outcome. Since hypoglycemia can
lead to organ dysfunction, hyperglycemia seems to boost surgical
site infections (SSI) [1]. It was shown that intensive insulin therapy
(IIT) reduced mortality in critically ill patients [2]. Unfortunately
several studies could not reproduce the eff ects [3,4]. In particular, IIT
bears the risk of accidental hypoglycemia which could even have a
negative eff ect on patient outcome [3,4]. In cardiac surgery, the use
of blood cardioplegia for cardiopulmonary bypass frequently leads to
high blood glucose levels during surgery. In particular, a computer-
based algorithm that guides the insulin therapy might be benefi cial. We hypothesized that in patients undergoing major cardiac surgery
with cardiopulmonary bypass and blood cardioplegia, the use of a
computer-based algorithm for the application of insulin will lead to a
tighter adherence of normoglycemia. Our primary study end-point was
the duration, in which the patients fulfi lled the predefi ned target range
of 80 to 150 mg/dl blood glucose. Patients with conventional blood
glucose therapy served as controls.i Results The response of the MPC controller to measured deviations in
glucose is shown in Figure 1. For glucose measurements below target,
glucose is administered, while insulin administration is used to lower
blood glucose from an elevated state to a desired target. The model
parameter pG2, representing patient insulin sensitivity (insulin action
on glucose uptake), was used by the MHE algorithm to tailor the model
response to simulated patient dynamics. In response to pG2 changes
in the simulated patient, MHE provided a 93% improvement in glucose
reference tracking performance. g
Conclusion The algorithm achieves tight glucose control in response
to multiple measured and unmeasured disturbances. Furthermore, the
MHE scheme updates patient parameters in real time in response to
changing patient dynamics. 1.
Roy et al.: Diab Tech Ther 2006, 8:617-626. P177 P178
Model-based regulation of glucose in critical care
SP Gawel1, G Clermont2, RS Parker1
1University of Pittsburgh, PA, USA; 2University of Pittsburgh Medical Center,
Pittsburgh, PA, USA
Critical Care 2012, 16(Suppl 1):P178 (doi: 10.1186/cc10785) Introduction Following van den Berghe’s landmark paper in 2001
(Leuven study) [1], the critical care community became very interested Introduction Glucose control in critical care has been shown to
improve patient outcome, yet tight glucose control has led to increased Figure 1 (abstract P176). Whole-cohort odds of living over ICU stay. Figure 1 (abstract P176). Whole-cohort odds of living over ICU stay. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S64 Critical Care 2012, Volume 16 Suppl 1
htt //
f
/
l
t /16/S1 http://ccforum.com/supplements/16/S1 Figure 1 (abstract P178). Figure 1 (abstract P178). Figure 1 (abstract P178). P179 hypoglycemia in the clinic. We employed a systems engineering
approach to assist clinicians in maintaining blood glucose within a
desired target range while avoiding hypoglycemia in the critically
ill. The long-term vision is a decision support system that provides
recommended insulin and glucose administrations leading to patient-
specifi c achievement of tight glucose control without hypoglycemia. Methods To achieve these goals, we employ a model predictive control
(MPC) algorithmic platform using two control inputs: insulin for glucose
control and glucose for hypoglycemia. The MPC controller is designed
based on a nonlinear dynamic model of glucose–insulin–fatty acid
interactions [1]. A moving horizon estimation (MHE) technique is used
to alter the tissue sensitivity to insulin based on deviations between
measurements and model predictions of glucose concentration as
a mechanism for tailoring the controller model to individual patient
dynamics. hypoglycemia in the clinic. We employed a systems engineering
approach to assist clinicians in maintaining blood glucose within a
desired target range while avoiding hypoglycemia in the critically
ill. The long-term vision is a decision support system that provides
recommended insulin and glucose administrations leading to patient-
specifi c achievement of tight glucose control without hypoglycemia. hypoglycemia in the clinic. We employed a systems engineering
approach to assist clinicians in maintaining blood glucose within a
desired target range while avoiding hypoglycemia in the critically
ill. The long-term vision is a decision support system that provides
recommended insulin and glucose administrations leading to patient-
specifi c achievement of tight glucose control without hypoglycemia. Methods To achieve these goals, we employ a model predictive control
(MPC) algorithmic platform using two control inputs: insulin for glucose
control and glucose for hypoglycemia. The MPC controller is designed
based on a nonlinear dynamic model of glucose–insulin–fatty acid
interactions [1]. A moving horizon estimation (MHE) technique is used
to alter the tissue sensitivity to insulin based on deviations between
measurements and model predictions of glucose concentration as
a mechanism for tailoring the controller model to individual patient
dynamics. References References
1. Ann Intern Med 2007, 146:233-243. 2. N Engl J Med 2001, 345:1359-1367. 3. N Engl J Med 2006, 354:449-461. 4. N Engl J Med 2009, 360:1283-1297. g
p
Methods All ICU patients from HUPR diagnosed with SCASTE within the
fi rst 24 hours from January 2005 to December 2010 were included in
this study and registered in the ARIAM-Andalucia Project. This database
gathers the whole PAI from preadmission (PH), ER, ICU, hemodynamics
laboratory and cardiology ward to discharge. Within these 6 years
three main interventions were carried out: fi brinolysis protocol PH with
ER and critical care unit EMS involving the ICU, continuous update of
protocols based on AHA clinical guidelines, and 24-hour availability of
the hemodynamic laboratory for primary coronary intervention (P-ICP
available since 1 February 2007). Revascularization indexes are analyzed
and grouped in 2-year periods (A, B, C), the time justifi ed as necessary
for modifi cation after the intervention, attention times and PH action. The latter was measured by a score (aspirin, nitroglycerine, ECG, vein
access, intravenous treatment and monitoring during transport) up to
6 points. A correct intervention must obtain at least 4 points. Statistical
processing was by the R-UCA pack from R-Commander. 1. Ann Intern Med 2007, 146:233-243. 2. N Engl J Med 2001, 345:1359-1367. 3. N Engl J Med 2006, 354:449-461. 4. N Engl J Med 2009, 360:1283-1297. P180
Effi cacy of the novel heart attack centre extension pathway: a pilot
study
D Perera1, B Hoonjan1, K Krishnathasan1, M Selvanyagam1, H Neugebauer2
1Barts and The London School of Medicine and Dentistry, London, UK;
2Queens Hospital, Barking Havering and Redbridge NHS Trust, London, UK
Critical Care 2012, 16(Suppl 1):P180 (doi: 10.1186/cc10787) Results A total of 590 patients were included in this study: 188 (A),
227 (B) and 175 (C). All groups were similar in mean age, gender, IAM
location and origin. A statistically signifi cant increase was found in the
revascularization and PHA attention between periods A versus C and
B versus C with P <0.0001 and CI (0.15 to 0.42)/(0.17 to 0.45) and (0.2
to 0.6)/(0.11 to 0.39). No statistically signifi cant diff erence was found
among groups A versus B. No signifi cant diff erence was observed in
attention times. Prognostic value of Killip classifi cation in terms of health-related
quality of life y
A Ioannidis1, D Tsounis1, A Pechlevanis2, M Paraskelidou2
1HOU, Kalamaria, Greece; 2GHT ‘Agios Pavlos’, Kalamaria, Greece
Critical Care 2012, 16(Suppl 1):P182 (doi: 10.1186/cc10789) A Ioannidis1, D Tsounis1, A Pechlevanis2, M Paraskelidou2
1HOU, Kalamaria, Greece; 2GHT ‘Agios Pavlos’, Kalamaria, Greece
Critical Care 2012, 16(Suppl 1):P182 (doi: 10.1186/cc10789) Results The average time for patients to have an angiography via the
IHT pathway was 5.5 days. Of the 33 patients (mean age 61 ± 15.2 SD)
transferred via HACX, 30 patients (91%) were appropriately identifi ed
for an angiogram. Seventeen patients (52%) required PCI, fi ve patients
(15%) required CABG, four patients (12%) required nonsurgical
intervention, and four patients (12%) required no treatment. Controls
included 37 patients (mean age 71 ± 12.6 SD) of whom 17 patients
(46%) required PCI, six patients (16%) required CABG, eight patients
(22%) required nonsurgical intervention and six patients (16%)
required no treatment. At 3-month follow-up, 32 patients (97%) in the
HACX cohort and 36 patients (97%) in the IHT cohort were alive.fi Introduction The aim of the study was to evaluate the prognostic value
of Killip classifi cation in terms of health-related quality of life (HRQoL). Methods The sample consisted of 112 patients treated for myocardial
infarction (MI), as onset manifestation of coronary artery disease (CAD),
during 2008/09 in a prefectural hospital in northern Greece. At 1-year
follow-up visit, HRQoL was measured using a generic and a disease-
specifi c instrument. The 15D consists of a visual analogue scale (VAS)
and a total score. The scoring algorithm of the MacNew generates a
global score, and three separate domains scores: emotional, physical
and social. Introduction The aim of the study was to evaluate the prognostic value
of Killip classifi cation in terms of health-related quality of life (HRQoL). Results Patients were grouped into the four Killip classes according
to the degree of pulmonary congestion at admission (Table 1). Mean
HRQoL for each group diff ered in the expected manner: the higher
the class, the lower the HRQoL. Statistical signifi cant diff erences were
observed in VAS of the 15D and the emotional and social domain scores
of the MacNew. Accordingly, the majority of patients with no signs of
pulmonary congestion at admission were classifi ed in NYHA functional
class I at 1-year follow-up visit. Integral assistance process implantation for ST-elevated acute
coronary syndrome Results There were no statistical diff erences between the groups
regarding age, height, weight, premedical history or intraoperative
amount of glucose administration during cardioplegia (33 ± 15 g). Blood glucose levels in groups 1 and 2 stayed signifi cantly longer in
the target interval compared with group 3 (75 ± 19% vs. 72 ± 19%;
vs. 50 ± 34%, P <0.01, n = 25, respectively). There was no signifi cant
diff erence between the groups regarding ICU or hospital stay and SSI
rates. JC Rodriguez-Yañez, M Celaya-Lopez, MJ Huertos-Ranchal, I Diaz-Torres,
C Navarro-Ramirez, J Gomez-Ramos
Hospital Universitario Puerto Real, Spain
Critical Care 2012, 16(Suppl 1):P181 (doi: 10.1186/cc10788) JC Rodriguez-Yañez, M Celaya-Lopez, MJ Huertos-Ranchal, I Diaz-Torres,
C Navarro-Ramirez, J Gomez-Ramos
Hospital Universitario Puerto Real, Spain
Critical Care 2012, 16(Suppl 1):P181 (doi: 10.1186/cc10788) Introduction The objective was to evaluate the implantation of
assistance process implantation (PAI) for ST-elevated acute coronary
syndrome (SCASTE) in our sanitary district. When we refer to PAI, we
mean protocolysed assistance guidelines developed and published
by Andalucia sanitary authorities that include recommendations to
direct the assistance from the beginning of the process until patient
discharge from the hospital. Conclusion Early computer-based insulin therapy allows one to better
warrant normoglycemia in patients undergoing major cardiac surgery
with the use of blood cardioplegia. References Introduction The Barts and the London Heart Attack Centre Extension
(HACX) programme was introduced to provide a direct pathway for
high-risk non-ST elevation myocardial infarction (NSTEMI) patients
from the A&E of a district general hospital to a tertiary intervention
centre. As a result, patients have earlier access to angiography and
subsequent treatment, including percutaneous coronary intervention
(PCI), coronary artery bypass grafting (CABG) or nonsurgical inter ven-
tions. There is no research on the eff ectiveness of this novel HACX
programme. Conclusion Coordination of the SCASTE attention, constant analysis
by continuous registry of diff erent action levels (ARIAM-Andalucia
registry), clinical guideline updates and adjustment to resources
and environment, in this case a rural setting, meaning quality
and a continuous improvement circle, reduce variability and lead
undoubtedly to better assistance for our patients. Methods Over 3 months, 33 patients transferred via the HACX pathway
and 37 patients transferred via the conventional interhospital transfer
pathway (IHT) were followed up. All patients with acute coronary
syndrome symptoms, relevant ECG changes (ST segment depression
in two or more contiguous leads >1 mm, pathological T-wave inversion
in V1 to V4, a GRACE score >88 and troponin I levels >0.1 ng/ml) were
discussed with the cardiology team at the interventional centre prior
to immediate transfer. We assessed patient suitability for angiography,
post-angiography procedures, and 3-month mortality outcomes. Data
were obtained from the hospital’s PAS computer system. P182 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Statistical analysis was performed with using ANOVA and the LPS post
hoc test. Data shown are mean ± standard deviation, n = number of
patients. P179 The adaptive MPC algorithm is currently
being validated using a retrospective cohort of critically ill patients at
the University of Pittsburgh Medical Center. Methods Seventy-fi ve patients were enrolled and randomized into
three groups. Start of therapy was determined as the beginning of
cardiopulmonary bypass. Group 1: therapy with computer-based
blood glucose control (TGC System; Braun, Melsungen, Germany)
and measurement of blood glucose every 30 minutes. Group 2:
same therapy as group 1 and measurement of blood glucose every
15 minutes. Group 3: conventional therapy using a fi xed insulin
dosing scheme. End of therapy was defi ned as discharge from the ICU. Acknowledgements Funded by NIH-R21-DK092813. Reference S65 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Prognostic value of Killip classifi cation in terms of health-related
quality of life No diff erence was observed in the type Conclusion HACX is an eff ective pathway that accurately identifi es and
rapidly transfers appropriate NSTEMI patients requiring early coronary
revascularisation. However, there was no additional mortality benefi t at
3-month follow-up compared to the conventional IHT pathway. Further
studies with larger patient cohorts and longer follow-up periods are
required to substantiate the benefi ts of the HACX programme in order
to consider whether this service could be implemented nationwide, or
whether this is a service that does not need to exist at all. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S66 of MI, although patients in higher Killip classes had more aff ected
arteries and were treated more often with CABG than PCI. Additionally,
Killip class I patients were favored in a number of parameters including
age, systolic blood pressure, heart rate, BMI, NT-proBNP level and LVEF. Conclusion Patients with MI as an onset manifestation of CAD present
ith
i d d
f
l
ti
Th
ti
l
Table 1 (abstract P182). Prognostic value of Killip classifi cation in terms of health-related
quality of life Methods In this retrospective study, the medical records of 619 patients
with an admitting diagnosis of STEMI from Tan Tock Seng Hospital,
Emergency Department between 1 January 2009 and 31 December
2009 were reviewed. We extracted data from the electronic records of
the emergency case notes and inpatient discharge summaries. Results Among 619 patients, 363 (58.6%) arrived by emergency medical
services (EMS) and 256 (41.4%) by self-transport. Three hundred and
thirty (53.3%) patients underwent emergency angiography, of which
313 (94.9%) were treated with percutaneous coronary intervention
(PCI), eight (2.4%) with coronary artery bypass grafting (CABG) and nine
(2.7%) were conservatively managed. The D2B time was signifi cantly
shorter in patients who arrived by EMS (60 vs. 82 minutes; P <0.001). There was no diff erence in D2B time between patients who arrived in
the day (06:00 to 17:59 hours) or at night (18:00 to 05:59 hours). Chest
pain, shortness of breath and diaphoresis were the three commonest
presenting symptoms in patients with STEMI regardless of their mode
of arrival. Previous myocardial infarction, PCI or CABG did not infl uence
the mode of transport. Patients who arrived by EMS had a higher
incidence of cardiogenic shock (20.7% vs. 11.7%; P = 0.020) and were
signifi cantly older (63 vs. 59 years; P = 0.004) than patients who arrived
by self-transport. Patients who arrived by EMS had a higher in-hospital
mortality rate (12.1% vs. 5.1%; P = 0.003) and a longer mean length
of stay compared to those who arrived by self-transport (6 vs. 4 days;
P = 0.004). C
l
i
I
t d
l ti
ti
t
ith STEMI
h
d EMS Table 1 (abstract P182). Patient characteristics according to Killip
classifi cation P183
Modes of arrival, door to balloon time and its impact on morbidity
and mortality for ST elevation myocardial infarct
YC Chia
Tan Tock Seng Hospital, Singapore
Critical Care 2012, 16(Suppl 1):P183 (doi: 10.1186/cc10790) P183
Modes of arrival, door to balloon time and its impact on morbidit
and mortality for ST elevation myocardial infarct
YC Chia
Tan Tock Seng Hospital, Singapore
Critical Care 2012, 16(Suppl 1):P183 (doi: 10.1186/cc10790) Introduction Timely reperfusion of the occluded coronary artery is
crucial in reducing the amount of myocardial damage in patients with
ST elevation myocardial infarct (STEMI). Prognostic value of Killip classifi cation in terms of health-related
quality of life Patient characteristics according to Killip
classifi cation
Class I
Class II
Class III
Class IV
P value
n (%)
52 (46.4)
40 (35.7)
14 (12.5)
6 (5.4)
NA
HRQoL (mean)
15D
VAS
78.9
76.9
72.9
70.8
0.025
Total
0.844
0.842
0.823
0.803
0.478
MacNew
Emotional
5.60
5.61
5.38
5.05
0.030
Physical
5.49
5.26
5.25
5.05
0.144
Social
5.72
5.47
5.30
5.14
0.014
Global
5.52
5.44
5.27
4.98
0.056
Age (years)
61.8
66.0
70.2
61.2
0.013
Gender (n, %)
Male (85)
40 (47.1)
31 (36.5)
12 (14.1)
2 (2.4)
0.080
Female (27)
12 (44.4)
9 (33.3)
2 (7.4)
4 (14.8)
ΒΜΙ
28.7
29.1
30.0
34.8
0.001
Systolic BP
127.5
122.5
115.7
140.0
0.000
Diastolic BP
75.8
73.6
70.7
76.7
0.173
Heart rate
64.9
68.7
72.3
71.7
0.030
CRP
3.6
4.9
6.0
3.8
0.087
NT-proBNP
741
1645
2193
1674
0.000
LVEF
61.9
55.2
49.0
45.0
0.000
MI type (n, %)
STEMI (48)
24 (50.0)
18 (37.5)
4 (8.3)
2 (4.2)
0.638
NSTEMI (64)
28 (43.8)
22 (55.0)
10 (15.6)
4 (6.3)
Aff ected arteries (n, %)
1 (38)
19 (50.0)
15 (39.5)
4 (10.5)
0 (0.0)
0.005
2 (30)
17 (56.7)
9 (30.0)
4 (13.3)
0 (0.0)
3 (44)
16 (36.4)
16 (36.4)
6 (13.6)
6 (13.6)
Revascularization technique (n, %)
None (14)
7 (50.0)
3 (21.4)
4 (28.6)
0 (0.0)
0.002
PCI (63)
35 (55.6)
22 (34.9)
6 (9.5)
0 (0.0)
CABG (35)
10 (28.6)
15 (42.9)
4 (11.4)
6 (17.1)
ΝΥΗΑ
Ι (73)
42 (57.5)
21 (28.8)
8 (11.0)
2 (2.7)
0.013
ΙΙ (37)
8 (21.6)
19 (51.4)
6 (16.2)
4 (10.8)
ΙΙΙ (2)
2 (100.0)
0 (0.0)
0 (0.0)
0 (0.0)
Rho
0.28
0.001 P183
Modes of arrival, door to balloon time and its impact on morbidity
and mortality for ST elevation myocardial infarct
YC Chia
Tan Tock Seng Hospital, Singapore
Critical Care 2012, 16(Suppl 1):P183 (doi: 10.1186/cc10790)
Introduction Timely reperfusion of the occluded coronary artery is
crucial in reducing the amount of myocardial damage in patients with
ST elevation myocardial infarct (STEMI). This study aims to examine the
common presenting symptoms of patients with STEMI, their modes of
arrival at the emergency department (ED) and its impact on door-to-
balloon (D2B) time and in-hospital morbidity and mortality. Prognostic value of Killip classifi cation in terms of health-related
quality of life This study aims to examine the
common presenting symptoms of patients with STEMI, their modes of
arrival at the emergency department (ED) and its impact on door-to-
balloon (D2B) time and in-hospital morbidity and mortality. Methods In this retrospective study, the medical records of 619 patients
with an admitting diagnosis of STEMI from Tan Tock Seng Hospital,
Emergency Department between 1 January 2009 and 31 December
2009 were reviewed. We extracted data from the electronic records of
the emergency case notes and inpatient discharge summaries. g
y
p
g
Results Among 619 patients, 363 (58.6%) arrived by emergency medical
services (EMS) and 256 (41.4%) by self-transport. Three hundred and
thirty (53.3%) patients underwent emergency angiography, of which
313 (94.9%) were treated with percutaneous coronary intervention
(PCI), eight (2.4%) with coronary artery bypass grafting (CABG) and nine
(2.7%) were conservatively managed. The D2B time was signifi cantly
shorter in patients who arrived by EMS (60 vs. 82 minutes; P <0.001). There was no diff erence in D2B time between patients who arrived in
the day (06:00 to 17:59 hours) or at night (18:00 to 05:59 hours). Chest
pain, shortness of breath and diaphoresis were the three commonest
presenting symptoms in patients with STEMI regardless of their mode
of arrival. Previous myocardial infarction, PCI or CABG did not infl uence
the mode of transport. Patients who arrived by EMS had a higher
incidence of cardiogenic shock (20.7% vs. 11.7%; P = 0.020) and were
signifi cantly older (63 vs. 59 years; P = 0.004) than patients who arrived
by self-transport. Patients who arrived by EMS had a higher in-hospital
mortality rate (12.1% vs. 5.1%; P = 0.003) and a longer mean length
of stay compared to those who arrived by self-transport (6 vs. 4 days;
P = 0.004). Conclusion In our study population, patients with STEMI who used EMS
tend to be older and arrived in cardiogenic shock. They therefore had a
higher incidence of in-hospital mortality and morbidity although their
D2B time was shorter compared to those who arrived by self-transport. Next-generation, fast and accurate point-of-care test for NT-proBNP
based on Magnotech technology
B Inçaurgarat1, J Nieuwenhuis2
1bioMérieux, Marcy L’Etoile, France; 2Philips, Eindhoven, the Netherlands
Critical Care 2012, 16(Suppl 1):P184 (doi: 10.1186/cc10791) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results Assay precision was characterised by CV levels of less than
10%. NT-proBNP results correlated well with VIDAS (r = 0.89), with a
corresponding slope of the regression line of 1.12 (95% CI 1.01 to 1.22)
and an intercept of 64.04 (95% CI –73.50 to 109.83). In the current
format under development, the NT-proBNP assay time with plasma
samples is only 5 minutes. We are in the process of adding a fi lter that
will allow measurements from whole blood directly. Flow experiments
show that the fi lling time of the cartridge with whole blood is less than
30 seconds, resulting in a total assay time of less than 6 minutes, and a
time-to-result of less than 8 minutes. involve psychic or physical stressors such as a devastating disaster,
but those clinical features have been not fully investigated. As Ibaraki
prefecture suff ered from the Great East Japan Earthquake, we tried to
clarify the characteristics of TC and investigate whether the Great East
Japan Earthquake increased the occurrence of TC or not. involve psychic or physical stressors such as a devastating disaster,
but those clinical features have been not fully investigated. As Ibaraki
prefecture suff ered from the Great East Japan Earthquake, we tried to
clarify the characteristics of TC and investigate whether the Great East
Japan Earthquake increased the occurrence of TC or not. Methods Eleven consecutive patients with TC (fi ve men, six women)
were enrolled between October 2009 and October 2011 in this study. Patients were diagnosed by echocardiography, left ventriculography,
or nuclear scintigraphy. Absence of signifi cant coronary stenosis
was confi rmed by coronary angiography or coronary computed-
tomography angiography. Clinical characteristics (age, season,
coronary risk factors, the condition that preceded onset as possible
triggering factors and so on), laboratory data (troponin T, creatinine
kinase, and so on) and data of electrocardiography (ECG) were obtained
from reviewing medical records. p
q
Methods Eleven consecutive patients with TC (fi ve men, six women)
were enrolled between October 2009 and October 2011 in this study. Patients were diagnosed by echocardiography, left ventriculography,
or nuclear scintigraphy. Absence of signifi cant coronary stenosis
was confi rmed by coronary angiography or coronary computed-
tomography angiography. Right ventricular apical versus septal pacing: impact on left
ventricular synchrony and function
I Atteia, A Alazab, K Hussein, N Abeed, H Nagi
Cairo University, Cairo, Egypt
Critical Care 2012, 16(Suppl 1):P185 (doi: 10.1186/cc10792) Right ventricular apical versus septal pacing: impact on left
ventricular synchrony and function
I Atteia, A Alazab, K Hussein, N Abeed, H Nagi
Cairo University, Cairo, Egypt
Critical Care 2012, 16(Suppl 1):P185 (doi: 10.1186/cc10792) Introduction Right ventricular apical pacing alters the LV activation
resulting in an adverse eff ect on LV function and synchrony. On
the contrary, RV septal pacing results in narrower QRS and may be
more physiological with less deleterious long-term eff ect on LV
echocardiographic and hemodynamic parameters. y
Methods Forty patients indicated for permanent DDD pacing were
studied. All patients were subjected to transthoracic echocardiography
calculating LVESD, LVEDD, EF% and CO together with tissue Doppler
imaging (TDI) to detect LV dyssynchrony. Patients were randomly
classifi ed into two groups, group I having RV apical pacing and group
II having RV septal pacing. The acute threshold, R-wave sensing and
fl uoroscopic time were measured in all patients and compared in both
groups. Both groups were followed-up over a period of 6 months.i p
Conclusion Although TC seems to mimic anterior STEMI, limb leads
did not tend to show ST change in ECG in our cases. The Great East
Japan Earthquake could increase patients with TC until the tremendous
damage caused by the disaster will be over. Results QRS durations were signifi cantly narrower in group II patients
(148 ± 6.9 vs. 162 ± 6 ms, P = 0.001). Electrical parameters at the time
of implantation were satisfactory for all patients (acute stimulation
threshold was 0.5 ± 0.18 V; R wave sensing was 11 ± 1.6 mV and
ventricular impedance was 630 ± 90 Ohm). No single patient needed
ventricular lead repositioning. The acute pacing threshold, R-wave
sensing, ventricular impedance and fl uoroscopic time did not change
signifi cantly in both groups. During follow-up, it was found that in
group II patients with RV septal pacing there was signifi cantly lower
LVESD (3.0 ± 0.6 vs. 3.4 ± 0.6 cm, P = 0.004), signifi cantly higher LVEF%
(69 ± 13 vs. 61 ± 8, P = 0.01), signifi cantly higher CO (4.9 ± 0.3 vs. 4.5 ± 0.6 l), and signifi cantly lower septal to lateral wall delay in LV using
TDI (72 ± 5 vs. 83 ± 6 ms, P = 0.001) if compared to group I patients with
RV apical pacing. P187 p
p
References 1. Kutarski A, Ruciniski P, Sodolski T, Trojnar M: Factors infl uencing diff erences
of RVA and RVOT pacing hemodynamic eff ects. Europace 2005, 7:288. doi:10.1016/j.eupc.2005.02.104. 2. Hafez M, Small GR, Hannah A, et al.: Impact of temporary right ventricular
pacing from diff erent sites on echocardiographic indices of cardiac
function. Europace 2011. doi: 10.1093/europace/eur 207. Results Out of 250 patients fi ve patients had preoperative CAD and
were excluded. Seven patients (incidence 2.8%) were diagnosed to have
SC. Five out of seven (71.4%) patients were ethanolic and vasopressor
requirement was high in all these patients (Figure 1). Echocardiography
revealed global hypokinesia with left ventricular ejection fraction
between 10 and 25%. They were managed with inotropic support
and four patients required an intraaortic balloon pump (IABP). Two
patients succumbed to cardiogenic shock on the second day (mortality
28.5%). IABP was weaned between 7 and 9 days. Patients had normal
cardiac status at the time of discharge around the fourth week post
liver transplant. Stress cardiomyopathy after live donor liver transplantation:
incidence, risk factors and mortality Introduction The incidence of cardiac complications in the post live
donor liver transplantation (LDLT) period has been reported to be
nearly 70% [1]. Stress cardiomyopathy (SC) is a severe complication
which has varied presentation and has grave prognosis if not diagnosed
and managed aggressively. g
gg
y
Methods Data for 250 LDLTs (June 2010 to July 2011) were collected
to assess incidence, risk factors and mortality due to SC. Diagnostic
criteria [2] for SC were taken as: global hypokinesia or new ST segment
elevation or T-wave inversion in absence of coronary artery disease
(CAD) or pheochromocytoma. Etiologies of chronic liver disease and
preoperative cardiac status along with intraoperative vasopressor use
and dosages were noted. Conclusion Long-term RV septal pacing is feasible, and reliable with
less adverse eff ects on LV synchrony and function when compared to
RV apical pacing. R f P187 Stress cardiomyopathy after live donor liver transplantation:
incidence, risk factors and mortality
S Gupta, D Govil, S Bhatnagar, S Patel, S Srinivasan, P Pandey, M Sodhi,
J KN, P Singh, S Saigal, A Soin, V Vohra, Y Mehta
Medanta – The Medicity, Gurgaon, India
Critical Care 2012, 16(Suppl 1):P187 (doi: 10.1186/cc10794) Next-generation, fast and accurate point-of-care test for NT-proBNP
based on Magnotech technology
B Inçaurgarat1, J Nieuwenhuis2
1bioMérieux, Marcy L’Etoile, France; 2Philips, Eindhoven, the Netherlands
Critical Care 2012, 16(Suppl 1):P184 (doi: 10.1186/cc10791) Introduction In the emergency care setting, where time is of the
essence, there is a need for fast and reliable information on NT-proBNP
levels for diagnosis and management of acute dyspnea. Rapid NT-
proBNP testing near the patient has the potential to streamline the
process of care, but only if it is robust, fast and accurate enough to
operate safely at the point of care (POC). Here we report on a novel
NT-proBNP POC test which can be entirely carried out in a handheld
device. This test has the potential to be rapid (<8 minutes), easy to use
(fi ngerprick sampling), and with good accuracy compared to state-of-
the-art automated laboratory assays. y
y
Methods This new NT-proBNP POC test is based on Magnotech
technology. A one-step sandwich immunoassay is performed in a
compact plastic disposable cartridge with on-board dry reagents and
magnetic nanoparticles. After a short incubation step the amount of
bound nanoparticles, proportional to the concentration of NT-proBNP
in the sample, is detected optically [1]. The precision of the assay was
determined for plasma samples with NT-proBNP levels at clinically
relevant values of 125 ng/l and 411 ng/l (10 replicates). Assay accuracy
was determined by measuring 104 patient samples (lithium heparin
plasma, NT-proBNP levels from 20 to 5,000 ng/l) on both the handheld
device and the bioMérieux VIDAS laboratory system, and comparing
results by Passing and Bablok regression analysis. S67 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Clinical characteristics (age, season,
coronary risk factors, the condition that preceded onset as possible
triggering factors and so on), laboratory data (troponin T, creatinine
kinase, and so on) and data of electrocardiography (ECG) were obtained
from reviewing medical records.i Conclusion In its current implementation the Magnotech-based NT-
proBNP assay shows promising performance for rapid, reliable NT-
proBNP testing at the POC in emergency settings. Development work is
presently focused on the integration of a blood fi lter into the cartridge,
to allow fi ngerprick tests. Results The number of cases of TC after the earthquake was fi ve for
7 months and that of before is six for 17 months. The occurrence rate of
TC seemed to increase after the earthquake. Reviewing all of our cases,
45.5% (n = 5/11) of patients have TC in the autumn, 72.7% (n = 8/11)
of patients suff ered from a physical stressor, and 27.3% (n = 3/11) of
patients a psychic stressor. No obvious stressor was found in only one
patient. The patients complained of chest pain or dyspnea (54.5% each). The rate of coronary risk factors were; family history, 10% (n = 1/10);
smoking, 60% (n = 6/11); diabetes, 57.1% (n = 4/7); hypertension, 63.6%
(n = 7/11); dyslipidemia, 44.4% (n = 4/9); and obesity, 22.2% (n = 2/9). Laboratory data showed that elevated troponin T was observed in
60% (n = 6/10), high CK and CK-MB were 45.5% (n = 5/11) and 100%
(n = 9/9), respectively. ECG fi ndings of all of the patients; ST elevation
was observed in precordial leads of V2 to V4 (27.3%, 54.5% and
27.3%, respectively) and ST depression was in V5 (36.4%). Reversed
r progression was observed in 18.2%, poor r progression was 27.3%,
abnormal Q was 18.2%, long QT interval was 72.7% and negative T was
63.6% of TC patients. Reference 1. Bruls DM, et al.: Lab Chip 2009, 9:3504-3510. 1. Bruls DM, et al.: Lab Chip 2009, 9:3504-3510. P188
Sh Short-term hemodynamic eff ects of nebivolol in acute
decompensated heart failure: a randomized clinical trial
R Puig, M Ochiai, J Cardoso, K Vieira, E Brancalhao, M Lima,
A Pereira Barretto
Hospital Auxiliar de Cotoxo – InCor – HCFMUSP, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P188 (doi: 10.1186/cc10795) Introduction The objective was to analyze clinical characteristics of
patients with infective endocarditis (IE) requiring surgery when the
disease is diagnosed. Introduction Acute decompensation heart failure in patients in use of
β-blocker has become frequent and maintenance of this drug remains
controversial, mainly in low cardiac output. Nitric-oxide-dependent
vasodilation of nebivolol could be useful in this situation. Methods A retrospective study of all patients, during 5 years in a
tertiary hospital in Spain, which required admission to the ICU with
the diagnosis of IE (Duke criteria modifi ed) and required surgery at
the same time. We compiled demographics, clinical characteristics and
complications. Data were analyzed with SPSS 17.i Methods We evaluated hospitalized patients with acute decompen-
sated heart failure, NYHA IV, EF <0.45, in use of dobutamine and
carvedilol. Intervention: patients were randomly assigned to
carvedilol maintenance or exchange to nebivolol according to Table 1. Hemodynamic parameters were compared using a noninvasive model
fl ow technique (Nexfi n®; BMEYE), 24 hours before, 6 and 24 hours after
the randomization. P <0.05 was signifi cant. p
y
Results We had 73 patients, 79% male, mean age 65. Forty-fi ve percent
had previous heart disease. Eighty-four percent presented with fever,
56.5% general syndrome, 56.2% heart failure, 19.2% pain, and 7%
coma. The duration of the clinic before diagnosis was mainly between
7 and 30 days (32%), followed by more than 30 days (27%). Less than
3 days duration represented 13%. Blood cultures were positive in
82%. The most common agent was Streptococcus (39%), followed by
Staphylococcus aureus MS (16%), SCN (12%), Enterococcus (12.3%),
S. aureus MR (1.4%), Escherichia coli (1.4%), Pseudomonas Aeruginosa
(1.4%), Aspergillus (1.4%), and polymicrobial (1.4%). Twelve percent
were negative cultures. The valve more frequently aff ected was
aortic. In all cases TTE was carried out for diagnosis. In 69 cases TEE
was performed. The principal echo fi ndings were: vegetation (42%),
new insuffi ciencies (26%), and also stenosis, perivalvular abscess and
normal echo. Fifty-eight percent of patients had no distal emboli. Other localizations: splenic (11%), hepatic (2.7%), bones (2.7%),
brain (4%), lung (5%) and more than one (11%). Consecutive case series of Takotsubo cardiomyopathy: a disease
potentially triggered by the Great East Japan Earthquake Mito Kyodo General Hospital, University of Tsukuba, Mito City, Japan
Critical Care 2012, 16(Suppl 1):P186 (doi: 10.1186/cc10793) Mito Kyodo General Hospital, University of Tsukuba, Mito City, Japan
Critical Care 2012, 16(Suppl 1):P186 (doi: 10.1186/cc10793) Introduction Takotsubo cardiomyopathy (TC) is a rare disease that
mimics ST elevated myocardial infarction (STEMI). TC is known to p
Conclusion Our incidence was 3%. SC generally presents on the
second to third postoperative day and usually recovers by the second Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S68 Critical Care 2012, Volume 16 Suppl 1
http //ccfor m com/s pplements/16/S1 http://ccforum.com/supplements/16/S1 Figure 1 (abstract P187). Figure 1 (abstract P187). Figure 1 (abstract P188). Systemic vascular resistance change: nebivolol
high×nebivolol low or carvedilol. Figure 1 (abstract P188). Systemic vascular resistance change: nebivolol
high×nebivolol low or carvedilol. week. Ethanolics and patients who require high vasopressor support
intraoperatively are more prone to develop SC. References 1. Therapondos G, et al.: Cardiac morbidity and mortality related to
orthotopic liver transplantation. Liver Transpl 2004, 10:1441-1453. 1. Therapondos G, et al.: Cardiac morbidity and mortality related to
orthotopic liver transplantation. Liver Transpl 2004, 10:1441-1453. 2. Bybee KA, et al.: Systematic review: Transient left ventricular apical
ballooning: a syndrome that mimics ST-segment elevation myocardial
infarction. Ann Intern Med 2004, 141:858-865. Figure 1 (abstract P188). Systemic vascular resistance change: nebivolol
high×nebivolol low or carvedilol. 2. Bybee KA, et al.: Systematic review: Transient left ventricular apical
ballooning: a syndrome that mimics ST-segment elevation myocardial
infarction. Ann Intern Med 2004, 141:858-865. 2. Bybee KA, et al.: Systematic review: Transient left ventricular apical
ballooning: a syndrome that mimics ST-segment elevation myocardial
infarction. Ann Intern Med 2004, 141:858-865. P189 P189
Patients with infective endocarditis patients in the ICU: how are they? P Fernandez Ugidos1, R Gomez Lopez1, P Vidal Cortes1,
AV Aller Fernandez2, JM Lopez Perez2
1Complejo Hospitalario Universitario Ourense, Spain; 2Complejo Hospitalario
Universitario A Coruña, Spain
Critical Care 2012, 16(Suppl 1):P189 (doi: 10.1186/cc10796) Malperfusion and branch compromise in acute type A aortic
syndrome syndrome
R Gomez Lopez1, P Fernandez Ugidos1, P Vidal Cortes1, J Lopez Perez2,
J Priego Sanz1, M Bouza Vieiro2, A Aller Fernandez2, L Seoane Quiroga2,
S Fojon Polanco2
1Complexo Hospitalario Universitario de Ourense, Spain; 2Complexo
Hospitalario Universitario de A Coruña, Spain
Critical Care 2012, 16(Suppl 1):P190 (doi: 10.1186/cc10797) i
y
Conclusion ECI ≥7 determines a poor CAD prognosis of coronary ischemic
events. Furthermore, ECI ≥7 may serve as a marker of the content of wall
calcium, obstruction level and composition of the plaques. ECI seems to
provide prognostic information as well as providing information about
the characteristics of the plaque of atheroma. Introduction Malperfusion is a factor associated with higher risk of
death and complications in patients with acute type A aortic syndrome
(AAAS). Our objective is to determine the incidence and characteristics
of this disease in our population and to verify the relevance in morbidity
and in-hospital mortality. Methods A historical cohort study that includes all patients with AAAS
admitted to the ICU after surgical management in a single institution
from January 2000 to July 2010. Anatomical, clinical, biochemical,
electrocardiographic and echocardiographic signs of ischemia were
considered. The events of interest were death or major complication
(neurological damage, multiorgan failure (MOF), acute lung injury (ALI),
postoperative hemorrhage) during hospitalization. P192 Echocardiography in the ICU: an audit of 3 years practice
A Hall, J Walker, I Welters
Royal Liverpool Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P192 (doi: 10.1186/cc10799) p
p
g
g
p
Results A total of 65 patients were identifi ed (24.6% women, 61.86 ± 12
years old, APACHE II score 12.9 ± 7.2, EuroSCORE 7.4 ± 2.6). Thirty-three
(50.8%) presented branch compromise, aff ecting coronary arteries in
12 patients (18.4%) (symptomatic (S) seven (10.5%), asymptomatic (A)
fi ve (7.7%)), nine (13.8%) carotid (S fi ve (7.7%), A four (6.1%)), 28 (43%)
brachiocephalic or subclavian (S 17 (26.1%), A 11 (16.9%)), 15 (22.8%)
mesenteric (S seven (10.5%), A eight (12.3%)), 13 (20%) renal (S nine
(13.8%), A four (6.1%)), and 31 (47.7%) iliac (S 16 (24.6%), A 15 (23%)). Twenty-eight (43.1%) showed clinical ischemia of at least one system
and 54 (83%) clinical signs of global hypoperfusion. Comparing patients
with and without data of hypoperfusion, diff erences in incidence of
death (45.5% vs. 18.8%, P = 0.03), neurological complication (35.7% vs. 10.8%, P = 0.03), MOF (16.6% vs. 25%. P = 0.07) and ALI (21.3% vs. Prognostic value of the echocardiographic-derived calcium index in
coronary artery disease y
y
J Jimenez, J Iribarren, J Lacalzada, A De La Rosa, R Juárez, A Barragán,
J Bonilla, G Blanco, R Pérez, M Brouard, I Laynez
Hospital Universitario de Canarias, La Laguna, Spain
Critical Care 2012, 16(Suppl 1):P191 (doi: 10.1186/cc10798) Conclusion Echocardiography in the ICU patient relies on numerous
factors including skill and equipment availability and patient windows
[1]. Our results confi rm that there is a role for echo in these patients,
important in a population where assessment of cardiac output and
fi lling status is notoriously diffi cult. Our results also show that TTE
performed by ICU physicians with basic training provides very useful
information for the management of patients. This makes the focused
courses on echocardiography very important [2,3]. Limitations of the
study: an unknown amount of missing data and a likelihood of patient
and operator bias as to which patients had echocardiography. In
conclusion, echocardiography is a useful tool in the management of
the haemodynamically unstable patients. R f Introduction Calcifi cation of diff erent cardiac structures is associated
with atherosclerotic risk factors. The aim of this study is to determine
whether the echocardiography-derived calcium index (ECI) assessed
by transthoracic echocardiography (TTE) predicts cardiovascular
events, besides determining the coronary artery calcium score (CACS),
the presence of obstructive coronary artery disease (CAD) and the
composition of plaques, all of which determined by multidetector
computed tomography (MDCT). Methods We carried out a prospective study of 82 consecutive patients,
with an intermediate likelihood for CAD, who were evaluated by
noninvasive coronariography by MDCT. ECI was blindly assessed by TTE. A 36-month follow-up was conducted to detect cardiovascular events. Methods We carried out a prospective study of 82 consecutive patients,
with an intermediate likelihood for CAD, who were evaluated by
noninvasive coronariography by MDCT. ECI was blindly assessed by TTE. A 36-month follow-up was conducted to detect cardiovascular events. Results The area under the ROC curve (AUC) of the Agatston score
scale as a predictor of signifi cant obstruction identifi ed by MDCT
was 0.80 (95% CI: 0.68 to 0.91); P <0.001. The optimal cut-off was 239. P191 Prognostic value of the echocardiographic-derived calcium index in
coronary artery disease
J Jimenez, J Iribarren, J Lacalzada, A De La Rosa, R Juárez, A Barragán,
J Bonilla, G Blanco, R Pérez, M Brouard, I Laynez
Hospital Universitario de Canarias, La Laguna, Spain
Critical Care 2012, 16(Suppl 1):P191 (doi: 10.1186/cc10798) P188
Sh This
corresponds with our patients: one-third of cases need urgent surgery,
56% have shock, about 60% ARF, and mortality reaches 30%. atrioventricular block, stroke, perioperative MI, and liver failure. The ICU
stay was 33 days (median 6). The hospital mortality was 31.5%. Conclusion IE has high morbi-mortality. The subgroup of patients
requiring early surgery presents the most severe disease. This
corresponds with our patients: one-third of cases need urgent surgery,
56% have shock, about 60% ARF, and mortality reaches 30%. Agatston score ≥239 has a sensitivity (Se) of 60.6% (95% CI: 0.42 to
0.77), specifi city (Sp) of 97.8% (95% CI: 0.88 to 0.99), positive predictive
value (PPV) of 95.2% and negative predictive value (NPV) of 77.2%. The
AUC of ECI to predict an optimal cut-off value for Agatston score was
0.90 (95% CI: 0.83 to 0.96); P <0.001. ECI ≥7 had a Se of 59.1% (95% CI:
0.36 to 0.79), a Sp of 93.3% (95% CI: 0.83 to 0.98), PPV of 76.5% and NPV
of 86.2%. There was a signifi cant linear trend of ECI, and ECI ≥7 has in
MDCT a greater presence of both severe calcifi ed wall and obstructive
CAD, number of aff ected vessels, and mixed/calcifi ed plaques (all
P <0.001). There were 23 coronary ischemic events. The AUC of ECI as a
predictor of adverse cardiac events post MDCT was 0.92 (95% CI: 0.852
to 0.987); P <0.001. ECI ≥7 had a Se of 77.3% (95% CI: 54.6 to 92.2), a
Sp of 90% (95% CI: 79.5 to 96.2), PPV of 73.9% and NPV of 91.5%. The Kaplan–Meier survival analyses show a statistically signifi cant
diff erence between patients with VCSI ≥7 or not regarding an ischemic
event (χ2: 52, P <0.001). This accumulation of risk occurs mainly in the
fi rst 2 years after the determination of ECI. atrioventricular block, stroke, perioperative MI, and liver failure. The ICU
stay was 33 days (median 6). The hospital mortality was 31.5%. atrioventricular block, stroke, perioperative MI, and liver failure. The ICU
stay was 33 days (median 6). The hospital mortality was 31.5%. Conclusion IE has high morbi-mortality. The subgroup of patients
requiring early surgery presents the most severe disease. This
corresponds with our patients: one-third of cases need urgent surgery,
56% have shock, about 60% ARF, and mortality reaches 30%. P188
Sh Forty-one percent of
patients required ICU admission before surgery with an average stay
of 5.6 days. A total of 31.5% suff ered multiorgan failure. Antibiotics
were given 17 days before surgery. In 6.8% it was not possible to give
them preoperatively. Eighty-two percent of patients took combination
therapy (19% four). Cephalosporins, aminoglucosids and vancomycin
were the most used. Two patients died before surgery. Thirty-fi ve
percent of the interventions were urgent. In 16.4%, reoperation was
necessary, mainly for bleeding, followed by prosthetic dysfunction,
recurrent IE, mediastinitis and pseudoaneurysm repair. A total 56% of
patients presented postoperative shock. MV was needed during 5 days
(range 0 to 53). Acute renal failure post surgery was present in 58%. Other complications were secondary infection, ventricular dysfunction, Table 1 (abstract P188)
Carvedilol
Nebivolol
6.25 mg/bid
2.5 mg/qd
12.5 mg/bid
5.0 mg/qd
25.0 mg/bid
10.0 mg/qd
Results We selected 30 patients, 75% men, age 56.0 (SD = 13.0) years,
ejection fraction 23.4 (SD = 7.2)%, ischemic myocardiopathy present in
16.7%, Chagas disease in 40% and 43.3% of patients were nonischemic/
non-Chagas. Baseline indexed systemic vascular resistance was 2,255.9
(SD = 792.4) dynes.second/cm5/m2, and cardiac index was 2.7 (SD = 0.6)
l/minute/m. In the nebivolol group (n = 15) the indexed systemic
vascular resistance reduced 0.6% and in the carvedilol group (n = 15)
it reduced 5.0% in 24 hours (mean diff erence 4.4%; 95% CI: –12.6 to
21.4%; P = 0.513). The cardiac index maintained unchanged (P = 0.274). Comparing patients that received a high dose of nebivolol (5 to 10 mg/
day) to those with a low dose (<5 mg/day) or carvedilol, we observed a
tendency to superiority of high dose in reduction of systemic vascular
resistance, although not statistically signifi cant (Figure 1). Conclusion Short-term nebivolol use in decompensated heart failure
was hemodynamically safe. Further studies should be done to clarify
this matter. Table 1 (abstract P188)
Carvedilol
Nebivolol
6.25 mg/bid
2.5 mg/qd
12.5 mg/bid
5.0 mg/qd
25.0 mg/bid
10.0 mg/qd S69 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 atrioventricular block, stroke, perioperative MI, and liver failure. The ICU
stay was 33 days (median 6). The hospital mortality was 31.5%. Conclusion IE has high morbi-mortality. The subgroup of patients
requiring early surgery presents the most severe disease. 1.
Orme R, et al.: Br J Anaesth 2009, 102:340-344.
2.
Vieillard-Baron et al.: Intensive Care Med 2008, 34:243-249.
3.
Jensen et al.: Eur J Anaesth 2004, 21:700-707. Malperfusion and branch compromise in acute type A aortic
syndrome 29.6%,
P = 0.09) were found.f Introduction Assessment of the haemodynamically unstable patient
is a core part of ICU management and relies predominantly on a
combination of clinical skill and measurement of physiological variables. Echocardiography in the ICU has become increasingly popular as a tool
for assessment of cardiac output, fl uid status and ventricular function. Traditionally transoesophageal echo (TOE) has been favoured due to
the belief that it gave superior images [1]. Transthoracic echo (TTE)
is not often performed as it relies on 24-hour availability of trained
personnel, availability of equipment and good patient windows [1]. There was also a perceived lack of benefi t; however, recent studies have
shown good or adequate images in over 85 to 90% of patients resulting
in a change of management in 48% [1]. g
g
Methods Data were collected prospectively in all patients undergoing
echocardiography in a teaching hospital ICU from January 2008 to January
2011. The main focus of our investigation was to ascertain the clinical
questions to be answered and the outcome of echo on management. Conclusion More than 80% of the patients with AAAS suff ered mal per-
fusion in our series. They had a higher risk of death and neurological
complication during hospitalization. Results A total of 238 echoes were performed on 216 patients with an
average age of 59.75 years (TTE: 198, TOE: 19, and both: 14). The most
commonly asked questions were on fi lling status and contractility
(40%) and left ventricular function (33%). Ninety percent of clinical
questions asked were answered fully (74%) or partially (16%) by echo. Sixty-one percent of echoes resulted in a change of management
(5% of which were to continue with increased confi dence). TTE
performed by operators with basic training resulted in a 54% change
in management. Changes included more fi lling (39%) and changes in
inotropes or diuretics. References 1. Orme R, et al.: Br J Anaesth 2009, 102:340-344. 2. Vieillard-Baron et al.: Intensive Care Med 2008, 34:243-249. 3. Jensen et al.: Eur J Anaesth 2004, 21:700-707. Results The area under the ROC curve (AUC) of the Agatston score
scale as a predictor of signifi cant obstruction identifi ed by MDCT
was 0.80 (95% CI: 0.68 to 0.91); P <0.001. The optimal cut-off was 239. 1. Orme R, et al.: Br J Anaesth 2009, 102:340-344. 2. Vieillard-Baron et al.: Intensive Care Med 2008, 34:243-249. 3. Jensen et al.: Eur J Anaesth 2004, 21:700-707. S70 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P193 Figure 1 (abstract P194). Characteristics of the data diff erences between
(a) free and (b) hold breathing. Figure 1 (abstract P194). Characteristics of the data diff erences between
(a) free and (b) hold breathing. P193
Left ventriculum diastolic dysfunction in pediatric septic shock
M Georgiyants, V Korsunov
Kharkov Medical Academy Post-Graduate Education, Kharkov, Ukraine
Critical Care 2012, 16(Suppl 1):P193 (doi: 10.1186/cc10800) Kharkov Medical Academy Post-Graduate Education, Kharkov, Ukraine
Critical Care 2012, 16(Suppl 1):P193 (doi: 10.1186/cc10800) Introduction One of the causes of septic mortality is a low cardiac
output secondary to preload failure. Same patients demonstrate
preload failure after aggressive volume replacement [1]. Methods Ultrasound impulse-wave Doppler evaluation of transmitral
fl ow: VmaxE, VmaxA, ejection time E,A; DT E wave, IVRT of LV. Ultrasound
evaluation of end-diastolic and end-systolic LV volume, stroke volume
(LVEDV, LVESV, SV) on Teichholz L. EDLVP = 1.06 + 15.15×VTI peakA/
VTI peakE. Coronary perfusion pressure (CPP) = EDLVP – diastolic BP. We evaluate these parameters in 34 patients (age 28.1 ± 8.0 months)
with septic shock (SS) diagnosed according to Consensus 2002. Control
(C) – 44 healthy children (age 40.7 ± 8.5 months). Statistical analyses
with t criteria. Figure 1 (abstract P194). Characteristics of the data diff erences between
(a) free and (b) hold breathing. improve the accuracy and reliability of diagnosis on early stages
[2]. If the device can be designed as portable, then it can be used
by heart disease patients for daily monitoring to avoid or minimize
heart attack accidents. To improve the accuracy of heart auscultation
analysis, usually the lung sound must be minimized, or vice versa. It
is very diffi cult. This study tried to use heart and lung interference
sounds as physiological parameters. P194
Existence of interference between the heart and respiratory sounds:
preliminary report 4. Mrowka R, Cimponeriu L, Patzak A, Rosenblum MG: Am J Physiol Regul Integr
Comp Physiol 2003, 285:R1395-R1401. Brawijaya University, Malang East Java, Indonesia j y
y
g
Critical Care 2012, 16(Suppl 1):P194 (doi: 10.1186/cc10801) 6. Toledo E, et al.: Med Eng Phys 2002, 24:45-52. 7. Darowski M: Front Med Biol Eng 2000, 10:157-165. Introduction Heart diseases still persist as one of the fi rst-ranked
causes of mortality in the world and Indonesia. Currently, mortality
from coronary heart diseases is estimated to reach 53.5 per 100,000
population [1]. Auscultation is a fundamental diagnostic method for
heart disease, noninvasive and inexpensive [2], but highly dependent
on the expertise and experience of the listener. Improved accuracy
of diagnosis is usually then performed through further examination
using the electrocardiogram, magnetic resonance imaging and the
computed tomography scan. Unfortunately, these tools require very
expensive investment costs that are only available in large hospitals [3]. This is the main reason for supporting the development of computer-
based auscultation technique tools that are cheaper and are able to References So this preliminary research aims
to prove that interference does occur between heart and respiratory
sounds. This interference sound will be used as an analysis technique
to improve the accuracy of a new auscultation device. Results The increase of VmaxA and decrease of VmaxE in patients of
SS are demonstrated. IVRT and DT are less than in control group. We
evaluated a decrease in E/A proportion. EDLVP in patients was more,
and CPP lower, than in controls. See Table 1. Table 1 (abstract P193). Diastolic function in pediatric septic shock Table 1 (abstract P193). Diastolic function in pediatric septic shock
Value
SS
C
P v Table 1 (abstract P193). Diastolic function in pediatric septic shock
Value
SS
C
P value
VmaxA
81
65
<0.05
VmaxE
99
108
>0.05
ETA
80
102
0.01
ETE
102
149
0.001
DTE
51
93
0.001
IVRT
48
87
0.01
E/A
1.3
1.7
0.01
EDLVP
23
9.8
<0.001
CPP
22
50
0.001
EDLVV
46
65
<0.001
SV
14
26
0.001 Methods This research was conducted on nine randomly chosen
volunteers whose heart sounds were recorded in two conditions: 30
seconds free and hold breathing. The heart sound recording process is
done electronically using a modifi ed standard stethoscope to generate
digital data. Modifi cations were performed using a mic condenser
combined with a voice processing system based on Windows XP. Accuracy of the equipment is ensured by the noise–signal ratio test. Methods This research was conducted on nine randomly chosen
volunteers whose heart sounds were recorded in two conditions: 30
seconds free and hold breathing. The heart sound recording process is
done electronically using a modifi ed standard stethoscope to generate
digital data. Modifi cations were performed using a mic condenser
combined with a voice processing system based on Windows XP. Accuracy of the equipment is ensured by the noise–signal ratio test. Results Generally, it can be seen (Figure 1) that there are pronounced
diff erences in heart sound data recorded in the conditions of free and
hold breathing. This means that the respiration process is likely to aff ect
the heart sounds heard on the chest surface. The diff erences that appear
are in the form of nodes and amplitude. Diff erences in the form of a
node indicate a diff erence in frequency of sounds and color (timbre),
while the amplitude diff erences may indicate diff erences in strength
and speed of sound propagation. References In general, the number of diff erences
in the recording position is close to the number of respiratory cycles so
that it is possible these diff erences are caused by respiratory processes. Conclusion The diff erences that can be noticed from the graphical
visualization of recorded sounds are in the form of nodes and
amplitude. These diff erences that indicate the frequency, sound color,
strength and speed of sounds improve the existence of an interference
wave between the heart and respiratory sounds. These characteristics
will be used to design the new portable auscultation device. References Conclusion Pediatric SS accompanied with LV diastolic dysfunction,
which decreases the eff ectiveness of volume restoration therapy,
reduces preload and cardiac output. f 1. Jardin F, et al.: Persistent preload defect in severe sepsis despite fl uid
loading. A longitudinal echocardiographic study in patients with septic
shock. Chest 1999, 116:1354-1359. 1. Jardin F, et al.: Persistent preload defect in severe sepsis despite fl uid
loading. A longitudinal echocardiographic study in patients with septic
shock. Chest 1999, 116:1354-1359. 1. Persatuan Perawat Nasional Indonesia [http://inna-ppni.or.id/html]
2. Javed F, Venkatachalam PA, Fadzil A: J Phys Conf Ser 2006, 34:1098-1105. 3. Stasis A, et al.: A Multiple Decision Tree Architecture for Medical Diagnosis: The
Diff erentiation of Opening Snap, Second Heart Sound Split and Third Heart
Sound. CMS Springer-Verlag; 2004:254-274. 4. Mrowka R, Cimponeriu L, Patzak A, Rosenblum MG: Am J Physiol Regul Integr
Comp Physiol 2003, 285:R1395-R1401. 5. Schikowski T, et al.: Respir Res 2007, 8:1-11. 6. Toledo E, et al.: Med Eng Phys 2002, 24:45-52. 7. Darowski M: Front Med Biol Eng 2000, 10:157-165. 1. Persatuan Perawat Nasional Indonesia [http://inna-ppni.or.id/html]
2. Javed F, Venkatachalam PA, Fadzil A: J Phys Conf Ser 2006, 34:1098-1105. 3. Stasis A, et al.: A Multiple Decision Tree Architecture for Medical Diagnosis: The
Diff erentiation of Opening Snap, Second Heart Sound Split and Third Heart
Sound. CMS Springer-Verlag; 2004:254-274. 2. Javed F, Venkatachalam PA, Fadzil A: J Phys Conf Ser 2006, 34:1098 1105. 3. Stasis A, et al.: A Multiple Decision Tree Architecture for Medical Diagnosis: The
Diff erentiation of Opening Snap, Second Heart Sound Split and Third Heart
Sound. CMS Springer-Verlag; 2004:254-274. P195
Eff ects of the intravenous administration of purine nucleosides
guanosine or inosine against hemorrhagic shock in pigs Eff ects of the intravenous administration of purine nucleosides
guanosine or inosine against hemorrhagic shock in pigs g
Schmidt, D Otsuki, DO Souza, J Auler Jr Faculdade de Medicina da Universidade de São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P195 (doi: 10.1186/cc10802) aculdade de Medicina da Universidade de São Paulo, Brazil ,
ritical Care 2012, 16(Suppl 1):P195 (doi: 10.1186/cc10802) Introduction Hemorrhagic shock leads to the appearance of substances
in plasma that depress Na/K ATPase activity, an eff ect that could be
related to signifi cant morbidity and mortality. Recently, some fi ndings S71 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 function, under similar hemodynamic conditions. Hepatic, renal and
myocardial respiration of the measured mitochondrial complexes did
not signifi cantly diff er between the two treatment groups, except for
renal Complex I, State 4 respiration. indicated that purine nucleosides such as guanosine, inosine or
adenosine might prolong survival in shocked rats, an eff ect potentially
related to the stimulation of Na/K ATPase activity. This study aimed
to evaluate the eff ects of intravenous administration of guanosine or
inosine combined with lactate Ringer solution (LR) on hemodynamic
and oxygenation parameters and survival in an experimental model of
hemorrhagic shock (HS). P197 P197
Goal-directed hemodynamic resuscitation in high-risk patients
undergoing cardiac surgery: a randomized controlled trial –
preliminary data (GRICCS STUDY)
E Osawa1, A Rhodes2, J Fukushima1, J Almeida1, F Jatene1, R Nakamura1,
M Sundin1, J Auler Jr1, R Kalil Filho1, F Galas1, L Hajjar1
1Heart Institute, São Paulo, Brazil; 2Charing Cross Hospital, Imperial College
NHS Trust, London, UK
Critical Care 2012, 16(Suppl 1):P197 (doi: 10.1186/cc10804) g
Methods HS was induced in 24 pigs (25 to 30 kg) by blood removal
for 20 minutes to target a mean arterial pressure (MAP) of 40 mmHg,
which was maintained for 60 minutes with additional blood removal
or retransfusion. Animals were treated with LR alone (three times the
volume of blood withdrawn) or associated to 1 mmol/l guanosine or
1 mmol/l inosine. Hemodynamic and oxygenation parameters were
evaluated at baseline, after HS, immediately after fl uid resuscitation,
and 30, 60, 120, 240 and 360 minutes after fl uid resuscitation. Primary
outcome was post-shock survival. Statistical analysis of parametric data
was performed with one-way ANOVA for repeated measures followed
by Student–Newman–Keuls. Goal-directed hemodynamic resuscitation in high-risk patients
undergoing cardiac surgery: a randomized controlled trial –
preliminary data (GRICCS STUDY) p
y
E Osawa1, A Rhodes2, J Fukushima1, J Almeida1, F Jatene1, R Nakamura1,
M Sundin1, J Auler Jr1, R Kalil Filho1, F Galas1, L Hajjar1
1Heart Institute, São Paulo, Brazil; 2Charing Cross Hospital, Imperial College
NHS Trust, London, UK
Critical Care 2012, 16(Suppl 1):P197 (doi: 10.1186/cc10804) Introduction Low cardiac output is a frequent clinical circumstance
after cardiac surgery and results in higher morbidity and mortality rates. Goal-directed therapy (GDT) is a validated design that has been proved
to reduce the number of perioperative outcomes. We investigated the
results of a cardiac index optimization protocol through the use of the
LiDCO rapid device. y
Results The hemodynamic and oxygenation parameters were not
signifi cantly diff erent among pigs treated with RL alone or in combi-
nation with guanosine or inosine. No eff ects on post-shock survival
were observed in any group. Methods A prospective study that randomized 34 high-risk patients
(EuroSCORE higher than 6 or LVEF lower than 45%) to a GDT protocol or a
conventional hemodynamic therapy. Patients from the GDT group were
resuscitated to a cardiac index higher than 3 l/minute/m2 through the
implementation of a three-step approach: (1) fl uid challenge of 250 ml
aliquots, (2) dobutamine infusion up to a dose of 20 μg/kg/minute, and
(3) blood transfusion to reach a hematocrit higher than 28%. The control
group was managed according to institutional protocol. Categorical
variables were compared using Fisher’s exact test and categorical
variables were compared using the Mann–Whitney U test. Conclusion The actual preliminary results did not demonstrate
any additional improvement induced by guanosine or inosine on
the hemodynamic and oxygenation parameters or on the post-
shock survival during HS. These fi ndings need to be confi rmed in
a larger group of animals and further investigation with cellular and
biochemical analysis may help to elucidate the eff ects of guanosine
and inosine during HS. g
Acknowledgments Supported by FAPESP and CNPq. References Acknowledgments Supported by FAPESP and CNPq. g
y
Results Sixteen patients from the GDT group were compared with
18 patients from the control group. There was a tendency towards
reduction in ICU stay in patients from GDT group in relation to the
control group (7 days vs. 6 days, P = 0.18). Economic evaluation of early-goal directed therapy for high-risk
surgical patients g
Methods In 16 anesthetized pigs, evolving septic shock after 12 hours
of fecal peritonitis was randomly treated with either norepinephrine
(0.8 ± 0.6 μg/kg/minute; mean ± SD) or angiotensin II (0.31 ± 0.37 μg/
kg/minute; n = 8, each) and fl uids for 48 hours. Organs were harvested
at the end of the experiment, and mitochondria isolated by tissue
homogenization and diff erential centrifugation. Mitochondrial oxygen
consumption (VO2) was measured by high-resolution respirometry
(Oroboros Instruments, Innsbruck, Austria). Groups were compared
using Mann–Whitney U test. In addition, mitochondrial respiration was
also compared to a similarly instrumented control group without fecal
peritonitis (n = 8; Kruskal–Wallis test). g
p
C Ebm, M Cecconi, H Aya, M Geisen, A Rhodes, M Grounds
St George’s Healthcare Trust, London, UK C Ebm, M Cecconi, H Aya, M Geisen, A Rhodes, M Grounds
St George’s Healthcare Trust, London, UK
Critical Care 2012, 16(Suppl 1):P198 (doi: 10.1186/cc10805) Introduction Early goal-directed therapy (EGDT) has been shown
to reduce postoperative morbidity and length of hospital stay. Our
objective was to analyse the cost-eff ectiveness of early goal-directed
proactive therapy versus standard reactive care in patients at high risk
of developing postoperative complications. p g p
p
p
Methods Patient-level outcome data used were based on a previous
randomised, controlled trial. A Markov decision model was constructed
to analyse costs and outcomes associated with the use of EGDT. Outcomes assessed were postoperative complications, mortality,
quality-adjusted life expectancy (QALY) and incremental costs/QALY. Results The main analysis, based on 28-day survival data of 122
patients, revealed an incremental cost-eff ectiveness ratio of EGDT of
£280.15 per patient. Additional costs of £525.43 per patient associated
with EGDT were mainly due to costs related to monitor acquisition
and staffi ng (two additional nurses). These costs were balanced by
savings due to the signifi cant reduction in length of stay in the hospital
and in the ICU and lower complication rates in the GDT arm (mean
expenditures/patient £4,511.25 vs. £5,218.75). This outcome was Methods Patient-level outcome data used were based on a previous
randomised, controlled trial. A Markov decision model was constructed
to analyse costs and outcomes associated with the use of EGDT. Outcomes assessed were postoperative complications, mortality,
quality-adjusted life expectancy (QALY) and incremental costs/QALY. Norepinephrine versus angiotensin II in septic shock: eff ects on
isolated kidney, heart and liver mitochondrial respiration
V Jeger, M Vuda, T Correa, J Takala, S Djafarzadeh, SM Jakob
Inselspital University Hospital Bern, Switzerland
Critical Care 2012, 16(Suppl 1):P196 (doi: 10.1186/cc10803) Norepinephrine versus angiotensin II in septic shock: eff ects on
isolated kidney, heart and liver mitochondrial respiration
V Jeger, M Vuda, T Correa, J Takala, S Djafarzadeh, SM Jakob
Inselspital University Hospital Bern, Switzerland
Critical Care 2012, 16(Suppl 1):P196 (doi: 10.1186/cc10803) Conclusion Goal-directed hemodynamic resuscitation with the use
of a minimally invasive device seems to be a promising perioperative
strategy aimed at reducing the rates of worse outcomes and the ICU
stay after cardiac surgery. p
y
p
Critical Care 2012, 16(Suppl 1):P196 (doi: 10.1186/cc10803) Introduction Mitochondrial dysfunction has been proposed to
infl uence organ function and outcome in sepsis. Both vasopressor
agents norepinephrine and angiotensin II can interfere with
mitochondrial function. The aim of this study was to compare
mitochondrial respiration after exposure of septic animals to either of
these two drugs. Goal-directed hemodynamic resuscitation in high-risk patients
undergoing cardiac surgery: a randomized controlled trial –
preliminary data (GRICCS STUDY) Comparison of the primary
endpoint variable (composite of death or major postoperative
complications within 30 days after surgery or before discharge)
between groups showed a reduced complication rate in the GDT group
(52.2% vs. 45.6%, P = 0.12), mainly attributed to worse acute renal
failure RIFLE criteria in the control group. 1. Darlington DN, Gann DS:. J Trauma 2005, 58:1055-1060. 2. Schmidt AP, et al.: Pharmacol Ther 2007, 116:401-416. 1. Darlington DN, Gann DS:. J Trauma 2005, 58:1055-1060. 2. Schmidt AP, et al.: Pharmacol Ther 2007, 116:401-416. P195
Eff ects of the intravenous administration of purine nucleosides
guanosine or inosine against hemorrhagic shock in pigs Kruskal–Wallis followed by the Dunn test
was used for analysis of nonparametric data. The post-shock survival
was evaluated by the Kaplan–Meier curve. 1.
Darlington DN, Gann DS:. J Trauma 2005, 58:1055-1060.
2.
Schmidt AP, et al.: Pharmacol Ther 2007, 116:401-416. What matters during a hypotensive episode: fl uids, vasopressors,
or both? What matters during a hypotensive episode: fl uids, vasopressors,
or both? J Lee1, R Kothari2, JA Ladapo3, DJ Scott1, LA Celi1
1Massachusetts Institute of Technology, Cambridge, MA, USA; 2Mount Sinai
School of Medicine, New York City, NY, USA; 3New York University School of
Medicine, New York City, NY, USA
Critical Care 2012, 16(Suppl 1):P199 (doi: 10.1186/cc10806) J Lee1, R Kothari2, JA Ladapo3, DJ Scott1, LA Celi1
1Massachusetts Institute of Technology, Cambridge, MA, USA; 2Mount Sinai
School of Medicine, New York City, NY, USA; 3New York University School of
Medicine, New York City, NY, USA g
Conclusion In septic patients with CVP >12 mmHg after resuscitation,
micro circulatory fl ow was signifi cantly lower as compared to patients
with CVP ≤12 mmHg, whereas capillary density did not diff er between
groups. y
Critical Care 2012, 16(Suppl 1):P199 (doi: 10.1186/cc10806) Introduction The objective of this retrospective study was to investigate
the relationships between fl uid and vasopressor interventions and
patient outcomes. In intensive care, it is imperative to resolve hypotensive
episodes (HEs) in a timely manner in order to minimize end-organ
damage. The current clinical practice is fi rst to attempt fl uid resuscitation
and then to follow with vasopressor therapy if fl uid resuscitation is
unsuccessful. However, the eff ects of fl uid and vasopressor interventions
on patient outcomes have not been clearly established.i Figure 1 (abstract P200). Boxplots of microvascular fl ow index (MFI) in
patients with a central venous pressure (CVP) ≤12 mmHg or >12 mmHg. p
y
Methods Hypotension was defi ned as MAP below 60 mmHg. The
primary outcome was in-hospital mortality. Secondary outcomes
included ICU LOS, HE duration, Hypotension Severity Index (HSI) (MAP
curve area below 60 mmHg during the HE), and rise in serum creatinine. The patient cohort included patients in the MIMIC-II database [1] who
experienced a single HE. Multivariate logistic regression and propensity
score analysis were employed. Sensitivity analyses were conducted in
subpopulations stratifi ed by treatment type and diagnosis. p pi
y
yp
g
Results A total of 3,163 patients in MIMIC-II met the inclusion criteria. The multivariate regression results showed that fl uid resuscitation was
signifi cantly associated with shorter ICU LOS (OR = 0.71, P = 0.007) and
greater HSI (OR = 1.26, P = 0.04). What matters during a hypotensive episode: fl uids, vasopressors,
or both? Vasopressor administration signifi cantly
decreased HE duration (OR = 0.29, P <0.001) and HSI (OR = 0.72,
P = 0.002) but was correlated with increased in-hospital mortality risk
(OR = 2.86, P <0.001) (even after propensity adjustment; OR = 2.44,
P <0.001), prolonged ICU LOS (OR = 1.29, P = 0.04), and rise in serum
creatinine (OR = 1.44, P = 0.002). Sensitivity analyses in treatment-
specifi c and diagnosis-specifi c subpopulations corroborated the
relationship between vasopressors and increased in-hospital mortality. Conclusion Regarding the relationship between vasopressor therapy
and in-hospital mortality, similar fi ndings have been reported in
previous studies analyzing sepsis [2], cardiac surgery [3], and heart
failure [4]. We speculate that benefi ts of vasopressor use may be
restricted to subsets of patients with specifi c conditions. This study
illustrates the utility of electronic medical records in research when
randomized controlled trials are diffi cult to conduct. f Figure 1 (abstract P200). Boxplots of microvascular fl ow index (MFI) in
patients with a central venous pressure (CVP) ≤12 mmHg or >12 mmHg. P199 g
y
y
Results A total of 345 measurements in 70 patients (APACHE II 21 (6.5)
(mean (SD))) were included. MFI in patients with CVP >12 mmHg was
signifi cantly lower than in CVP ≤12 mmHg (1.83 (0.92 to 2.75) vs. 2.25
(1.35 to 2.90) (median (IQR)), P = 0.032), whereas TVD in both groups
did not diff er signifi cantly (14 (12.84 to 15.75) vs. 14.3 (13 to 15.8) mm/
mm2, P = 0.38). See also Figure 1. P201 Human protein C concentrate to restore physiological values in
adult septic shock patients: eff ects on microcirculationf Human protein C concentrate to restore physiological values in
adult septic shock patients: eff ects on microcirculationf Economic evaluation of early-goal directed therapy for high-risk
surgical patients Results Achieved blood pressure levels and cardiac output were not
diff erent between the two septic groups, and both groups received
the same amount of fl uids (norepinephrine: 1.6 ± 0.5 ml/kg/hour,
angiotensin II: 1.3 ± 0.8 ml/kg/hour; P = NS). Compared to controls,
mitochondrial VO2 was not diff erent in septic animals. The only
diff erence between the two septic groups was higher renal Complex I,
State 4 respiration in norepinephrine-treated (median (range): 309 (164
to 415) pmol/(second*mg)) versus angiotensin-II-treated animals (210
(89 to 273) pmol/(second*mg); P = 0.05).if Results The main analysis, based on 28-day survival data of 122
patients, revealed an incremental cost-eff ectiveness ratio of EGDT of
£280.15 per patient. Additional costs of £525.43 per patient associated
with EGDT were mainly due to costs related to monitor acquisition
and staffi ng (two additional nurses). These costs were balanced by
savings due to the signifi cant reduction in length of stay in the hospital
and in the ICU and lower complication rates in the GDT arm (mean
expenditures/patient £4,511.25 vs. £5,218.75). This outcome was Conclusion We found no signifi cant eff ects of septic shock treated with
either angiotensin II or norepinephrine and fl uids on mitochondrial Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S72 Table 1 (abstract P198)
Outcome
Unit
GDT
Standard
Ward stay
(days)
11 (7 to 15)
14 (11 to 27)
Incr. costs
(£)
525.43
–
Inc. eff ect
(QALY)
1.88
–
ICER
(£/QALY)
280.15
–
ICER, incremental cost-eff ectiveness ratio. P200
Elevated central venous pressure in septic patients is associated
with impairment of microcirculatory blood fl ow
N Vellinga1, C Ince2, EC Boerma1
1Medisch Centrum Leeuwarden, the Netherlands; 2Erasmus Medical Center,
Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P200 (doi: 10.1186/cc10807) P200
Elevated central venous pressure in septic patients is associated
with impairment of microcirculatory blood fl ow
N Vellinga1, C Ince2, EC Boerma1
1Medisch Centrum Leeuwarden, the Netherlands; 2Erasmus Medical Center,
Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P200 (doi: 10.1186/cc10807) Critical Care 2012, 16(Suppl 1):P200 (doi: 10.1186/cc10807) Introduction The microcirculation plays a pivotal role in oxygen delivery
to the tissue. Microcirculatory alterations have been observed to occur
independently of the major infl ow variable for microcirculation: mean
arterial pressure. According to physiological theory, the microcirculation
is considered to be a low-pressure compartment. Maximum optimal
central venous pressure (CVP) according to Surviving Sepsis Campaign
(SSC) guidelines is 12 to 15 mmHg in mechanically ventilated patients. We hypothesized that a CVP >12 mmHg would hamper microcirculatory
perfusion but not diff usion, by acting as outfl ow obstruction. robust to variations in treatment eff ect (probability of morbidity and
mortality) and sensitive to implementation costs of EGDT. See Table 1. Conclusion The implementation of EGDT appears clinical and cost-
eff ective. Additional implementation costs will be off set by savings
due to a marked decrease in complication rates and hospital length of
stay. We conclude that GDT provides signifi cant benefi ts with respect
to both clinical and fi nancial outcomes. Reference Methods We retrospectively analyzed combined measurements of CVP
and sidestream dark-fi eld derived sublingual microcirculatory variables
in patients with severe sepsis or septic shock. Measurements were made
0, 0.5, 2, 12 and 24 hours after resuscitation in accordance with SSC
guidelines. Diff erences in small vessel microvascular fl ow index (MFI) and
total vessel density (TVD) between two groups (CVP ≤12 mmHg and CVP
>12 mmHg) were analyzed with a Mann–Whitney U test. 1. Pearse R, Dawson D, Fawcett J, Rhodes A: Early goal directed therapy after
major surgery reduces complications and duration of hospital stay. A
randomized, controlled trial. Crit Care 2005, 9:R687-R693. P201
Human protein C concentrate to restore physiological values in
adult septic shock patients: eff ects on microcirculation
A Morelli 1, A Donati2, A Di Russo1, F D’Ippolito1, C Raff one1, A D’Egidio1,
MR Lombrano2, S Tondi2, E Damiani2, V Cecchini1, A Orecchioni1, P Pietropaoli1
1University La Sapienza, Rome, Italy; 2Marche Polytechnique University,
Ancona, Italy
Critical Care 2012, 16(Suppl 1):P201 (doi: 10.1186/cc10808) References
1.
Saeed M, et al.: Crit Care Med 2011, 39:952-960.
2.
Dunser M, et al.: Crit Care 2009, 13:R181.
3.
Shahin J, et al.: Crit Care 2011, 15:R162.
4
Thackraya S et al : Eur J Heart Fail 2002 4:515-529 1.
Saeed M, et al.: Crit Care Med 2011, 39:952-960 P202 Heart rate reduction with esmolol in septic shock: eff ects on
microcirculation
A Morelli1, A Donati2, A Di Russo1, F D’Ippolito1, A Carsetti2, R Domizi2,
A D’Egidio1, C Raff one1, C Scarcella2, C Ertmer3, S Rehberg3, P Pietropaoli1,
M Westphal3
1University La Sapienza, Rome, Italy; 2Marche Polytechnique University,
Ancona, Italy; 3University Hospital of Muenster, Germany
Critical Care 2012, 16(Suppl 1):P202 (doi: 10.1186/cc10809) Heart rate reduction with esmolol in septic shock: eff ects on
microcirculation A Morelli1, A Donati2, A Di Russo1, F D’Ippolito1, A Carsetti2, R Domizi2,
A D’Egidio1, C Raff one1, C Scarcella2, C Ertmer3, S Rehberg3, P Pietropaoli1,
M Westphal3 p
1University La Sapienza, Rome, Italy; 2Marche Polytechnique University,
Ancona, Italy; 3University Hospital of Muenster, Germany
Critical Care 2012, 16(Suppl 1):P202 (doi: 10.1186/cc10809) Results Infusion of E. coli resulted in a hypodynamic state of sepsis
despite fl uid administration. Signifi cant decreases in MFI and PPV of
small vessels were in sublingual, conjunctival, jejunal and rectal lodges
3 and 5 hours after the start of E. coli infusion in comparison to baseline
variables. Correlation between sublingual and conjunctival (r = 0.80,
P = 0.036), sublingual and jejunal (r = 0.94, P = 0.005), sublingual and
rectal (r = 0.79, P = 0.03) MFI was observed 3 hours after onset of sepsis. There was no correlation in change of MFI and PPV between sublingual
mucosa and other evaluated regions. However, the sublingual mucosa
exhibited the most pronounced alterations of microcirculatory fl ow in
comparison to conjunctival, jejunal and rectal mucosa microvasculature
(P <0.05). Introduction Preclinical and clinical studies report that β-blockers
may be an interesting option to attenuate the deleterious eff ects of
prolonged catecholamine exposure during septic shock. Nevertheless,
there are concerns that β-blockers may have negative chronotropic
and inotropic eff ects leading to inappropriately low cardiac output. The objective of the present study was therefore to elucidate
whether a reduction in heart rate (HR) with esmolol may negatively
aff ect microcirculation in patients with septic shock who remained
tachycardic after hemodynamic optimization. Conclusion Microcirculatory alterations were observed in all investi-
gated lodges, including sublingual, jejunal and rectal mucosa, and
conjunctiva of the eye at the same time point during experimental
sepsis. There is a clear association between sublingual microcirculation
and conjunctival, jejunal or rectal microcirculation in the very early
course of an extreme hypodynamic state of sepsis. Methods After 36 hours of initial hemodynamic stabilization, 11 septic
shock patients with HR >95 bpm and requiring norepinephrine (NE)
to maintain mean arterial pressure (MAP) between 65 and 75 mmHg,
despite adequate volume resuscitation, received a continuous esmolol
infusion to maintain HR between 94 and 80 bpm. NE was titrated to
achieve a MAP between 65 and 75 mmHg. Data from right heart
catheterization and sidestream dark-fi eld imaging were obtained at
baseline and after 24 hours. Early course of microcirculatory perfusion in the eye and digestive
tract during experimental sepsis A Pranskunas1, R Rasimaviciute1, E Milieskaite1, A Vitkauskiene1,
P Dobozinskas1, V Veikutis2, Z Dambrauskas1, D Vaitkaitis1, V Pilvinis1
1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Institute of
Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
Critical Care 2012, 16(Suppl 1):P203 (doi: 10.1186/cc10810) Table 1 (abstract P201). Microcirculatory variables
Baseline
24 hours
48 hours
72 hours
MFIs
Treated
2.8(2.6; 3)
3 (2.7; 3)
2.9 (2.8; 3)
3 (2.9; 3)
Controls
2.8 (2.1; 2.9)
2.8 (2.1; 2.8)
2.8 (2.2; 3)
3 (2.6; 3)
PVD
Treated
17.8 (16.5; 22.2) 19.7 (17.4; 22.5) 19.7 (18.1; 23)
19.9 (17; 22.2)
Controls
20.2 (17.4; 23.5) 18.8 (17.6; 20.2) 19.4 (17.5; 20.7) 18.7 (17.5; 21.2)
Conclusion The administration of human PC concentrate did not
i fl
i
i
l
bl
d fl
i
i
h
k
i Table 1 (abstract P201). Microcirculatory variables Introduction Studies show that sublingual mucosa is a reproducible
part for small intestine mucosal microcirculatory perfusion in sepsis,
when they are not exposed by local factors. However, it is of great
interest how sublingual microcirculation can refl ect other beds of
microcirculation. The aim of the study is to evaluate and compare the
microcirculatory perfusion of potentially available parts of the body,
such as sublingual mucosa, conjunctiva of the eye, mucosa of jejunum
and rectum, at the same time points during experimental sepsis. p
g
p
p
Methods Pigs were randomly assigned to sepsis (n = 9) and sham
(n = 4) groups. The sepsis group received a fi xed dose of live Escherichia
coli infusion over 1 hour. Animals were observed 5 hours after the start
of E. coli infusion. In addition to systemic hemodynamic assessment,
we performed conjunctival, sublingual, jejunal and rectal evaluation
of microcirculation using sidestream dark-fi eld videomicroscopy at the
same time points: at baseline, 3 and 5 hours after the start of live E. coli infusion. Assessment of microcirculatory parameters of convective
oxygen transport (microvascular fl ow index (MFI), proportion of
perfused vessels (PPV)) and diff usion distance (perfused vessel density,
total vessel density) was done using a semiquantitative method. References y
Critical Care 2012, 16(Suppl 1):P201 (doi: 10.1186/cc10808) References
1. Saeed M, et al.: Crit Care Med 2011, 39:952-960. 2. Dunser M, et al.: Crit Care 2009, 13:R181. 3. Shahin J, et al.: Crit Care 2011, 15:R162. 4. Thackraya S, et al.: Eur J Heart Fail 2002, 4:515-529. Introduction We investigated whether human protein C (PC) concen-
trate to restore physiological values in adult septic shock patients can
infl uence microcirculatory blood fl ow. S73 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods We enrolled 36 septic shock patients with plasma protein
C activity <60%. Patients were randomly allocated to be treated with
either a continuous infusion of PC concentrate at 3 UI/kg/hour for
72 hours to reach plasma protein C activity between 70 and 120% or
a standard treatment (control; each n = 18). In both groups, NE was
titrated to achieve a MAP between 65 and 75 mmHg. Data from right
heart catheterization and sidestream dark-fi eld imaging were obtained
at baseline and after 24, 48 and 72 hours.if the small vessels (MFIs) and norepinephrine requirements did not vary
during the 24-hour observational period. Results are summarized in
Table 1. Conclusion In patients with established septic shock who remained
tachycardic after hemodynamic optimization in accordance with the
current guidelines, titration of esmolol to reduce the HR to a predefi ned
threshold did not aff ect microcirculatory blood fl ow. Results For the same MAP and cardiac output, no signifi cant diff erences
were found between groups in terms of microvascular fl ow index of
the small vessels (MFIs) and perfused vessel density (PVD). Results are
summarized in Table 1. P203 P203 Early course of microcirculatory perfusion in the eye and digestive
tract during experimental sepsis
A Pranskunas1, R Rasimaviciute1, E Milieskaite1, A Vitkauskiene1,
P Dobozinskas1, V Veikutis2, Z Dambrauskas1, D Vaitkaitis1, V Pilvinis1
1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Institute of
Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
Critical Care 2012, 16(Suppl 1):P203 (doi: 10.1186/cc10810) P204 Results Apart from a statistically signifi cant decrease in HR and cardiac
index (CI) (P <0.05), stroke volume (SV), microvascular fl ow index of P204
Microcirculation and blood transfusion: eff ects of three diff erent
types of concentrated red blood cells – preliminary results
A Donati, E Damiani, R Domizi, C Scorcella, A Carsetti, MR Lombrano,
V Fiori, P Pelaia
Università Politecnica delle Marche, Ancona, Italy
Critical Care 2012, 16(Suppl 1):P204 (doi: 10.1186/cc10811) Table 1 (abstract P202)
Baseline
24 hours
HR
119 ± 12
85 ± 9*
CI
4.4 ± 1
3.1 ± 1*
SV
81 ± 35
80 ± 23
MFIs
2.6 ± 0.6
2.8 ± 0.3
NE
0.7 ± 0.7
0.5 ± 0.4
*P <0.05. Introduction Red blood cell (RBC) transfusions are used to increase
oxygen delivery; however, a restrictive transfusion strategy (predefi ned
hemoglobin threshold of 7 g/dl) was demonstrated to be associated
with lower mortality and incidence of nosocomial infections than
a liberal one [1,2]. This may be related to the storage process, which
could aff ect the ability of RBCs to transport and delivery oxygen, or to
immunomodulating eff ects of cytokines from residual leukocytes [2]. Introduction Red blood cell (RBC) transfusions are used to increase
oxygen delivery; however, a restrictive transfusion strategy (predefi ned
hemoglobin threshold of 7 g/dl) was demonstrated to be associated
with lower mortality and incidence of nosocomial infections than
a liberal one [1,2]. This may be related to the storage process, which
could aff ect the ability of RBCs to transport and delivery oxygen, or to
immunomodulating eff ects of cytokines from residual leukocytes [2]. S74 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 explores the relationship between peripheral perfusion parameters
and macrohemodynamic, metabolic, hepatosplanchnic, and micro-
circulatory-related parameters during hyperdynamic septic shock. Figure 1 (abstract P204). De Backer score pre and post transfusion in
group 2. Methods Thirty-nine sets of parallel assessments of hemodynamic or
perfusion-related parameters were performed in 13 hyperdynamic
(cardiac index >2.5 l/minute/m2) septic shock patients (age 68 ± 18
years, APACHE II score 26 ± 6, SOFA score 11 ± 4, ICU mortality 2/13)
during the fi rst 24 hours of resuscitation. P204 Assessment included:
echocardiographic and pulmonary artery catheter-derived parameters;
indocyanine green plasma disappearance rate (ICG-PDR, Limon) and
gastric tonometry; metabolic parameters (lactate, SvO2 and p(v-a)
CO2); sublingual microcirculatory assessment (SDF); thenar StO2 and
vascular occlusion test (VOT) derived parameters (NIRS); peripheral
perfusion parameters including capillary refi ll time and central to toe
temperature diff erence. Results Peripheral perfusion was normal in 22 sets (56%) and abnormal
in 17 (44%). A normal peripheral perfusion was associated with lower
APACHE II scores (23.2 ± 3 vs. 28.4 ± 7, P = 0.009), better metabolic
parameters (lactate: 2.3 ± 0.6 mmol/l vs. 3.5 ± 1.1 mmol/l, P = 0.002 and
SvO2: 78.1 ± 6% vs. 73.9 ± 5%, P = 0.049), and better StO2 recovery slope
after VOT (3.54 ± 1.4 vs. 0.94 ± 0.5%/second, P <0.001) as compared
with an abnormal one. No correlation could be demonstrated with
macrohemodynamic parameters, hepatosplanchnic perfusion para meters
(gastric tonometry and ICG-PDR), or with sublingual microcirculatory
parameters. p
Conclusion A normal peripheral perfusion is associated with
normal metabolic perfusion parameters and less impaired micro-
vascular reactivity. No relation between peripheral perfusion and
hepatosplanchnic or sublingual microcirculatory fl ow could be
established in this study.i Figure 1 (abstract P204). De Backer score pre and post transfusion in
group 2. The aim of the study is to evaluate the eff ects, on microcirculation of
septic patient, of three types of RBCs. y
ClinicalTrials.gov Identifi er: NCT01271153 y
ClinicalTrials.gov Identifi er: NCT01271153 i
owledgements Supported by grant FONDECYT 1100610 (Ch i
Acknowledgements Supported by grant FO Methods A controlled randomized prospective study on 45 patients
with sepsis, severe sepsis or septic shock requiring RBC transfusion. Patients are randomized into three groups receiving: (1) fresh standard
RBCs (storage <10 days); (2) leukodepleted RBCs; and (3) old standard
RBCs (storage >20 days) respectively. Before and 1 hour after the
transfusion, microcirculation is evaluated using sidestream dark-fi eld
imaging [3] and near-infrared spectroscopy with a vascular occlusion
test. We also monitor temperature, heart rate, mean blood pressure,
hemochrome, blood gases, blood lactates and SOFA score. P206 P206
Hyperoxia aff ects peripheral tissue microcirculation in patients with
pulmonary arterial hypertension
S Dimopoulos, G Tzanis, C Manetos, A Tasoulis, A Mpouchla, E Tseliou,
I Vasileiadis, N Diakos, J Terrovitis, S Nanas
University of Athens, Greece
Critical Care 2012, 16(Suppl 1):P206 (doi: 10.1186/cc10813) g
Results Preliminary data on 18 patients, six for each group: before and
after transfusion, in group 2, but not in groups 1 and 3, there is a trend
to an increase in MFIs (P = 0.09), DeBacker score (Figure 1, P <0.05),
PPV (P = 0.07) and PVD (P = 0.07). No relevant diff erences for other
parameters. Introduction Pulmonary microcirculation abnormalities play a central
role in pulmonary arterial hypertension (PAH) pathophysiology. We hypothesized that PAH patients also have systemic muscle
microcirculation alterations compared to healthy subjects. The aim
of this study was to investigate peripheral muscle microcirculation
by near-infrared spectroscopy (NIRS) in PAH patients and to test the
eff ects of hyperoxia into their tissue microcirculation. p
Conclusion After transfusion, microcirculation seems to be improved
in the leukodepleted RBC group with a signifi cant improvement of
De Backer score and a trend to improve the other microcirculatory
parameters, while in the other three groups there was not this trend. References f
yp
Methods Eight PAH patients and eight healthy subjects matched for
age, gender and body mass index underwent NIRS evaluation. Tissue
O2 saturation (StO2, %), defi ned as the percentage of hemoglobin
saturation in the microvasculature compartments, was measured
on the thenar muscle. Subsequently, the 3-minute brachial artery
occlusion technique was applied before, during, and after 15 minutes
of 100% of O2-breathing. Main measurements included the oxygen
consumption rate (OCR, %/minute), the reactive hyperemia time (RHT,
minutes), and the time needed for StO2 to reach its baseline values after
the release of the occlusion. 1. Hebert PC: N Engl J Med 1999, 340:409-417. 1. Hebert PC: N Engl J Med 1999, 340:409-417. 2. Rosemary L: Blood Transfusion 2010, 8(Suppl 3):S26. 2. De Backer D: Crit Care 2007, 11:R101. P207
Supraclavicular ultrasound-guided subclavian vein cannulation in
infants under 5 kg
P Kenderessy
Faculty Children Hospital, Banska Bystrica, Slovakia
Critical Care 2012, 16(Suppl 1):P207 (doi: 10.1186/cc10814) 16%). All right-sided catheters lay at an angle <30°. However, 38%
(14/37) of left-sided catheters had not crossed the midline, and 59%
(22/37) lay at an angle >30° to the vertical. Only 11% (4/37) of left-sided
catheters had crossed the midline and lay at an angle of <30°, and all of
these lay below the level of the carina. No immediate complications of
insertion were identifi ed. See Table 1. Table 1 (abstract P208). Site of CVC insertion (n = 137)
Internal jugular
Subclavian
Right
95
5
Left
32
5 Introduction Central venous cannulation is at some point diffi cult in
small children and is associated with many complications especially in
multiple-attempt cases. Various techniques exist to achieve successful
cannulation. Ultrasound (US)-guided techniques are reported to be
safe and reduce the rate of complications for internal jugular vein (IJV)
cannulation. We describe an US-guided supraclavicular approach to
another central vein – the subclavian vein (SCV). The supraclavicular
approach to the SCV with anatomical landmarks was described by
Yoff a, but physicians are hesitant to use this technique because of the
short distance to pleura.i Conclusion There was a wide variation of catheter tip placements
accepted without re-positioning. Left-sided catheter tips are more at
risk of less precise (and thus potentially nonoptimal) placement. Our
results indicate that a clearer placement strategy is required. References p
Methods The principle of the US-navigated technique is to fi nd the SCV
at the supraclavicular level and to obtain a longitudinal view of the SCV
and to allow access to the vein in-plane view (absolute control of the
needle). The ultrasound probe (2.5 cm, 6 to 13 MHz) was placed above
the clavicle to visualize the IJV and tilted showing the subclavian artery
and SCV in longitudinal view. This view permitted an in-plane puncture
of the vein avoiding arterial or plural hit. 1. Stonelake PA, et al.: The carina as a radiological landmark for central venous
catheter tip position. Br J Anaesth 2006, 96:335-340. p p
2. Bodenham A: Reducing major procedural complications from central
venous catheterization. Anaesthesia 2011, 66:1-9. Results Seventy-eight infant and newborns under 5 kg (1.2 to 5 kg) and
83 SCV cannulations were enrolled in this observational study during a
period of 11 months (January 2011 to November 2011). Central venous catheter placement: where is the end of the line?
K Tizard, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P208 (doi: 10.1186/cc10815) Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P208 (doi: 10.1186/cc10815) Conclusion Power-injectable PICCs have many advantages in the
ICU: they can be used as multipurpose central lines for any type of
infusion including high-fl ow infusion, for hemodynamic monitoring,
and for high-pressure injection of contrast media during radiological
procedures. Their insertion is successful in 100% of cases and is not
associated with signifi cant risks, even in patients with coagulation
disorders. Their maintenance is associated with an extremely low rate
of infective and noninfective complications. Introduction There is still controversy regarding safe placement
of central venous catheters (CVCs) as to where the tip should lie to
avoid mechanical complications whilst maintaining eff ective use
[1,2]. The carina has previously been suggested as a useful landmark
to avoid intracardiac placement and its associated risks, and also that
the catheter tip should lie within the superior vena cava parallel to
its walls [1,2]. However, this has been disputed and there remains no
consensus as to optimal tip placement. To gauge our current practice
we performed a retrospective review of CVCs placed via the internal
jugular or subclavian route in intensive care patients to assess where
CVC tips were placed. P209
Power-injectable peripherally inserted central catheters in intensive
care patients MG Annetta, C Marano, A Brutti, D Celentano, M Pittiruti
Catholic University, Rome, Italy Introduction In ICUs, peripherally inserted central catheters (PICCs)
may be an alternative option to standard central venous catheters,
particularly in patients with coagulation disorders or at high risk
for infection. Some limits of PICCs (such as low fl ow rates) may be
overcome by the use of power-injectable catheters. Methods We have retrospectively reviewed all of the power-injectable
PICCs inserted in adult and pediatric patients in the ICU during a
12-month period, focusing on the rate of complications at insertion
and during maintenance. All PICCs were inserted by specifi cally trained
nurses, using ultrasound guidance and the microintroducer technique,
according to a specifi c insertion protocol. p
p
Conclusion A supraclavicular US-guided approach to SCV cannulation
is safe and eff ective possibility for central vein cannulation in small
infants. More studies are needed to establish a learning curve for pure
paediatric intensivists without experience with US navigation. Results We have collected 89 power-injectable PICCs (65 in adults and
24 in children), 4 to 6 Fr, both multiple and single lumen. All insertions
were successful. There were no major complications at insertion and no
episodes of local infection or catheter-related bloodstream infection. Noninfective complications during management were not clinically
relevant. There was one episode of symptomatic thrombosis during
the stay in the ICU and one episode after transfer of the patient on a
nonintensive ward. P205 P205
Peripheral perfusion is correlated to metabolic perfusion
parameters and microvascular reactivity but not with
hepatosplanchnic or microcirculatory fl ow parameters in
hyperdynamic septic shock
G Hernandez1, T Regueira1, A Bruhn1, P Mcnab1, E Veas1, C Pedreros1,
A Fuentealba1, E Kattan1, G Bugedo1, M Rovegno1, R Castro1, C Ince2
1Pontifi cia Universidad Catolica de Chile, Santiago, Chile; 2University of
Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P205 (doi: 10.1186/cc10812) Results PAH patients had a signifi cantly lower resting StO2 (65.8 ± 14.9
vs. 82.1 ± 4.0, P = 0.01), a lower OCR (35.3 ± 9.1 vs. 43.4 ± 19.7) and
a higher RHT (3.0 ± 0.6 vs. 2.0 ± 0.3, P <0.001) compared to controls. Hyperoxic breathing increased StO2 (65.8 ± 14.9 to 71.4 ± 14.5, P <0.05)
in PAH patients, while OCR was reduced (35.3 ± 9.1 to 25.1 ± 6.6,
P <0.05) and RHT was further increased (3.0 ± 0.6 to 4.2 ± 0.7, P <0.01). Conclusion PAH patients present a signifi cant impairment of peripheral
tissue microcirculation as assessed by the NIRS occlusion technique. Acute hyperoxic breathing aff ects peripheral microcirculatory
function in PAH patients, possibly due to oxidative stress and evoked
vasoconstriction. Introduction Peripheral perfusion assessment is increasingly being
recognized as a potential surrogate of global perfusion parameters
during septic shock resuscitation. Nevertheless, its correlation
with other perfusion parameters is not well established. This study S75 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P207
Supraclavicular ultrasound-guided subclavian vein cannulation in
infants under 5 kg
P Kenderessy
Faculty Children Hospital, Banska Bystrica, Slovakia
Critical Care 2012, 16(Suppl 1):P207 (doi: 10.1186/cc10814) P207
Supraclavicular ultrasound-guided subclavian vein cannulation
infants under 5 kg
P Kenderessy
Faculty Children Hospital, Banska Bystrica, Slovakia
Critical Care 2012, 16(Suppl 1):P207 (doi: 10.1186/cc10814) P207
Supraclavicular ultrasound-guided subclavian vein cannulation in
infants under 5 kg
P Kenderessy
Faculty Children Hospital, Banska Bystrica, Slovakia
Critical Care 2012, 16(Suppl 1):P207 (doi: 10.1186/cc10814) All cannulations
were performed by a single anesthesiologist trained for ultrasound
in central line cannulation with established eye–hand coordination
(5 years experience with peripheral blocks under US). For all cases
the SCV was easily and quickly visualized, one case had an extremely
narrow SCV. The US window for cannulation was always established
for free in-plane placement of the needle. The overall success rate for
puncture was 100% and for cannulation was 98%. In the case with an
extremely narrow vein (because of oedema and stricture) the SCV was
punctured but it was impossible to pass the catheter in. The success
rate of puncture at fi rst attempt was 97%, at second attempt was
100%. A second attempt was necessary in two cases because needle
visualization and angle of the needle movement were not considered
correct. No complication was reported. P212 in pediatric cardiac surgery in terms of success rate and mechanical and
infectious complications. Errors in the arterial blood pressure measurement
F Franchi1, V De Palo1, A Faltoni1, S Cecchini1, L Cubattoli2, P Giomarelli1
1University of Siena, Italy; 2Hospital of Siena, Italy
Critical Care 2012, 16(Suppl 1):P212 (doi: 10.1186/cc10819) Methods After Ethics Committee approval and written informed
consent from the parents of the children were obtained, 200 children
who were scheduled for cardiac surgery were randomly allocated to IJV
(n = 100) and SV (n = 100) groups. Introduction The artefacts aff ecting arterial wave morphology may
compromise recorded values of arterial blood pressure (ABP) and
can lead to therapeutic errors. The aim of this study is to evaluate the
errors between invasive and noninvasive arterial pressure values, the
incidence of artefacts due to an inadequate dynamic response of the
transducer-tubing system, and their detection by the ICU staff . g
p
Results The mean age was 37 months (95% CI, 29 to 45 months) in group
IJV and 35 months (95% CI, 29 to 42 months) in group SV (P = 0.619). The
95% CI for weight in groups IJV and SV were 10.4 to 14.2 kg and 10.2 to
13.0 kg, respectively (P = 0.595). The CVC success rates at fi rst attempt
for groups IJV and SV were 67% and 70%, respectively (P = 0.761). An alternative location was required to perform CVC in 90 patients
in group IJV and in 92 patients in group SV (P = 0.806). The overall
frequency of mechanical complications during the catheter insertion
and its use was 26% in group IJV and 28% in group SV (log-rank test:
P = 0.753). Signifi cantly more arterial punctures occurred in group IJV
than in group SV (14% vs. 4%, P = 0.024). Catheter tip misplacement
was observed more frequently in group SV than group IJV (12% vs. 1%, P = 0.003). Catheter colonization rates were signifi cantly higher in
group IJV than group SV (15% vs. 5%, log-rank test: P = 0.020). There
was no diff erence in bloodstream infection per 1,000 catheter days
between group IJV and group SV (3.4 vs. 1.4, respectively: P = 0.319). Methods Seventy-fi ve consecutive patients (50 male, mean age 55 ± 18)
admitted to the ICU for heterogeneous pathologies were enrolled. The T-Line TL-200 system for continuous noninvasive blood
pressure measurement in medical ICU patients The T-Line TL-200 system for continuous noninvasive blood
pressure measurement in medical ICU patients The T-Line TL-200 system for continuous noninvasive blood
pressure measurement in medical ICU patients
B Saugel, F Fassio, A Hapfelmeier, AS Meidert, RM Schmid, W Huber
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P213 (doi: 10.1186/cc10820) B Saugel, F Fassio, A Hapfelmeier, AS Meidert, RM Schmid, W Huber
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P213 (doi: 10.1186/cc10820) Introduction The T-Line TL-200 (Tensys Medical Inc., San Diego, CA,
USA) is a noninvasive arterial blood pressure (BP) monitoring system
allowing continuous beat-to-beat monitoring of systolic arterial
pressure (SAP), mean arterial pressure (MAP), and diastolic arterial
pressure (DAP). It provides a real-time BP waveform like that obtained
using an arterial catheter for BP monitoring. The aim of this study was
to compare BP measurements obtained using the T-Line TL-200 system
with simultaneous invasive BP measurements using a femoral arterial
catheter in unselected critically ill medical patients. Results A total of 856 lines performed in 602 patients were evaluated. In 607 US-guided cannulating internal jugular veins with only four
cases of malposition, there were no cases of pneumothorax recorded. A total of 161 subclavian veins were cannulated with no US, of which six
cases of pneumothorax were reported; two cases needed intercostal
tube insertion. Eighty-eight femoral vein cannulations with no US were
performed and no complications were recorded. Conclusion Chest X-ray is not necessary after US-guided CVL place-
ment. Cutting out the chest X-ray procedure post insertion proved to
be cost-eff ective. y
Methods In 28 patients treated in a medical ICU of a German university
hospital, BP values were simultaneously obtained using a femoral
arterial catheter and the T-Line TL-200 device. All recorded data were
included in the fi nal analysis. For comparison of BP measurements,
Bland–Altman analysis accounting for repeated measurements was
performed. P213 Methods A retrospective study of 856 lines placed in 602 patients being
evaluated over a period of 11 months. All cases were performed in a
controlled ICU environment. Chest X-rays were performed 30 minutes
post-insertion in the D0 adult ICU unit in a tertiary medical center in
Abu Dhabi, UAE. The D0 ICU has a capacity of 24 beds with an average
admission rate of 55 to 60 patients per month. Records were assessed
and evaluated, and data collected and statistically studied. Ultrasound-guided central venous line placement in critically
ill patients: is chest X-ray needed to assess post-insertion
pneumothorax? Ultrasound-guided central venous line placement in critically
ill patients: is chest X-ray needed to assess post-insertion
pneumothorax? O Samir Abdel Gelil Kotb, A Ali Abel Aziz, Y Awad
Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
Critical Care 2012, 16(Suppl 1):P211 (doi: 10.1186/cc10818) Ultrasound-guided central venous line placement in critically
ill patients: is chest X-ray needed to assess post-insertion
pneumothorax? p
O Samir Abdel Gelil Kotb, A Ali Abel Aziz, Y Awad
Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
Critical Care 2012, 16(Suppl 1):P211 (doi: 10.1186/cc10818) Introduction Critically ill patients, mostly on positive pressure
ventilation, are at higher risk of pneumothorax as well as their need for
a central venous line (CVL) to optimize fl uid status, CVP measurement,
and so forth, and where the CVL is not being placed in the best
circumstances with the patients being critically ill, unstable and with
higher chances of error predisposed by pre-existing lung disease,
obesity or whatever the admitting diagnosis. Before CVL placement
was a blind technique relying on the anatomical positions identifying
the position of major blood vessels and thus post-insertion X-ray was
needed to confi rm correct placement and to assess for pneumothorax. But with ultrasound (US) being more widely available, and most CVLs
placed as US guided, the ultimate question develops: is post-insertion
chest X-ray still needed? Conclusion The bias between invasive and noninvasive ABP measure
can be relevant and mislead in the therapeutic management. These
errors can be avoided by identifying the artefacts that aff ect arterial
signal and so the ICU staff must pay attention to the recognition of
arterial dumping in critically ill patients. P212 Inclusion criteria were: the presence of an intra-arterial catheter (IAC)
for invasive blood pressure monitoring, and age >18 years. Pregnancy
was excluded. At admission and every time the IAC was replaced we
acquired invasive systolic, diastolic, and medium arterial pressure
values (I-SP, I-DP, I-MP) during hemodynamic stability (variations of
mean arterial pressure <10%); at the same time, noninvasive systolic
and diastolic arterial pressure values (Ni-SP, Ni-DP) were measured
with a sphygmomanometer at the same arm of the IAC. Noninvasive
medium arterial pressure (Ni-MP) was calculated as follows: (SP + 2DP) / 3. At every time of the study, before ABP value acquisition, medical and
nursing staff answered a questionnaire on the reliability of the arterial
waveform. The staff could perform the fast fl ush test if considered
appropriate. However, the fast fl ush test was executed by the main
investigator at the end of questionnaire in all patients. Bland–Altman
analysis was performed. Conclusion In pediatric cardiac surgery patients, IJV and SV catheters
had similar success rates as well as overall mechanical complication
rates. Although the catheter colonization rate was signifi cantly higher
with IJV than SV, both access routes had similar rates of bloodstream
infection. y
p
Results We compared 130 pairs of Ni-SP, Ni-DP and Ni-MP and I-SP,
I-DP and I-MP. The mean bias between Ni-SP and I-SP was –11 mmHg
(limit of agreement (LoA) –43.6 to 21.4 mmHg). The mean bias between
Ni-DP and I-DP and between Ni-MP and I-MP was 6.1 mmHg (LoA
–15.5 to 27.7 mmHg) and 0.37 mmHg (LoA –21.0 to 21.7 mmHg),
respectively. We performed the fast fl ush test 130 times; an inadequate
dynamic response of the transducer-tubing system was observed 55
times: in 45 cases the arterial signal was underdumped and in 10 cases
was overdumped. The arterial dumping was correctly detected by the
medical staff in 95% of cases, by nursing staff and postgraduates in 35%
of cases. Reference . Pickering TG: Principles and techniques of blood pressure measurement. Cardiol Clin 2002, 20:207-223. Comparison of internal jugular and subclavian access for central
venous catheterization in pediatric cardiac surgery
A Pirat1, A Camkiran1, P Zeyneloglu1, M Ozkan1, E Akpek2, G Arslan1
1Baskent University, Ankara, Turkey; 2Acibadem University, Istanbul, Turkey
Critical Care 2012, 16(Suppl 1):P210 (doi: 10.1186/cc10817) Comparison of internal jugular and subclavian access for central
venous catheterization in pediatric cardiac surgery
A Pirat1, A Camkiran1, P Zeyneloglu1, M Ozkan1, E Akpek2, G Arslan1
1Baskent University, Ankara, Turkey; 2Acibadem University, Istanbul, Turkey
Critical Care 2012, 16(Suppl 1):P210 (doi: 10.1186/cc10817) Methods We retrospectively reviewed the chest radiographs of 197
consecutive intensive care patients admitted on and before 30 June
2011. A total of 101 patients had evidence of 137 new CVCs. For each
new catheter the Picture Archiving & Communication System was used
to record the tip position (after any repositioning) in relation to the
carina and the degree of angulation from the vertical.i Introduction Central venous catheterization (CVC) is an essential com-
po nent of perioperative care in pediatric cardiac surgery. Traditionally
the internal jugular vein (IJV) is used for CVC in cardiac surgery. The aim
of this study was to compare IJV and subclavian vein (SV) routes for CVC Introduction Central venous catheterization (CVC) is an essential com-
po nent of perioperative care in pediatric cardiac surgery. Traditionally
the internal jugular vein (IJV) is used for CVC in cardiac surgery. The aim
of this study was to compare IJV and subclavian vein (SV) routes for CVC Results Twenty-fi ve per cent (34/137) of all catheter tips lay >10 mm
below the carina, therefore potentially increasing the likelihood of
intracardiac placement. This was reduced for left-sided catheters (6/37; S76 Critical Care 2012, Volume 16 Suppl 1
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Results Mean age was 69 ± 13 years, 14 patients received noradrenaline,
eight patients dobutamine, and nine patients volume expansion. During the whole record, the number of episodes of Ov or At ranged
from 0 to 15 with a duration of 0 to 6 hours: 17 patients had at least one
episode of Ov and/or At tracing, 10 patients had at least two episodes,
eight patients had at least fi ve episodes. Seven episodes lasted more
than 20 minutes and three more than 1 hour. During the fi rst hour, sAP
was overestimated by 5.0 ± 1.4 mmHg (P <0.0001) (range: 0.3 to 5.9)
or by 4.3 ± 0.9% (range: 0.4 to 15.9%), raw PPV was 9.5 ± 7.3 versus
10.0 ± 7.8 for the corrected PPV (range from –2.6 to 4.3); raw dP/dt was
overestimated by 134 ± 47 mmHg/second (P <0.0001) (range: –13 to
353) or by 24 ± 6%. 1.
Wax DB, et al.: Anesthesiology 2011, 115:973-978. P215 Results A total of 76,826 pairs of BP measurements (each consisting
of SAP, MAP, and DAP) were analyzed. For MAP, Bland–Altman analysis
revealed a mean diff erence of +0.47 mmHg (95% limits of agreement:
–16.53 to +17.46 mmHg). For SAP and DAP, the bias and 95% limits of
agreement were –9.01 mmHg (–37.47 to +19.45 mmHg) and +5.22
mmHg (–13.50 to +23.94 mmHg), respectively. Right/left ventricular area ratio does not correlate with right
ventricular impedance
F Paalvast1, D Reis Miranda1, M Knook2, A Rossi1, J Van Bommel1,
D Gommers1
1Erasmus Medical Centre, Rotterdam, the Netherlands; 2Reinier de Graaf
Ziekenhuis, Delft, the Netherlands
Critical Care 2012, 16(Suppl 1):P215 (doi: 10.1186/cc10822) Reliability of radial arterial pressure monitoring after cardiac
surgery
C Lavault1, MC Fevre2, A Hebrard2, M Durand2, F Grimbert1, Y Lavault1,
P Albaladejo2
1UJF – Grenoble1/CNRS/TIMC-IMAG UMR 5525 (Equipe PRETA), Grenoble,
France; 2CHU Grenoble, France
Critical Care 2012, 16(Suppl 1):P214 (doi: 10.1186/cc10821) Introduction Invasive monitoring in critically ill patients allows a
continuous measurement of arterial pressure, cardiac output, and the
derivation of dynamic predictors of fl uid responsiveness. However, the
pressure signal may be altered by the dynamic characteristics of the
fl uid-fi lled tubing. The aim of the present study was to evaluate the
reliability of radial artery blood pressure measurement and derived
indexes during the early period after cardiac surgery. Methods After IRB approval, 30 patients admitted to the ICU after
elective cardiac surgery (CABG: 16, valve surgery: 11; combined: 3)
with a radial artery catheter were included. In the ICU, an independent
continuous recording of arterial pressure during at least 18 hours
was started via a double-head pressure transducer (Flotrac; Edwards
Lifesciences, Irvine, CA, USA) for a retrospective analysis and three
fast fl ushes were performed. First, the whole record was examined
for episodes of overdamping (Ov) or attenuation (At). Ov was defi ned
as a decrease in systolic (sAP), an increase diastolic (dAP), and an
unchanged mean pressure (mAP). At was defi ned as a decrease in sAP,
dAP and mAP. Second, three periods of 10 minutes during the fi rst hour
were analysed assuming that the dynamic characteristics remained
constant. This allowed the correction of the distorted raw signals and
the study of the consequences of an underdamped signal on sAP, pulse
pressure variation (PPV) and dP/dt as an estimate of left ventricular
contractility. A paired t test was used for statistical comparison, P <0.05
was considered statistically signifi cant. Results Cardiac output dropped from 4.4 ± 0.8 to 1.7 ± 0.9 l/minute. The relations between occluder resistance and RV/LV area ratio during
diastole and during systole were not signifi cant (r = 0.48 resp. r = 0.54). Conclusion The RV/LV area ratio does not correlate with right
ventricular impedance in this closed pericardium model. References 1. Bouferrache K: Acute respiratory distress syndrome, mechanical
ventilation, and right ventricular function. Curr Opin Crit Care 2011,
17:30-35. 2. Mansencal N: Comparison of diff erent echocardiographic indexes
secondary to right ventricular obstruction in acute pulmonary embolism. Am J Cardiol 2003, 92:116-119. Right/left ventricular area ratio does not correlate with right
ventricular impedance
F Paalvast1, D Reis Miranda1, M Knook2, A Rossi1, J Van Bommel1,
D Gommers1
1Erasmus Medical Centre, Rotterdam, the Netherlands; 2Reinier de Graaf
Ziekenhuis, Delft, the Netherlands
Critical Care 2012, 16(Suppl 1):P215 (doi: 10.1186/cc10822) D Gommers1
1Erasmus Medical Centre, Rotterdam, the Netherlands; 2Reinier de Graaf
Ziekenhuis, Delft, the Netherlands
Critical Care 2012, 16(Suppl 1):P215 (doi: 10.1186/cc10822) g
g
p
y
Conclusion The T-Line TL-200 system allows determination of MAP with
a satisfactory agreement when compared to invasive assessment of
MAP using a femoral arterial catheter in unselected critically ill medical
patients. Higher mean diff erences and 95% limits of agreement for SAP
and DAP measurements might be explainable by limited comparability
of central (femoral) and peripheral (radial) SAP and DAP measurements. Introduction The right ventricular/left ventricular (RV/LV) area ratio is
often used to titrate airway pressure during mechanical ventilation [1]. This ratio has only been validated for detecting pulmonary embolism
[2]. The purpose of this study was to evaluate the relationship between
RV/LV area ratio and RV impedance in a pig model with a closed
pericardium. P214 Reliability of radial arterial pressure monitoring after cardiac
surgery
C Lavault1, MC Fevre2, A Hebrard2, M Durand2, F Grimbert1, Y Lavault1,
P Albaladejo2
1UJF – Grenoble1/CNRS/TIMC-IMAG UMR 5525 (Equipe PRETA), Grenoble,
France; 2CHU Grenoble, France
Critical Care 2012, 16(Suppl 1):P214 (doi: 10.1186/cc10821) Methods Eight anesthetized pigs were instrumented with closed
pericardium for the measurement of arterial blood pressure, central
venous pressure, RV and pulmonary pressure. On the main pulmonary
artery, an ultrasonic fl owprobe (MA14PAX; Transonic) was positioned
to obtain pulmonary fl ow. Distally, a balloon occluder was positioned
facilitating gradual constriction of the pulmonary artery. To obtain a
stepwise pressure diff erence increment over the banding we gradually
infl ated the balloon occluder. Occluder resistance is computed as the
systolic right ventricle pressure minus systolic pulmonary pressure
divided by cardiac output times 79.9. An ECG-gated CT scan of the
heart was performed, 10 minutes after each banding. The RV/LV area
ratio was computed by reconstructing the CT images to a typical
echocardiographic four-chamber view and dividing the RV area by the
LV area. All measurements were performed in triplicate and averaged. As repeated measurements in eight independent animals were used, a
signifi cant relation was sought between RV/LV area ratio and occluder
resistance with ANOVA. Correlation was obtained by a Spearson’s
correlation. f
References 1. Ultrasound detects central line placement and postprocedure 1. Ultrasound detects central line placement and postprocedure
pneumothorax. Emerg Med 2009. pneumothorax. Emerg Med 2009. 2. Ultrasound-guided central line placement: no X-ray needed. Emerg Med
2011. S77 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Eff ects of cardiac output levels on the measurement of
transpulmonary thermodilution cardiac output in patients with
acute lung injury Figure 1 (abstract P218). K Kao, H Hu, C Hung, C Chang, C Huang probe (CardioQ™; Deltex Medical, UK) was inserted, connected to the
CardioQ-ODM™ monitoring system and correct positioning verifi ed. Simultaneous determination of cardiac output by ODM and ECOM™
was performed before and after cross-clamping of the aorta. Results Cardiac output ranged from 1.4 to 13.1 l/minute. Linear
regression is represented by the equation y = 0.30x + 2.2 and the
correlation coeffi cient r2 = 0.15. The bias was +1.5 l/minute with 95%
limits of agreement between –2.1 and 5.1 l/minute (Figure 1). Conclusion Using the CardioQ™ as a reference, the ECOM™ system
cannot be recommended as a clinical cardiac output measurement
technique in abdominal aortic surgery, due to its poor correlation and
wide limits of agreement. probe (CardioQ™; Deltex Medical, UK) was inserted, connected to the
CardioQ-ODM™ monitoring system and correct positioning verifi ed. Simultaneous determination of cardiac output by ODM and ECOM™
was performed before and after cross-clamping of the aorta. Introduction Transpulmonary thermodilution cardiac output (CO)
correlates closely with pulmonary artery (PA) thermodilution CO. Levels of CO may contribute varying amounts of thermal indicator
loss and recirculation during thermodilution CO measurement. This
study aimed to investigate the eff ects of CO levels on the agreement
between transpulmonary and PA thermodilution CO in acute lung
injury (ALI) patients. p
p g
Results Cardiac output ranged from 1.4 to 13.1 l/minute. Linear
regression is represented by the equation y = 0.30x + 2.2 and the
correlation coeffi cient r2 = 0.15. The bias was +1.5 l/minute with 95%
limits of agreement between –2.1 and 5.1 l/minute (Figure 1). p
p g
Results Cardiac output ranged from 1.4 to 13.1 l/minute. Linear
regression is represented by the equation y = 0.30x + 2.2 and the
correlation coeffi cient r2 = 0.15. The bias was +1.5 l/minute with 95%
limits of agreement between –2.1 and 5.1 l/minute (Figure 1). Conclusion Using the CardioQ™ as a reference, the ECOM™ system
cannot be recommended as a clinical cardiac output measurement
technique in abdominal aortic surgery, due to its poor correlation and
wide limits of agreement. y
Methods Twenty-two ALI patients were prospectively enrolled. Techniques to measure cardiac output: minimally invasive method
versus thermodilution MostCare is resulted to be reliable and accurate even in
hemodynamically unstable patients. It would be interesting to study
the new device before and after having modifi ed the therapy, such as
fl uid challenge or inotropic therapy or the use of vasopressors. References 1. Zangrillo A, et al.: J Cardiothorac Vasc Anesth 2010, 24:265-269. 2. Scolletta S, et al.: Br J Anaesth 2005, 95:159-165. 3. Romano SM, et al.: Crit Care Med 2002, 30:1834-1841. 1. Zangrillo A, et al.: J Cardiothorac Vasc Anesth 2010, 24:265-269. 2. Scolletta S, et al.: Br J Anaesth 2005, 95:159-165. 3. Romano SM, et al.: Crit Care Med 2002, 30:1834-1841. Techniques to measure cardiac output: minimally invasive method
versus thermodilution versus thermodilution
A Donati, S Tondi, A Carsetti, R Domizi, C Melia, D Kolgjini, C Munch,
C Scorcella, P Pelaia
Università Politecnica delle Marche, Ancona, Italy
Critical Care 2012, 16(Suppl 1):P216 (doi: 10.1186/cc10823) Università Politecnica delle Marche, Ancona, Italy
Critical Care 2012, 16(Suppl 1):P216 (doi: 10.1186/cc10823) Introduction Hemodynamic monitoring is important to manage
critically ill patients. The thermodilution pulmonary catheter is
considered the gold standard; however, it is invasive and associated
with the onset of complications. Our study compared cardiac output
(CO) obtained with the MostCare (COMC), which uses the pressure
recording analytical method, to CO obtained with a Swan–Ganz (COSG)
catheter in hemodynamically unstable patients. Introduction Hemodynamic monitoring is important to manage
critically ill patients. The thermodilution pulmonary catheter is
considered the gold standard; however, it is invasive and associated
with the onset of complications. Our study compared cardiac output
(CO) obtained with the MostCare (COMC), which uses the pressure
recording analytical method, to CO obtained with a Swan–Ganz (COSG)
catheter in hemodynamically unstable patients. Conclusion These results showed that frequent artefacts and
distortions induced by the fl uid-fi lled tubing could modify the arterial
waveform and could lead to inaccurate therapy [1]. More attention
should be paid to the quality of the pressure signal. Reference Methods We conducted a prospective clinical study in our cardiosurgical
ICU. Sixteen post-cardiosurgical adult patients were enrolled. They had
a Swan–Ganz catheter and were mechanically ventilated. The Swan–
Ganz catheter was connected to the monitor Vigilance Edwards®, while
the MostCare was connected to the patient’s artery. For each patient
three measurements of CO have been carried out and the mean was
considered for statistical analysis. The correlation coeffi cient, Bland–
Altman test and percentage of error were measured. Results The correlation coeffi cient between COSG and COMC was 0.824
(0.567 to 0.935, 95% CI; P <0.001) The Bland–Altman analysis showed S78 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Figure 1 (abstract P218). a mean diff erence between the two methods (bias) of 0.22 ± 0.55 l/
minute/m2 with lower and upper 95% limits of confi dence of –0.87 and
1.30 l/minute/m2 respectively. The percentage of error was of 25%. Figure 1 (abstract P218). p
y
p
g
Conclusion This study demonstrated a good correlation between the
two methods. P217f Eff ects of cardiac output levels on the measurement of
transpulmonary thermodilution cardiac output in patients with
acute lung injury
K Kao, H Hu, C Hung, C Chang, C Huang
Chang Gung Memorial Hospital, Kwei-Shan,Taoyuan, Taiwan
Critical Care 2012, 16(Suppl 1):P217 (doi: 10.1186/cc10824) p
References References
1. Harvey S, et al.: Lancet 2005, 366:472-477. 2. Koo KKY, et al.: Crit Care Med 2011, 39:1613-1618. 1. Harvey S, et al.: Lancet 2005, 366:472-477. 2. Koo KKY, et al.: Crit Care Med 2011, 39:1613-1618. Methods Seven consecutive patients (seven male, zero female), mean
age 56.5 (± 12) years, were enrolled into the study. ICO data were Eff ects of cardiac output levels on the measurement of
transpulmonary thermodilution cardiac output in patients with
acute lung injury Paired bolus transpulmonary thermodilution cardiac index (BCItp)
and continuous PA thermodilution cardiac index (CCIpa) data were
recorded at baseline and repeated immediately and at 2, 4, and 6 hours
after volume expansion with a 500 ml infusion of 10% pentastarch (HES
200/0.5). Cardiac output monitoring in cirrhotic patients: EV1000 versus
pulmonary artery catheter – preliminary data
G Costa, T Cecconet, D Baron, G Serena, P Chiarandini, L Pompei,
L Vetrugno, G Della Rocca
University of Udine, Italy
Critical Care 2012, 16(Suppl 1):P219 (doi: 10.1186/cc10826) Results One hundred and ten paired CI measurements were recorded
and divided into four quartiles from the lowest to the highest CCIpa. The mean BCItp was higher than CCIpa, and the Bland–Altman analysis
revealed a bias of 0.57 ± 0.75 l/minute/m2. The limits of agreement (2SD)
were +2.07 to –0.93 l/minute/m2. BCItp correlated closely with CCIpa
(R = 0.887). CCIpa negatively correlated with the diff erence between
BCItp and CCIpa (R = –0.26). The bias of quartile 1 with the least CCIpa
was signifi cantly greater than those of the three other quartiles. Introduction The EV1000 platform, a new calibrated device for
intermittent and continuous cardiac output monitoring, has recently
been introduced into clinical practice [1]. This study aims to assess
the level of agreement between intermittent and continuous cardiac
output obtained from VolumeView (ICOvv and CCOvv) connected
to the EV1000 platform (Edwards Lifesciences, Irvine, CA, USA) and
intermittent (ICOvig) and continuous cardiac output (CCOvig) obtained
using an advanced pulmonary artery catheter (PAC) connected to
the Vigilance System (Edwards Lifesciences) in cirrhotic patients
undergoing liver transplantation. i
Conclusion In ALI patients, transpulmonary thermodilution is a clinically
acceptable and interchangeable alternative to PA thermodilution for
CO measurement. Levels of CO weakly and negatively correlate with the
diff erence between BCItp and CCIpa. There is greater overestimation of
BCItp over CCIpa in low than in high CO states. Comparison of bioimpedance and oesophageal Doppler cardiac
output monitoring during abdominal aortic surgery Agreement and precision
between CO values were evaluated with Bland–Altman analysis. The
percentage error (PE) was calculated as 2SD / mean CO [2]. Results Twenty-one ICO data pairs were compared. Two patients were
excluded from CCO data analysis for technical reasons. A total 240 CCO
data pairs from fi ve patients were analysed. Data yielded were analysed
as total and for CO values lower and higher than 8 l/minute (Table 1). Conclusion These data, even if very preliminary, showed low agreement
and high PE either for intermittent and continuous CO obtained from
the VolumeView. However, for CO data lower than 8 l/minute the PE
was improved. percentage error (PE) was calculated as 2SD / mean CO [2]. Results Twenty-one ICO data pairs were compared. Two patients were
excluded from CCO data analysis for technical reasons. A total 240 CCO
data pairs from fi ve patients were analysed. Data yielded were analysed
as total and for CO values lower and higher than 8 l/minute (Table 1). Conclusion These data, even if very preliminary, showed low agreement
and high PE either for intermittent and continuous CO obtained from
the VolumeView. However, for CO data lower than 8 l/minute the PE
was improved. Results Twenty-one ICO data pairs were compared. Two patients were
excluded from CCO data analysis for technical reasons. A total 240 CCO
data pairs from fi ve patients were analysed. Data yielded were analysed
as total and for CO values lower and higher than 8 l/minute (Table 1). TPTD
Conclusion The PCCO method cannot replace the transpulmonary
thermodilution method in critically ill children. Conclusion These data, even if very preliminary, showed low agreement
and high PE either for intermittent and continuous CO obtained from
the VolumeView. However, for CO data lower than 8 l/minute the PE
was improved. P221 References 1. Bendjelid et al.: Crit Care 2010, 14:R209. 2. Cecconi et al.: Crit Care 2009, 13:201. 1. Bendjelid et al.: Crit Care 2010, 14:R209. Introduction With respect to a radial arterial pressure measurement, a
more central achievement of this pressure should improve the reliability
of endotracheal bioimpedance cardiac output (CO) monitoring. We
therefore compared prospectively the impact on accuracy of this
device, in comparison with thermodilution (TD) CO. P221 Impact of arterial catheter location on the accuracy of cardiac
output provided by an endotracheal bioimpedance device
F Gennart, S Beckers, C Verborgh, A De baerdemaeker, J Poelaert
UZ Brussels, Belgium
Critical Care 2012, 16(Suppl 1):P221 (doi: 10.1186/cc10828) Comparison of bioimpedance and oesophageal Doppler cardiac
output monitoring during abdominal aortic surgery Table 1 (abstract P219). Bias, 2SD and PE for all data pairs and for CO higher
and lower than 8 l/minute Table 1 (abstract P219). Bias, 2SD and PE for all data pairs and for CO higher
and lower than 8 l/minute
Bias
2SD
PE (%)
ICO
Total
–0.89
3.6
49
<8
–1.37
2.4
40
>8
–0.05
4.8
52
CCO
Total
–0.83
4.88
63
<8
–1.8
2.4
37
>8
2.07
5.64
47 g
g
Littlebaelt Hospital Kolding, Denmark Introduction Abdominal aortic surgery is a high-risk procedure. Cardiac
output monitoring allowing haemodynamic optimisation may reduce
the complication rate. Minimally invasive, continuous techniques
are preferable. Cardiac output using oesophageal Doppler has been
validated in several studies, showing good agreement with the gold
standard. The aim of this study was to assess the degree of correlation
and agreement between cardiac output measured by oesophageal
Doppler and bioimpedance obtained from an endotracheal tube. Methods Twelve patients scheduled for elective abdominal aortic
surgery were included. Patients were intubated with an ECOM™
endotracheal tube (ConMed Corporation, NY, USA) which was
connected to the ECOM™ monitoring system. An oesophageal Doppler S79 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 5 hours and 33 minutes (range 14 minutes to 15 hours). The correlation
coeffi cient between the COTPTD and PCCO was 0.85 (P <0.0001). The
Bland–Altman analysis showed a mean bias of 0.06 l/minute (limits of
agreement (LoA) ± 2.22 l/minute) (Figure 1). The percentage error was
43%. The correlation coeffi cient between the recalibration interval and
the bias between COTPTD and PCCO was –0.26 (P = 0.05). There was no
correlation between COTPTD and PCCO (r = 0.09 (P = 0.57)). Conclusion The PCCO method cannot replace the transpulmonary
thermodilution method in critically ill children. obtained from the two devices after ICU admission (T0) and after 12
(T12) and 24 hours (T24). CCOvig and CCOvv were recorded every hour
from T0 up to 48 hours after ICU admission. Agreement and precision
between CO values were evaluated with Bland–Altman analysis. The
percentage error (PE) was calculated as 2SD / mean CO [2]. obtained from the two devices after ICU admission (T0) and after 12
(T12) and 24 hours (T24). CCOvig and CCOvv were recorded every hour
from T0 up to 48 hours after ICU admission. Haemodynamic changes during the peri-extubation period using
bioreactance fl ow monitoringi l
g
J Thirsk, D Magimairaj, A Douiri, D Hadfi eld, P Hopkins
Ki
’ H
lth P t
L
d
UK King’s Health Partners, London, UK Results The sample was 19 males, nine females, age 60.2 ± 11.8 years;
APACHE II score 23.3± 5.4. The 280 pairs of CIpc and CItd showed a
signifi cant correlation (P <0.001; r = 0.907). There was no diff erence
between CIpc versus CItd (4.15 ± 1.46 vs. 4.09 ± 1.41 l/minute*sqm;
P = 0.265). Bland–Altman analysis demonstrated a mean bias of
–0.061 ± 0.603 l/minute*sqm (lower and upper levels of agreement
–1.24 and 1.12l/minute*sqm; percentage error of 28.7%). In univariate
analyses, the bias CItd2–CIpc was not correlated to the interval to the
last calibration (P = 0.705; r = –0.023), but it was correlated to CIpc
immediately before recalibration (r = –0.275; P <0.001) and to changes
from CIpc versus the previous CItd1 (Delta-CIpc–CItd1; r = –0.504;
P <0.001). These fi ndings were confi rmed in the validation collective
(P <0.001). Multiple regression analysis demonstrated independent
association of the bias to Delta-CIpc–CItd1. This association was best
described by bias CItd2–CIpc = –0.014 – 0.372x + 0.145x2 – 1.260x3
with x = Delta-CIpc–CItd1. This formula as a potential calibration index
provided ROC AUCs of 0.882 and 0. 751 (P <0.001) to predict a bias
CItd2–CIpc >20% or <–20% in the evaluation collective. This formula was
confi rmed with ROC AUCs of 0.809 and 0.714 (P <0,001) to predict a bias
CItd2–CIpc >20% or <–20% in the independent validation collective. Conclusion The diff erence CIpc–CItd1 is an independent predictor of
the bias CItd2–CIpc. A calibration index was developed and validated. It could be a useful decision support to initiate the next TD. King’s Health Partners, London, UK
Critical Care 2012, 16(Suppl 1):P224 (doi: 10.1186/cc10831) g
Critical Care 2012, 16(Suppl 1):P224 (doi: 10.1186/cc10831 Introduction Here we present a prospective, observational study
examining the eff ect of extubation on cardiac index, measured
by bioreactance (Nicom Cheetah), in critically ill patients with or
without a history of left ventricular impairment [1]. A number of
simple interventions are known to improve the process of weaning
patients from mechanical ventilation. Despite this progress, the
pathophysiology underlying failure to wean remains incompletely
understood. In particular, the role of cardiac ventricular dysfunction
may be underestimated [2]. P223 Methods Fourteen patients undergoing cardiac surgery with cardiac
output monitoring by TD have been enrolled. A specially designed
endotracheal tube (ECOM; ConMed) was placed in conjunction with
a catheter located either in the brachial (18 G) or in the radial (20 G)
artery in each group of seven patients. Six individual measurements
have been carried out in each patient at fi xed period, resulting in a
total of 42 measurements for each subset. The mean CO by TD was
compared with CO by ECOM for each operative period and assessed
for agreement by linear regression, Bland–Altmann analysis and
percentage error methods. The measurement error should not exceed
30% to be considered as valid, according to Critchley and colleagues. P224
Haemodynamic changes during the peri-extubation period using
bioreactance fl ow monitoring
J Thirsk, D Magimairaj, A Douiri, D Hadfi eld, P Hopkins
King’s Health Partners, London, UK
Critical Care 2012, 16(Suppl 1):P224 (doi: 10.1186/cc10831) P224
Haemodynamic changes during the peri-extubation period using
bioreactance fl ow monitoring
J Thirsk, D Magimairaj, A Douiri, D Hadfi eld, P Hopkins
King’s Health Partners, London, UK
Critical Care 2012, 16(Suppl 1):P224 (doi: 10.1186/cc10831) g
References 1. Critchley et al.: J Clin Monit 1999, 15:85-91. 2. Bland et al.: Lancet 1986, i:307-310. p
y
p
p g
Methods A prospective study in 51 patients undergoing open elective
abdominal aortic surgery – 30 patients with AAD and 21 with AOD. CF
values were obtained at baseline, before induction of anaesthesia (T1)
and 30 minutes after reperfusion (T2). Cardiac output monitoring using the LiDCOplus™ monitor in
abdominal aortic surgery: changes in calibration factor in aortic
aneurysm disease versus aortic occlusive disease y
HK Jørgensen, J Bisgaard, T Gilsaa
Lillebaelt Hospital, Kolding, Denmark
Critical Care 2012, 16(Suppl 1):P223 (doi: 10.1186/cc10830) y
HK Jørgensen, J Bisgaard, T Gilsaa
Lillebaelt Hospital, Kolding, Denmark
Critical Care 2012, 16(Suppl 1):P223 (doi: 10.1186/cc10830) y
HK Jørgensen, J Bisgaard, T Gilsaa
Lillebaelt Hospital, Kolding, Denmark
Critical Care 2012, 16(Suppl 1):P223 (doi: 10.1186/cc10830) Introduction Monitoring of cardiac output (with subsequent
haemodynamic optimisation) may improve outcome after high-risk
surgery. The pulmonary artery catheter is still considered the gold
standard, but has potential serious complications. Much eff ort has
been put into developing equally good, but less invasive techniques. One of these, the LiDCOplus™ system, uses pulse power analysis
to calculate cardiac output and is calibrated by a lithium indicator
dilution technique. Since cardiac output is aff ected by the compliance
of the aorta, the LiDCO calculates a calibration factor (CF) each time
it is calibrated. The purpose of this study was to investigate whether
insertion of aortic prosthetic material would aff ect aortic compliance
and thereby the CF. It was hypothesised that the change in CF would be
larger in patients with aortic occlusive disease (AOD) than in patients
with aortic aneurysm disease (AAD), since previous studies have shown
that these two groups diff er considerably on both haemodynamic
capacity and their response to aortic cross-clamping [1]. g
y
g
Results Mean patient age was 71 years (56 to 89) (13 male, one female). R2 values of 0.47 (P <0.01) and 0.63 (P <0.01) in the linear regressions
and errors of 41% and 50% were found for the radial and brachial
catheter data, respectively. See Figures 1 and 2. y
Conclusion Accuracy was considerably improved using a brachial
artery catheter. Nevertheless, measurement errors between TD and
ECOM using either a radial or brachial catheter both exceed 30%. Based on these results and under the current technical conditions,
ECOM should not replace TD in CO monitoring for patients undergoing
cardiac surgery. Pulse contour cardiac output monitoring is less reliable in critically
ill children Pulse contour cardiac output monitoring is less reliable in critically
ill children
JC Verheul, A Nusmeier, J Lemson
Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P220 (doi: 10.1186/cc10827) JC Verheul, A Nusmeier, J Lemson
Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P220 (doi: 10.1186/cc10827) JC Verheul, A Nusmeier, J Lemson JC Verheul, A Nusmeier, J Lemson
Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Critical Care 2012, 16(Suppl 1):P220 (doi: 10.1186/cc10827) Figure 2 (abstract P221). Figure 1 (abstract P221). Figure 1 (abstract P221). Introduction Intermittent cardiac output measurement using the
transpulmonary thermodilution (TPTD) method is considered to be
the gold standard in young children but a validated continuous cardiac
output technique is not available in these patients. We compared the
continuous pulse contour cardiac output (PCCO) measurements with
the TPTD method in critically ill children. y
Methods We compared PCCO, measured with the PiCCO device
(Pulsion, Munich, Germany), with TPTD measurements (COTPTD) using
the same device in a general pediatric intensive care (PICU) population. Because PCCO is calibrated with each TPTD measurement (COTPTD) we
compared the mean PCCO value just before a new TPTD measurement
was done. We approved only COTPTD measurement consisting of three
consecutive TPTD measurements and we checked the thermodilution
curve for a temperature diff erence of at least 0.2°C and a normal
appearance. Only the intervals between two approved series of TPTD
measurements were analysed. We calculated the correlation coeffi cient
and used the Bland–Altman method for analysis. y
Results Sixty-one measurements in 10 children were included. Mean
age was 24.5 (range 5 to 123) months; mean weight was 11.2 (range 3.8
to 18) kg, mean heart rate was 131/minute (range 87 to 193) and the
mean blood pressure was 73 (range 49 to 96) mmHg. The mean COTPTD
was 2.60 (range 0.66 to 5.64) l/minute, mean cardiac index was 5.16
(range 2.76 to 10.83) l/minute/m2 and mean duration of the interval was Figure 1 (abstract P221). Figure 1 (abstract P221). Figure 1 (abstract P220). Bland–Altman analysis of COTPTD and PCCO. Figure 2 (abstract P221). Figure 1 (abstract P220). Bland–Altman analysis of COTPTD and PCCO. Figure 2 (abstract P221). Figure 2 (abstract P221). S80 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Reference 1. Shteinberg D, et al.: Eur J Vasc Endovasc Surg 2000, 20:462-465. Methods In 28 consecutive patients 56 datasets each including six
TDs were recorded. In each triplicate TD measurement, CIpc was
recorded immediately before recalibration by TD and compared to
CItd. Results derived from this evaluation collective were validated in
an independent second collective of 48 patients with 67 datasets. SPSS
19 software was used. 1. Shteinberg D, et al.: Eur J Vasc Endovasc Surg 2000, 20:462-465. Accuracy of the PiCCO2-derived pulse contour cardiac index
(CIpc): development and validation of a calibration index in two
independent collectives Results AAD patients were older (70 vs. 65 years, P <0.05), predominantly
males (80% vs. 47%), weighed more (80 kg vs. 73 kg, P <0.1) and
preoperative cardiac co-morbidity was more prevalent (43% vs. 14%). No diff erence was found in the use of epidural analgesia, vasopressors,
or inotropes between the groups. At T1, CF was signifi cantly higher for
AAD = 0.83 versus AOD = 0.68 (P = 0.01). After reperfusion, T2, there was
no signifi cant diff erence in CF, AAD = 0.86 versus AOD = 0.81 (P = 0.53). The percentage change in CF from T1 to T2 was signifi cantly larger in
AOD than in AAD (20% vs. 1.3%) (P <0.05). p
W Huber, J Koenig, B Saugel, T Schuster, R Schmid, S Mair
Klinikum Rechts der Isar, Technical University of Munich, Germany
Critical Care 2012, 16(Suppl 1):P222 (doi: 10.1186/cc10829) Introduction After calibration by thermodilution (TD), the PiCCO device
is able to assess CO using pulse contour (PC) analysis. Despite an overall
good correlation of CItd and CIpc in several studies, the manufacturer
suggests recalibration by TD after 8 hours. A calibration index derived
from PC parameters indicating a certain probability of a relevant
bias and triggering the next calibration would be of great practical
use. Therefore, it was the aim of our study to prospectively evaluate
predictors of the bias CItd–CIpc exactly 1 hour, 2 hours, 4 hours, 6 hours
and 8 hours after the last calibration. Conclusion Operative insertion of an abdominal aortic prosthesis
signifi cantly aff ects the calibration factor in patients with AOD,
indicating an increase in aortic compliance and the need for
recalibration of the LiDCOplus™. No signifi cant change was seen in
patients with aortic aneurysm disease. Reference P222 Accuracy of the PiCCO2-derived pulse contour cardiac index
(CIpc): development and validation of a calibration index in two
independent collectives
W Huber, J Koenig, B Saugel, T Schuster, R Schmid, S Mair
Klinikum Rechts der Isar, Technical University of Munich, Germany
Critical Care 2012, 16(Suppl 1):P222 (doi: 10.1186/cc10829) Accuracy of the PiCCO2-derived pulse contour cardiac index
(CIpc): development and validation of a calibration index in two
independent collectives Left ventricular stroke volume measurement by impedance
cardiography correlates with echocardiography in neonates
l h
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1 ,
,
,
,
,
g
1University Medical Center Hamburg – Eppendorf, Hamburg, Germany;
2University Center for Cardiology and Cardiothoracic Surgery, Hamburg,
Germany Introduction Thermodilution (TD) is a gold standard for cardiac index
(CI) measurement. The aim of this study is to compare intermittent
bolus TDCI with intermittent automatic calibration CI (AutoCI) and
continuous CI (CCI) obtained by pulse contour analysis with PiCCO2
(PiCCI) and Pulsiofl ex (PuCCI). Critical Care 2012, 16(Suppl 1):P225 (doi: 10.1186/cc10832) Introduction The aim of this study was to validate impedance
cardiography (electrical velocimetry (EV)) as a continuous noninvasive
cardiac output monitoring in neonates and infants. As the reference
method, discontinuous transthoracic echocardiography (TTE) was
used. l
Methods A prospective study in 20 patients (all mechanically ventilated,
14 male). Age 54.4 ± 16.7, BMI 28.1 ± 7.3, SAPS II 52.9 ± 13.4, APACHE II
score 26.7 ± 7.8 and SOFA score 10 ± 3. All patients underwent PiCCO
monitoring via a femoral line whilst the radial line was kept in place
during four 8-hour time periods (in the fi rst two periods the Pulsiofl ex
was connected to the radial line, in the last two it was connected to
the femoral line). In the fi rst and third 8-hour periods the Pulsiofl ex
was calibrated with the TDCI obtained at baseline, for the second and
fourth 8-hour periods the Pulsiofl ex was calibrated with the AutoCI
value. Simultaneous PiCCI and PuCCI measurements were obtained
every 2 hours while simultaneous TDCI and AutoCI were obtained
every 8 hours. The PiCCI and PuCCI values were recorded within
5 minutes before TDCI was determined. We also looked at the eff ects of
22 interventions: passive leg raise (n = 6), fl uid bolus (n = 5), change in
vasopressor (n = 9) or dobutamine (n = 1), increase in sedation (n = 1). Statistical analysis was performed using Pearson correlation and
Bland–Altman analysis. Methods In a prospective single-center observational study,
simultaneous left ventricular stroke volume (LVSV) measurements by
EV (using an Aesculon® Monitor) and by TTE were compared. LVSV
measurement by TTE was based on the aortic valve velocity time
integral multiplied by the area of the aortic valve outfl ow tract. Haemodynamic changes during the peri-extubation period using
bioreactance fl ow monitoringi Methods Cardiac index was measured by bioreactance monitoring
at 30-second to 60-second intervals for 1 hour pre and 1 hour post
extubation. Individual data were presented by box plot, showing
median and interquartile ranges (Figure 1). Combined results from
multiple patients in each test group were analysed by covariance (Stata
version 11.2). Results Group A (n = 5) had impaired left ventricular systolic function,
documented on formal transthoracic echo, of which three had ejection
fractions <25%. One patient in this group failed extubation due to
cardiogenic pulmonary oedema. Group B (n = 6) had normal systolic
function. Figure 1 shows representative absolute data obtained from Conclusion The diff erence CIpc–CItd1 is an independent predictor of
the bias CItd2–CIpc. A calibration index was developed and validated. It could be a useful decision support to initiate the next TD. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1 S81 Figure 1 (abstract P224). a patient in each group. There was a statistical diff erence between the
two groups (P = 0.02). In the impaired LV group, the cardiac index fell
from 3.2 l/minute/m2 (± 0.5) to 2.9 l/minute/m2 (± 2.5). higher LVSVs resulting in higher EV than TTE measurements. The
bias defi ned by the diff erence of the means of the two methods was
9.65%, with a mean percentage error of the individual measurements
of 55%. Based on the Bland–Altman analysis, a deduced approximated
correction factor between TTE-LVSV and EV-LVSV was TTE-LVSV = EV-
LVSV0.539×100.335 (EV-LVSV)×2.2. Conclusion In this small observational study we demonstrated a
consistent fall in cardiac index post extubation in patients with known
cardiac ventricular dysfunction when compared with patients with
normal hearts. These data suggest that bioreactance monitoring may
be valuable during spontaneous breathing trials and extubation. References Conclusion Correlation between EV and TTE in LVSV measurement
was signifi cant. Bland–Altman analysis showed that – despite a large
mean error of the individual measurements of 55% – the bias between
the means of the two methods was only 9.65%. A correction factor
between TTE and EV could be deduced. 1. Benomar B, Ouattara A, Estagnasie P, Brusset A, Squara P: Fluid
responsiveness predicted by non-invasive bioreactance-based passive leg
raise test. Intensive care Med 2010, 36:1875-1881. 2. Papanikolaou J, Makris D, Saranteas T, et al.: New insights into weaning from
mechanical ventilation: left ventricular diastolic dysfunction is a key
player. Validation of less-invasive hemodynamic monitoring with Pulsiofl ex
in critically ill patients Validation of less-invasive hemodynamic monitoring with Pulsiofl e
in critically ill patients
M Peetermans, W Verlinden, J Jacobs, A Verrijcken, S Pilate,
N Van Regenmortel, I De laet, K Schoonheydt, H Dits, ML Malbrain
ZNA Stuivenberg, Antwerp, Belgium
Critical Care 2012, 16(Suppl 1):P226 (doi: 10.1186/cc10833) M Peetermans, W Verlinden, J Jacobs, A Verrijcken, S Pilate,
N Van Regenmortel, I De laet, K Schoonheydt, H Dits, ML Malbrain
ZNA Stuivenberg, Antwerp, Belgium
C iti
l C
2012 16(S ppl 1) P226 (d i 10 1186/
10833) Haemodynamic changes during the peri-extubation period using
bioreactance fl ow monitoringi Intensive Care Med 2011, 37:1976-1985. P225 Left ventricular stroke volume measurement by impedance
cardiography correlates with echocardiography in neonates
ME Blohm1, J Hartwich1, D Obrecht1, G Müller2, J Weil2, D Singer1
1University Medical Center Hamburg – Eppendorf, Hamburg, Germany;
2University Center for Cardiology and Cardiothoracic Surgery, Hamburg,
Germany
Critical Care 2012, 16(Suppl 1):P225 (doi: 10.1186/cc10832) P227 P227
A preliminary study on the use of noninvasive hemodynamic
monitoring with the Nexfi n monitor in critically ill patients
M Peetermans, W Verlinden, J Jacobs, A Verrijcken, S Pilate,
N Van Regenmortel, I De laet, K Schoonheydt, H Dits, ML Malbrain
ZNA Stuivenberg, Antwerp, Belgium
Critical Care 2012, 16(Suppl 1):P227 (doi: 10.1186/cc10834) Results The models accurately predicted maximum ventricular
pressures and volumes, not used in the identifi cation process, to
mean percentage errors of 7.1% and 6.7% (less than measurement
error ~10%). Mean modelled pulmonary vascular resistances (PVR)
compared well (R2 = 0.81 for APE and R2 = 0.95 for SS) to experimentally
derived values. Importantly, in the APE study a 91% rise from baseline
in the mean PVR was identifi ed with an 89% increase seen in the SS
pigs. Contrasting behaviour between the two studies was observed for
systemic vascular resistance (SVR) with a maximum drop of 40% from
baseline recorded at T120 for SS, indicating a loss of vascular tone as
expected, where at the same time in the APE study the average SVR
had increased by 13%. An increase in the ratio of right to left ventricle
end volume was identifi ed in all nine pigs, indicating right ventricular
distension and a leftward shift in the intraventricular septum.i Introduction Noninvasive hemodynamic monitoring may become a new
tool in the ICU armamentarium. The Nexfi n monitor (BMEYE, Amsterdam,
the Netherlands) enables continuous noninvasive analysis of the fi nger
blood pressure waveform using an infl atable fi nger cuff , a technology
based on the volume-clamp principle of Penaz in combination with
the physical criteria of Wesseling. The aim of the present study was to
validate the Nexfi n in a mixed population of medical ICU patients and to
look for a pattern recognition that may be linked with outcome. g
y
Methods A prospective study in 40 patients admitted to the medical
ICU (17 patients mechanically ventilated, M/F ratio 1/1). Age 63.5 ± 16.7,
BMI 26.4 ± 5.4, APACHE II score 20.8 ± 9.5, SAPS II 45.9 ± 18.9, SOFA score
7.2 ± 4.2. For all patients, simultaneous recording of arterial pressure by
radial line (n = 46), by PiCCO monitor (n = 15) or by NIBP measurement
with arm cuff (n = 17) was compared with noninvasive hemodynamic
parameters obtained with the Nexfi n monitor. P227 Statistical analysis was
performed with Student’s t test, Pearson correlation and Bland–Altman
analysis. Conclusion These results indicate that subject-specifi c cardiovascular
models are capable of tracking well-known global hemodynamic
trends of two common forms of shock in the ICU. The method shows
potential and could provide a means for continuous cardiovascular
monitoring at little extra cost as no extra measurements or expensive
devices are required. P229 y
Results A total of 69 measurements in 40 patients were performed. In three patients measurement with the Nexfi n was not possible. For
CO (26 paired measurements), values were 6.4 ± 2.1 l/minute (range
3.3 to 12). The Pearson correlation coeffi cient comparing Nexfi n-CO
with reference CO showed a good correlation (R2 = 0.5). Bland–Altman
analysis comparing both CO techniques revealed a mean bias ±2SD
(LA) of 0.7 ± 3.9 l/minute (58.3% error). The MAP was 84.6 ± 17.7 mmHg
(57.5 to 131.5) and values obtained with the Nexfi n correlated well with
the reference method (PiCCO in eight; radial line in 43) with an R2 of
0.75. Bland–Altman analysis comparing both MAP techniques revealed
a mean bias ±2SD (LA) of 0.2 ± 19.7 mmHg (23.3% error). However,
Nexfi n-MAP did not correlate well with NIBP (R2 = 0.1). The nine patients
that died in the ICU had higher APACHE II (P = 0.07), SAPS II (P = 0.07)
and SOFA (P = 0.01) scores and signifi cantly lower MAP (P = 0.028) and
lower dp/dtmax (P = 0.029), a marker for contractility. There were no
outcome diff erences with regard to subgroup analysis in patients with
either low or high CO or SVR. A Ercole, SM Bishop, SI Yarham, VU Navapurkar, DK Menon
University of Cambridge, UK y
g
Critical Care 2012, 16(Suppl 1):P229 (doi: 10.1186/cc10836) y
g
Critical Care 2012, 16(Suppl 1):P229 (doi: 10.1186/cc10836) Introduction Physiological instability is a common clinical problem in
the critically ill. Physiological adaptation can be regarded as a dynamic
process, with stability being conferred by a number of apparently
complex, fl uctuating homeokinetic processes [1]. Many natural
systems are nonlinear, and seemingly random fl uctuations may result
as a consequence of their underlying dynamics. Fractal geometry off ers
a method to characterize the underlying nonlinear state, providing a
technique for monitoring complex physiology in real time, which may
be of clinical importance. Methods We employ the wavelet modulus maxima technique to
characterize the multifractal properties of physiological time series such
as heart rate (HR) and mean arterial pressure (MAP) under conditions of
clinical physiological instability. We calculated point estimates for the
dominant Hölder exponent (hm) and multifractal spectrum width-at-
half-height (WHH). We investigated how these parameters changed
with pharmacological interventions such as vasoconstriction. Conclusion The preliminary results of this ongoing prospective trial
indicate that in unstable critically ill patients CO and MAP can be
monitored noninvasively with the Nexfi n. The exact patient population
for this technology has yet to be defi ned and more patients are
probably needed for pattern recognition, although the results indicate
that low MAP and dp/dtmax are associated with poor outcome. g
Results Hypotensive patients showed lower values of hm for MAP,
consistent with a more highly fl uctuating, antipersistent and
complex behavior. Blood pressure support with pharmacological
vasoconstriction led to a transient increase in hm for MAP (Figure 1)
revealing the appearance of longer-range correlations, but did not
aff ect hm as estimated for HR. On the other hand, supporting the heart
rate with atropine had no eff ect on hm for MAP, but did tend to increase
hm for HR. Left ventricular stroke volume measurement by impedance
cardiography correlates with echocardiography in neonates
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1 A total
of 102 healthy neonates with normal biventricular cardiac morphology
(including PDA or patent foramen ovale) were included – further
patient details: 43 female, 59 male, median weight 3.32 kg, median
length 51 cm, median age 49.24 hours, mean heart rate 133 ± 22/
minute. In total 328 simultaneous LVSV measurements in triplicate
irrespective of respiratory cycle were analyzed. Results Signifi cant correlations (P <0.05) were noted between EV-LVSV
and body weight, TTE-LVSV and body weight, EV-LVSV and age,
TTE-LVSV and age. A signifi cant inverse correlation was seen between
EV-LVSV and heart rate, and TTE-LVSV and heart rate. No signifi cant
correlation was found for EV-LVSV and age (if age ≤120 hours). No
signifi cant eff ect was seen for a small persistent foramen ovale (n = 66)
and a small PDA (n = 26) on EV-LVSV and TTE-LVSV in the observed
cohort. Bland–Altman analysis of logarithmic data showed a bias of the
EV-LVSV measurements in comparison to the TTE-LVSV measurements
with smaller LVSVs resulting in lower EV than TTE measurements and y
Results In total, 305 paired PiCCI–PuCCI and 128 paired AutoCI–TDCI
values were obtained. TDCI values ranged from 1.5 to 6.7 l/minute/m2
(mean 3.9 ± 1), AutoCI from 2.4 to 6.5 (3.8 ± 0.8), PiCCI from 1.5 to 7.1
(3.8 ± 1.2) and PuCCI from 2 to 7.6 (3.8 ± 1). The Pearson correlation
coeffi cient comparing all and mean PuCCI and PiCCI values had an R2 of
0.77 and 0.86 respectively; for AutoCI and TDCI, R2 was 0.76. The above
R2 values were 0.73, 0.84 and 0.71 respectively when the Pulsiofl ex
was connected to a radial line. Changes in AutoCI correlated well with
changes in TDCI (R2 = 0.68), as did changes in PuCCI versus changes S82 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 immunocompromised and immobile state of ICU patients. This
research retrospectively tests the ability of a computer-based method
to monitor acute hemodynamic changes in pigs. If proven, this method
could assist ICU staff by providing a clear physiological, patient-specifi c
picture of cardiovascular status for decision support. in PiCCI (R2 = 0.53). PPV obtained from Pulsiofl ex and PiCCO correlated
better than SVV (R2 = 0.86 vs. 0.62). Left ventricular stroke volume measurement by impedance
cardiography correlates with echocardiography in neonates
l h
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1 Changes in PiCCI and PuCCI induced
by an intervention correlated well with each other (R2 = 0.94). Bland–
Altman analysis comparing AutoCI with TDCI revealed a mean bias
±2SD (LA) of 0.05 ± 0.94 l/minute/m2 (with 27.3% error) while analysis
of PuCCI versus PiCCI showed a bias ±LA of 0.01 ± 1.12 (29.1% error). Conclusion Although TDCI remains a gold standard, the preliminary
results of an ongoing prospective study indicate that in unstable
critically ill patients CI can be reliably monitored with Pulsiofl ex
technology. Moreover, the Pulsiofl ex was also able to keep track of
changes in CI. in PiCCI (R2 = 0.53). PPV obtained from Pulsiofl ex and PiCCO correlated
better than SVV (R2 = 0.86 vs. 0.62). Changes in PiCCI and PuCCI induced
by an intervention correlated well with each other (R2 = 0.94). Bland–
Altman analysis comparing AutoCI with TDCI revealed a mean bias
±2SD (LA) of 0.05 ± 0.94 l/minute/m2 (with 27.3% error) while analysis
of PuCCI versus PiCCI showed a bias ±LA of 0.01 ± 1.12 (29.1% error). in PiCCI (R2 = 0.53). PPV obtained from Pulsiofl ex and PiCCO correlated
better than SVV (R2 = 0.86 vs. 0.62). Changes in PiCCI and PuCCI induced
by an intervention correlated well with each other (R2 = 0.94). Bland–
Altman analysis comparing AutoCI with TDCI revealed a mean bias
±2SD (LA) of 0.05 ± 0.94 l/minute/m2 (with 27.3% error) while analysis
of PuCCI versus PiCCI showed a bias ±LA of 0.01 ± 1.12 (29.1% error). p
pp
Methods In two porcine studies, APE (n = 5) and SS (n = 4) were induced
using autologous blood clots and endotoxin infusions. Hemodynamic
measurements were recorded every 30 minutes for 4 hours (n = 80). Subject-specifi c cardiovascular models were identifi ed from typical ICU
measurements obtained from each of these datasets, including aortic
and pulmonary artery pressure, stroke volume, heart rate, global end-
diastolic volume, and mitral and tricuspid valve closure times. Model
outputs and identifi ed parameters were compared to experimentally
derived indices, measurements not used in the identifi cation process,
and known trends to validate the accuracy of the models. Conclusion Although TDCI remains a gold standard, the preliminary
results of an ongoing prospective study indicate that in unstable
critically ill patients CI can be reliably monitored with Pulsiofl ex
technology. Moreover, the Pulsiofl ex was also able to keep track of
changes in CI. Homeodynamic complexity: multifractal analysis of physiological
instability Homeodynamic complexity: multifractal analysis of physiological
instability A Ercole, SM Bishop, SI Yarham, VU Navapurkar, DK Menon
University of Cambridge, UK P228 P228
Computer-based monitoring of global cardiovascular dynamics
during acute pulmonary embolism and septic shock in swine
JA Revie1, DJ Stevenson1, JG Chase1, BC Lambermont2, A Ghuysen2,
P Kolh2, GM Shaw3, T Desaive2
1University of Canterbury, Christchurch, New Zealand; 2University of Liege,
Belgium; 3Christchurch Hospital, Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P228 (doi: 10.1186/cc10835) P228
Computer-based monitoring of global cardiovascular dynamics
during acute pulmonary embolism and septic shock in swine
JA Revie1, DJ Stevenson1, JG Chase1, BC Lambermont2, A Ghuysen2,
P Kolh2, GM Shaw3, T Desaive2
1University of Canterbury, Christchurch, New Zealand; 2University of Liege,
Belgium; 3Christchurch Hospital, Christchurch, New Zealand
Critical Care 2012, 16(Suppl 1):P228 (doi: 10.1186/cc10835) P230 Accuracy of conventional urinary output monitoring in the ICU
E Bouwhuijsen, A Oude Lansink, MW Nijsten, W Dieperink
University of Groningen, University Medical Center Groningen, the
Netherlands
Critical Care 2012, 16(Suppl 1):P230 (doi: 10.1186/cc10837) Introduction In patients who are treated in the ICU an accurate
fl uid balance is an important tool to assess their hydration status. In
most ICUs, intake of fl uid is monitored precisely by sophisticated
volumetric infusion and feeding pumps. In contrast to fl uid intake,
fl uid output – especially urine as its most important component – is
usually monitored visually by hourly assessment of the amount of
fl uid lost and urine production. Thus measurement of urinary output
is a repetitive procedure 24 times a day which requires handling of
the urinary collection system, visual assessment and manual data
recording, actions that are easily aff ected by human errors. l
g
Results One patient was excluded due to missing data. There were
signifi cant increases in mean arterial pressure (MAP), left ventricular
dimensions at the end of diastole and systole, stroke volume (SV),
cardiac output (CO) and BNP after the fl uid challenge, while the heart
rate decreased. Impaired cardiac contractility was defi ned as an ejection
fraction (EF) <50%. The left ventricular end-systolic dimension (LVESd)
before (4 cm vs. 2.9 cm) and after the fl uid challenge (4.2 cm vs. 3.29 cm)
was signifi cantly greater (statistically and beyond reference intervals) in
the EF <50% group compared to the EF >50% group. In the group with
EF <50, the median LVEDd2 and LVESd2 post fl uid challenge increased
to values of 5.72 cm and 4.28 cm respectively (above the reference
thresholds). For the group with EF >50, the median post-challenge
LVEDd2 and LVESd2 increased signifi cantly (P = 0.01) to 5.38 cm and
3.39 cm but within the reference thresholds. The BNP increased by
53.6% in the EF <50 group in contrast to a decrease by 12.7% in the
EF >50 group. The median EF in the EF <50 and EF >50 groups were
signifi cantly diff erent (0.44 vs. 0.66 respectively). .
Pirracchio R, et al.: Impaired plasma BNP clearance in human septic shock.
Cri Care Med 2008, 36:2542-2546. Computer-based monitoring of global cardiovascular dynamics
during acute pulmonary embolism and septic shock in swine m
Conclusion We demonstrate increasing signal complexity under
physiological challenge consistent with the activation of homeokinetic
processes. Diff erential fractal behavior for HR and MAP suggests that
the homeokinetic systems are recruited in a targeted way depending Introduction Acute pulmonary embolism (APE) and septic shock
(SS) are highly prevalent dysfunctions in the ICU due to the Introduction Acute pulmonary embolism (APE) and septic shock
(SS) are highly prevalent dysfunctions in the ICU due to the S83 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1 pp
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P229). Figure 1 (abstract P229). on the physiological challenge. Pharmacological restoration of homeo-
stasis leads to system decomplexifi cation suggesting that homeokinetic
mechanisms are derecruited as physiology is restored. We suggest
fractal geometry provides a method for characterizing physiological
instability and measuring the homeokinetic stress response during
physiological challenges. Reference 1. Goldberger AL, Amaral LAN, Hausdorff JM, Ivanov PC, Peng C-K, Stanley HE:
Proc Natl Acad Sci U S A 2002, 99:2466-2472. Introduction The aim of the study is to describe the hemodynamic
changes and relate them to the changes in B-type natriuretic peptide
(BNP) following fl uid challenge in patients with severe sepsis and septic
shock. Methods This prospective observational study enrolled 30 patients
with severe sepsis or septic shock who required a fl uid challenge
within 48 hours of admission to the ICU. All patients had a basic
cardiac echocardiogram (echo) performed, blood for BNP collected
and baseline hemodynamic measurements recorded. A 500 ml
colloid challenge was administered within 30 minutes. The echo and
hemodynamic measurements were repeated at this point. One hour
after the fl uid challenge the BNP test was repeated. Changes in B-type natriuretic peptide and related hemodynamic
parameters following a fl uid challenge in patients with severe
sepsis or septic shock Changes in B-type natriuretic peptide and related hemodynamic
parameters following a fl uid challenge in patients with severe
sepsis or septic shock S Omar, LR Mathivha, A Ali Wits University, Johannesburg, South Africa Critical Care 2012, 16(Suppl 1):P231 (doi: 10.1186/cc10838) Reference Assessment fl uid responsiveness in septic shock patients:
a comparison of automated pulse pressure variation and manually
calculated pulse pressure variation Results At baseline, PP and EKG were both <12%. PP were signifi cantly
correlated with EKG (r2 = 0.89, P <0.001). Volume loss induced by
haemorrhage increased signifi cantly PP and EKG. Moreover, during
this state, PP were signifi cantly correlated with EKG (r2 = 0.86, P <0.001). Retransfusion signifi cantly decreased both PP and EKG, and PP were
signifi cantly correlated with EKG (r2 = 0.90, P <0.001). S Panyawatanaporn, B Khwannimit S Panyawatanaporn, B Khwannimit y
p
Prince of Songkla University, Hat Yai, Thailand Prince of Songkla University, Hat Yai, Thailand
Critical Care 2012, 16(Suppl 1):P234 (doi: 10.1186/cc10841) g
y
Critical Care 2012, 16(Suppl 1):P234 (doi: 10.1186/cc10841) Introduction Pulse pressure variation (PPV) is an accurate predictor of
fl uid responsiveness in mechanically ventilated patients. The aim of this
study was the assessment and comparison of the ability of automated
PPV, when measured by an IntelliVue MP 70 monitor, and manually
calculated PPV to predict fl uid responsiveness in mechanically
ventilated septic shock patients. gi
y
Conclusion Available correlations between PP and EKG at each time
of the study were observed, meaning that EKG is a reliable parameter
to estimate the changes in intravascular volume status and provide
experimental confi rmation of the Brody eff ect [2]. References i
yf
References p
p
Methods We conducted a prospective study on 36 septic shock patients. Automated and manually calculated PPV and other hemodynamic
data were recorded before and after fl uid administration of 500 ml of
6% hydroxyethyl starch (130/0.4) over 30 minutes. Responders were
defi ned as patients with an increase in their cardiac index >15% after
fl uid loading. 1. Cannesson M, Keller G, Desebbe O, Lehot JJ: Relations between respiratory
changes in R-wave amplitude and arterial pulse pressure in mechanically
ventilated patients. J Clin Monit Comput 2010, 24:203-207. p
p
2. Brody DA: A theoretical analysis of intracavitary blood mass infl uence on
the heart–lead relationship. Circ Res 1956, 4:731-738. 2. Brody DA: A theoretical analysis of intracavitary blood mass infl uence on
the heart–lead relationship. Circ Res 1956, 4:731-738. Results The agreement (mean bias ± SD) between automated and
manually calculated PPV was 4.03 ± 7.37%. The baseline automated PPV
correlated with the baseline manually calculated PPV (r = 0.79, P <0.01). Twenty-three (63.9%) patients were classifi ed as fl uid responders. References 1. Intensive Care Med 2011, 37:233-240. 2. Crit Care Med 2088, 36:2810-2816. P232
The Brody eff ect to detect hypovolemia in clinical practice
R Giraud, N Siegenthaler, DR Morel, K Bendjelid
Hôpitaux Universitaires de Genève, Switzerland
Critical Care 2012, 16(Suppl 1):P232 (doi: 10.1186/cc10839) P232
The Brody eff ect to detect hypovolemia in clinical practice
R Giraud, N Siegenthaler, DR Morel, K Bendjelid
Hôpitaux Universitaires de Genève, Switzerland
Critical Care 2012, 16(Suppl 1):P232 (doi: 10.1186/cc10839) Table 1 (abstract P233). Hemodynamic variables at 0 and 24 hours
Variable
0 hours
24 hours
P value
CVP
15.51
16.2
>0.1
MAP
73.6
76.4
>0.1
SVV%
13.61
10.8
>0.1
Arterial lactate
3.9 ± 2.6
2.3 ± 1.5
<0.001
PO2/FiO2
120.6 ± 42
193.4 ± 76
<0.001 Introduction The electrocardiogram (EKG) is a common monitoring
method in intensive care medicine. Several studies suggest that changes
in EKG morphology may refl ect changes in volume status. The Brody
eff ect, a theoretical analysis of left ventricular chamber size infl uence
on QRS-wave amplitude, is the key element of this phenomenon. It is
characterized by an increase in QRS-wave amplitude induced by an
increase in ventricular preload [1]. This study investigated the infl uence
of changes in intravascular volume status on respiratory variations of
QRS-wave amplitude (EKG) compared with respiratory pulse pressure
variations (PP). study period were 5.1 ± 2.6 l. Arterial lactates reduced signifi cantly
without worsening of hypoxia. The PO2/FiO2 ratio increased signifi cantly
at 24 hours. Twenty-two out of 37 survived (59.45%) until hospital
discharge. See Table 1.l g
Conclusion SVV guided fl uid therapy in septic shock with ARDS may
improve shock by optimizing preload in a targeted way without
worsening oxygenation. Methods In 17 pigs, EKG and arterial pressure were recorded. QRS-
wave amplitude was measured from the Biopac recording ensuring
that in all animals EKG electrodes were always at the same location. Maximal QRS amplitude (EKGmax) and minimal QRS amplitude
(EKGmin) were determined over one respiratory cycle. EKG was
calculated as 100×((EKGmax – EKGmin) / (EKGmax + EKGmin) / 2). EKG
and PP were simultaneously recorded. Measurements were performed
during normovolaemic conditions, after haemorrhage and following
retransfusion with constant tidal volume (10 ml/kg) and respiration
rate (15/minute).i Stroke volume variation guided fl uid therapy in septic shock with
ARDS S Jog, D Patel, M Patel, S Sable S Jog, D Patel, M Patel, S Sable
Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2012, 16(Suppl 1):P233 (doi: 10.1186/cc10840) g,
,
,
eenanath Mangeshkar Hospital and Research Centre, Pune, India Deenanath Mangeshkar Hospital and Research Centre, Pune, India
Critical Care 2012, 16(Suppl 1):P233 (doi: 10.1186/cc10840) Introduction Optimal fl uid resuscitation guided by central venous
pressure (CVP) in patients having septic shock with ARDS is a perplexed
issue having risk of underfi lling and worsening of shock versus fl uid
overload leading to pulmonary edema. Whether stroke volume
variation (SVV) (Flotrac-Vigileo system) guided fl uid resuscitation has
an impact on improvement of shock, oxygenation and mortality were
tested in this single-center prospective study [1,2]. i
Conclusion Our results indicate that the automated PPV, obtained by
the IntelliVue MP 70 monitor, and manually calculated PPV, showed
comparable performance for predicting fl uid responsiveness in
passively ventilated septic shock patients. Methods Inclusion criteria were: (1) septic shock patients with dose
of norepinephrine ≥0.1 μg/kg/minute or dopamine ≥10 μg/kg/
minute; (2) CVP ≥12 mmHg; (3) PO2/FiO2 ratio ≤200 with ARDSnet
protocol ventilation under deep sedation. Exclusion criteria were
atrial/ventricular arrhythmias, spontaneous triggering of inspiration,
established renal failure needing continuous renal replacement
therapy (CRRT). During the 24-hour study period, SVV was continuously
monitored with the third-generation Flotrac-Vigileo system (version
3.02). Intravenous fl uids were given in the boluses of 250 to 500 cm3 to
keep SVV <12% throughout the study period. Vasopressor infusion was
titrated to keep MAP >70 mmHg. Assessment fl uid responsiveness in septic shock patients:
a comparison of automated pulse pressure variation and manually
calculated pulse pressure variation Automated PPV and manually calculated PPV were signifi cantly higher
in responders than in nonresponders (16.0 ± 4.5% vs. 7.2 ± 2.0% and
11.1 ± 5.6 vs. 4.6 ± 2.8%, respectively; P <0.001 for both). The area
under the receiver operating characteristic curves of automated PPV
was signifi cantly greater than the manually calculated PPV (0.982 vs. 0.87, respectively; P = 0.04). The optimal threshold values for predicting
fl uid responsiveness were 11% for automated PPV (sensitivity 91.3%,
specifi city 92.3%) and 13% for manually calculated PPV (sensitivity
73.9%, specifi city 84.6%). P230 Multiple regression
analysis found LV dimension at end diastole at baseline was one of four
independent predictors of an increase in %BNP.il g
yf
y
Methods In a bench test we investigated the accuracy and precision
of conventional urinary output monitoring, by visual hourly readings
and manual data recording, as performed by experienced intensive
care nurses with the purpose to provide insight into potential errors
in urinary output measurement as well as identifying systematic
sources of error. Two diff erent types of ordinary 24-hour urine meters
were used. The meters were fi lled with a predetermined amount (gold
standard) of yellow lemonade. Both urine meters were fi lled with
variable but identical volumes for a range of 8 to 325 ml, to a total
amount of 3,600 ml. Hereafter the nursing staff manually recorded the
reading of 48 prefi lled urine meters. p
p
Conclusion A signifi cant increase in %BNP after a fl uid challenge
(irrespective of initial value) may indicate that cardiac contractility is
impaired and the LV dilated, indicating a strategy away from fl uid
resuscitation and towards inotrope use. i
Results Forty-eight nurses performed 2,285 urine volume measure-
ments in two diff erent types of ordinary urine meters (Bard Urine meter
drainage bag; Bard Medical, Covington, Georgia, USA and Rüsh U-bag;
Jiangsu, People’s Republic of China). The mean measured output for
the Bard urine meter was 3,688 ml, SD ±45 and for the Rüsh urine
meter 3,692 ml, SD ±55. The limits of agreement between both types of
urine meters were 2.4% to 2.6% respectively. Compared with the gold
standard, analysis demonstrated deviations of 2.6% for both types of
urine meters. Reference Conclusion Conventional urinary output measurement with ordinary
urine meters constitutes a simple and accurate method for measuring
urine volume in the ICU. S84 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P233). Hemodynamic variables at 0 and 24 hours P237 Microcirculatory blood fl ow is related to clinical signs of impaired
organ perfusion, and its dynamics to the macrohemodynamic
concept of fl uid responsiveness
A Pranskunas1, M Koopmans2, V Pilvinis3, P Koetsier2, EC Boerma2
1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Medical Centre
Leeuwarden, the Netherlands; 3Hospital of Lithuanian University of Health
Sciences, Kaunas, Lithuania
Critical Care 2012, 16(Suppl 1):P237 (doi: 10.1186/cc10844) Microcirculatory blood fl ow is related to clinical signs of impaired
organ perfusion, and its dynamics to the macrohemodynamic
concept of fl uid responsiveness
A Pranskunas1, M Koopmans2, V Pilvinis3, P Koetsier2, EC Boerma2
1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Medical Centre
Leeuwarden, the Netherlands; 3Hospital of Lithuanian University of Health
Sciences, Kaunas, Lithuania
Critical Care 2012, 16(Suppl 1):P237 (doi: 10.1186/cc10844) Microcirculatory blood fl ow is related to clinical signs of impaired
organ perfusion, and its dynamics to the macrohemodynamic
concept of fl uid responsiveness Results Ninety volume expansions in 68 patients were performed
during the study period. Central venous catheter was present 58.9% of
the time. In 41.1% of the cases patients were in spontaneous ventilation. No patients used a pulmonary artery catheter. An echocardiography
machine with an attending physician trained for critical care
echocardiography was available in 8.9%. An arterial catheter was
available in 21% of the volume expansions and mechanical ventilation
was present in 31.1% of the cases (67.3% of ventilated patients were
using controlled mode of ventilation). The association of mechanical
ventilation in controlled mode with an arterial catheter in place and no
restrictions for performing analysis of dynamic parameters was present
in only 7.7% of patients. Considering all dynamic parameters described
here, the use of any method for predicting fl uid responsiveness was
possible in 15.6% of the volume expansions performed in our ICU.l Introduction Fluid responsiveness is not equal to a clinical need for
fl uid therapy. The aim of our study was to assess the incidence of
microcirculatory fl ow alterations, according to a predefi ned arbitrary
cut-off value, in patients with clinical signs of impaired organ perfusion. The secondary endpoint was to establish the correlation between the
microcirculatory and macrocirculatory response to a fl uid challenge. Methods We performed a prospective, single-centre, observational
study. Included were ICU patients ≥18 years with invasive hemo-
dynamic monitoring and clinical signs of impaired organ perfusion,
as the principal reason for fl uid administration. P237 Fluid challenge was
performed by the infusion of 500 ml crystalloid or a balanced colloid
(Volulyt®) solution in 30 minutes. Before and after fl uid challenge,
systemic hemodynamics and direct in vivo observation of the micro-
circulation were obtained with sidestream dark-fi eld imaging. Assess-
ment of microcirculatory parameters of convective oxygen transport
(microvascular fl ow index (MFI) and proportion of perfused vessels),
and diff usion distance (perfused vessel density and total vessel density)
was done using a semiquantitative method. p
p
p
Conclusion The use of dynamic parameters for predicting fl uid
responsiveness in the ICU may have restricted applicability since the
necessary conditions are often not present. P236 Fluid responsiveness during weaning from mechanical ventilation
M Geisen, UM Schmid, O Dzemali, A Zollinger, CK Hofer
Triemli City Hospital, Zürich, Switzerland
Critical Care 2012, 16(Suppl 1):P236 (doi: 10.1186/cc10843) g
Results We enrolled 50 patients. MFI <2.6 was present in 66% of the
patients. After fl uid challenge, signs of impaired organ perfusion
reduced from 100% to 68% of the patients, P <0.001. The incidence of
MFI <2.6 decreased to 46%, and was higher in patients with persistent
signs of impaired organ perfusion: 56% versus 25%, P = 0.04. Median
MFI increased from 2.5 (2.3 to 2.8) at baseline to 2.7 (2.4 to 2.8) after
fl uid challenge, P = 0.003, but its change was only signifi cant in fl uid-
responsive patients. Introduction To overcome the limited accuracy of functional
hemodynamic parameters such as stroke volume and pulse pressure
variation (SVV and PPV) during spontaneous breathing, a passive leg
raising (PLR) maneuver has been suggested as a reliable predictor of
fl uid responsiveness [1,2]. The aim of this study was to evaluate fl uid
responsiveness using SVV, PPV and PLR during the transition from
controlled to spontaneous breathing. Conclusion These data demonstrate a relationship between clinical
signs of impaired organ perfusion and MFI <2.6. Fluid responsiveness
did not discriminate between patients with and without clinical
signs of impaired organ perfusion or MFI <2.6. However, signifi cant
improvement of microvascular alterations and attenuation of clinical
signs of impaired organ perfusion was restricted to patients who were
fl uid responsive. Noninvasive assessment of microvascular perfusion
may help to defi ne patients with potential need for fl uid therapy, and
to evaluate its eff ect. Methods Thirty-four patients after off -pump CABG were enrolled. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion Prediction of a fl uid response with SVV/PPV was less
reliable in spontaneous breathing. PLR predicted fl uid responsiveness,
but was less accurate than previously reported. Conclusion Prediction of a fl uid response with SVV/PPV was less
reliable in spontaneous breathing. PLR predicted fl uid responsiveness,
but was less accurate than previously reported. To ensure appropriate indication of fl uid administration, evaluation of
fl uid responsiveness by dynamic parameters is suggested, although
it requires specifi c conditions not always present in ICU patients. The
aim of this study was to analyze the applicability of parameters for
evaluation of fl uid responsiveness in the ICU. y
References
1. Marik et al.: Crit Care Med 2009, 37:2642-2647. 2. Monnet et al.: Crit Care Med 2006, 34:1402-1407. References
1. Marik et al.: Crit Care Med 2009, 37:2642-2647. 2. Monnet et al.: Crit Care Med 2006, 34:1402-1407. l
Methods We conducted a prospective observational study in two
ICUs. Volume expansions performed in ICU patients at the discretion
of the physician in charge were analyzed for the presence of
conditions that allowed adequate fl uid responsiveness evaluation. The
presence of central venous, pulmonary arterial or peripheral arterial
catheters, invasive mechanical ventilation and ventilator settings,
echocardiography availability, presence of arrhythmias, use of sedation
and vasoactive drugs were registered. Percentages of patients who
fulfi lled conditions for dynamic parameters (such as pulse pressure
variation, stroke volume variation and echocardiographic analysis)
were recorded. P237 Measurements were performed in the ICU using a PiCCO2 system. Fluid
(500 ml) was given: (A) during controlled mechanical ventilation, (B)
during pressure support ventilation with spontaneous breathing and
(C) after extubation. The stroke volume (SV), SVV and PPV as well as
the mean arterial pressure and heart rate were assessed. A PLR was
performed before fl uid administration at all three time points. Fluid
response was defi ned as an increase in SV >15%. Prediction of fl uid
responsiveness was tested using ROC analysis.i P238 P238
Frank–Starling and Guyton together at bedside during a fl uid
challenge
H Aya, M Cecconi, M Geisen, C Ebm, M Grounds, N Fletcher, A Rhodes
St George’s Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P238 (doi: 10.1186/cc10845) P235 P235
Applicability of methods for fl uid responsiveness prediction in the ICU
P Mendes1, L Miranda1, M Park1, L Azevedo1, B Rodrigues2, E Queiroz2,
G Schettino2, L Taniguchi1
1Hospital das Clinicas, São Paulo, Brazil; 2Hospital Sirio Libanes, São Paulo,
Brazil
Critical Care 2012, 16(Suppl 1):P235 (doi: 10.1186/cc10842) Critical Care 2012, 16(Suppl 1):P235 (doi: 10.1186/cc10842 Results Thirty-seven patients with severe sepsis-induced multiorgan
dysfunction syndrome with average APACHE II score of 24.6 and PEEP
of 8.2 cm were enrolled. SVV guided fl uids received during the 24-hour Introduction Volume expansion is a frequent and widely used therapy
in hemodynamically unstable patients but may lead to complications. Introduction Volume expansion is a frequent and widely used therapy
in hemodynamically unstable patients but may lead to complications. S85 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Prediction of fl uid responsiveness in intensive care (PREFERENCE
study): fl uid challenge versus passive leg raising in high-risk
surgical patients Prediction of fl uid responsiveness in intensive care (PREFERENCE
study): fl uid challenge versus passive leg raising in high-risk
surgical patients Introduction Massive fl uid resuscitation followed by hypoperfusion
abnormalities in the ICU is a risk factor for development of intra-
abdominal hypertension (IAH). The aim of our study was to determine
what infl uence would have the control of daily fl uid balance on the
incidence of IAH in patients after extensive abdominal surgery or after
abdominal trauma. g
p
M Cecconi, F Caliandro, J Mellinghoff , D Dawson, S Ranjan, M Hamilton,
M Grounds, A Rhodes
St Georges Hospital, London, UK
Critical Care 2012 16(Suppl 1):P239 (doi: 10 1186/cc10846) Introduction The aim of this study is to evaluate whether the passive leg
raising (PLR) maneuver could be used to predict fl uid responsiveness
in awake postoperative patients admitted to the ICU. PLR has been
demonstrated to be a good indicator of fl uid responsiveness even
in spontaneously breathing patients, but few data are available in
the immediate postoperative period. Nexfi n is a new cardiac output
monitor that measures and tracks stroke volume (SV) by analyzing the
arterial pressure pulse contour noninvasively from a fi nger probe. Methods A prospective observational study included a total of 82 adult
patients (age: 59 ± 10 years, APACHE II score at admission: 18 ± 11,
predicted mortality according to APACHE II score at admission: 34%,
observed in-hospital mortality: 20%), number of patients with intra-
abdominal pressure (IAP) above 12 at admission: 23 (28%), admitted
to a single ICU with the diagnosis of abdominal trauma (n = 22) or
after abdominal surgery (n = 60). During fi rst 7 days the fl uid intake
and balance was monitored and corrected at 6-hour intervals not to
exceed 1,500 ml positivity over 24 hours (oncodiuretic therapy was
administered – repeated boluses of starch solutions and/or albumin
followed by furosemide). IAP was measured from admission twice daily
(standardized measurement by instillation of 25 ml normal saline into
the bladder). A sustained elevation of the IAP above 12 mmHg in two
consecutive measurements was considered as IAH.l p
p
yi
g
p
Methods We enrolled self-ventilating patients admitted to the ICU
postoperatively. A PLR maneuver (45° bed tilt from the 30 to 45° head
up) was performed and followed by a fl uid challenge (FC, 250 ml
fl uid bolus over 5 minutes). Frank–Starling and Guyton together at bedside during a fl uid
challenge Results In 34 patients signifi cant hemodynamic changes were
observed, with 19 (55.9%), 22 (64.7%), and 13 (40.6%) responders at
time points A, B and C, respectively. Prediction of fl uid responsiveness
is depicted in Table 1. H Aya, M Cecconi, M Geisen, C Ebm, M Grounds, N Fletcher, A Rhodes
St George’s Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P238 (doi: 10.1186/cc10845) Table 1 (abstract P236). Prediction of fl uid responsiveness
A
B
C
AUC P value TS%
AUC P value TS%
AUC P value TS%
SVV
0.88
0.0001
15.5
0.70
0.056
12.5
0.56
0.604
13.5
PPV
0.83
0.001
14.5
0.69
0.063
11.0
0.48
0.863
11.5
PLR SV%
0.72
0.028
8.0
0.74
0.021
10.0
0.70
0.058
8.0
TS, threshold. Table 1 (abstract P236). Prediction of fl uid responsiveness Introduction According to Guyton, the diff erence between mean
systemic fi lling pressure (Pms) and right atrial pressure (RAP) is the
venous pressure gradient (VP). This is proportional to venous return
and cardiac output (CO). According to the Frank–Starling law a fl uid
challenge successfully increases the stroke volume if the preload
increases in the ascending part of the curve. The aim of this study was
to assess the signifi cance of the analogue of the Pms (Pmsa) measured
with the Navigator™ (Applied Physiology, St Leonards, Australia), the
central venous pressure (CVP) (as a surrogate of RAP) and the VP during
a fl uid challenge. Introduction According to Guyton, the diff erence between mean
systemic fi lling pressure (Pms) and right atrial pressure (RAP) is the
venous pressure gradient (VP). This is proportional to venous return
and cardiac output (CO). According to the Frank–Starling law a fl uid
challenge successfully increases the stroke volume if the preload
increases in the ascending part of the curve. The aim of this study was
to assess the signifi cance of the analogue of the Pms (Pmsa) measured
with the Navigator™ (Applied Physiology, St Leonards, Australia), the
central venous pressure (CVP) (as a surrogate of RAP) and the VP during
a fl uid challenge. S86 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods A prospective observational study was performed in
postsurgical patients. Patients were monitored with a central venous
catheter, an arterial line, a calibrated LiDCO™plus (LiDCO, Cambridge,
UK) and the Navigator™. P240 P240
Tight control of fl uid balance may reduce incidence of intra-
abdominal hypertension in patients after major abdominal surgery
and trauma: a pilot study
P Szturz1, J Maca1, J Neiser1, J Jahoda1, R Kula1, JT Tichy2
1Faculty Hospital Ostrava, Czech Republic; 2Yeovil District Hospital, Yeovil, UK
Critical Care 2012, 16(Suppl 1):P240 (doi: 10.1186/cc10847) P240
Tight control of fl uid balance may reduce incidence of intra-
abdominal hypertension in patients after major abdominal surgery
and trauma: a pilot study Conclusion Our study demonstrates that the Navigator™ may be used
to monitor the eff ect of fl uid challenges by assessing the change in VP
to the challenge. Frank–Starling and Guyton together at bedside during a fl uid
challenge A 250 ml fl uid challenge was used to maximise
the stroke volume (SV). Data were recorded before and after the fl uid
challenge which was given over 5 minutes. A positive response to the
fl uid challenge was defi ned as either a stroke volume or CO increase of
10% or more. P240
Tight control of fl uid balance may reduce incidence of intra-
abdominal hypertension in patients after major abdominal surgery
and trauma: a pilot study
P Szturz1, J Maca1, J Neiser1, J Jahoda1, R Kula1, JT Tichy2
1Faculty Hospital Ostrava, Czech Republic; 2Yeovil District Hospital, Yeovil, UK
Critical Care 2012, 16(Suppl 1):P240 (doi: 10.1186/cc10847)
Figure 1 (abstract P239). Figure 1 (abstract P239). UK) and the Navigator™. A 250 ml fl uid challenge was used to maximise
the stroke volume (SV). Data were recorded before and after the fl uid
challenge which was given over 5 minutes. A positive response to the
fl uid challenge was defi ned as either a stroke volume or CO increase of
10% or more. Results Twenty-fi ve fl uid challenges in 14 patients were observed. In
seven cases (28%), the fl uid challenge increased SV (and CO) by ≥10%
(Table 1). At baseline there were no diff erences between HR, Pmsa, CVP
or ΔVP for responders or nonresponders. The responders had greater
changes in ΔVP in response to the challenge. Table 1 (abstract P238). Haemodynamic parameters in responders and
nonresponders
Nonresponders
Responders
P value
MAP
78.4
71.4
0.07
Pmsa
17
15
0.3
CVP
9.7
9
0.7
HR
89
91
0.7
ΔVP
7.2
6
0.09
ΔPmsa
19.3
22.1
0.6
ΔCVP
2.9
1.6
0.1
Δ(ΔVP)
1.1
24.8
<0.01
Conclusion Our study demonstrates that the Navigator™ may be used
to monitor the eff ect of fl uid challenges by assessing the change in VP
to the challenge Table 1 (abstract P238). Haemodynamic parameters in responders and
nonresponders P239 P239
Prediction of fl uid responsiveness in intensive care (PREFERENCE
study): fl uid challenge versus passive leg raising in high-risk
surgical patients
M Cecconi, F Caliandro, J Mellinghoff , D Dawson, S Ranjan, M Hamilton,
M Grounds, A Rhodes
St Georges Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P239 (doi: 10.1186/cc10846) P241 P241
Negative fl uid balance 48 hours after admission improves survival
at 28 days in critically ill patients
M Cuartero, AJ Betbese, K Nuñez, J Baldira, L Zapata
Hospital De Sant Pau, Barcelona, Spain
Critical Care 2012, 16(Suppl 1):P241 (doi: 10.1186/cc10848) yf
Results Data of 58 patients were collected. The mean length of hospital
stay was 9 ± 3 days. Postoperative complications included suture
leak (3.4%), surgical site infection (6.9%), and heart failure (3.4%)
with no other medical or surgical complications. Total fl uids during
surgery were 2,775 ± 934 ml (1,259 ± 498 ml crystalloids, 1,302 ± 622
ml colloids, 214 ± 330 ml RBC). Fluid infusion and urine output were
10.6 ± 3.2 and 1.8 ± 1.2 ml/kg hour respectively. Hemodynamic data
are shown in Table 1. Introduction Fluid infusion may be lifesaving in critically ill patients, but
following initial resuscitation a positive fl uid balance is associated with
increased mortality. This study aimed to determine whether a negative
fl uid balance (≤–500 ml) within the fi rst 48 hours of admission in the
ICU is associated with improved survival at 28 days in a heterogeneous
cohort of critically ill patients. Table 1 (abstract P242). Hemodynamic variables
Start SG
End SG
P value
CI
2.85 ± 0.9
3.16 ± 0.4
0.020
SVI
40 ± 10
41 ± 8
0.59
HR
70 ± 12
77 ± 12
<0.001
PPV
7 ± 5
4 ± 2
0.001
MAP
76 ± 14
83 ± 14
0.002
SVRI
2051 ± 588
2026 ± 551
0.74
Conclusion GDT with MostCare® resulted in a low incidence of
postoperative complications and provided an optimal hemodynamic
management during major colon surgery. References
1. Gan TJ, et al.: Anesthesiology 2002, 97:820-826. 2. Vincent JL, et al.: Crit Care 2011, 15:229. Table 1 (abstract P242). Hemodynamic variables Table 1 (abstract P242). Hemodynamic variables y
p
Methods We conducted a retrospective study in a 20-bed ICU at a
university-affi liated teaching hospital. Patients admitted for acute
heart failure, those who required dialysis before admission and those
who died within 24 hours after admission were excluded. Demographic
data, SAPS II and APACHE II scores were recorded at admission and
SOFA, fl uid balance, hemodynamic, respiratory and renal variables once
per day. Variables were compared between survivors and nonsurvivors
and between patients who did and those who did not achieve negative
fl uid balance by day 2 of admission. Prediction of fl uid responsiveness in intensive care (PREFERENCE
study): fl uid challenge versus passive leg raising in high-risk
surgical patients Changes in SV during PLR and after
administration of FC were monitored with the Nexfi n monitor. Receiver
operator characteristic (ROC) analysis was performed.i y
Results Forty-fi ve patients were enrolled. Twenty-three patients
responded to the FC with an increase of SV >5%. Twenty-eight patients
(62%) were excluded from the PLR analysis as a result of haemodynamic
instability (diff erence in heart rate, mean arterial pressure or SV
baselines pre PLR and pre FC >5%). Seventeen patients were analyzed. The area under the curve for the ROC analysis was 0.93 (SE = 0.06;
P = 0.003) (Figure 1). A SV increase >1% during a PLR test predicts a SV
increase >5% after FC with a sensitivity of 75% and a specifi city of 78%. Conclusion In 62% of patients a PLR test could not be performed due
to haemodynamic instability. In these patients, FC is the best way to
assess fl uid responsiveness. During haemodynamic stability PLR shows
great sensitivity and specifi city to predict fl uid responsiveness. The
Nexfi n monitor can be used to track SV changes both during FC and
during a PLR test. Results The incidence of IAH in relation to daily fl uid intake and daily
fl uid balance is shown in Figure 1. Conclusion The incidence of IAH in patients after abdominal surgery
or abdominal trauma may exceed the value of 40%, especially in
situations associated with massive fl uid resuscitation [1]. We have
identifi ed a close relationship of the daily dynamics of changes in IAP
and fl uid balance. When we maintained the daily fl uid balance not
to exceed the positivity of 1,500 ml/24 hours, the incidence of IAH in
our study dropped from 28% to less than 20%, despite high daily fl uid
intake (about 5,000 to 8,000 ml/day). Tight control of the fl uid balance
seems an eff ective method to prevent the development of IAH. Reference Ball ChG, et al.: The secondary abdominal compartment syndrome: not just
another post-traumatic complication. Can J Surg 2008, 51:399-405. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S87 Figure 1 (abstract P240). Fluid intake, fl uid balance and incidence of IAH. 1.
Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA: Fluid resuscitation in
septic shock: a positive fl uid balance and elevated central venous
pressure are associated with increased mortality. Crit Care Med 2011,
39:259-265. P241 Multiple logistic regression was
used to identify variables signifi cantly associated with ICU mortality
in the univariate analysis. Survival was assessed using Kaplan–Meier
analysis. y
Results We studied 87 patients: 53 males, mean age 58 ± 18 years, SAPS
II 39.3 ± 15.8, APACHE II score 15.9 ± 7.5, SOFA score 5.0 ± 3.4, and ICU
stay 10.3 ± 9.8 days. The main syndrome diagnosis at admission was
septic shock (n = 26), acute respiratory failure (n = 19), trauma (n = 13),
neurocritical illness (n = 14) and others (n = 15). Overall mortality in the
ICU reached 20.7% and survival at 28 days was 73.6%. When patients
were classifi ed according to 28-day outcome, we observed statistically
signifi cant diff erences in negative fl uid balance at 48 hours (P <0.001),
SAPS II (P <0.001), APACHE II score (P = 0.007), age (P = 0.046) and
incidence of acute kidney injury at admission (P = 0.02; defi ned as
at least Risk in RIFLE criteria), but urinary output, hemodynamic and
respiratory parameters did not diff er. Multivariate analysis showed that
negative fl uid balance at 48 hours was independently associated with
improved survival: odds ratio = 7.9 (P = 0.013). Kaplan–Meier analysis
showed that survival was signifi cantly lower in patients without
negative fl uid balance at 48 hours (P = 0.015).il P243 P243
Implementation of an optimal fl uid management protocol using
the PiCCO system delays development of ARDS secondary to severe
sepsis
N Saito, T Yagi, Y Hara, H Matsumoto, K Mashiko
Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan
Critical Care 2012, 16(Suppl 1):P243 (doi: 10.1186/cc10850) P243
Implementation of an optimal fl uid management protocol using
the PiCCO system delays development of ARDS secondary to severe
sepsis Introduction Acute respiratory distress syndrome (ARDS) is often
associated with sepsis, and one recommended approach in the fl uid
management of ARDS is to keep sepses dry. On the other hand,
optimal fl uid management after the early phase of septic shock
remains unknown. An excessive positive fl uid balance in patients with
septic shock is associated with increased mortality and morbidity. We
implemented an optimal fl uid management (OFM) protocol using
the PiCCO system from April 2009. The purpose of this study was to Introduction Acute respiratory distress syndrome (ARDS) is often
associated with sepsis, and one recommended approach in the fl uid
management of ARDS is to keep sepses dry. On the other hand,
optimal fl uid management after the early phase of septic shock
remains unknown. An excessive positive fl uid balance in patients with
septic shock is associated with increased mortality and morbidity. We
implemented an optimal fl uid management (OFM) protocol using
the PiCCO system from April 2009. The purpose of this study was to Conclusion Our fi ndings show that negative fl uid balance 48 hours
after admission may correlate with better outcome in a heterogeneous
population of critically ill patients. Goal-directed fl uid and hemodynamic therapy in major colon
surgery with the pressure recording analytical method cardiac
output monitor (MostCare®-PRAM®): prospective analysis of 58
patients Goal-directed fl uid and hemodynamic therapy in major colon
surgery with the pressure recording analytical method cardiac
output monitor (MostCare®-PRAM®): prospective analysis of 58
patients JM Alonso-Iñigo, MJ Fas, V Osca, A Nacher, JE Llopis
Hospital Universitario de la Ribera, Alzira, Spain
Critical Care 2012, 16(Suppl 1):P242 (doi: 10.1186/cc10849) Introduction Optimal fl uid therapy in colon surgery is controversial. The aim of this study is to assess the impact on postoperatory
complications, fl uid administration, and length of hospital stay, of GD
fl uid and hemodynamic therapy protocol based on PRAM®-MostCare®
hemodynamic variables. y
Methods Patients scheduled for elective colorectal operations were
included. The MostCare® was connected to a radial artery catheter
for hemodynamic monitoring. Hemodynamic variables including
the stroke volume index (SVI), cardiac index (CI), and pulse pressure
variation (PPV) were measured. Fluids and hemodynamic drugs were
administered to achieve the primary endpoints: CI 2.5 to 4.5, PPV <13%,
SVRI >1,500, MAP similar to basal values. Hemodynamic data were
noted at induction and at the end of surgery. Data of fl uids, urine
output, postoperative complications and length of stay were assessed. Descriptive statistics were used. A paired-simple t test was used for the
analysis of the diff erences between variables. Indexation of extravascular lung water in unselected adult patients
with and without mechanical ventilation: a prospective study in
50 patients with 843 transpulmonary thermodilutions
W Huber, B Saugel, D Paradellis, J Hoellthaler, V Phillip, C Schultheiss,
P Thies, U Mayr, A Herrmann, RM Schmid
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P245 (doi: 10.1186/cc10852) Indexation of extravascular lung water in unselected adult patients
with and without mechanical ventilation: a prospective study in
50 patients with 843 transpulmonary thermodilutions
W Huber, B Saugel, D Paradellis, J Hoellthaler, V Phillip, C Schultheiss,
P Thies, U Mayr, A Herrmann, RM Schmid
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P245 (doi: 10.1186/cc10852) Indexation of extravascular lung water in unselected adult patients
with and without mechanical ventilation: a prospective study in
50 patients with 843 transpulmonary thermodilutions
W Huber, B Saugel, D Paradellis, J Hoellthaler, V Phillip, C Schultheiss,
P Thies, U Mayr, A Herrmann, RM Schmid
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P245 (doi: 10.1186/cc10852) Methods A retrospective study was conducted in a Japanese mixed
ICU of a tertiary-care teaching hospital from July 2007 to March 2011. Our protocol includes daily volume assessment using the PiCCO system
after ICU admission and a change of fl uid therapy after evaluation; for
example, additional diuretic use or fl uid restriction. We retrospectively
analyzed 96 consecutive patients with severe sepsis or septic shock
who required mechanical ventilation between July 2007 and December
2010. We divided patients into the OFM protocol group (P; n = 49; April
2009 to December 2010) and the control group (C; n = 47; July 2007 to
March 2009) and compared their clinical and laboratory data. Introduction Extravascular lung water (EVLW) has been indexed to
actual BW (BW-act), termed the EVLW index (ELWI). Since in obese
patients indexation to BW-act might inappropriately diminish the
indexed ELWI-act, ELWI indexed to predicted BW (ELWI-pred) has been
introduced. Indexation of EVLW to height might be superior to ELWI-
pred/-act. Recent data in a selected collective of ARDS patients suggest
that indexation to height might improve the predictive capabilities of
ELWI regarding pO2/FiO2. We aimed to investigate which indexation of
EVLW provides the best association of ELWI and pO2/FiO2 in patients
without pulmonary impairment or without ventilation. Results Median (IQR) age was 69.5 (55.5 to 78.5) years, and the median
APACHE II score and SOFA score were 23.0 (19.0 to 27.0) and 10.0 (7.0
to 12.0), respectively. The proportion of patients with septic shock was
75%. There was no diff erence in patient characteristics between the
two groups. At 28 days, the mortality rate was similar in both groups (P:
14.3%; C: 17.0%; P = 0.78). P246 Methods We studied 20 septic poytraumatized patients (mean ISS
score 35) with ARDS syndrome and ELWI >10, with good renal function
and on medical treatment with levophed. We administered furosemide
10 mg/hour, for 24 hours, while at the same time we confronted the
septic source. During all these we noted PO2/FiO2, MAP, CVP and ELWI
every 8 hours. Moreover, we noted the changes in the levophed dose
and the total balance of fl uid at the end of the 24-hour interval. How to perform indexing of extravascular lung water data
S Wolf 1, A Riess2, J Landscheidt2, C Lumenta2, L Schuerer2, P Friederich2
1Charite Berlin, Germany; 2Klinikum Bogenhausen, Munich, Germany
Critical Care 2012, 16(Suppl 1):P246 (doi: 10.1186/cc10853) Introduction Extravascular lung water (EVLW) is a marker for the
severity of acute lung injury. To allow assessment of normal and
pathologic states, traditionally EVLW data are either indexed to real
or predicted body weight. Surprisingly and despite widespread
use, this has so far not been validated in a larger cohort of subjects
without cardiopulmonary compromise. The aim of the study was to
prospectively evaluate a diff erent ways of indexing EVLW data. l
Results The ELWI rate was up 12 to 16 before the administration of
furosemide. We marked that after the administration of furosemide and
at the end of the fi rst 8-hour interval, the ELWI rate decreased about 2
to 3 units but we had to increase the dose of vasoconstriction, until the
end of the 24-hour interval the ELWI rate restored to the initial high
level and could not manage to decrease the dose of vasoconstriction
to have a negative balance of fl uids. The improvement of PO2/FiO2 was
insignifi cant statistically and we confronted operatively the septic
source for fi ve to 20 patients at the end of the 24-hour interval. yf
y
g
Methods EVLW was measured using single indicator transpulmonary
thermodilution at predefi ned time points in 101 patients requiring
elective brain tumor surgery. This database was used to investigate the
properties of indexing EVLW data to real and predicted body weight,
body surface area and body height. Conclusion We managed to decrease very little the ELWI rate, only
temporarily after the administration of furosamide about a 24-hour
interval. P245 examine the eff ect of the OFM protocol in comparison with historical
controls. Reference 1. Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA: Fluid resuscitation in
septic shock: a positive fl uid balance and elevated central venous
pressure are associated with increased mortality. Crit Care Med 2011,
39:259-265. S88 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Indexation of extravascular lung water in unselected adult patients
with and without mechanical ventilation: a prospective study in
50 patients with 843 transpulmonary thermodilutions
W Huber, B Saugel, D Paradellis, J Hoellthaler, V Phillip, C Schultheiss,
P Thies, U Mayr, A Herrmann, RM Schmid
Klinikum Rechts der Isar, Technischen Universität München, Munich, Germany
Critical Care 2012, 16(Suppl 1):P245 (doi: 10.1186/cc10852) The incidence of ARDS after ICU admission in
the P group was signifi cantly lower than that in the C group (P: 20.4%; C:
57.4%; P = 0.02). In addition, the onset of ARDS in the P group occurred
later than that in the C group (P <0.01). Achievement of a negative
water balance in the P group occurred earlier than in the C group. The
incidence of AKI (RIFLE criteria: failure) and another organ failure was
similar in both groups. Multivariate regression analysis revealed that
the OFM protocol independently suppressed the onset of ARDS (OR
0.17 (P = 0.001; 95% CI: 0.06 to 0.51)). p
y
p
Methods In 50 consecutive ICU patients with PiCCO monitoring, 843
triplicate measurements of EVLW and simultaneous blood gas analysis
were performed. The endpoint was prediction of pO2/FiO2 <200 mmHg
and other critical thresholds provided by unindexed EVLW as well as
ELWI indexed to ideal BW, adjusted BW, BMI, body surface area, height
and total lung capacity. Results Measurements in patients without pulmonary impairment
463/843 (54.9%); acute 188/843 (22.3%), chronic 106/843 (12.6%), and
both acute and chronic pulmonary disease 86/843 (10.2%). Mechanical
ventilation in 458/843 (54.3%) measurements. The largest ROC AUCs
regarding pO2/FiO2 <200 mmHg were found for ELWI-height (AUC
0.658; 95% CI 0.554 to 0.735) and EVLW (0.655; 95% CI 0.544 to 0.732),
the lowest AUC for ELWI-act (0.629; 95% CI 0.514 to 0.742). Similarly
ELWI-height and unindexed EVLW provided the largest ROC AUCs
regarding pO2/FiO2 >300 mmHg (0.659 and 0.657), normal pO2/FiO2
(>381 mmHg; 0.665 and 0.657) and acute and/or chronic pulmonary
impairment (0.622 and 0.625). All these associations were signifi cant
with P <0.001. Among patients with pulmonary impairment, fi rst values
of ELWI-height and EVLW provided the largest ROC AUCs regarding
mortality (0.815 and 0.815; P = 0.016) compared to ELWI-act (0.694;
P = 0.136) and APACHE II score (0.792; P = 0.025). Conclusion Implementation of an OFM protocol using the PiCCO
system signifi cantly decreased the development of ARDS secondary to
severe sepsis with no other complications. P244 Confrontation of the increase in ELWI rate regarding the septic
polytraumatised patient administering furosemide: is it eff ective? P Sarafi dou, E Pappa, D Dimitriadou, D Litis, I Pavlou
KAT General Hospital Kifi sia, Athens, Greece
Critical Care 2012, 16(Suppl 1):P244 (doi: 10.1186/cc10851) Conclusion Indexation to BW-act results in reduced predictive
capabilities compared to no indexation at all. ELWI-pred performs
slightly better than ELWI-act, but our data do not support that
ELWI-pred is superior to no indexation at all in adult ICU patients. In
this unselected and prospectively evaluated collective, the highest
predictive capabilities regarding several predefi ned thresholds were
found for ELWI-height. Introduction The ELWI rate (measurable with the PICCO catheter)
conveys the extravascular lung water. The increase of the ELWI rate
is a frequent fi nding in heavily septic patients and it is connected
with very high mortality. The purpose of this study is to fi nd out if
the administration of furosemide is possible to reduce eff ectively the
ELWI rate and if this decrease can be maintained regardless of the
confrontation of the sepsis. P247 P247
Near-normal values of extravascular lung water in children
J Lemson1, C Cecchetti2, A Nusmeier1
1Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;
2IRCS Bambino Gesù Roma, Rome, Italy
Critical Care 2012, 16(Suppl 1):P247 (doi: 10.1186/cc10854) Introduction Extravascular lung water (EVLW) refl ects the amount
of pulmonary edema and can be measured at the bedside using the
transpulmonary thermodilution method (TPTD) incorporated in the
PiCCO device (Pulsion, Germany). Currently, normal values of EVLW for
the use in children are unavailable. This study was designed to collect
near-normal values of EVLW in children after recovery from critical
illness. g
Results Twenty patients were enrolled in this study. All patients
had septic shock. Six of all had lung involvement. Twelve patients
received mechanical ventilation. The mean of net fl uid balance was
+2,228 ± 1,982 ml and the mean of duration between two ultrasound
measurements was 31 ± 13 hours. The means of TBS at pre and post
fl uid therapy were 37 ± 26 and 64 ± 29 respectively (P <0.0001, 95% CI
13.47 to 33.67). This increase was found in all areas of measurement. In
particular, the number of B-lines measured at the anterior axillary line
area very well correlated to the TBS (r = 0.90, P <0.01) and its increment
had reverse correlation to the PaO2/FiO2 ratio (r = 0.704, P <0.05). The volume of fl uid per one B-line increasing was 119 ± 134 ml. The
interobserver reliability between two ultrasound readers was very high
(r = 0.92, P <0.01). The changing of TBS did not correlated to that of the
chest radiologic score for EVLW assessment (r = 0.002, P >0.05). There
was no linear correlation observed between net fl uid balance and total
number of increasing B-lines.il Methods In this prospective observational multicenter study (fi ve
sites), pediatric TPTD measurements were collected from children
admitted to a pediatric ICU without or after resolution of pulmonary
abnormalities. Inclusion criteria were minimal or no respiratory support
and stable hemodynamics. We searched typically for the last lung water
measurement prior to removal of the PiCCO system. EVLW was indexed
using predicted body weight (EVLWI) calculated using height, based
upon WHO data. p
Results Fifty-fi ve children aged from 0 to 16 years were included. P247 Mean
values (range) were: age 6.5 (0.04 to 16) years, weight 25.8 (3.7 to 80)
kg, mean arterial blood pressure 79 (48 to 131) mmHg, PaO2/FiO2 ratio
388 (171 to 662) mmHg, cardiac index (CI) 4.5 (2.2 to 6.7) l/minute/m2,
global end-diastolic volume (GEDVI) 490 (211 to 718) ml/m2, EVLWI 12.7
(4.7 to 34.6) ml/kg. Figure 1 shows the logarithmic relation between
EVLWI and age with an r2 of 0.7. There was no signifi cant correlation
between GEDVI or CI and age. g
Conclusion The number of B-lines defi nitely increased after fl uid
resuscitation in shock and correlated to the deterioration of pulmonary
gas exchange. These data support the benefi t of transthoracic portable
ultrasound for assessment of the increment of EVLW in shock patients
receiving fl uid resuscitation. P248 indexing to body height presents an alternative method without
dependence on physical properties or gender of a patient, yielding a
uniform 95% confi dence interval of normal values from 0.22 to 0.43 l/m. Conclusion Traditional ways of indexing EVLW data do not resolve
value dependence on physical properties or gender. Therefore,
the currently used defi nition of a normal range from 3 to 8 ml/kg
seems to be invalid. Our data suggest indexing EVLW to plain body
height instead of weight-based methods. As we are not aware of any
abnormal hemodynamic profi le for brain tumor patients, we propose
our fi ndings as a close approximation to normal values. This will require
further validation in critically ill patients. indexing to body height presents an alternative method without
dependence on physical properties or gender of a patient, yielding a
uniform 95% confi dence interval of normal values from 0.22 to 0.43 l/m. Conclusion Traditional ways of indexing EVLW data do not resolve
value dependence on physical properties or gender. Therefore,
the currently used defi nition of a normal range from 3 to 8 ml/kg
seems to be invalid. Our data suggest indexing EVLW to plain body
height instead of weight-based methods. As we are not aware of any
abnormal hemodynamic profi le for brain tumor patients, we propose
our fi ndings as a close approximation to normal values. This will require
further validation in critically ill patients. P246 The small improvement of the PO2/FiO2 fi nally leads to a
decrease of the ELWI rate but it is not important statistically and on
the other side leads to an increase of vasoconstriction. Therefore, this
method is not eff ective. We gain only a short time for the safer surgical
treatment if it is needed Results EVLW indexed to predicted body weight was inversely
correlated with a patient’s body height (P <0.001), while values
indexed to real body weight remained inversely dependent on weight
(P <0.001). Indexing to estimated body surface area, again based on
real or predicted body weight, provided no advantage. In contrast, S89 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 gl
References l
References 1. Bouhemad B, Zhang M, Lu Q, et al.: Clinical review: Bedside lung ultrasound
in critical care practice. Crit Care 2007, 11:205. 1. Bouhemad B, Zhang M, Lu Q, et al.: Clinical review: Bedside lung ultrasound
in critical care practice. Crit Care 2007, 11:205. Conclusion Near-normal values of EVLW in children are strongly
correlated with age. Based upon these data, normal values can be
constructed for future clinical use. 2. Soldati G, Copetti R, Sher S: Sonographic interstitial syndrome: the sound of
lung water. J Ultrasound Med 2009, 28:163-174. 2. Soldati G, Copetti R, Sher S: Sonographic interstitial syndrome: the sound of
lung water. J Ultrasound Med 2009, 28:163-174. Figure 1 (abstract P247). Transthoracic ultrasound assessment of B-lines for identifying the
increment of extravascular lung water in shock patients requiring
fl uid resuscitation Transthoracic ultrasound assessment of B-lines for identifying the
increment of extravascular lung water in shock patients requiring
fl uid resuscitation l
P Theerawit, N Tomuan, Y Sutherasan, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P248 (doi: 10.1186/cc10855) l
P Theerawit, N Tomuan, Y Sutherasan, S Kiatboonsri
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P248 (doi: 10.1186/cc10855) Introduction Sonographic B-lines are commonly observed in cases of
increasing extravascular lung water (EVLW). These fi ndings became
prominent when interstitial and alveolar tissues were fi lled with fl uid
[1,2]. Thus, we hypothesized that the increment of sonographic B-lines
would be observed when the EVLW increased after fl uid resuscitation
in shock patients and be associated with the impaired gas exchange. Introduction Sonographic B-lines are commonly observed in cases of
increasing extravascular lung water (EVLW). These fi ndings became
prominent when interstitial and alveolar tissues were fi lled with fl uid
[1,2]. Thus, we hypothesized that the increment of sonographic B-lines
would be observed when the EVLW increased after fl uid resuscitation
in shock patients and be associated with the impaired gas exchange. Methods Transthoracic portable ultrasound before and after fl uid
resuscitation was performed. Patients with pleural disease were
excluded. The B-lines were measured in 23 lung zones. The total
numbers of B-lines seen in each patient were counted as the total B-line
score (TBS). The primary outcome was to demonstrate the increase of
TBS after fl uid resuscitation. The secondary outcome was to examine
the magnitude of the incremental number of TBS. p
p
g
g
Methods Transthoracic portable ultrasound before and after fl uid
resuscitation was performed. Patients with pleural disease were
excluded. The B-lines were measured in 23 lung zones. The total
numbers of B-lines seen in each patient were counted as the total B-line
score (TBS). The primary outcome was to demonstrate the increase of
TBS after fl uid resuscitation. The secondary outcome was to examine
the magnitude of the incremental number of TBS. P252 Evaluation of eff ectiveness and safety of hydroxyethyl starch
(HES 130 kDa/0.4) in burn resuscitation
A Mokline, I Rahmani, L Gharsallah, H Oueslati, B Gasri, I Harzallah,
A Ksontini, A Messadi
Burn and Trauma Center, Tunis, Tunisia
Critical Care 2012, 16(Suppl 1):P252 (doi: 10.1186/cc10859) Methods This study was a prospective, randomized, active-controlled
study comparing the hemodynamics, effi cacy, and safety of HES 130/0.4
to that of albumin in patients undergoing pancreaticoduodenectomy. Eligible adult patients of both sexes were assigned following the
surgery into either the HES group or the albumin group at a ratio of 1:1. Crystalloids for hydration and colloid therapy for volume support were
administered. The primary endpoint of this study was the hemodynamic
evaluation. Secondary endpoints were measurement of the input–
output, ICU stay, ventilation time, length of hospital stay, time to liquid
mealtime and the use of blood products. Safety assessment was carried
out by performing physical examination, laboratory examination, and
assessment of any adverse events during the study period. Introduction Excessive fl uid resuscitation of large burn injuries has
been associated with adverse outcomes including worsening of burn
oedema, conversion of superfi cial into deep burns, and compartment
syndromes. So, there have been eff orts recently to address these
concerns, particularly with the use of physiologically balanced fl uids. Starches, as eff ective plasma expanders, may limit resuscitation
requirements and burn oedema. This study aims to evaluate clinical
results of HES in early burn resuscitation of major burn-injured patients. Methods A case–control study conducted in a burn care center in
Tunis. Adult burned patients admitted within the fi rst 24 hours post
burn, with a burn injury exceeding 30% of total body surface area,
from 1 January to 31 December 2010 were included. Exclusion criteria
were pregnancy, history or biochemical evidence of renal impairment
on admission (serum creatinine >130 μmol/l), history or hematological
evidence of disorders of hemostasis. Fluid volume resuscitation was
evaluated according to the Parkland formula. HES supplementation
was limited to 33 ml/kg/24 hours. The HES supplementation group was
compared with a group of patients from the same center matched in
age, sex and severity of burns at baseline. y
g
y p
Results A total of 50 patients were randomized to study groups (25
each). Eff ect of balanced versus unbalanced HES solution on cytokine
response in a rat model of peritonitis Eff ect of balanced versus unbalanced HES solution on cytokine
response in a rat model of peritonitis M Schläpfer1, M Urner1, S Voigtsberger1, R Schimmer2, B Beck-Schimmer1
1University Hospital Zurich, Switzerland; 2University of Zurich, Switzerland
Critical Care 2012, 16(Suppl 1):P251 (doi: 10.1186/cc10858) M Schläpfer1, M Urner1, S Voigtsberger1, R Schimmer2, B Beck-Schimmer1
1University Hospital Zurich, Switzerland; 2University of Zurich, Switzerland
Critical Care 2012, 16(Suppl 1):P251 (doi: 10.1186/cc10858) Introduction Sepsis with multiple organ failure remains a leading cause
of death in ICUs. Acute renal failure is a common complication of severe
sepsis and septic shock. The eff ect of hydroxyethyl starch (HES) on the
kidney as well as on liver tissue remains controversial and has never
been tested in detail. We investigated in a model of fecal peritonitis
the infl uence of fl uid resuscitation with HES 6% in unbalanced versus
balanced solutions on infl ammatory mediator expression in renal and
hepatic tissue. y
Results The EG patients with degree I shock had higher hemodynamics
parameters (BPsys, BPdias, MAP) and less expressed tachycardia as
compared to the CG patients with degree I shock (P <0.05). The EG
patients with degree II shock had higher hemodynamics parameters
(BPsys, MAP, ESV, CI, SVR) as compared to the CG patients with degree
II shock (P <0.05). The change of the fl uid therapy tactics in the EG
resulted in the normalization of the HR, SVR and in the increase of the
BPsys, MAP, ESV and CI in patients of both degrees of shock during
transportation. The values of the EG were higher than in the CG during
all periods of the transportation (P <0.05).l Methods Cecal ligation and puncture was performed in anesthetized
Wistar rats (CLP group). Sham group animals were treated in the
same manner but without CLP. One hour after this procedure, Ringer
lactate (RL) was intravenously infused to all animals at a volume of
30 ml/kg. Two hours after initiation of injury rats received RL (control,
75 ml/kg), unbalanced HES 130/0.42 (HES, 25 ml/kg) or balanced HES
130/0.42 (Tetraspan, 25 ml/kg). Animals were euthanized 4 hours after
induction of peritonitis. Monocyte chemotactic protein-1, intercellular
adhesion molecule-1, and TNFα mRNA expression were assessed in the
kidneys and liver. Linear regression was used to evaluate infl uence of
the diff erent fl uid resuscitation procedures on infl ammatory mediator
expression. Eff ect of balanced versus unbalanced HES solution on cytokine
response in a rat model of peritonitis p
p
Conclusion Inclusion of the HES 130/04 starch in the fl uid therapy
complex of the patients with traumatic shock in polytrauma allows
one to normalize hemodynamics values at short notice and to support
them adequately during all periods of transportation. A prospective, randomized, clinical trial comparing the
hemodynamics, effi cacy, and safety of 6% hydroxyethyl starch
130/0.4 compared to albumin in postoperative patients undergoing
pancreaticoduodenectomy Results CLP had a signifi cant eff ect on production of infl ammatory
mediators in the kidneys (P ≤0.03) and liver (P ≤0.02). While HES did
not alter expression of infl ammatory mediators compared to RL,
fl uid resuscitation with Tetraspan provoked a burst in infl ammatory
mediator expression, which was at least threefold higher in the kidneys
(P <0.001) and eightfold in the liver (P = 0.001) compared to the RL
group.l p
y
SK Hong1, K Kyoung2, Y Kim1, S Kim1
1Ulsan University College of Medicine, Asan Medical Center, Seoul, South
Korea; 2Inje University College of Medicine, Harundae Paik Hospital, Busan,
South Korea
Critical Care 2012, 16(Suppl 1):P250 (doi: 10.1186/cc10857) Conclusion While unbalanced HES did not show a proinfl ammatory
eff ect on renal and hepatic tissue in early sepsis, the balanced HES
solution upregulated infl ammatory mediators. Further studies have to
be performed to elucidate this phenomenon in detail and to assess the
functional implication of these results. Critical Care 2012, 16(Suppl 1):P250 (doi: 10.1186/cc10857) Introduction Hypovolemia is often present in patients undergoing
extensive abdominal surgery. As the fi rst colloid used in the clinical
setting, albumin is still widely employed during perioperative
periods. We hypothesized that 6% hydroxyethyl starch (HES) 130/0.4
is equally effi cacious and has the added advantages of its low cost
and convenience of use. This study’s objective is to compare the
hemodynamics, effi cacy, and safety of HES 130/0.4 compared with that
of albumin. P252 P250 P250
A prospective, randomized, clinical trial comparing the
hemodynamics, effi cacy, and safety of 6% hydroxyethyl starch
130/0.4 compared to albumin in postoperative patients undergoing
pancreaticoduodenectomy
SK Hong1, K Kyoung2, Y Kim1, S Kim1
1Ulsan University College of Medicine, Asan Medical Center, Seoul, South
Korea; 2Inje University College of Medicine, Harundae Paik Hospital, Busan,
South Korea
Critical Care 2012, 16(Suppl 1):P250 (doi: 10.1186/cc10857) P251 24 hours after trauma. The distance was 177 ± 9 km. The components
of the fl uid therapy in the CG were crystalloids and dextrans. The latter
were not used in degree I shock. Crystalloid infusion was carried out on
the basis of 3 ml crystalloids per 1 ml blood loss. The crystalloids and
HES 130/04 starch were used in the EG. The dose of HES 130/04 starch
comprised 10 to 25 ml/kg of the body mass and depended on the
shock severity state. Statistical analysis was performed using Statistica
6.1. We used the Mann–Whitney criterion. Fluid therapy tactics in patients with polytrauma during
interhospital transportation D Skopintsev, S Kravtsov, A Shatalin, V Agadzhanyan
Federal State Budgetary Medical Prophylactic Institution, Scientifi c Clinical
Center of Miners’ Health Protection, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P249 (doi: 10.1186/cc10856) Introduction The study’s aim was to carry out a comparative evaluation
of fl uid therapy’s infl uence using 130/04 hydroxyethyl (HES) starch and
dextrans on hemodynamics values in patients with traumatic shock in
polytrauma during interhospital transportation. Introduction The study’s aim was to carry out a comparative evaluation
of fl uid therapy’s infl uence using 130/04 hydroxyethyl (HES) starch and
dextrans on hemodynamics values in patients with traumatic shock in
polytrauma during interhospital transportation. Figure 1 (abstract P247). p y
g
p
p
Methods Eighty patients with polytrauma were included in the
study. Mean age was 35 ± 1 years. All patients were divided into two
similar groups: experimental (EG) and control (CG). Each group was
apportioned by two subgroups depending on the shock severity. Subgroup 1 consisted of patients with degree I shock, subgroup 2
comprised patients with degree II shock. The Algover–Burry index
was used to evaluate the shock severity. ISS was applied to determine
the injuries’ severity. The injuries’ severity values of the EG were the
following: in subgroup 1, 25 ± 1 points; in subgroup 2, 46 ± 2 points. The values of the CG were 26 ± 1 in the fi rst subgroup and 44 ± 2 points
in the second subgroup. All patients were transported during the fi rst S90 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P252 The volume of the crystalloid was the same in both groups;
however, signifi cantly more colloids were infused after 24 hours post
surgery in the HES group than in the albumin group, the voluven
patient group had lower heart rates, and the diff erence in the lowest
MAP value was –1.64 mmHg (lower limit of confi dence interval,
–8.228 mmHg) than in the albumin group. Routine hematology and
biochemical profi les, including blood coagulation test and renal
function assessment, were comparable in the two groups. The mean
duration of the ICU stay, ventilation, hospital stay, and tolerance of a
liquid meal were similar. The mean cost of the colloid was signifi cantly
lower in the HES 130/0.4 group than in the albumin group (P <0.001). Conclusion This study demonstrated that 6% HES 130/0.4 may be
used as a valuable alternative to 5% albumin in patients undergoing
extensive abdominal surgery, as its low cost is also of value. g
y
Results Patients were assigned to two groups: G1 (n = 15): HES
supplemented, and G2 (n = 15): crystalloids only. The mean age was
44 ± 18 years old for G1 and 43 ± 17 years old for G2. The average
TBSA was 51.8% ± 19 for G1 versus 43.6 ± 7 for G2. The addition of S91 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 biomarkers in a pilot study of early septic shock patients resuscitated
with either 5% albumin or normal saline. HES 130 kDa/0.4 reduces signifi cantly body weight gain within the
fi rst 72 hours after injury: 8 kg for G1 versus 13.6 kg for G2 (P = 0.002),
occurrence of ALI (35% for G1 versus 65% for G2) (P = 0.01), and length
of ICU stay (19 days ± 13 for G1 vs. 30 days ± 15 for G2). There was no
evidence of renal dysfunction with the use of HES in burns patients
comparative to the crystalloids group. Methods Patients presenting in early septic shock received albumin
or saline in a randomized, double-blind pilot study. Blood and urine
was collected at enrolment and 6, 12, 24, 72 hours and 7 days later
and processed using standard operating procedures. A panel of 27
cytokines, chemokines and growth factors was measured by multiplex
technology. f
References 1. Maitland K, et al.: N Engl J Med 2011, 364:2483-2495. 2. Prange HD, et al.: J Appl Physiol 2001, 91:33-38. Methods This was an observational study performed during 4 July
2007 to 31 March 2009 in the 10-bed ICU of Pramongkutklao Hospital
in severe sepsis or septic shock patients who already had a central
venous catheter inserted. Two blood samples were collected and sent
to the laboratories for blood gas analysis. We then calculated for the
correlation using correlation and linear regression analysis. Study of the correlation between central venous oxygen saturation
and venous saturation from the antecubital vein in severe sepsis/
septic shock patients
K Piyavechviratana, W Tangpradubkiet
Phramongkutklao Hospital, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P255 (doi: 10.1186/cc10862) Study of the correlation between central venous oxygen saturation
and venous saturation from the antecubital vein in severe sepsis/
septic shock patients
K Piyavechviratana, W Tangpradubkiet
Phramongkutklao Hospital, Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P255 (doi: 10.1186/cc10862) Introduction Early goal-directed therapy has been used for severe
sepsis and septic shock in the ICU to achieve a balance between
systemic oxygen delivery and oxygen demand before global tissue
hypoxia develops and proceeds to multiorgan failure. One of the
resuscitation end points includes normalized values for central venous
oxygen saturation (ScvO2) that needs insertion of a central venous
catheterization, which is still impractical in small-to-medium-sized
hospitals in Thailand. The purpose of this study was to examine whether
the venous oxygen saturation from the antecubital vein has correlation
with the central venous oxygen saturation or can be applied instead of
the central venous oxygen saturation. f
Conclusion Saline infusion worsens lactic acidosis, despite similar blood
pressure, when compared to plasmalyte. The mechanisms responsible
for this eff ect are unclear. However, deoxygenated hemoglobin readily
binds hydrogen ions, forming HbH+, which is stabilized in the presence
of chloride [2]. Consequently, the oxygen affi nity for hemoglobin is
reduced, which could impair oxygen delivery, perpetuating the lactic
acidosis. Further study is needed to better understand the mechanisms
of this eff ect and their clinical relevance. Normal saline resuscitation worsens lactic acidosis in experimental
sepsis
h
h
b
l
ll p
F Zhou, ME Cove, ZY Peng, J Bishop, K Singbartl, JA Kellum
University of Pittsburgh Medical School, Pittsburgh, PA, USA
Critical Care 2012, 16(Suppl 1):P253 (doi: 10.1186/cc10860) Introduction Infusing large volumes of 0.9% sodium chloride (saline)
causes hyperchloremic acidosis. The clinical relevance of this eff ect
remains contentious and saline is still the most commonly used
resuscitation fl uid in the US. However, a recent trial showed that saline
or albumin in saline increased mortality in children with malarial sepsis,
compared to no fl uid [1]. Infusion of these fl uids may have perpetuated
the underlying metabolic acidosis sepsis, causing cardiovascular
collapse and death. In this study, we investigated the eff ect of
saline versus a balanced crystalloid (plasmalyte) in a cecal ligation
and puncture (CLP) model of sepsis. We hypothesized that saline
resuscitation would increase acidosis and worsen hemodynamics,
compared to resuscitation using a balanced crystalloid. Conclusion In this cohort of patients treated with albumin or saline
in early septic shock, there appeared to be a marked increase in the
clustering of early T-cell-mediated immune responses. Also striking was
the blunted rise in urine NGAL over time for patients in the albumin
fl uid group. These results should be considered hypothesis generating
and prompt further studies to explore possible biological mechanisms
for albumin resuscitation in sepsis. y
Methods Fifty adult male Sprague–Dawley rats were subjected to
CLP (25% cecum length, two punctures with a 25-gauge needle). Eighteen hours later, they were randomly assigned to receive either
30 ml/kg saline (n = 25) or plasmalyte (n = 25) over 4 hours. Arterial
blood gases, serum creatinine, urea, and lactate were measured at
baseline, 18 hours after CLP (before resuscitation), after resuscitation,
and 24 hours after resuscitation. Blood pressure and pulse rate were
measured during fl uid infusion.i P255 l
Results Saline-treated animals developed signifi cantly higher levels of
serum chloride (111 mmol/l vs. 102 mmol/l, P <0.0001) and lower pH
(7.35 v. 7.44, P <0.01) compared to plasmalyte. In addition, lactate was
signifi cantly higher after fl uid infusion in the saline group (4.8 mmol/l
vs. 2.5 mmol/l, P <0.001) compared to plasmalyte, despite being similar
before infusion (2.61 vs. 2.39, P >0.05). However, neither mean arterial
blood pressure (83 mmHg vs. 91 mmHg, P >0.10) nor heart rate (310 vs. 299, P >0.10) diff ered between the two groups. P252 Mean values were separated by treatment and analyzed
using R to generate heat maps, by principal component analysis (PCA)
and hierarchal clustering. Urinary neutrophil gelatinase-associated
lipocalin (NGAL) was measured by ELISA.i Conclusion HES supplementation in early burn resuscitation allows, for
smaller fl uid volume requirement, less tissue oedema. This along with a
signifi cantly lower in ALI occurrence and length of ICU stay. P253 p
y
Results Twenty-fi ve patients (median age 66 years, median APACHE II
score 26) received albumin (median amount 3 l) and 21 (median age
62 years, median APACHE II score 22) received normal saline (median
amount 3.5 l) as study fl uid over 7 days. PCA revealed that 60% of
the variance in the chemokines was accounted for with the fi rst two
components. Analyzing the fi rst component using a threshold of
greater than 0.5 or –0.5 we saw a clustering of IL-17, IL-12p70, IL-9 and
IL-5. Heat map analysis suggests that by 72 hours albumin-resuscitated
patients are distinguished by the cluster of IL-17, IL-9 and Il-12p70 and
VEGF when compared to saline. Hierarchal clustering also separates
IL-17, IL-19, IL-12p70 and IL-2 in the albumin-treated patients but not
the saline-treated patients at 72 hours. At enrolment, mean urine
NGAL levels were greater than 1,000 ng/ml (albumin 1,121 ± 2,172
(n = 21), saline 1,375 ± 3,197 (n = 17)). Over the next 24 hours there was
a marked increase in urine NGAL in the saline-resuscitated patients,
peaking at 5,793 ± 15,948 ng/ml, whereas levels remain blunted over
the fi rst 12 hours, peaking at 2,216 ± 3,177 ng/ml at 24 hours in the
albumin group. Normal saline resuscitation worsens lactic acidosis in experimental
sepsis
F Zhou, ME Cove, ZY Peng, J Bishop, K Singbartl, JA Kellum
University of Pittsburgh Medical School, Pittsburgh, PA, USA
Critical Care 2012, 16(Suppl 1):P253 (doi: 10.1186/cc10860) Curve analysis of tissue oxygen desaturation after a venous
occlusion test does not identify the central venous hemoglobin
oxygen saturation Curve analysis of tissue oxygen desaturation after a venous
occlusion test does not identify the central venous hemoglobin
oxygen saturation yg
G Friedman1, C Alan2, A Meregalli2, A Lima3, J Bakker3
1UFRGS, Porto Alegre, Brazil; 2Complexo Hospitalar Santa Casa, Porto Alegre,
Brazil; 3University Medical Center Erasmus, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P257 (doi: 10.1186/cc10864) y
G Friedman1, C Alan2, A Meregalli2, A Lima3, J Bakker3
1UFRGS, Porto Alegre, Brazil; 2Complexo Hospitalar Santa Casa, Porto Alegre,
Brazil; 3University Medical Center Erasmus, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P257 (doi: 10.1186/cc10864) Introduction We aim to compare the time for the equivalence of tissue
oxygen saturation (StO2) with central venous hemoglobin oxygen
saturation (ScvO2) measured at depths of 15 and 25 mm. Methods Twenty-one critically ill patients were included. The ScvO2
was measured by blood gas analysis. Thenar StO2 was continuously
monitored (Model 650 InSpectra Tissue Spectrometer; Hutchinson
Technology Inc., MN, USA) in 15 mm (StO2_15) and 25 mm (StO2_25)
depths. The venous occlusion was performed using an automatic
pneumatic device maintaining infl ation pressure 10 mmHg above the
diastolic pressure. A StO2 desaturation curve was plotted to identify the
time for equivalence to ScvO2. Introduction We aim to compare the time for the equivalence of tissue
oxygen saturation (StO2) with central venous hemoglobin oxygen
saturation (ScvO2) measured at depths of 15 and 25 mm. Introduction We aim to compare the time for the equivalence of tissue
oxygen saturation (StO2) with central venous hemoglobin oxygen
saturation (ScvO2) measured at depths of 15 and 25 mm. 2
Methods Twenty-one critically ill patients were included. The ScvO2
was measured by blood gas analysis. Thenar StO2 was continuously
monitored (Model 650 InSpectra Tissue Spectrometer; Hutchinson
Technology Inc., MN, USA) in 15 mm (StO2_15) and 25 mm (StO2_25)
depths. The venous occlusion was performed using an automatic
pneumatic device maintaining infl ation pressure 10 mmHg above the
diastolic pressure. A StO2 desaturation curve was plotted to identify the
time for equivalence to ScvO2. the predicting equation were 69.23%, 77.41%, 85.71% and 56.25%
respectively. The accuracy was 75%. See Figure 1. q
2
Results Age: 59 ± 17 years, APACHE II score: 21 ± 7, SOFA score: 7 ± 4,
ScvO2: 75 ± 6%, blood lactate: 1.6 ± 1.2 mmol/l, capillary refi ll time:
9.1 ± 8.1 seconds, body temperature: 36.7 ± 1.1°C. Measurements were
performed for up to three consecutive days (total measurements: 43). Albumin in early septic shock resuscitation: examination of plasma
and urine infl ammatory markers Albumin in early septic shock resuscitation: examination of plasma
and urine infl ammatory markers
A Fox-Robichaud1, C Leger2, KD Burns3, E Sabri3, B Lo1, P Kubes2,
LA McIntyre3
1McMaster University, Hamilton, Canada; 2University of Calgary, Canada;
3Ottawa Hospital Research Institute, Ottawa, Canada
Critical Care 2012, 16(Suppl 1):P254 (doi: 10.1186/cc10861) A Fox-Robichaud1, C Leger2, KD Burns3, E Sabri3, B Lo1, P Kubes2,
LA McIntyre3
1M M
U i
i
H
il
C
d
2U i
i
f C l
C Results Of the 44 enrolled patients, 24 were males (54.54%). Mean
age was around 69.86 ± 16.819 years. A total of 84.1% was in septic
shock. The most common source of infection was pneumonia (38.6%). The central ScvO2 and peripheral venous oxygen saturation ranges
and means were 46.0 to 93.2%, 31.5 to 99.0% and 71.66 ± 10.39%,
71.18 ± 19.79% respectively. The correlation between ScvO2 and
antecubital venous oxygen saturation signifi cant P value was 0.000:
calculated ScvO2 = 52.386 + 0.271(peripheral), R2 = 0.266. The specifi city,
sensitivity, positive predictive value and negative predictive value of y
1McMaster University, Hamilton, Canada; 2University of Calgary, Canada;
3Ottawa Hospital Research Institute, Ottawa, Canada
Critical Care 2012, 16(Suppl 1):P254 (doi: 10.1186/cc10861) Introduction A recent meta-analysis has suggested that albumin may
be benefi cial in sepsis; however, there is no clear biological rationale
for the pharmacological use of this negative acute-phase protein. Our
objective was to describe the temporal production of plasma and urine Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1 S92 Figure 1 (abstract P255). Central and peripheral oxygen saturation
range. P257 5
Curve analysis of tissue oxygen desaturation after a venous
occlusion test does not identify the central venous hemoglobin
oxygen saturation
G Friedman1, C Alan2, A Meregalli2, A Lima3, J Bakker3
1UFRGS, Porto Alegre, Brazil; 2Complexo Hospitalar Santa Casa, Porto Alegre,
Brazil; 3University Medical Center Erasmus, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P257 (doi: 10.1186/cc10864) Curve analysis of tissue oxygen desaturation after a venous
occlusion test does not identify the central venous hemoglobin
oxygen saturation Curve analysis of tissue oxygen desaturation after a venous
occlusion test does not identify the central venous hemoglobin
oxygen saturation In four patients the equivalence was not identifi ed. The curve analysis
showed that StO2 desaturation time equivalency for ScvO2 was greater
for StO2_15 than for StO2_25 (88 ± 54 seconds vs. 79 ± 56 seconds,
P <0.01). The Pearson correlation index for equivalence times for
StO2_15 and StO2_25 was 0.92 (P <0.001), but Bland–Altman analysis
showed a signifi cant diff erence between the times (mean diff erence:
StO2_25 – StO2_25: –7.9 ± 37.8 seconds). An arbitrary time of 80 seconds
identifi es the ScvO2 in 58% of cases. Conclusion Venous oxygen saturation from the antecubital vein was
not the exact value of central venous oxygen saturation but there were
signifi cant correlations. Central venous hyperoxia is related to changes in tissue perfusion
and morbi-mortality of patients in shock
G Friedman1, A Do Canto2, D Araujo2
1UFRGS, Porto Alegre, Brazil; 2Complexo Hospitalar Santa Casa, Porto Alegre,
Brazil
Critical Care 2012, 16(Suppl 1):P256 (doi: 10.1186/cc10863) Central venous hyperoxia is related to changes in tissue perfusion
and morbi-mortality of patients in shock
G Friedman1, A Do Canto2, D Araujo2
1UFRGS, Porto Alegre, Brazil; 2Complexo Hospitalar Santa Casa, Porto Alegre,
Brazil
Critical Care 2012, 16(Suppl 1):P256 (doi: 10.1186/cc10863) i
2
Conclusion The analysis of the StO2 desaturation curve does not
adequately identify the hemoglobin central venous oxygen saturation. References Introduction Mixed or central venous hyperoxia is associated with
organ dysfunction and worse mortality. Venous hyperoxia may refl ect
altered tissue oxygen extraction. We aim to assess the relationship
between central venous hyperoxia (ScvO2) and markers of tissue
perfusion; and to evaluate the relationship between central venous
hyperoxia and morbidity. 1. Lima A, et al.: The relation of near-infrared spectroscopy with changes in
peripheral circulation in critically ill patients. Crit Care Med 2011, 39:1649. 2. Bezemer R, et al.: Assessment of tissue oxygen saturation during a vascular
occlusion test using near-infrared spectroscopy: the role of probe spacing
and measurement site studied in healthy volunteers. Crit Care 2009,
13(Suppl 5):S4. y
y
Methods The setting was a university general ICU with 18 beds. The
population was adult patients (age >18 years) in circulatory shock. Blood lactate, arterial and central venous blood gases were collected
on admission to the study and after 6, 12, 18 and 24 hours of shock. Venous hyperoxia was defi ned as a ScvO2 ≥85%. The severity of the
patients was assessed using the APACHE II score on admission to the
study. Mortality was evaluated in the ICU and after 28 days. 3. Lima A, et al.: Low tissue oxygen saturation at the end of early goal-
directed therapy is associated with worse outcome in critically ill patients. Crit Care 2009, 13(Suppl 5):S13. 3. Lima A, et al.: Low tissue oxygen saturation at the end of early goal-
directed therapy is associated with worse outcome in critically ill patients. Crit Care 2009, 13(Suppl 5):S13. 1.
Pope JV, et al.: Multicenter study of central venous oxygen saturation
(ScvO2) as a predictor of mortality in patients with sepsis. Ann Emerg Med
2010, 55:40-46. Lactate in burn patients: biomarker of sepsis and mortality y
y
y
Results Preliminary data from 40 patients (205 measurements) are
presented. Mean blood lactate levels were higher (3.2 vs. 2.3 mmol/l),
the mean venoarterial CO2 diff erence was lower (4.7 vs. 5.8 mmHg),
and the mean base defi cit was greater (11 vs. 8 mEq/l) for patients with
venous hyperoxia at any time. Mean APACHE II score was higher (28 vs. 24) for patients with venous hyperoxia. The ICU mortality was higher
(4/5 (80%) vs. 17/35 (46%)) among patients who already had venous
hyperoxia at time 0. The proportion of death remained the same in the
next day among patients that persisted or developed venous hyperoxia
in the following 18 hours. A Mokline, L Gharsallah, A Abdenneji, H Oueslati, I Rahmani, B Gasri,
I Jami, A Ghanem, A Messadi A Mokline, L Gharsallah, A Abdenneji, H Oueslati, I Rahmani, B Gasri,
I Jami, A Ghanem, A Messadi Can we predict arterial lactate from venous lactate in the
emergency department? A Mikami1, S Ohde2, G Deshpande2, T Mochizuki1, N Otani1, S Ishimatsu1
1St Luke’s International Hospital, Tokyo, Japan; 2St Luke’s Life Science Institute,
Tokyo, Japan Results BL and TL were higher in septic shock patients compared to
nonseptic shock patients (AUCs of 276 vs. 176 and 355 vs. 273 mmol/
l*hours, respectively; Welch’s t test: P <0.0001). X-ApEn for MDL/BL was
lower in septic shock patients compared to those without septic shock
(mean ± SD: 0.79 ± 0.12 vs. 1.14 ± 0.13, respectively; t test: P <0.0001). Cross-correlation of TL versus BL was stronger in septic shock patients,
with TL leading BL by 4 hours compared to TL versus BL with no lag
time (r = +0.85, P <0.0001 and r = +0.66, P <0.0001, respectively) than
in nonseptic shock patients (r = +0.58, P = 0.0003 with TL leading BL by
4 hours and r = +0.66, P <0.0001 with no lag time; z statistic = 2.41 and
P = 0.016 for leading BL compared to z statistic=0.036, P = 0.971 for no
lag time). Introduction Analysis of arterial blood has an important role in the
clinical assessment of critically ill patients. Particularly, measured
arterial lactate (a-Lac) provides valuable information on peripheral
circulatory failure, although it is invasive and frequent measurement
is often impractical. The aim of this study is to clarify the relationship
between a-Lac and the more easily accessed venous lactate (v-Lac) and
to generate a formula to predict a-Lac using v-Lac and other laboratory
data. Conclusion In septic shock patients, tissue lactate levels – measured by
MD – are higher compared to nonseptic shock patients. Furthermore,
TL is better correlated with and precedes – within 4 hours – BL in septic
shock patients compared to nonseptic shock patients. Further studies
are warranted to assess the clinical value of serial TL monitoring. Methods A prospective cohort study was conducted from June to
November 2011 in the emergency department at a tertiary-level
community hospital in Tokyo, Japan. Patients were eligible for entry
into the study if an arterial blood gas (ABG) analysis was required for
appropriate diagnostic care by the treating physician. Arterial and
venous samples were taken within 5 minutes of each other from the
ipsilateral radial artery and cephalic vein. Samples were analyzed
as soon as possible after collection on the same blood gas analyzer. P261
d Admission lactate and outcome after high-risk surgery
M Geisen, HD Aya, C Ebm, N Arulkumaran, MA Hamilton, M Grounds,
A Rhodes, M Cecconi
St George’s Hospital NHS Trust, London, UK
Critical Care 2012, 16(Suppl 1):P261 (doi: 10.1186/cc10868) Introduction The aim of this study was to assess the ability of serum
lactate level in patients admitted to the ICU after surgery to predict
outcome. Introduction The aim of this study was to assess the ability of serum
lactate level in patients admitted to the ICU after surgery to predict
outcome. Methods A retrospective, clinical observational study in patients
undergoing high-risk surgery admitted to a 17-bed ICU of a large
teaching hospital. Data were obtained during haemodynamic
optimization using an established GDT protocol in the fi rst 8 hours after
admission and included demographic data as well as haemodynamic
and laboratory parameters. Outcome data included morbidity (defi ned
as >1 complications on the postoperative morbidity survey) and clinical
outcome (hospital mortality, length of ICU stay, length of hospital stay,
readmission to the ICU). i
Results Seventy-two arterial samples from 72 patients (61% male;
mean age, 58.2 years) were included in the study. Indications for ABG
included respiratory failure (16%), assessment of shock (21%), altered
mental status (26%), and others (36%). An initial regression equation
was derived from univariate linear regression analysis: (a-Lac) = –0.259
+ (v-Lac)×0.996. Subsequent multivariate forward stepwise logistic
regression analysis, incorporating venous lactate and venous pO2
(v-pO2), generated the following equation: (a-Lac) = –0.469 + (v-
pO2)×0.005 + (v-Lac)×0.997. Calculated R-squared values by single and
multiple regression were 0.94 and 0.96, respectively. Results Sixty-seven patients were included. Lactate clearance (decrease
of lactate >10% in 2 hours) occurred in 64 patients (96%). Sixty patients
developed at least one surgical complication. There were no signifi cant
correlation between lactate levels on admission and development of Conclusion Venous lactate estimates showed a high correlation with
arterial values and our data provide two clinically useful equations
to calculate a-Lac from v-Lac data. Considering clinical fl exibility,
Lac = –0.259 + VLac×0.996 might be more useful, while avoiding a
time-consuming and invasive procedure. Table 1 (abstract P261). A Mokline, L Gharsallah, A Abdenneji, H Oueslati, I Rahmani, B Gasri,
I Jami, A Ghanem, A Messadi Burn and Trauma Center, Tunis, Tunisia Critical Care 2012, 16(Suppl 1):P258 (doi: 10.1186/cc10865) Introduction In this study, we attempted to assess whether the
early plasma lactate (PL) level is a useful biomarker to predict septic
complications and outcome in burn patients. Methods A retrospective study was conducted in the burn care center
in Tunis. Patients admitted within 24 hours from the thermal injury,
from 1 January 2009 to 30 June 2010, were included. PL was measured
early in the fi rst 24 hours and controlled more than twice. For each
measurement, 5 ml venous blood was drawn into a heparin-coated
syringe. The normal lactate value was defi ned as 1 ± 0.5 mmol/l. Conclusion These preliminary data suggest that the presence of central
venous hyperoxia is associated with persistent changes in perfusion. The presence of venous hyperoxia at both the onset of shock and in the
following hours is associated with a worse clinical outcome. Reference i
Results Over an 18-month period of study, 80 patients were enrolled. There were 60 males and 20 females. The mean age was 40.7 ± 19.5 and
the average TBSA was 32 ± 21%. Upon admission, patients with an initial
lactate value of more than 2 mmol/l were 86.7%. Fifty-eight percent
of them have a lactate initial value of more than 4 mmol/l. In order
to evaluate the potential impact of using early lactate measurements
(H24 post burn injury) as predictor biomarker of sepsis in burn patients,
a linear discrimination function was performed, by measuring the area
under the ROC curve, and found that initial lactate value of more than
4 mmol/l provides the best sensitivity and specifi city: 88% and 79% 1. Pope JV, et al.: Multicenter study of central venous oxygen saturation
(ScvO2) as a predictor of mortality in patients with sepsis. Ann Emerg Med
2010, 55:40-46. S93 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 is a good prognostic fi nding, whereas persistent BL elevation portends
poor outcome. Microdialysis (MD) enables direct monitoring of tissue
metabolic changes. This study aimed to describe the dynamics of
MD-assessed tissue lactate (TL) vis-à-vis BL in septic patients with and
without shock. respectively. Also, the PL cut-off value for prediction of mortality was
4 mmol/l with a good sensitivity (86%) and specifi city (92%). P261
d Lactate on admission, complications and clinical
outcome
Lactate
Lactate
<1.7 mmol
>1.7 mmol
(n = 46)
(n = 21)
P value
Complications
41 (89%)
19 (90.5%)
NS
Complications >1
36 (78.3%)
16 (76.2%)
NS
Total complications per patient
3 (2 to 7)
4 (2 to 7)
NS
Hospital stay
14 (8 to 39)
13 (8 to 24)
NS
ICU stay
1 (1 to 2)
2 (1 to 10)
0.045
Readmission to ICU
3 (6.5%)
6 (28.6%)
0.022
Mortality
2 (4.3%)
3 (14.3%)
NS Table 1 (abstract P261). Lactate on admission, complications and clinical
outcome P259 Can we predict arterial lactate from venous lactate in the
emergency department? A Mikami1, S Ohde2, G Deshpande2, T Mochizuki1, N Otani1, S Ishimatsu1
1St Luke’s International Hospital, Tokyo, Japan; 2St Luke’s Life Science Institute,
Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P259 (doi: 10.1186/cc10866) A Mokline, L Gharsallah, A Abdenneji, H Oueslati, I Rahmani, B Gasri,
I Jami, A Ghanem, A Messadi The area
under the ROC curve was 0.96. Conclusion Lactate appears to be a powerful predictor biomarker
of sepsis and mortality in burn patients. A serum lactate of 4 mmol/l
provides the best sensitivity and specifi city. Methods We measured BL and thigh adipose tissue TL serially every
4 hours for 6 days in 88 patients with septic shock and 45 patients
at various sepsis stages hospitalized in a tertiary-care hospital ICU. Analysis was done with measurement of the area under the curve
(AUC) of lactate*hours, cross-approximate entropy (X-ApEn) and
cross-correlation. Comparisons of septic shock versus nonseptic shock
patients’ results were done with t tests and z statistics. Can we predict arterial lactate from venous lactate in the
emergency department? Univariate linear regression analysis was conducted to generate
an equation to calculate a-Lac incorporating only v-Lac. Then, a
multivariate forward stepwise logistic regression model (P value of 0.05
for entry, 0.1 for removal) was used to generate an equation including
v-Lac and other potentially relevant variables including age, sex,
systolic blood pressure, heart rate, and venous blood parameters (pH,
pO2, pCO2, hemoglobin, creatine kinase, potassium). A Bland–Altman
plot was drawn and the two equations were compared for model
fi tting using R-squared. P260 Cross-correlation analysis of blood and microdialysis-assessed
tissue lactate monitoring: a study in critically ill septic patients
I Ilias1, P Kopterides2, N Nikitas2, D Vassiliadi2, M Theodorakopoulou2,
E Papadomichelakis2, M Lygnos2, A Flevari2, M Rizos2, F Frantzeskaki2,
C Diakaki2, E Paramythiotou2, E Dimitriadou2, S Orfanos2, A Armaganidis2,
I Dimopoulou2
1‘Elena’ Hospital, Athens, Greece; 2‘Attiko’ University Hospital, Haidari, Athens,
Greece
Critical Care 2012, 16(Suppl 1):P260 (doi: 10.1186/cc10867) Cross-correlation analysis of blood and microdialysis-assessed
tissue lactate monitoring: a study in critically ill septic patients
I Ilias1, P Kopterides2, N Nikitas2, D Vassiliadi2, M Theodorakopoulou2,
E Papadomichelakis2, M Lygnos2, A Flevari2, M Rizos2, F Frantzeskaki2,
C Diakaki2, E Paramythiotou2, E Dimitriadou2, S Orfanos2, A Armaganidis2,
I Dimopoulou2
1‘Elena’ Hospital, Athens, Greece; 2‘Attiko’ University Hospital, Haidari, Athens,
Greece
Critical Care 2012, 16(Suppl 1):P260 (doi: 10.1186/cc10867) Critical Care 2012, 16(Suppl 1):P260 (doi: 10.1186/cc10867) Introduction In the critical care setting, blood lactate (BL) concentration
is measured to assess – albeit indirectly – tissue oxygenation. In
addition, serial BL measurements are clinically useful since a drop in BL S94 Critical Care 2012, Volume 16 Suppl 1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P262). Figure 1 (abstract P261). Prediction of ICU readmission according to
initial lactate concentration. Figure 1 (abstract P262). Figure 1 (abstract P262). consecutive hours on the fi rst, third, and fi fth days postoperatively. The second group (G2; n = 26) in addition to oxygen received NAC
200 mg/day for 5 days. The third group (G3; n = 26) was the control
group which did not receive any oxygen variation. On postoperative
day 6, hemoglobin, hematocrit and reticulocytes were measured and
compared to the baseline values. A total of fi ve patients (three in G1
and two in G2) were excluded for discontinuing oxygen and/or early
discharge from hospital. Figure 1 (abstract P261). Prediction of ICU readmission according to
initial lactate concentration. g
Results The reticulocyte count in G1 showed statistically diff erent
values compared to G2 and G3. These fi ndings correlate with other
clinical trials [2]. The fact that no statistical diff erence of hemoglobin
level was recorded could be attributed to the lack of follow-up after
patient discharge (postoperative day 6). See Figure 1.f complications and length of hospital stay. Nine patients (13%) were
readmitted to the ICU. P260 A receiving operator characteristic analysis
for readmission to the ICU showed an area under the curve of 0.79. A
lactate higher than 1.7 mmol/l on admission had a sensitivity of 75%
and a specifi city of 74% to predict ICU readmission (Figure 1). Patients
with a lactate on admission >1.7 mmol/l also had a longer length of ICU
stay (Table 1). Conclusion Induced relative hypoxia seems to be an eff ective stimulus
for reticulocyte synthesis. However, further investigations are needed
to confi rm these fi ndings and their impact on hemoglobin. References Conclusion Lactate on admission correlates with length of ICU stay and
readmission to the ICU. 1. Balestra C, et al.: J Appl Physiol 2006, 100:512-518. 2. Theunissen et al.: Crit Care 2011, 15(Suppl 1):P422. References 2. Jansen TC, et al.: Am J Respir Crit Care Med 2010, 182:752-761. 1.
Balestra C, et al.: J Appl Physiol 2006, 100:512-518.
2.
Theunissen et al.: Crit Care 2011, 15(Suppl 1):P422. P263 P262
Eff ects of induced relative hypoxia during the postoperative period
of abdominal oncologic surgery, on hemoglobin and reticulocyte
levels: a prospective, randomized controlled clinical trial
M Khalife1, K Wiams1, M Ben Aziz1, M Paesmans1, C Balestra2, M Sosnowski1
1Institut Jules Bordet, Brussels, Belgium; 2Divert Alert Network Europe Research
Division, Brussels, Belgium
Critical Care 2012, 16(Suppl 1):P262 (doi: 10.1186/cc10869) P263
Pre-emptive hypothermia during resuscitated porcine hemorrhagic
shock
J Matallo1, W Stahl1, M Gröger1, A Seifritz1, O Mccook1, M Georgieff 1,
P Asfar2, M Matejovic3, E Calzia1, P Radermacher1, F Simon1
1University Medical School, UIm, Germany; 2University Hospital, Angers,
France; 3Charles University, Plzeñ, Czech Republic
Critical Care 2012, 16(Suppl 1):P263 (doi: 10.1186/cc10870) Carbon monoxide therapy protects against hepatic microvascular
injury in a mouse model of murine hemorrhagic shock and
resuscitationi Carbon monoxide therapy protects against hepatic microvascular
injury in a mouse model of murine hemorrhagic shock and
resuscitationi H Gomez, I Nassour, P Loughran, J Brumfi eld, L Otterbein, B Zuckerbraun
University of Pittsburgh, PA, USA g
p
g
Results All models presented good fi t (P >0.05) and discrimination. An
AUC of 0.83 and 0.86 was obtained for the pneumonia and pancreatitis
subgroups, respectively, compared to an AUC of 0.81 obtained for the
general population of patients. A set of common predictive variables
was found for the general population of patients: arterial base excess,
noninvasive blood pressure and lactic acid. Additionally, group-
specifi c predictive variables were found for each of the two subgroups
of patients: white blood cell count for pneumonia patients, and
temperature for pancreatitis patients. y
g
Critical Care 2012, 16(Suppl 1):P264 (doi: 10.1186/cc10871) Introduction The purpose of this study is to evaluate the eff ects
of inhaled carbon monoxide (CO) as an adjunct to resuscitation on
hepatic microvascular and endothelial integrity in a murine model of
hemorrhagic shock and resuscitation (HSR). Others and ourselves have
previously demonstrated that CO can protect against organ injury in
experimental models of HSR [1]. Additionally, CO can prevent tissue
hypoxia during hemorrhage. Based upon this we hypothesized that CO
prevents hepatic injury and prevents hepatic hypoxia by maintaining
endothelial integrity and the hepatic microvascular circulation. Conclusion Generally, accurate and well-calibrated predictive risk
models were obtained for the impending use of vasopressors in an ICU. However, signifi cantly more accurate and well-calibrated models were
developed for the two subpopulations – pneumonia and pancreatitis –
than for the general population of ICU patients. This fi nding challenges
one-model-fi ts-all approaches to overall predictive risk modeling and
instead supports tailored modeling that is at least stratifi ed at a disease
level. Methods Male C57BL/6 mice underwent sham operation or
hemorrhage to a target MAP of 25 mmHg. Mice were maintained at this
pressure for 120 minutes and then resuscitated with Ringer’s lactate at
two times the volume of total shed blood. Mice were sacrifi ced 4 hours
after resuscitation. Mice were randomized to receive room air or inhaled
CO (250 ppm) for 30 minutes starting 90 minutes into the shock period
(n = 6 to 8 per group). Relative hepatic hypoxia was determined using
EF5 immunofl uorescence. Pre-emptive hypothermia during resuscitated porcine hemorrhagic
shockf J Matallo1, W Stahl1, M Gröger1, A Seifritz1, O Mccook1, M Georgieff 1,
P Asfar2, M Matejovic3, E Calzia1, P Radermacher1, F Simon1
1University Medical School, UIm, Germany; 2University Hospital, Angers,
France; 3Charles University, Plzeñ, Czech Republic
Critical Care 2012, 16(Suppl 1):P263 (doi: 10.1186/cc10870) Critical Care 2012, 16(Suppl 1):P262 (doi: 10.1186/cc10869) Introduction Anemia is a frequent complication in oncologic patients. Erythropoietin (EPO) stimulating agents are known as alternatives
to transfusion. However, they expose patients to thrombosis and are
expensive. Recently, a new phenomenon, the normobaric oxygen
paradox (NOP), has been described. In brief, transient hyperoxia
followed by a prolonged return to normoxia acts as an eff ective trigger
for EPO production. The mechanism depends on free oxygen radicals
and on reduced glutathione (GSH) availabilities. Also, N-acetylcystein
(NAC) is known to regenerate the stock of GSH. Very few clinical trials
have investigated this phenomenon [1]. The goal of this study was to
test the NOP theory on the evolution of hemoglobin and reticulocytes
in patients receiving intermittent oxygen with or without NAC
compared to a control group. Introduction The role of hypothermia in hemorrhagic shock is still a
matter of debate [1]. Therefore, we studied the eff ects of deliberate,
pre-emptive hypothermia on hemodynamics and organ function
during long-term porcine hemorrhage and resuscitation. Methods Anesthetized and instrumented pigs were randomly assigned
to 32°C (n = 7), 35°C (n = 7), and 38°C (n = 6) of core temperature and
subjected to 4 hours of hemorrhage (removal of 40% of the calculated
blood volume, additional removal/retransfusion of blood to maintain
mean arterial pressure (MAP) = 30 mmHg). After 12 hours of reperfusion
comprising retransfusion of shed blood, colloid fl uid resuscitation and
noradrenaline to keep MAP at pre-shock levels, animals were rewarmed
to 38°C. Data (median, quartiles) were obtained before and at the
end of the shock phase as well as at 12 and 22 hours of resuscitation,
intergroup diff erences were analyzed using a Kruskal–Wallis ANOVA on
ranks. Methods This prospective, randomized study included 78 patients
(three groups). The fi rst group (G1; n = 26) received 60% FiO2 for 2 S95 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results Fluid balance and noradrenaline requirements did diff er
between groups. 1.
Kim HS, Loughran PA, Rao J, Billiar TR, Zuckerbraun BS: Am J Physiol 2008,
295:G146-G152. P265 Two modeling approaches were used – fuzzy modeling
(FM) and logistic regression (LR) – combined with a sequential forward
feature selection process. For each group of patients, the selected
dataset was divided into two parts: one for feature selection and the
other for 10-fold cross-validation. The models’ calibration was assessed
using the Hosmer–Lemeshow goodness-of-fi t test, and discrimination
using the area under the receiver-operating curve (AUC).i P264 Carbon monoxide therapy protects against hepatic microvascular
injury in a mouse model of murine hemorrhagic shock and
resuscitation
H Gomez, I Nassour, P Loughran, J Brumfi eld, L Otterbein, B Zuckerbraun
University of Pittsburgh, PA, USA
Critical Care 2012, 16(Suppl 1):P264 (doi: 10.1186/cc10871) P265 Customized modeling to predict the use of vasopressors in ICUs
A Fialho1, F Cismondi1, S Vieira2, S Reti3, L Celi3, M Howell3, J Sousa3,
S Finkelstein1
1Massachusetts Institute of Technology, Cambridge, MA, USA; 2Technical
University of Lisbon, Instituto Superior Técnico, Lisbon, Portugal; 3Beth Israel
Deaconess Medical Centre, Boston, MA, USA
Critical Care 2012, 16(Suppl 1):P265 (doi: 10.1186/cc10872) Customized modeling to predict the use of vasopressors in ICUs
A Fialho1, F Cismondi1, S Vieira2, S Reti3, L Celi3, M Howell3, J Sousa3,
S Finkelstein1 Introduction Vasopressors belong to a powerful class of drugs
extremely useful for managing hypotension in patients with systemic
shock. Being able to predict a patient’s impending use of vasopressors
could be benefi cial as the central line insertion protocol could be
initiated in a safe and timely fashion and, a central line would only be
inserted if the patient has a likely future vasopressor need. Our goal in
this work was to develop predictive risk models for the impending use
of vasopressors in an ICU, and to make model comparisons between
the general population and patients with pneumonia and pancreatitis. Methods We performed a retrospective cohort study using data from
four diff erent adult ICUs at a tertiary-care hospital. Data contained
1,484 adult ICU patients, including a subgroup of 475 patients with
an ICD9 diagnosis of pneumonia and 104 with an ICD9 diagnosis of
pancreatitis. Two modeling approaches were used – fuzzy modeling
(FM) and logistic regression (LR) – combined with a sequential forward
feature selection process. For each group of patients, the selected
dataset was divided into two parts: one for feature selection and the
other for 10-fold cross-validation. The models’ calibration was assessed
using the Hosmer–Lemeshow goodness-of-fi t test, and discrimination
using the area under the receiver-operating curve (AUC).i Conclusion Deliberate, pre-emptive moderate hypothermia slowed
but did not protect against hemorrhagic shock and resuscitation-
induced organ dysfunction, possibly due to a delayed but not
attenuated infl ammatory response. Acknowledgements Supported by the Bundesministerium der
Verteidigung (M/SABX/8A004). Reference 1. Tisherman S: J Intensive Care Med 2010, 25:240-242. Methods We performed a retrospective cohort study using data from
four diff erent adult ICUs at a tertiary-care hospital. Data contained
1,484 adult ICU patients, including a subgroup of 475 patients with
an ICD9 diagnosis of pneumonia and 104 with an ICD9 diagnosis of
pancreatitis. Carbon monoxide therapy protects against hepatic microvascular
injury in a mouse model of murine hemorrhagic shock and
resuscitationi Sinusoidal integrity was determined by
scanning electron microscopy of the hepatic sinusoidal endothelium
and Evan’s blue tissue levels. Leukocyte stasis, rolling, and adhesion
were determined using intravital microscopy of post-sinusoidal hepatic
venules. Statistical analysis was determined by ANOVA. Pre-emptive hypothermia during resuscitated porcine hemorrhagic
shockf At 12 hours of reperfusion – that is, immediately
before rewarming – the 32°C group showed the lowest blood levels of
creatinine (P = 0.026), troponin I (P = 0.053), the thrombin–antithrombin
complexes (P = 0.012), and von Willebrand factor (P = 0.012). At the
end of the experiment – that is, after rewarming – all these intergroup
diff erences had disappeared, but the 32°C group presented with arterial
hypotension (P = 0.039), the most severe visceral organ acidosis (portal
and hepatic venous base excess: P = 0.044, P = 0.022, respectively), and
the highest TNFα blood levels (P = 0.030). P267 Examination of out-of-hospital cardiac arrest patients with the
Utstein style in Saga prefecture, Japan
T Iwamura, Y Sakamoto, N Kutsukata, T Hitomi, K Seki, M Koga,
T Yamashita, A Nakashima, Y Nishimura, M Yahata, K Yamada
Saga University, Saga, Japan
Critical Care 2012, 16(Suppl 1):P267 (doi: 10.1186/cc10874) Results Cardiac massage was not performed adequately in 48%
of laypersons. This was statistically signifi cantly more than among
lifeguards (16%) and instructors (23%). The median response times of
laypersons and lifeguards were 15 seconds and 16 seconds, respectively;
this was statistically (P <0.05) longer than instructors (12 seconds). The
median percentage of the time of massaging in group of laypersons
was 51% (56 to 58%, 25th to 75th percentiles), which was statistically
signifi cantly smaller than in the group of lifeguards (64%, 62 to 66%)
and in the control group (67%, 62 to 69%). Introduction Saga Prefecture is a small prefecture with an area of
2,439 km2 (place-of-residence 1,339 km2), a population of 849,709, and
is located in northwestern Kyushu in the western part of Japan. Saga
University has the only medical department in Saga Prefecture, Japan,
and it is in charge of both the online and offl ine medical control of Saga. This report examined the present status of OHCA in Saga, which should
be improved, and it aimed at exploring policies that can contribute to
the improvement in a ROSC rate. g
p
Conclusion The majority of all laypersons approach CPR in about
15 seconds from identifi cation of unconsciousness. However, only
about one-half of laypersons after the mandatory CPR course perform
qualitative cardiac massage, which is signifi cantly less than among
motivated laypersons. The latter perform qualitative massage and
achieve the same percentage of the massaging time as instructors. Results suggest that widespread promotion of the CPR protocol with
an AED among laypersons has limitations. Therefore, education of
laypersons should particularly focus on groups that have intrinsic
motivation. p
Methods The study examined 785 OHCA cases using the emergency
conveyance record (the Utstein style) submitted for the purpose of
MC verifi cation by the fi re-fi ghting organization in Saga from 1 July
2010 to 31 June 2011. The fi re-fi ghting organization was classifi ed into
fi ve areas (A to E) for every near medical classifi cation. Survival after out-of-hospital cardiac arrest during nights and
weekends Survival after out-of-hospital cardiac arrest during nights and
weekends Results Age, gender, cardiac arrest cause, initial waveform, witness,
shock and drug use pre-hospital did not diff er signifi cantly between
the fi ve regions. The ROSC rate was signifi cantly higher in A and C
areas than in D and E areas (A: 40.1% to D: 24.4% P <0.01, A: 40.1% to
E: 26.8% P <0.05, C: 39.9% to D: 24.4% P <0.05), and the ROSC rate of a
hospital waveform of asystole was signifi cantly higher in A and C areas
than in the other areas (A: 32.0% to B: 15.3%, D: 13.2%, E: 12.2% P <0.01,
C: 27.8% to B: 15.3%, E: 12.2% P <0.05). There were signifi cantly fewer
examples of oral instruction enforcement in the E area in comparison
to the other areas (E: 39.7% to A: 62.5%, B: 65.7%, C: 65.9%, D: 62.0%
P <0.01), and there were fewer examples of CPR enforcement in the D
and E areas in comparison to the B and C areas (D: 50.8% to B: 63.9%
P <0.05, E: 42.3% to B: 63.9% P <0.01, E: 42.3% to C: 59.7% P <0.05). CPR was not always delivered without oral instruction because the
bystander CPR-less rate of the oral-instruction-less example to citizens
was not less than 80% in all the areas. K Maekawa, K Tanno, M Hase, K Mori, Y Asai
Sapporo Medical University, Sapporo, Japan
Critical Care 2012, 16(Suppl 1):P269 (doi: 10.1186/cc10876) Introduction Out-of-hospital cardiac arrest (OOHCA) still has a low
survival rate, despite considerable eff orts including early applications
of basic life support and defi brillation in the pre-hospital setting. Post-
resuscitation care after hospitalization, infl uencing the fi nal outcome,
may be less available during nights and weekends because of hospital,
staffi ng, and response factors. We sought to determine whether
outcomes after OOHCA diff er during nights and weekends (off -hours)
compared with daytimes of weekdays (on-hours). Methods We performed a retrospective analysis of 4-year data
collected prospectively in a single institute. Adults with witnessed
OOHCA of cardiac origin were recruited. The therapeutic strategy
after hospitalization, including extracorporeal cardiopulmonary
resuscitation (ECPR), therapeutic hypothermia (TH) and primary
percutaneous coronary intervention (PCI), was dependent on the
critical care physicians in charge. We used a propensity-score matching Conclusion An improvement of the quality of oral instruction could
improve the ROSC rate. P268f all post-cardiac arrest syndrome patients were concentrated in a
hospital having facilities for post-resuscitation management and
provided intensive care, including appropriate hemodynamic and
pulmonary management, therapeutic hypothermia, and percutaneous
coronary intervention. The primary outcome measure was patient
survival at 1 month with a favorable neurological outcome.i P267 Comparative
examinations were conducted between the background (age, gender,
cardiac arrest cause, initial waveform, and hospital waveform, witness,
bystander CPR, oral instruction, and pre-hospital medical examination
(shock, advanced airway management, and drug use)) and the ROSC
rate between the fi ve areas. Statistical analyses included the chi-square
test and Fisher’s test. Implementation of the fi fth link of the Chain of Survival concept for
out-of-hospital cardiac arrest Implementation of the fi fth link of the Chain of Survival concept for
out-of-hospital cardiac arrest Implementation of the fi fth link of the Chain of Survival concept for
out-of-hospital cardiac arrest
T Tagami1, R Tosa2, M Omura2, H Yokota1, H Hirama1
1Nippon Medical School, Tokyo, Japan; 2Aizu Chuo Hospital, Fukushima,
Japan
Critical Care 2012, 16(Suppl 1):P266 (doi: 10.1186/cc10873) y
y
Results EF5 staining demonstrated that hemorrhagic shock induced
liver hypoxia, which was prevented by CO treatment. Scanning EM
imaging of hepatic sinusoids demonstrated that HSR results in loss
of normal endothelium, with loss of fenestrations, rounding of cells,
and adherent circulating cells. CO therapy prevented these changes. Relative hepatic levels of Evans blue, suggesting endothelial leak,
were increased 1.7 ± 0.23-fold in HSR compared to sham-operated
mice (P <0.05). CO treatment minimized endothelial leak, resulting in
a 1.23 ± 0.21-fold increase compared to sham (P <0.05 compared to
air-treated HSR). In addition, leukocyte rolling and adhesion were
signifi cantly diminished by CO as compared to the air-treated group
in HSR. T Tagami1, R Tosa2, M Omura2, H Yokota1, H Hirama1
1Nippon Medical School, Tokyo, Japan; 2Aizu Chuo Hospital, Fukushima,
Japan p
Critical Care 2012, 16(Suppl 1):P266 (doi: 10.1186/cc10873) Introduction The 2010 resuscitation guidelines of the American
Heart Association–International Liaison Committee on Resuscitation
recommend an additional fi fth link (post-resuscitation care in a
regional center) in the Chain of Survival concept for out-of-hospital
cardiac arrest (OHCA) in addition to early access to emergency medical
care (fi rst link), early cardiopulmonary resuscitation (second link),
early defi brillation (third link), and early advanced cardiac life support
(fourth link). However, no direct evidence supports its implementation. Our study aimed to determine the eff ectiveness of this fi fth link. Conclusion CO protected the hepatic sinusoidal endothelium from
HSR-induced injury. Further investigations into the mechanisms of
action are necessary. CO therapy may prove to be a useful resuscitative
adjunct in the treatment of HSR. Methods This multicenter, region-wide, prospective clinical study
involved all eligible OHCA patients in the Aizu region (n = 1,482,
suburban/rural, Fukushima, Japan). Primary outcomes before (January
2006 to April 2008) and after (January 2009 to December 2010) the
implementation of the fi fth link were evaluated. After implementation, S96 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Eff ectiveness and limitations of learning cardiopulmonary
resuscitation with an automated external defi brillator in the
curriculum of First Aid courses among lay people
U Kovačič1, L Kosec2
1Faculty of Medicine, University of Ljubljana, Slovenia; 2General Hospital in
Novo Mesto, Slovenia
Critical Care 2012, 16(Suppl 1):P268 (doi: 10.1186/cc10875) g
Results The primary outcome improved signifi cantly from 0.5%
(before, 4/770) to 3.0% (after, 21/712) (P <0.0001). The multivariate
odds ratio for the primary outcome was 8.3 (95% CI, 2.6 to 26.6) after
the implementation of the fi fth link, 7.1 (CI, 2.0 to 25.1) for a bystander-
witnessed arrest, and 5.0 (CI, 2.6 to 26.6) for early defi brillation. Introduction The eff ectiveness and limitations of widespread
promotion of cardiopulmonary resuscitation (CPR) with an automated
external defi brillator (AED) among the laity was investigated. Early,
qualitative and continuous cardiac massage has been stressed in the
2010 ERC guidelines. Since 2009 about 45,000 laypersons attended the
mandatory First Aid courses for drivers (organised by Slovenian Red
Cross), which include learning CPR with an AED. i
Conclusion The proportion of OHCA patients with a favorable
neurological outcome improved signifi cantly after the implementation
of the fi fth link of the Chain of Survival. This fi nding may require
confi rmation in an urban setting and/or with randomized trials. Trial registration University Hospital Medical Information Network
Clinical
Trials
Registry:
UMIN000001607
[http://apps.who.int/
trialsearch/trial.aspx?trialid=JPRN-UMIN000001607] Methods One hundred laypersons who attended 4-hour classes
in CPR before the driving lessons were compared to 60 motivated
laypersons who attended 6-hour classes in CPR before starting to work
as lifeguards in pools. Sixty instructors served as the control group. All participants (randomly assigned in pairs) got the same 6-minute
case-based scenario on a manikin. Rescuers were changing every
2 minutes. Basic skills in CPR were determined by the two instructors
and by a sensored manikin. Massage was assessed as qualitative if at
least 90% of massages were provided with proper hand placement,
adequate compression depth and adequate frequency. We measured
the response time from the call for help to the start of heart massaging
and the percentage of the time of massaging regarding the total time
from start of massaging to the end of the scenario. P270 CPR initiated after telephone-assisted instruction produces a
better outcome of bystander-witnessed out-of-hospital cardiac
arrests than no bystander CPR but is less eff ective than CPR on the
bystander’s own initiative
H Inaba1, T Kamikura1, K Takase1, W Omi2, S Sakagami2, Y Myojo3,
J Taniguchi3
1Kanazawa University Graduate School of Medicine, Kanazawa, Japan;
2Kanazawa Medical Center, Kanazawa, Japan; 3Ishikawa Prefectural Central
Hospital, Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P270 (doi: 10.1186/cc10877) CPR initiated after telephone-assisted instruction produces a
better outcome of bystander-witnessed out-of-hospital cardiac
arrests than no bystander CPR but is less eff ective than CPR on the
bystander’s own initiative Methods From the Japanese nationwide database for 431,968 OHCAs
that occurred from January 2005 to December 2008, we extracted
and analyzed 112,144 bystander-witnessed OHCAs without any
involvement of physicians, using multiple logistic regression analysis. Results The analysis for all bystander-witnessed OHCAs revealed that
both CC-only and conventional CPR following telephone CPR produce
better outcomes than no bystander CPR (Table 1). The analysis for
bystander-witnessed OHCAs with bystander CPR disclosed that CPR
on the bystander’s own initiative produces a better outcome than CPR
following telephone CPR (Table 2). Methods From the Japanese nationwide database for 431,968 OHCAs
that occurred from January 2005 to December 2008, we extracted
and analyzed 112,144 bystander-witnessed OHCAs without any
involvement of physicians, using multiple logistic regression analysis. Results The analysis for all bystander-witnessed OHCAs revealed that
both CC-only and conventional CPR following telephone CPR produce
better outcomes than no bystander CPR (Table 1). The analysis for
bystander-witnessed OHCAs with bystander CPR disclosed that CPR
on the bystander’s own initiative produces a better outcome than CPR
following telephone CPR (Table 2). g
1Kanazawa University Graduate School of Medicine, Kanazawa, Japan;
2Kanazawa Medical Center, Kanazawa, Japan; 3Ishikawa Prefectural Central
Hospital, Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P270 (doi: 10.1186/cc10877) g
1Kanazawa University Graduate School of Medicine, Kanazawa, Japan;
2Kanazawa Medical Center, Kanazawa, Japan; 3Ishikawa Prefectural Central
Hospital, Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P270 (doi: 10.1186/cc10877) Introduction Telephone CPR has been shown to increase the incidence
of bystander CPR and is expected to improve the outcomes of out-of-
hospital cardiac arrests (OHCAs). Critical times in pediatric out-of-hospital cardiac arrest
J Tij
1 C Zh
2 C P
h
1 L M
i
2 J H
hi
1 Table 1 (abstract P270). Comparison of survival between OHCAs without
bystander CPR and bystander CPR in bystander-witnessed OHCAs
Factor
Adjusted odds ratio
95% CI
Type of CPR
No bystander CPR
Reference
CC-only CPR following telephone-CPR
1.66
1.49 to 1.84
Conventional CPR following telephone-CPR
1.67
1.48 to 1.89
CC-only CPR on bystander’s own initiative
2.22
1.99 to 2.49
Conventional CPR on bystander’s own initiative
2.36
2.10 to 2.66
Aetiology
Presumed cardiac
2.44
2.27 to 2.63
Noncardiac
Reference
Time intervals
Witness-call
0.98
0.97 to 0.98
Witness-fi rst CPR performed either by
0.97
0.96 to 0.98
citizens or by EMTs
Call-arrival at patients
0.93
0.92 to 0.94
Comparisons of 1-month survival with favourable neurological outcomes
between OHCAs without bystander CPR and with four types of bystander CPR in
bystander-witnessed OHCAs (multiple logistic regression analysis). Table 1 (abstract P270). Comparison of survival between OHCAs without
bystander CPR and bystander CPR in bystander-witnessed OHCAs Introduction Pediatric out-of-hospital cardiac arrest (OHCA) has a less
than 10% survival. Studies of the scene time and level of emergency
medical services (EMS) training in pediatric OHCA are lacking. The
objectives of this study are to describe the scene time, level of training
and the order and timing of arrival of fi rst responders to pediatric OHCA
in a large, densely populated area, the Toronto region. Methods The Resuscitation Outcomes Consortium (ROC) Epistry-
Cardiac Arrest database was queried for all patients <19 years old from
December 2005 to November 2011 in the Toronto region for age, sex,
event characteristics, underlying conditions, cause of the cardiac arrest,
level of EMS care, time to EMS arrival, scene time, return of spontaneous
circulation (ROSC) and survival to hospital discharge. Patients were
excluded if they were declared dead at the scene. y
Results Four hundred and fi fty-two patients with OHCA were included. Thirty-one percent were infants, 29.4% age 1 to 11 years (child), and
37.4% age 1 to 18 (adolescent) years with 62.8% of cases male. Thirty
percent had a signifi cant past medical history. The causes of the cardiac
arrest were trauma (14.4%), drowning (6.2%), sudden infant death
syndrome (4.0%), and unknown in 63%. The fi rst EMS responders
were fi re in 52.2%, advanced care paramedics in 25%, and primary
care paramedics in 22.3%. Survival was increased the earlier the EMS
arrived (P = 0.015). Survival after out-of-hospital cardiac arrest during nights and
weekends BLS education to the area, a re-examination
of the oral instruction manual in the applicable areas, and the suitable
evaluation of various examples of agonal respiration are together
expected to improve the ROSC rate. S97 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Table 2 (abstract P270). Eff ects of type and origin by bystander CPR on
survival of bystander-witnessed OHCAs having bystander CPR Table 2 (abstract P270). Eff ects of type and origin by bystander CPR on
survival of bystander-witnessed OHCAs having bystander CPR
Factor
Adjusted odds ratio
95% CI
Type of CPR
CC-only CPR
0.96
0.88 to 1.04
Conventional CPR
Reference
Origin of CPR
Following telephone-CPR
0.73
0.67 to 0.80
On bystander’s own initiative
Reference
Aetiology
Presumed cardiac
2.27
2.05 to 2.51
Noncardiac
Reference
Time intervals
Witness-call
0.99
0.98 to 0.99
Witness-fi rst CPR performed either by
0.98
0.97 to 0.99
citizens or by EMTs
Call-arrival at patients
0.88
0.87 to 0.90
Eff ects of type and origin by bystander CPR on 1-month survival with favourable
neurological outcomes of bystander-witnessed OHCAs having bystander CPR
(multiple logistic regression analysis). to reduce the diff erences of pre-hospital variables between patients
arriving during off -hours and on-hours. Primary endpoint was 90-day
survival after cardiac arrest. We evaluated the survival diff erence using
the log-rank test and identifi ed the signifi cant interventions aff ecting
outcome using the Cox regression model. Adjusted odds ratio
95% CI g
g
Results Of 185 patients, 131 arrived during off -hours (the off -hours
group) and 54 arrived during on-hours (the on-hours group). The
matching process selected 37 patients each from both groups. The
matched off -hours group had a lower survival rate than the matched
on-hours group (10.8% vs. 37.8%; log-rank P = 0.025). Multivariate Cox
regression analysis showed that TH was associated with 90-day survival
after cardiac arrest (adjusted hazard ratio (HR), 0.43; 95% CI, 0.23 to
0.79), but there were no signifi cant associations of ECPR (adjusted HR,
0.83; 95% CI, 0.50 to 1.37) and primary PCI (adjusted HR, 0.76; 95% CI,
0.42 to 1.38). Conclusion Lower survival rates after OOHCA during nights and
weekends were seen at our institute. TH was more likely to be induced
in patients arrived during daytimes of weekdays, and independently
associated with survival benefi t. P270 The aim of present study was to clarify
if the outcomes of bystander-witnessed OHCAs having CC-only and
conventional CPR following telephone CPR may be better than those
having no bystander CPR and if the type (CC-only and conventional)
and origin (following telephone CPR and on bystander’s own initiative)
may aff ect the outcomes of bystander-witnessed OHCAs with
bystander CPR. g
p
Conclusion Telephone CPR improves the outcomes of bystander-
witnessed OHCAS. However, eff orts to increase the incidence of early
CPR on the bystander’s own initiative would be necessary to obtain a
higher incidence of survival in bystander-witnessed OHCAs. Reference 1. Peberdy MA, Ornato JP, Larkin GL, et al.: Survival from in-hospital cardiac
arrest during nights and weekends. JAMA 2008, 299:785-792. Eff ects of type and origin by bystander CPR on 1-month survival with favourable
neurological outcomes of bystander-witnessed OHCAs having bystander CPR
(multiple logistic regression analysis). P271 P271
Critical times in pediatric out-of-hospital cardiac arrest
J Tijssen1, C Zhan2, C Parshuram1, L Morrison2, J Hutchison1
1Hospital for Sick Children, Toronto, Canada; 2University of Toronto, Canada
Critical Care 2012, 16(Suppl 1):P271 (doi: 10.1186/cc10878) P272 Don’t stop your heart in front of your family: family as a bystander is
associated with poor outcome of bystander-witnessed, bystander-
CPR-performed out-of-hospital cardiac arrest Conclusion Despite educational eff orts, most family members do not
appear to be good CPR performers. The fi rst responder system that
enables a good CPR performer to reach the scene quickly may be
needed for OHCAs witnessed by the family. H Inaba1, K Takase1, T Nishi1, T Kamikura1, Y Wato2, H Hamada3
1Kanazawa University Graduate School of Medicine, Kanazawa, Japan;
2Kanazawa Medical University, Uchinada, Japan; 3Suzu General Hospital,
Suzu, Japan H Inaba1, K Takase1, T Nishi1, T Kamikura1, Y Wato2, H Hamada3
1Kanazawa University Graduate School of Medicine, Kanazawa, Japan;
2Kanazawa Medical University, Uchinada, Japan; 3Suzu General Hospital,
Suzu, Japan p
Critical Care 2012, 16(Suppl 1):P272 (doi: 10.1186/cc10879) Critical Care 2012, 16(Suppl 1):P272 (doi: 10.1186/cc10879) Introduction Early CPR with a considerable quality is essential for
survival from out-of-hospital cardiac arrest (OHCA). This study was Table 1 (abstract P272). Backgrounds, characteristics and outcomes of OHCAs with reference to relation of bystander to victim
Relation of bystander to victim
Family
Friends, colleagues and
Others
Background, characteristics and outcome
(n = 25,119)
passers-by (n = 5,191)
(n = 14,938)
P value
Patient’s age, median (25 to 75%)
77 (66 to 84)
61 (50 to 73)
84 (75 to 90)
<0.001
Sex – male (%)
61.6
76.8
44.7
<0.001
CPR following telephone CPR (%)
75.1
42.7
36.1
<0.001
Initial rhythm shockable (%)
16.3
33.4
9.8
<0.001
Tune intervals, minutes, median (25 to 75%)
Collapse-call
2 (0 to 5)
2 (0 to 4)
2 (0 to 5)
<0.001
Collapse-bystander CPR
3 (1 to 6)
1 (0 to 4)
0 (0 to 2)
<0.001
Call arrival at patient
8 (6 to 11)
8 (6 to 11)
8 (6 to 10)
<0.001
Outcomes
1-month survival (%)
8.1
17.2
9.2
<0.001
1-month survival with favorable
4.0
11.9
4.8
<0.001
neurological outcomes (%) Table 1 (abstract P272). Backgrounds, characteristics and outcomes of OHCAs with reference to relation of b Table 1 (abstract P272). Backgrounds, characteristics and outcomes of OHCAs with reference to relation of bystander to victim
Relation of bystander to victim tract P272). Backgrounds, characteristics and outcomes of OHCAs with reference to relation of bystander to victim Table 2 (abstract P272). Critical times in pediatric out-of-hospital cardiac arrest
J Tij
1 C Zh
2 C P
h
1 L M
i
2 J H
hi
1 The timing of arrival of advanced paramedics at the
scene appeared to be associated with survival although this was not
statistically signifi cant (P = 0.22). Infants had a shorter scene time (P
<0.001) and an earlier arrival of advanced care paramedics at the scene p
g
between OHCAs without bystander CPR and with four types of bystander CPR in
bystander-witnessed OHCAs (multiple logistic regression analysis). between OHCAs without bystander CPR and with four types of bystander CPR in
b
t
d
it
d OHCA (
lti l l
i ti
i
l
i ) S98 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 conducted to test our hypothesis that the relation of the bystander to
the victim may aff ect the outcomes of OHCAs. (P = 0.04). A shorter scene time was associated with ROSC on arrival
at the emergency department (P <0.001) and a nonsignifi cant trend
for improved survival (P = 0.13). Adolescents were more likely to have
ROSC on arrival at the emergency department (P <0.001) and more
likely to survive (P <0.05) compared to children or infants. the victim may aff ect the outcomes of OHCAs. Methods From a Japanese nationwide database for 431,968 OHCAs
that occurred from January 2005 to December 2008, we extracted and
then analyzed 45,248 bystander-witnessed, bystander-CPR-performed
OHCAs without any involvement of physicians. Backgrounds,
characteristics and outcomes were compared among the three groups
of OHCAs categorized by the bystander’s relation to victims. Multiple
logistic regression analysis was applied to clarify if the relation may
aff ect the 1-month survival with favourable neurological outcomes. Results When the bystander was family, CPR was more frequently
initiated following telephone-assisted instruction and the interval
between collapse and bystander CPR was signifi cantly prolonged. Univariate analysis followed by multiple logistic regression analysis
revealed that family as a CPR performer signifi cantly decreases the
1-month survival with favourable neurological outcomes. See Tables 1
and 2.f yf
Methods From a Japanese nationwide database for 431,968 OHCAs
that occurred from January 2005 to December 2008, we extracted and
then analyzed 45,248 bystander-witnessed, bystander-CPR-performed
OHCAs without any involvement of physicians. Backgrounds,
characteristics and outcomes were compared among the three groups
of OHCAs categorized by the bystander’s relation to victims. Critical times in pediatric out-of-hospital cardiac arrest
J Tij
1 C Zh
2 C P
h
1 L M
i
2 J H
hi
1 Multiple
logistic regression analysis was applied to clarify if the relation may
aff ect the 1-month survival with favourable neurological outcomes. Conclusion The timing of arrival of advanced paramedics at the scene
may have been associated with survival and a larger study is needed
to confi rm this trend. A shorter scene time was associated with ROSC
and a trend for increased survival. However, infants have shorter scene
times but worse outcomes. To provide increased power and scope
for this study we will expand it to include all 10 Regional Clinical ROC
Centers and future analyses will include the remaining Utstein data
fi elds and compare the eff ects of advanced versus basic life support
interventions during resuscitation. f
g
Results When the bystander was family, CPR was more frequently
initiated following telephone-assisted instruction and the interval
between collapse and bystander CPR was signifi cantly prolonged. Univariate analysis followed by multiple logistic regression analysis
revealed that family as a CPR performer signifi cantly decreases the
1-month survival with favourable neurological outcomes. See Tables 1
and 2.f P272 End-tidal carbon dioxide levels should be monitored during CPR and
considered a useful prognostic value for determining the outcome of
resuscitative eff orts and when to cease CPR in the fi eld. y
y
y
Methods A total of 11 female pigs, body weights 50.3 ± 3.4 kg, were
enrolled into a protocol of prolonged cardiac arrest treated by FF
or FS ECMO ± IABP in a randomized fashion. Animals under general
anesthesia had undergone 15 minutes of ventricle fi brillation (VF)
with basal ECMO fl ow of 5 to 10 ml/kg/minute simulating low-fl ow CA
followed by continued VF with ECMO fl ow of 100 ml/kg/minute. CPP,
myocardial lactate metabolism and myocardial oxygen extraction were
determined. P275i P275
Modifi ed clinical decision rule for termination-of-resuscitation in
cases of refractory out-of-hospital cardiac arrest
Y Goto1, T Maeda1, Y Goto2, H Inaba3
1Kanazawa University Hospital, Kanazawa, Japan; 2Yawata Medical Center,
Komatsu, Japan; 3Kanazawa University Graduate School of Medicine,
Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P275 (doi: 10.1186/cc10882) Results CPP decreased from baseline of 85 mmHg (72, 94.5) to
15 mmHg (10, 20.5) during CA. The fi rst CPP value on ECMO increased
to 34 mmHg (26.5, 44) and during the further protocol gradually rose to
signifi cantly higher CPP of 68 mmHg (45.5, 82) before CPR (P = 0.003). This phenomenon of gradual rise was even more pronounced in FF
ECMO, animals started on FF ECMO completed the protocol with
identical CPP values as at baseline (85 mmHg (80, 99) vs. 86 mmHg
(78, 86), P = 0.55). Following CA, signifi cantly higher lactate levels
were detected in animals started on FS ECMO in all post-arrest periods
(P = 0.016 and P = 0.035 for diff erence in arterial and coronary sinus
lactate levels, respectively). Oxygen extractions after a steep increase
during CA declined immediately after ECMO initiation and remained
further with no statistically signifi cant diff erences between respective
ECMO arms (P for diff erence = 0.547). Resuscitability was high, we gained
5 minutes return of spontaneous circulation (ROSC) in eight animals
(73%) and 60 minutes ROSC was present still in eight animals (73%).i Introduction Two international termination-of-resuscitation (TOR)
rules for the emergency medical services (EMS) personnel have been
proposed to identify nonsurvivors after out-of-hospital cardiac arrest
(OHCA). P272 P273
Coronary perfusion pressure in a pig model of prolonged cardiac
arrest treated by diff erent modes of venoarterial extracorporeal
membrane oxygenation and intraaortic balloon counterpulsation
J Bělohlávek1, M Mlcek2, M Huptych3, S Havranek1, P Ostadal4, A Linhart1,
O Kittnar2
1General Teaching Hospital Prague, Czech Republic; 21st Medical School,
Charles University, Prague, Czech Republic; 3Technical Institute Prague, Czech
Republic; 4Homolka Hospital, Prague, Czech Republic
Critical Care 2012, 16(Suppl 1):P273 (doi: 10.1186/cc10880) Coronary perfusion pressure in a pig model of prolonged cardiac
arrest treated by diff erent modes of venoarterial extracorporeal
membrane oxygenation and intraaortic balloon counterpulsation
J Bělohlávek1, M Mlcek2, M Huptych3, S Havranek1, P Ostadal4, A Linhart1,
O Kittnar2 1General Teaching Hospital Prague, Czech Republic; 21st Medical School,
Charles University, Prague, Czech Republic; 3Technical Institute Prague, Czech
Republic; 4Homolka Hospital, Prague, Czech Republic
Critical Care 2012, 16(Suppl 1):P273 (doi: 10.1186/cc10880) p
Results PetCO2 after 20 minutes of advanced life support averaged
0.97 ± 0.33 kPa in patients who did not have ROSC and 4.85 ± 1.74 kPa
in those who did (P <0.001). PetCO2 after 15 minutes of advanced life
support averaged 1.11 ± 0.39 kPa in patients who did not have ROSC
and 3.65 ± 0.98 kPa in those who did (P <0.001). End-tidal carbon dioxide
values of 1.9 kPa (14.3 mmHg) or less discriminated between the 578
patients with ROSC and 502 patients without. When a 20-minute end-
tidal carbon dioxide value of 1.9 kPa (14.3 mmHg) or less was used as
a screening test to predict ROSC, the sensitivity, specifi city, positive
predictive value, and negative predictive value were all 100%. The
15-minute petCO2 value of 1.8 kPa had a sensitivity and NPV of 100%
with high specifi city PPV value (98%). Introduction An extracorporeal membrane oxygenation (ECMO)-
based approach is increasingly used in cardiac arrest (CA). However,
little is known about coronary perfusion pressure progress over time
in CA managed by ECMO. The aim of this study was to assess femoro-
femoral (FF) compared to femoro-subclavian (FS) venoarterial ECMO
in a pig model of prolonged CA on coronary perfusion pressure (CPP),
myocardial metabolic recovery and resuscitability. g
pi
y
Conclusion End-tidal carbon dioxide levels of more than 1.9 kPa (14.3
mmHg) after 20 minutes may be used to predict ROSC with accuracy. P274 p
g
y
Methods We analysed 289,769 OHCA adult patients with presumed
cardiac causes, using a prospectively recorded nationwide Utstein-style
database in Japan over 5 years (2005 to 2009). The primary endpoint
was 1-month survival with unfavourable neurological outcome, or
Glasgow–Pittsburgh cerebral performance category (CPC) scale = 3 to 5. Results The overall rates of 1-month survival with CPC = 1 or 2 and
collective 1-month survival were 2.55% and 5.22%, respectively. The incidences of misclassifi cation in the BLS, ALS and modifi ed BLS
TOR rules for 1-month survival with CPC = 3 to 5 were 0.20%, 0.15%
and 0.13%, respectively. The specifi city (95% CI) in the BLS, ALS and
modifi ed BLS TOR rules for 1-month survival with CPC = 3 to 5 were
0.941 (0.935 to 0.946), 0.981 (0.978 to 0.984) and 0.972 (0.968 to 0.975),
respectively. The area under the receiver operating characteristic curve
in the BLS, ALS and modifi ed BLS TOR rules for 1-month survival with
CPC = 3 to 5 were 0.865, 0.654 and 0.765, respectively.i P274
Capnometry successfully predicts outcome and determination of
the cessation of cardiopulmonary resuscitation eff orts
EH Hajdinjak1, ŠG Grmec2, MK Križmarić3, ET Torkar2, MS Skufca2,
DB Buić-Rerečić2, MK Kovač2, MZ Zelinka2
1Center for Emergency Medicine Maribor, University of Maribor, University of
Ljubljana, Slovenia, Maribor, Slovenia; 2Community Health Centre Ljubljana,
University of Ljubljana, University of Maribor, Ljubljana, Slovenia; 3Faculty of
Medicine, University of Maribor, Slovenia
Critical Care 2012, 16(Suppl 1):P274 (doi: 10.1186/cc10881) P272 The fi rst is for use by responders providing basic life support
(BLS) which includes three criteria: not witnessed by EMS personnel,
no shocks are administered and no return of spontaneous circulation
(ROSC). The other is for use by responders providing advanced life
support (ALS) which adds two criteria: unwitnessed by a bystander
and no bystander cardiopulmonary resuscitation. Simpler criteria as
a universal TOR rule may be desirable for any level of EMS personnel. We performed this study to validate two TOR rules and a modifi ed BLS
TOR rule which includes three criteria: unwitnessed arrest, no shocks
administered and no ROSC achieved before arrival at hospital for
predicting refractory OHCAs. Conclusion Our experimental study confi rmed that, in a pig model of
prolonged cardiac arrest, VA ECMO, mainly the FF approach, increases
signifi cantly the CPP over time, assures good metabolic recovery and
off ers sustained reasonable resuscitability. Morrison LJ, et al.: N Engl J Med 2006, 355:478-487. P272 Relation of bystander to victim as a factor associated with 1-month survival of bystander-witnessed OHCAs having bystander CPRi Table 2 (abstract P272). Relation of bystander to victim as a factor associated with 1-month survival of bystander-witnessed OHCAs having bystander CPR
Adjusted odds ratio (95% confi dence interval)
Bystander-witnessed OHCAs
Of presumed
Of presumed cardiac etiology
Factor
with bystander CPR
cardiac etiology
with shockable initial rhythm
Etiology of arrest
Presumed cardiac
1.39 (1.24 to 1.55)
Undefi ned
Undefi ned
Noncardiac
Reference
Initial rhythm
Shockable
4.38 (3.95 to 4.85)
4.82 (4.29 to 5.42)
Undefi ned
Nonshockable
Reference
Reference
Reference
Patient’s age
0.97 (0.97 to 0.98)
0.97 (0.97 to 0.97)
0.98 (0.97 to 0.98)
Sex
Male
1.14 (1.02 to 1.26)
1.16 (1.02 to 1.32)
1.07 (0.90 to 1.26)
Female
Reference
Reference
Reference
Relation of bystander to victim
Family
Reference
Reference
Reference
Friend, colleague and passers-by
1.70 (1.49 to 1.95)
1.40 (1.19 to 1.64)
1.61 (1.42 to 1.81)
Others
1.59 (1.42 to 1.78)
1.46 (1.27 to 1.68)
1.32 (1.10 to 1.59) elation of bystander to victim as a factor associated with 1-month survival of bystander-witnessed OHCAs having bystander CPR Table 2 (abstract P272). Relation of bystander to victim as a factor associated with 1-month survival of bystander-witnessed O y
y
Adjusted odds ratio (95% confi dence interval) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S99 P273 and partial pressure of end-tidal carbon dioxide (PetCO2) values
were collected for each patient in cardiac arrest by the emergency
physician. We hypothesized that an end-tidal carbon dioxide level of
1.9 kPa (14.3 mmHg) or more after 20 minutes and 1.8 kPa or more after
15 minutes of standard advanced cardiac life support would predict
restoration of spontaneous circulation (ROSC). P276
Survival benefi t for patients receiving antibiotics following out-of-
hospital cardiac arrest KJ Davies, ID Kerslake, J Walters, MJ Thomas
Bristol Royal Infi rmary, Bristol, UK
Critical Care 2012, 16(Suppl 1):P276 (doi: 10.1186/cc10883) Introduction Therapeutic hypothermia (TH) has become standard
management following out-of-hospital cardiac arrest (OHCA). Recent evidence suggests TH increases the risk of pneumonia. We
retrospectively assessed infective indicators after OHCA and evaluated
the eff ect of antibiotics on survival. Results One-hundred and four patients survived more than 24 hours
out of all 1,026 patients analyzed. Mean IL-6, S-100B and NSE levels in
nonsurvivors (n = 51) were signifi cantly higher than those in survivors
(n = 53) at all timepoints (P <0.01). Those in poor neurological outcome
(n = 74) were signifi cantly higher than those in favorable neurological
outcome (n = 29) at all timepoints (P <0.01). From the results of ROC
analysis and multivariate analysis, IL-6 >240 pg/ml at 6 hours and
S-100B >0.37 ng/ml on admission were chosen as an independent
predictors of nonsurvival, and S-100B >0.07 ng/ml at 24 hours was
chosen as that of poor neurological outcome. Subgroup analysis
of 56 patients showed that mean levels of IL-6 at 6 hours, S-100B at
6 hours and S-100B at 24 hours in the maintained (n = 29) group were
signifi cantly lower than those in the not-maintained group (n = 27)
(P <0.05). f
Methods We identifi ed all patients admitted to the ICU of a regional
primary angioplasty hospital following OHCA from May 2007 to
December 2010. We recorded ICNARC predicted mortality scores, blood
and respiratory (protected catheter aspiration) culture results, white
blood cell count (WBC) and C-reactive protein (CRP), hospital outcome
and ICU length of stay. All chest radiographs (CXRs) were reviewed by
a respiratory consultant (JW). Any antibacterial therapy was recorded. Results A total of 144 patients were admitted to the ICU following
OHCA. Mean age was 61.7 years (95% CI 59.0 to 64.4). The mortality rate
was 66.67% (58.62 to 73.84) with mean ICNARC predicted mortality of
77.11% (73.84 to 80.39). Of 144 patients, 138 (95.8%; 91.1 to 98.1) had
at least one positive marker of infection within 72 hours. Sixty-four had
microbiology samples analysed, 34 of which were positive (53.1%; 41.1
to 64.8%). Of 88 patients who had a CXR, 26 (29.6%; 21.0 to 39.8) had
consolidation. P277 P277
Correlation between IL-6 and S-100B blood levels and outcome
of post-cardiac arrest syndrome and infl uence of therapeutic
hypothermia on these mediator blood levels
K Shinozaki 1, S Oda2, T Sadahiro2, M Nakamura2, E Watanabe2, R Abe2,
T Nakada2, Y Morita2, K Nakanishi3, N Kitamura4, H Hirasawa2
1Chiba Aoba Municipal Hospital, Chiba City, Japan; 2Chiba University, Chiba
City, Japan; 3Narita Red Cross Hospital, Narita City, Japan; 4Kimitsu Chuo
Hospital, Kisarazu City, Japan
Critical Care 2012, 16(Suppl 1):P277 (doi: 10.1186/cc10884) Correlation between IL-6 and S-100B blood levels and outcome
of post-cardiac arrest syndrome and infl uence of therapeutic
hypothermia on these mediator blood levels K Shinozaki 1, S Oda2, T Sadahiro2, M Nakamura2, E Watanabe2, R Abe2,
T Nakada2, Y Morita2, K Nakanishi3, N Kitamura4, H Hirasawa2
1Chiba Aoba Municipal Hospital, Chiba City, Japan; 2Chiba University, Chiba
City, Japan; 3Narita Red Cross Hospital, Narita City, Japan; 4Kimitsu Chuo
Hospital, Kisarazu City, Japan
Critical Care 2012, 16(Suppl 1):P277 (doi: 10.1186/cc10884) Results Overall rates of 1-month survival and that with favorable
neurological outcome were 56.7% (n = 5,604) and 40.6% (n = 4,013),
respectively. Multivariate logistic regression analysis revealed that
the odds ratio for age, shockable initial rhythm and collapse–ROSC
time interval were 0.964 (95% CI 0.961 to 0.967), 3.564 (95% CI 3.232
to 3.934) and 0.967 (95% CI 0.963 to 0.970), respectively, and that
these variables were identifi ed as the best variables for developing a
prediction model. A statistical outcome prediction model using these
three variables was as follows: Pf = exp(B) / [1 + exp(B)], where Pf is
the probability of a favorable outcome and exp(B) is the exponential
function of B: B = –0.037×age (years) + 0.635×(shockable rhythm (1 or
0)) – 0.034×(collapse–ROSC time interval (minutes)) + 2.540. The area
under the receiver operating characteristic curve of this model for
predicting 1-month favourable neurological outcome was 0.764. Introduction To elucidate the signifi cance of IL-6, S-100B and NSE in
pathophysiology of post-cardiac arrest syndrome (PCAS), blood levels
of those mediators sampled within the fi rst 24 hours after cardiac arrest
(CA) were compared between groups classifi ed according to survival
and neurological outcomes. Furthermore, infl uence of stability of core
temperature with therapeutic hypothermia (TH) on these mediator
blood levels was also investigated. Methods Nontraumatic out-of-hospital CA patients were included. Blood was sampled on admission, at 6 hours and 24 hours after CA,
respectively. Capnometry successfully predicts outcome and determination of
the cessation of cardiopulmonary resuscitation eff orts Capnometry successfully predicts outcome and determination of
the cessation of cardiopulmonary resuscitation eff orts
Š j
j
DB Buić-Rerečić2, MK Kovač2, MZ Zelinka2
1Center for Emergency Medicine Maribor, University of Maribor, University of
Ljubljana, Slovenia, Maribor, Slovenia; 2Community Health Centre Ljubljana,
University of Ljubljana, University of Maribor, Ljubljana, Slovenia; 3Faculty of
Medicine, University of Maribor, Slovenia
Critical Care 2012, 16(Suppl 1):P274 (doi: 10.1186/cc10881) Introduction Prognosis in patients suff ering out-of-hospital cardiac
arrest is poor. Higher survival rates have been observed only in patients
with ventricular fi brillation who were fortunate enough to have basic
and advanced life support initiated soon after cardiac arrest. An ability
to predict cardiac arrest outcomes would be useful for resuscitation. Changes in expired end-tidal carbon dioxide levels during cardio-
pulmonary resuscitation (CPR) may be a useful, noninvasive predictor
of successful resuscitation and survival from cardiac arrest, and could
help in determining when to cease CPR eff orts. Conclusion We found that each TOR rule had high specifi city (ability
to predict survivors with favourable neurological outcome) and low
misclassifi cation rate as a universal TOR rule. The modifi ed BLS TOR rule is
simpler and as reliable as the other two rules. In Japan, as EMS providers
are legally prohibited from terminating resuscitation in the fi eld, the
amendment of related laws and the establishment of national consensus
would be necessary to apply these rules in the Japanese EMS system. Reference f
Methods This is a prospective, observational study of 1,080 cases
of out-of-hospital cardiac arrest. The patients were intubated and
measurements of end-tidal carbon dioxide taken. Data according
to the Utstein criteria, demographic information, medical data, Morrison LJ, et al.: N Engl J Med 2006, 355:478-487. S100 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P276 poor neurological outcome (CPC 3 to 5) and favorable neurological
outcome (CPC 1 to 2), respectively. Factors signifi cantly correlated with
survival and neurological outcomes were investigated by comparing
baseline characteristics and mediator blood levels. Patients receiving
TH were also included into subgroup analysis. If the core temperature
was maintained at 33 ± 1°C for more than 18 hours within the fi rst
24 hours, the patient was classifi ed into maintained, and if not into not-
maintained, and mediator blood levels were compared between the
subgroups. P276
Survival benefi t for patients receiving antibiotics following out-of-
hospital cardiac arrest Ninety-six of 115 patients (83.5%; 75.6 to 89.1) had a
CRP >100 mg/l (normal value <10 mg/l) within 72 hours and 82 of 115
(71.3%; 62.5 to 78.8) had an abnormal WBC (<4.0 or >11.0×109/l). Fifty-
six of 144 patients (38.9%; 31.3 to 47.0) received antibiotics during the
fi rst 7 days of their ICU stay (mean time to fi rst dose 2.17 days; 1.69 to
2.66). The hospital mortality rate for these patients 53.6% (40.7 to 66.0)
was signifi cantly less than those not receiving antibiotics 75.0% (65.0
to 82.9) (χ2 6.14, P = 0.01) with absolute risk reduction of 0.214 (0.055 to
0.365) and NNT of 5 (3 to 18). There was no diff erence in age (59.9 ± 4.2
vs. 62.9 ± 3.5) or ICNARC predicted mortality (75.1 ± 5.2 vs. 78.4 ± 4.2)
between the groups. Conclusion IL-6 and S-100B levels within 24 hours after CA, but not
NSE, are related to survival and neurological outcome. IL-6 and S-100B
are considered to be important mediators for the pathophysiology of
PCAS and TH may infl uence blood levels of these mediators. Early neurological outcome prediction model after
bystander-witnessed out-of-hospital cardiac arrest: a nationwide
population-based study Early neurological outcome prediction model after
bystander-witnessed out-of-hospital cardiac arrest: a nationwide
population-based study
Y Goto1, T Maeda1, Y Goto2, H Inaba3
1Kanazawa University Hospital, Kanazawa, Japan; 2Yawata Medical Center,
Komatsu, Japan; 3Kanazawa University Graduate School of Medicine,
Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P278 (doi: 10.1186/cc10885) Y Goto1, T Maeda1, Y Goto2, H Inaba3
1Kanazawa University Hospital, Kanazawa, Japan; 2Yawata Medical Center,
Komatsu, Japan; 3Kanazawa University Graduate School of Medicine,
Kanazawa, Japan
Critical Care 2012, 16(Suppl 1):P278 (doi: 10.1186/cc10885) g
Conclusion The post-arrest management of OHCA is commonly
complicated by infections, the diagnosis of which is delayed by a
universal increase in infl ammatory markers, body temperature control,
delay in the processing of samples and poor quality radiography. We
have shown a signifi cant reduction in mortality in patients receiving
antibiotics compared with patients who do not, despite there being no
diff erence in age or predicted mortality between the groups. This could
be due to treatment of an aspiration pneumonia, an anti-infl ammatory
eff ect or that some patients did not survive long enough to receive
antibiotics. It suggests that a formal clinical trial is warranted. Critical Care 2012, 16(Suppl 1):P278 (doi: 10.1186/cc10885 Introduction Identifi cation of prehospital prognostic factors in out-of-
hospital cardiac arrests (OHCAs) with prehospital return of spontaneous
circulation (ROSC) and establishment of a prediction model for survival
with favorable neurological outcome may minimize the costs and
save the medical resources. In this study, we developed a best model
for predicting 1-month survival with favorable neurological outcome
(defi ned as Glasgow–Pittsburgh cerebral performance category (CPC)
scale = 1 or 2), using a logistic regression analysis. g
g
g
y
Methods Of 522,801 resuscitation-attempted adult patients after
OHCAs, 9,876 bystander-witnessed arrests of presumed cardiac origin
with prehospital ROSC were analyzed in a prospectively recorded
nationwide Utstein-style database in Japan over 5 years (2005 to
2009). The endpoint was 1-month survival with favorable neurological
outcome. We performed multivariate logistic regression analysis to
develop a prediction model using the prehospital factors. P277 Population cooled post cardiac arrest
D/C (n = 12)
Died (n = 26)
VF arrest
10 (83%)
18 (75%)
P = 0.69
DT >30 minutes
1 (8%)
14 (58%)
P = 0.005
First CPR <5 minutes
11 (92%)
17 (71%)
P = 0.22
Cardiac aetiology
10 (83%)
16 (67%)
P = 0.44
Conclusion Survival is improved in patients cooled post-out-of-
hospital cardiac arrest [1,2]. Downtime is statistically signifi cant in the
survival of cooled patients. Achieving optimal timing of cooling was
no better in surviving versus dying populations. Cooling post-out-of-
hospital cardiac arrest is expensive and time-consuming; selection
criteria need to be evaluated to concentrate this resource on patients
where there is a higher prospect of a positive outcome [2] Table 1 (abstract P280). Population cooled post cardiac arrest Table 1 (abstract P280). Population cooled post cardiac arrest Introduction Most patients admitted to the ICU after cardiac arrest die
or have an unfavourable neurological outcome due to brain damage. Currently, the only treatment to reduce brain injury after cardiac arrest
is mild hypothermia. Helium inhalation has shown promising results
as a neuroprotective agent in animal models of cerebral infarction. If helium inhalation ameliorates neurological damage by reducing
reperfusion injury in humans as well, this could be of great benefi t
to patients. As no studies exist that investigate the use of helium
ventilation in patients after cardiac arrest we investigated whether this
treatment is safe and feasible. Conclusion Survival is improved in patients cooled post-out-of-
hospital cardiac arrest [1,2]. Downtime is statistically signifi cant in the
survival of cooled patients. Achieving optimal timing of cooling was
no better in surviving versus dying populations. Cooling post-out-of-
hospital cardiac arrest is expensive and time-consuming; selection
criteria need to be evaluated to concentrate this resource on patients
where there is a higher prospect of a positive outcome [2]. Methods A single-centre open-label intervention study was performed
in a mixed 30-bed academic ICU, approved by the local medical
ethics committee. Inclusion criteria: admission after a witnessed
cardiac arrest, presenting with ventricular fi brillation or tachycardia,
return of spontaneous circulation within 30 minutes, treatment with
hypothermia. Exclusion criteria: pre-existing neurological disorders or
the need for a FiO2 >50% or >10 mmHg PEEP on ICU admission. Helium
was administered during 3 hours as a 1:1 mixture with oxygen, using
a Servo-i ventilator. P281 P281
Therapeutic hypothermia for nonventricular fi brillation/ventricular
tachycardia cardiac arrest
S Jog1, D Patel1, M Patel1, R Kulkarni1, N Chouthai2
1Deenanath Mangeshkar Hospital and Research Centre, Pune, India; 2Wayne
State University, Detroit, MI, USA
Critical Care 2012, 16(Suppl 1):P281 (doi: 10.1186/cc10888) Therapeutic hypothermia for nonventricular fi brillation/ventricular
tachycardia cardiac arrest p
p
p
Results In total 25 patients were included, 20 (80%) male, age
64.8 ± 12.1 years, APACHE II score 20.0 ± 8.6, SAPS II 53.6 ± 18.6. Helium
treatment was started 4:57 ± 0:54 hours after arrest. In one patient the
treatment was stopped due to inadequate ventilation using the preset
limits. This was not due to the helium ventilation and no adverse events
due to helium ventilation were noted. Overall, nine (36%) patients had
a poor outcome. S Jog1, D Patel1, M Patel1, R Kulkarni1, N Chouthai2
1Deenanath Mangeshkar Hospital and Research Centre, Pune, India; 2Wayne
State University, Detroit, MI, USA
Critical Care 2012, 16(Suppl 1):P281 (doi: 10.1186/cc10888) Introduction Although effi cacy of therapeutic hypothermia (TH)
for cardiac arrest following ventricular tachycardia (VT)/ventricular
fi brillation (VF) is a recommended therapy, the effi cacy of TH for non-
VF/VT cardiac arrest is still not well studied. We conducted a study
to evaluate effi cacy and outcomes of TH in non-VF/VT cardiac arrest
patients in terms of survival and neurological outcome. Conclusion In this small study, we encountered no problems associated
with helium treatment in patients admitted to the ICU after cardiac
arrest. This opens the way for studies investigating the hypothesis that
helium treatment reduces neurological injury in these patients. Methods TH was initiated with intravenous ice-cold saline and
maintained with an external servo controlled cooling system (ESCCS);
by Blanketrol II Hypo-Hyperthermia system (Cincinnati Sub-Zero
Inc.) between 34 and 32°C for 24 hours. Gradual rewarming was also
done with ESCCS. Non-VF/VT cardiac arrest patients with GCS ≤7 at 60
minutes of return of spontaneous circulation (ROSC) were enrolled. Standard hemodynamic monitoring and management was continued
in all patients. P277 Then, patients that died within 24 hours after CA were
excluded. Patients were classifi ed into nonsurvivors (died within 28
days) and survivors (survived for 28 days or longer), and classifi ed into Conclusion Three prehospital prognostic factors (age, shockable initial
rhythm and collapse–ROSC time interval) were identifi ed as the best
variables in predicting favorable neurological outcomes in OHCAs with
prehospital ROSC. A model using these prehospital prognostic factors S101 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results Seventy patients had a hospital admission of post-cardiac
arrest. Five failed the inclusion criteria and six fulfi lled exclusion criteria. A total of 36 (51%) were cooled (Table 1). Twelve (33%) of the cooled
population survived to hospital discharge (D/C), one (8%) cooled
within 4 hours, three (25%) cooled for over 12 hours. Ten (28%) patients
were cooled despite not having a cardiac cause. One (4%) of the 23
noncooled patients survived to hospital discharge, four (17%) had
a cardiac cause. The median age of cooled population was 66 years
(quartile range 53.5 to 74 years) and 44 years (quartile range 41 to 52
years) of the noncooled. Results Seventy patients had a hospital admission of post-cardiac
arrest. Five failed the inclusion criteria and six fulfi lled exclusion criteria. A total of 36 (51%) were cooled (Table 1). Twelve (33%) of the cooled
population survived to hospital discharge (D/C), one (8%) cooled
within 4 hours, three (25%) cooled for over 12 hours. Ten (28%) patients
were cooled despite not having a cardiac cause. One (4%) of the 23
noncooled patients survived to hospital discharge, four (17%) had
a cardiac cause. The median age of cooled population was 66 years
(quartile range 53.5 to 74 years) and 44 years (quartile range 41 to 52
years) of the noncooled. has shown a good predictive value for estimating 1-month survival
with favorable neurological outcome in OHCA patients. Although this
novel model needs to be validated using another external dataset, this
model may help to minimize the cost and save medical resources. P279 P279
Helium ventilation is safe and feasible in ICU patients admitted
after cardiac arrest
D Brevoord, C Beurskens, N Juff ermans, W Van den Bergh, W Lagrand,
B Preckel, J Horn
Academic Medical Centre, University of Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P279 (doi: 10.1186/cc10886) Table 1 (abstract P280). P277 An independent data safety monitoring board
reviewed all problems arising from the helium ventilation itself and all
fatalities. Poor outcome was assessed with the Glasgow Outcome Score
at 30 days: death and vegetative state were defi ned as poor outcome. Data are presented as mean ± SD or numbers and proportions. References
1. Holzer M, et al.: Crit Care Med 2005, 33:414-418. 2. Hay A, et al.: Anaesthesia 2008, 63:15-19. References
1. Holzer M, et al.: Crit Care Med 2005, 33:414-418. 2. Hay A, et al.: Anaesthesia 2008, 63:15-19. Therapeutic hypothermia in an out-of-hospital arrest population:
are we selecting appropriately? The decrease in cerebral oxygenation during induction of TH
was not associated with a major change in hemodynamic parameters
(MAP before induction of TH: 79 mmHg ± 19; at 33°C: 82 mmHg ± 9), nor
with a major change in systemic oxygenation (SpO2 before TH: 99% ± 1;
at 33°C: 97% ± 3). In patients who survived until hospital discharge,
SctO2 returned to baseline values, 3.5 hours after induction of TH,
before the target temperature of 33°C was reached. In patients who
did not survive the hospital stay, SctO2 remained lower than baseline
values until the target temperature was reached. In these nonsurvivors,
SctO2 values did only return to baseline values during maintenance
of TH (10 hours after induction of TH). During maintenance of TH and
rewarming (0.3°C), no further signifi cant changes in SctO2 values were
observed. P282
Comparison of cold crystalloid and colloid infusions for induction of
therapeutic hypothermia
RS Skulec, AT Truhlar, ZT Turek, RP Parizkova, VC Cerny
Charles University in Prague, University Hospital Hradec Kralove, Czech
Republic
Critical Care 2012, 16(Suppl 1):P282 (doi: 10.1186/cc10889) p
Critical Care 2012, 16(Suppl 1):P282 (doi: 10.1186/cc10889) Introduction While cold crystalloids have been used for induction of
therapeutic hypothermia after cardiac arrest [1,2], the eff ectiveness of
cold colloids has not so far been evaluated. Therefore, we investigated
the cooling eff ect of rapid intravenous infusion of cold crystalloid
compared to colloid in a porcine model of ventricular fi brillation (VF). Methods VF was electrically induced in 22 anesthetized domestic
pigs (33 ± 2 kg). Defi brillation was attempted after 15 minutes CPR
using the AutoPulse (Zoll Medical, USA) and artifi cial ventilation. After
spontaneous circulation was restored, the animals were randomized to
receive either 1,500 ml of 1°C cold normal saline (group A; n = 9) within
20 minutes using a Zoll Power Infuser, or 1,500 ml of 1°C cold Voluven
(6% hydroxyethyl starch 130/0.4 in 0.9% NaCl) (group B; n = 9), or no
infusion (group C; n = 4). The animals were observed for 90 minutes
following infusion. Cerebral, rectal, intramuscular, pulmonary artery,
and subcutaneous fat body temperatures (BT) were continuously
recorded using GES 130 temperature probes and GMH 3250 digital
thermometers (Greisinger Electronic, Germany). Data were analyzed
with JMP 3.2 software (SAS Institute, USA) and are expressed as a
mean ± SD. P <0.05 was considered statistically signifi cant. Survey on the management of patients treated with therapeutic
hypothermia post cardiac arrest in London hospitals
A Walecka, SC Robert, A Prasad
The Royal Free Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P284 (doi: 10.1186/cc10891) y
gi
Results In total, 46.6 ± 3.2 ml/kg cold normal saline was infused in
group A, and 45.7 ± 2.7 ml/kg cold colloid in group B. The animals
treated with cold fl uids achieved a signifi cant decrease of BT in all
measurement sites while there was a spontaneous increase in group C
(P <0.05). At the time of fi nishing infusion there was a greater decrease
in cerebral and pulmonary artery BT in group A compared to group B
(–1.7 ± 0.4 vs. –1.1 ± 0.3 °C, P = 0.002; and –2.1 ± 0.3 vs. –1.6 ± 0.2 °C,
P <0.001 respectively). Area under the curve analysis of the decrease
in intracerebral BT revealed a more vigorous cooling eff ect in group
A compared to B (–91 ± 30 vs. –62 ± 27 °C/minute, P = 0.047). There
was also a higher calculated enthalpy for crystalloid solution compared
to colloid in the time-point of maximal BT decrease (33.9 ± 5.7 vs. 26.6 ± 3.4 kJ/kg, P <0.05). A Walecka, SC Robert, A Prasad The Royal Free Hospital, London, UK Introduction The second UK national survey on therapeutic
hypothermia (TH) post cardiac arrest demonstrated an impressive
increase in its implementation across the UK (from 28% to 85.6%) [1]. Therapeutic hypothermia, however, induces numerous physiological
and pathophysiological changes and therefore should be performed in
a standardised and controlled manner in order to be safe and eff ective. We carried out a telephone survey to determine the current TH practice
in London hospitals. p
Methods Thirty-two London intensive care units (ITUs) were contacted
by telephone. The data were analysed using Excel spreadsheets. Conclusion Cold crystalloid infusions resulted in a more intense cooling
eff ect than colloid infusions of the same temperature and infusion rate
in this porcine model of cardiac arrest. by telephone. The data were analysed using Excel spreadsheets. Results Of the 32 ITUs contacted, 30 (93.7%) had been using
therapeutic hypothermia following cardiac arrest. Fifteen (50%) of
them were teaching hospitals and the remaining 15 (50%) were district
general hospitals. Twenty-two (73.3%) hospitals had a protocol in place. External cooling was the preferred method used by 28 (93.3%) hospitals. Therapeutic hypothermia in an out-of-hospital arrest population:
are we selecting appropriately? A Short, M Brett, L Donaldsoni Glasgow Royal Infi rmary, Glasgow, UK p
Results A total of 13 patients with average GCS of 3.4 at 1 hour
after ROSC were enrolled in the study. Average time for ROSC was
16.5 minutes. Demographic and baseline variables were comparable
amongst survivors and nonsurvivors except age (survivors 43 years
and nonsurvivors 65 years). Average duration to achieve target
temperature was 4.9 hours. Five out of 13 (38.46%) patients survived
without any neurological defi cit or cognitive dysfunction (Cerebral
Performance Category – 1). Out of eight nonsurvivors, six died due to
cardiogenic shock, one died due to refractory hypoxia and in one case
relatives opted for withhold of aggressive care. Cardiac arrest was out
of hospital in eight patients (three survivors and fi ve nonsurvivors) and
intra-hospital in fi ve (two survivors and three nonsurvivors). Introduction We question how appropriately we select patients to
undergo therapeutic hypothermia following out-of-hospital cardiac
arrest. Methods The
population
was
identifi ed
through
searching
Wardwatcher between August 2006 and February 2011. Inclusion
criteria were all patients with an ICU admission of out-of-hospital
cardiac arrest. Exclusion criteria were: no CPR within the preceding
24 hours; admission from theatre; insuffi cient data. Data were gathered
from Wardwatcher, Careview and patients’ case notes for age, arrest
rhythm, downtime (DT) – time from arrest to return of spontaneous
circulation, time to initiation of CPR, temperatures at various time
points, cause of arrest and outcome. Statistical analysis was performed
with Fisher’s exact test, signifi cance level of P <0.05. Permission for use
of patient notes was granted from the consultant group of the ICU
audited. i
Conclusion TH may have benefi cial eff ects in the neurological outcome
of patients having non-VT/VF cardiac arrest. Additional controlled
studies are warranted to establish effi cacy of TH as a treatment for non-
VT/VF cardiac arrest. S102 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P282 impairment. Temperature at admission was 34.6°C (±0.5°C). Patients
reached the target temperature of 33°C, 4 hours after induction of
TH. Two patients died during maintenance of TH due to refractory
hemodynamic shock. In all patients, SctO2 values started above 65%. Two and a half hours after induction of TH, SctO2 values decreased with
9% (±3%). P284
S Survey on the management of patients treated with therapeutic
hypothermia post cardiac arrest in London hospitals
A Walecka, SC Robert, A Prasad
The Royal Free Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P284 (doi: 10.1186/cc10891) Survey on the management of patients treated with therapeutic
hypothermia post cardiac arrest in London hospitals
A Walecka, SC Robert, A Prasad
The Royal Free Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P284 (doi: 10.1186/cc10891) The target temperature varied from 32 to 35ºC with two (6.7%) ITUs
targeting a temperature of 32ºC, 11 (36.7%) of 33ºC, six (20%) of 34ºC,
one (10%) of 32 to 33ºC, seven (23.4%) of 32 to 34ºC and one (10%) of
34 to 35ºC. The time of cooling varied between 12 and 48 hours. The
cooling period was measured from initiation of cooling by 22 (73.3%)
ITUs and from achievement of target temperature by six (20%) ITUs. Two responders were not sure how it was measured. Twenty-fi ve
(83.3%) units measured core temperature during the cooling. Passive
rewarming was used by 20 (66.6%) responders. Twenty-four (80%)
units maintain normothermia post therapeutic hypothermia. From
additional aspects of the management of the induced hypothermia, 20
(66.6%) ITUs adjusted drug doses while starting TH, 15 (50%) monitored
the depth of sedation, and 17 (56.6%) regularly checked train of four in
paralyzed patients. Shivering was treated with sedation and paralysis
by 25 (83.3%) of responders. Pregnancy status of all women younger
than 50 years old was checked by 10 (33.3%) units. Fifteen (50%) units
do not audit the practice regularly.i Results Of the 32 ITUs contacted, 30 (93.7%) had been using
therapeutic hypothermia following cardiac arrest. Fifteen (50%) of
them were teaching hospitals and the remaining 15 (50%) were district
general hospitals. Twenty-two (73.3%) hospitals had a protocol in place. External cooling was the preferred method used by 28 (93.3%) hospitals. Acknowledgements The study was supported by grant MZO 00179906. References 1. Kim F, et al.: Circulation 2007, 115:3064-3070. 1. Kim F, et al.: Circulation 2007, 115:3064-3070. 2. Skulec R, et al.: Crit Care 2010, 14:R231. 2. Skulec R, et al.: Crit Care 2010, 14:R231. Cerebral oxygenation during induction of therapeutic hypothermia
after cardiac arrest I Meex, J Dens, F Jans, C De Deyne I Meex, J Dens, F Jans, C De Deyne y
Ziekenhuis Oost-Limburg, Genk, Belgium y
Ziekenhuis Oost-Limburg, Genk, Belgium g
g
Critical Care 2012, 16(Suppl 1):P283 (doi: 10.1186/cc10890) Critical Care 2012, 16(Suppl 1):P283 (doi: 10.1186/cc10890) Introduction Induced mild hypothermia (32 to 34°C) improves survival
and neurological outcome after CA. Near-infrared spectroscopy (NIRS)
measures cerebral tissue oxygen saturation (SctO2). As of today, no data
are available on SctO2 monitoring during therapeutic hypothermia
(TH). Therefore, SctO2 was measured in this study during the fi rst
36 hours after CA. Methods After IRB approval, data were collected from 23 patients. Cold
saline (30 ml/kg) was administered as soon as possible after hospital
admission. TH (33°C) was induced by endovascular or surface cooling
and maintained for 24 hours. All patients were sedated (propofol/
remifentanil) for the duration of TH. NIRS sensors were bilaterally
applied to the frontotemporal area before start of TH. Patients were
monitored during induction, maintenance and recovery of TH. Results Of 23 patients, 11 patients did not survive until hospital
discharge due to post-ischemic brain damage. Twelve patients survived
until hospital discharge, of whom eight without any neurological Methods After IRB approval, data were collected from 23 patients. Cold
saline (30 ml/kg) was administered as soon as possible after hospital
admission. TH (33°C) was induced by endovascular or surface cooling
and maintained for 24 hours. All patients were sedated (propofol/
remifentanil) for the duration of TH. NIRS sensors were bilaterally
applied to the frontotemporal area before start of TH. Patients were
monitored during induction, maintenance and recovery of TH. Conclusion There are signifi cant variations in practice between
London hospitals which probably refl ect the ongoing debate on the
optimal management of patients treated with TH. Of note is that 50%
of surveyed hospitals do not audit the current practice regularly which
may have an impact on the quality and eff ectiveness of therapeutic
cooling. g
Reference y
Results Of 23 patients, 11 patients did not survive until hospital
discharge due to post-ischemic brain damage. Twelve patients survived
until hospital discharge, of whom eight without any neurological Therapeutic hypothermia in an out-of-hospital arrest population:
are we selecting appropriately? Conclusion Noninvasive monitoring revealed a decrease in cerebral
oxygenation during induction of mild hypothermia in patients after
cardiac arrest. We observed a diff erence in oxygenation between
hospital survivors and nonsurvivors. Binks AC, et al.: Therapeutic hypothermia after cardiac arrest –
implementation in UK intensive care units. Anaesthesia 2010, 65:260-265. Reference . Binks AC, et al.: Therapeutic hypothermia after cardiac arrest –
implementation in UK intensive care units. Anaesthesia 2010, 65:260-265. S103 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P285
Simplifi ed EEG/aEEG to monitor the injured brain after cardiac
arrest
H Friberg1, M Rundgren1, E Westhall1, N Nielsen2, T Cronberg1
1Lund University, Lund, Sweden; 2Helsingborg Hospital, Helsingborg, Sweden
Critical Care 2012, 16(Suppl 1):P285 (doi: 10.1186/cc10892) maintained for 48 hours and rewarmed to 36°C over another 48 hours. As induction of patients’ sedation, we injected 5 mg midazolam and
0.2 μg fentanyl intravenously just as we recognized patients’ movement
or immediately before induction of TH. For maintenance of sedation,
midazolam at dose 0.1 mg/kg/hour, dexmedetomidine at dose 0.4 μg/
kg/hour and fentanyl at doses 0.8 μg/kg/hour were administrated
continuously. The midazolam and the dexmedetomidine infusion were
adjusted to a target BIS value of 40 or less. BIS monitoring was ceased
after completion of both rewarming and discontinuation of sedative
drugs. maintained for 48 hours and rewarmed to 36°C over another 48 hours. As induction of patients’ sedation, we injected 5 mg midazolam and
0.2 μg fentanyl intravenously just as we recognized patients’ movement
or immediately before induction of TH. For maintenance of sedation,
midazolam at dose 0.1 mg/kg/hour, dexmedetomidine at dose 0.4 μg/
kg/hour and fentanyl at doses 0.8 μg/kg/hour were administrated
continuously. The midazolam and the dexmedetomidine infusion were
adjusted to a target BIS value of 40 or less. BIS monitoring was ceased
after completion of both rewarming and discontinuation of sedative
drugs. Introduction Once hemodynamics is stabilized, the main concern in
the comatose cardiac arrest patient is the status of the brain and the
potential recovery of brain functions. Approximately 30% of comatose
cardiac arrest patients develop electrographic seizures, many of whom
have associated clinical seizures that may be concealed by sedation
and paralyzers. As part of the Lund coma project, we have continuously
monitored and evaluated simplifi ed EEG/aEEG in consecutive
hypothermia-treated cardiac arrest patients. g
Results In all six patients, TH was completed without severe
complication, especially shivering movement and serious hypostatic
pneumonia. Three patients presenting unstable BIS values lower than
10 during TH showed poor neurological outcome, while the other
three patients presenting stable BIS values about 40 showed favorable
neurological outcome. Usefulness of a Bispectral index oriented sedative method without
neuromuscular blocker for therapeutic hypothermia after cardiac
arrest Usefulness of a Bispectral index oriented sedative method withou
neuromuscular blocker for therapeutic hypothermia after cardiac
arrest
S Shiraishi, Y Ohta, T Tagami, Y Ono, T Masuno, H Yokota
Nippon Medical School, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P286 (doi: 10.1186/cc10893) g
p
Results There were 33 PROSC patients: 27 (81%) survived and 14 (42%)
achieved a favorable neurological outcome. The cause of the CPA
was cardiac attack in 17, noncardiac attack in 10, and unknown in six
patients. Average age in the favorable recovery group was signifi cantly
younger than in the poor recovery group (62.5 vs. 70.3, P <0.05). The
favorable group was all the proportion of patients with ventricular
fi brillation (VF) at the scene. Of the 14 that achieved a favorable
neurological outcome, the cause of the CPA was cardiac attack in 12
and unknown in two patients. On the other hand, electrocardiograms
of poor neurological outcome showed VF, pulseless electrical activity,
and asystole. The cause of the CPA was cardiac attack in fi ve, noncardiac
attack in 10, and unknown in four. Average pH of artery blood gas
(ABG) in the favorable recovery group was signifi cantly higher than in
the poor recovery group (7.31 vs. 7.17, P <0.004). The receiver-operator
characteristic curve for pH of ABG on arrival was analyzed. The area
under the curve was 0.76. S Shiraishi, Y Ohta, T Tagami, Y Ono, T Masuno, H Yokota
Nippon Medical School, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P286 (doi: 10.1186/cc10893) Introduction During therapeutic hypothermia (TH) after cardiac
arrest (CA), neuromuscular blockers are often used to prevent or treat
thermogenic shivering [1]. But the following risks due to neuromuscular
paralysis are encountered: prolonged muscle weakness, hypostatic
pneumonia and venous thromboembolism. So we evaluated the
usefulness of Bispectral index (BIS) oriented sedation without
neuromuscular blocker in six cases of post CA patients receiving TH. Methods Six consecutive patients admitted after CA and treated
with TH by the same attending physicians’ group were included. BIS
monitoring was applied immediately after the admission to ER. After
initial resuscitation and radiological examination, including coronary
angiography and angioplasty, patients were admitted to the ICU and
cooled down to a target body temperature of 34°C using a surface
cooling system with an external pad. Target body temperature was Introduction During therapeutic hypothermia (TH) after cardiac
arrest (CA), neuromuscular blockers are often used to prevent or treat
thermogenic shivering [1]. Reference Myoclonic movement or convulsion, regarded
as signs of bad outcome, was observed in two poor neurological
outcome patients. Cough refl ex was observed in two favorable
neurological outcome patients throughout their TH. yp
p
Methods Needle electrodes corresponding to the F3 to P3 and F4 to
P4 leads were applied at admission to the ICU. The Nervus NicoletOne®
monitor (CareFusion Inc.) was used to display the continuous raw
EEG curves as well as the amplitude integrated EEG (aEEG). The EEG
data were available to the treating intensivist and were linked to the
Department of Neurophysiology, where the accumulated data were
interpreted once daily, 5 days a week. Conclusion BIS oriented sedation without neuromuscular blocker is
feasible in maintaining TH for survivors from CA. By keeping muscular
function, both noxious and benefi cial movements are preserved and
these help us to predict neurological outcome and prevent patients
from hypostatic disorders. R f Results Monitoring of aEEG was successfully applied in all patients. Four dominating patterns were defi ned; fl at, continuous, suppression-
burst (SB) and electrographic status epilepticus (ESE) [1]. We identifi ed
three groups of patients: one group with mild brain injury and a good
outcome, characterized by a return of a continuous EEG pattern during
the fi rst 24 hours. A second group with severe brain injury and a poor
outcome had a fl at EEG or a SB pattern during the fi rst 24 hours, which
evolved into alfa-coma or a treatment refractory ESE. In this group,
early myoclonus was common. The third group with a presumed
intermediate brain injury often developed a late ESE during rewarming,
from a continuous and sometimes reactive background EEG. In this
third group, which presented with low brain damage biomarkers and
unremarkable MR brain imaging, there were survivors, some of whom
received prolonged care in the ICU [2]. y
Reference 1. Chamorro et al.: Anesth Analg 2010, 110:1328-1335. 1. Chamorro et al.: Anesth Analg 2010, 110:1328-1335. p
References 1. Rundgren M, et al.: Crit Care Med 2010, 38:1838. 2. Cronberg T, et al.: Neurology 2011, 77:623. 1. Rundgren M, et al.: Crit Care Med 2010, 38:1838. Predictive factors of neurologic outcome in therapeutic
hypothermia after prehospital return of spontaneous circulation
Y Ohta, S Shiraishi, Y Ono, G Matsumoto, T Tagami, T Masuno, H Yokota
Nippon Medical School, Tokyo, Japan
Critical Care 2012 16(Suppl 1):P287 (doi: 10 1186/cc10894) Predictive factors of neurologic outcome in therapeutic
hypothermia after prehospital return of spontaneous circulation
Y Ohta, S Shiraishi, Y Ono, G Matsumoto, T Tagami, T Masuno, H Yokota
Nippon Medical School, Tokyo, Japan
C iti
l C
2012 16(S
l 1) P287 (d i 10 1186/
10894) pp
y
p
Critical Care 2012, 16(Suppl 1):P287 (doi: 10.1186/cc10894) Introduction Induction of hypothermia is generally accepted to
improve neurologic recovery of out-of-hospital cardiopulmonary
arrest (CPA). Early prognostication of post-CPA patients is challenging. The aim of the present study was to evaluate the predictive factors
for neurologic outcome in out-of-hospital cardiac arrest patients who
returned their spontaneous circulation in a prehospital setting (PROSC)
and underwent therapeutic hypothermia (TH). p
g
Conclusion Simplifi ed EEG/aEEG is easily applied and well adapted
to the ICU environment. In combination with the raw EEG, the aEEG
serves as a trend monitor of the injured brain in the comatose patient
after cardiac arrest. The simplifi ed EEG/aEEG helps detect ESE and is
of importance for guiding anticonvulsive treatment. The evolution of
the EEG pattern mirrors the natural recovery of cortical function after
cardiac arrest and gives useful positive as well as negative prognostic
information. Simplifi ed EEG/aEEG serves the needs of the intensivist
and has the potential to become part of a standard monitoring regimen. References y
Methods PROSC patients transported to our institution between
January 2007 and May 2011 were retrospectively analyzed. TH was
performed for all comatose PROSC patients admitted to the hospital
for post-resuscitation care, regardless of the etiology of cardiac arrest
or patient’s age, except for those whose hemodynamic and pulmonary
status could not be maintained. Neurological outcome at 1 month
was compared as a primary end-point using the Pittsburgh cerebral
performance category (CPC) scale and patients were classifi ed into a
favorable outcome group (CPC 1 and 2) or poor outcome group (CPC
3 to 5). Clinical parameters were compared between patients whose
neurologic outcomes were favorable and poor. P290 P290
Noninvasive cerebral oxygenation monitoring during rapid
ventricular pacing in transcutaneous aortic valve implant
J Dens, I Meex, F Jans, H Gutherman, C De Deyne
Ziekenhuis Oost-Limburg, Genk, Belgium
Critical Care 2012, 16(Suppl 1):P290 (doi: 10.1186/cc10897) y
Methods From 30 June 2004 to 30 June 2009, OHCA patients between
18 and 65 years of age treated with TIMH were identifi ed by the Danish
National Patient Registry and intensive unit registrations. Data were
collected from ambulance and hospital records. Employment status
was registered prior to and 1 year after OHCA from the Danish Ministry
of Employment and Welfare database, using fi ve work categories (WC):
WC 1, working full-time and independent of any social welfare; WC 2,
unemployed but able to work; WC 3, on sick leave and receiving social
welfare; WC 4, substantially reduced ability to work: and WC 5, on early
retirement.i Introduction Most recent attention in interventional cardiology is now
directed towards treatment of valvular heart disease. In patients with
high-risk cardiac surgery, transcutaneous aortic valve implantation
(TAVI) could off er a therapeutic solution. Near-infrared spectroscopy
(NIRS) has been introduced as a useful noninvasive cerebral monitoring
technique assessing cerebral oxygenation. As of today, no reports
have been published on the use of any NIRS technology during TAVI
procedures. During valve prosthesis implantation, a cardiac standstill
by rapid ventricular pacing (RVP) is induced to minimize cardiac motion. While RVP is advantageous for valve positioning, a combination of
rapid heart rate and ventricular hypertrophy can induce a complete
loss of cardiac output. In most cases, this hemodynamic defi cit is well
tolerated, due to the brief duration of RVP. But as of today no data are
available on cerebral oxygenation during these critical periods of RVP. Methods We report on 10 consecutive patients (>75 years, major
comorbidities) suff ering from severe aortic stenosis. Bilateral ForeSight
sensors were applied after induction of anesthesia. We were especially
interested if any change in cerebral oxygenation (SctO2 monitoring)
occurred during these RVP periods. Results One hundred and thirty-three patients were identifi ed. Forty
eight patients were excluded from the fi nal analysis, of which 29
patients were not able to work at baseline (WC 3 to 5), 14 patients in
WC 1 to 2 at baseline died in hospital, three patients died after hospital
discharge and two patients had turned 65 years of age at follow-up
and went on regular retirement. Usefulness of a Bispectral index oriented sedative method without
neuromuscular blocker for therapeutic hypothermia after cardiac
arrest But the following risks due to neuromuscular
paralysis are encountered: prolonged muscle weakness, hypostatic
pneumonia and venous thromboembolism. So we evaluated the
usefulness of Bispectral index (BIS) oriented sedation without
neuromuscular blocker in six cases of post CA patients receiving TH. p
p
g
Methods Six consecutive patients admitted after CA and treated
with TH by the same attending physicians’ group were included. BIS
monitoring was applied immediately after the admission to ER. After
initial resuscitation and radiological examination, including coronary
angiography and angioplasty, patients were admitted to the ICU and
cooled down to a target body temperature of 34°C using a surface
cooling system with an external pad. Target body temperature was Conclusion A suitable pH at the time of hospital arrival was associated
with a favorable neurologic outcome among post-cardiac arrest
patients without presumed noncardiac etiology. S104 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P288 times the serum levels, and remained high after the peak of 23,500 pg/
ml at the time of admission. CSF and serum IL-10 levels were high, but
not abnormally high as for IL-6 and IL-8, and decreased with time. The
diff erence in CSF and serum levels, as seen for IL-6 and IL-8, was not
seen for IL-10. P288
Employment status 1 year after out-of-hospital cardiac arrest in
comatose patients treated with therapeutic hypothermia
K Kragholm1, M Skovmoeller1, AL Christensen1, K Fonager2, HH Tilsted2,
H Kirkegaard3, I De Haas1, BS Rasmussen1
1Cardiovascular Research Center, Aalborg, Denmark; 2Aarhus University
Hospital, Aalborg, Denmark; 3Aarhus University Hospital, Skejby, Aarhus,
Denmark
Critical Care 2012, 16(Suppl 1):P288 (doi: 10.1186/cc10895) Conclusion We elucidated the following points concerning the acute
infl ammatory response following severe traumatic brain injury. High
levels of IL-6 and IL-8 are maintained in both CSF and serum. CSF levels
of IL-6 and IL-8 are one or two orders of magnitude greater than serum
levels. Upregulation of IL-10 is minimal in comparison with IL-6 and IL-8,
suggesting that in neuroinfl ammation IL-10 functions poorly as an anti-
infl ammatory cytokine. Introduction Therapeutic-induced mild hypothermia (TIMH) with a
core temperature of 32 to 34°C for 12 to 24 hours for comatose survivors
of out-of-hospital cardiac arrest (OHCA) with ventricular fi brillation or
tachycardia has improved survival and neurologic outcome [1,2]. The
aim of this study was to evaluate the incidence of patients returning to
work 1 year after survival of OHCA treated with TIMH. References Results In all patients, the procedure was technically successfully
performed. Mean SctO2 before RVP was 67% (59 to 71%) and
immediately decreased during RVP to mean 54% (37 to 70%). In seven
patients, RVP resulted in SctO2 decreases below 55% (mean 44%; range
37 to 52%). These decreases lasted for mean 20 minutes (14 seconds to
87 minutes). Systolic blood pressure before RVP was mean 135 mmHg
(95 to 165 mmHg) and decreased to mean 74 mmHg (112 to 42 mmHg)
during RVP. In six patients, RVP resulted in a decrease in systolic blood
pressure below 90 mmHg, which was immediately countered by
vasoactive drugs (adrenaline). In two patients, extensive hypotension
persisted despite vasoactive support and CPR had to be initiated. In
one patient, SctO2 values remained below 55% for 87 minutes and the
patient was declared brain dead 48 hours later. 1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K:
Treatment of comatose survivors of out of hospital cardiac arrest with
induced hypothermia. N Engl J Med 2002, 346:557-563. 2. Hypothemia After Cardiac Arrest Study Group: Mild therapeutic
hypothermia to improve the outcome after cardiac arrest. N Engl J Med
2002, 346:549-556. P291 P291 Changes in cerebrospinal fl uid and serum cytokine levels in severe
traumatic brain injury patients Changes in cerebrospinal fl uid and serum cytokine levels in severe
traumatic brain injury patients
T Saito1, H Kushi2, J Sato1, A Yoshino1, K Tanjo1
1Nihon University, School of Medicine, Tokyo, Japan; 2Nihon University, College
of Humanities and Sciences, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P289 (doi: 10.1186/cc10896) Conclusion Transcutaneous cardiac interventions, especially those
with transient cardiac standstill, can induce longlasting intraprocedural
inadequacy of cerebral perfusion, despite immediate restoration of
normal blood pressure. Future strategies should therefore be focused
on optimalizing cerebral oxygenation before RVP. T Saito1, H Kushi2, J Sato1, A Yoshino1, K Tanjo1
1Nihon University, School of Medicine, Tokyo, Japan; 2Nihon University, College
of Humanities and Sciences, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P289 (doi: 10.1186/cc10896) Introduction Infl ammatory response following brain injury begins
with brain tissue injury triggered neuroinfl ammation, which induces
a systemic infl ammatory response syndrome. We investigated the
characteristics of the acute infl ammatory response following severe
traumatic brain injury through changes in cerebrospinal fl uid (CSF) and
serum cytokine levels. P290 A total of 85 patients in WC 1 to 2 at
baseline were included in the fi nal analysis, of which 55 (64.7%) of these
initially comatose patients with OHCA treated with TIMH had returned
to work 1 year after OHCA. Conclusion Approximately two-thirds of the survivors belonging to WC
1 to 2 at baseline have returned to work at 1 year follow-up after OHCA
treated with TIMH. A larger study is needed to confi rm these results and
to determine predictors of returning to work in comatose patients after
OHCA treated with TIMH. References Table 1 (abstract P291). Model performance Elevated ICP
GOS 1 to 2 static
GOS 1 to 2 dynamic
AUROC
0.87
0.72
0.90
HL P value
0.12
0.51
0.95
Brier scaled
39.4%
7.7%
46% Figure 1 (abstract P292). Receiver operating characteristic curve. Figure 1 (abstract P292). Receiver operating characteristic curve. Conclusion Dynamic data in continuous MAP and ICP monitoring
allows prediction of elevated ICP. Adding information of the fi rst
24 hours of ICP and MAP to known risk factors allows accurate
prediction of neurological outcome at 6 months. R f References
1. Piper I, et al.: Acta Neurochir 2003, 145:615-628. 2. Murray GD, et al.: J Neurotrauma 2007, 24:329-337. 3. CRASH Trial Collaborators: BMJ 2008, 336:425-429. 1. Piper I, et al.: Acta Neurochir 2003, 145:615-628. 2. Murray GD, et al.: J Neurotrauma 2007, 24:329-337. Novel models to predict elevated intracranial pressure during
intensive care and long-term neurological outcome after TBI
F Guiza1, B Depreitere1, I Piper2, G Van den Berghe1, G Meyfroidt1
1UZ Leuven, Belgium; 2Southern General Hospital, Glasgow, UK
Critical Care 2012, 16(Suppl 1):P291 (doi: 10.1186/cc10898) Novel models to predict elevated intracranial pressure during
intensive care and long-term neurological outcome after TBI
F Guiza1, B Depreitere1, I Piper2, G Van den Berghe1, G Meyfroidt1
1UZ Leuven, Belgium; 2Southern General Hospital, Glasgow, UK
Critical Care 2012, 16(Suppl 1):P291 (doi: 10.1186/cc10898) Methods The subjects were 24 patients with severe traumatic brain
injury. We measured levels of the proinfl ammatory cytokines IL-6 and
IL-8, and the anti-infl ammatory cytokine IL-10 in peripheral blood and
CSF on four occasions, at the time of admission and after 24 hours,
72 hours and 1 week. Introduction Elevated intracranial pressure (ICP) episodes are
associated with poor outcome and should be prevented. We developed
models to predict these episodes 30 minutes in advance, and to predict
long-term neurological outcome by using dynamic characteristics of
continuous ICP and mean arterial pressure (MAP) monitoring. Introduction Elevated intracranial pressure (ICP) episodes are
associated with poor outcome and should be prevented. We developed
models to predict these episodes 30 minutes in advance, and to predict
long-term neurological outcome by using dynamic characteristics of
continuous ICP and mean arterial pressure (MAP) monitoring. Results CSF and serum IL-6 levels continued to rise until 72 hours after
admission. CSF IL-6 levels were 50 to 400 times serum levels. Serum
IL-8 levels remained at 20 to 30 pg/ml. CSF IL-8 levels were 100 to 800 S105 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
h
//
f
/
l
/16/S1 http://ccforum.com/supplements/16/S1 Figure 1 (abstract P291). Elevated ICP episode. achieve favourable outcome. In the literature the value of noninvasive
measurement of transcranial Doppler (TCD)-derived pulsatility index
(PI) in predicting increased intracranial pressure remains questionable. The aim of this study was to examine the value of PI in predicting
hydrocephalus in patients with aSAH. Methods The Brain-IT [1] dataset has records for 264 patients from 22
neuro-ICUs in 11 European countries. Logistic regression and Gaussian
processes (machine learning method) were used. CRASH [2] and
IMPACT [3] predictors were used together with dynamic data. Results Predictions of elevated ICP episodes (Figure 1) were externally
validated with good calibration and discrimination (AUROC 0.87). Prediction of poor neurological outcome at 6 months (GOS 1 to 2) with
static data had 0.72 AUROC; adding dynamic information increased
performance to 0.9 (Table 1). Novel models to predict elevated intracranial pressure during
intensive care and long-term neurological outcome after TBI
F Guiza1, B Depreitere1, I Piper2, G Van den Berghe1, G Meyfroidt1
1UZ Leuven, Belgium; 2Southern General Hospital, Glasgow, UK
Critical Care 2012, 16(Suppl 1):P291 (doi: 10.1186/cc10898) Methods In a retrospective cohort study from January 2010 to June
2011, 61 patients with aSAH were diagnosed with hydrocephalus on
CT scan during treatment in our ICU. On 93 occasions of TCD recordings
of the middle cerebral artery, PI was calculated on the same day. y,
y
Results See Table 1 and Figure 1. Ninety-three CT scans could be
correlated with PI on the same day of the scan. Using a cut-off value Transcranial cerebral oximetry in newborn infants on mechanical
ventilation as a method for prevention of hyperoxia and oxidative
stress P295
Deoxyhaemoglobin as a biomarker of cerebral autoregulation
D Highton1, A Ghosh1, I Tachtsidis2, C Kolyva2, J Panovska2, C Elwell2,
M Smith1
1National Hospital for Neurology and Neurosurgery, London, UK; 2UCL,
London, UK
Critical Care 2012, 16(Suppl 1):P295 (doi: 10.1186/cc10902) Deoxyhaemoglobin as a biomarker of cerebral autoregulation
D Highton1, A Ghosh1, I Tachtsidis2, C Kolyva2, J Panovska2, C Elwell2,
M Smith1 1National Hospital for Neurology and Neurosurgery, London, UK; 2UCL,
London, UK Critical Care 2012, 16(Suppl 1):P295 (doi: 10.1186/cc10902) Introduction Cerebral autoregulation (CA) maintains cerebral blood
fl ow over a range of perfusion pressure. Continuous CA monitoring
might defi ne pressure targets minimising secondary brain injury, but
application is limited by available monitoring modalities. Near-infrared
spectroscopy (NIRS) is a noninvasive optical technique characterising
aspects of CA. The NIRS-derived tissue oxygenation index (TOI) is
correlated with blood pressure (BP) to produce an index of vascular
reactivity (TOx) [1]. The contribution from extracerebral tissues, optical
complexity of injured brain and complex physiology represented
by NIRS are likely to limit agreement with other techniques. NIRS-
measured deoxyhaemoglobin (HHb) may have advantages as its
physiological confounds are less complicated and are predominantly
in the cerebral venous circulation. This study compares HHb with
established indices of reactivity – the mean velocity index (Mx) and
oxygen reactivity index (ORx). Results Determined by the age norm, TCO indicators for healthy infants
amounted in the left hemisphere of the brain to 79.2 ± 4.06% (P <0.01),
and in the right hemisphere to 84.89 ± 5.1% (P <0.01). We established
in the group of infants where the mode selection ventilation and FiO2
were carried out on the basis of TCO indicators, an average FiO2 in
the inspired mixture of 21% with an average pO2 in blood capillaries
61.95 ± 20.16%, in contrast to FiO2 55% with pO2 –78.01 ± 18.93% in
patients of group 2. Patients of group 1 showed signifi cantly (in all
cases P <0.01) decreased length of stay on mechanical ventilation (from
9.4 to 5.6 bed-days), compared with the control group. Investigation of
the activity markers of oxidative stress showed three times reduction
of the oxidation products of proteins (AOPP) and twofold reduction of
peroxides in patients in the study group, compared with the control
group, to 10 days of observation (P <0.05). Methods Thirteen brain-injured patients were studied. Transcranial cerebral oximetry in newborn infants on mechanical
ventilation as a method for prevention of hyperoxia and oxidative
stress V Estrin, A Simonova
Scientifi c Research Institute of Obstetrics and Pediatrics, Rostov on Don,
Russia
Critical Care 2012, 16(Suppl 1):P293 (doi: 10.1186/cc10900) Critical Care 2012, 16(Suppl 1):P293 (doi: 10.1186/cc10900) Introduction The aim of this research was the eff ectiveness of
respiratory therapy in infants with respiratory distress syndrome (RDS)
who are ventilated by correcting the oxygen status and parameter
optimization of ventilation by determining the oxygen saturation in
the brain by transcranial cerebral oximetry (TCO). y
Conclusion In this small cohort of patients, the onset of brain death
was accompanied in all cases by a sharp and large decrease in SctO2
from 67% to 55% (mean, n = 5) and remained stable. SctO2 values only
reached minimal values (25%, n = 3) at complete circulatory arrest. Our
data suggest that SctO2 measurement may be helpful in the timing of
the diagnosis of brain death, especially in those patients without ICP or
continuous EEG monitoring. y
y
Methods A total of 24 infants born in the physiological department
of a maternity hospital in RNIIAP was studied. All of the children were
measured for the saturation of brain tissue oxygen (SctL, SctR) with a
cerebral oximeter (ForeSight; USA) at 1, 3 and 5 days after birth. Later
in the study, two groups of newborn infants on mechanical ventilation
were included. Patients of group 1 (n = 38), modes of mechanical
ventilation and FiO2 were determined under control TCO to bring rates
of cerebral oxygenation to the age norm. Patients of group 2 (n = 37),
mode selection and ventilator FiO2 were carried out under the control of
pulse oximetry and partial oxygen tension (pO2) in acid–base balance,
without regard for performance of TCO. In all patients were determined
serum peroxides (Oxystat test; BIOMEDICA GRUPPE, Germany), as well
as the oxidation products of proteins (AOPP) in the serum of a set of
AOPP (Immunodiagnostik, USA) for 1, 5 and 10 days. We measured
blood gas parameters with an automatic analyzer (ABL; Denmark). Transcranial Doppler pulsatility index is a poor predictor of
hydrocephalus in patients with aneurysmal subarachnoid
haemorrhage Negative and positive predictive values were 71.6% resp. 58.3%. The
receiver operating characteristic curve showed an area under the curve
of 0.67. The likelihood ratio for a negative (LR–) resp. positive (LR+) test
was 0.83 resp. 2.94. Pretest probability of 32% increased to 57% post-
test probability with PI >1.4 and decreased to 28% with PI ≤1.4. Conclusion PI with a cut-off value of 1.4 has a poor sensitivity and a
high specifi city. PI has limited value in ruling in and out hydrocephalus
in aSAH patients due to a low LR+ and LR–. yi
Methods We retrospectively analyzed the cerebral oximetry data of
seven patients with severe TBI or diff use cerebral edema who evolved
to brain death while being treated in the ICU. Absolute SctO2 values
were continuously measured with ForeSight technology (Casmed) with
sensors applied bilaterally to the forehead. pp
y
Results Three patients (one TBI and two SAH) with continuous ICP
and SctO2 monitoring suff ered, despite maximal medical treatment,
a sudden (over 1 to 3 hours) increase in mean ICP from 32 mmHg to
91 mmHg (equalization of ICP and MAP). Over the same time period,
a parallel decrease in mean SctO2 from 71% to 54% ICP was observed. One patient (cerebral edema after asphyxia) had continuous EEG and
SctO2 monitoring: a sharp decrease in SctO2 from 67% to 56% over
30 minutes was accompanied by an increase in suppression ratio from
70% to 100%. The absence of cerebral blood fl ow was confi rmed by
CT angiography. One patient (cerebral edema after prolonged CPR)
had only SctO2 measurement for cerebral monitoring: during his stay
in the ICU, there was a sudden decrease in SctO2 from 64% to 54% over
a 90-minute period. Shortly after this, the pupils became dilated and
fi xed. Brain death was confi rmed by full EEG. Three brain-dead patients
with documented absence of cerebral blood fl ow were monitored for
SctO2 during subsequent organ donation procedure: SctO2 remained at
a mean value of 59% during the procedure, and fell sharply only at the
onset of circulatory arrest to reach a stable value of 25%. P293
Transcranial cerebral oximetry in newborn infants on mechanical
ventilation as a method for prevention of hyperoxia and oxidative
stress
V Estrin, A Simonova
Scientifi c Research Institute of Obstetrics and Pediatrics, Rostov on Don,
Russia
Critical Care 2012, 16(Suppl 1):P293 (doi: 10.1186/cc10900) Transcranial Doppler pulsatility index is a poor predictor of
hydrocephalus in patients with aneurysmal subarachnoid
haemorrhage g
MH Kiel, AW Oldenbeuving, M Sluzewski, JA Van Oers, D Ramnarain
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P292 (doi: 10.1186/cc10899) MH Kiel, AW Oldenbeuving, M Sluzewski, JA Van Oers, D Ramnarain
St Elisabeth Hospital, Tilburg, the Netherlands
Critical Care 2012, 16(Suppl 1):P292 (doi: 10.1186/cc10899) Introduction Hydrocephalus is a common complication of aneurysmal
subarachnoid haemorrhage (aSAH). The increase in intracranial
pressure is associated with increased mortality and morbidity. Early
recognition and intervention in these patients is essential in order to Figure 1 (abstract P292). Receiver operating characteristic curve. S106 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P292). The 2×2 table for PI 1.4
Index test
Hydrocephalus +
Hydrocephalus –
Total
PI >1.4
7
5
12
PI ≤1.4
23
58
81
Total
30
63
93 of PI >1.4, sensitivity was low (23.3%) and specifi city was high (92.1%). Negative and positive predictive values were 71.6% resp. 58.3%. The
receiver operating characteristic curve showed an area under the curve
of 0.67. The likelihood ratio for a negative (LR–) resp. positive (LR+) test
was 0.83 resp. 2.94. Pretest probability of 32% increased to 57% post-
test probability with PI >1.4 and decreased to 28% with PI ≤1.4. Conclusion PI with a cut-off value of 1.4 has a poor sensitivity and a
high specifi city. PI has limited value in ruling in and out hydrocephalus
in aSAH patients due to a low LR+ and LR–. Table 1 (abstract P292). The 2×2 table for PI 1.4
Index test
Hydrocephalus +
Hydrocephalus –
Total
PI >1.4
7
5
12
PI ≤1.4
23
58
81
Total
30
63
93 P294
Cerebral oximetry and brain death in the ICU: data from seven cases
N Billet1, I Meex2, M Vanderlaenen1, R Heylen1, W Boer1, C De Deyne1,
FV Jans 1
1Ziekenhuis Oost-Limburg, Genk, Belgium; 2University of Hasselt, Diepenbeek,
Belgium
Critical Care 2012, 16(Suppl 1):P294 (doi: 10.1186/cc10901) g
Critical Care 2012, 16(Suppl 1):P294 (doi: 10.1186/cc10901) Introduction Cerebral oximetry, using near-infrared spectroscopy to
measure cerebral tissue oxygen saturation (SctO2), is being increasingly
used in the ICU. We hypothesized that if a patient becomes brain dead
in the ICU, this must be refl ected in SctO2 values. This might help in
the timing of invasive procedures such as angiography, sometimes
necessary in the confi rmation of brain death. of PI >1.4, sensitivity was low (23.3%) and specifi city was high (92.1%). Study of the acoustic stem evoked potentials in blood circulation
disorder in the vertebral basilar basin I Vlasova, T Vizilo, V Tsiuriupai p
Scientifi c Clinical Center of Miners’ Health Protection, Leninsk-Kuznetsky,
Russia Methods ICU patients mechanically ventilated for at least 3 days were
included. Exclusion criteria: polynomic or autonomic neuropathy,
admission after stroke or cardiac arrest. HRV was investigated using
power spectral analysis of continuous 5-minute ECG recordings [1]. The
simulated SWT was used and wrinkling was assessed on a fi ve-point
scale [2]. Under continuous ECG recording a cold pack was applied to
measure the CFT [3]. Changes in SWT and CFT results over time were
compared to the changes in the SOFA score. Studies procedures were
also performed in 17 healthy controls. Critical Care 2012, 16(Suppl 1):P296 (doi: 10.1186/cc10903) Introduction Acoustic brainstem evoked potentials (ABEP) off er a
possibility to objectivise disorder of the brain stem structure function.l Introduction Acoustic brainstem evoked potentials (ABEP) off er a
possibility to objectivise disorder of the brain stem structure function. Methods There were fl icks of 9.5 Hz with intensity 70 dB higher than
the hearing threshold. The latency time of the I to V peaks, the interpeak
intervals (IPI), the peak amplitudes (PA) and the amplitude correlations
were measured. The clinical neurophysiological assessment of 30
patients (16 men and 14 women, age from 40 to 70 years) with
clinical presentation of ischemic stroke in the vertebral basilar basin
(VBB) allowed us to determine the following forms of acute ischemic
disorders of the brain circulation: transitory ischemic attacks (TIA)
(n = 16), lacunar infarction (LI) (n = 10), and nonlacunar infarction (NLI)
in VBB (n = 4). p
y
Results Twelve patients were included (mean age: 54 (SD: 15)). HRV
analysis showed decreased heart rate variability in all patients (median
total power: 32 ms2 (IQR: 11 to 320)). The SWT could be performed in 10
patients. SWT results were abnormal (score ≤2) in 60% of cases (6% in
healthy controls; P <0.01). The CFT was done in nine patients. Critically
ill patients showed a blunted response on the CFT (2.5% increase in
RR length (95% CI: –0.2% to 5.2%) vs. 7.1% in healthy controls (95% CI:
3.7% to 10.5%; P = 0.03)). Figure 1 displays the CFT results over time. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Photonics). ORx and Mx were derived from continuous correlation
between BP and neuromonitoring [1]. HHb was compared identically
deriving HHBx. Comparisons used Pearson correlation, subsequent
analysis characterised time lags between BP and monitored variables
(0.05 to 0.003Hz) with wavelet lag coherence. of the brainstem were observed. There was a tendency to increase of
the I to III and III to V intervals in 46 to 61% in TIA. The I to III and III to
V IPI were signifi cantly increased in LI and NLI, in 35% and 47% cases
respectively. The patients with NLI demonstrated an increase of the I to
V IPI. There was such neurophysiological dynamics. The reconstruction
of the amplitude and peak latency in TIA was observed in 100% of cases
in the treatment process. This was not registered in LI and NLI. g
Results There was correlation between HHBx (r = –0.62, P <0.01),
ORx (r = 0.52, P <0.05) and Mx. TOx showed no signifi cant correlation
(r = 0.18) as individual recordings demonstrated TOI fl uctuations
paradoxical to other monitoring. The mean lag between BP and HHb
(24 seconds) was shorter than PbrO2 (68 seconds). p
g
Conclusion All strokes in the VBB are characterized by functional
changes on the part of the brain stem structures predominantly
at the pontomedullary and pontomesencephalic levels. There is a
dependence between stroke severity, brainstem structure damage and
neurophysiological dynamics. ABEP allow one to objectivise the brain
stem structure dysfunction in the VBB’s disturbed circulation. 2
Conclusion HHb may provide a surrogate to inform cerebrovascular
reactivity assessment. Complexity in the oxyhaemoglobin component
of TOI may be introduced by vasopressor-related skin artefact or
arterial volume changes [2] explaining poor agreement of TOx. HHb is
theoretically free of this eff ect but will vary with cerebral metabolism,
venous dynamics and oxygenation and demonstrates lag behind
BP changes. Future analyses might compensate using model-based
analysis [3], potentially describing measures of vascular reactivity from
multiple NIRS and neuromonitoring variables, incorporating widely
diff erent aspects of cerebral physiology. P297 Examination of the autonomic nervous system in the ICU: a pilot
study y
L Wieske, E Kiszer, C Verhamme, IN Van Schaik, MJ Schultz, J Horn
Academic Medical Center, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P297 (doi: 10.1186/cc10904) L Wieske, E Kiszer, C Verhamme, IN Van Schaik, MJ Schultz, J Horn
Academic Medical Center, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P297 (doi: 10.1186/cc10904) f
References References
1. Zweifel C, et al.: Stroke 2010, 41:1963-1968. 2. Ogoh S, et al.: Clin Physiol Funct Imaging 2011, 31:445-451. 3. Banaji M, et al.: PLoS Comput Biol 2008, 11:e1000212. Introduction The most widely used test for autonomic dysfunction
in the ICU is the heart rate variability (HRV) test [1]. HRV is thought
to be a very sensitive but less specifi c test [1]. Several other tests are
available. For this pilot study we have investigated the ability of two
tests, the skin wrinkle test (SWT), a test for postganglionic sympathetic
function, and the cold face test (CFT), a refl ex slowing heart rate after
cold application to the forehead, to detect autonomic dysfunction in
critically ill patients alongside the HRV. Transcranial cerebral oximetry in newborn infants on mechanical
ventilation as a method for prevention of hyperoxia and oxidative
stress Ipsilateral
60-minute recordings included intracranial pressure, brain tissue
oxygen (PbrO2), transcranial Doppler and NIRS (NIRO 100; Hamamatsu Conclusion Monitoring of oxygen saturation in the brain tissue by
TCO in infants with RDS reduces the mortality rate and the term of
mechanical ventilation and hyperoxia. S107 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review Among those, one was found to be a duplicate
publication. Seven studies were thus included (n = 404). Four studies
presented data on mortality (3 or 6 months) and four studies used the
GOS (6 or 12 months) as an outcome measure. We found signifi cant
associations between serum GFAP levels and mortality in pooled
analysis of three studies (GMR 14.73 (95% CI 5.93 to 34.12); I2 = 79%),
and between GFAP and GOS ≤3 in three studies (GMR 8.80 (95% CI 3.94
to 19.66); I2 = 77%). Two studies could not be used in pooled analyses:
one presented means of GFAP levels from multiple samplings over time
(GMR 1.98 (95% CI 1.06 to 3.70)) while the other presented the highest
peak levels of GFAP during the acute phase of care (GMR 3.20 (95% CI
1.82 to 5.65)). i
y
Results Among 12,514 citations, we included 55 studies (4,648
patients). Patients suff ered from mild (11.9%, n = 555), moderate (7.9%,
n = 367) and severe (30.4%, n = 1,415) TBI, others being of unknown
severity. Prevalences of pituitary axis dysfunction are reported in
Table 1. Few studies considering mainly moderate/severe TBI patients
were at low risk of bias. Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review j
y
y
F Lauzier1, O Lachance1, B Senay2, I Côté2, P Archambault2, F Lamontagne3,
A Boutin1, L Moore1, F Bernard4, C Gagnon2, D Cook5, AF Turgeon1
1CHA-Hôpital de l’Enfant-Jésus, Université Laval, Québec, Canada; 2Université
Laval, Québec, Canada; 3Université de Sherbrooke, Canada; 4Université de
Montréal, Canada; 5McMaster University, Hamilton, Canada
Critical Care 2012, 16(Suppl 1):P299 (doi: 10.1186/cc10906) Introduction Biomarkers have been proposed as potential prognostic
indicators following a traumatic brain injury (TBI). Among those, glial
fi brillary acidic protein (GFAP) has been one of the most studied. The
objective of this study was to assess the prognostic value of GFAP levels
in patients with moderate to severe TBI. Introduction Pituitary disorders are an often-neglected consequence
of traumatic brain injury (TBI). We systematically reviewed their
prevalence in studies with low risk of bias including moderate/severe
TBI patients. Methods We systematically searched Medline, Embase, Cochrane
Central, Scopus, BIOSIS, TRIP, conference abstracts, bibliography of
selected studies and narrative reviews. Cohort studies including
≥4 patients with moderate or severe TBI and reporting GFAP levels
(sampled within the fi rst 24 hours of care) from any biological tissue
or fl uid, and mortality or Glasgow Outcome Scale (GOS), were eligible. Two independent reviewers screened all citations, selected eligible
studies and extracted data using a standardized data extraction
form. Pooled results from random eff ect models are presented using
geometric mean ratios (GMRs). I2 tests were used to measure statistical
heterogeneity. Methods We searched EMBASE, MEDLINE, Scopus, Cochrane Central
Register, BIOSIS, Trip Database, references of included studies and
narrative reviews. We included cohort studies, cross-sectional studies
and RCTs that tested the integrity of ≥1 pituitary axis in adult victims
of TBI. Two investigators independently reviewed selected citations,
extracted data and assessed the risk of bias. Studies including <10% of
mild TBI victims were considered as involving mainly moderate/severe
TBI patients. Prevalence is reported as weighted mean (lowest and
highest prevalence) in three time-frames: acute (<1 month post TBI),
mid (3 to 12 months) and long-term setting (>12 months). Studies were
considered at low risk of bias if the authors defi ned inclusion/exclusion
criteria, avoided voluntary sampling, and tested >90% of included
patients with proper detailed diagnostic criteria. Studies testing all
pituitary axes were considered as evaluating hypopituitarism, which
was defi ned as the dysfunction of at least one axis. Results We retrieved 4,709 citations and eight studies were deemed
potentially eligible. Study of the acoustic stem evoked potentials in blood circulation
disorder in the vertebral basilar basin P298
Predictive value of glial fi brillary acidic protein for prognosis
in patients with moderate and severe traumatic brain injury: a
systematic review and meta-analysis
E Laroche1, AF Turgeon1, A Boutin1, E Mercier1, F Lauzier1, R Zarychanski2,
L Moore1, J Granton3, P Archambault1, F Lamontagne4, F Rousseau1,
F Légaré1, E Randell5, J Lapointe1, J Lacroix6, D Fergusson7
1Université Laval, Québec, Canada; 2University of Manitoba, Canada; 3University
of Toronto, Ontario, Canada; 4Université de Sherbrooke, Québec, Canada;
5Memorial University, NewFoundland, Canada; 6Université de Montréal, Québec,
Canada; 7Ottawa Hospital Research Institute, Ontario, Canada
Critical Care 2012, 16(Suppl 1):P298 (doi: 10.1186/cc10905) Study of the acoustic stem evoked potentials in blood circulation
disorder in the vertebral basilar basin Results According to the ABEP the common feature in all groups of
patients was the decrease of the correlation of the V PA to I PA that
was signifi cant in 56% cases in NLI, in 47% cases in LI and in 15% cases
in TIA; the decrease of all PA (to 0.12 to 0.15 mkV) was signifi cant in
49% cases in NLI and in 39% cases in LI. A distinct tendency to the
laterality of the peak latency increase in TIA and LI in 49% of cases,
and a signifi cant laterality of the peak latency increase in 35% that
refl ected the dissymmetric disorder of the neuronal acoustic activity y
Conclusion CFT detected autonomic dysfunction in critically ill patients
better than the SWT and was easier to perform. Diagnostic accuracy
and prognostic value need to be investigated. References 1. Buchman TG, et al.: Curr Opin Crit Care 2002, 8:311-315. 2. Wilder-Smith EP, et al.: Clin Neurophysiol 2009, 120:953-958. 3. Reyners AK, et al.: Eur J Appl Physiol 2000, 82:487-492. 1. Buchman TG, et al.: Curr Opin Crit Care 2002, 8:311-315. 2. Wilder-Smith EP, et al.: Clin Neurophysiol 2009, 120:953-958. 3. Reyners AK, et al.: Eur J Appl Physiol 2000, 82:487-492. 1. Buchman TG, et al.: Curr Opin Crit Care 2002, 8:311-315. Figure 1 (abstract P297). Changes in cold face test (CFT) results over time. Figure 1 (abstract P297). Changes in cold face test (CFT) results over time. S108 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion Serum GFAP levels following TBI were signifi cantly higher
in patients showing an unfavourable prognosis (death or GOS ≤3). The small number of studies included precluded further exploration
of statistical heterogeneity. More investigations of the association
between serum GFAP levels and prognosis following TBI are needed
before recommending for routine use for neuroprognostication. Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review Factors
other than methodological quality and TBI severity are likely to explain
the observed wide prevalence ranges. The clinical signifi cance of TBI-
associated pituitary disorders also requires further rigorous evaluation. anticoagulants for 4 weeks along with the induction therapy. They were
assessed for; their clinical presentation, disease severity (progressive or
nonprogressive), hospital course, adverse eff ects of the used treatment
and outcome. Reports of their neuroimaging studies were also
collected. Results Studied patients were 42 (62.76%) boys and 26 (38.23%)
girls. Their mean age was 8.5 ± 3.5 years. The commonest presenting
symptoms were motor defi cit (70%), headache (64%) and fever (20%),
while the commonest presenting neurological signs were hemiparesis
(60%), seizure 55% (focal 35%, generalized 20%), and decreased
level of consciousness (30%). Neuroradiological studies of the brain
revealed: ischemic strokes in 50 children (73.5%), hemorrhagic
strokes in 10 (14.7%) and ischemic–hemorrhagic lesions in eight
(11.8%). Conventional angiography (CA) and/or magnetic resonance
angiography (MRA) at the time of admission revealed that 51 (75%)
patients had nonprogressive and 17 (25%) had evidence of progressive
arteriopathy. Out of the studied patients, 56 (81.5%) survived and
12 (18.5%) died. Male sex, deep coma and intracerebral bleeding
causing severe raised intracranial pressure were poor prognostic signs. Survivors were discharged on oral aspirin and 15 of them commenced
also on azathioprine. On follow-up it was found that out of the 56
survivors, 11 were normal (19.65%), 14 (25%) had minor disabilities,
another 11 (19.65%) had moderate disabilities and 20 (35.7%) had
severe disabilities. P300
Mannose binding lectin defi ciency attenuates neurobehavioral
defi cits following experimental traumatic brain injury
L Longhi1, F Orsini2, N Fedele2, N Stocchetti1, MG De Simoni2
1University of Milano, Milan, Italy; 2Mario Negri Institute, Milan, Italy
Critical Care 2012, 16(Suppl 1):P300 (doi: 10.1186/cc10907) Introduction Mannose binding lectin (MBL) is the activator of the
lectin complement pathway. After cerebral ischemia it has been
shown that MBL could be a mediator of secondary brain damage, in
contrast after traumatic brain injury (TBI) there are data suggesting
that it could be linked to neuroprotection. We tested the hypothesis
that MBL is involved in the pathophysiology of TBI. We characterized (1)
the temporal activation of MBL and (2) the eff ects of its inhibition in a
model of experimental TBI. Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review Table 1 (abstract P299)
Hypopituitarism
GH
ACTH
TSH
Gonadal
ADH
Acute phase
All studies,
58.3% (32.3 to 76.1),
28.7% (8.8 to 77.2),
14.3% (0.7 to 45.7),
9.4% (0 to 40.6),
44.3% (7.7 to 91.7),
12.6% (0 to 27.2),
n (patients)
6 (513)
9 (784)
11 (958)
12 (837)
10 (827)
13 (1821)
Low risk of bias,
71.3% (52.9 to 76.1),
36.8% (8.8 to 77.2),
14.5% (0.7 to 23.6),
10.1% (1.6 to 32.6),
54.3% (23.5 to 80.0),
18.8% (0 to 27.2),
n (patients)
3 (216)
5 (389)
4 (385)
6 (523)
5 (337)
5 (739)
+ moderate/severe,
70.0% (52.9 to 74.3),
36.1% (8.8 to 77.2),
14.5% (0.7 to 23.6),
5.2% (1.6 to 14.7),
61.4% (23.5 to 80.0),
23.8% (0 to 27.2),
n (patients)
2 (170)
4 (321)
4 (385)
4 (406)
3 (220)
4 (303)
Mid-term
All studies,
32.1% (8.9 to 56.4),
14.8% (6.3 to 25.0),
9.7% (0 to 50.0),
4.3% (0 to 22.2),
18.8% (0 to 66.7),
3.8% (0 to 14.0),
n (patients)
9 (608)
11 (643)
12 (669)
11 (629)
15 (792)
11 (691)
Low risk of bias,
–
12.1% (6.3 to 22.2),
16.7% (4.2 to 50.0),
6.1% (0 to 22.2),
25.2% (0 to 56.3),
11.2% (8.3 to 14.0),
n (patients)
5 (231)
4 (215)
5 (231)
5 (218)
2 (98)
+ moderate/severe,
–
12.1% (6.32 to 22.2),
16.7% (4.2 to 50.0),
6.1% (0 to 22.2),
25.2% (0 to 56.3),
8.3% (–),
n (patients)
5 (231)
4 (215)
5 (231)
5 (218)
1 (48)
Long-term
All studies,
29.1% (0.9 to 73.3),
15.0% (0 to 51.8),
10.2% (0 to 64.4),
6.3% (0 to 31.8),
12.2% (0 to 50.0),
2.7% (0 to 18.2),
n (patients)
19 (1418)
27 (1966)
26 (1782)
25 (1698)
25 (1798)
17 (1108)
Low risk of bias,
31.1% (–),
16.6% (7.2 to 28.0),
6.8% (0 to 18.8),
8.2% (1.0 to 20.0),
12.9% (1.5 to 29.3),
5.0% (0 to 6.9),
n (patients)
1 (45)
8 (499)
6 (369)
10 (734)
9 (707)
3 (200)
+ moderate/severe,
31.1% (–),
15.7% (7.2 to 21.7),
7.3% (1.4 to 18.8),
8.6% (1.0 to 20.0),
12.7% (1.5 to 29.3),
6.7% (6.3 to 6.9),
n (patients)
1 (45)
5 (381)
4 (301)
7 (616)
6 (589)
2 (150) S109 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Conclusion Pituitary disorders frequently arise after TBI, but prevalence
remains uncertain due to low overall quality of available data. Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review Methods (1) Male C57/Bl6 mice were subjected to intraperitoneal
anesthesia (pentobarbital, 65 mg/kg) followed by the controlled
cortical impact brain injury model of experimental TBI (injury
parameters: velocity of 5 m/second and 1 mm depth of deformation). MBL immunostaining was evaluated at various time points after TBI:
30 minutes, 1, 6, 12, 24, 48, 96 hours and 1 week using anti MBL-A
and MBL-C antibodies (n = 3). (2) The eff ects of MBL inhibition were
evaluated by comparing functional and histologic outcomes in C57/
Bl6 mice (WT) and in MBL knockout (–/–) mice. Functional outcome was
tested using the Composite Neuroscore and Beam Walk test weekly up
to 4 weeks postinjury (n = 11). Histologic outcome was evaluated by
calculating the contusion volume at 4 weeks postinjury (n = 6). Sham-
operated mice received identical anesthesia without brain injury. Conclusion The spectrum of cPACNS includes progressive and non-
progressive forms. Characteristic features on presentation may predict
later progression and outcome; identify a distinct high-risk cPACNS
cohort; and guide the selection of patients for immunosuppressive
therapy. Further studies are required to substantiate our fi ndings. Changes of ribosomal protein S3 immunoreactivity and its
new expression in microglia in the mice hippocampus afte
lipopolysaccharide treatment
JH Cho, CW Park, HY Lee, MH Won
Kangwon National University, Chuncheonsi, South Korea
Critical Care 2012, 16(Suppl 1):P302 (doi: 10.1186/cc10909) p
j
y
Results We observed a robust MBL-positive immunostaining in the
injured cerebral cortex starting at 30 minutes postinjury and up to
1 week, suggestive of an activation of this pathway following TBI. MBL was observed both at endothelial and tissue levels. Consistently,
injured WT and MBL (–/–) mice showed neurological motor defi cits up
to 4 weeks postinjury when compared to their sham controls. Notably,
MBL (–/–) mice showed attenuated behavioral defi cits when compared
to their WT counterpart at 2 to 4 weeks postinjury (P <0.01 for both
Neuroscore and Beam Walk test). In contrast we observed similar
contusion volumes at 4 weeks postinjury (WT = 15.6 ± 3.2 cm3 and MBL
KO = 13.9 ± 3.2 cm3, P = 0.3). Introduction Lipopolysaccharide (LPS) has been commonly used as
a reagent for a model of systemic infl ammatory response. Ribosomal
protein S3 (rpS3) is a multifunctional protein that is involved in
transcription, metastasis, DNA repair and apoptosis. Prevalence of pituitary disorders associated with traumatic brain
injury: a systematic review In the present
study, we examined the changes of rpS3 immunoreactivity in the
mouse hippocampus after systemic administration of 1 mg/kg LPS. Conclusion We observed that: (1) MBL deposition and/or synthesis
is increased following TBI; and (2) MBL defi ciency is associated with
functional neuroprotection, suggesting that MBL modulation might be
a potential therapeutic target after TBI. Methods Six-week-old male ICR mice were purchased from the Jackson
Laboratory (Bar Harbor, ME, USA). LPS (Sigma, St Louis, MO, USA) was
dissolved in saline, and administered intraperitoneally with 1.0 mg/
kg/10 ml dose. The control animals were injected with the same volume
of saline. Mice (n = 7 at each time point) were sacrifi ced at designated
times (3, 6, 12, 24, 48 and 96 hours after LPS treatment). The brain
tissues were cryoprotected by infi ltration with 30% sucrose overnight. Thereafter, frozen tissues were serially sectioned on a cryostat (Leica,
Wetzlar, Germany) into 30-μm coronal sections, and they were then
collected into six-well plates containing 0.1 M PBS. 30
Azathioprine and aspirin in treatment of childhood primary arterial
stroke: therapeutic benefi ts and side eff ects
A Alhaboob, G Ahmed P303
Neuronal damage using Fluoro-Jade B histofl uorescence and
gliosis in the striatum after various durations of transient cerebral
ischemia in gerbils
JH Cho, CW Park, HY Lee, MH Won
Kangwon National University, Chuncheonsi, South Korea
Critical Care 2012, 16(Suppl 1):P303 (doi: 10.1186/cc10910) P303
Neuronal damage using Fluoro-Jade B histofl uorescence and
gliosis in the striatum after various durations of transient cerebral
ischemia in gerbils P303
Neuronal damage using Fluoro-Jade B histofl uorescence and
gliosis in the striatum after various durations of transient cerebral
ischemia in gerbils g
JH Cho, CW Park, HY Lee, MH Won
Kangwon National University, Chuncheonsi, South Korea
Critical Care 2012, 16(Suppl 1):P303 (doi: 10.1186/cc10910) Introduction Ischemic damage occurs well in vulnerable regions of
the brain, including the hippocampus and striatum. In the present
study, we examined neuronal damage/death and glial changes in the
striatum 4 days after 5, 10, 15 and 20 minutes of transient cerebral
ischemia using the gerbil. Spontaneous motor activity was shown to
be increased with the duration time of ischemia–reperfusion (I-R). y
yp
Conclusion The experimental model of bilateral carotid artery
occlusion and systemic hypotension-induced cerebral ischemia in pigs
is a useful tool to investigate the mechanism of cerebral ischemia and/
or neuroprotection (medications, hypothermia, and so forth). Methods To examine neuronal damage, we used Fluoro-Jade B (F-JB,
a marker for neuronal degeneration) histofl uorescence staining. F-JB-
positive cells were detected only in the 20-minute ischemia group, not
in the other groups. In addition, we examined gliosis of astrocytes and
microglia using antiglial fi brillary acidic protein (GFAP) and anti-ionized
calcium-binding adapter molecule 1 (Iba-1), respectively. P305 Molecular, histological and microcirculatory modeling of cerebral
ischemia in pigs Results Both N2O and xenon administration reduced the number of
ischaemic neurons in the cortex. In xenon-treated rats, fewer ischaemic
neurons were also observed in the CA1 region of the hippocampus. The
xenon group demonstrated a signifi cant reduction of c-fos expression
compared to control and N2O groups. See Figure 1. Molecular, histological and microcirculatory modeling of cerebral
ischemia in pigs
O Suchadolskiene1, A Pranckunas1, B Kumpaitiene1, P Dobozinskas1,
Z Dambrauskas1, V Veikutis2, K Stasaitis1, G Baliutyte3, D Vaitkaitis1,
V Borutaite3
1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Institute of
Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania;
3Institute of Neurosciences, Lithuanian University of Health Sciences, Kaunas,
Lithuania
Critical Care 2012, 16(Suppl 1):P304 (doi: 10.1186/cc10911) O Suchadolskiene1, A Pranckunas1, B Kumpaitiene1, P Dobozinskas1,
Z Dambrauskas1, V Veikutis2, K Stasaitis1, G Baliutyte3, D Vaitkaitis1,
V Borutaite3 O Suchadolskiene1, A Pranckunas1, B Kumpaitiene1, P Dobozinskas1,
Z Dambrauskas1, V Veikutis2, K Stasaitis1, G Baliutyte3, D Vaitkaitis1,
V Borutaite3 1Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Institute of
Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania;
3Institute of Neurosciences, Lithuanian University of Health Sciences, Kaunas,
Lithuania Figure 1 (abstract P305). Regulation of c-fos expression after
administration of N2O or xenon. Critical Care 2012, 16(Suppl 1):P304 (doi: 10.1186/cc10911) Introduction Ischemic brain injury due to stroke and/or cardiac arrest is
a major health issue in modern society requiring urgent development
of new eff ective therapies. The use of appropriate animal models is
essential to study the mechanisms of ischemia-induced injury and
neuroprotection. The goal of our study was to establish a reliable
and reproducible model of brain ischemia in pigs (with the ischemia-
induced microcirculatory, mitochondrial and structural alterations) for
further research. Methods Eighteen pigs (18 to 22 kg) were anesthetized and randomly
assigned to the one of the following groups: 1 – control, 2 – unilateral
carotid occlusion, 3 – bilateral carotid occlusion, 4 – bilateral
carotid occlusion + hypotension (MAP 40 to 50 mmHg). In order to
investigate the eff ects and mechanisms of cerebral ischemia, we
assessed the mitochondrial respiration (high-resolution respirometry),
microcirculation (in vivo SDF videomicroscopy) and histological
structure (light microscopy) of brain tissue in healthy control animals
and after 3 hours of brain ischemia (three diff erent models). Results LEAK respiration (measured in the presence of pyruvate +
malate but without ADP) was not aff ected by ischemia in any model. P305 Delayed post-ischaemic administration of xenon reduces brain
damage in a rat model of global ischaemia
V Metaxa1, R Lagoudaki2, S Meditskou2, O Thomareis2, A Sakadamis2
1St Bartholomew’s Hospital, London, UK; 2Aristotle University, Thessaloniki,
Greece
Critical Care 2012 16(Suppl 1):P305 (doi: 10 1186/cc10912) Results In the 5-minute ischemia group, GFAP-immunoreactive
astro cytes were distinctively increased in number, and the immuno-
reactivity was stronger than that in the sham group. In the 10-minute,
15-minute and 20-minute ischemia groups, GFAP immunoreactivity
was more increased with the duration of I-R. On the other hand, the
immunoreactivity and number of Iba-1-immunoreactive microglia
were distinctively increased in the 5-minute and 10-minute ischemia
groups. In the 15-minute ischemia group, microglia were largest in
size, and the immunoreactivity was highest; however, in the 20-minute
ischemia group, the immunoreactivity was low compared to the
15-minute ischemia group. The results of western blotting for GFAP and
Iba-1 were similar to the immunohistochemical data.i Introduction Cerebral ischaemia is among the leading causes of
death, disability and economic expense in the world. Xenon has been
shown to be neuroprotective both in vivo and in vitro, predominantly
when administered as a preconditioning agent. We have used a rat
model of global ischaemia to investigate whether xenon-induced
neuroprotection is observed following an ischaemic insult. Methods Adult male Wistar rats underwent bilateral common carotid
artery occlusion and were ventilated for 1 hour with 21% O2/78% N2. The animals were randomized to receive 21% O2/78% N2, 50% O2/50%
N2O or 50% O2/50% xenon (n = 10). After a further 45 minutes, they were
killed and their brains were removed for histological, immunochemical
and molecular analysis. The numbers of ischaemic neurons in the
cortex and the hippocampus as well as the expression of c-fos were
evaluated on adjacent brain sections. Conclusion These fi ndings indicate that neuronal death was detected
only in the 20-minute ischemia group 4 days after I-R; in addition, the
change pattern of astrocytes and microglia were apparently diff erent
according to the duration time of I-R. 30
Azathioprine and aspirin in treatment of childhood primary arterial
stroke: therapeutic benefi ts and side eff ects
A Alhaboob, G Ahmed p
g
Results From 6 hours after LPS treatment, rpS3 immunoreactivity was
decreased in pyramidale cells of the hippocampus proper and granule
cells of the dentate gyrus. At this point in time, rpS3 immunoreactivity
began to increase in nonpyramidal cells and nongranule cells in the
hippocampus. From 1 day after LPS treatment, rpS3 immunoreactivity
in pyramidal and granule cells was hardly detected, and nonpyramidal
and nongranule cells showed strong rpS3 immunoreactivity. Based
on double immunofl uorescence staining, microglia, not astrocytes,
expressed strong rpS3 immunoreactivity at 1 and 2 days after LPS
treatment. King Khalid University Hospital and College of Medicine, King Saud University,
Riyadh, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P301 (doi: 10.1186/cc10908) Introduction The objectives were to describe a cohort of children
presenting with medium/large vessel childhood primary angiitis of the
central nervous system (PACNS); to report their short-term neurological
outcome; and to evaluate effi cacy and safety of implemented
management. g
Methods The study included 68 patients, aged less than 16 years. They had their symptoms within 14 days of admission. They
received induction therapy with pulses of intravenous steroids and/
or intravenous immunoglobulin followed by maintenance therapy
with azathioprine and low-dose aspirin. They were also treated with Conclusion
These
results
indicate
that
changes
in
rpS3
immunoreactivity in pyramidal and granule cells and rpS3 expression
in activated microglia after LPS treatment may be associated with the
neuroinfl ammatory responses in the brain. S110 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P303 respectively, resulting in the decrease of RCI (ADP/PM) by 14% and
73%. The OXPHOS capacity with succinate as substrate remained
constant after unilateral carotid artery occlusion but decreased by 53%
after bilateral carotid artery occlusion and hypotension compared to
the control level (P <0.05, n = 3 to 6). Mitochondrial respiration rates
after addition of atractyloside and cytochrome c were the same in all
experimental groups, suggesting that intactness of mitochondrial outer
membrane was not aff ected by cerebral ischemia. Microcirculatory and
histological alterations also demonstrated increasing derangement
and reversible structural changes after bilateral carotid occlusion and
vascular occlusion combined with systemic hypotension. Seizures in the respiratory ICU: single-center study of patients with
new-onset seizures
D Talwar, V Nair, J Chudiwal
Metro Center for Respiratory Diseases, Noida, India
Critical Care 2012, 16(Suppl 1):P306 (doi: 10.1186/cc10913) Seizures in the respiratory ICU: single-center study of patients with
new-onset seizures
D Talwar, V Nair, J Chudiwal
Metro Center for Respiratory Diseases, Noida, India
Critical Care 2012, 16(Suppl 1):P306 (doi: 10.1186/cc10913) Methods In this prospective, randomized, double-blind and placebo-
controlled trial critically ill patients with clinical evidence for incipient
CIP, a diagnosis of SIRS/sepsis and failure of at least two organ
systems were randomized to be treated either with IgM-enriched
IVIG or with human albumin 1% as placebo over a period of 3 days. The primary objective was to demonstrate that administration of IVIG
prevents and/or mitigates CIP in critically ill patients, measured by
electrophysiological stimulation of the median, ulnar and tibial nerves
on days 0, 4, 7 and 14. Electrophysiological measures were graded
according to compound muscle action amplitude size (CIP score) of the
respective nerve. Secondary objectives were mortality from any cause
within a 28-day period and lengths of ICU stay. D Talwar, V Nair, J Chudiwal Critical Care 2012, 16(Suppl 1):P306 (doi: 10.1186/cc10913) Introduction New-onset seizures in the ICU are a diagnostic and
management challenge as patients have multiple comorbidities and
receive various antibiotics. In the respiratory ICU with diff erent patient
profi les, etiopathogenesis of seizures is unreported.i i
g
Methods We retrospectively analyzed the profi le of 3,342 patients
admitted to the RICU from 2006 to 2011. A computerized search
revealed 79 patients (2.4%) with new-onset seizures. Complete clinical,
laboratory, radiological and treatment profi les were recorded and
statistically analyzed using the chi-square test, odds ratio and relative
risk of individual variable. Results Thirty-eight critically ill patients were included and randomized
to either receiving IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics including CIP score on day 0 were similar
between the two groups. CIP could not be improved signifi cantly by
IVIG treatment for three consecutive days, represented by similar CIP
scores of all three measured nerves on days 4, 7 and 14 in the IVIG and
the placebo group. Mean CIP score levels of all three nerves signifi cantly
increased from baseline to day 4 in both groups. Results Of 79 patients, 44 patients (55.7%) were males and the mean
age was 61.28 ± 19.57 years. Severe sepsis was diagnosed in 32 (40.5%)
and multiorgan failure in 19 (24.1%). Head CT done in 65 (82.3%)
patients was reported abnormal in 34 (52.3%; P = 0.072) patients. Intracranial pressure monitoring in acute liver failure:
a retrospective cohort study Intracranial pressure monitoring in acute liver failure:
a retrospective cohort study
C Karvellas1, O Fix2, H Battenhouse3, V Durkalski3, C Sanders4, W Lee4
1University of Alberta, Edmonton, Canada; 2UCSF, San Francisco, CA, USA;
3Medical University of South Carolina, Charleston, SC, USA; 4University of
Texas-Southwestern, Dallas, TX, USA
Critical Care 2012, 16(Suppl 1):P308 (doi: 10.1186/cc10915) Table 1 (abstract P306). Attributable causes of seizures in RICU cases (n = 79) Table 1 (abstract P306). Attributable causes of seizures in RICU cases (n = 79)
Anoxia
8
10.1%
Metabolic
15
19.0%
Drugs only
16
20.3%
CNS infection
5
6.3%
Trauma
2
2.5%
Alcohol
5
6.3%
Multiple
22
27.8%
Miscellaneous
6
7.6% ,
,
,
Critical Care 2012, 16(Suppl 1):P308 (doi: 10.1186/cc10915 Introduction Intracranial hypertension (ICH) complicates roughly 25%
of acute liver failure (ALF) patients with grade III/IV encephalopathy. Intracranial pressure (ICP) monitoring is controversial due to
complications in 5 to 20% and absence of documented mortality
benefi t. i
Methods Using prospectively collected data from the US Acute Liver
Study Group registry, we reviewed 630 ALF patients with severe
encephalopathy (grade III/IV) and INR >1.5 enrolled between 1 March
2004 through 31 August 2011. ICP monitoring was used in 143 patients
(23%); 487 control patients with grade III/IV hepatic coma (n = 487)
were not monitored. Conclusion New-onset seizure in RICU cases is multifactorial in origin. Use of levofl oxacin in combination had the highest relative risk of
developing seizure although when given alone the risk is rare (2.1%). Severe sepsis with multiorgan failure being seen in nearly one-half of
RICU cases may decrease seizure threshold in these patients. Results The most common etiology of ALF was acetaminophen (51%,
P = 0.13 between groups). Of ICP monitored (ICPM) patients, 85%
(n = 121) received devices within 24 hours of admission to study. ICPM
patients were signifi cantly younger (36 ± 6 years vs. 43 ± 15 years,
P <0.001) than controls, more likely to be on renal replacement therapy
(48% vs. 31%, P <0.001) but less likely to be on vasopressors (20% vs. 32%, P = 0.008). ICPM patients were given more ICH directed therapies
(mannitol 43% vs. 13%, hypertonic saline 21% vs. 6%, hypothermia 29%
vs. 11%, P <0.001 for each comparison). For ICPM patients, the median
INR on the day of monitor insertion was 2.2 (1.6 to 2.9) and platelet
count 116 (84 to 171); 74% were given FFP (vs. Molecular, histological and microcirculatory modeling of cerebral
ischemia in pigs The OXPHOS capacity with pyruvate + malate as substrates decreased
by 20% and 79% compared to the control level after bilateral carotid
artery occlusion and bilateral carotid occlusion + hypotension, Methods Eighteen pigs (18 to 22 kg) were anesthetized and randomly
assigned to the one of the following groups: 1 – control, 2 – unilateral
carotid occlusion, 3 – bilateral carotid occlusion, 4 – bilateral
carotid occlusion + hypotension (MAP 40 to 50 mmHg). In order to
investigate the eff ects and mechanisms of cerebral ischemia, we
assessed the mitochondrial respiration (high-resolution respirometry),
microcirculation (in vivo SDF videomicroscopy) and histological
structure (light microscopy) of brain tissue in healthy control animals
and after 3 hours of brain ischemia (three diff erent models). Results LEAK respiration (measured in the presence of pyruvate +
malate but without ADP) was not aff ected by ischemia in any model. The OXPHOS capacity with pyruvate + malate as substrates decreased
by 20% and 79% compared to the control level after bilateral carotid
artery occlusion and bilateral carotid occlusion + hypotension, Figure 1 (abstract P305). Regulation of c-fos expression after
administration of N2O or xenon. S111 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 of the mobilization phase. Although the exact etiopathogenesis has
not yet been fully elucidated, sepsis, systemic infl ammatory response
syndrome, and multiple organ failure seem to play an important
role. CIP is diagnosed by signs of denervation in electromyography. Although there is no causal treatment for CIP, retrospective data
suggest that early IgM-enriched intravenous immunoglobulin (IVIG)
application may prevent or mitigate CIP. Therefore we aimed to
investigate the use of IVIG in the early treatment of CIP in critically ill
patients in a prospective, randomized, double-blind and placebo-
controlled setting. of the mobilization phase. Although the exact etiopathogenesis has
not yet been fully elucidated, sepsis, systemic infl ammatory response
syndrome, and multiple organ failure seem to play an important
role. CIP is diagnosed by signs of denervation in electromyography. Although there is no causal treatment for CIP, retrospective data
suggest that early IgM-enriched intravenous immunoglobulin (IVIG)
application may prevent or mitigate CIP. Therefore we aimed to
investigate the use of IVIG in the early treatment of CIP in critically ill
patients in a prospective, randomized, double-blind and placebo-
controlled setting. Molecular, histological and microcirculatory modeling of cerebral
ischemia in pigs Conclusion In our model of global cerebral ischaemia, the administration
of xenon reduced the number of ischaemic neurons compared to
control, both in the cerebral cortex and in the hippocampus. 1. Wilhelm S, et al.: Eff ects of xenon on in vitro and in vivo models of neuronal
injury. Anesthesiology 2002, 96:1485-1489. Seizures in the respiratory ICU: single-center study of patients with
new-onset seizures
D Talwar, V Nair, J Chudiwal
Metro Center for Respiratory Diseases, Noida, India
Critical Care 2012, 16(Suppl 1):P306 (doi: 10.1186/cc10913) Lumbar puncture was done in 40 (50.6%) with fi ve (12.5%) patients
having meningitis. Thirteen of 37 (35.1%) patients showed focal
activity on EEG (P = 0.27; OR = 1.73). Electrolyte abnormalities were:
hypermagnesemia in 20 patients (25.3%), hypocalcemia in 17 patients
(21.5%), and hypernatremia in 13 patients (16.5%), hyponatremia
in three patients (3.8%) and hypomagnesia in four (5.17%) cases. The antibiotics received revealed 27 (34.2%; RR = 1.27) patients on
levofl oxacin alone or in combination. Twenty-eight of 79 (35.4%)
patients were on carbapenems with meropenem in 23/79 (29.1%;
RR = 1.21) and imipenem in 5/79 (6.32%; RR = 0.41). See Table 1. y
g
p
Conclusion Results suggest that early treatment with IVIG neither
signifi cantly improves CIP nor infl uences the length of stay or mortality
in critically ill patients. Consistent with the literature, CIP deteriorated
during the course of disease in critically ill patients with a diagnosis of
SIRS/sepsis and failure of two organ systems. P308 Intracranial pressure monitoring in acute liver failure:
a retrospective cohort study 46% controls, P <0.001)
and 19% (vs. 14% controls, P = 0.14) received platelets. ICP monitoring
was also strongly associated with listing (78% vs. 27%, P <0.001) and
receipt of liver transplant (42% vs. 18%, P <0.001). Twenty-one-day
mortality was similar between ICPM patients (33%) and controls (37%, Retrospective observation of 6-month survival following
decompressive craniectomy in a London major trauma and stroke
centre We will now
prospectively collect these data including quality-of-life measures. References
1. Cooper DJ, et al.: N Engl J Med 2011, 364:1493-1502. 2. Hofmeijer J, et al.: Lancet Neurol 2009, 8:326-333. P310
Feasibility of a multicenter prospective cohort study on the
evaluation of prognosis in severe traumatic brain injury
AF Turgeon1, F Lauzier1, M Thibodeau1, A Rigamonti2, M Meade3,
F Bernard4, K Burns2, K Reddy3, D Scales2, L McIntyre5, R Green6,
D Griesdale7, L Moore1, M Savard1, D Jichici3, J Paquet1, D Zygun8,
D Fergusson5, for the Canadian Critical Care Trials Group5
1Université Laval, Québec, Canada; 2University of Toronto, Ontario, Canada;
3McMaster University, Ontario, Canada; 4Université de Montréal, Québec,
Canada; 5University of Ottawa, Ontario, Canada; 6University Dalhousie,
Nova Scotia, Canada; 7University of British Columbia, Canada; 8University of
Calgary, Alberta, Canada
Critical Care 2012, 16(Suppl 1):P310 (doi: 10.1186/cc10917)
Introduction Conducting prospective research in severe traumatic
brain injury (TBI) patients is challenging To prepare for a large-scale Table 1 (abstract P309) P311 Table 1 (abstract P309)
Neurosurgical/
Total Hospital
6-month
MCA
Year
total
DC
survival
survival
TBI
stroke
Other
2006
292/1,839
2
2
2
1
0
1
2007
298/1,652
2
2
2
0
2
0
2008
286/1,563
11
10
8 (1N/A)
7
4
0
2009
493/1,840
18
11
10
7
8
3
2010
505/1,835
21
16
15 (1N/A)
11
9
1
2011
274/918
17
7
5 (2N/A)
7
10
0
5.5-year 2,148/9,647
71
48
42 (4N/A)
33
33
5
data Predictive value of neuron-specifi c enolase following moderate
and severe traumatic brain injury: a systematic review and
meta-analysis
E Mercier1, AF Turgeon1, A Boutin1, F Lauzier1, R Zarychanski2,
P Archambault1, J Granton3, F Lamontagne4, L Moore1, F Rousseau1,
F Légaré1, E Randell5, J Lacroix6, J Lapointe1, D Fergusson7
1Université Laval, Québec, Canada; 2University of Manitoba, Canada; 3Université
of Toronto, Ontario, Canada; 4Université de Sherbrooke, Québec, Canada;
5Memorial University, NewFoundland, Canada; 6Université de Montréal, Québec,
Canada; 7Ottawa Hospital Research Institute, Ontario, Canada
Critical Care 2012, 16(Suppl 1):P311 (doi: 10.1186/cc10918) Introduction Biomarkers such as the neuron-specifi c enolase (NSE)
have been proposed as potential prognostic markers following
traumatic brain injury (TBI) [1,2]. However, the use of NSE is not
currently recommended for prognostic evaluation. Our objective was
to systematically review the prognostic value of NSE levels following
moderate or severe TBI. Conclusion Survival following DC in this institution compares
favourably with published data. Reduced survival in 2011 may be
a case-mix eff ect related to increased tertiary referrals. We will now
prospectively collect these data including quality-of-life measures. References Methods We systematically searched MEDLINE, Embase, Cochrane,
Biosis, Scopus, Trip, references of eligible studies, reviews and
conference proceedings. Eligible studies were cohort studies
including ≥4 patients with moderate or severe TBI having measured
the association between NSE levels (fi rst 24 hours) and mortality or
the Glasgow Outcome Scale (GOS). Independently, two reviewers
selected studies and extracted data using a standardized form. Pooled results using random-eff ect models were used using weighted
mean diff erences (WMD); heterogeneity was assessed using I2 tests. Sensitivity analyses were planned to explain statistical heterogeneity
(for example, extracerebral injuries). P307 P307
Early treatment with intravenous immunoglobulins in patients with
critical illness polyneuropathy: a randomized controlled, double-
blinded study
R Brunner, W Rinner, R Kitzberger, T Sycha, J Warszawska, U Holzinger,
C Madl
Medical University of Vienna, Austria
Critical Care 2012, 16(Suppl 1):P307 (doi: 10.1186/cc10914) Introduction Critical illness polyneuropathy (CIP) is a severe
complication of critical illness. The clinical features of CIP are muscle
weakness and atrophy causing delayed weaning and prolongation S112 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P = 0.33) when all or only nontransplanted patients (46% vs. 45%,
0.8) were considered. Of 66 ICPM patients with detailed information,
18 (29%) had evidence of ICH (ICP >25 mmHg) at the time of ICPM
insertion (maximum ICP on day 1 ~18 (12 to 26) mmHg). Of 49 patients
with a known ICPM device, 14 patients received epidural catheters, six
subdural, 11 intraparenchymal, seven intraventricular and 11 lumbar
monitors. In only one of 49 ICPM patients was intracranial hemorrhage
reported, and this patient survived. multicenter study to evaluate long-term prognosis in severe TBI,
we conducted a prospective pilot study evaluating the patterns of
enrollment, the compliance to the schedule of prognostic tests and the
completeness of follow-up for 6-month functional outcome measures. Methods We conducted a pilot study in nine level I trauma centers in
Canada. Adult patients with severe TBI expected to require mechanical
ventilation for ≥48 hours were enrolled on their fi rst day in the ICU. Prognostic tests were performed on arrival (CT scan), day 1 (serum
biomarker), day 3 (serum biomarker, CT scan) and day 7 (serum
biomarker, CT scan, MRI, SSEP, EEG) with time windows of 24 or 48 hours
depending on the test. Prognostic measures were collected during the
fi rst week in the ICU to examine the association with the extended
Glasgow Outcome Scale score. We considered as appropriate a
compliance to the schedule of prognostic tests ≥90% and a proportion
of lost to follow-up <10%. We obtained REB approval from participating
centers and written informed consent from SDMs. multicenter study to evaluate long-term prognosis in severe TBI,
we conducted a prospective pilot study evaluating the patterns of
enrollment, the compliance to the schedule of prognostic tests and the
completeness of follow-up for 6-month functional outcome measures. P310 Feasibility of a multicenter prospective cohort study on the
evaluation of prognosis in severe traumatic brain injury
AF Turgeon1, F Lauzier1, M Thibodeau1, A Rigamonti2, M Meade3,
F Bernard4, K Burns2, K Reddy3, D Scales2, L McIntyre5, R Green6,
D Griesdale7, L Moore1, M Savard1, D Jichici3, J Paquet1, D Zygun8,
D Fergusson5, for the Canadian Critical Care Trials Group5
1Université Laval, Québec, Canada; 2University of Toronto, Ontario, Canada;
3McMaster University, Ontario, Canada; 4Université de Montréal, Québec,
Canada; 5University of Ottawa, Ontario, Canada; 6University Dalhousie,
Nova Scotia, Canada; 7University of British Columbia, Canada; 8University of
Calgary, Alberta, Canada
C iti
l C
2012 16(S
l 1) P310 (d i 10 1186/
10917) P307 Methods We conducted a pilot study in nine level I trauma centers in
Canada. Adult patients with severe TBI expected to require mechanical
ventilation for ≥48 hours were enrolled on their fi rst day in the ICU. Prognostic tests were performed on arrival (CT scan), day 1 (serum
biomarker), day 3 (serum biomarker, CT scan) and day 7 (serum
biomarker, CT scan, MRI, SSEP, EEG) with time windows of 24 or 48 hours
depending on the test. Prognostic measures were collected during the
fi rst week in the ICU to examine the association with the extended
Glasgow Outcome Scale score. We considered as appropriate a
compliance to the schedule of prognostic tests ≥90% and a proportion
of lost to follow-up <10%. We obtained REB approval from participating
centers and written informed consent from SDMs. p
p
Conclusion In ALF patients, ICP monitor placement is strongly
associated with liver transplantation but not with overall or transplant
free mortality. In the absence of ICP monitoring, ALF patients may be
less aggressively treated for intracranial hypertension. The value of
ICP monitoring in ALF remains to be determined but ICPM placement
clearly aff ects the frequency of interventions for elevated ICP. Retrospective observation of 6-month survival following
decompressive craniectomy in a London major trauma and stroke
centre Results Among 116 consecutive eligible patients, 50 were enrolled over
a total of 204 weeks of screening between May 2010 and May 2011. Two centers used a deferred consent approach. Patients were primarily
male with a median age of 45 years and a GCS of 5 (25th to 75th: 3
to 7). The two main reasons for nonenrollment were the time window
for inclusion being after regular working hours (35%, n = 23) and
oversight (24%, n = 16). The compliance to the diff erent tests ranged
from 93 (three missing tests) to 100%. All blood samples but one (day
7) were performed. The main reason for missing a test was the patient’s
instability (hemodynamic or increased ICP) (n = 5). In six patients, the
MRI had to be delayed due to the presence of material not compatible
with the procedure. No patient was lost to follow-up at 6 months. J Dawson, P Hopkins, J Ling, D Walsh, C Tolias
King’s Health Partners, London, UK
Critical Care 2012, 16(Suppl 1):P309 (doi: 10.1186/cc10916) Introduction This study describes 5.5 years of retrospective data
examining hospital and 6-month outcome of patients following
decompressive craniectomy (DC). The eff ectiveness of DC remains
uncertain with confl icting results in patients with TBI and stroke [1,2]. Methods Data were drawn (1 January 2006 to 30 June 2011) from three
hospital databases following approval by the institutional board. Results There were 2,148 neurosurgical admissions with 71 undergoing
DC. Forty-eight of 71 (67.6%) survived to hospital discharge and 21/33
in both TBI and stroke groups survived to 6 months. See Table 1. Conclusion These results demonstrate the feasibility of enrollment and
complying to a structured protocol of prognostic tests in a prospective
multicenter study in severe TBI patients. Table 1 (abstract P309)
Neurosurgical/
Total Hospital
6-month
MCA
Year
total
DC
survival
survival
TBI
stroke
Other
2006
292/1,839
2
2
2
1
0
1
2007
298/1,652
2
2
2
0
2
0
2008
286/1,563
11
10
8 (1N/A)
7
4
0
2009
493/1,840
18
11
10
7
8
3
2010
505/1,835
21
16
15 (1N/A)
11
9
1
2011
274/918
17
7
5 (2N/A)
7
10
0
5.5-year 2,148/9,647
71
48
42 (4N/A)
33
33
5
data
Conclusion Survival following DC in this institution compares
favourably with published data. Reduced survival in 2011 may be
a case-mix eff ect related to increased tertiary referrals. P312
Blood–brain barrier permeability following traumatic brain injury
M Jungner, P Bentzer
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P312 (doi: 10.1186/cc10919) Blood–brain barrier permeability following traumatic brain injury
M Jungner, P Bentzer
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P312 (doi: 10.1186/cc10919) Introduction There is substantial evidence to suggest that oxidative
stress is associated with cerebral vasospasm following subarachnoid
hemorrhage (SAH). Urinary 8-OHdG is the most common biomarker of
DNA damage by oxidative stress. The aim of this study was to determine
whether 8-OHdG is a good indicator of vasospasm occurrence
following SAH. y
Critical Care 2012, 16(Suppl 1):P312 (doi: 10.1186/cc10919) Introduction Brain edema and intracranial hypertension is deleterious
after traumatic brain injury (TBI), but the underlying pathophysiology
is complex and poorly understood. One major subject of controversy
is the time course and extent of blood–brain barrier dysfunction
following trauma, and previous studies in humans have only provided
semi-quantitative data. The objective of the present study was
therefore to quantify changes in blood–brain barrier permeability in
the early course of TBI. Methods The subjects were 23 patients who received surgical clipping
or endovascular coiling within 24 hours after the onset of SAH. We
classifi ed the patients according to the occurrence of angiographic
vasospasm. We examined the urinary 8-OHdG levels with high-
performance liquid chromatography for 10 days following SAH. The
urinary 8-OHdG levels were adjusted according to serum creatinine
levels. Methods Seventeen nonconsecutive brain trauma patients and
two controls were included in this prospective observational study. Following i.v. injection of iohexol and CT perfusion scans, patients were
scanned eight times from 4 to 25 minutes. The blood-to-brain transfer
constant (Ki) for iohexol, refl ecting permeability and area available for
diff usion, was calculated by Patlak plot analysis of the enhancement
curves of intracerebral large venous vessels and pericontusional brain
parenchyma. Results The urinary 8-OHdG levels were elevated on day 2 compared
with those on day 1 only in the vasospasm (+) group. The urinary 8-OHdG
levels in the vasospasm (+) group were signifi cantly higher than those
in the nonvasospasm (–) group on days 1, 2, 8 and 9. Furthermore,
we examined the correlations between the urinary 8-OHdG levels
on admission to the ICU and the grades of the World Federation of
Neurologic Surgeons and Fisher, but none were observed. Discussion
An elevated urinary 8-OHdG level on day 2 was observed only in the
vasospasm group. Therefore, we speculated that free radicals may
have a role in inducing vasospasm in the early phase following SAH. Feasibility of a multicenter prospective cohort study on the
evaluation of prognosis in severe traumatic brain injury Results We retrieved 4,711 citations and included 22 studies (n = 757). Seventeen studies used the GOS as an outcome measure while 10
studies reported mortality. Most studies evaluated outcomes at
6 months or beyond (range: 1 to 12 months). Ten studies could not
be included in the pooled analyses: three reported mean levels of
serial samplings, two presented peak levels, two reported medians,
one did not report any measure of dispersion and data could not be
extracted from two studies. We observed a signifi cant association
between serum NSE levels and mortality (fi ve studies: WMD 25.90 (95% Critical Care 2012, 16(Suppl 1):P310 (doi: 10.1186/cc10917) Introduction Conducting prospective research in severe traumatic
brain injury (TBI) patients is challenging. To prepare for a large-scale S113 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 CI 15.97 to 35.83), I2 = 60%) and GOS ≤3 (10 studies: WMD 17.69 (95%
CI 12.14 to 23.24), I2 = 64%). Similar results were found with or without
extracerebral injuries. The number of studies included in pooled
analyses precluded performing relevant sensitivity analyses.i References References
1. Patlak et al.: Graphical evaluation of blood-to-brain transfer constants from
multiple-time uptake data. J Cereb Blood Flow Metab 1983, 3:1-3. 2. Maeda et al.: Ultra-early study of edema formation in cerebral contusion
using diff usion MRI and ADC mapping. Acta Neurochir Suppl 2003,
86:329-331. Conclusion We observed a signifi cant association between serum
NSE levels and unfavorable outcomes (mortality or GOS ≤3) not
infl uenced by extracerebral injuries. Further studies need to evaluate
the usefulness of serum NSE levels for prognosis assessment in TBI and
its potential impact on clinical decision-making. R f 1. Papa L, et al.: Use of biomarkers for diagnosis and management of
traumatic brain injury patients. Exp Opin Med Diagn 2008, 2:937-945. P313 P313
Can urinary 8-OHdG be a good indicator of vasospasm occurrence
following subarachnoid hemorrhage? K Ikeda, T Ikeda, H Taniuchi, S Suda, Y Ikeda, H Jimbo
Tokyo Medical University, Hachioji Medical Center, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P313 (doi: 10.1186/cc10920) 2. Zitnay GA, et al.: Traumatic brain injury research priorities: the Conemaugh
International Brain Injury Symposium. J Neurotrauma 2008, 25:1135-1152. 2. Zitnay GA, et al.: Traumatic brain injury research priorities: the Conemaugh
International Brain Injury Symposium. J Neurotrauma 2008, 25:1135-1152. P312
Blood–brain barrier permeability following traumatic brain injury
M Jungner, P Bentzer
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P312 (doi: 10.1186/cc10919) The urinary 8-OHdG levels were higher in the vasospasm group than
in the nonvasospasm group, but we did not fi nd any correlation with
severity of SAH. We suspect that the higher urinary 8-OHdG levels on
days 8 and 9 in the vasospasm group indicated ischemic brain injury
after vasospasm. Results Fourteen patients were included within 1 day and three were
included within 5 days of the injury. In nonischemic tissue surrounding
contusions and hematomas, Ki was focally increased in 11 of all included
trauma patients and in six of seven patients with raised intracranial
pressure. In noninjured areas and in controls, Ki was about 0.06 ml/
minute/100 g and increased by 100 to 2,000% in pericontusional tissue. See Figure 1. g
Conclusion TBI is associated with early focal increases in blood–brain
barrier permeability. The results suggest that in the injured brain,
capillary hydrostatic and oncotic pressures are likely to infl uence
edema formation. Conclusion We believe that oxidative stress has a role in the
development of cerebral vasospasm and that urinary 8-OHdG may be a
good indicator of vasospasm occurrence following SAH. Figure 1 (abstract P312). CBF (left) and permeability (right) maps, and contrast-enhanced CT scan (middle). igure 1 (abstract P312). CBF (left) and permeability (right) maps, and contrast-enhanced CT scan (middle). S114 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P314
Cortical capillary recruitment by rosuvastatin in experimental brain
trauma is associated with increased NO production
P Bentzer, M Jungner
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P314 (doi: 10.1186/cc10921) P314 P314
Cortical capillary recruitment by rosuvastatin in experimental brain
trauma is associated with increased NO production
P Bentzer, M Jungner
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P314 (doi: 10.1186/cc10921) Results We excluded two patients with bleeding for more than
72 hours. There was no signifi cant change in the levels of CK total, renal
or liver function. We included 21 patients, 11 in the SVT group and
nine in the control group. The mortality was eight patients (38%), six
patients in the control group and two of the SVT group. Vasospasm was
confi rmed by cerebral arteriography examination in four patients in the
control group and one patient in the SVT group. All patients that had a
bad outcome (death) had Fisher IV scale. P312
Blood–brain barrier permeability following traumatic brain injury
M Jungner, P Bentzer
Lund University, Lund, Sweden
Critical Care 2012, 16(Suppl 1):P312 (doi: 10.1186/cc10919) Introduction Microvascular dysfunction, characterized by edema
formation secondary to increased blood–brain barrier (BBB)
permeability and decreased blood fl ow, contributes to poor outcome
following brain trauma. Recent studies have indicated that statins may
counteract edema formation following brain trauma but little is known
about other circulatory eff ects of statins in this setting. The objective
of the present study was to investigate whether statin treatment
improves brain microcirculation early after traumatic brain injury, and
whether microvascular eff ects are associated with altered production
of nitric oxide and prostacyclin.l Conclusion SVT at a dose of 80 mg was eff ective in reducing the
mortality (18.1% against 66%) compared to the group that did not use
SVT, and also decreased the incidence of cerebral vasospasm despite
the APACHE II score being higher in the group that used SVT (14.3
vs. 10.7). There was less morbidity in the SVT group with an average
Glasgow Outcome Scale of 3.25 vs. 2.1. Eff ects of sinvastatin in prevention of vasospasm in nontraumatic
subarachnoid hemorrhage: preliminary data Introduction Some trials have shown that statins in the acute phase
of aSAH reduce the incidence, morbidity and mortality of cerebral
vasospasm. Independent of their cholesterol-lowering eff ect, statins
have multiple biological properties, including downregulating
infl ammation and upregulating endothelial NO synthase. The purpose
of this study is to evaluate the potential of sinvastatin (SVT) as
prevention against vasospasm. Conclusion In women with preeclampsia signifi cant changes in
ophthalmic hemodynamics take place – mFV in arterial and venous
ophthalmics increases while PI values go down. This might be evidence
of orbital hyperperfusion in preeclamptic pregnant women. Low PI
values may be used as the markers of severe preeclampsia. Reference 1. Gosling RG, King DH: Arterial assessment by Doppler shift ultrasound. Proc
R Soc Med 1974, 67:447-449. 1. Gosling RG, King DH: Arterial assessment by Doppler shift ultrasound. Proc
R Soc Med 1974, 67:447-449. g
Methods We realized a prospective study, randomized, nonblind, with
the use of 80 mg SVT (night) in the fi rst 72 hours of the beginning of
bleeding, and a control group that did not use SVT, for 21 days, between
January and December 2008. Informed consent was obtained for all
patients. CT scans were performed as control and another CT scan in
patients with altered neurological signals. In the presence of changes
suggestive of vasospasm or correlation in clinical and CT scans, the
patients were taken for cerebral arteriography examination followed
by an angioplasty procedure if necessary. Liver and renal function and
LDL cholesterol were evaluated every 3 days. Exclusion criteria: liver
and renal disease, pregnancy, elevation of serum transaminases (three
times the value of normality), creatinine ≥2.5, rhabdomyolysis or CK
total ≥1,000 U/l. P315f P315
Eff ects of sinvastatin in prevention of vasospasm in nontraumatic
subarachnoid hemorrhage: preliminary data
S Macedo, V Aguiar, PF Rosa, IT Ladeia, YK Castro, LA Ferreira, DR De Melo,
LG Rezende
São Jose do Avai Hospital, Itaperuna, Brazil
Critical Care 2012, 16(Suppl 1):P315 (doi: 10.1186/cc10922) Evaluation of arterial and venous ophthalmic hemodynamics in
preeclamptic pregnant women p
p
g
M Shifman, NV Khramchenko, SV Sokologorskiy EM Shifman, NV Khramchenko, SV So EM Shifman, NV Khramchenko, SV Sokologorskiy
Federal Centre for Obstetrics, Gynecology & Neonatology, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P316 (doi: 10.1186/cc10923) y
Results Trauma resulted in brain edema, BBB dysfunction, and reduced
cortical blood fl ow, and no eff ect of treatment on these parameters
could be detected. Trauma also induced a reduction in the number of
perfused capillaries, which was improved by statin treatment. Statin
treatment led to increased plasma NOx levels and reduced mean
arterial blood pressure. The 6-keto-PGF-1α levels tended to increase
after trauma, and were signifi cantly reduced by rosuvastatin. , y
gy
gy,
Critical Care 2012, 16(Suppl 1):P316 (doi: 10.1186/cc10923) Introduction The aim of the study was to evaluate arterial and venous
ophthalmic blood fl ow parameters in mild and severe preeclampsia
pregnancies and in normotensive pregnancies. Introduction The aim of the study was to evaluate arterial and venous
ophthalmic blood fl ow parameters in mild and severe preeclampsia
pregnancies and in normotensive pregnancies. Methods A total of 117 women 25 to 30 years old with singleton
pregnancies 30 to 40 weeks of gestation were recruited. Among
them 40 pregnant women developed severe preeclampsia, 42 mild
preeclampsia, and 35 were normotensive. Using color fl ow mapping
(CFM) and pulse-wave Doppler imaging (PWD), maximum blood
fl ow velocity (mFV) in the right/left arterial and venous ophthalmics
along with Gosling’s Doppler pulsatility index (PI) [1] in both arterial
ophthalmics were evaluated. Mean blood pressure in all patients was
also registered. gi
y
y
Conclusion Rosuvastatin treatment improves microcirculation after
traumatic brain injury by increasing the number of perfused capillaries. This eff ect is associated with increased NO and reduced prostacyclin
production. R f p
References 1. Béziaud et al.: Crit Care Med 2011, 39:2300-2307. 2. Cherian, Robertson: J Neurotrauma 2003, 20:77-85. 3. Prinz, Endres: Anesth Analg 2009, 109:572-584. Results The highest mFV values (59.2 ± 4.61 and 23.6 ± 4.03 cm/second)
were in the severe preeclampsia group while in the mild preeclampsia
group mFV increased slightly or remained normal (35.6 ± 2.97 and
13.6 ± 0.81 cm/second). There was no mFV increase in the normotensive
pregnancy group (31.5 ± 2.21 cm/second). No signifi cant correlation
was found between gestation age and mentioned hemodynamic
parameters in the normotensive pregnancy group. PI values in the
arterial ophthalmic in normotensive pregnant women were 2.92 ± 0.59
and the highest in all groups. In group with mild preeclampsia this
parameter was 1.47 ± 0.30 and the lowest one was in patients with
severe preeclampsia – 1.17 ± 0.08. g
References 1. Lynch JR, Wang H, et al.: Simvastatin reduces vasospasm after aneurysmal
subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke 2005, 36:2024-2026. 1. Lynch JR, Wang H, et al.: Simvastatin reduces vasospasm after aneurysmal
subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke 2005, 36:2024-2026. p
y
Methods After fl uid percussion injury, rats were randomized to
intravenous treatment with 10 mg/kg rosuvastatin or vehicle. Brain
edema (wet/dry weight), BBB integrity (51Cr-EDTA blood to brain
transfer), cerebral blood fl ow (14C-iodoantipyrine autoradiography), and
the number of perfused cortical capillaries (FITC-albumin fl uorescence
microscopy) were measured at 4 and 24 hours. Production of NO and
prostacyclin was estimated by measuring the stable degradation
products nitrite and nitrate (NOx), and 6-keto-PGF-1α in plasma. Sham
injured animals were treated with vehicle and analyzed at 4 hours. 2. McGirt MJ, Lynch JR: Simvastatin increases endothelial nitric oxide
synthase and ameliorates cerebral vasospasm resulting from
subarachnoid hemorrhage. Stroke 2002, 33:2950-2956. Clinical outcomes in neonates following maternal magnesium
sulfate therapy in preeclampsia/eclampsia
G Tikhova, E Shifman
Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia
Critical Care 2012, 16(Suppl 1):P319 (doi: 10.1186/cc10926) Combined injury in occipital–
frontal lobes (29.3%) and occipital–temporal (27.6%) lobes were
observed in almost one-third of patients. Synchronous injury in the
temporal and frontal lobes was the least common (6.9%). Simultaneous
damage of three and more lobes was observed quite rarely (14.6%). Most abnormalities were bilateral with frequency not less than 78.0%. Unsymmetrical injury observed in some patients was located in the
right lobe in most cases. All analyzed cases include only 7.1% of single
left injury and all of them were located in the occipital lobe. Vasogenic
edema occurred in 83.5% of cases, while ischemic damage was
observed in 10.4%. The incidence of hemorrhage was 6.1%. Methods Trials were searched for in the PubMed database among
English-language articles published in 1990 to 2010. Analysis includes
randomized controlled prospective clinical trials comparing MST with
no treatment, placebo or other anticonvulsant. The following neonatal
outcomes were chosen as the main endpoints of the study: neonatal
death, neonatal hypotonia, Apgar score <7 at 1 and 5 minutes, intuba-
tion at place of delivery, admission to the NICU, treatment in NICU
>7 days. The total eff ect of MST was measured as the relative risk of
adverse outcome in the MST group compared with control and its
95% CI. Meta-analysis of neonatal outcomes was performed under a
random-eff ect model for seven endpoints and a fi xed-eff ect model for
three endpoints. p
Results Neonatal mortality in the MST group was compared with
diff erent control groups. Each of these studies showed no signifi cant
diff erence between two groups: MST/mixed (0.89, 95% CI 0.80 to 0.99),
MTS/no treatment-placebo (0.99, 95% CI 0.93 to 1.05), MTS/diazepam
(1.09, 95% CI 0.91 to 1.29), MTS/fenitoin (0.75, 95% CI 0.56 to 1.02). The
neonatal hypotonia rate is signifi cantly higher in the MST group (3.57,
95% CI 2.89 to 4.42), although signifi cant heterogeneity of the control
group may be a valuable confounding factor. There was no evidence
for changing incidence of Apgar <7 at 1 and 5 minutes in the MTS
group compared with control (0.79, 95% CI 0.70 to 0.89 and 0.80, 95%
CI 0.64 to 0.99 correspondingly). The same results were observed for
intubation at place of delivery (1.04, 95% CI 0.90 to 1.29) and admission
to NICU (0.96, 95% CI 0.85 to 1.08). Clinical outcomes in neonates following maternal magnesium
sulfate therapy in preeclampsia/eclampsia
G Tikhova, E Shifman
Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia
Critical Care 2012, 16(Suppl 1):P319 (doi: 10.1186/cc10926) Clinical outcomes in neonates following maternal magnesium
sulfate therapy in preeclampsia/eclampsia
G Tikhova, E Shifman
Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia
Critical Care 2012, 16(Suppl 1):P319 (doi: 10.1186/cc10926) Critical Care 2012, 16(Suppl 1):P319 (doi: 10.1186/cc10926) ji
Methods We collected cases of neurological complications of eclampsia
reported in English-language medical journals from 1980 to 2008. The
study methods include structural and frequency analysis of brain MRT/
CT image protocols. Introduction Magnesium sulfate therapy (MST) is the method of choice
in prophylaxis and treatment of eclamptic seizures in many countries. A lot of high-quality clinical trials and meta-analyses proved its effi cacy
and safety for mothers. But the eff ect of maternal MST on the fetus
and neonate is still controversial. The goal of the study was to analyze
available trials concerning this problem in order to prove statistically
that maternal MST given as prophylaxis or treatment of eclamptic
seizures has no adverse eff ects on the mature fetus and term neonate. Methods Trials were searched for in the PubMed database among
English-language articles published in 1990 to 2010. Analysis includes
randomized controlled prospective clinical trials comparing MST with
no treatment, placebo or other anticonvulsant. The following neonatal
outcomes were chosen as the main endpoints of the study: neonatal
death, neonatal hypotonia, Apgar score <7 at 1 and 5 minutes, intuba-
tion at place of delivery, admission to the NICU, treatment in NICU
>7 days. The total eff ect of MST was measured as the relative risk of
adverse outcome in the MST group compared with control and its
95% CI. Meta-analysis of neonatal outcomes was performed under a
random-eff ect model for seven endpoints and a fi xed-eff ect model for
three endpoints. g p
Results The analyzed sample included 77 cases of neurological
complications of eclampsia. We extracted the following positions from
the plain texts of MRT/CT descriptions: brain injury areas (occipital,
temporal, parietal and frontal lobes); injury depth (cortical and/or
subcortical matter); brain structures undergoing injury (classifi cation
was too complicated); injury nature (vasogenic/ischemic edema,
hemorrhage). Abnormalities in occipital (84.6%) and parietal (70.7%)
lobes were the most frequent, injuries in temporal lobes were quite
rare (26.9%), but damage in frontal lobes was the most uncommon
(24.4%). Combined injury in occipital and parietal lobes was recorded
in more than two-thirds of cases (72.4%). P318 3 8
Eleven years of critical obstetric pathology: epidemiologic study
L Calejman, V Nunes Velloso, E Canedo, M Deheza
Hospital Rivadavia, Capital Federal, Argentina
Critical Care 2012, 16(Suppl 1):P318 (doi: 10.1186/cc10925) Introduction The objective was to describe the characteristics of
pregnant and puerperal women admitted to the ICU from February
2000 to February 2011. Conclusion Maternal MST given as prophylaxis or treatment of
eclamptic seizures does not aff ect neonatal mortality and incidence of
neonatal hypotonia, Apgar <7 at 1 and 5 minutes, intubation at place of
delivery and admission to the NICU in a population of term newborns. Maternal MST signifi cantly reduces the risk of neonate treatment in
NICU >7 days in this population. Methods Patients admitted between the mentioned periods were
grouped by age, sex, nationality, APACHE II score, days in the ICU, cause of
admission: hypertensive syndromes in pregnancy (HSP), preeclampsia
(P), eclampsia (E), HELLP syndrome (H), gestational diabetes, sepsis and
placentary disorders; need for mechanical ventilation (MV) and dialysis,
maternal mortality, and if they had proper prenatal care. P320 Results A total of 3,568 patients were admitted, from which 471
patients (13.2%) were of obstetric cause; average age was 24 years,
APACHE II score of 6. There were 39 cases of arterial hypertension and
26 of diabetes mellitus before pregnancy. Sixty-eight percent were fi rst
pregnancy. The most frequent causes of admission were hypertension
secondary to pregnancy (HSP) in 353 patients (75%): P 44% (n = 156), E
8% (n = 28), H 33% (n = 116), H/E combined 15% (n = 53). Other causes
of admission: sepsis 16% (n = 75), placental disorders 7% (n = 33), and
neurological deterioration (CVA/S SHEEHAN) 2% (n = 10). They required
an average of two drugs to control blood pressure for the patients
who needed it in 68% (n = 320). The average stay in the ICU was 6.5
days. From a total of 471 patients, 73 patients required mechanical
ventilation (15%) and 118 (25%) patients presented high levels of
urea and creatinine, 11 patients (2%) required dialysis. With respect to
nationality 301 patients (64%) were Argentinean, the others reported
were from Bolivia, Paraguay and Peru. Prenatal checks occurred in only
35% (n = 165) of the patients. The mortality rate was 6% (n = 28). Sleep monitoring by actigraphy in short-stay ICU patients
AW Van der Kooi1, JH Tulen2, AW De Weerd3, MM Van Eijk1, MJ Van Uitert4,
SE De Rooij4, BC Van Munster4, AJ Slooter1
1University Medical Center Utrecht, the Netherlands; 2Erasmus MC, University
Medical Center Rotterdam, the Netherlands; 3Sein, Zwolle, the Netherlands;
4Academic Medical Center, Amsterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P320 (doi: 10.1186/cc10927) Introduction Sleep deprivation is common in ICU patients, but
diffi cult to investigate [1]. The gold standard for sleep monitoring,
polysomnography (PSG), is impractical for use in ICU patients [2]. Actigraphy proved to be a good alternative in non-ICU patients [3]. However, in prolonged mechanically ventilated patients, actigraphy
was inaccurate, probably due to ICU-acquired weakness and resulting
inactivity [2]. Short-stay ICU patients do not suff er from ICU-acquired
weakness, and the accuracy of actigraphy in these patients has not yet
been studied [4]. The aim of this study was to investigate actigraphy for
sleep assessment in short-stay ICU patients. Introduction Sleep deprivation is common in ICU patients, but
diffi cult to investigate [1]. The gold standard for sleep monitoring,
polysomnography (PSG), is impractical for use in ICU patients [2]. P319 computer tomography (CT) examinations of the brain in patients
with neurological complications of eclampsia; to defi ne the MRT/
CT examination data structure; and to perform frequency analysis of
main MRT/CT characteristics and estimate their frequency distributions
defi ned by studied pathology. The data included in the study were
reported in medical journals and met defi nite criteria for inclusion. Methods We collected cases of neurological complications of eclampsia
reported in English-language medical journals from 1980 to 2008. The
study methods include structural and frequency analysis of brain MRT/
CT image protocols. computer tomography (CT) examinations of the brain in patients
with neurological complications of eclampsia; to defi ne the MRT/
CT examination data structure; and to perform frequency analysis of
main MRT/CT characteristics and estimate their frequency distributions
defi ned by studied pathology. The data included in the study were
reported in medical journals and met defi nite criteria for inclusion. computer tomography (CT) examinations of the brain in patients
with neurological complications of eclampsia; to defi ne the MRT/
CT examination data structure; and to perform frequency analysis of
main MRT/CT characteristics and estimate their frequency distributions
defi ned by studied pathology. The data included in the study were
reported in medical journals and met defi nite criteria for inclusion. Data classifi cation of magnetic resonance tomography and
computer tomography images of brain in parturients with
neurological complications of eclampsia
kh
h f Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia Critical Care 2012, 16(Suppl 1):P317 (doi: 10.1186/cc10924) Introduction The goal of the study was to classify protocol data
recorded during magnetic resonance tomography (MRT) and S115 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Clinical outcomes in neonates following maternal magnesium
sulfate therapy in preeclampsia/eclampsia
G Tikhova, E Shifman
Kulakov Scientifi c Center of Obstetrics, Gynecology and Perinatology, Moscow,
Russia
Critical Care 2012, 16(Suppl 1):P319 (doi: 10.1186/cc10926) The incidence of treatment in the
NICU >7 day was signifi cantly lower in MST group than in control (0.54,
95% CI 0.52 to 0.78). Conclusion The analysis reveals a general picture of the most distinctive
features of brain damage following neurological complications of
eclampsia. Quality and quantity of sleep in multipatient versus single-room
ICUs
M Van Eijk, A Slooter
University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P321 (doi: 10.1186/cc10928) Quality and quantity of sleep in multipatient versus single-room
ICUs
M Van Eijk, A Slooter
University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P321 (doi: 10.1186/cc10928) Methods Double-blind RCT between placebo and melatonin (3 mg
bid, 8:00 and 12:00 p.m., from third ICU day until discharge). Inclusion:
age >18, SAPS II >32, expected mechanical ventilation (MV) >4 days,
practicability of the gastroenteric tract. Patients were treated according
to local guidelines [2], titrating sedatives to a conscious target
(Richmond Agitation Sedation Scale (RASS) = 0) as early as possible. Each day, the physician in charge stated the RASS target; nurses
assessed the actual RASS. Introduction Sleep fragmentation and deprivation is common in ICU
patients [1]. It is assumed that the ICU environment (overexposure
to sound and light during night-time) leads to disturbed sleep [2]. In our hospital, a new ICU was built with quiet, single-patient rooms
with much daylight. This created an opportunity to study the eff ects
of nursing environment on sleep quality and quantity in ICU patients. Introduction Sleep fragmentation and deprivation is common in ICU
patients [1]. It is assumed that the ICU environment (overexposure
to sound and light during night-time) leads to disturbed sleep [2]. In our hospital, a new ICU was built with quiet, single-patient rooms
with much daylight. This created an opportunity to study the eff ects
of nursing environment on sleep quality and quantity in ICU patients. Methods We included 21 postcardiothoracic surgery patients: 11
subjects were admitted to the old, ward-like ICU, and 10 patients to the
new, single-room ICU (see Figure 1). Hypnograms were derived from a
polysomnography from 07:00 p.m. to 07:00 a.m. Results Eighty-two patients enrolled: age 72 (60 to 77), SAPS II 41 (34
to 54), MV length 11 (6 to 22) days. Fifteen pancreatitis, 33 acute lung
diseases, 13 acute heart diseases, 21 other. The analgesic/sedative
therapy during the fi rst 3 days was not diff erent between groups. Melatonin administration determined early weaning from sedatives
and analgesics. The prevalence of conscious sedation (RASS = 0) was
higher in the melatonin group (67.9 vs. 60.1%, P <0.01), while deeper
levels of sedation (RASS = –3/–4) were lower in the melatonin group
(RASS –3: 2.4 vs. 7.7%, P <0.01; RASS –4: 1.9 vs. 4.3%, P <0.01). Melatonin
administration caused no oversedation (26.3 vs. 24.2%, P = 0.94), while
decreased undersedation (18.6% vs. 26.2%, P = 0.05). References 1. Iapichino et al.: Crit Care Med 2006, 34:1039. 1. Iapichino et al.: Crit Care Med 2006, 34:1039. 2. Cigada et al.: J Crit Care 2008, 23:349. 1. Iapichino et al.: Crit Care Med 2006, 34:1039. 2. Cigada et al.: J Crit Care 2008, 23:349. Figure 1 (abstract P321). New, single-room ICU. 2. Cigada et al.: J Crit Care 2008, 23:349. Quality and quantity of sleep in multipatient versus single-room
ICUs
M Van Eijk, A Slooter
University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P321 (doi: 10.1186/cc10928) RASS targets were
joined more frequently in the melatonin group, even if not signifi cantly
(55.1 vs. 49.6%, P = 0.12). of nursing environment on sleep quality and quantity in ICU patients. Methods We included 21 postcardiothoracic surgery patients: 11
subjects were admitted to the old, ward-like ICU, and 10 patients to the
new, single-room ICU (see Figure 1). Hypnograms were derived from a
polysomnography from 07:00 p.m. to 07:00 a.m.f y
g
y
Results Both groups did not diff er with respect to age, duration
of surgery or use of psychoactive medication. Polysomnography
recordings showed no diff erences in total sleep time and awakenings
(63 ± 26 in the old ICU and 56 ± 30 in the new ICU). The mean
percentage of sleep stages in the old versus new situation did not
essentially diff erent either: N1: 12.9% versus 8.0%, P = 0.21, ANOVA; N2:
80.3% versus 87.2%, P = 0.07, ANOVA; N3: 5.2% versus 2.5%, P = 0.18,
ANOVA. Only REM sleep latency was longer in the old ICU: 314.7 versus
633.5 minutes, P = 0.02, ANOVA. Conclusion Oral melatonin increased the prevalence of conscious
sedation in high-risk critically ill patients; it allowed a better
achievement of RASS target, particularly decreasing undersedation
episodes. Conclusion Except for REM onset latency, sleep improvement was
not achieved by changing a ward-like into a single-patient-room ICU
environment. When striving for more natural sleep, attitudes towards Oral melatonin in high-risk critically ill patients: quality of sedative
eff ect f
G Sabbatini, G Mistraletti, B Cerri, S Miori, I Galluccio, M Tozzi, C Villa,
M Umbrello, F Fraschini, G Iapichino
Università degli Studi di Milano, Milan, Italy
Critical Care 2012, 16(Suppl 1):P322 (doi: 10.1186/cc10929) Conclusion Actigraphy is not reliable for one-night sleep–wake
detection in short-stay postoperative ICU patients. References Conclusion Actigraphy is not reliable for one-night sleep–wake
detection in short-stay postoperative ICU patients. 1. Figueroa-Ramos M, et al.: Intensive Care Med 2009, 35:781-795. 2. Beecroft J, et al.: Intensive Care Med 2008, 34:2076-2083. 3. de Souza L, et al.: Sleep 2003, 26:81-85. 4. Schweickert WD, et al.: Chest 2007, 131:1541-1549. Introduction Analgesic/sedative therapy is necessary in ICU patients;
however, it presents important side eff ects. Critically ill patients have
altered circadian rhythm, delirium and agitation often requiring
additional sedation. The dramatically reduced endogenous blood
melatonin level (basal and night peaks) could play a role in this
context. We evaluated the eff ects of oral melatonin administration on
the adaptation to critical illness and invasive procedures in high-risk
critically ill patients [1] consciously sedated [2]. 1. Figueroa-Ramos M, et al.: Intensive Care Med 2009, 35:781-795. 2. Beecroft J, et al.: Intensive Care Med 2008, 34:2076-2083. 3. de Souza L, et al.: Sleep 2003, 26:81-85. 4. Schweickert WD, et al.: Chest 2007, 131:1541-1549. References References References
1. Cooper AB, et al.: Chest 2000, 117:809-818. 2. Gabor JY, et al.: Am J Respir Crit Care Med 2003, 167:708-715. g
p y
Results The only parameter that showed a signifi cant correlation
between PSG and actigraphy was the number of awakenings (r = 0.76,
P = 0.049, high threshold setting). Actigraphy underestimated wake
time after sleep onset and overestimated total sleep time and sleep
effi ciency. The median specifi city for actigraphy was below 19% and
the median sensitivity above 94% for all threshold settings. Conclusion Actigraphy is not reliable for one-night sleep–wake
detection in short-stay postoperative ICU patients. References Results The only parameter that showed a signifi cant correlation
between PSG and actigraphy was the number of awakenings (r = 0.76,
P = 0.049, high threshold setting). Actigraphy underestimated wake
time after sleep onset and overestimated total sleep time and sleep
effi ciency. The median specifi city for actigraphy was below 19% and
the median sensitivity above 94% for all threshold settings. P320 Actigraphy proved to be a good alternative in non-ICU patients [3]. However, in prolonged mechanically ventilated patients, actigraphy
was inaccurate, probably due to ICU-acquired weakness and resulting
inactivity [2]. Short-stay ICU patients do not suff er from ICU-acquired
weakness, and the accuracy of actigraphy in these patients has not yet
been studied [4]. The aim of this study was to investigate actigraphy for
sleep assessment in short-stay ICU patients. p
y
Conclusion Critical obstetrical pathology is common in the ICU, HSP as
the main cause. A high number of fi rst pregnancy patients with little
prenatal care was observed. This type of patient requires low levels of
life support. y
Conclusion Critical obstetrical pathology is common in the ICU, HSP as
the main cause. A high number of fi rst pregnancy patients with little
prenatal care was observed. This type of patient requires low levels of
life support. Methods PSG and actigraphy measurements were conducted in
seven postcardiothoracic surgery patients. Total sleep time, sleep S116 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 nursing and medication may play a more important role than ICU
design. nursing and medication may play a more important role than ICU
design. effi ciency, number of awakenings and wake time after sleep onset
were determined with actigraphy and compared to PSG. The accuracy,
sensitivity (percentage correctly scored as sleep) and specifi city
(percentage correctly scored as awake) were calculated for actigraphy
using high, medium, low and automatic threshold sensitivity settings
of the actigraphy software. n in the ICU: nurses’ perceptions of practices and infl uenci Sedation in the ICU: nurses’ perceptions of practices and infl uencing
factors B Sneyers1, PF Laterre2, MM Perreault3, A Spinewine1
1Université catholique de Louvain, Louvain Drug Research Institute, Brussels,
Belgium; 2Université catholique de Louvain, Cliniques Universitaires St-Luc,
Brussels, Belgium; 3Université de Montreal, Canada
Critical Care 2012, 16(Suppl 1):P324 (doi: 10.1186/cc10931) Introduction Our goals are to describe adherence to sedation
recommendations [1] in Belgian ICUs and to identify major factors
infl uencing practices. l
Methods A national survey including all nurses working in Belgian ICUs
was conducted with seven nurses sampled per hospital. A validated
self-administered paper survey was designed based on a literature
review and data from a previous qualitative study. Topics addressed
were current practices and reasons for (non)compliance to sedation
recommendations such as use of sedation scales and daily sedation
interruption (DSI). Four postal reminders were sent. Conclusion In mechanically ventilated patients of a medical ICU
including also patients with neurologic diseases, a sedation goal of
RASS 0 to –2, as recommended by a current guideline, could only be
achieved in a minority of patients despite intensive instructions and
a motivated team. In most cases the nurses were able to provide
reasonable medical explanations for a deeper sedation or an otherwise
impaired consciousness. Results The response rate was 70% (n = 587/840 nurses from 99/120
hospitals). Sedation scales are available to 89% of nurses and frequency
of use is variable (≤1×/day: 13%, 3 to 4×/day: 31%, ≥6×/day: 56%). When
sedation scales are available, perceived indications are monitoring
of sedation and analgesia (96% and 31% of nurses respectively) and
dosing adjustment for sedatives and analgesics (14% and 28% of
nurses respectively). DSI is infrequently used (never used: 38% of
respondents, used for <25% of patients: 47% of respondents, used for
25 to 75% of patients: 12% of respondents, used for >75% of patients:
3% of respondents). Numerous barriers for wide implementation are
identifi ed, mainly lack of outcome expectancy, as DSI is perceived to
impair patient outcomes. It is perceived that DSI increases the risk of
complications such as unplanned extubation and pulling of lines and
tubes (79% of nurses agree), impairs patients’ comfort (59% of nurses
agree), and creates traumatic memories in the intubated patients
(36% of nurses agree). Moreover, 63% of nurses agree that they would
prefer no DSI if they were an intubated patient. P323
Sedation depth and mortality in mechanically ventilated critically
ill adults 1. Jacobi et al.: Crit Care Med 2002, 30:119-141. p
y
p
y
Results We studied 259 patients with mean (SD) age 53.1 (15.9) years
and APACHE II score 21.3 (8.2), ventilated for median (IQR) 5 (3 to 8.8)
days. Hospital mortality was 82 (31.7%). Midazolam and morphine were
the commonest agents used, given to 241 (93.1%) and 201 (77.6%)
patients respectively. Over 2,657 study days, 13,836 assessments
were conducted. Deep sedation was recorded in 187 (72%) patients
within 4 hours of commencing ventilation and in 159 (61%) patients at
48 hours. Daily interruption was used on 20% of study days. Delirium
occurred in 114 (43%) of assessed patients with a mean (SD) duration
of 1.3 (2.2) days. Early deep sedation independently predicted time
to hospital death (HR 1.11, 95% CI 1.05 to 1.18, P <0.001) and time to
extubation (HR 0.93, 95% CI 0.89 to 0.96, P = 0.001) but not time to
delirium occurring after 48 hours (HR 0.98, 95% CI 0.93 to 1.03, P = 0.46). Midazolam cumulative dose in the fi rst 48 hours was signifi cantly
associated with the number of RASS assessments ≤–3 (P <0.001).i P324 Results The independent observer documented only in 13% (47/364)
of all measurements a RASS of 0 to –2. We analyzed 295 questionnaires,
in which 368 reasons for a deviation from a RASS of 0 to –2 were
stated (multiple answers were possible). In 113 questionnaires (38%)
the nurses mentioned that a short-term increase in sedation depth
was required for nursing procedures or medical interventions. In 89
questionnaires (30%) a RASS of 0 to –2 was considered reasonable
but could not be achieved at the time of measurement with the
current medication (n = 32) or the consciousness was impaired by CNS
diseases (n = 52). In 100 questionnaires (34%) a RASS of 0 to –2 was
not considered reasonable. The following reasons were stated: disease
with coma (n = 25), controlled ventilation (n = 32), distressed patient
(n = 12), increased intracranial pressure (n = 7), status epilepticus
(n = 7), hypothermia (n = 4), dying patient (n = 4), delirium/(auto)
aggression (n = 4). Other reasons were mentioned in 66 questionnaires
(22%), most commonly a physician order for a deeper sedation (n = 19)
or a missing sedation goal (n = 14). Reference 1. Devlin JW: The pharmacology of over sedation in mechanically ventilated
adults. Curr Opin Crit Care 2008, 14:403-407. P325 3 5
Implementation of a national guideline for analgesia and sedation:
how often can a RASS of 0 to –2 be achieved? R Riessen, P Tränkle, R Pech, G Blumenstock, M Haap
University Hospital Tübingen, Germany
Critical Care 2012, 16(Suppl 1):P325 (doi: 10.1186/cc10932) Introduction Based on a new national guideline we implemented in
our medical ICU an interdisciplinary algorithm for the management of
analgosedation, in which nurses had to adjust the dose of the analgesics
and sedatives based on sedation goals given by the physicians. Within
this project we investigated in what portion of mechanically ventilated
patients a sedation level of Richmond Agitation and Sedation Scale
(RASS) of 0 to –2, which is generally recommended by the guideline,
can be achieved. We also asked the nurses for an explanation when this
goal was not reached. Conclusion Early ICU sedation depth is a modifi able risk factor
for delayed extubation and increased risk of death and should be
considered in future sedation trials. g
Methods After an educational program the level of sedation was
measured 364 times in 37 mechanically ventilated patients at diff erent
time points by an independent observer. In all cases in which the RASS
was outside the desired level of 0 to –2, the nurse in charge was asked
to fi ll out a structured as well as open questionnaire, in which the
reasons for this deviation could be stated. Reference P323
Sedation depth and mortality in mechanically ventilated critically
ill adults Y Shehabi1, S Kadiman2, L Chan3, W Ismail4, M Saman5, A Alias6
1University New South Wales, Randwick, Australia; 2National Heart Institute,
Kuala Lumpur, Malaysia; 3University Malaya, Kuala Lumpur, Malaysia; 4Raja
Perempuan Zainab II Hospital, Kota Bharu, Malaysia; 5Sarawak General
Hospital, Kuching, Malaysia; 6Malacca General Hospital, Malacca, Malaysia
Critical Care 2012, 16(Suppl 1):P323 (doi: 10.1186/cc10930) Introduction Deep sedation is common in ventilated patients,
particularly in the fi rst 48 hours in the ICU, which may adversely aff ect
outcomes such as mortality. This period is usually unobserved in clinical
trials due to late randomisation. We investigated the relationship
between early sedation depth, sum of Richmond Agitation Sedation
Scale (RASS) –3 to –5 and clinical outcomes, including mortality. Figure 1 (abstract P321). New, single-room ICU. Methods A waiver of consent was granted. In collaboration with the
Australian New Zealand Intensive Care Research Centre, we conducted S117 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Conclusion Sedation scales are widely used in Belgium, while use of
DSI is low. Barriers impairing adherence to recommendations were
identifi ed. Perception that sedation scales are not used for sedative
dosing adjustments is present, as well as inadequate use for analgesia. Fear of worsening patient outcomes using DSI is present, contrasting
with current literature. A similar survey addressing physicians’
perceptions is ongoing. Reference Conclusion Sedation scales are widely used in Belgium, while use of
DSI is low. Barriers impairing adherence to recommendations were
identifi ed. Perception that sedation scales are not used for sedative
dosing adjustments is present, as well as inadequate use for analgesia. Fear of worsening patient outcomes using DSI is present, contrasting
with current literature. A similar survey addressing physicians’
perceptions is ongoing. Reference a multicentre prospective longitudinal cohort study in 11 centers in
Malaysia. Critically ill patients ventilated and sedated ≥24 hours were
followed from ICU admission to hospital discharge. The administration
of all sedatives was measured daily. Four-hourly RASS assessments
were conducted and delirium assessed daily (CAM-ICU during light
sedation RASS –2 to +1). Multivariable Cox regression proportional
hazard was used to quantify relationships between early deep sedation
and time to extubation and delirium occurring after 48 hours and
hospital mortality adjusting for diagnosis, age, gender, APACHE II score,
operative, elective, early use of vasopressors and dialysis. 1. Jacobi et al.: Crit Care Med 2002, 30:119-141. Cerebral ischemia–reperfusion model in rabbits: relationship
between dexmedetomidine and biochemical parameters in
lowering intraparenchymal pressure g
y
Results In the baseline phase (36 patients/422 measurements) using
the RAMSAY score, sedation depth documented by the nurses and
the observer matched in only 39% of the measurements. The nurses
documented in 246 (58%) measurements a lighter sedation and in 12
measurements (3%) a deeper sedation than the observer. In the post-
implementation phase (37 patients/346 measurements) using the RASS,
we found a signifi cantly higher matching rate of 76% between nurses
and observer compared to RAMSAY (P <0.001). Nurses documented
in 47 measurements a lighter (14%) and in 37 measurements (11%) a
deeper sedation than the observer. The nurses evaluated the RASS in
terms of the ability to describe the actual depths of sedation with a
mean of 1.7 on the six-point Likert scale signifi cantly better than the
RAMSAY score with 3.2 (P <0.001). Similar results were found regarding
the discrimination between diff erent levels of sedation (RASS 1.7,
RAMSAY 3.1, P <0.001). g
y
A Tavlan1, ME Ustun1, A Yosunkaya1, A Ak1, A Kiyici1, HK Bardakcı2, F Gok1
1Selcuk University, Meram Medical Faculty, Konya, Turkey; 2Farabi Hospital,
Konya, Turkey
Critical Care 2012 16(Suppl 1) P328 (doi 10 1186/cc10935) y
y
Critical Care 2012, 16(Suppl 1):P328 (doi: 10.1186/cc10935) Introduction The eff ect of dexmedetomidine in two diff erent doses on
the levels of endothelin-1 (ET-1) and prostoglandin I2 (PGI2) in blood
and cerebrospinal fl uid (CSF) of rabbits via the transient global cerebral
ischemia model was studied to determine its intraparenchymal
pressure (IPP) reduction mechanism. Methods Twenty-four New Zealand type rabbits were employed and
randomly distributed into four groups. Group I (sham group, n = 6):
craniotomy was performed only. Group II (control group, n = 6):
bilateral carotid arteries were clamped for 60 minutes after craniotomy,
then reperfusion was performed for 60 minutes. In Group III (n = 6)
and Group IV (n = 6), 80 μkg–1 and 320 μkg–1 dexmedetomidine was
administered within the fi rst 10 minutes of the reperfusion procedure
respectively. Blood and CSF samples were collected 120 minutes after
craniotomy. Mean arterial pressures (MAP), heart rates (HR), IPP and
temperature values were recorded. Conclusion In routine use the RAMSAY score showed a poor
performance regarding the measurement of sedation depth. After
implementation of the RASS, measurement of sedation depth
appeared signifi cantly improved. Results There was no signifi cant diff erence in MAP values between
groups (P ≥0.05). n in the ICU: nurses’ perceptions of practices and infl uenci Other barriers are
related to knowledge, as 26% of nurses do not know the practice, and
to behaviour, as 53% of respondents feel DSI is diffi cult to implement
because of organizational constraints. P326 Comparison of the RAMSAY score and the Richmond Agitation
Sedation Score for the measurement of sedation depth
R Riessen, R Pech, P Tränkle, G Blumenstock, M Haap
University Hospital Tübingen, Germany
Critical Care 2012, 16(Suppl 1):P326 (doi: 10.1186/cc10933) Introduction We implemented an interdisciplinary algorithm for
the management of analgosedation in mechanically ventilated
patients based on a new national guideline. As part of this project
we investigated whether the newly introduced Richmond Agitation
Sedation Score (RASS) allowed a better monitoring of sedation depth
than the formerly used RAMSAY score. Introduction We implemented an interdisciplinary algorithm for
the management of analgosedation in mechanically ventilated
patients based on a new national guideline. As part of this project
we investigated whether the newly introduced Richmond Agitation
Sedation Score (RASS) allowed a better monitoring of sedation depth
than the formerly used RAMSAY score. S118 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Methods During the baseline phase of the study we investigated the
RAMSAY score, which had been routinely used for several years in our
unit. Following an educational program the RAMSAY was replaced by
the RASS. During both study phases the actual sedation score was
determined within a short period of time by the nurse in charge and an
independent observer. In addition, the nurses were asked to evaluate
on a six-point Likert scale whether the score appeared to be suitable
to describe the actual state of sedation or to discriminate between
diff erent levels of sedation (1 = very good). The measurements took
place at three defi ned time points (7, 9 and 12 o’clock) during the
morning shift on weekdays. P328 P328 3 8
Cerebral ischemia–reperfusion model in rabbits: relationship
between dexmedetomidine and biochemical parameters in
lowering intraparenchymal pressure
A Tavlan1, ME Ustun1, A Yosunkaya1, A Ak1, A Kiyici1, HK Bardakcı2, F Gok1
1Selcuk University, Meram Medical Faculty, Konya, Turkey; 2Farabi Hospital,
Konya, Turkey
Critical Care 2012, 16(Suppl 1):P328 (doi: 10.1186/cc10935) Dexmedetomidine is associated with better outcomes in patients
undergoing cardiac surgery PG Brandão1, S Lobo1, M Nassau Machado1, J Duarte1, F Lobo1, Y Sakr2
1Hospital de Base de São José do Rio Preto, Brazil; 2Friedrich Schiller University
Hospital, Jena, Germany
Critical Care 2012, 16(Suppl 1):P327 (doi: 10.1186/cc10934) Introduction Cardiac anesthesia has changed over the years from high-
dose opioids to fast-track surgery. The use of high doses of opioids was
justifi ed based on the hemodynamic stability [1] at a cost of prolonged
mechanical ventilation support. Our study aims to analyze the use of
dexmedetomidine as an anesthesia adjuvant during the induction and
maintenance of anesthesia for patients undergoing coronary artery
bypass graft (CABG) and valvular heart surgeries. Conclusion Dexmedetomidine could decrease intraparenchymal
pressure in the transient global cerebral ischemia model when
administered at low doses [1,2]. It probably contributed to this
reduction by preventing an increase of endothelin levels in blood and
CSF as well as decreasing PGI2 levels in CSF. g
2
Referencesf References yp
g
g
Methods This study is a retrospective analysis from a prospective
database collected from January 2003 to April 2011. The patients
were divided into two groups, based on the use of dexmedetomidine
(DEX group) intraoperatively or conventional opioid-based technique
(Control group). Isofl urane was used for anesthesia maintenance in
both groups. 1. Zornow MH, Scheller MS, Sheehan PB: Intracranial pressure eff ects of
dexmedetomidine in rabbits. Anesth Analg 1992, 75:232-237. 2. Jolkkonen J, Puurunen K, Koistinaho J, et al.: Neuroprotection by the alpha
2-adrenoceptor agonist, dexmedetomidine in rat focal cerebral ischemia. Eur J Pharmacol 1999, 7:31-36. g
p
Results We included 1,302 consecutive patients undergoing cardiac
surgery during the study period (63% male; median age = 57 years),
796 patients in the DEX group and 506 patients in the control group. CABG was the most commonly performed surgery (63%) followed by
valve surgeries (37%). The overall 30-day hospital mortality rate was
5.8%. Length of stay was signifi cantly lower for patients in the Dex
group (3.7 ± 4.4 days) than for patients in the control group (4.5 ± 6.3
days) (P = 0.02). Thirty-day mortality rates were 3.4% in the Dex group
and 9.7% in the control group (P <0.001). In the multivariable Cox
regression analysis with in-hospital death as the dependent variable,
dexmedetomidine (OR = 0.39, 95% CI: 0.23 to 0.64, P ≤0.001), a high
L-EuroSCORE (OR= 1.05, 95% CI: 1.01 to 1.10, P = 0.004) and older age
(OR = 1.03, 95% CI: 1.01 to 1.05, P = 0.003) were independently related
to in-hospital death. Need for reoperation (2.0% vs. 2.8%, P = 0.001),
neurologic lesion type 1 (2.0% vs. 4.7%, P = 0.005) and prolonged
hospitalization (3.1% vs. 7.3%, P = 0.001) were signifi cantly less frequent
in the DEX group than in the control group. P327 Dexmedetomidine is associated with better outcomes in patients
undergoing cardiac surgery
PG Brandão1, S Lobo1, M Nassau Machado1, J Duarte1, F Lobo1, Y Sakr2
1Hospital de Base de São José do Rio Preto, Brazil; 2Friedrich Schiller University
Hospital, Jena, Germany
Critical Care 2012, 16(Suppl 1):P327 (doi: 10.1186/cc10934) Cerebral ischemia–reperfusion model in rabbits: relationship
between dexmedetomidine and biochemical parameters in
lowering intraparenchymal pressure A decrease of HR in Group IV was signifi cantly lower
after reperfusion (P <0.05). IPP values after the reperfusion in Groups II
and IV were signifi cantly higher than Group I (P <0.05), but no signifi cant
increase in Group III (P ≥0.05). ET-1 levels of both blood and CSF were
increased in the group with performed ischemia and reperfusion
and no treatment (Group II) and the group administered high-dose
dexmedetomidine (Group IV) (P <0.05), while the group administered
low-dose dexmedetomidine (Group III) was similar to the sham group
(P ≥0.05). However, PGI2 levels of CSF were signifi cantly decreased in
the group administered low-dose dexmedetomidine (P <0.05). References 1. Lowenstein E, et al.: Cardiovascular response to large doses of intravenous
morphine in man. N Engl J Med 1969, 281:1389-1393. 2. Jalonen J, et al.: Dexmedetomidine as an anesthetic adjuvant in coronary
artery bypass grafting. Anesthesiology 1997, 86:331-345. 1. Lowenstein E, et al.: Cardiovascular response to large doses of intravenous
morphine in man. N Engl J Med 1969, 281:1389-1393. 2. Jalonen J, et al.: Dexmedetomidine as an anesthetic adjuvant in coronary
artery bypass grafting. Anesthesiology 1997, 86:331-345. 1. Lowenstein E, et al.: Cardiovascular response to large doses of intravenous
morphine in man. N Engl J Med 1969, 281:1389-1393. 2. Jalonen J, et al.: Dexmedetomidine as an anesthetic adjuvant in coronary
artery bypass grafting. Anesthesiology 1997, 86:331-345. 2. Jalonen J, et al.: Dexmedetomidine as an anesthetic adjuvant in coronary
artery bypass grafting. Anesthesiology 1997, 86:331-345. P329 Evaluation of sedation using pupilometry in ICUs: a pilot study
O Rouche, A Wolak-Thierry, Q Destoop, L Milloncourt, T Floch, P Raclot,
J Cousson
Centre Hospitalier Universitaire, Reims, France
Critical Care 2012, 16(Suppl 1):P329 (doi: 10.1186/cc10936) Evaluation of sedation using pupilometry in ICUs: a pilot study
O Rouche, A Wolak-Thierry, Q Destoop, L Milloncourt, T Floch, P Raclot,
J Cousson Centre Hospitalier Universitaire, Reims, France
Critical Care 2012, 16(Suppl 1):P329 (doi: 10.1186/cc10936) Centre Hospitalier Universitaire, Reims, France
Critical Care 2012, 16(Suppl 1):P329 (doi: 10.1186/cc10936) Introduction The depth of hypnosis is correlated with the decrease
in photomotor refl ex (PMR) [1]. It would be benefi cial to develop an
automated, noninvasive, simple and reproducible technique allowing
one to effi ciently evaluate the depth of sedation in ICUs. The objective of
this observational study is to evaluate the eff ectiveness of pupilometric
video in comparison to the Bispectral index (BIS). Introduction The depth of hypnosis is correlated with the decrease
in photomotor refl ex (PMR) [1]. It would be benefi cial to develop an
automated, noninvasive, simple and reproducible technique allowing
one to effi ciently evaluate the depth of sedation in ICUs. The objective of
this observational study is to evaluate the eff ectiveness of pupilometric
video in comparison to the Bispectral index (BIS). Methods Sedation level was based on the Richmond Score (RASS
between –4 and –5). Exclusion criteria were neurological pathologies
interfering with the PMR. Following a 320 lux fl ash of light, the PMR
was measured by the Neurolight (IDmed). Three measurements a day Conclusion Use of dexmedetomidine as anesthesia adjuvant was asso-
ciated with better outcomes in patients undergoing cardiac surgery. S119 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 correlated with EEG frequency, with maximal slowing in the delta
(≤4 Hz) range. were taken during 48 hours along with the collection of the BIS value
(Bis Vista Anandic Medical Systems). The data collected included the
variation of pupillary diameter (PD), latency time (LT) and maximal
speed of pupillary constriction (Vmax). These parameters were analyzed
after having classifi ed BIS values into three groups. Conclusion Midazolam concentrations while on continuous infusion
were associated with EEG tracings suggestive of deep sedation. Although clearance was relatively preserved, it varied over a wider
range than found in healthy populations. Eff ect of critical illness on the pharmacokinetics and dose–response
relationship of midazolam p
g
p
y
Results We included 15 patients; APACHE II score was (median) 17.5
points and SOFA score 9 points. The Bispectral index was lower in
the midazolan group (43 vs. 48.5 points, P = 0.005), although RASS
was the same for both groups. Large-vessel perfusion was similar for
both groups. The small perfusion vessel proportion was signifi cantly
reduced with propofol (92 vs. 96.3%, P = 0.003). The microvascular
fl ow index was also lower during propofol infusion (MFI – 2.4 vs. 2.7,
P = 0.002). We observed a higher heterogeneity index when patients
were sedated with propofol (0.4 vs. 0.19, P = 0.01). Introduction Critically ill patients require sedation to tolerate the
interventions necessary to facilitate their care. There is growing
evidence, however, that use of sedatives, such as the benzodiazepine
midazolam, is associated with delirium and other complications
that can lead to prolonged ICU stay and increased mortality. The
pharmacokinetics of midazolam in healthy populations has been
well characterized, and pharmacodynamic studies demonstrate a
predictable dose–response relationship. However, in critical illness,
where midazolam is often administered as a continuous infusion,
the pharmacokinetic properties are often altered. We sought to
investigate whether analysis of midazolam plasma concentrations in
combination with electroencephalography (EEG) will better defi ne the
eff ect of critical illness on the pharmacokinetics and clinical response
to midazolam, while providing a method to assess the adequacy of
sedation thereby minimizing the risks associated with prolonged or
over-sedation. Conclusion Propofol reduces small-vessel perfusion and increases the
heterogeneity of circulation in the sublingual mucosa, when compared
with the use of midazolan in septic shock patients. P329 The apparent lower threshold
for onset of coma may be a refl ection of illness severity, concomitant
medication use, and variable clearance during the course of illness. These preliminary results suggest that the combination of continuous
bedside EEG and therapeutic drug monitoring may be useful for
titrating midazolam infusions and to guide tapering to avoid prolonged
coma in patients with variable clearance of midazolam. i
Results A total of 186 analyses of PMR and BIS were conducted on 31
patients. The averages and standard deviations for each class of BIS
were as shown in Table 1. We conducted an analysis of variance in order
to compare these three groups of BIS. For the values Vmax and the PD,
the ANOVA was signifi cant. Therefore, we proceeded to compare the
groups two by two using Bonferroni tests. They revealed signifi cant
diff erence between the BIS <40 and 40 ≤ BIS ≤ 60 group (P <0.0001 for
both variables) and between BIS <40 and BIS >60 (Vmax P <0.0001 and
PD P <0.05). There was no correlation between any of the BIS groups
and the LT variable. P331
Eff ect of propofol and midazolan on microcirculation of septic
shock patients
G Penna1, F Fialho2, A Japiassu3, D Salgado4, P Kurtz1, G Nobre1,
M Kalichsztein1, N Villela5, E Bouskela5
1Casa de Saúde São José, Rio de Janeiro, Brazil; 2IFF-FIOCRUZ, Rio de Janeiro,
Brazil; 3IPEC-FIOCRUZ, Rio de Janeiro, Brazil; 4UFRJ, Rio de Janeiro, Brazil;
5UERJ, Rio de Janeiro, Brazil
Critical Care 2012, 16(Suppl 1):P331 (doi: 10.1186/cc10938) 33
Eff ect of propofol and midazolan on microcirculation of septic
shock patients
G P
1 F Fi lh
2 A J
i
3 D S l
d
4 P K
t 1 G N b
1 Table 1 (abstract P329). Values of Vmax, PD and TL
BIS <40 (n = 68)
40 ≤ BIS ≤ 60 (n = 62)
BIS >60 (n = 37)
Vmax (mm/second)
0.98 ± 0.44
1.45 ± 0.73
1.66 ± 0.95
TL (ms)
253.8 ± 68.6
241.6 ± 41.8
240.6 ± 52.2
PD%
12.95 ± 5.58
18.3 ± 6.12
17.7 ± 6.72
Conclusion The Vmax and the PD seem to be relevant criteria when
compared to the BIS. This noninvasive technique of monitoring the
depth of sedation could be benefi cial especially with patients under
myorelaxant drugs. A larger study is necessary in order to confi rm these
results and enable one to set cut-off values for the Vmax and PD. Reference
1
Leslie K et al : Anesthesiology 1996 84:52 63 Table 1 (abstract P329). Values of Vmax, PD and TL BIS <40 (n = 68)
40 ≤ BIS ≤ 60 (n = 62)
BIS >60 (n = 37)
Vmax (mm/second)
0.98 ± 0.44
1.45 ± 0.73
1.66 ± 0.95
TL (ms)
253.8 ± 68.6
241.6 ± 41.8
240.6 ± 52.2
PD%
12.95 ± 5.58
18.3 ± 6.12
17.7 ± 6.72 Introduction Septic shock patients are submitted to many therapeutic
strategies, including sedation. It is unknown if diff erent sedative drugs
infl uence microcirculation. Methods We performed a prospective observational study, using
sidestream dark-fi eld imaging (SDF), to evaluate sublingual mucosa
of septic shock patients admitted to our ICU. SDF was applied in two
settings: continuous sedation with propofol and with midazolan. We
repeated each examination after an interval of 30 minutes. Eight fi elds
(videos) were analyzed during propofol and midazolan infusion. Two
videos were obtained from each side of the tongue. The Bispectral
index was monitored along with the Richmond Agitation Sedation
Scale: the dose of both sedatives was titered to maintain light sedation. All demographic and severity of illness data were collected. Vasopressor
agents were maintained to a mean arterial pressure of 70 mmHg and
the cardiac index was kept stable through the protocol study. 1. Leslie K, et al.: Anesthesiology 1996, 84:52-63. P330f P330
Eff ect of critical illness on the pharmacokinetics and dose–response
relationship of midazolam
D Ovakim, KJ Bosma, GB Young, M Sen, LE Norton, F Priestap, RG Tirona,
R Kim, GK Dresser
University of Western Ontario, London, Canada
Critical Care 2012, 16(Suppl 1):P330 (doi: 10.1186/cc10937) P335 Methods Ninety patients admitted to the RRCEM urgently with chest
traumatic injuries have been examined. They were divided into two
groups against the applied method of anesthesia. First (control) group
(47 patients, 38.5 ± 2.4 years): IPA was done before the induction of
anesthesia into the second intercostal space from the damaged side
with bupivakain at a dose of 75 to 100 mg. Analgesic component
maintained by the abovementioned IPA and phentanyl bolus dosing. The second group (43 patients, 36.8 ± 5.4 years): one-sided TPVB
maintained before the induction at ThIV, ThVII levels 0.5% – 5 ml (25 mg)
bupivakain dosing (at the average total 75 to 100 mg) with posterior
paravertebral area catheterization. Analgesic component maintained
by paravertebral analgesia and phentanyl bolus dosing.f Long-term adverse neuropsychological functioning in children who
survived meningococcal septic shock: is there a relationship with
sedation and analgesia during paediatric ICU admission? HL Van Zellem1, E Utens1, SN De Wildt1, WC Hop2, NJ Vet1, KF Joosten1,
C Buysse1
1Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands;
2Erasmus MC, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P335 (doi: 10.1186/cc10942) Long-term adverse neuropsychological functioning in children who
survived meningococcal septic shock: is there a relationship with
sedation and analgesia during paediatric ICU admission? HL Van Zellem1, E Utens1, SN De Wildt1, WC Hop2, NJ Vet1, KF Joosten1,
C Buysse1 y
1Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands;
2Erasmus MC, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P335 (doi: 10.1186/cc10942) Introduction Our objective was to evaluate the association between
the use of sedative and analgesic agents during paediatric intensive
care unit (PICU) treatment and long-term neuropsychological outcome
in children who survived meningococcal septic shock (MSS). Results The diff erences in hemodynamics indexes appeared at the
traumatic moment of operation. In the group using IPA, medium
hypertension with ABP rise in 25.5%, higher rate of HR in 26.1% and
GPVR in 22% were observed and were followed by the decrease of SV
on 24.6% and EF on 13% compared with the second group. Conducting
anesthesia in the fi rst group, hyperdynamic reactions of the systemic
hemodynamics at the separate traumatic levels of operation were
followed by unbalance of hemodynamic rhythms indicating insuffi cient
prevention from surgical aggression. In the second group, as the result
of development of segmental sympathetic block the indexes of ABP, HR
and GPVR were not higher than normal. P334 and nonteaching hospitals (85%) in comparison to academic hospitals
(15%). Most ICUs (94%) use a standardized pain score in the group of
patients who are capable of verbal communication: the Visual Analogue
Scale (57%), Numerical Rating Scale (48%) and Faces Pain Scale (5%)
being the most frequently used scores. In the group of patients who are
unable to communicate, ICUs less frequently use pain scores (19%), with
the Critical-Care Pain Observation Tool (6%) and Behaviour Pain Scale
(5%) being used most frequently. Measurement of pain was considered
most important for patients with burn wounds (67%), trauma patients
(64%), postoperative patients (57%) and those who receive end-of-life
care (64%). Barriers to use pain measurements included the patient’s
inability to communicate (82%), interference with pain assessment due
to sedation (79%), hemodynamic instability (64%), insuffi cient dosages
of analgesics (60%) and the unavailability of a standard pain scoring
system (51%). In addition, guidelines for management of sedation and
analgesics from the Netherlands Association for Intensive Care (NVIC)
had been read by only 20% of the respondents. Factors that were
mentioned to be useful in contributing to an improvement in pain
assessment and eff ective pain control included adequate analgesic
dosage (87%), utilization of protocols and directives (86%), enthusiastic
and motivated personnel (81%) and the utilization of standardized
pain measurement tools. Effi ciency estimation of intrapleural and thoracic paravertebral
block in combination with general anesthesia at thoracoscopic
interventions g
g
Conclusion Preoperatively diclofenac reduces postcraniotomy head-
ache compared to placebo, and reduces postoperative analgesic
requirements. Introduction Chest injuries and traumas have become one of the
most common reasons for admitting patients to emergency surgical
hospitals in recent years. P333fi Effi ciency estimation of intrapleural and thoracic paravertebral
block in combination with general anesthesia at thoracoscopic
interventions
J Sabirov, A Khadjibaev, V Sharipova
Republican Reseach Centre of Emegency Medicine, Tashkent, Uzbekistan
Critical Care 2012, 16(Suppl 1):P333 (doi: 10.1186/cc10940) Preoperative diclofenc reduces postcraniotomy headache: a
randomized, placebo-controlled trial Preoperative diclofenc reduces postcraniotomy headache: a
randomized, placebo-controlled trial p
C Molnár, É Simon, J Gál, P Siró, Á Kazup, B Fülesdi
University of Debrecen, Hungary
Critical Care 2012, 16(Suppl 1):P334 (doi: 10.1186/cc10941) p
C Molnár, É Simon, J Gál, P Siró, Á Kazup, B Fülesdi
University of Debrecen, Hungary
Critical Care 2012, 16(Suppl 1):P334 (doi: 10.1186/cc10941) Introduction We tested the hypothesis that 100 mg oral preoperative
diclofenac reduces postcraniotomy headache. Methods A total of 145 patients having elective craniotonomies
were randomly assigned to diclofenac or placebo. Severity of pain
was assessed by an independent observer using a visual analogue
scale on the day of surgery, on the fi rst postoperative day, and on the
fi fth postoperative day. The total amount of analgesics administered
during the fi rst fi ve postoperative days was converted to intramuscular
morphine equivalents. Results were compared using unpaired, two-
tailed t tests; P <0.05 was considered statistically signifi cant. Results In total, 104 patients had supratentorial and 41 had infratentorial
interventions. Sixty-two patients were assigned to placebo and 83 were
assigned to diclofenac. The results of VAS scores are shown in Table 1. Table 1 (abstract P334). Results of VAS scores
Placebo
DICLO
P value
Day of surgery
4.9 ± 3.5
2.2 ± 3.5
<0.001
First postoperative day
5.5 ± 3.4
3.7 ± 3.5
<0.01
Fifth postoperative day
4.3 ± 3.8
2.6 ± 2.9
<0.01 Table 1 (abstract P334). Results of VAS scores Table 1 (abstract P334). Results of VAS scores p
Conclusion Most Dutch ICUs measure pain frequently (94%) in patients
who are able to communicate. However, in the group of patients who
cannot communicate only 19% of the Dutch ICUs use a standardized
pain score. This fi nding applied to both academic and nonacademic
ICUs, which suggests that eff orts should be put into implementing pain
measures in Dutch ICUs. The relative effi cacy of diclofenac was similar in patients having
supratentorial and infratentorial surgery. Diclofenac also appeared to
be comparably eff ective in both men and women. Systemic analgesic
requirements were reduced during the initial fi ve postoperative days in
patients assigned to diclofenac (intramuscular morphine equivalents:
placebo = 5.3 ± 4.3 mg vs. diclofenac = 3.6 ± 3.3 mg). P332
Current use of pain scores in Dutch ICUs: a postal survey in the
Netherlands M Van der Woude1, L Bormans1, J Hofhuis2, P Spronk2
1Atrium Medical Center, Heerlen, the Netherlands; 2Gelre Hospitals, Apeldoorn,
the Netherlands
Critical Care 2012, 16(Suppl 1):P332 (doi: 10.1186/cc10939) Methods For this observational study, patients admitted to the ICU with
a diagnosis of sepsis and receiving a continuous infusion of midazolam
were screened for inclusion. Upon enrollment, a continuous subhairline
EEG was applied and blood samples were collected daily for plasma
midazolam quantifi cation. Clinical data and laboratory parameters
were followed. Plasma midazolam levels were quantifi ed using liquid
chromatography with tandem mass spectroscopy. Critical Care 2012, 16(Suppl 1):P332 (doi: 10.1186/cc10939 Introduction Pain is a common problem for patients admitted to
the ICU, causing patient discomfort, agitation and accidental self-
extubation. For this reason the recognition of pain and its severity
is extremely important. Several pain scores and protocols are in use. We aimed to elucidate current practice of pain measurements and
treatment in Dutch ICUs. Results Data were available for nine patients. Midazolam clearance
demonstrated wide intersubject variability (range 31 ml/minute to
1,157 ml/minute) although average clearance among all patients
(418 ml/minute) was comparable to that of healthy controls. Mean
midazolam concentrations for patients with coma were signifi cantly
higher than for patients without coma (218 ± 185 ng/ml vs. 106 ± 107 ng/ml). The plasma midazolam concentration inversely Methods In March 2011, a questionnaire was sent to all Dutch adult
ICUs irrespective of the number of ICU beds with active follow-up by
telephone calls to optimize the participation rate. Results A total of 84 ICUs (84/107) returned the survey, representing
a response rate of 87%. Most ICUs are community teaching hospitals S120 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P336 Delirium could be an indicator of sepsis in patients under 65 years
old with urinary tract infections
U Yamada, K Yokota, D Ohta, K Furukawa
St Luke’s International Hospital, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P336 (doi: 10.1186/cc10943) Introduction Delirium, known as sepsis-associated encephalopathy, is
a frequent complication of sepsis and may be an independent predictor
of mortality of septic patients [1]. A recent study reported delirium
could be a predictor or an early marker of sepsis in CABG patients [2]. Urinary tract infection (UTI) often complicates sepsis and delirium;
however, relations between delirium and sepsis in UTI patients have
not been well investigated. We assessed the relationship between
delirium and sepsis in patients with UTI. Figure 1 (abstract P337). ROC curve: CAM-ICU (solid line and circles) and
ICDSC (dashed line and squares). Methods This study was conducted at St Luke’s International Hospital
in Tokyo, Japan between January 2009 and October 2011. UTI and
sepsis were diagnosed based on positive bacterial cultures and clinical
symptoms. Delirium was screened with the Delirium Screening Tool (the
11-item questionnaire, sensitivity 98% and specifi city 76%) by trained
physicians and nurses. Medical records of patients were reviewed
to collect information including age, sex and complications. The
association between possible risk factors and delirium was analyzed by
chi-squared tests and t tests. Statistical analysis was performed using
SPSS software version 15.0J. had to be diagnosed based on appropriate criteria by a delirium expert. The outcomes assessed were: sensitivity, specifi city, likelihood ratios
and summary receiver-operating characteristic (ROC) curves.i had to be diagnosed based on appropriate criteria by a delirium expert. The outcomes assessed were: sensitivity, specifi city, likelihood ratios
and summary receiver-operating characteristic (ROC) curves. Results Fifteen studies covering 1,404 participants and fi ve screening
tools were included in the systematic review. The pooled sensitivities
and specifi cities for CAM-ICU for detection of delirium in critically ill
patients were 76.0% and 95.7% and for ICDSC were 74.4% and 75.2%,
respectively. All but one study was performed in a research setting, and
that one study suggested that, with routine use of CAM-ICU, one-half of
the patients with delirium were not detected. See Figure 1. Conclusion The CAM-ICU was the most specifi c bedside tool for
assessment of delirium in critically ill patients. However, there was
signifi cant heterogeneity of the results. p
References 1. Ebersoldt M, Sharshar T, Annane D: Sepsis-associated delirium. Intensive Care
Med 2007, 33:941-950. 1. Ebersoldt M, Sharshar T, Annane D: Sepsis-associated delirium. Intensive Care
Med 2007, 33:941-950. 2. Martin BJ, Buth KJ, Arora RC, Baskett RJ: Delirium as a predictor of sepsis in
post-coronary artery bypass grafting patients: a retrospective cohort
study. Crit Care 2010, 14:R171. 2. Martin BJ, Buth KJ, Arora RC, Baskett RJ: Delirium as a predictor of sepsis in
post-coronary artery bypass grafting patients: a retrospective cohort
study. Crit Care 2010, 14:R171. Introduction Up to 80% of patients experience delirium during their
ICU stay [1,2]. The most sensitive screenings tool for delirium in a
research setting is the Confusion Assessment Method for the ICU (CAM-
ICU), but the low sensitivity of the CAM-ICU in daily practice (47%)
hampers early detection of delirium and thereby delays treatment
[3,4]. Therefore, there is a need for an objective tool for continuous
delirium monitoring. Diagnosis of delirium can also be conducted
using electroencephalography (EEG) [5]. EEG with a limited number of
electrodes and automatic processing may be a more sensitive approach
for delirium monitoring. The aim of this systematic review is to explore
opportunities for automatic detection of delirium by summarizing EEG
characteristics of delirium. P335 and adverse outcome on multiple domains of neuropsychological
functioning (full-scale IQ (P = 0.02; Z = –2.28), verbal IQ (P = 0.02;
Z = –2.32), verbal reasoning (P = 0.02; Z = –2.34), social comprehension
(P = 0.01; Z = –2.56), visual–motor integration (P = 0.03; Z = –2.17)). After
univariate analysis, correcting for socioeconomic status, age at follow-
up and severity of illness, these correlations remained signifi cant.i and adverse outcome on multiple domains of neuropsychological
functioning (full-scale IQ (P = 0.02; Z = –2.28), verbal IQ (P = 0.02;
Z = –2.32), verbal reasoning (P = 0.02; Z = –2.34), social comprehension
(P = 0.01; Z = –2.56), visual–motor integration (P = 0.03; Z = –2.17)). After
univariate analysis, correcting for socioeconomic status, age at follow-
up and severity of illness, these correlations remained signifi cant.i Conclusion The use of opioids during PICU admission was signifi cantly
associated with long-term adverse neuropsychological outcome in
MSS survivors. P335 g
Methods This study is part of a medical and psychological follow-
up study of all consecutive MSS survivors requiring PICU treatment
between 1988 and 2001 at the Erasmus MC – Sophia Children’s Hospital,
a tertiary-care university hospital. This follow-up study revealed
that MSS survivors showed long-term (at least 4 years after PICU
admission) impairments on several domains of neuropsychological
functioning. Severity of illness was no signifi cant predictor of adverse
neuropsychological outcome. The use (type, number and dose) of
sedatives and analgesics was retrospectively evaluated. Conclusion Both methods of regional anesthesia cut short pain
syndrome suffi ciently and safely in patients with chest injuries before
an operative intervention. Introduction of the TPVB component into
the anesthesia scheme of thoracoscopic operative interventions
allows one to provide additional antinociceptive protection in the
intraoperative period with minimal stress of central and peripheral
parameters and promotes the reduction of narcotic analgesic use due
to signifi cant analgesic effi ciency and neurovegetative protection. Results The study population consisted of 77 patients (52% male
(n = 40), median age 25 months at time of PICU admission). In 45 patients
(58%) one or more analgesic and/or sedative drugs were administered
during PICU admission. Benzodiazepines were the most commonly
used drugs (n = 39; 51%), followed by opioids (n = 23; 30%). In total
15 diff erent kinds of analgesic or sedative drugs were given. There
was a statistically signifi cant correlation between the use of opioids
(both as continuous (cumulative dose) and dichotomous variable) S121 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 and adverse outcome on multiple domains of neuropsychological
functioning (full-scale IQ (P = 0.02; Z = –2.28), verbal IQ (P = 0.02;
Z = –2.32), verbal reasoning (P = 0.02; Z = –2.34), social comprehension
(P = 0.01; Z = –2.56), visual–motor integration (P = 0.03; Z = –2.17)). After
univariate analysis, correcting for socioeconomic status, age at follow-
up and severity of illness, these correlations remained signifi cant. Conclusion The use of opioids during PICU admission was signifi cantly
associated with long-term adverse neuropsychological outcome in
MSS survivors. Figure 1 (abstract P337). ROC curve: CAM-ICU (solid line and circles) and
ICDSC (dashed line and squares). P338
Electroencephalography-based monitoring of delirium in the ICU:
what are the opportunities?
AW Van der Kooi, FS Leijten, RJ Van der Wekken, AJ Slooter
University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P338 (doi: 10.1186/cc10945) P338
Electroencephalography-based monitoring of delirium in the ICU:
what are the opportunities? AW Van der Kooi, FS Leijten, RJ Van der Wekken, AJ Slooter
University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P338 (doi: 10.1186/cc10945) P336 These fi ndings were largely
obtained in research settings, and the low sensitivity of the CAM-ICU in
routine, daily practice may limit its use as a screening test. y
p
g
Results Fifteen studies covering 1,404 participants and fi ve screening
tools were included in the systematic review. The pooled sensitivities
and specifi cities for CAM-ICU for detection of delirium in critically ill
patients were 76.0% and 95.7% and for ICDSC were 74.4% and 75.2%,
respectively. All but one study was performed in a research setting, and
that one study suggested that, with routine use of CAM-ICU, one-half of
the patients with delirium were not detected. See Figure 1.i Results Of all 1,727 UTI patients, 905 were men and the mean age
was 73.65 ± 14.1. In total, 425 patients (24.6%) became delirious, and
247 patients (14.3%) had sepsis. There was no signifi cant association
between sepsis and delirium (P = 0.051). However, in the younger
population (age <65) delirium occurred signifi cantly more frequently
in septic patients than in nonseptic patients (22.9% vs. 10%, P <0.001). Conclusion Among UTI patients, sepsis may increase the complication
of delirium. Especially in patients under 65 years old with UTI, delirium
symptoms can be a marker for complication of sepsis. In contrast,
delirium of patients aged 65 or over could be associated with not only
sepsis but also other factors such as dementia, aging and UTI itself. p
g
Conclusion The CAM-ICU was the most specifi c bedside tool for
assessment of delirium in critically ill patients. However, there was
signifi cant heterogeneity of the results. These fi ndings were largely
obtained in research settings, and the low sensitivity of the CAM-ICU in
routine, daily practice may limit its use as a screening test. P338 Delirium screening in critically ill patients: a systematic review and
meta-analysis A Serpa Neto1, AP Nassar Júnior2, SO Cardoso1, JA Manetta1, VG Pereira1,
DC Esposito1, MC Damasceno1, AJ Slooter3
1ABC Medican School, Santo André, Brazil; 2São Camilo Hospital, São Paulo,
Brazil; 3University Medical Center Utrecht, the Netherlands
Critical Care 2012, 16(Suppl 1):P337 (doi: 10.1186/cc10944) Introduction Despite its frequency and impact, delirium in critically ill
patients is poorly recognized. Our aim was to systematically review the
accuracy of delirium screening instruments in critically ill patients. Introduction Despite its frequency and impact, delirium in critically ill
patients is poorly recognized. Our aim was to systematically review the
accuracy of delirium screening instruments in critically ill patients. Methods Systematic review and meta-analysis of publications between
1966 and 2011. The Medline and Embase databases were searched for
studies on delirium in critically ill patients in ICUs, surgical wards or
emergency rooms. The delirium screening tool had to be feasible in a
clinical setting for use by a nonexpert. As the gold standard, delirium Methods A systematic literature search was conducted in Embase
and Medline. Articles concerning quantitative EEG and delirium were
included. Per article, the diff erences between delirious and nondelirious
subjects in EEG characteristics were noted. Methods Systematic review and meta-analysis of publications between
1966 and 2011. The Medline and Embase databases were searched for
studies on delirium in critically ill patients in ICUs, surgical wards or
emergency rooms. The delirium screening tool had to be feasible in a
clinical setting for use by a nonexpert. As the gold standard, delirium Results Fourteen studies were included, which were predominantly
conducted in older patients. The relative power of the theta frequency
band was most often and without exception signifi cantly diff erent (7/14
studies) in delirious subjects. Other frequently measured parameters S122 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods A prospective observational study in a university hospital
including patients over 18 years old, in the fi rst 48 hours of ICU
admission, with an expected ICU stay of at least 72 hours and signed
informed consent. Pregnancy, cognitive impairment prior to admission,
hepatic encephalopathy, Glasgow Coma Scale ≤9, active psychiatric
illness, need for sedation or neuromuscular blockade, aphasia, foreign
language, deafness and brain death were exclusion criteria. CAM-ICU
was applied and doctors and nurses asked about the presence of
delirium. Demographic data, SOFA score, mechanical ventilation and
drugs used were determined. g p
Reference y
Results A total of 225 patients were included. The incidence of delirium
was 24%. Patients who develop delirium during the ICU stay were older
(OR 1.04, 1.02 to 1.07) and more likely to have a previous diagnosis of
hypertension (OR 2.36, 1.24 to 4.52). The SAPS 3 (OR 1.09, 1.06 to 1.13)
score, SOFA (OR 1.23, 1.09 to 1.39) score, and mechanical ventilation
requirement (OR 3.6; 1.35 to 9.60) were higher among patients with
delirium. These patients had longer ICU and hospital length of stay, and
a higher crude mortality rate (24.07 vs. 7.02%). In a multivariate analysis,
age (OR 1.03, 1.00 to 1.05), use of mechanical ventilation (OR 3.91, 1.22
to 12.96) and SAPS 3 score (OR 1.08, 1.04 to 1.12) were independently
associated with delirium. SAPS 3 performed well in predicting delirium
with an AUR ROC of 0.785 (0.714 to 0.856, best cut-off value ≥54 points)
and a GoF of 0.175. 1. Ely EW, et al.: Crit Care Med 2001, 29:1370-1379. P341 Performance of SAPS 3 in predicting delirium among critically ill
patients p
T Cosentino, J Biatto, I Souza, M Dutra, L Ilnicki, P Martins, G Schettino,
F Machado
Hospital Sírio-Libanês, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P339 (doi: 10.1186/cc10946) Introduction Delirium is a common complication in critically ill patients,
occurring in up to 80% of patients on mechanical ventilation [1]. Recent studies showed that sicker patients at ICU admission, assessed
by severity scores, are more susceptible to developing delirium [2]. To
further evaluate this hypothesis, we undertook this study to assess the
performance of SAPS 3 in predicting delirium, among adult patients
admitted to a general ICU. Table 1 (abstract P340). κ values
Health provider
Delirium
Hypoactive
Attending physicians
0.530
0.019
Medical residents
0.615
0.018
Nurses
0.588
0.025 g
Methods This was a prospective observational cohort study performed
between June 2010 and June 2011, in a 26-bed ICU at Hospital Sírio-
Libanês, São Paulo, Brazil. All consecutive adult patients admitted to
the ICU were included. Patients with a previous diagnosis of advanced
dementia and those with acute neurological disease (Glasgow <13)
were excluded. The evaluation of delirium was performed using the
CAM-ICU during routine bedside rounds in the morning. Discrimination
and calibration of SAPS 3 in predicting delirium were assessed by the
area under the receiver operating curve (AUR ROC) and the goodness of
fi t (GoF) test, respectively. Secondary outcomes were hospital mortality
and lengths of stay among patients with delirium. Conclusion Delirium had a higher incidence in intensive care patients
and was related to longer hospital stay and higher mortality. Specifi c
tests should be used for diagnosis, since the clinical suspicion has
low sensitivity, especially in cases of hypoactive delirium and among
attending physicians. References 1. Ely EW, et al.: JAMA 2001, 286:2703-2710. 1. Ely EW, et al.: JAMA 2001, 286:2703-2710. 1. Ely EW, et al.: JAMA 2001, 286:2703-2710. 2. Van Rompaey B, et al.: Crit Care 2009, 13:R77. 1. Ely EW, et al.: JAMA 2001, 286:2703 2710. 2. Van Rompaey B, et al.: Crit Care 2009, 13:R77. 2. Van Rompaey B, et al.: Crit Care 2009, 13:R77. y
Methods A prospective cohort study over 8 weeks in a 25-bed ICU
setting. Daily CAM-ICU assessments were done by three trained
doctors. It was noted whether the ICU team had assessed the individual
patient for delirium. If the patient was delirious, the team was informed
and their management was noted. Eligible patients had to have a RASS
score above –4 and be able to comply with the assessment. The Fisher’s
exact test was used to calculate statistical signifi cance of detection and
treatment. Delirium screening in critically ill patients: a systematic review and
meta-analysis Patients were followed for 14 days or
until discharge from the ICU. The agreement between CAM-ICU and
clinical diagnosis was assessed using Cohen’s kappa statistic (κ). Risk
factors were assessed by a multivariate regression model. were the relative power of the delta and alpha frequency band and the
peak frequency. None of these studies addressed the optimal electrode
deviation or the question of how to distinguish sleep from delirium. Conclusion Given the feasibility for continuous EEG monitoring in ICU,
EEG delirium monitoring in ICU patients seems to be promising. References 1. Ely EW, et al.: JAMA 2004, 291:1753-1762. 2. Girard TD, et al.: Lancet 2008, 371:126-134. 3. van Eijk MM, et al.: Am J Respir Crit Care Med 2011, 184:340-344. 4. van Eijk MMJ, et al.: Crit Care Med 2009, 37:1881-1885. 5. Romano J, et al.: Arch Neurol Psychiatry 1944, 51:356-377. Investigation into detection and treatment rates of hyperactive and
hypoactive delirium in the ICU setting S Kudsk-Iversen, J Wong, H Kingston, L Poole S Kudsk-Iversen, J Wong, H Kingston, L Poole g
g
The Royal Liverpool University Hospital, Liverpool, UK y
p
y
p
,
p
,
Critical Care 2012, 16(Suppl 1):P341 (doi: 10.1186/cc10948) Introduction We aimed to investigate the link between the type of
delirium (that is, hyperactive or hypoactive), its detection by the day
staff and the subsequent treatment. The morbidity related to delirium
is well known to critical care medical staff ; however, some fi ndings
suggest insuffi cient and inconsistent recognition and management
of delirium [1]. Hypoactive delirium, despite being more common in
the ICU setting, often goes undetected and undertreated due to its
withdrawn and drowsy presentation [2]. Conclusion We found that SAPS 3 was a good parameter for predicting
delirium during the ICU stay. Future studies are needed to confi rm our
results in a larger and diff erent patient sampling. References P339 y
g
Results In the 119 patients included, the incidence of delirium
was 24.4% (29 patients) and time to development of delirium was
68.3 ± 63.6 hours. The agreement between clinical diagnoses and CAM-
ICU was better for medical residents (Table 1). Patients with delirium
had a longer ICU (10.83 ± 15.08 and 4.98 ± 9.57, P = 0.015) and hospital
(36.93 ± 31.33 and 19.10 ± 19.48, P = 0.0004) length of stay, higher ICU
mortality (13.79% and 2.22%, OR = 7.04 (1.22 to 40.7)) and hospital
mortality (27.6% and 6.66%, OR = 5.33 (1.67 to 17.04)) than patients
without delirium. Risk factors were: mechanical ventilation (P = 0.018,
OR = 3.09 (1.21 to 7.86)) and APACHE II score greater than 8.5 (P = 0.011,
OR = 5.35 (1.48 to 19.43)). Incidence of delirium and inadequacy of the clinical diagnosis in
patients in intensive carei Hyperactive and hypoactive cases and their
treatment rate P343
Using tramadol to monitor hepatic drug metabolism in the critically
ill
K Lane1, JJ Dixon1, D McKeown2, A Johnston2, I MacPhee1, BJ Philips1
1Acute Kidney Injury Research Group, St George’s, University of London, UK;
2Analytical Services International Ltd, St George’s, University of London, UK
Critical Care 2012, 16(Suppl 1):P343 (doi: 10.1186/cc10950) the delirium was recognised, 76% of the hyperactive and 20% of the
hypoactive cases were started on targeted treatment (P = 0.0038). See
Tables 1 and 2. Conclusion Although the study had a higher rate of hyperactive
delirium compared to otherwise available research, the fi ndings
confi rmed that a signifi cant proportion of hypoactive delirium goes
undetected and remains largely undertreated. Introduction Previously, we have demonstrated signifi cant inhibition
of hepatic drug metabolism by the enzymes cytochrome P450 (CYP)
3A4 and 3A5 in acute kidney injury (AKI) using midazolam as a probe
drug [1,2]. We are now developing the use of tramadol as a probe drug
to test the hypothesis that CYP2D6 function is also inhibited by AKI in
critical illness. In this study we sought to determine whether a single
timepoint tramadol concentration could be identifi ed as a reliable
surrogate for measurement of a full area under the concentration time
curve after intravenous administration in adults. Introduction Previously, we have demonstrated signifi cant inhibition
of hepatic drug metabolism by the enzymes cytochrome P450 (CYP)
3A4 and 3A5 in acute kidney injury (AKI) using midazolam as a probe
drug [1,2]. We are now developing the use of tramadol as a probe drug
to test the hypothesis that CYP2D6 function is also inhibited by AKI in
critical illness. In this study we sought to determine whether a single
timepoint tramadol concentration could be identifi ed as a reliable
surrogate for measurement of a full area under the concentration time
curve after intravenous administration in adults. Methods We conducted a study of 10 critically ill patients in our
hospital’s general critical care unit. Tramadol 10 mg was given
intravenously, and serum was taken at 0.5, 1, 2, 3, 4 and 8 hours for
determination of concentrations of tramadol ([tramadol]) and its two
main metabolites. Inclusion criteria: age >18 years, predicted ICU
stay >48 hours. Exclusion criteria: recent receipt of tramadol or major
CYP2D6 inhibitors, hepatic failure, pregnancy/breastfeeding. P342
Memories and post-traumatic stress-related symptoms in older,
post-cardiac surgery patients: substudy of an RCT
N Hammond, F Bass, Y Shehabi
Prince of Wales Hospital, Randwick, Australia
Critical Care 2012, 16(Suppl 1):P342 (doi: 10.1186/cc10949) N Hammond, F Bass, Y Shehabi g
y
g
Results There was a strong correlation between the area under the
curve (AUC) of the [tramadol]–time graph and t = 4 hours [tramadol],
P <0.0001, r = 0.983. See Figure 1. The [tramadol] at other timepoints
correlated less strongly with the AUC. The mean [tramadol] at 4 hours
was 29.7 ng/ml (24.3 to 35.1) and the mean AUC was 257 ng/hour/ml
(211 to 303). Analysis of tramadol metabolites confi rmed that CYP2D6
was predominantly responsible for tramadol metabolism. Introduction The majority of ICU survivors display little evidence of
severe psychological sequelae. However, there is evidence of post-
traumatic stress disorder (PTSD)-related symptoms such as anxiety,
depression, panic attacks, distressing memories and fl ashbacks
within the fi rst 3 months post ICU discharge [1,2]. This substudy of
the DEXCOM trial 3 (randomised controlled trial of neurobehavioural
eff ects of dexmedetomidine or morphine for sedation and analgesia in
patients 60 years or older, undergoing coronary artery bypass grafting
and/or valve replacement) aims to explore any negative memories
of the ICU and development of PTSD-related symptoms between
treatment groups of patients at high risk of developing delirium. Conclusion A single blood sample, taken 4 hours post-intravenous
tramadol injection, reliably predicts integral tramadol exposure in
critically ill adults and may be useful for assessing CYP2D6 function.l A larger study of the infl uences of AKI and CYP genotype on hepatic
drug metabolism in the critically ill is underway. Incidence of delirium and inadequacy of the clinical diagnosis in
patients in intensive carei Results A total of 139 patients were included, providing a total of 507
patient-days. On 32 occasions (6%) the patient assessed was found
to be delirious. Twelve patients in ITU (19%) and nine in HDU (9%)
were delirious at least once. Of the 32 cases of delirium, 53% were
hyperactive. Seventy-six percent of the hyperactive and 27% of the
hypoactive cases had been detected by the day team (P = 0.0118). Once Introduction This study aims to assess the incidence, risk factors
and impact of delirium on outcome and to analyze the concordance
between the Confusion Assessment Method for the Intensive Care
(CAM-ICU) and clinical diagnosis. S123 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 a convenience sample so was not powered to detect a signifi cant
diff erence. No diff erences in factual or delusional memories or PTSD-
related symptoms between the treatment groups were found. These
data could be the basis of a sample size calculation for a larger study. References
1. Schelling G, et al.: Crit Care Med 1998, 26:651-659. 2. Stoll C, et al.: J Thorac Cardiovasc Surg 2000, 120:505-512. 3. Shehabi Y, et al.: Anesthesiology 2009, 111:1074-1083. Table 1 (abstract P341). Hyperactive and hypoactive cases and their
detection rate
Number of
Number of
hyperactive (%)
hypoactive (%)
Detected
13 (76)
4 (27)
Not detected
4 (24)
11 (73)
T bl 2 ( b
P3
) H
i
d h
i
d h i Table 1 (abstract P341). Hyperactive and hypoactive cases and their
detection rate a convenience sample so was not powered to detect a signifi cant
diff erence. No diff erences in factual or delusional memories or PTSD-
related symptoms between the treatment groups were found. These
data could be the basis of a sample size calculation for a larger study. References Schelling G, et al.: Crit Care Med 1998, 26:651-659. Stoll C, et al.: J Thorac Cardiovasc Surg 2000, 120:505-512. Shehabi Y, et al.: Anesthesiology 2009, 111:1074-1083. Table 2 (abstract P341). 1.
Kirwan CJ, et al.: Intensive Care Med 2009, 35:1271-1275.
2.
Kirwan CJ, et al.: Intensive Care Med 2012, 38:76-84. P344
Data mining techniques for predicting acute kidney injury after
elective cardiac surgery
J Van Eyck, J Ramon, F Guiza, G Meyfroidt, M Bruynooghe,
G Van den Berghe
K.U. Leuven, Heverlee, Belgium
Critical Care 2012, 16(Suppl 1):P344 (doi: 10.1186/cc10951) P344 change in creatinine). Nine patients (33% of all patients, 64% of AKI
patients) received RRT. ICU mortality was three out of 14 (21%) patients
with AKI and one out of 13 (8%) patients without AKI. This diff erence
was not statistically signifi cant. Thirteen out of 20 (65%) ventilated
patients developed AKI, compared with one out of seven (14%)
nonventilated patients. This diff erence was statistically signifi cant
(P = 0.0329). Excluding fatalities, the duration of IPPV was longer in
patients with AKI (median 11 days, range 0 to 54 days) than in patients
without AKI (median 1 day, range 0 to 20 days). This diff erence was
statistically signifi cant (P <0.05). Excluding fatalities, the length of stay
was longer in patients with AKI (median 19 days, range 10 to 68 days)
than in patients without AKI (median 5 days, range 2 to 29 days). This
diff erence was statistically signifi cant (P <0.02). P344
Data mining techniques for predicting acute kidney injury after
elective cardiac surgery
J Van Eyck, J Ramon, F Guiza, G Meyfroidt, M Bruynooghe,
G Van den Berghe
K.U. Leuven, Heverlee, Belgium
Critical Care 2012, 16(Suppl 1):P344 (doi: 10.1186/cc10951) Introduction Development of acute kidney injury (AKI) during the
postoperative period is associated with increases in both morbidity
and mortality. The aim of this study is to develop a statistical model
capable of predicting the occurrence of AKI in patients after elective
cardiac surgery. f
y
gi
Conclusion We noted a higher incidence of AKI in critical illness
associated with A/H1N1 (52%) compared to that of a larger study [1]. AKI was associated with the incidence as well as duration of mechanical
ventilation and length of stay in the ICU. The use of RRT in the current
study (60%) was much higher than in the modeling study (16%). We
found a trend towards greater mortality with AKI, although (unlike
Petillä and colleagues [1]) this failed to reach signifi cance. Methods A total of 810 adult (>18 years) elective cardiac surgery
patients, admitted to the surgical ICU of the University Hospital
of Leuven between 18 January 2007 and 8 January 2009, were
retrospectively selected for this study. Patients with an ICU stay of less
than 24 hours, as well as patients suff ering from chronic kidney disease,
were excluded. Relevant patient records were extracted from an
electronic database system and analyzed using data mining techniques
[1]. Reference 1. Pettilä V, et al.: Acute kidney injury in patients with infl uenza A (H1N1)
2009. Intensive Care Med 2011, 37:763-767 . Results In this study, two separate models were developed for predicting
the occurrence of AKI (defi ned as RIFLE stage three or need for renal
replacement therapy) within a week after the patient’s admission. An
initial model was built using only readily available admission data
(including demographic information, previous treatments and pre-
admission values for physiological variables). This resulted in an AUC
of 0.6056 (95% CI, 0.4874 to 0.7239) on the validation cohort. The initial
model was then extended by adding information on administered
medication, measurements of physiological parameters and laboratory
results available during the fi rst four hours of the patient’s ICU stay. This
new model resulted in an AUC of 0.8339 (95% CI, 0.7364 to 0.9315) on
the validation cohort. A RIFLE score-based trigger for renal replacement therapy and
survival after cardiac surgery
A Schneider, G Eastwood, S Seevanayagam, G Matalanis, R Bellomo
Austin Health, Heidelberg, Australia
Critical Care 2012, 16(Suppl 1):P346 (doi: 10.1186/cc10953) Acute kidney injury in critically ill patients with A/H1N1
pneumonitis in 2010/11 Acute kidney injury in critically ill patients with A/H1N1
pneumonitis in 2010/11
M Atkinson, A Krige, S Chukkambotla
East Lancashire Hospitals NHS Trust, Blackburn, UK
Critical Care 2012, 16(Suppl 1):P345 (doi: 10.1186/cc10952) Acute kidney injury in critically ill patients with A/H1N1
pneumonitis in 2010/11 Acute kidney injury in critically ill patients with A/H1N1
pneumonitis in 2010/11
M Atkinson, A Krige, S Chukkambotla
East Lancashire Hospitals NHS Trust, Blackburn, UK
Critical Care 2012, 16(Suppl 1):P345 (doi: 10.1186/cc10952) p
M Atkinson, A Krige, S Chukkambotla g
East Lancashire Hospitals NHS Trust, Blackburn, UK y
Conclusion After cardiac surgery, RRT is typically applied to patients
with the most severe clinical presentation irrespective of creatinine
levels. A RIFLE score-based trigger for RRT is unlikely to improve patient
survival. p
Critical Care 2012, 16(Suppl 1):P345 (doi: 10.1186/cc10952) Introduction A/H1N1 infection is a major seasonal cause of illness
requiring critical care admission. A high proportion of these patients
develop acute kidney injury (AKI) [1]. P344
Data mining techniques for predicting acute kidney injury after
elective cardiac surgery
J Van Eyck, J Ramon, F Guiza, G Meyfroidt, M Bruynooghe,
G Van den Berghe
K.U. Leuven, Heverlee, Belgium
Critical Care 2012, 16(Suppl 1):P344 (doi: 10.1186/cc10951) The main advantage of these techniques is that they are capable of
automatically selecting the variables that are relevant to a particular
problem. Using such a data mining algorithm, predictive models were
built on a development cohort of 385 patients and validated on a
separate cohort of 425 patients. A RIFLE score-based trigger for renal replacement therapy and
survival after cardiac surgery A Schneider, G Eastwood, S Seevanayagam, G Matalanis, R Bellomo
Austin Health, Heidelberg, Australia
Critical Care 2012, 16(Suppl 1):P346 (doi: 10.1186/cc10953) Introduction It is controversial whether all critically ill patients with
RIFLE-F class acute kidney injury (AKI) should receive renal replacement
therapy (RRT). We reviewed the outcome of open-heart surgery
patients with severe AKI who did not receive RRT.i Methods We identifi ed all patients who developed AKI after cardiac
surgery during a 4-year period, and obtained baseline characteristics,
intraoperative details and in-hospital outcomes. We analyzed
physiological and biochemical features at the time of RRT initiation or
at peak creatinine if no RRT was provided. Conclusion In this study, we have shown that data mining techniques
are a viable option for developing predictive models in a clinical
setting. Furthermore, we have shown that by adding information
gathered during the patient’s stay, a model’s performance can
drastically improve compared to a model using only admission data. Thus, it might be possible to further improve existing scoring systems
such as the Thakar score [2] and the simplifi ed renal index [3]. References p
p
Results We reviewed 1,504 patients. Of these, 137 (9.1%) developed
postoperative AKI with 71 meeting RIFLE-F criteria and 23 (32.4% of
RIFLE-F cases) not receiving RRT. Compared with RRT-treated RIFLE-F
patients, no-RRT patients had lower APACHE III scores, less intra-
aortic balloon pump requirements, shorter intensive care stay and a
trend toward lower mortality. At peak creatinine, their urinary output,
arterial pH and PaO2/FIO2 ratio were all signifi cantly higher. Their serum
creatinine was also higher (304 vs. 262 μmol/l, P = 0.02). Only three died
in-hospital. Detailed review of cause and mode of death was consistent
with non-RRT-preventable deaths. In contrast, 27 patients with RIFLE-R
or RIFLE-I class received RRT. Compared with RRT-treated RIFLE-F
patients, they had a trend towards a more severe presentation and a
higher mortality (51.8% vs. 29.2%, P = 0.02). See Figure 1. 1. Meyfroidt G, et al.: Best Pract Res Clin Anaesthesiol 2009, 23:127-143. 2. Thakar C, et al.: J Am Soc Nephrol 2005, 16:162-168. 3. Duminda N, et al.: JAMA 2007, 297:1801-1809. P347f Methods We studied all A/H1N1-positive admissions to a district
general hospital (DGH) ICU during the months of December 2010 and
January 2011. The study aimed to describe the incidence of AKI using
the creatinine score from the RIFLE criteria and its associations with
mortality, incidence and duration of intermittent positive pressure
ventilation (IPPV), length of stay in the ICU and provision of renal
replacement therapy (RRT). Eff ect of off -pump versus on-pump coronary artery bypass grafting
in patients with chronic kidney disease
ME Schroeder1, L Chawla1, Y Zhao2, F Lough1, F Najam1, M Seneff 1,
JM Brennan3
1George Washington University Hospital, Washington, DC, USA; 2Duke Clinical
Research Institute, Raleigh, NC, USA; 3Duke University Medical Center, Raleigh,
NC, USA
Critical Care 2012, 16(Suppl 1):P347 (doi: 10.1186/cc10954) References 1. Kirwan CJ, et al.: Intensive Care Med 2009, 35:1271-1275. 2. Kirwan CJ, et al.: Intensive Care Med 2012, 38:76-84. g
p
p
g
p g
Methods At 8 weeks post ICU discharge, patients completed three
assessment tools, by mail or telephone. Tools used were Depression
Anxiety Stress Scale, ICU memory assessment tool and impact of events
scale. Figure 1 (abstract P343). Correlation of [tramadol] at t = 4 hours and
AUC [tramadol]–time graph. iv, intravenous. Results A total of 153 patients completed the substudy; 72 patients in
the [M]orphine group and 81 in the [D]exmedetomidine group. The
mean age (years) in the M group was 72 (SD 5) and in the D group 69
(SD 6), with 71% (n = 51) males in the M group and 84% (n = 68) in
the D group. The mean ICU hours for M and D were 58 (SD 40) and 48
(SD 32) respectively. No signifi cant diff erences of memories or PTSD-
related symptoms between the two treatment groups, for each of the
three assessment tools, were found. From the ICU memory tool, 21%
(n = 15/70) of M group patients and 15% (n = 12/81) of the D patients
remember being in the ICU. Just over one-half of the patients in both
groups did not remember all of their ICU stay with clarity (M group:
54%, n = 39/72; D group: 51%, n = 40/78). Furthermore, 23% (n = 15/64)
of M patients and 14% (n = 10/73) of D patients had intrusive memories
whilst in the ICU. Figure 1 (abstract P343). Correlation of [tramadol] at t = 4 hours and
AUC [tramadol]–time graph. iv, intravenous. Conclusion Patients undergoing cardiac surgery with ICU stay do not
have clear memories of this episode. A small number had intrusive
memories, which are more common in M patients. The study used S124 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Eff ect of off -pump versus on-pump coronary artery bypass grafting
in patients with chronic kidney diseasef Results Twenty-seven patients were admitted to the ICU who tested
positive for A/H1N1. Fourteen (52%) met the RIFLE criteria for AKI. Of
these, three (11%) met the RIFLE criterion for Risk (>150% change in
creatinine), three (11%) met the criterion for Injury (>200% change
in creatinine), and eight (30%) met the criterion for Failure (>300% Critical Care 2012, 16(Suppl 1):P347 (doi: 10.1186/cc10954) Introduction Patients with chronic kidney disease (CKD) have been
largely excluded from clinical trials of off -pump coronary artery bypass S125 Critical Care 2012, Volume 16 Suppl 1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P346). Flow chart. ASCTS, Australian Society of Cardio Thoracic Sugery. Figure 1 (abstract P346). Flow chart. ASCTS, Australian Society of Cardio Thoracic Sugery. dopamine to protect the kidneys against hypoperfusion injury following
cardiac surgery remains controversial. Cystatin C has been described
as a sensitive biomarker of early renal tubular injury. We aimed to
evaluate the eff ect of renal-dose dopamine on renal tubular functions
in patients undergoing coronary artery bypass grafting (CABG) surgery. Methods Thirty-six patients undergoing CABG surgery were prospec-
tively randomized to receive either 2 μg/kg/minute dopamine infusion
(Group D, n = 19) or saline as placebo (Group P, n = 17) starting from
induction of anesthesia for 48 hours. Serial blood and urine samples
after induction of anesthesia and 2, 12, 24, 48 hours post CPB
were collected to measure serum cystatin C, creatinine levels and
urinary β2-microglobulin. Intraoperative and daily measurements of
hemodynamic parameters and urine output were recorded. grafting (OPCAB). We sought to determine if the pump status aff ected
outcomes in patients with CKD. Methods Using a nonrandomized cohort of 742,909 nonemergent,
isolated CABG cases (including 158,561 OPCAB cases) in the Society
of Thoracic Surgery Database from 2004 through 2009, we evaluated
the association between pump status (off -pump vs. on-pump) and
in-hospital death or incidence of renal replacement therapy (RRT)
across strata of preoperative renal function. We used both propensity
methods and an instrumental variable (IV) approach to account for
imbalances in baseline patient risk.f Results Compared with on-pump cases, off -pump cases were of similar
age (65.6 vs. 64.9 years) with a similar distribution of preoperative
estimated glomerular fi ltration rate (eGFR). Eff ects of renal-dose dopamine on renal tubular functions following
coronary artery bypass grafting surgery Eff ects of renal-dose dopamine on renal tubular functions following
coronary artery bypass grafting surgery
P Zeyneloglu, H Ozdemir, O Komurcu, N Bayraktar, A Sezgin, A Pirat,
G Arslan
Baskent University, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P348 (doi: 10.1186/cc10955) Eff ects of renal-dose dopamine on renal tubular functions following
coronary artery bypass grafting surgery
P Zeyneloglu, H Ozdemir, O Komurcu, N Bayraktar, A Sezgin, A Pirat,
G Arslan
Baskent University, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P348 (doi: 10.1186/cc10955) y
y yp
g
g
g
y
P Zeyneloglu, H Ozdemir, O Komurcu, N Bayraktar, A Sezgin, A Pirat,
G Arslan
Baskent University, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P348 (doi: 10.1186/cc10955) Conclusion The results suggest that renal-dose dopamine does not
exacerbate the severity of renal tubular injury when compared with the
untreated controls during the early postoperative period of patients
undergoing CABG surgery. Reference y
y
Critical Care 2012, 16(Suppl 1):P348 (doi: 10.1186/cc10955) Introduction Cardiopulmonary bypass (CPB) is regarded as an
important contributor to acute kidney injury and use of renal-dose Eff ect of off -pump versus on-pump coronary artery bypass grafting
in patients with chronic kidney diseasef In a propensity weighted
analysis, OPCAB was associated with a reduction in composite in-
hospital death or RRT, with a progressively increased benefi t among
those with lower preoperative renal function (eGFR ≥90 ml/minute:
risk diff erence = 0.05 per 100 patients (on-pump minus off -pump), 95%
confi dence interval = –0.06 to 0.16; 60 to 89 ml/minute: 0.14, 0.05 to 0.23;
30 to 59 ml/minute: 0.66, 0.45 to 0.87; and 15 to 29 ml/minute: 3.66, 2.14
to 5.18). A similar trend was observed for both component endpoints. However, while the IV analysis confi rmed the protective eff ect of OPCAB
on composite in-hospital death or RRT among patients with a reduced
eGFR, this result was driven by an eff ect on RRT and not mortality. y
p
p
Results The groups were similar in terms of physical characteristics,
perioperative hemodynamic measurements, urine outputs and surgical
times. Serum cystatin C levels demonstrated similar increases during
12, 24 and 48 hours post CPB in the dopamine and placebo groups
(P >0.05 for all). See Table 1. No diff erences were detected with respect
to serum creatinine and urine β2-microglobulin levels between the
groups (P >0.05 for both). GFR was preserved equally in both groups on
postoperative day 2 (104.1 ± 23.1 vs. 101.4 ± 35.8 ml/minute, P >0.05). Table 1 (abstract P348). Serum cystatin C levels (ng/ml) of the patients
Group D (n = 19)
Group P (n = 17)
P value
Induction
803 ± 173
789 ± 285
0.987
2 hours CPB
857 ± 236
861 ± 347
0.664
12 hours CPB
807 ± 239
1,132 ± 396
0.052
24 hours CPB
906 ± 211
1,158 ± 432
0.149
48 hours CPB
1,296 ± 341
1,129 ± 350
0.296 Table 1 (abstract P348). Serum cystatin C levels (ng/ml) of the patients yf
y
Conclusion Patients with CKD experience less death or incidence of
RRT when treated with off -pump versus on-pump CABG; however,
this composite eff ect is driven by a reduction in incidence of RRT (not
death) among low eGFR patients. Prospective trials comparing these
procedures in patients with impaired preoperative renal function are
warranted. P351 P351
Plasma and urine neutrophil gelatinase-associated lipocalin as
markers of acute kidney injury in critically ill adults
R Matsa1, E Ashley2, J Osypiw2, V Sharma1, A Walden2, L Keating2
1Oxford University Hospitals NHS Trust, Oxford, UK; 2Royal Berkshire NHS
Foundation Trust, Reading, UK
Critical Care 2012, 16(Suppl 1):P351 (doi: 10.1186/cc10958) Methods This was a multicenter, prospective, longitudinal study. The
study population included 216 nurses who work in the ICU, inpatient
care unit, and emergency unit at six public and private hospitals. Data
collection was performed from October 2010 to February 2011 using
a 10-question questionnaire related to prevention, diagnosis, and
treatment of AKI. Introduction Acute kidney injury (AKI) has signifi cant impact both on the
morbidity and mortality in patients on the ICU. The current defi nition and
classifi cation of AKI [1] uses changes in both the serum creatinine and
urine output. This occurs late in the evolution of AKI and so the diagnosis
can be delayed. Early detection of AKI could allow earlier recognition and
treatment of the condition. Neutrophil gelatinase-associated lipocalin
(NGAL) is a 25-kDa protein produced in response to infl ammation,
infection and kidney injury [2] and is found in blood and urine samples
obtained from patients soon after the onset of AKI [3]. Earlier studies have
shown that NGAL can be detected as early as 2 hours following AKI [2]. The predictive value of NGAL in the ICU may help the earlier recognition
of AKI. The aim of the study is to determine whether plasma and/or urine
NGAL levels can predict the earlier incidence of AKI (as defi ned by RIFLE
criteria) in critically ill patients. Results Data showed that 81.7% of the nurses gave correct answers
regarding the association of urine volume rate in the identifi cation of
AKI; 57.2% did not know how to identify the clinical manifestations of
AKI; 67.1% made a mistake by answering that the subtle increase of
creatinine has no great impact on a mortality rate; 66.8% answered the
question incorrectly on measures to prevent AKI; 60.4% were correct
when they answered that the use of loop diuretics in the prevention of
AKI is not recommended; and 92.5% said they had no knowledge of the
Acute Kidney Injury Network classifi cation. Conclusion The results showed that most nurses do not have enough
knowledge for the early identifi cation of AKI. References References
1. Bellomo R, et al.: Crit Care 2004, 8:R204-R212. 2. Mishra J, et al.: Lancet 2005, 365:1231-1238. 3. Mishra J, et al.: Pediatr Nephrol 2006, 21:856-863. References
1. Bellomo R, et al.: Crit Care 2004, 8:R204-R212. 2. Mishra J, et al.: Lancet 2005, 365:1231-1238. h
l
d
h l 3. Mishra J, et al.: Pediatr Nephrol 2006, 21:856-863. Results Postoperative fl uid overload was present in 15% of patients
with a mean positive fl uid balance of 12 ± 9 kg. Patients who survived
the hospital stay had a lower positive fl uid balance of 2.8 l (25th to
75th percentiles: 1.5 to 5.5) compared to patients who died (23.0 l
(25th to 75th percentiles: 14.5 to 24.0)); P = 0.010. A positive fl uid
balance predicted in-hospital mortality with AUC 0.94 (95% CI 0.83
to 0.99), sensitivity 100% and specifi city 80% at a cut-off >6 l. Urine
NGAL predicted fl uid overload (AUC-ROC 0.80 (95% CI 0.64 to 0.93))
and mortality (AUC-ROC 0.88 (95% CI 0.78 to 0.97)). Serum creatinine
did not predict fl uid overload (AUC-ROC 0.51 (95% CI 0.24 to 0.78)) or
mortality (AUC-ROC 0.61 (95% CI 0.16 to 0.99)).i P352 P352
Plasma and urine neutrophil gelatinase-associated lipocalin in
septic and nonseptic ICU patients
CS Vrettou1, S Kokkoris2, K Apostolou2, M Parisi2, E Haritatos2,
S Dimopoulos2, S Nanas1
1National and Kapodistrian University of Athens, Greece; 2Evaggelismos
Hospital, Athens, Greece
Critical Care 2012, 16(Suppl 1):P352 (doi: 10.1186/cc10959) g
g
Reference Sumeray M, et al.: J Nephrol 2001, 14:397-402. Sumeray M, et al.: J Nephrol 2001, 14:397-402. S126 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P349
Nurses’ knowledge regarding the early identifi cation of acute
kidney injury
S Agege Lobo, RM Matheus
Faculdade de Medicina de São José do Rio Preto – FAMERP, São José do Rio
Preto, Brazil
Critical Care 2012, 16(Suppl 1):P349 (doi: 10.1186/cc10956) P351 This highlights the
importance of training programs for nurses who work at hospital
units, with the purpose of developing professional competences and
aptitudes regarding both prevention and detection of AKI. Methods This single-centre prospective observational study is currently
recruiting 200 consecutive adult patients with no AKI on presentation
to the ICU. Serial samples of plasma and urine are collected on all
patients included in the study at 0 hours and then every 24 hours in
the ICU stay up to 72 hours and assayed for NGAL using a turbidimetric
assay on the standardised automated analyser.i P349
Nurses’ knowledge regarding the early identifi cation of acute
kidney injury Critical Care 2012, 16(Suppl 1):P349 (doi: 10.1186/cc10956) Critical Care 2012, 16(Suppl 1):P349 (doi: 10.1186/cc10956) Introduction The objective was to evaluate nurses’ knowledge on the
early identifi cation of acute kidney injury (AKI) in an ICU, inpatient care
unit, and emergency unit. P351 P350 Neutrophil gelatinase-associated lipocalin predicts postoperative
fl uid overload, a potentially modifi able risk factor for mortality after
cardiac surgery
M Haase1, P Mertens1, M Plaß2, R Bellomo3, A Haase-Fielitz1
1Otto-von-Guericke University Magdeburg, Germany; 2German Heart Center,
Berlin, Germany; 3Austin Health, Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P350 (doi: 10.1186/cc10957) Neutrophil gelatinase-associated lipocalin predicts postoperative
fl uid overload, a potentially modifi able risk factor for mortality after
cardiac surgery Neutrophil gelatinase-associated lipocalin predicts postoperative
fl uid overload, a potentially modifi able risk factor for mortality after
cardiac surgery y
y
Results Results on the fi rst 27 patients are currently available. The
predictive performance of pNGAL at admission for AKI (24 hours prior
to creatinine-based (RIFLE) diagnosis) was good (AUC-ROC 0.8 (95%
CI 0.88 to 1.03)). The predictive performance of uNGAL at admission
for the occurrence of AKI (24 hours prior to creatinine-based (RIFLE)
diagnosis) (AUC-ROC 0.77 (95% CI 0.47 to 1.07)) was fair. See Table 1. M Haase1, P Mertens1, M Plaß2, R Bellomo3, A Haase-Fielitz1
1Otto-von-Guericke University Magdeburg, Germany; 2German Heart Center,
Berlin, Germany; 3Austin Health, Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P350 (doi: 10.1186/cc10957) Introduction In most previous studies, neutrophil gelatinase-
associated lipocalin (NGAL), measured immediately following cardiac
surgery, has been demonstrated to predict postoperative increases in
serum creatinine and decline in urine output. In patients undergoing
cardiac surgery, postoperative fl uid overload is a typical complication. In this study, we investigated the early postoperative value of NGAL to
predict subsequent fl uid overload, a potentially modifi able risk factor
in these patients. Table 1 (abstract P351). Sensitivity and specifi city of pNGAL (time ‘0) to
diagnose AKI occurrence at 24 hours
Cut-off (ng/ml)
Sensitivity (95% CI)
Specifi city (95% CI)
<270.0
82.6 (61.2 to 95)
100 (37.6 to 100)
<316.5
86.9 (66.4 to 97.2)
100 (37.6 to 100)
<381.0
91.3 (71.9 to 98.9)
100 (37.6 to 100) Table 1 (abstract P351). Sensitivity and specifi city of pNGAL (time ‘0) to
diagnose AKI occurrence at 24 hours p
Methods We studied 100 adult cardiac surgery patients assigned to the
control arm of a randomized controlled trial. Urine and serum were sampled
immediately after admission to the ICU. Urine NGAL was measured on
the ARCHITECT laboratory platform (Abbott Diagnostics) and serum
creatinine using an enzymatic assay. Postoperative fl uid overload was
defi ned as positive fl uid balance with >10% excess of preoperative body
weight within 48 hours. An area under the curve of the receiver-operating
characteristics (AUC-ROC) of 0.5 indicates the predictive ability equaling
the toss of a coin and >0.7 of a useful biomarker.l Conclusion Early results on pNGAL suggest that it could be an
independent predictor of AKI in an unselected population of critically
ill adults. Further results are awaited. P349
Nurses’ knowledge regarding the early identifi cation of acute
kidney injury
S Agege Lobo, RM Matheus
Faculdade de Medicina de São José do Rio Preto – FAMERP, São José do Rio
Preto, Brazil
Critical Care 2012, 16(Suppl 1):P349 (doi: 10.1186/cc10956) P349 mortality. Early postoperatively measured urine NGAL is a good
predictor of fl uid overload and mortality whereas measurement of
serum creatinine at the same time equals the toss of a coin. Early NGAL-
guided adjustments of fl uid management might reduce organ edema
and potentially improve patient outcomes after cardiac surgery. Our
fi ndings should be validated in larger patient cohorts. Additive value to clinical judgement of blood neutrophil gelatinase-
associated lipocalin in diagnosis of acute kidney injury and
prediction of mortality in patients hospitalized from the emergency
department p
L Magrini1, B De Berardinis1, R Marino1, G Gagliano1, E Ferri1, P Moscatelli2,
P Ballarino2, B Gliozzo3, G Carpinteri3, S Di Somma1
1S. Andrea Hospital ‘Sapienza’ University, Rome, Italy; 2S. Martino Hospital,
Genoa, Italy; 3S. Elia Hospital, Catania, Italy
Critical Care 2012, 16(Suppl 1):P354 (doi: 10.1186/cc10961) p
L Magrini1, B De Berardinis1, R Marino1, G Gagliano1, E Ferri1, P Moscatelli2,
P Ballarino2, B Gliozzo3, G Carpinteri3, S Di Somma1
1S. Andrea Hospital ‘Sapienza’ University, Rome, Italy; 2S. Martino Hospital,
Genoa, Italy; 3S. Elia Hospital, Catania, Italy
Critical Care 2012, 16(Suppl 1):P354 (doi: 10.1186/cc10961) i
y
Methods Ninety-six patients consecutively admitted to the ICU were
included in the study. Exclusion criteria were chronic renal failure,
AKI prior to ICU admission, brain death, pregnancy, age <18 years
and predicted ICU stay less than 48 hours. Patients’ demographic
characteristics, APACHE II and SOFA score, existing comorbidities,
primary reason for admission to intensive care, pNGAL, uNGAL, white
cell count and C-reactive protein levels were recorded on admission,
while the RIFLE score and sepsis status were recorded until day 7 post
admission. The Mann–Whitney U test was used to compare pNGAL and
uNGAL levels in septic and nonseptic patients. Introduction Acute kidney injury (AKI) is a common and diffi cult to
diagnose complication among hospitalized patients with increasing
incidence. Introduction Acute kidney injury (AKI) is a common and diffi cult to
diagnose complication among hospitalized patients with increasing
incidence. Methods A total of 665 (357 M:308 F; mean age 74 ± 14 years)
emergency department (ED) patients designated for hospitalization
were included in a multicenter prospective study to evaluate the utility
of blood neutrophil gelatinase-associated lipocalin (NGAL) assessments
as an aid in the early risk evaluation for AKI. NGAL and serum creatinine
(sCr) were determined at ED presentation (T0), 6, 12, 24 and 72 hours
after hospitalization. The clinical certainty of AKI was determined by ED
physician (Ph) while blinded to NGAL results. p
p
p
Results Out of 96 patients included, 56 were male, 12 had AKI and 30
had sepsis on admission. The mean age was 55.5 ± 19.6 years, the mean
APACHE II score was 14.8 ± 5.6 and the mean admission SOFA score was
6.6 ± 2.9. There were 43 medical admissions, 17 elective surgical, and 36
emergency surgical including trauma. Both pNGAL and uNGAL were higher in patients with AKI on admission
(P <0.001). Additive value to clinical judgement of blood neutrophil gelatinase-
associated lipocalin in diagnosis of acute kidney injury and
prediction of mortality in patients hospitalized from the emergency
department Their levels were also found to be higher in septic compared
with nonseptic patients (septic pNGAL = 153.13 ± 144.86 vs. nonseptic
pNGAL = 102.45 ± 95.65, P = 0.076; septic uNGAL = 306.66 ± 532.88 vs. nonseptic uNGAL = 123.41 ± 354.07, P = 0.002). When patients with
AKI as well as patients who developed AKI within the fi rst 7 days post
admission were excluded from the analysis, higher uNGAL and pNGAL
values in the group of septic patients were not signifi cant at the level
of 5%. The estimated sample size for signifi cance 5% and power 80%
is 74 for uNGAL (2,200 for pNGAL). Moreover pNGAL and uNGAL had
a similar area under the ROC curve (0.773 and 0.779 respectively) for
predicting AKI in septic patients. y
Results Preliminary diagnosis of AKI by the ED Ph occurred in 218/665
patients (33%). Final adjudicated AKI clinical diagnosis was confi rmed
in 49/665 patients (7%). The AUC for NGAL alone in the fi nal diagnosis
of AKI was 0.80 (± 0.07). When NGAL was added to the ED Ph’s clinical
judgement in a logistic model, the AUC was increased to 0.89 (± 0.06). The AUCs for the additional endpoints are shown in Table 1. When the
same model combining NGAL with the ED Ph’s clinical judgement was
compared to a clinical model combining T0 sCr results with the ED Ph’s
clinical judgement, the net reclassifi cation index was 32.4%, meaning
that the correction classifi cation of AKI improved 32.4 percentage
points. Conclusion Both biomarkers are increased in the case of sepsis in
our population. Septic AKI aff ecting uNGAL more than pNGAL could
explain the smaller P value for uNGAL in the group of patients with
sepsis. Table 1 (abstract P354)
Event
No event
AUC (95% CI)
Diagnosis of AKI
49
616
0.80 (0.07)
RIFLE
25
640
0.72 (0.12)
sCr bump
10
655
0.85 (0.10)
Oliguria
14
651
0.81 (0.14)
Mortality
27
638
0.76 (0.11) P354 (pNGAL and uNGAL) levels are aff ected by the presence of sepsis in a
general ICU population. These novel biomarkers are currently being
evaluated for acute kidney injury (AKI) prediction. However, they are
also increased in sepsis, which can be a confounding factor regarding
their specifi city for AKI [1,2]. References 1. Int Care Med 2010, 36:1333-1340. 2. Am J Respir Crit Care Med 2011, 183:907-914. 2. Am J Respir Crit Care Med 2011, 183:907-914. Urinary neutrophil gelatinase-associated lipocalin as an early
marker of acute kidney injury complicating circulatory shock
H Sherif, M Foda, M Shehata, A Ibrahim Urinary neutrophil gelatinase-associated lipocalin as an early
marker of acute kidney injury complicating circulatory shock
H Sherif, M Foda, M Shehata, A Ibrahim Urinary neutrophil gelatinase-associated lipocalin as an early
marker of acute kidney injury complicating circulatory shock
H Sherif, M Foda, M Shehata, A Ibrahim
Faculty of Medicine, Cairo University, Cairo, Egypt
Critical Care 2012, 16(Suppl 1):P353 (doi: 10.1186/cc10960) Conclusion Our study demonstrated that blood NGAL measurements
in patients hospitalized from the ED for critical conditions may improve
the clinical diagnosis of AKI development. The routine use of NGAL in
the ED may provide utility in deciding the appropriate treatment and
management strategies for patients at risk for AKI development. Faculty of Medicine, Cairo University, Cairo, Egypt y
y
gyp
Critical Care 2012, 16(Suppl 1):P353 (doi: 10.1186/cc10960) Introduction We evaluated the novel urinary neutrophil gelatinase-
associated lipocalin (NGAL) as an early biomarker that rapidly releases
in acute kidney injury (AKI) complicating circulatory shock. y
j
y
p
g
y
Methods We measured the urinary NGAL level from collected urine in
45 patients with circulatory shock, during the fi rst 6 hours and after 24
hours. Eleven patients responded to fl uid infusion ± vasopressors and
were considered as a separate control group. P352
Plasma and urine neutrophil gelatinase-associated lipocalin in
septic and nonseptic ICU patients p
p
p
CS Vrettou1, S Kokkoris2, K Apostolou2, M Parisi2, E Haritatos2,
S Dimopoulos2, S Nanas1
1National and Kapodistrian University of Athens, Greece; 2Evaggelismos
Hospital, Athens, Greece
Critical Care 2012, 16(Suppl 1):P352 (doi: 10.1186/cc10959) Introduction In this prospective cohort study we investigate how
admission plasma and urine neutrophil gelatinase-associated lipocalin Conclusion Fluid overload frequently occurs during the fi rst 48 hours
after cardiac surgery and is strongly correlated with postoperative S127 Critical Care 2012, Volume 16 Suppl 1
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Is cystatin C reliable in the anesthetized pig? An experimental study
with special reference to septic shock
M Eriksson1, E Söderberg1, M Lipcsey1, J Sjölin2, M Castegren3, M Sjöquist4,
A Larsson5
1Surgical Sciences, Anesthesia & Intensive Care, Uppsala, Sweden; 2Medical
Sciences, Infectious Disease, Uppsala, Sweden; 3Centre for Clinical Research,
Eskilstuna, Sweden; 4SLU, Uppsala, Sweden; 5Medical Sciences, Clinical
Chemistry, Uppsala, Sweden
Critical Care 2012, 16(Suppl 1):P355 (doi: 10.1186/cc10962) Is cystatin C reliable in the anesthetized pig? An experimental study
with special reference to septic shock p
g
p
Results The estimated urinary NGAL at day 1 and day 2 post circulatory
shock could predict AKI presented at days 2 and 3 and days 3 and 4
(P <0.05, P <0.001 and P <0.001, P <0.001) respectively. Apart from all
conventional kidney parameters and biomarkers, signifi cant inverse
correlations could be detected only between urinary NGAL at days
1 and 2 with the corresponding urine output in the patient group
(r = –0.51 and –0.64, P <0.05 and P <0.001, respectively). The best cut-
off value of urinary NGAL at day 1 was 26 ng/ml, for which sensitivity
was 62% and 69% and specifi city was 75% and 80% for prediction of
AKI presented at days 2 and 3, respectively. While the best cut-off at day
2 was 29 ng/ml, for which sensitivity was 70% and 74% and specifi city
was 90% and 80% for prediction of AKI presented at days 3 and 4,
respectively. Urinary NGAL at day 2 could signifi cantly predict mortality
complicating AKI rather than at day 1 (P <0.05). Introduction Our aim was to investigate renal function during 24 hours
of endotoxemic shock with special focus on the reliability of analysis
options in kidney damage. Methods Twenty anesthetized pigs received randomly a continuous
24-hour endotoxin infusion at 0.063 μg/kg/hour (n = 8) or 0.25 μg/kg/
hour (n = 9) or NaCl (controls n = 3). Boluses (10 ml/kg) of succinylated
gelatin were given when the arterial blood pressure was 50 mmHg or
below. Samples for analysis of cystatin C as well as clearances of inulin,
PAH and creatinine were noted and urine was collected. Conclusion Urinary NGAL seems to be a potential early and sensitive
biomarker for AKI and a persistently increased level at day 2 can predict
mortality following circulatory shock. S128 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Results Cystatin C was, already at baseline, not normally distributed. This was in contrast to the other renal variables. Five pigs had baseline
values of cystatin C in plasma >0.6 mg/l (one control; four endotoxemic
pigs), whereas 15 pigs had plasma levels <0.3. Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate
J Dixon1, K Lane1, N Dalton2, I MacPhee1, B Philips1
1St George’s Hospital, London, UK; 2King’s College, London, UK
Critical Care 2012, 16(Suppl 1):P358 (doi: 10.1186/cc10965) Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate Introduction The aim of our study was to evaluate the utility of two
cystatin-C-based equations, as a surrogate of the renal function
(glomerular fi ltration rate (GFR)) in a group of critically ill patients. i
y
Methods This was a monocentric, prospective and observational study
including 146 samples respecting 22 ICU patients. Daily evaluation of
seric creatinine, seric cystatin C (CC) and 24-hour creatinine clearance
(24CrCL) was performed during the ICU stay. Comparisons were done
between two CC-based equations (Hoek (H) and Larsson (L) formulas)
and: 24CrCL; Cockroft–Gault (CG); modifi ed Cockroft–Gault (mCG); and
six-variable Modifi cation of Renal Disease (MDRD6) formulas. Patients
with chronic renal failure were excluded. Correlation, precision, bias
and discrimination power were assessed using Spearman coeffi cient,
Bland–Altman plots and receiver operating characteristic curves. Introduction We have designed a method of continuous measurement
of the glomerular fi ltration rate (GFR) with the intention of applying the
method in patients with acute kidney injury (AKI). The aim of the study
was to prove the method in healthy volunteers (HV) and patients with
chronic kidney disease (CKD). Methods HV and patients with CKD were randomly allocated to
measurement of GFR using iohexol, either by the established method
of single injection and measurement of its rate of elimination (gold
standard), or by the continuous infusion of a very low dose of iohexol
(0.5 ml/hour for 12 hours). The GFR was measured again, using the
other method, after a washout period of 4 to 28 days. Plasma iohexol
concentration was measured at 10 time points and plotted on a two-
phase exponential decay graph. The GFR was calculated by dividing
the infusion concentration by the plateau concentration. The t test
compared results with 4-hour creatinine clearance (4-CrCl), and the
CKD-EPI equation. Results The average age of the patients was 63.4 years and male
gender was predominant (68%). The APACHE II score was 16.8 ± 5.7. Is cystatin C reliable in the anesthetized pig? An experimental study
with special reference to septic shock When individual values
were noted over time, it became obvious that, with the exception of
the four endotoxemic animals, which shifted considerably over time,
there appears to be two subgroups of pigs regarding their cystatin C
values. There were only minor diff erences in cystatin C over time for
each individual pig compared with the baseline value, except for the
four pigs that shifted considerably over time. There were no major
diff erences in urinary output between untreated controls and any of
the two endotoxemic groups of pigs during the 24-hour experimental
period. There was no obvious relation between the administration
of bolus doses of gelatin and subsequent diuretic response. Cystatin
C did not correlate to creatinine clearance (r2 = 0.06), PAH clearance
(r2 = 0.05), inulin×urine (r2 = 0.04) or diuresis (r2 = 0.004). No similar
subgroupings were noted for any of the other renal variables, although
it should be noted that correlations between all variables were weak. Are serum cystatin-C-based estimates better than those derived
from serum creatinine in critically ill patients?
JP Baptista, SC Teixeira, J Pimentel
Coimbra Universitary Hospital, Coimbra, Portugal
Critical Care 2012, 16(Suppl 1):P356 (doi: 10.1186/cc10963) JP Baptista, SC Teixeira, J Pimentel p
Coimbra Universitary Hospital, Coimbra, Portugal P358 Assessment of glomerular fi ltration rate in trauma patients in early
resuscitation phase Lipcsey, et al.: Crit Care Med 2009, 37:2782-2790. 2. Benes J, et al.: Crit Care 2011, 15:R256. Conclusion Incidence of glomerular hyperfi ltration is relatively
common in critically ill multitrauma patients in the fi rst 24 hours. This
should be taken into account while deciding drug dosing in this group
of patients. 2. Benes J, et al.: Crit Care 2011, 15:R256. 2. Benes J, et al.: Crit Care 2011, 15:R256. Assessment of glomerular fi ltration rate in trauma patients in early
resuscitation phase M Bhattacharyya1, R Kumar2, S Todi1
1AMRI Hospitals, Kolkata, India; 2Jadavpur University, Kolkata, India
Critical Care 2012, 16(Suppl 1):P357 (doi: 10.1186/cc10964) M Bhattacharyya1, R Kumar2, S Todi1
1AMRI Hospitals, Kolkata, India; 2Jadavpur University, Kolkata, India
Critical Care 2012, 16(Suppl 1):P357 (doi: 10.1186/cc10964) Introduction An estimate of the glomerular fi ltration rate (GFR) is
important to individualize drug dosages. Trauma leads to systemic
infl ammatory response syndrome, which has an eff ect on GFR. The
main objective of this study was to assess the GFR in trauma patients
during the fi rst 24 hours of admission. gi
Methods A prospective observational study of 50 trauma patients
aged between 18 and 90 years admitted to the ICU. Exclusion: patients
with chronic kidney disease and structural kidney damage. The study
population was assessed for GFR by the measurement of creatinine
clearance from 24-hour urine creatinine and from serum creatinine. Demographic parameters were documented. g
p
p
Results Total patients admitted to the ITU during July 2010 to April
2011 with trauma were 67, of which 50 patients were included in the
study. The mean age of the study group was 39 years, male 86%, mean
APACHE IV score 32 and mean Injury Severity Score 10. Out of 50 trauma
patients, 13 (26%) patients developed glomerular hyperfi ltration (GHF)
within 24 hours of admission. Mean creatinine clearance in the GHF
group was 177.92 ± 29 and minimum/maximum values were 151.4 and
254.3 ml/minute/1.73 m2 respectively. Compared to the GHF group,
mean creatinine clearance levels were considerably lower in non-
GHF patients (86.03 ± 29) with a range of values from 41 to 138.5 ml/
minute/1.73 m2.i Conclusion In this experiment, we noted that there appears to be two
populations of pigs regarding their cystatin C values. This result is in
contrast to a previous study from our group [1]. Our fi ndings may be
explained by the alterations that occur in renal vascular resistance
[2], although these fi ndings may also indicate a genetic variation
infl uencing either the levels of cystatin C or the antigen determinants
of cystatin C. Until our data have been confi rmed or disproved, we
strongly suggest that porcine Cystatin C values should be interpreted
with great care as a marker for glomerular fi ltration rate in pigs. R f 1. Lipcsey, et al.: Crit Care Med 2009, 37:2782-2790. 1. Lipcsey, et al.: Crit Care Med 2009, 37:2782-2790 1. P358 y
p
g
Critical Care 2012, 16(Suppl 1):P356 (doi: 10.1186/cc10963) Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate S129 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods The Critical Care Minimum Dataset records of patients
admitted to our mixed general ICU were investigated. Those patients
who received renal organ support were investigated further. The
change in serum creatinine levels in the 48 hours prior to institution of
RRT was used to determine the AKIN score. Patients in whom there was
not a signifi cant rise in creatinine, but who received RRT, were staged
zero. Unfortunately, urine output data were not available to improve
accuracy. to reach steady state. However, given the simplicity of the method
we hypothesise that changes in iohexol concentration may provide
valuable real-time information about the GFR in AKI. Changes are likely
to occur before serum creatinine rises. In conclusion, the continuous
iohexol infusion method of measuring GFR appears to be accurate and
precise. In stable subjects, a steady plasma concentration is achieved
before it is observed with creatinine changes. y
Results There were a total of 276 patients whose records were
adequate for this audit. Several records were incomplete and not used. Demography and APACHE II scores were similar across all groups. Length of stay and days of RRT were similar across the groups. ICU
survival was as follows: AKIN stage: (0) 42.2%, (1) 50.6%, (2) 51.7%, (3)
70.4%. Pearson chi-square P <0.001. P359 Investigation into the eff ects of commencing haemodialysis in the
critically ill
R Docking1, L Moss1, M Sim1, D Sleeman2, J Kinsella1
1University of Glasgow, UK; 2University of Aberdeen, UK
Critical Care 2012, 16(Suppl 1):P359 (doi: 10.1186/cc10966) q
Conclusion We were not able to demonstrate improved survival when
RRT was initiated at an earlier AKIN stage. A small nonsignifi cant trend
was observed with increasing stage and the diff erences between
groups were signifi cant. Very early initiation of RRT was associated with
increased mortality. Stage (3) included patients with chronic kidney
disease, which probably skewed the results in this group. We cannot
recommend the use of the AKIN score as a pointer to when to initiate
RRT, based on these data. Introduction We aimed to describe haemodynamic changes when
haemodialysis is instituted in the critically ill. Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate The medians of H and L estimates were 50.5 (28 to 77.6) and 47.7 (24.5
to 79.2) respectively, as compared to 69.8 (29.8 to 115.7), 60.7 (42.6
to 101.4), 58.9 (42.6 to 65.1) and 59.2 (40.6 to 106.8) ml/minute/1.73
m2, respectively to 24CrCL (reference method), CG, mCG and MDRD6. Correlation (r) between H, F, CG, mCG, MDRD6 and 24CrCL was
0.83/0.83/0.73/0.70/0.74, respectively. H and L formulas showed the
smallest bias and limits of agreement, when compared with formulas
based on serum creatinine, respectively –17.5/±52 ml/minute/1.73 m2
and –21/±52.8 ml/minute/1.73 m2. The sensibility for the identifi cation
of acute renal dysfunction (24CrCL under 60 ml/minute/1.73 m2) was
high for H and L formulas (area under the curve of 0.94 for both). In
the subgroup of 29 samples with 24CrCL above 130 ml/minute/1.73 m2
(patients with hyperfi ltration) these two formulas had low sensibility
(between 8 and 22%) for identifi cation of this condition. q
Results Six HV and seven CKD patients volunteered, with fi ve in each
group completing the study. There was no diff erence between the two
groups (P = 0.79). In HV, the mean GFR measured by single injection
was 105 ± 7.3 and 109.4 ± 9.9 ml/minute/1.73 m2 by infusion (Pearson
r = 0.95, P = 0.0002). In CKD patients, the mean GFR measured by single
injection was 40 ± 5.4 and 44.8 ± 6.2 ml/minute/1.73 m2 by infusion
(Pearson r = 0.99, P <0.0001). The infusion method depends on reaching
a steady plasma concentration, which took 165 ± 84 minutes in HV and
483 ± 127 minutes in CKD patients to be within 10% of the steady state. The GFR is overestimated by 4-CrCl (by 13.9 ± 12.9 ml/minute/1.73 m2,
P <0.0001) and by CKD-EPI (by 8.4 ± 9.6 ml/minute/1.73 m2, P <0.0001). Conclusion In future work, we aim to validate this method in critically
ill patients with AKI. We predict the steady state achieved will be
increased. Anticipated problems include increased time or failure Conclusion In this population of critically ill patients, cystatin-C-derived
Hoek and Larsson equations underestimated 24CrCL; however, they
have a better performance than the classic estimates (CG and MDRD6). Nevertheless, they are inaccurate when applied to ICU patients with
hyperfi ltration (GFR >130 ml/m/1.73 m2). Validation of a continuous low-dose iohexol infusion to measure
the glomerular fi ltration rate Three hypotheses are
tested: (1) the initial session is associated with cardiovascular instability;
(2) the initial session is associated with more cardiovascular instability
compared to subsequent sessions; and (3) looking at unstable sessions
alone, there will be a greater proportion of potentially harmful changes
in the initial sessions compared to subsequent ones. References References
1. Uchino S, et al.: Intensive Care Med 2007, 33:1563-1570. 2. Bagshaw SM, et al.: J Crit Care 2009, 24:129-140. 3. Mehta RL, et al.: Crit Care 2007, 11:R31. 1. Uchino S, et al.: Intensive Care Med 2007, 33:1563-1570. 2. Bagshaw SM, et al.: J Crit Care 2009, 24:129-140. 3. Mehta RL, et al.: Crit Care 2007, 11:R31. Methods Data were collected for 209 patients, identifying 1,605
dialysis sessions. Analysis was performed on hourly records, classifying
sessions as stable/unstable by a cut-off >±20% change in baseline
physiology (HR/MAP). Data from 3 hours prior to and 4 hours after
dialysis were included, and average and minimum values derived. Three
time comparisons were made (pre-HD:during, during HD:post, pre-
HD:post). Initial sessions were analysed separately from subsequent
sessions to derive two groups. If a session was identifi ed as being
unstable, then the nature of instability was examined by recording
whether changes crossed defi ned physiological ranges. The changes
seen in unstable sessions could be described as to their eff ects: being
harmful/potentially harmful, or benefi cial/potentially benefi cial. Timing for initiation of continuous renal replacement therapy in
patients with septic shock and acute kidney injury Conclusion Our results reject the claims that using haemodialysis is an
inherently unstable choice of therapy. Although proportionally more of
the initial sessions are classed as unstable, the majority of MAP and HR
changes are benefi cial in nature. Table 1 (abstract P361). Baseline characteristics and parameters on initiation
of CRRT
Early
Late
P value
Age
70.7 ± 15.1
69.3 ± 13.1
0.614
APACHE IV
119 ± 31
131 ± 37
0.110
Starting GFR
36.2 ± 20.9
18.1 ± 8.2
<0.001
Start SOFA
11.6 ± 3.3
13.3 ± 2.7
0.006
Table 2 (abstract P361). Outcome parameters
Early
Late
P value
NR SOFA 0 to 48
–0.52 ± 3.91
–0.71 ± 3.57
0.827
Hospital death
17 (54.8%)
48 (53.9%)
0.931
28-day survival
16 (51.6%)
46 (51.7%)
0.994 Table 1 (abstract P361). Baseline characteristics and parameters on initiation
of CRRT P361 P361
Timing for initiation of continuous renal replacement therapy in
patients with septic shock and acute kidney injury
HP Shum, KC Chan, MC Kwan, WT Yeung, WS Cheung, WW Yan
Pamela Youde Nethersole Eastern Hospital, Hong Kong
Critical Care 2012, 16(Suppl 1):P361 (doi: 10.1186/cc10968) Timing for initiation of continuous renal replacement therapy in
patients with septic shock and acute kidney injury Introduction The optimal timing for initiation of renal replacement
therapy (RRT) in septic acute kidney injury (AKI) remains controversial. The aim of this study is to investigate the impact of early versus late
initiation of continuous RRT (CRRT), as defi ned using the simplifi ed
RIFLE classifi cation, on organ dysfunction among patients with septic
shock and AKI. Results Discarding incomplete data, 181 initial and 1,382 subsequent
sessions were analysed. A session was deemed to be stable if there was
no signifi cant change (>±20%) in the time-averaged or minimum MAP/
HR across time comparisons. By this defi nition 85/181 initial sessions
were unstable (47%, 95% CI SEM 39.8 to 54.2). Therefore Hypothesis 1
is accepted. This compares to 44% of subsequent sessions (95% CI 41.1
to 46.3). Comparing these proportions and their respective CI gives a
95% CI for the standard error of the diff erence of –4% to 10%. Therefore
Hypothesis 2 is rejected. In initial sessions there were 92/1,020 harmful
changes. This gives a proportion of 9.0% (95% CI SEM 7.4 to 10.9). In
the subsequent sessions there were 712/7,248 harmful changes. This
gives a proportion of 9.8% (95% CI SEM 9.1 to 10.5). Comparing the two
unpaired proportions gives a diff erence of –0.08% with a 95% CI of the
SE of the diff erence of –2.5 to +1.2. Hypothesis 3 is rejected. Fisher’s exact
test gives a result of P = 0.68, reinforcing the lack of signifi cant variance. Methods Patients were divided into early (sRIFLE Risk) or late (sRIFLE
Injury or Failure) initiation of RRT. Patients with chronic kidney disease
stage 5 or on dialysis were excluded. Results One hundred and twenty patients admitted within a 3.5-year
period fulfi lled inclusion criteria. Thirty-one (26%) underwent early, 89
(74%) had late CRRT. No signifi cant diff erence was noted between the
two groups with respect to change in total SOFA score/non-renal SOFA
score in the fi rst 24/48 hours after initiation of CRRT, vasopressor use,
dialysis requirement and mortality (at 28 days, 3 months and 6 months). The change of nonrenal SOFA score 48 hours after CRRT correlated with
the SOFA score at the start of CRRT (P = 0.034) and the APACHE IV risk of
death (P = 0.000), but not the glomerular fi ltration rate (GFR) at the start
of CRRT (P = 0.348). See Tables 1 and 2. Amino acid concentrations in serum, urine and dialysate/ultrafi ltrate
solutions of continuous venovenous hemodiafi ltration patients
JM Lee, YJ Lee, J Hong Amino acid concentrations in serum, urine and dialysate/ultrafi ltrate
solutions of continuous venovenous hemodiafi ltration patients
JM Lee, YJ Lee, J Hong
Ajou University School of Medicine, Suwon, Kyeonggi-do, South Korea
Critical Care 2012, 16(Suppl 1):P364 (doi: 10.1186/cc10971) Amino acid concentrations in serum, urine and dialysate/ultrafi ltrate
solutions of continuous venovenous hemodiafi ltration patients
JM Lee, YJ Lee, J Hong Ajou University School of Medicine, Suwon, Kyeonggi-do, South Korea
Critical Care 2012, 16(Suppl 1):P364 (doi: 10.1186/cc10971) Table 1 (abstract P362)
Variable
First group
Second group
Third group
Age
42 ± 15
39 ± 13
47 ± 16
BMI
31 ± 5
29 ± 4
29 ± 5
APACHE II score
17 (5)
17 (9)
15 (7)
SOFA score
5 (4)
5 (3)
5 (3)
Ranson score
8 (6)
8 (7)
10 (9)
Early mortality (%)
27
10*
42
Infection (%)
47
35
29
Overall mortality (%)
49
25*
51
Data presented as median (IQR). *P <0.05, second group versus third group. Introduction A prospective study was performed for evaluating the
amino acid losses during continuous venovenous hemodiafi ltration
(CVVHDF). Introduction A prospective study was performed for evaluating the
amino acid losses during continuous venovenous hemodiafi ltration
(CVVHDF). Methods Serum, 24-hour urine and dialysate/ultrafi ltrate solutions of
CVVHDF were obtained on days 1, 3, and 5 from 11 critically ill patients
(fi ve males, six females, mean age 63.0 ± 18.1 (24 to 90)) in the surgical
ICU. We analyzed 40 kinds of amino acid concentrations in serum
(34 samples), urine (15 samples) and dialysate/ultrafi ltrate solutions
(30 samples) by high-performance liquid chromatography analysis. The mean dialysate amount was 918.2 ml (600 to 1,500 ml), mean
replacement fl uid amount 1,136.4 ml (1,000 to 2,000 ml) and mean
blood fl ow rate 175 ml (100 to 200 ml), respectively. Nutritional support
for CVVHDF patients was guided as protein intake at 1.2 to 1.5 g/kg/
day, caloric intake at 30 kcal/kg/day.i Results Among the analyzed 40 amino acids, the fi ve highest mean
concentration levels of 24-hour dialysate/ultrafi ltrate solutions were
glutamine (65,178.3 μmol/l (hereafter, all units for amino acids are
μmol/l)), alanine (48,633.3), glycine (33,959.5), proline (27,701.5), lysine
(26,519.4); of serum were glutamine (694.4), alanine (438.1), glycine
(349.7), lysine (275.7), proline (262.4); and of 24-hour urine were glycine
(1,523.0), histidine (957.5), alanine (920.7), glutamine (904.6), lysine
(699.1), respectively. Early application of CVVH In the complex treatment of patients with
early severe acute pancreatitis y
p
I Aleksandrova, M Ilynsky, S Rei, G Berdnikov, L Marchenkova, V Kiselev
Hospital Research Institute for Emergency Medicine N.V. Sklifosovsky, Moscow,
Russia
Critical Care 2012 16(Suppl 1):P362 (doi: 10 1186/cc10969) Introduction A large population-based study of 1,024 deaths from acute
pancreatitis (AP) has revealed that the median time lapse between the
onset of AP and death was 6 days [1]. A number of authors considered
the patients with persistent or progressive early multiple organ failure
(MOF) as patients with early severe acute pancreatitis (ESAP) [2].fi g
g
Conclusion Timing of RRT, stratifi ed into early and late by RIFLE and
BUN, showed no signifi cant diff erence in 28-day mortality in patients
with severe sepsis and septic shock. Methods The aim of current study was to evaluate the effi ciency of
early CVVH in a complex treatment of ESAP. The retrospective analysis
involved 106 patients. The patients were divided into three groups: the
fi rst group (n = 45) received CVVH dose <30 ml/kg/hour, the second
group (n = 20) received the dose >30 ml/kg/hour, and in the third
group (n = 41) CVVH was not used during the early phase of disease
(Table 1). In the fi rst and second groups the median time interval
between admission and start of CVVH was 2 (2; 3) days. P364 y
References y
Conclusion The highest concentration level of 24-hour dialysate/
ultrafi ltrate solution was glutamine. The amount of amino acid loss
after CVVHDF was correlated with the serum amino acid amount and
increased according to CVVHDF progression. 1. Mole DJ, et al.: HPB 2009, 11:166-170. 2. Isenmann R, et al.: Pancreas 2001, 22:274-278. Amino acid concentrations in serum, urine and dialysate/ultrafi ltrate
solutions of continuous venovenous hemodiafi ltration patients
JM Lee, YJ Lee, J Hong Amino acid concentrations of 24-hour dialysate/
ultrafi ltrate solutions showed signifi cant correlation with amino acid
concentrations of serum (P = 0.000). The mean amount of total amino
acid loss on day 5 of CVVHDF was 2.8 times that of day 1 and 1.7 times
that of day 3. The increase of amino acid loss according to CVVHDF
progression was most prominent in glutamic acid (8.9 times from day
1 to day 5). Results As compared to reference group 3, signifi cant (P = 0.022)
reduction of early mortality (14 days) was observed in the second group,
and decreasing tendency (P = 0.093) of mortality rate was detected in
the fi rst group. The median time interval between admission and death
was 14 days (in the fi rst and second groups) and 5 days in the third
group. g
p
Conclusion The early application of the CVVH increases time interval
for care delivery and allows reducing early mortality. The best results
were obtained in the group of patients who were treated with the
higher dose of CVVH (earlier restoration of homeostasis and decreased
severity of early MOF). P360 The timing of RRT was categorized
into early (Risk, and Injury) and late (Failure) by RIFLE criteria and also
categorized into early (BUN <75 mg/dl) and late (BUN ≥75 mg/dl). Comparing the relationship between RIFLE criteria (Risk and Injury vs. Failure) and 28-day mortality showed no signifi cant diff erence (70.8%
vs. 73.3%, P = 0.81). The timing of RRT by serum BUN also showed no
signifi cant diff erence in 28-day mortality before start of RRT by BUN
≥75 mg/dl versus BUN <75 mg/dl (77.3% vs. 69.6%, P = 0.50).i Methods All patients diagnosed with severe sepsis and septic shock
and treated at the medical ICU in a university-affi liated, tertiary-referral
center, from January 2005 to December 2006 were reviewed. Timing of
RRT was stratifi ed into early and late by RIFLE (Risk, Injury, Failure, Loss,
and End-stage) criteria and blood urea nitrogen (BUN) at the time RRT
was started. The primary outcome was 28-day death from any cause. P362 Results Of the 326 patients diagnosed with severe sepsis and septic
shock and admitted to the medical ICU during the study period, 78
patients received RRT. The mean age of the patients was 61.5 ± 14.7 years
and 54 patients were male (69.2%). The timing of RRT was categorized
into early (Risk, and Injury) and late (Failure) by RIFLE criteria and also
categorized into early (BUN <75 mg/dl) and late (BUN ≥75 mg/dl). Comparing the relationship between RIFLE criteria (Risk and Injury vs. Failure) and 28-day mortality showed no signifi cant diff erence (70.8%
vs. 73.3%, P = 0.81). The timing of RRT by serum BUN also showed no
signifi cant diff erence in 28-day mortality before start of RRT by BUN
≥75 mg/dl versus BUN <75 mg/dl (77.3% vs. 69.6%, P = 0.50). P360 P360
Is the AKIN score useful as an indicator of the optimum time for
intervention with renal replacement therapy in critically ill patients? S Mousdale, J Bannard-Smith
Royal Blackburn Hospital, Blackburn, UK
Critical Care 2012, 16(Suppl 1):P360 (doi: 10.1186/cc10967) Introduction Acute kidney injury represents a signifi cant workload and
economic burden for critical care units. In the critical care setting AKI
is usually associated with a variety of aetiologies such as septic shock,
major surgery and heart failure [1]. Controversy exists as to the optimal
time for the institution of renal replacement therapy (RRT) [2]. Scoring
systems such as AKIN have used the rise in serum creatinine combined
with reduced urine output over a period of 48 hours as indicative of the
degree of injury [3]. We used this scoring system to see if ITU mortality
correlated with increasing AKIN score. S130 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 is to evaluate the relationship between timing of RRT and 28-day
mortality in patients with severe sepsis and septic shock. Conclusion For septic shock with AKI, no signifi cant diff erence in organ
function and outcome was noted when the timing of initiation of CRRT
was classifi ed using sRIFLE criteria. Subsequent improvement of organ
function correlated with initial SOFA and APACHE scores instead of
the GFR (which determine sRIFLE class) on starting of CRRT. The use of
more global assessment tools, such as the SOFA score, for stratifi cation
purposes on appropriate timing of CRRT warrants further investigation. is to evaluate the relationship between timing of RRT and 28 day
mortality in patients with severe sepsis and septic shock. Methods All patients diagnosed with severe sepsis and septic shock
and treated at the medical ICU in a university-affi liated, tertiary-referral
center, from January 2005 to December 2006 were reviewed. Timing of
RRT was stratifi ed into early and late by RIFLE (Risk, Injury, Failure, Loss,
and End-stage) criteria and blood urea nitrogen (BUN) at the time RRT
was started. The primary outcome was 28-day death from any cause. Results Of the 326 patients diagnosed with severe sepsis and septic
shock and admitted to the medical ICU during the study period, 78
patients received RRT. The mean age of the patients was 61.5 ± 14.7 years
and 54 patients were male (69.2%). P365 Conclusion Although needing confi rmation in an adequate number of
patients, protocol B was able to provide a buff er balance more positive
than protocol A and allowed one to adequately control the A–B status
without additional NaHCO3 infusion and in the absence of alkalosis,
despite the use of a standard HCO3
– concentration HF solution. Furthermore, the combination of a phosphate-containing replacement
fl uid appeared eff ective to prevent hypophosphatemia. Finally, the use
of a mathematical model allowed predicting the eff ects of diff erent
replacement solutions and/or RCA-CVVH settings on the mass balance
of the main solutes. (P = NS), BE –2.8 ± 2.1 versus –1.6 ± 1.2 (P <0.01), serum phosphate
0.85 ± 0.2 versus 1.3 ± 0.5 mmol/l (P = 0.027), serum K+ 4 ± 0.2 versus
4.2 ± 0.3 mmol/l (P = NS) with KCl infusion 4 ± 0.2 versus 1.4 ± 1.5 mmol/
hour (P <0.0001). Protocol A required NaHCO3 and Na-phosphate
infusion (8.9 ± 2.8 mmol/hour and 5g/day, respectively) while protocol
B allowed one to stop both supplementations. Systemic and circuit Ca2+
were easily maintained in the target range with both protocols.i py
Methods Fourteen mongrel dogs were anesthetized, instrumented,
and received CVVH with the test (n = 6) or negative control article (n = 8)
for 6 hours. The test article was Accusol 35 with induced precipitate
formation prior to CVVH. The test article contained visible particles
and subvisible particles 36× higher than the maximum concentration
specifi ed in the European Pharmacopoeia (EP). The negative control
article was Accusol 35 containing no visible particles and subvisible
particles within EP specifi cation. One-half of the dogs in the negative
control article group received a central venous injection of Sephadex
G-50 beads (10 mg/kg) following CVVH as a positive control. Select
cardiovascular (CV) parameters were monitored continuously or were
calculated at predetermined times. Arterial samples were obtained
at predetermined times for analysis of blood gases and electrolytes. Samples of the test and negative control articles were obtained hourly
during CVVH for determination of pH and subvisible particles. Dogs
were euthanized and lung tissue samples were examined histologically. Results All CV parameters remained stable and no diff erences were
observed between the test and negative control articles. Sephadex
beads caused an increase (P <0.01) in mean pulmonary arterial
pressure due solely to a similar increase (P <0.01) in pulmonary vascular
resistance. P366 P366
Regional citrate anticoagulation in CVVH: a new protocol combining
citrate solution with a phosphate-containing replacement fl uid
S Morabito1, V Pistolesi1, L Tritapepe1, E Vitaliano2, E Strampelli1,
F Polistena1, L Zeppilli1, A Pierucci1
1Policlinico Umberto I, Rome, Italy; 2Pertini H, Rome, Italy
Critical Care 2012, 16(Suppl 1):P366 (doi: 10.1186/cc10973) Results In 30 patients at high bleeding risk (age 70.5 ± 9.3, SOFA
score 13.7 ± 2.5) the AC modality was switched to RCA-CVVH from no
AC or Hep. CVVH initial settings: dialysis dose 33.6 ± 3.4 ml/kg/hour;
Qb 135 ± 14 ml/minute; Q Citr 1,703 ± 250 ml/hour; Q postdilution
761 ± 181 ml/hour; Citr load 11.6 ± 2.1 mmol/hour; CaCl2 3.7 ± 1.5 ml/
hour. Target circuit Ca2+ and s-Ca2+ were maintained (0.37 ± 0.09 and
1.18 ± 0.13 mmol/l) with few modifi cations of Citr and CaCl2 infusion
rates. We used 146 RCA-CVVH circuits with fi lter life 50.5 ± 35.8 hours
(median 41; total 7,372). RCA-stopping causes: 34% CVC malfunction,
24% alarm handling/technical issues, 20% scheduled, 14% medical
procedures, 8% others. Before starting RCA, we used 69 Hep circuits
(2,015 hours) and 74 no-AC circuits (1,827 hours) with a fi lter life of
29.2 ± 20.7 hours (median 22) and 24.7 ± 20.6 hours (median 20), shorter
than RCA (P <0.0001). Circuits running at 24, 48 and 72 hours (%): RCA
73, 42 and 28; Hep 43, 23 and 10; and no-AC 38, 12 and 5 (log-rank test
P <0.0001). During RCA-CVVH no patients had bleeding complications
and the transfusion rate was lower if compared to other AC modalities
(0.29 vs. 0.69 blood units/day, P = 0.001). PLT count (P = 0.018) and
AT-III activity (P = 0.009) increased throughout days of RCA, reducing
supplementation needs. RCA has been stopped for Citr accumulation
in one patient (calcemia/s-Ca2+ >2.5). Introduction Regional citrate anticoagulation (RCA) is a highly eff ective
anticoagulation (AC) method in CRRT and diff erent combinations of
citrate (Citr) and CRRT solutions can aff ect the acid–base (A–B) balance. Regardless of the AC protocol, hypophosphatemia occurs frequently in
CRRT (80%). The aim was to evaluate safety and eff ects on A–B balance
of a new RCA-CVVH protocol using 18 mmol/l Citr solution combined
with a phosphate-containing hemofi ltration (HF) solution. P367 Regional citrate anticoagulation with a low-concentration solution
in predilution–postdilution CVVH
V Pistolesi, S Morabito, L Tritapepe, L Cibelli, M Ambrosino, F Polistena,
L Zeppilli, E Strampelli, MI Sacco, A Pierucci
Policlinico Umberto I, Rome, Italy
Critical Care 2012, 16(Suppl 1):P367 (doi: 10.1186/cc10974) Introduction Systemic anticoagulation (AC) can increase the bleeding
risk in CRRT. However, regional citrate anticoagulation (RCA) is a valid
alternative to heparin (Hep) in patients at high risk of bleeding. The
aim was to evaluate effi cacy and safety of RCA-CVVH using a low-
concentration citrate (Citr) solution. g
Conclusion CVVH performed on anesthetized dogs for 6 hours using
Accusol 35 containing visible and subvisible particles 36× higher than
the maximum concentration specifi ed in the EP resulted in no adverse
eff ects on CV parameters, blood gases and electrolytes, and lung
histology as compared with Accusol 35 containing no visible particles
and subvisible particles that were within EP specifi cation. Methods In cardiac surgery patients with AKI we adopted RCA-CVVH
as an alternative to Hep or no-AC CRRT. Criteria for switching to RCA:
early circuit clotting (24 hours) or Hep-related complications. RCA-
CVVH was performed with a predilution Citr solution (12 mmol/l) and
a postdilution hemofi ltration solution (HCO3
– 32 mEq/l). In relation to
blood fl ow rate (Qb), the Citr solution rate was set to meet a circuit
Citr concentration of 3 mmol/l and modifi ed to obtain circuit Ca2+
<0.4 mmol/l. CaCl2 (10%) was infused to maintain systemic Ca2+ (s-Ca2+)
of 1.1 to 1.25 mmol/l. To facilitate CVVH settings, we developed a
mathematical model to estimate the metabolic Citr load, buff er balance
and Ca2+ loss. P366 P365 P365
Evaluation of the potential adverse eff ects associated with calcium
carbonate precipitate during continuous venovenous hemofi ltration
J McKee, B Brooks, J Daller, J Gass, D Pantaleone, P Zieske
Baxter, Round Lake, IL, USA
Critical Care 2012, 16(Suppl 1):P365 (doi: 10.1186/cc10972) P365
Evaluation of the potential adverse eff ects associated with calcium
carbonate precipitate during continuous venovenous hemofi ltration
J McKee, B Brooks, J Daller, J Gass, D Pantaleone, P Zieske
Baxter, Round Lake, IL, USA
Critical Care 2012, 16(Suppl 1):P365 (doi: 10.1186/cc10972) Evaluation of the potential adverse eff ects associated with calcium
carbonate precipitate during continuous venovenous hemofi ltration
J McKee, B Brooks, J Daller, J Gass, D Pantaleone, P Zieske
Baxter, Round Lake, IL, USA
Critical Care 2012, 16(Suppl 1):P365 (doi: 10.1186/cc10972) Seoul Asan Hospital, Seoul, South Korea Seoul Asan Hospital, Seoul, South Korea p
Critical Care 2012, 16(Suppl 1):P363 (doi: 10.1186/cc10970) Critical Care 2012, 16(Suppl 1):P363 (doi: 10.1186/cc10970) ,
,
,
Critical Care 2012, 16(Suppl 1):P365 (doi: 10.1186/cc10972) Introduction Timing of renal replacement therapy (RRT) in critically
ill severe sepsis and septic shock patients with acute kidney injury is
highly subjective and may infl uence outcome. The aim of this study Introduction This study evaluated the potential adverse eff ects
associated with exposure to calcium carbonate precipitate during S131 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 continuous venovenous hemofi ltration (CVVH). The clinical use of
Accusol 35 Solution (Accusol 35) has been associated with occasional
formation of calcium carbonate precipitate in the tubing set during
therapy. (P = NS), BE –2.8 ± 2.1 versus –1.6 ± 1.2 (P <0.01), serum phosphate
0.85 ± 0.2 versus 1.3 ± 0.5 mmol/l (P = 0.027), serum K+ 4 ± 0.2 versus
4.2 ± 0.3 mmol/l (P = NS) with KCl infusion 4 ± 0.2 versus 1.4 ± 1.5 mmol/
hour (P <0.0001). Protocol A required NaHCO3 and Na-phosphate
infusion (8.9 ± 2.8 mmol/hour and 5g/day, respectively) while protocol
B allowed one to stop both supplementations. Systemic and circuit Ca2+
were easily maintained in the target range with both protocols. P365 No diff erences in blood gases or electrolytes were observed
between the test and negative control articles. Sephadex beads caused
a decrease (P >0.05) in arterial blood PO2 and an increase (P >0.05) in
arterial blood PCO2. No diff erences in lung histology were observed
between the test and negative control articles. The lungs from all dogs
given Sephadex beads contained multiple intravascular particles in
large-caliber blood vessels. y
g
g
p
Conclusion Although needing confi rmation in an adequate number of
patients, protocol B was able to provide a buff er balance more positive
than protocol A and allowed one to adequately control the A–B status
without additional NaHCO3 infusion and in the absence of alkalosis,
despite the use of a standard HCO3
– concentration HF solution. Furthermore, the combination of a phosphate-containing replacement
fl uid appeared eff ective to prevent hypophosphatemia. Finally, the use
of a mathematical model allowed predicting the eff ects of diff erent
replacement solutions and/or RCA-CVVH settings on the mass balance
of the main solutes. Exposure to intermittent hemodialysis and renal recovery after
acute kidney injury: a systematic review A Schneider1, M Bagshaw2, NJ Glassford1, R Bellomo1
1Austin Health, Heidelberg, Australia; 2University of Alberta, Edmonton,
Canada Critical Care 2012, 16(Suppl 1):P368 (doi: 10.1186/cc10975) Introduction Sustained low-effi ciency dialysis (SLED) as primary renal
replacement therapy in acute renal failure is still not widely used
compared to continuous venovenous hemodiafi ltration (CVVHDF),
despite possible economical advantages. Based on one key paper [1]
we use SLED as primary renal replacement therapy. However, since
medical and economical data with SLED are scarce, we evaluated costs
and outcome in a 5-year retrospective study on our ICU. Introduction Renal replacement therapy (RRT) in critically ill patients can
be applied in a continuous (CRRT) or intermittent (IRRT) fashion. To date,
there is no systematic comparison on the impact of these two modalities
on renal recovery after an episode of acute kidney injury (AKI). We sought
to compare the rates of renal recovery with RRT independence between
CRRT and IRRT as an initial modality for RRT in AKI. y
p
y
Methods During 2006 to 2010 we performed a search on our KIS
selecting all patients with the diagnoses N17 and N18 who were
treated with SLED or CVVHDF on our ICU. We excluded all patients with
a stay <2 days or with an extrarenal indication for dialysis or with pre-
existing chronic dialysis. The following variables were extracted from
the chart: number of SLED, stay in ICU and hospital, mortality in ICU and
hospital, SAPS II, TISS 28, blood urea and creatinine, C-reactive protein,
mechanical ventilation, and diagnoses. We evaluated the long-term
outcome by sending all discharged patients a questionnaire. y
Methods We searched MEDLINE and EMBASE. We retrieved all studies
published between 2000 and 2010 that report original data on renal
recovery to RRT dependence after AKI in adults. Authors of studies
with incomplete data were contacted. Search date: January 2011. Two
authors independently assessed the trial quality and extracted data. Pooled analyses were performed and a chi-square test performed. Sensitivity analyses were performed after stratifi cation by premorbid
chronic kidney disease, number of centers, type of study and illness
severity index. In a subsequent analysis we pooled the studies according
to the percentage of patients exposed to IHD into low-exposure (<50%
of patients exposed) or high-exposure (>50% patients exposed).i y
Results During the period from 2006 to 2010, 3,247 SLED treatments
in 421 patients (mean SAPS II was 52 patients) were performed. P368 P369
Sustained low-effi ciency dialysis for renal replacement therapy in
the ICU: a cost–benefi t analysis of the years 2006 to 2010
T Neuenfeldt, HB Hopf
Asklepios Klinik, Langen, Germany
Critical Care 2012, 16(Suppl 1):P369 (doi: 10.1186/cc10976) p
Reference p
Reference 1. Vinsonneau C, et al.: Lancet 2006, 368:379-385. 1. Vinsonneau C, et al.: Lancet 2006, 368:379-385. Exposure to intermittent hemodialysis and renal recovery after
acute kidney injury: a systematic review ICU
mortality was 36% and hospital mortality was 46%. A persistent need
for dialysis (end-stage kidney disease) was registered in 9%. Total costs
for SLED were €518.431 and total reimbursements amount to €734.996
(Figure 1). Assuming for cost comparisons also 3,247 CVVHDF-days,
we estimated costs of €722.734 with reimbursements of €690.876 for
CVVHDF. Results We identifi ed 50 studies (14,796 patients). Overall, as compared
with those that received IRRT as an initial modality (IRRT group), those
that received CRRT (CRRT group) had higher average illness severity
scores (mean APACHE III equivalent 88 vs. 72, P <0.01) and higher in-
hospital mortality (57.7% vs. 37.9%, P <0.0001). When reported at 28
days after initiation of RRT (outcome reported in 25 studies), 19.4% of
survivors were RRT dependent in the CRRT group versus 26.9% in the
IRRT group (P = 0.004). At hospital discharge (reported in 26 studies),
RRT dependence was present in 10.9% of the CRRT group versus 20.8%
in the IRRT group (P <0.0001). At day 90 (reported in 22 studies), RRT
dependence was 7.8% in the CRRT group versus 36.1% in the IRRT
group (P <0.0001). The sensitivity analyses confi rmed these fi ndings in
all subgroups. The rates of RRT dependency in the low-exposure group
and the high-exposure group at days 28, 90 and hospital discharge were
19.6%, 8.8% and 12.4% versus 43.2%, 26.8% and 14.0% respectively (all
P <0.0001, except for hospital discharge P = NS). Conclusion Thus, since short-term and long-term outcome of our
patients was comparable to published outcome data with CVVHDF,
SLED is at least comparable to CVVHDF even in a busy ICU environment. Moreover, in view of costs, SLED is the preferable dialysis form for renal
replacement therapy also in the ICU. P366 p
p
gi
Methods In our center, RCA-CVVH is routinely performed with
a 12 mmol/l predilution Citr solution (Prismocitrate 10/2) and a
postdilution HF solution (HCO3
– 32, Ca2+ 1.75, Mg2+ 0.5, K+ 2 mmol/l)
(protocol A). In the case of persistent acidosis, not related to Citr
accumulation, NaHCO3 infusion is started. In order to optimize the
buff er balance, a new protocol has been designed throughout a
mathematical model developed to estimate Citr and HCO3
– mass
transfer. Recently introduced solutions have been adopted: 18 mmol/l
predilution Citr solution (Prismocitrate 18), postdilution HF solution
(Phoxilium, HCO3
– 30, phosphate 1.2, Ca2+ 1.25, Mg2+ 0.6, K+ 4 mmol/l)
(protocol B). In relation to Qb, the Citr solution rate was set to meet
the target circuit Citr concentration (3 mmol/l). To maintain systemic
Ca2+ (1.1 to 1.25 mmol/l), CaCl2 10% was started according to estimated
Ca2+ loss. Conclusion In this experience, RCA allowed one to safely prolong the
fi lter life, decreasing the transfusion rate and supplementation needs
for AT-III and PLT. The use of a mathematical model allowed one to
simplify the CVVH settings. Therefore, RCA should be worthy of more
consideration as the fi rst-choice CRRT AC modality in patients at high
risk of bleeding. Results In a cardiac surgery patient with AKI, A–B status and electrolytes
have been evaluated comparing protocol A (fi ve circuits, 301 hours)
versus protocol B (two circuits, 97 hours): pH 7.39 ± 0.03 versus
7.44 ± 0.03 (P <0.0001), blood HCO3
– 22.3 ± 1.8 versus 22.6 ± 1.4 mmol/l S132 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P369). Cost–benefi t ratio for SLED compared to CVVHDF. Figure 1 (abstract P369). Cost–benefi t ratio for SLED compared to CVVHDF. P372 P372
Evaluation of microcirculation before and during continuous renal
replacement therapy and the impact of dose prescription
C Pipili1, CS Vrettou2, S Poulaki3, A Papastylianou3, M Parisi3, ES Tripodaki3,
S Ioannidou3, S Kokkoris3, E Douka3, S Nanas2
1Aretaieion University Hospital, Athens, Greece; 2National and Kapodistrian
University of Athens, Greece; 3Evaggelismos Hospital, Athens, Greece
Critical Care 2012, 16(Suppl 1):P372 (doi: 10.1186/cc10979) Table 1 (abstract P370). Dialysis methods and clinical parameter
CRRT
PD
Low Qb HD
Mini-SLED
(n = 25)
(n = 3)
(n = 21)
(n = 12)
NIHSS (score)
30.8 ± 17.2
34.6 ± 16.4
31.7 ± 20.8
32 ± 19.8
Rebleed (n, %)
6, 24%
1, 33%
4, 19.0%
0, 0%
Mortality (n, %)
5, 20%
1, 33%
5, 23.8%
2, 16%
Kt/V (daily)
0.68 ± 0.32
0.25 ± 0.16
0.86 ± 0.23
0.72 ± 0.23
Cost ($/1 treat)
498 ± 30.2
92.4 ± 22.6
82.5 ± 12.5
86.7 ± 14.3
Conclusion Our Mini-SLED methods are eff ective and safe for dialyzing
acute brain stroke patients. Table 1 (abstract P370). Dialysis methods and clinical parameter Introduction Microcirculation (MC) might provide evidence for the
solute exchange taking place during the dialysis process. Near-infrared
spectroscopy (NIRS) with combination of vascular occlusion technique
(VOT) allows evaluation of peripheral tissue oxygen utilization and
restoration mainly depending on integrity and functionality of
vascular endothelium. Our purpose was to evaluate the acute eff ect of
continuous renal replacement therapy (CRRT) on the MC as assessed
by NIRS and VOT and to explore the impact of delivered CRRT dose on
MC alterations. Methods A total of 43 critically patients who underwent CRRT were
eligible to participate in the study. The mean age of our population was
66 ± 17 years and 40% were females. The APACHE II score was 20 ± 6,
the mean serum creatinine before the CRRT initiation was 2.6 ± 1.6
mg/dl and the mean CRRT delivered dose was 23 ± 6 ml/kg/hour. The
median value of dose was used to form groups of high (>22.5 ml/kg/
hour) and low (≤22.5ml/kg/hour) delivered dose. NIRS parameters
were evaluated before CRRT initiation (H0), at 6 hours (H6) and at
24 hours (H24) during the CRRT process. Tissue oxygen saturation
(StO2, %), defi ned as the percentage of hemoglobin saturation in the
microvasculature compartments, was measured with a probe placed
on the thenar muscle. Investigation into haemodynamic stability during intermittent
haemodialysis in the critically ill Introduction Studies that have reported cardiovascular (CVS) instability
with haemodialysis (HD) are outdated and small. By analysing sessions
in detail it will be possible to identify the frequency and nature of
CVS instability. Hypothesis 1: haemodialysis is associated with CVS
instability in the majority of sessions. Hypothesis 2: the majority of CVS
changes in unstable sessions will be harmful/potentially harmful. 2
Results Two-way repeated-measures ANOVA were performed for
StO2, OCR, RS and hyperemia recovery area at H0, H6 and H24. StO2
correlated with RIFLE on admission and at the time of CRRT initiation
(r = 0.283, P = 0.03 and r = 0.45, P <0.0001 respectively). There was a
signifi cant decrease in OCR with time (hours on CRRT process) (within-
subjects ANOVA F = 4.83, P = 0.014) and especially between H0 and H24
(–10.5 ± 9.4 vs. –12 ± 8.3, P = 0.008). Furthermore, a signifi cant increase
in RS was found in patients who received a high CRRT dose (between-
subjects ANOVA F = 4.5, P <0.05), especially at H6 post CRRT initiation
(76 ± 117 vs. 86 ± 128, P = 0.05). g
y
Methods Data were collected for 209 patients, identifying 1,605
dialysis sessions. Analysis was performed on hourly records, classifying
sessions as stable/unstable by a cut-off >±20% change in baseline
physiology (HR/MAP). Data from 3 hours prior to and 4 hours after
dialysis were included, and average and minimum values derived. Three time comparisons were made: pre-HD:during, during HD:post,
pre-HD:post-HD. If a session was identifi ed as being unstable, then
the nature of instability was examined by recording whether changes
crossed defi ned physiological ranges. The changes seen in unstable
sessions could be described as to their eff ects: being harmful/
potentially harmful, or benefi cial/potentially benefi cial. Conclusion Critically ill patients, receiving a dialysis dose higher than
22.5 ml/kg/hour, showed improved MC. Further studies are needed to
investigate the role of NIRS technology as a tool to assess the need for
CRRT initiation in acute renal failure. ii
Results Discarding incomplete data, 1,563 sessions were analysed. A
session was deemed to be stable if there was no change >±20% in
time-averaged or minimum MAP/HR across three time comparisons. In 1,563 sessions there was stability in 874 sessions (55.8%, 95%
CI for SEM 53.2 to 58.4). Hypothesis 1 is rejected. The new dialysis method Mini-SLED is useful for dialyzing acute
brain stroke patients
F Taki, Y Komatsu
St Luke’s International Hospital, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P370 (doi: 10.1186/cc10977) Conclusion The preponderance of the available evidence suggests that
CRRT is associated with a higher rate of renal recovery in AKI survivors
compared with IRRT. p
F Taki, Y Komatsu Introduction Hemodialysis (HD) patients are known to be a high-risk
population for brain stroke. On acute phase of stroke, standard HD
treatment may increase cerebral damage by changing serum and S133 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 of 7,464/8,268 (90.3%, 95% CI SEM 89.6 to 90.9). Therefore Hypothesis
2 is rejected. tissue osmolarity. For low clearance dialysis, CRRT, PD or low Qb HD
were used but there are some complications. To dialyze these patients
more safely and simply, we modifi ed a new dialysis method, Mini-SLED
(sustained low-effi ciency dialysis). Conclusion The results above are encouraging, especially given the
stringent defi nitions of instability used. By making multiple time-period
comparisons the validity of the claims of haemodynamic stability are
enforced, compared to previous papers. The number of sessions and
measurement points combine to add weight to our fi ndings, supported
by robust confi dence interval data. fi
Methods We conducted a retrospective observational study from June
2006 to October 2011. Maintenance HD patients who onset acute
brain stroke, including hemorrhage and ischemic infarction, were
observed. We divided patients into four groups by dialysis modality
and compared the clinical parameters. Determination of Mini-SLED was
Qb 200 ml/minute, QD 100 to 200 ml/minute, duration for 2 to 3 hours. Results Sixty-one patients were observed in this study. Mean age 72.5
years, 39 patients were male, 45 patients had diabetes. Major clinical
parameters and outcomes are presented in Table 1. Patients treated
with Mini-SLED have lower risk of rebleeding compared to low Qb HD
or CRRT, and were more cost-eff ective than PD. Delivered Kt/V of Mini-
SLED was 0.72 ± 0.23. Modality diff erence did not aff ect mortality. P372 A 3-minute brachial VOT was applied to evaluate
the oxygen consumption rate (OCR, %/minute), the recovery slope (RS,
%/minute), and the hyperemia recovery area as the area (units/minute)
under the StO2% curve above baseline values. Conclusion Our Mini-SLED methods are eff ective and safe for dialyzing
acute brain stroke patients. Investigation into haemodynamic stability during intermittent
haemodialysis in the critically ill Each session had
12 potential comparisons of MAP, HR and time, therefore in the
689 unstable sessions there were 8,268 potential changes ±20%
(689×12). There were 804/8,268 harmful/potentially harmful changes,
922/8,268 benefi cial/potentially benefi cial changes and 6,542/8,268
opportunities for change where none occurred. Therefore, looking at
harmful/potentially harmful changes there were 804/8,268 (9.7%, 95%
CI for SEM 9.1 to 10.4). Looking at potentially benefi cial changes this
occurred in 922/8,268 (11.2%, 95% CI for SEM 10.5 to 11.9), and if these
were combined with the nonsignifi cant changes this gave a proportion P373i P373
Ultrafi ltration during continuous hemofi ltration in stabilized
ICU patients is not associated with microcirculatory perfusion
derangements
B Scheenstra, G Veenstra, M Koopmans, WP Kingma, H Buter,
HM Hemmelder, EC Boerma
Medical Centre Leeuwrden, the Netherlands
Critical Care 2012, 16(Suppl 1):P373 (doi: 10.1186/cc10980) Degree of impaired kidney function at hospital discharge has
a major impact on long-term survival of critically ill patients
recovered from renal failure S Stads, G Fortrie, J Van Bommel, R Zietse, M Betjes
Erasmus MC, Rotterdam, the Netherlands
Critical Care 2012, 16(Suppl 1):P375 (doi: 10.1186/cc10982) Table 1 (abstract P373). (Micro)circulatory variables during ultrafi ltration
T1
T2
P value
RR mean
71 (65 to 94)
66 (63 to 95)
0.87
Heart rate
97 (78 to 126)
94 (75 to 123)
0.03
MFI
2.9 (2.7 to 3)
3 (3 to 3]
0.34
TVD
20 (18 to 22)
21 (17 to 23)
0.5
Conclusion A negative net fl uid balance of 50 ml/hour during ultra-
fi ltration in CVVH is not associated with microcirculatory perfusion
alterations. References
1. Bemelmans et al.: Nephrol Dial Transplant 2009, 24:3487-3492. 2. Pottecher et al.: Intensive Care Med 2010, 36:1867-1874. P374
Plasmapheresis without apparatus in complex care of victims with
crush syndrome during the fi rst hours after extrication in a fi eld
hospital of EMERCOM of Russia in emergency areas
A Popov1, I Yakirevich1, A Skorobulatov1, V Shabanov2
1EMERCOM of Russia, Zhukovsky, Moscow Region, Russia; 2All-Russian Centre
of Disaster Medicine, Moscow, Russia Table 1 (abstract P373). (Micro)circulatory variables during ultrafi ltration
T1
T2
P value
RR mean
71 (65 to 94)
66 (63 to 95)
0.87
Heart rate
97 (78 to 126)
94 (75 to 123)
0.03
MFI
2.9 (2.7 to 3)
3 (3 to 3]
0.34
TVD
20 (18 to 22)
21 (17 to 23)
0.5
Conclusion A negative net fl uid balance of 50 ml/hour during ultra-
fi ltration in CVVH is not associated with microcirculatory perfusion
alterations. References
1. Bemelmans et al.: Nephrol Dial Transplant 2009, 24:3487-3492. 2. Pottecher et al.: Intensive Care Med 2010, 36:1867-1874. Table 1 (abstract P373). (Micro)circulatory variables during ultrafi ltration Table 1 (abstract P373). (Micro)circulatory variables during ultrafi ltration
T1
T2
P value
RR mean
71 (65 to 94)
66 (63 to 95)
0.87
Heart rate
97 (78 to 126)
94 (75 to 123)
0.03
MFI
2.9 (2.7 to 3)
3 (3 to 3]
0.34
TVD
20 (18 to 22)
21 (17 to 23)
0.5 Introduction Renal replacement therapy (RRT) in critically ill patients
with acute kidney injury (AKI) is associated with high mortality. However, little is known about the prognosis of renal function after ICU
discharge and the eff ect of persisting impaired kidney function on long-
term survival. Ultrafi ltration during continuous hemofi ltration in stabilized
ICU patients is not associated with microcirculatory perfusion
derangements g
B Scheenstra, G Veenstra, M Koopmans, WP Kingma, H Buter,
HM Hemmelder, EC Boerma
Medical Centre Leeuwrden, the Netherlands
Critical Care 2012, 16(Suppl 1):P373 (doi: 10.1186/cc10980) Introduction Ultrafi ltration during intermittent haemodialysis has
been associated with reduction in microcirculatory perfusion, as
observed with sidestream dark-fi eld (SDF) imaging [1]. This technique
has also been useful in the evaluation of volume status in critically Introduction Ultrafi ltration during intermittent haemodialysis has
been associated with reduction in microcirculatory perfusion, as
observed with sidestream dark-fi eld (SDF) imaging [1]. This technique
has also been useful in the evaluation of volume status in critically S134 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 ill patients [2]. To date no data are available on the infl uence of
ultrafi ltration during continuous venovenous hemofi ltration (CVVH) on
microcirculatory perfusion. ill patients [2]. To date no data are available on the infl uence of
ultrafi ltration during continuous venovenous hemofi ltration (CVVH) on
microcirculatory perfusion. with 25 to 30% hematocrit; correction of the blood coagulation system;
detoxication with the application of active methods of homeostasis
correction; prevention and elimination of purulent and septic
complications; primary surgical debridement and excision of necrotic
mass areas carried out with general anesthesia, no excision conducted;
and transport immobilization before evacuation. y p
Methods In this single-centre, prospective, observational study
patients with acute renal failure on CVVH were included after
hemodynamic stabilization and written informed consent A fi xed
dose of net ultrafi ltration was calculated for each patient, aiming at a
negative total fl uid balance of 50 ml/hour. Microcirculatory perfusion
was observed with sublingual SDF imaging after 1 hour of zero balance
CVVH (T1) and additionally after 1 hour of negative fl uid balance
ultrafi ltration (T2). The primary outcome was a change in microvascular
fl ow index (MFI) between T1 and T2. Data are presented as median
(IQR). Diff erences are calculated with a nonparametric test for paired
data. Results Among all victims, hemodynamics stabilization was noted in
28 ± 6 hours, and dieresis increased up to 1,200 ± 100 ml/day in 18 ± 8
hours. Acute renal failure cases were not noted. All victims in stable
condition were evacuated to specialized hospitals by helicopter. No
mortality rate during medical aid rendering was noted. References References
1. Bemelmans et al.: Nephrol Dial Transplant 2009, 24:3487-3492. 2
Pottecher et al : Intensive Care Med 2010 36:1867 1874 1. Bemelmans et al.: Nephrol Dial Transplant 2009, 24:3487-3492. 1. Bemelmans et al.: Nephrol Dial Transplant 2009, 24:3487 3492. 2. Pottecher et al.: Intensive Care Med 2010, 36:1867-1874. Results In-hospital mortality was 54.9%. After hospital discharge,
the overall mortality was 75.3% after a median follow-up of 8.5 years
(range 1 to 17 years). Univariate analysis showed that age, surgical or
nonsurgical reason for ICU admission and kidney function at discharge
were associated with overall survival. Multivariate Cox regression
analysis of the association of kidney function at hospital discharge with
patient survival was performed, adjusting for age, sex and surgical or
nonsurgical admission type. The eGFR at hospital discharge remained
independently associated with long-term survival (P <0.001). Only 87
(15.8%) patients were discharged with an eGFR >90 ml/minute (using
the MDRD formula). In this group 5-year and 10-year survival were
respectively 77.6% and 66.7%. The mortality risk increased for every
increase in stage of chronic kidney disease (hazard ratio 1.25, P <0.001). Patients discharged with an eGFR <30 ml/minute (CKD 4 to 5, 37.3% of
patients at hospital discharge) had a 5-year and 10-year survival of only
42.5% and 28.5%. P374
Plasmapheresis without apparatus in complex care of victims with
crush syndrome during the fi rst hours after extrication in a fi eld
hospital of EMERCOM of Russia in emergency areas y
A Popov1, I Yakirevich1, A Skorobulatov1, V Shabanov2 A Popov1, I Yakirevich1, A Skorobulatov1, V Shabanov2
1EMERCOM of Russia, Zhukovsky, Moscow Region, Russia; 2All-Russian Centre
of Disaster Medicine, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P374 (doi: 10.1186/cc10981) Introduction This is the generalization of the experience of
membranous plasmapheresis without apparatus (MPPA) application
in the complex care of victims with crush syndrome (CS) in the fi eld
hospital (FH) of EMERCOM of Russia during elimination of medical
consequences of earthquakes (Pakistan, 2005; China, 2008; Haiti, 2010). Methods Thirty-eight victims with CS (19 males, 19 females, age 34.5 ± 4)
were in the resuscitation department of the FH. Compound fractures
of tubular bones and crushed tissues necrosis were observed. Joint
movement was severely restricted and artery pulsation was uncertain. Condition severity: according to the Glasgow Coma Scale 12 ± 1,
according to APACHE II score 29 ± 4. The tendency to hypotension and
tachycardia, increase of body temperature and dyspnea intensifi cation
were observed, diurnal diuresis decreased. Plasmapheresis treatment
was carried out by the MPPA method. A total of 2 ± 1 procedures
were conducted to each patient with the removal of 70 ± 10% of the
plasma circulation volume per session. Removed plasma volume was
calculated for each victim individually on the basis of average volume
before plasma exchange. The procedure frequency was once per day. Substitution means: crystalloids, hydroxyethylized starch, proteins. The
MPPA procedure time was from 60 to 120 minutes. MPPA was carried
out in all victims during complex care for CS: elimination of painful
impact and stressful situation; restoration of acid–alkaline conditions
and water–electrolytic balance of blood, maintenance of hemodilution Conclusion ICU patients with AKI who received CRRT have a high
mortality risk. This is more outspoken for patients who experience
incomplete recovery of renal function at hospital discharge. Impaired
kidney function at discharge has a major negative impact on their long-
term survival. These results stress the importance of preserving kidney
function in ICU patients and the need for long-term nephrological
follow-up. Future research will have to identify possible determinants
in the period following hospital discharge that can be used to prolong
survival in these patients. Degree of impaired kidney function at hospital discharge has
a major impact on long-term survival of critically ill patients
recovered from renal failure The objective of this study was to evaluate the overall
long-term mortality in a cohort of ICU patients with AKI necessitating
RRT. We hypothesized that both patient characteristics and the degree
of renal insuffi ciency at hospital discharge will infl uence long-term
mortality. y
Methods A retrospective cohort study was performed including all
patients older than 18 years admitted to the ICU of a tertiary-care center
between 1994 and 2010, who underwent continuous RRT during their
ICU stay (n = 1,220). Ultrafi ltration during continuous hemofi ltration in stabilized
ICU patients is not associated with microcirculatory perfusion
derangements y
g
g
Conclusion MPPA application allows one to reduce the rate of compli-
cations and mortality. MPPA application is the method of extra-
corporeal homeostasis correction option for victims with CS in a FH in
emergencies. Results Eleven patients were eligible for the study; one denied
informed consent. One patient could not be evaluated due to the
unavailability of the research team and in two patients we were unable
to obtain images of proper quality. The median APACHE II score was
26 (21 to 29); at baseline LOS ICU was 5 (3 to 6) days and fl uid balance
+7.9 (5.1 to 14.2) l. Hemodynamic and microcirculatory variables are
depicted in Table 1. P375 P376 Long-term survival for ICU patients with acute kidney injury
D Scott1, F Cismondi2, J Lee1, T Mandelbaum3, LA Celi1, RG Mark1, D Talmor2
1MIT, Cambridge, MA, USA; 2Beth Israel Deaconess Medical Center, Boston, MA,
USA; 3Sheba Medical Center, Tel Hashomer, Israel
Critical Care 2012, 16(Suppl 1):P376 (doi: 10.1186/cc10983) Introduction A recently published study [1] validated the criteria
used in the Acute Kidney Injury Network (AKIN) defi nitions [2] of the S135 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 immunoglobulins (κ-FLC) (23 kDa) and albumin (68 kDa) clearances
were measured at 15 minutes, 1 hour, 4 hours, 12 hours, 24 hours and
48 hours. β2-M and κ-FLC were chosen as a middle molecular weight
marker. A linear mixed-eff ects model compared clearances between
groups. three stages of acute kidney injury (AKI) using in-hospital mortality. In the present study, we validate the clinical applicability of the AKIN
classifi cations through long-term survival analysis of AKI patients. three stages of acute kidney injury (AKI) using in-hospital mortality. In the present study, we validate the clinical applicability of the AKIN
classifi cations through long-term survival analysis of AKI patients. i
y
Methods From over 17,000 adult ICU patients in the MIMIC II database
[3,4] (V2.5), we excluded patients having end-stage renal disease and
those with insuffi cient data and determined AKI stages for each patient. Multivariate Cox regression was used to determine hazard ratios (HRs)
for 2-year survival, controlling for: age, sex, nonrenal Sequential Organ
Failure Assessment (SOFA) score and selected co-morbidities. g
p
Results Twenty-four patients were included, 12 in the SHF-HD
group (32 sessions) and 12 in CVVH (30 sessions). κ-FLC and albumin
clearances were higher in the SHF-HD group over time. No diff erence
was observed for creatinine (P = 0.18) and β2-M (P = 0.98) clearances. Plasma albumin levels and the amount of albumin infused did not
diff er between groups. See Figure 1. Results Among the fi nal cohort of 14,525 patients, 43% had no AKI and
39%, 14% and 4% developed AKI 1, 2 and 3 respectively. The results of
the regression analysis show that AKI 1 (HR 1.12, P <0.05), AKI 2 (HR 1.10,
P = 0.05) and AKI 3 (HR 1.64, P <0.001) were signifi cantly associated with
increased 2-year mortality. Super high-fl ux continuous hemodialysis: an effi cient compromise
for blood purifi cation in sepsis p
p
Methods Thirty-fi ve patients diagnosed with sepsis (ARDS (n = 10),
pyelonephritis (n = 5), cholangitis (n = 5), tsutsugami in Scrub typhus
disease (n = 1), mamushi snake bite (n = 1), haemophagocytic syn-
drome (n = 1), antineutrophil cytoplasmic antibody lung disease
(n = 1), beriberi heart disease (n = 1) and unknown causes (n = 8)) were
enrolled in this study between August 2010 and November 2011.The
common cause for ARDS in older patients was aspiration pneumonia. Our study group comprised 15 men and 20 women, aged 35 to 85 years
(median age 68 years). i
T Rimmelé, M Page, C Ber, F Christin, J Baillon, J Crozon, C Chapuis-Cellier,
R Ecochard, B Allaouchiche
Edouard Herriot Hospital, Hospices Civils de Lyon, France
Critical Care 2012, 16(Suppl 1):P377 (doi: 10.1186/cc10984) i
T Rimmelé, M Page, C Ber, F Christin, J Baillon, J Crozon, C Chapuis-Cellier,
R Ecochard, B Allaouchiche
Edouard Herriot Hospital, Hospices Civils de Lyon, France
Critical Care 2012, 16(Suppl 1):P377 (doi: 10.1186/cc10984) Introduction High cut-off membranes are proposed for blood purifi -
cation therapy in septic shock. However, albumin loss related to these
membranes is a major drawback limiting their clinical acceptance. Super High-Flux membranes with an optimized cut-off may combine
enhanced middle molecule clearances (infl ammatory mediators)
with limited albumin loss. The aim of our study was to compare small,
middle molecule clearances and albumin loss between continuous
hemodialysis using a Super High-Flux membrane (SHF-HD) and
conventional continuous hemofi ltration (CVVH). (
g
y
)
Results Before initiating treatment with the PMMA-CHDF, the
average APACHE score of these patients was 17.5 ± 3.6, whereas
the average Sepsis-related Organ Failure Assessment score was
6.5 ± 1.3. The duration of PMMA-CHDF treatment was 5.2 ± 2.3 days. Following initiation of PMMA-CHDF treatment, early improvement of
haemodynamics was observed, along with an increase in the urine
output. The average survival rates of patients were 75.6%. The lowest
survival rate among diseases (35%) belonged to the unknown group. The highest survival rate for patients with ARDS was 95%. Moreover,
the urine output signifi cantly increased in the survival group. i
Methods After approval by the ethics committee, patients were enrolled
in a single-blind RCT. Effi cacy of continuous haemodiafi ltration using a
polymethylmethacrylate membrane haemofi lter in the treatment of
sepsis and acute respiratory distress syndrome y
p
Conclusion AKI stages 1, 2 and 3 are signifi cant indicators of 2-year
mortality. The diff erence between AKI 1 and 2 is smaller than that
between AKI 2 and 3 and it may be prudent to re-examine the criteria
used to defi ne AKI to provide better separation among the three
classes. Shintakeo Hospital, Takeo, Japan
Critical Care 2012, 16(Suppl 1):P378 (doi: 10.1186/cc10985) Shintakeo Hospital, Takeo, Japan
Critical Care 2012, 16(Suppl 1):P378 (doi: 10.1186/cc10985) Super high-fl ux continuous hemodialysis: an effi cient compromise
for blood purifi cation in sepsis Patients with septic shock and acute kidney injury
received either SHF-HD (EMiC2® fi lter; Fresenius Medical Care) (cut-
off = 40 kDa, dialysate fl ow rate of 40 ml/kg/hour) or conventional
CVVH (cut-off = 30 kDa, UF fl ow rate of 40 ml/kg/hour). Each patient
received a maximum of three sessions of 48 hours each. Creatinine
(113 Da), β2-microglobulin (β2-M) (11.8 kDa), kappa free light chain of i
Conclusion The present study suggests that cytokine-oriented critical
care using PMMA-CHDF might be eff ective in the treatment of sepsis
and ARDS, particularly in the treatment of ARDS associated with
aspiration pneumonia in older patients. Figure 1 (abstract P377). Figure 1 (abstract P377). References Introduction CHDF using a polymethylmethacrylate membrane is
currently widely applied for nonrenal indications in Japan; this tech-
nique is used in the treatment not only of patients with sepsis but also
of those with cytokine-induced critical illness such as acute respiratory
distress syndrome (ARDS) and pancreatitis. This study aimed to
investigate the clinical effi cacy of continuous haemodiafi ltration using
a polymethylmethacrylate membrane haemofi lter (PMMA-CHDF) in
the treatment of patients with sepsis and ARDS. 3. Saeed M, et al.: Crit Care Med 2011, 39:952-960. 4. MIMIC II databases [http://physionet.org/mimic2] P376 In addition, age (HR 1.04, P <0.001), gender
(M) (HR 0.93, P <0.05), nonrenal SOFA score (HR 1.05, P <0.001) and all
co-morbidities were signifi cant predictors. Adjusted and unadjusted
Kaplan–Meier curves for patients with AKI 3 are remarkably diff erent
from each other, suggesting that in these most severely ill patients AKI
is only one aspect of their illness.i f
g
p
g
Conclusion The removal of middle molecular weight molecules is
higher with SHF-HD. Albumin loss was limited in both groups, even with
SHF-HD. Therefore, SHF membranes seem to represent an alternative to
high cut-off membranes for blood purifi cation therapies. P378fi P379 However, we have shown
that greater than 2 hours duration of PMX treatment signifi cantly
improved hemodynamics and signifi cantly decreased administration
of norepinephrine than 2 hours duration of PMX treatment. Our
hypothesis was that PMX treatment had the ability of endotoxin
removal during 24 hours. Therefore, the purpose of this study was to
evaluate the endotoxin adsorption ability of 24 hours duration of PMX
treatment. Introduction Endotoxin plays an important role in the pathogenesis
of septic shock. Endotoxin adsorption therapy by Polymyxin
B-immobilized fi ber column (PMX) hemoperfusion has been used
for the treatment of septic shock patients in Japan. According to the
company’s recommendation, the standard duration of PMX treatment
for patients with septic shock is 2 hours. However, we have shown
that greater than 2 hours duration of PMX treatment signifi cantly
improved hemodynamics and signifi cantly decreased administration
of norepinephrine than 2 hours duration of PMX treatment. Our
hypothesis was that PMX treatment had the ability of endotoxin
removal during 24 hours. Therefore, the purpose of this study was to
evaluate the endotoxin adsorption ability of 24 hours duration of PMX
treatment. Figure 2 (abstract P379). Immunoelectron microscopy using anti-
HMGB1 polyclonal antibodies. contributes to HMGB1, with a heparin-binding protein, adsorption on
AN69ST. Methods The test solution contained 100 g HMGB1 and 35 g albumin
in 1,000 ml substitution fl uid. We executed three diff erent experimental
hemofi ltrations with solution fl ow of 100 ml/minute and: ultrafi ltrate
fl ow 1,000 ml/hour using AN69ST primed with a heparinized saline,
F(+) and H(+); ultrafi ltrate fl ow 1,000 ml/hour using AN69ST with no
heparinized saline, F(–) and H(+); and ultrafi ltrate fl ow of 0 ml/hour
using AN69ST with no heparinized saline, F(–) and H(–). In addition,
AN69ST membrane was immunostained using an antibody that
confi rmed dying on human kidney tissue. Methods In this study, we measured plasma endotoxin concentrations
of blood drawn from the radial artery and the outlet circuit of the
PMX column after 24 hours duration of PMX treatment in septic shock
patients. The assay for endotoxin was performed with separated
plasma from heparinized whole blood samples centrifuged at 3,000
rpm for 40 seconds. The high-sensitivity assay was performed by
kinetic turbidimetric Limulus assay using a MT-358 Toxinometer (Wako
Pure Chemical Industries, Ltd, Japan). This Limulus assay test is specifi c
to endotoxin and has no cross-reaction to β-glucan. High mobility group box 1 levels in septic disseminated
intravascular coagulation patients undergoing Polymixin-B
immobilized fi ber-direct hemoperfusion High mobility group box 1 levels in septic disseminated
intravascular coagulation patients undergoing Polymixin-B
immobilized fi ber-direct hemoperfusion
Y Ishibe, Y Suzuki, H Sato, G Takahashi, M Kojika, N Matsumoto, Y Inoue,
S Endo
Iwate Medical University, Morioka, Japan
Critical Care 2012, 16(Suppl 1):P380 (doi: 10.1186/cc10987) i
p
Y Ishibe, Y Suzuki, H Sato, G Takahashi, M Kojika, N Matsumoto, Y Inoue,
S Endo
Iwate Medical University, Morioka, Japan
Critical Care 2012, 16(Suppl 1):P380 (doi: 10.1186/cc10987) Conclusion These fi ndings suggest that 24 hours duration of PMX
treatment is eff ective to remove endotoxin. Further studies are needed
to confi rm this ability. y,
,
p
Critical Care 2012, 16(Suppl 1):P380 (doi: 10.1186/cc10987) P379 3 9
Possible adsorption mechanism of high mobility group box 1
protein on a polyacrylonitrile (AN69ST) membrane fi lter
O Nishida1, M Yumoto1, K Moriyama1, Y Shimomura1, T Miyasho2,
S Yamada3
1Fujita Health University School of Medicine, Toyoake, Japan; 2Rakuno Gakuen
University, Ebetsu, Japan; 3Shino-Test Corporation, Sagamihara, Japan
Critical Care 2012, 16(Suppl 1):P379 (doi: 10.1186/cc10986) Introduction At ISICEM 2011, we reported that AN69ST showed the
highest capacity to adsorb high mobility group box 1 protein (HMGB1)
when compared with polymethylmethacrylate, polysulfone and high
cut-off membrane [1]. Here we focus on whether fi ltration or surface
heparin on AN69ST by a priming circuit with a heparinized saline Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 S136 Figure 1 (abstract P379). Time course of HMGB1 levels in the test
solution. Figure 2 (abstract P379). Immunoelectron microscopy using anti-
HMGB1 polyclonal antibodies. Figure 1 (abstract P379). Time course of HMGB1 levels in the test
solution. coagulation (DIC) undergoing Polymixin-B immobilized fi ber-direct
hemoperfusion (PMX-DHP). Methods The subjects were 16 patients with serum endotoxin levels of
1.1 pg/ml or over. The average APACHE II score was 32.2, the average
SOFA score 12.4, and the average DIC score 5.5. Results Following PMX-DHP, the serum endotoxin level decreased to
below the limit of detection in all patients. The serum HMGB1 level
decreased signifi cantly to 31.2, 16.6 and 7.9 ng/ml on days 0, 1, and
2, respectively. The average of the DIC score improved from 5.6 to 3.9
to 2.9. Overall, the 30-day, 60-day, 90-day and 180-day mortality rates
were 0, 6.3%, 12.5% and 12.5%, respectively. y
Conclusion Following initiation of PMX-DHP, the serum HMGB1 level
decreased and the DIC score also decreased accordingly. Figure 1 (abstract P379). Time course of HMGB1 levels in the test
solution. Figure 2 (abstract P379). Immunoelectron microscopy using anti-
HMGB1 polyclonal antibodies. P381
Polymyxin B-immobilized fi ber column hemoperfusion has the
ability of endotoxin removal during 24 hours
C Mitaka, Y Ueda, Y Miyawaki, M Yamauchi, T Toyofuku, G Haraguchi,
T Kudo
Tokyo Medical and Dental University, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P381 (doi: 10.1186/cc10988) Introduction Endotoxin plays an important role in the pathogenesis
of septic shock. Endotoxin adsorption therapy by Polymyxin
B-immobilized fi ber column (PMX) hemoperfusion has been used
for the treatment of septic shock patients in Japan. According to the
company’s recommendation, the standard duration of PMX treatment
for patients with septic shock is 2 hours. P379 The endotoxin
removal rate was defi ned by the equation: ((radial artery endotoxin
concentration – outlet circuit of PMX column endotoxin concentration) /
radial artery endotoxin concentration)×100%. The endotoxin removal
rate represents endotoxin adsorption ability. Five patients with septic
shock were studied. i
Results The concentration decreases of HMGB1 at 0, 60 and 360
minutes indicated no signifi cant diff erences among the three diff erent
hemofi ltration experiments (Figure 1). At 60 minutes, reduction rates
of HMGB1 were: F(+) and H(+), 97.3%; F(+) and H(–), 94.8%; and F(–)
and H(–), 96.4% respectively. HMGB1 was not detected in bulk layers by
immunostaining (Figure 2). g
g
Conclusion Surface heparin or fi ltration might not contribute to
HMGB1 adsorption on the AN69ST membrane. Remarkable adsorption
on AN69ST is likely to be infl uenced by material characteristics,
hydrogel structure with moisture content, or negative electric charge
and may occur not in bulk layers but on large surfaces of membranes. Reference Results The APACHE II scores of these patients were 26.2 ± 5.9
(mean ± SD, range 18 to 34) at admission to the ICU. Three patients
survived and two patients died. Before the start of PMX treatment,
heart rates were 119 ± 19 bpm, mean arterial pressures were 60 ± 19
mmHg, and plasma endotoxin concentrations of radial arterial
blood were 91.4 ± 7.4 pg/ml (mean ± SD). After 24 hours duration of
PMX treatment, plasma endotoxin concentrations decreased from
55.0 ± 58.9 pg/ml (radial arterial blood) to 19.4 ± 29.5 pg/ml (outlet
circuit of PMX column). The endotoxin removal rate was 62.8 ± 22.1%,
suggesting that endotoxin adsorption ability is still retained during 24
hours PMX treatment.i 1. Yumoto M, et al.: Ther Apher Dial 2011, 15:385-393. 1. Yumoto M, et al.: Ther Apher Dial 2011, 15:385-393. coagulation (DIC) undergoing Polymixin-B immobilized fi ber-direct
hemoperfusion (PMX-DHP). coagulation (DIC) undergoing Polymixin-B immobilized fi ber-direct
hemoperfusion (PMX-DHP).
Methods The subjects were 16 patients with serum endotoxin levels of
1.1 pg/ml or over. The average APACHE II score was 32.2, the average
SOFA score 12.4, and the average DIC score 5.5.
Results Following PMX-DHP, the serum endotoxin level decreased to
below the limit of detection in all patients. The serum HMGB1 level
decreased signifi cantly to 31.2, 16.6 and 7.9 ng/ml on days 0, 1, and
2, respectively. The average of the DIC score improved from 5.6 to 3.9
to 2.9. Overall, the 30-day, 60-day, 90-day and 180-day mortality rates
were 0, 6.3%, 12.5% and 12.5%, respectively.
C
l
i
F ll
i
i iti ti
f PMX DHP th
HMGB1 l
l 1.
Yumoto M, et al.: Ther Apher Dial 2011, 15:385-393. coagulation (DIC) undergoing Polymixin-B immobilized fi ber-direct
hemoperfusion (PMX-DHP).
Methods The subjects were 16 patients with serum endotoxin levels of
1.1 pg/ml or over. The average APACHE II score was 32.2, the average
SOFA score 12.4, and the average DIC score 5.5.
Results Following PMX-DHP, the serum endotoxin level decreased to
below the limit of detection in all patients. The serum HMGB1 level
decreased signifi cantly to 31.2, 16.6 and 7.9 ng/ml on days 0, 1, and
2, respectively. The average of the DIC score improved from 5.6 to 3.9
to 2.9. Overall, the 30-day, 60-day, 90-day and 180-day mortality rates
were 0, 6.3%, 12.5% and 12.5%, respectively.
Conclusion Following initiation of PMX DHP the serum HMGB1 level Methods The subjects were 16 patients with serum endotoxin levels of
1.1 pg/ml or over. The average APACHE II score was 32.2, the average
SOFA score 12.4, and the average DIC score 5.5. P383 Methods Ten critically ill patients were studied who were on SHEDD-
fA, at QB = 150 ml/minute, QF = 1,500 ml/hour (post dilution) and
QD = 300 to 500 ml/minute as a nonrenal indication. In order to
maximize cytokine adsorption effi ciency, we used a large-size (2.1 m2)
PMMA dialyzer. Blood samples were taken to measure the CL of plasma
cytokines (HMGB-1, IL-6, IL-8, IL-10, G-CSF, MCP-1 and MIP-1) at 1 hour
and 3 hours after initiation (in one cytokine by 62 to 107 samples). Results The median values of CL with interquartile ranges of each
cytokine (molecular weight: kDa) were: HMGB1 (30 kDa), 53.1 ml/
minute (2.1 to 12.5); IL-6 (21 kDa), 39.9 ml/minute (12.4 to 70.6); IL-8
(8 kDa), 64.1 ml/minute (–0.5 to 82.0); IL-10 ml/minute (35 to 40 kDa),
45.6 ml/minute (0.5 to 88.3); G-CSF (19 kDa), 33.2 ml/minute (9.3 to
60.8); MCP-1 (8.7 kDa), 68.5 ml/minute (–14.4 to 125.4); and MIP-1 (7.8
kDa), 66.5 ml/minute (18.6 to 100.0). In particular, CL of HMGB1 was
positively correlated with pre-SHEDD-fA blood levels, indicating the
mechanism of HMGB1 removal was through adsorption. As a result of
enhancing the intensity of the dosage, CL (53 ml/minute) of HMGB1
was higher than that (25 ml/minute) of an in vitro experiment that we
reported at the 31st ISICEM 2011. See Figure 1. Results One hundred and sixty-six patients (98 men, 68 women; age
range 24 to 92 years (mean 64.7 ± 13.3)) were studied. The mortality rate
was 34.9% at 28 days after PMX-DHP. There were 129 (77.7%) emergency
surgical patients and 37 (22.3%) medical patients. The APACHE II score
on the day of PMX-DHP was not signifi cantly diff erent between surgical
and medical patients (20.3 ± 7.0 vs. 19.2 ± 8.1, P = 0.417). Mean arterial
pressure (MAP) signifi cantly improved in emergency surgical patients
before and after PMX-DHP therapy (73.7 ± 24.8 vs. 79.7 ± 26.0 mmHg,
P = 0.017), while MAP was not statistically diff erent in medical patients
(69.7 ± 24.2 vs. 76.7 ± 27.1 mmHg, P = 0.178). The inotropic score had
no statistical diff erence between before and after PMX-DHP in both
surgical and medical patients (13.2 ± 19.8 vs. 12.6 ± 19.2, P = 0.61;
16.8 ± 27.3 vs. 13.8 ± 23.6, P = 0.65, respectively). P383 P382 P382
Polymyxin B-direct hemoperfusion therapy could contribute to
hemodynamics and outcomes in emergency surgical patients
M Yokota, T Goto, T Harada, M Takeda, R Moroi, M Namiki, A Yaguchi
Tokyo Women’s Medical University, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P382 (doi: 10.1186/cc10989) P383
Clinical impact of enhanced cytokine clearance with sustained high-
effi ciency daily diafi ltration using a mediator-adsorbing membrane
(SHEDD-fA) in patients with severe sepsis
O Nishida1, T Nakamura1, N Kuriyama1, K Moriyama1, T Miyasho2,
S Yamada3
1Fujita Health University School of Medicine, Toyoake, Japan; 2Rakuno Gakuen
University, Ebetsu, Japan; 3Shino-Test Corporation, Sagamihara, Japan
Critical Care 2012, 16(Suppl 1):P383 (doi: 10.1186/cc10990) Clinical impact of enhanced cytokine clearance with sustained high-
effi ciency daily diafi ltration using a mediator-adsorbing membrane
(SHEDD-fA) in patients with severe sepsis O Nishida1, T Nakamura1, N Kuriyama1, K Moriyama1, T Miyasho2,
S Yamada3 1Fujita Health University School of Medicine, Toyoake, Japan; 2Rakuno Gakuen
University, Ebetsu, Japan; 3Shino-Test Corporation, Sagamihara, Japan
Critical Care 2012, 16(Suppl 1):P383 (doi: 10.1186/cc10990) 1Fujita Health University School of Medicine, Toyoake, Japan; 2Rakuno Gakuen
University, Ebetsu, Japan; 3Shino-Test Corporation, Sagamihara, Japan
Critical Care 2012, 16(Suppl 1):P383 (doi: 10.1186/cc10990) Introduction
Polymyxin
B-direct
hemoperfusion
(PMX-DHP)
(Toraymyxin®; Toray Medical Co., Tokyo, Japan) has been approved to
treat patients with endotoxemia and/or severe sepsis due to Gram-
negative infection since 1994 in Japan. However, its effi cacy and
indication are still controversial. Recently, randomized controlled
studies were performed in other countries. Our hypothesis is that
PMX-DHP may be useful for emergency-operated patients to eliminate
endotoxins from the systemic circulation after removal of the source
of infection. Introduction SHEDD-fA is an eff ective modality that makes the best
use of three principles in the treatment of severe sepsis: diff usion,
convection and adsorption. We reported the effi cacy of SHEDD-fA for
the treatment of severe sepsis at the 31st ISICEM 2011 [1]. Here we
present the blood clearance (CL) of seven important cytokines with
SHEDD-fA. Methods From July 1994 to May 2011, all adult patients treated with
PMX-DHP in our ICU were included in this retrospective observational
study. Patients’ clinical and microbiological data were collected
from medical archives. The emergency postoperation patients and
the medical patients were compared for severity, mortality, and
hemodynamic status. Values are expressed as mean ± SD. Data were
analyzed by Mann–Whitney U test, chi-square test and Fisher’s exact
probability test. P <0.05 was considered statistically signifi cant. 1.
Nishida O, et al.: Contrib Nephrol 2011, 173:172-181. i
References Introduction The serum levels of high mobility group box 1 (HMGB1)
were examined in patients with septic disseminated intravascular Introduction The serum levels of high mobility group box 1 (HMGB1)
were examined in patients with septic disseminated intravascular . Mitaka C, et al.: Shock 2009, 32:478-483. Kambayashi J, et al.: J Biochem Biophys Methods 1991, 22:93-100. Kambayashi J, et al.: J Biochem Biophys Methods 1991, 22:93-100. 2. Kambayashi J, et al.: J Biochem Biophys Methods 199 S137 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P383 This study was
performed over 10 years (from January 2000 to July 2010) and included
231 consecutive patients hospitalized for major trauma, requiring
intubation at the roadside and in whom prehospital petCO2 has
been recorded. Patients younger than 16 years and those with severe
hypothermia were excluded from the study. There were 156 males and
75 females, age range 16 to 84, mean 43.6 ± 17.8 years. In hospital we
calculated the APACHE II scoring system for each patient. For every
scoring system, the sensitivity, specifi city, correct outcome prediction
and area under the ROC curve were determined.f Introduction In El Salvador there are a limited number of ICU beds. The ICU bed per inhabitant ratio is only 0.7 per 100,000 in a country
with a population of 6,071,774 [1]. The aim of this study was to show
the impact that the ICU bed defi cit has on the mortality of the patients
admitted to the internal medicine fl oor. l
Methods We conducted a descriptive, cross-sectional study. A
nonprobabilistic sample was estimated using EPIDAT 4.0 (mortality
rate 16%, 95% CI, P <0.05). We enrolled 513 patients admitted to the
Internal Medicine ward, from June to November 2011. All patients were
evaluated using the ICU admission priority criteria of the Society of
Critical Care Medicine (SCCM). We divide the patients into high priority
(SCCM priority levels 1 and 2) and low priority (SCCM priority levels 3
and 4) for ICU admission. The probability of death using APACHE II score
and mortality rate was calculated for each group, in order to obtain the
Standardized Mortality Ratio (SMR). A t test and a Mantel–Haenszel test
were used for statistical analysis between groups. Results For prediction of mortality, the best cut-off points were 19 for
MEES and 22 for MEESc. The area under the ROC curve was 0.63 for
MEES, 0.81 for MEESc (P = 0.02 vs. MEES) and 0.84 for APACHE II (P <0.01
vs. MEES).if y
Results A total of 513 patients were included in the study; 101 patients
in the high priority group and 412 patients in the low priority group. There was a signifi cantly higher mortality (P = 0.048) in the high priority
level group especially with an APACHE score less than 9.0 (Figure 1). Conclusion There were signifi cant diff erences between MEES and
MEESc. P383 The mortality rates at
28 days, 90 days, 0.5 year and 1 year after PMX-DHP were signifi cantly
diff erent between surgical and medical patients (28.7 vs. 56.8, 43.8 vs. 83.3, 52.2 vs. 85.7, 54.5 vs. 91.2%, P <0.0001, respectively). Conclusion Taking into account the fact that the creatinine CL of native
kidney function is 100 ml/minute, our fi ndings suggest that SHEDD-fA
is a feasible adjusted modality for the treatment of patients with severe
sepsis, with or without acute kidney injury. Considering our other
laboratory fi ndings, deep fi ltration may enhance blood clearance. Reference Conclusion MAP increased in surgical patients but did not change
in medical patients after PMX-DHP, and the inotropic score was not
signifi cantly diff erent in both sets of patients. The mortality was
signifi cantly lower in surgical patients than in medical patients. Figure 1 (abstract P383). Correlation between clearance and blood level of cytokines. Figure 1 (abstract P383). Correlation between clearance and blood level of cytokines. S138 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P384 systems in trauma patients. We present an improved Mainz Emergency
Evaluation Scoring (MEES) in combination with capnometry (MEESc). MEESc is a new scoring system. We compared the prognostic role of
outcome of these two prehospital descriptive scoring systems with the
prognostic scoring system APACHE II. systems in trauma patients. We present an improved Mainz Emergency
Evaluation Scoring (MEES) in combination with capnometry (MEESc). MEESc is a new scoring system. We compared the prognostic role of
outcome of these two prehospital descriptive scoring systems with the
prognostic scoring system APACHE II. P384
Mortality and priority level for ICU admission in the setting of
limited critical care beds in El Salvador
V Segura, NR Reyes, ME Tejada, EM Zolano
Hospital San Rafael, Santa Tecla, El Salvador
Critical Care 2012, 16(Suppl 1):P384 (doi: 10.1186/cc10991) p
g
g y
Methods In a prehospital setting, the values of MEES and capnometry
(initial and fi nal) were collected from each patient. We added fi nal
values of petCO2 to the MEES scoring system and ranked from 0 to
2 so that the fi nal maximum sum of the scoring system would be 30
without any change in the minimal score being 10. P385 Introduction The aim of this study was to investigate and compare
Ranson criteria (RC) and RC + serum CRP levels as a feasible, practical
and precise method in acute pancreatitis (AP) cases admitted to the ICU
in respect of length of stay (LOS) predicting severity of disease. Predicting outcome in the ICU: comparison of Ranson criteria and
Ranson + CRP levels in acute pancreatitis
V Inal L Yamanel B Comert Predicting outcome in the ICU: comparison of Ranson criteria and
Ranson + CRP levels in acute pancreatitis
V Inal, L Yamanel, B Comert
GATA, Ankara, Turkey
Critical Care 2012, 16(Suppl 1):P386 (doi: 10.1186/cc10993) Reference 1. Boletin de indicadores del Sistema Nacional de_Salud 2009 [http://www. salud.gob.sv/archivos/pdf/Boletin_de_indicadores_del_Sistema_Nacional_
de_Salud_2009.pdf] P383 MEESc improved the results of MEES in predicting outcome for
severe trauma patients. The prehospital use of the improved MEESc
could be an effi cient communication protocol between the prehospital
and hospital settings (MEESc is comparable with APACHE II). y
Conclusion The study shows that there is an increased mortality rate
in patients with high priority level for admission to the ICU with an
APACHE II score less than 9 points. This represents 90 patients/year
whose survival and prognosis could be improved by increasing the
number of ICU beds available. Mainz Emergency Evaluation Scoring in combination with
capnometry predicts outcome in trauma patients The most frequent comorbidity was hypertension (41.8%), followed
by dyslipemia (24.6%), cardiac disease (17.2%), DM and pulmonary
pathology (13.1%). Solid or hematologic malignancy (10.6%),
chronic renal failure (9%) and hepatic pathology (5.7%) were other
comorbidities. Biliary etiology was the most frequent (48.5%), followed
by alcoholic AP (20.5%) and unknown etiology (17.2%); 3.3% were post-
biliary manipulation (surgery or ERCP) AP. The mean APACHE II score at
admission was 16.42 ± 7.64. In total, 56.6% patients needed mechanical
ventilation, 50.8% vasopressors and 40.2% renal support during their
ICU stay. The ICU length of stay (LOS) was 16.55 ± 21.6, hospital LOS
45.39 ± 45.42 days. A total of 28.7% patients died in the ICU, and
38.5% during their hospital stay. We did not fi nd any relation between
comorbidities or AP etiology and outcome. Mortality predictors in
AP patients were: PaFi relation (–0.007, P = 0.006), mean and systolic
arterial pressure (–0.39, P = 0.019 and –0.038, P = 0.001 respectively),
pH (–5.641, P = 0.001), HCO3 (–0.081, P = 0.050), creatinine (0.347,
P <0.001), urea (0.008, P = 0.002), 24-hour diuresis (–0.001, P = 0.002)
and Glasgow Coma Scale (–0.312, P = 0.050). results. In addition, necrotizing cases were assumed to increase CRP
levels more than predicted and were also excluded. After the exclusion
of cases, 89 patients’ data were collected and compared for LOS in the
ICU between 2005 and 2009. Results Statistical analysis of patients’ data for signifi cance and receiver
operating curve (ROC) analysis to predict LOS, therefore pointing to
disease severity, was executed. All of the statistical comparisons were
found signifi cant for predicting LOS; RC (P <0.05), RC + CRP together
(P <0.01) and CRP alone (P <0.04). Severity of the disease and therefore
LOS were increased for RC score >3 and CRP levels >50 mg/l. ROC
analysis resulted in RC (AUC 0.895), RC + CRP (AUC 0.901) and CRP (AUC
0.823) for LOS. Conclusion AP cases usually require ICU care and treatment. There are
some consented scoring systems such as RC, APACHE II and Glasgow
in predicting disease severity and guiding the physician’s approach. Although the most sensitive and specifi c method seemed to be
APACHE II scoring, it is time consuming and complex. On the other
hand, RC and Glasgow scorings need to be evaluated in 48 hours. System biology prediction model based on clinical data: highly
accurate outcome prediction in patients with acute-on-chronic liver
failure System biology prediction model based on clinical data: highly
accurate outcome prediction in patients with acute-on-chronic liver
failure
MJ McPhail, DL Shawcross, RD Abeles, T Chang, GL Lee, MA Abdulla,
C Willars, E Sizer, G Auzinger, W Bernal, JA Wendon
King’s College Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P389 (doi: 10.1186/cc10996) Introduction The aim of the study was to establish if the number of
organs failing at admission to the ICU and the response to support had
a bearing on outcome in patients with severe acute pancreatitis (SAP). Methods Only SAP patients requiring organ support were included
in the analysis. Gallstones (55%) and alcohol were the commonest
aetiologies. The proportion of patients with one, two or three system
failures at baseline, 24, 48, and 72 hours were calculated and related
to outcome. Introduction Present outcome prediction tools for patients with acute-
on-chronic liver failure during critical illness are only of moderate
accuracy. Regression methods on latent variables (usually applied to
top-down system biology applications with spectroscopic data) may
off er signifi cant advantages over logistic regression techniques as
multiple cross-correlations are acceptable in this form of modelling. Results A total of 123 patients (85 male and 38 female) with a mean age
of 58 years met the study criteria. The numbers of patients presenting
with one, two and three organ failures were 29, 70 and 24 respectively,
of which the mortality was six (21%), 29 (41%) and 14 (48%). Subsequent
fi gures were 24, 57 and 39 with mortalities of four (17%), 19 (33%), and
24 (62%) at 24 hours; 21, 53 and 43 with mortalities of two (10%), 18
(34%), and 26 (60%) at 48 hours; and 17, 49 and 45 with mortalities of
zero (0%), 16 (33%), and 28 (62%) at 72 hours. Methods Between 1 January 2000 and 31 December 2010 all patients
admitted to the Liver Intensive Therapy Unit (LITU) at King’s College
Hospital had daily prospective collection of demographic, biochemistry
and bedside physiology. Logistic regression modelling (LRM) and
partial least-squares discriminant analysis (PLSDA), Model for End-
stage Liver Disease (MELD) and APACHE II scores were compared using
receiver operating characteristic (ROC) curve analysis. Conclusion These data allow prognostication of patients with SAP
requiring organ support. At 72 hours, the prognosis of patients with
single organ failure is excellent and that of patients with three-organ
failure remains poor. Mainz Emergency Evaluation Scoring in combination with
capnometry predicts outcome in trauma patients Mainz Emergency Evaluation Scoring in combination with
capnometry predicts outcome in trauma patients
EH Hajdinjak1, ŠG Grmec2, MK Križmarić3, ET Torkar2, DB Buić-Rerečić2,
MZ Zelinka2, MŠ Škufca2
1Center for Emergency Medicine, University of Ljubljana, University of
Maribor, Maribor, Slovenia; 2Community Health Centre Ljubljana, University
of Ljubljana, University of Maribor, Ljubljana, Slovenia; 3Faculty of Medicine,
University of Maribor, Slovenia
Critical Care 2012, 16(Suppl 1):P385 (doi: 10.1186/cc10992) p
y p
p
EH Hajdinjak1, ŠG Grmec2, MK Križmarić3, ET Torkar2, DB Buić-Rerečić2,
MZ Zelinka2, MŠ Škufca2 g
y
g
y
Methods This study was based on determination of RC scores in AP
cases in a retrospective manner. On the other hand, this study included
only the patients’ zero-time RC scores, not the 48-hour scores, for
the sake of more practical precision. Serum CRP levels were found to
have prognostic importance in AP, signifi cantly more than 150 mg/l
in necrotizing AP, at 50 mg/l in this study. Therefore, patients’ were
evaluated for RC and RC + CRP scores for comparison. However, RC had
been etiologically modifi ed for presence of gall bladder stones (GBS);
only the cases without GBS were included in order to prevent bias of 1Center for Emergency Medicine, University of Ljubljana, University of
Maribor, Maribor, Slovenia; 2Community Health Centre Ljubljana, University
of Ljubljana, University of Maribor, Ljubljana, Slovenia; 3Faculty of Medicine,
University of Maribor, Slovenia y
,
Critical Care 2012, 16(Suppl 1):P385 (doi: 10.1186/cc10992) y
,
Critical Care 2012, 16(Suppl 1):P385 (doi: 10.1186/cc10992) Introduction This prospective study assessed the effi cacy of the
predicting power for mortality of two diff erent prehospital scoring Figure 1 (abstract P384). SMR according to APACHE II and SCCM criteria. Figure 1 (abstract P384). SMR according to APACHE II and SCCM criteria. S139 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 and readmissions were excluded. Demographic characteristics, co-
morbidities and parameters included in severity scores (APACHE II,
SAPS II, SOFA) were studied. A Cox proportional hazard regression
model was used to assess the eff ect of each variable on patient survival. Results A total of 122 patients diagnosed with AP were admitted to our
ICU between January 2000 and December 2009 (68.9% men, mean age:
60.5 ± 14 years); 43.4% were smokers and 41.8% alcohol consumers. System biology prediction model based on clinical data: highly
accurate outcome prediction in patients with acute-on-chronic liver
failure y
Results A total of 986 patients (median age 52 (range 16 to 90) years;
603 (62%) male) with cirrhosis and emergency LITU admission were
identifi ed. The median APACHE II score was 21 (5 to 50) and the median
MELD score 23 (3 to 50). Overall LITU survival was 63% and survival to
hospital discharge 51%. Predictive accuracy at day 3 was improved
in all models over admission values. The AUROC for LITU survival for
MELD and APACHE scores on day 3 was 0.78 (95% CI 0.75 to 0.82,
sensitivity 72%, specifi city 75%) and 0.83 (0.78 to 0.83, sensitivity 83%,
specifi city 63%) respectively. A LRM utilising nine variables had an
AUROC of 0.85 (95% CI 0.82 to 0.87, sensitivity 72%, specifi city 83%). Two-component PLSDA identifi ed 30 variables with independent
prognostic signifi cance. Performance in outcome prediction was
improved over logistic regression at day 3 – sensitivity 86%, specifi city
81%, AUROC 0.91 (0.89 to 0.93, P <0.001 for all comparisons) in a model
incorporating 30 variables. Cross-validation and permutation analysis
confi rmed the internal validity of this method. Mainz Emergency Evaluation Scoring in combination with
capnometry predicts outcome in trauma patients In
the end, in the hardworking hours on the ICU, we need a more practical
method of provision. In this study, we have found no priority of RC, RC
+ CRP and CRP alone in predicting AP outcome, excluding GBS disease
and necrotizing cases. We conclude that, practically, ICU physicians
could substantially depend on CRP levels alone in the evaluation and
approach in these specifi c cases of AP. Conclusion Comorbidities and AP etiology are not predictors of ICU
mortality. Of the variables included in severity scores, only those
related to organ dysfunction (hemodynamic – SAP, MAP, pH, HCO3
–;
respiratory –PaFi relation; and renal – Cr, urea and 24-hour diuresis) are
ICU mortality predictors in AP patients. Number of failed organs and response to therapy determine
outcome in patients with acute pancreatitis requiring level 1 organ
supportf Number of failed organs and response to therapy determine
outcome in patients with acute pancreatitis requiring level 1 organ
support
G Morris-Stiff , A Baker, A Breen, A Smith
Leeds Teaching Hospitals, Leeds, UK
Critical Care 2012, 16(Suppl 1):P387 (doi: 10.1186/cc10994) P389 Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure Results A total of 1,150 patients were admitted, 129 cases (11.2%) were
identifi ed as having excess alcohol consumption. Of these cases 34%
were women, whilst 48% of the controls were female. The median age
of the cases was 54 years versus 68 years for the controls (P <0.001). The cases had a lower APACHE II score, 14.3 vs. 15.8 (P = 0.002). Twenty-
four (18.6%) of the cases with excess alcohol consumption died on the
ICU compared to 141 controls (13.8%) (P >0.1). The hospital mortality
was similar between the two groups, 28 (21.7%) against 215 (21.1%)
controls (P >0.5). The cases spent longer on the ICU, median 3.95 days
versus 2.9 in the controls (P <0.001). On admission the cases required
a median of 2.0 organ supportive therapies compared to 1.8 in the
control group (P <0.001). The cases were ventilated for a mean of
4.1 days compared to 2.4 days in the controls (P <0.001). There was
no diff erence in the rate of sepsis between either group, 10% in the
cases and 9.8% in the controls. Twenty-six patients were admitted with
known alcoholic cirrhosis (0.23%), 10 with oesophageal varices and
three with acute pancreatitis related to alcohol. liver failure
E McCarron, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P391 (doi: 10.1186/cc10998) E McCarron, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P391 (doi: 10.1186/cc10998) Introduction Patients with liver failure in the critical care unit frequently
provide physicians with problems about management and prognosis. Alcoholic liver disease (ALD) in particular is showing an increase in
admission and mortality in the UK [1]. Current biochemical tests make
it diffi cult to diff erentiate between types and severity of liver damage
and fail to give a true idea about prognosis and outcome, often only
showing low-grade derangements before hyperacute decompensation
of liver function. The aim of this study was to look at various liver
function tests (LFTs) routinely recorded in patients admitted to
critical care with liver failure, to see whether they diff ered between
ALD and nonalcoholic aetiologies (NALD); that is, drug overdose and
nonalcoholic steatohepatitis, and so forth. References 1. Thomson SJ, et al.: Alcohol Alcohol 2008, 43:416-422. 1. Thomson SJ, et al.: Alcohol Alcohol 2008, 43:416-422. 2. Antoine DJ, et al.: Keratin-18 and HMGB1 as predictive biomarkers for
mode of cell death and clinical prognosis during acetaminophen
hepatotoxicity in man. J Hepatol 2012. [Epub ahead of print] Methods One-hundred and ninety-seven critically ill patients were
studied at the Medical University Vienna: 72 patients with HH, 22 with
ALF, 58 with AoCLF and 45 critically patients without evidence for liver
disease. Arterial ammonia concentrations were assessed on a daily
basis in all patients and compared among the four study groups as well
as between 28-day survivors and nonsurvivors. p
y
p
p
3. Zhou RR, et al.: BMC Gastroenterol 2011, 11:21. P388 Mortality predictors in acute pancreatitis admitted to the ICU
P Vidal-Cortés1, P Lameiro-Flores1, A Aller-Fernández2, M Mourelo-Fariña2,
R Gómez-López1, P Fernández-Ugidos1, M Alves-Pérez1,
E Rodríguez-García1
1CHU Ourense, Spain; 2CHU A Coruña, Spain
Critical Care 2012, 16(Suppl 1):P388 (doi: 10.1186/cc10995) p
p
Critical Care 2012, 16(Suppl 1):P388 (doi: 10.1186/cc10995) Introduction Patients diagnosed with acute pancreatitis (AP) are
usually admitted to our units. Despite using a lot of scores, none has
proved an acceptable yield to identify patients with higher mortality
risk. Our purpose is to identify mortality predictors of patients admitted
to our ICU diagnosed with AP. Methods We performed a retrospective study in which we analyzed
patients diagnosed with AP admitted to a 24-bed ICU between January
2000 and December 2009. Postcardiopulmonary bypass pancreatitis i
Conclusion This application of latent variable regression modelling
techniques to intensive care datasets demonstrates high accuracy of S140 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 deranged LFTs (P <0.001) and clotting studies (P <0.001). ALD patients
also had longer ITU stays (P <0.001) and higher mortality rates (45.45%
ALD vs. 13.2% NALD). Receiver-operated curve analysis revealed that
current biochemical markers (ALT, PT, GGT, albumin) are not sensitive
and specifi c enough in detecting ALD. The prothrombin time yielded
the best area under the curve with 80.4% in ALD versus 71.7% in NALD. None of the markers was discriminatory for determining the type of
liver damage. prediction. Liver-specifi c outcome schema based on logistic regression
may not fully describe the complex cross-correlating interactions that
PLS techniques are designed to incorporate. Further validation in other
centres and disease groups is warranted. prediction. Liver-specifi c outcome schema based on logistic regression
may not fully describe the complex cross-correlating interactions that
PLS techniques are designed to incorporate. Further validation in other
centres and disease groups is warranted. P390 P392 y
Results The 28-day mortality rates in HH, ALF, AoCLF and in the control
group were 54% (n = 39), 27% (n = 6), 53% (n = 31) and 27% (n = 12),
respectively. Peak arterial ammonia levels in patients with HH were
signifi cantly higher in 28-day nonsurvivors compared to survivors
(P <0.01). Cox regression identifi ed peak arterial ammonia concentrations
as an independent predictor for 28-day mortality (P <0.01). Peak arterial
ammonia levels in 28-day transplant-free ALF survivors were signifi cantly
lower compared to ALF patients who died or underwent liver
transplantation (P <0.05). There was no association between outcome
and arterial ammonia in AoCLF patients and in the control group. Incidence, morbidity and mortality of admissions related to alcohol
consumption on critical care: a single-centre experience
A Retter, F Tait, M Stockwell
St Helier Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P392 (doi: 10.1186/cc10999) Introduction Excessive alcohol consumption is a major challenge to
public health. In 2000 it accounted for 4% of the global disease burden. However, the relationship between alcohol and health is complex and
the burden it places on admissions to critical care is uncertain. p
g
p
Conclusion Elevated arterial ammonia levels are frequently observed in
critically ill patients with liver injury but not in patients of comparable
severity of illness without hepatic impairment. They indicate poor
prognosis in HH and ALF, but not AoCLF. Methods We conducted a retrospective analysis of prospectively
collected data on the infl uence of excess alcohol consumption on
the outcome of patients admitted from July 2009 to July 2011. The
admitting physician determined the relationship between alcohol use
and admission. No patients were excluded. All continuous data are
expressed as medians and were compared using the Wilcoxon Mann–
Whitney U test. Categorical data were compared using the chi-squared
test. P391 Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure
E McCarron, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P391 (doi: 10.1186/cc10998) Prognostic relevance of arterial ammonia levels in diff erent acute
and acute-on-chronic liver diseases Prognostic relevance of arterial ammonia levels in diff erent acute
and acute-on-chronic liver diseases
V Fuhrmann, A Drolz, B Jaeger, M Wewalka, R Saxa, T Horvatits,
T Perkmann, C Zauner, P Ferenci
Medical University Vienna, Austria
Critical Care 2012, 16(Suppl 1):P390 (doi: 10.1186/cc10997) g
Conclusion Our results suggest that currently used markers of liver
disease are neither sensitive nor specifi c enough in patients with failure
secondary to ALD. Research is needed to develop novel biomarkers to
better prognosticate outcome. Aetiology of acute-on-chronic liver
failure plays a major role in determining outcome, and subgroups
of liver patients should be analysed individually. Studies [2,3] have
shown that various markers are released depending on the type of
damage and diff er in acute liver damage of diff erent origin. Better
understanding of their role could prove useful in these patients. References V Fuhrmann, A Drolz, B Jaeger, M Wewalka, R Saxa, T Horvatits,
T Perkmann, C Zauner, P Ferenci
Medical University Vienna, Austria
Critical Care 2012, 16(Suppl 1):P390 (doi: 10.1186/cc10997) Introduction Increased levels of arterial ammonia in patients with
acute liver failure (ALF) are associated with increased mortality. There
is a lack of data for prognostic impact of arterial ammonia in patients
with acute-on-chronic liver failure (AoCLF) and hypoxic hepatitis (HH). We evaluated arterial ammonia levels and their prognostic relevance
in patients with HH, ALF, AoCLF and without evidence for any liver
disease. Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure We also aimed to assess
their prognostication value and relation to severity of disease scores. Methods A total of 119 patients admitted to the ITU with liver failure
(66 ALD and 53 NALD) between 2008 and 20011 were included. Each
patient had admitting electrolytes, haematology, LFTs and clotting
studies along with APACHE II score, length of stay and ventilation and
vital organ support requirement. Conclusion To our knowledge this is the largest single-centre
assessment of the burden of excess alcohol consumption on patients
admitted to critical care. Eleven per cent of all admissions to the ICU
were complicated by excess alcohol consumption. The ITU mortality of
these patients was increased when compared to the controls, despite
the patients having an equivalent APACHE score on admission and
tending to be younger. The cases spent less time in hospital than the
controls. This was due to a bimodal distribution of their survival curve. Our study is limited by its retrospective design and the risk of selection
bias. g
y
Methods A total of 119 patients admitted to the ITU with liver failure
(66 ALD and 53 NALD) between 2008 and 20011 were included. Each
patient had admitting electrolytes, haematology, LFTs and clotting
studies along with APACHE II score, length of stay and ventilation and
vital organ support requirement. Results ALD patients were found to have lower sodium (mean 135.56;
P = 0.004) and be hypocalcaemic (P = 0.015), as well as having more S141 Critical Care 2012, Volume 16 Suppl 1
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Changing outcomes in patients with chronic liver disease in
intensive care: a decade of experience
MJ McPhail, DL Shawcross, RD Abeles, G Huei-Lee, M Abdulla, T Chang,
C Willars, E Sizer, G Auzinger, W Bernal, J Wendon
King’s College Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P393 (doi: 10.1186/cc11000) haemofi ltration), lactate and APACHE II score on ICU admission and at
the time of transplantation were also analysed. The primary outcome
measure was patient survival at 3 months. Statistical analysis was by
Mann–Whitney test, logistic regression and area under the receiver-
operator curve analysis. p
y
Results Eighty-one patients were transplanted from the ICU with
cirrhosis complications. Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure Statistical signifi cance was demonstrated for
admission lactate (P = 0.032), transplant lactate (P <0.000), transplant
APACHE II score (P = 0.001), admission inotropic support (P = 0.019),
transplant inotropic support (P <0.000) and transplant renal support
(P <0.000) when comparing 3-month survival with death on univariate
analysis. On multivariate logistic regression analysis, high lactate (OR
1.28, 95% CI 1.08 to 1.51, P = 0.003) and use of renal replacement
therapy (OR 3.52, 95% CI 1.42 to 8.74, P = 0.006) at the time of trans-
plantation were independently associated with poor outcome. A
combination of these two measures had an AUROC of 0.883 (0.791 to
0.945, P <0.001, sensitivity 86%, specifi city 86%) for prediction of death
within 3 months. Introduction Patients with chronic liver disease requiring intensive
care are thought to carry a poor prognosis in comparison with
noncirrhotic patients with similar severity of illness. During the last
decade improvements in multiple areas of management in patients in
the ICU have occurred but improvement in outcomes in patients with
cirrhosis has not been shown. Methods Between 1 January 2000 and 31 December 2010 all patients
admitted to the Liver Intensive Therapy Unit (LITU) at King’s College
Hospital had daily prospective collection of demographic, biochemistry
and bedside physiology. These data were used to quantify the severity
of illness (APACHE II and Model for End-stage Liver Disease (MELD)) and
outcomes in these patients. Conclusion Patients with chronic liver disease transplanted from the
ICU have a worse outcome if they require renal support or demonstrate
hyperlactataemia on the day of transplantation. f p
Results A total of 958 patients (median age 52 (range 16 to 90) years;
603 (62%) male) with cirrhosis and emergency LITU admission were
identifi ed. Aetiology of cirrhosis was alcohol in 43%, viral in 10%,
autoimmune disease in 10% and nonalcoholic fatty liver disease/
metabolic in the remainder. The pattern of aetiology of cirrhosis did not
change over time and a viral aetiology was associated with improved
outcome (OR 0.53, 95% CI 0.34 to 0.81, P = 0.003); alcohol was not
associated with poorer outcome (P = 0.09). The primary reasons for
admission were bleeding (33%), sepsis (27%), hepatic encephalopathy
(17%), metabolic (7%) and other (16%). The median APACHE II score
was 21 (5 to 50) and the median MELD score 23 (3 to 50). Overall LITU
survival was 63% and survival to hospital discharge 51%. P394 Multivariate regression analysis of outcomes following orthotopic
liver transplantation in decompensated cirrhotics transplanted
from the ICU
T Hughes, M McPhail, M Al-Freah, D Abeles, W Bernal, G Auzinger,
J Wendon, C Willars
Institute of Liver Studies, King’s College Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P394 (doi: 10.1186/cc11001) Results A total of 198 cirrhotics (mean age 53 years, 66% male) were
reviewed. The most common etiologies were hepatitis C (31%) and
alcohol (15%). LT occurred a median time of 29 (5 to 101) days from
listing and 5 (3 to 10) days from ICU admission. In total, 88% of patients
required vasopressors, 56% received RRT prior and 87% were ventilated
prior to LT. The median MELD score was 34 (26 to 39) on ICU admission
and 34 (27 to 40) on the day of LT respectively. SOFA scores were 12
(10 to 15) and 13 (10 to 17) on ICU admission and on the day of LT
respectively. Comparing patients who were alive (n = 166, 84%) versus
dead (n = 32, 16%) at 90 days, there were no statistically signifi cant
diff erences in MELD score on admission or day of LT (P >0.6 for both). There were also no statistically signifi cant diff erences between SOFA
score on admission or day of LT (P >0.17 for both). Patients alive at
90 days were signifi cantly younger (52 vs. 56 years, P = 0.007). Patients
over 60 had signifi cantly higher 90-day mortality (27% vs. 13%, P = 0.04)
and a trend towards increased 1-year mortality (37% vs. 23%, P = 0.09). There were no signifi cant diff erences in donor characteristics (donor
age >60, cold ischemia time >8 hours, split graft, donor cerebrovascular
event) comparing patients alive at 90 days to nonsurvivors. Introduction Patients listed for orthotopic liver transplantation (OLT)
frequently develop complications resulting in transfer to the ICUs of
tertiary centres. The ICU mortality for cirrhotics has been variously
reported from 38% to in excess of 90% [1]. The APACHE II score, MELD
score and bacteraemia are independent predictors of mortality [2]. The aim of this study was to identify the risk factors relating to early
mortality after OLT in cirrhotics transplanted from the ICU. Methods A retrospective analysis of 1,284 patients transplanted
between the dates of 1 January 2000 and 31 December 2008 in a major
UK liver transplant centre was performed. References 1. Austin MJ, et al.: Curr Opin Crit Care 2008, 14:202-207. 2. Karvellas CJ, et al.: Crit Care Med 2010, 38:121-126. 1. Austin MJ, et al.: Curr Opin Crit Care 2008, 14:202-207. 1. Austin MJ, et al.: Curr Opin Crit Care 2008, 14:202-207. 2. Karvellas CJ, et al.: Crit Care Med 2010, 38:121-126. 2. Karvellas CJ, et al.: Crit Care Med 2010, 38:121-126. Liver failure secondary to alcoholic liver disease carries a worse
prognosis than other aetiologies of liver failure: retrospective
analysis of routine biochemical markers in critically ill patients with
liver failure LITU survival
increased from 47% to 73% over the study period (2000 to 2010) with
hospital outcome improving from 40% to 63%. The median admission
APACHE II score fell from 23.4 to 21.9 over the study period (P <0.001)
with the MELD score falling from 23.4 to 18.3 (P <0.001). Length of LITU
stay did not change signifi cantly over the study period (P = 0.092). The reduction in illness severity was predominantly due to a smaller
percentage of patients with renal failure and those with three or more
organs in failure (32% up to 2005 and 24% post 2005, P = 0.004). The
reduction in MELD score related to decreased renal dysfunction;
creatinine over the study period (1.9 mg/dl to 1.6 mg/dl, P <0.001)
with no change in bilirubin, and by contrast a small rise in international
normalised ratio (INR 1.8 to 2.2, P = 0.07). P395 Liver transplantation in the critically ill: a Canadian collaboration
C Karvellas1, T Lescot2, H Vahidy1, P Goldberg3, P Chaudhury3, P Metrakos3,
N Kneteman1, G Meeberg1, M Sharpe4, J Ronco5, E Renner6, E Cook7,
S Bagshaw1 1University of Alberta, Edmonton, Canada; 2Hôpital Saint-Antoine, Paris,
France; 3McGill University, Montreal, Canada; 4University of Western Ontario,
London, Canada; 5University of British Columbia, Vancouver, Canada;
6University of Toronto, Canada; 7Harvard School of Public Health, Boston, MA,
USA Critical Care 2012, 16(Suppl 1):P395 (doi: 10.1186/cc11002) Introduction Critically ill cirrhotic patients awaiting liver transplan-
ta tion (LT) often receive prioritization for organ allocation. Outcomes
in these patients are multifactorial, and identifi cation of patients most
likely to benefi t is essential. Despite the need for evidence-based
allocation criteria based on patient factors and physiology scores, few
data currently exist on outcomes. Scoring systems such as MELD and
SOFA (Sequential Organ Failure Assessment) are in use, but have not
been evaluated in predicting outcome with LT. Conclusion Survival of patients with cirrhosis admitted to the specialist
LITU is improving over time. The factors relating to this may be resultant
upon earlier admission to critical care and a lower incidence of renal
dysfunction. Alcohol aetiology is not relevant to outcome. Methods In a fi ve-center Canadian study (Edmonton, Montreal,
Toronto, London and Vancouver), all cirrhotics admitted to the ICU
requiring organ support (mechanical ventilation, vasopressors or renal
replacement therapy (RRT)) prior to undergoing LT between January
2000 and December 2009 were examined. MELD and SOFA scores were
evaluated at ICU admission and the day of LT along with other donor
factors. Acute respiratory distress syndrome: analysis of incidence and
mortality in a university hospital critical care unit Introduction The aim was to determine the incidence of acute
respiratory distress syndrome (ARDS) in patients admitted to a
university hospital ICU, analyse the ICU and the in-hospital mortality,
and evaluate the associated factors. Methods A prospective study in an ICU from October 2008 to January
2011. The ICU comprises 20 beds in a medical–surgical area, 10 in a
critical burns area. All patients who underwent mechanical ventilation
(MV) during 48 hours or more and who fulfi lled ARDS criteria as defi ned
by the 1994 American–European Consensus Conference on ARDS were
included. All patients were ventilated following the protective MV
strategy recommended. Conclusion In this large multicenter cohort, severe sepsis and septic
shock were independently associated with an increased risk of death. Our data underscore the regional variability in the epidemiology and
outcome of sepsis syndromes and may be useful for resource allocation. gy
Results During this period 1,900 patients were admitted, 697 needed
MV for at least 48 hours and 108 fulfi lled the ARDS criteria (5.6%
of those admitted, 17% of the group on MV); 63% were male. The
patients’ age was 52 ± 12. The APACHE II score on admission was 23 ± 7,
in survivors (S) 20 ± 7 and 24 ± 6 in nonsurvivors (NS) (P = 0.002). ARDS was primary in 70% and secondary in 30%. The most common
aetiology was pneumonia (53%) followed by sepsis of intra-abdominal
origin (15%). Duration of MV was 32.7 ± 30.2 days in S, 20.79 ± 20.73
in NS (P = 0.019). Survivors’ mean length of stay was 35 ± 24 days,
23 ± 20 for NS (P = 0.007). ICU mortality was 49% and in-hospital
mortality was 55%. Primary ARDS had an ICU mortality of 47%, an in-
hospital mortality of 52%. Secondary ARDS had a 55% ICU mortality,
an in-hospital mortality of 64%. Duration of primary ARDS was longer,
15.3 ± 12.2 versus 8.7 ± 79. Globally the main cause of death was
multiple organ dysfunction, predominantly respiratory failure (55%). In
primary ARDS the main cause of death was chiefl y pulmonary (69%),
while in secondary ARDS it was mainly multiple organ dysfunction
associated with septic shock (71%). Factors associated with increased
mortality were APACHE II score >23 and the presence of multiple organ
dysfunction. P398 Outcome of faecal peritonitis in the ICU
J S
G Si
L M
I W lt J Sayer, G Simpson, L Mccrossan, I Welters
Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P398 (doi: 10.1186/cc11005) Introduction Faecal peritonitis often leads to intensive care admission. Anecdotally, patients with co-existing malignancy had an improved
outcome. A retrospective analysis of all patients admitted to intensive
care over 7 years was conducted to investigate this observation and
identify factors that are associated with outcome from faecal peritonitis
in intensive care. Methods A retrospective analysis of all cases of faecal peritonitis
admitted to the Royal Liverpool University Hospital ICU over 7 years. Clinical records, laboratory results, histology reports and radiological
data were accessed. Statistical analysis was performed using chi-
squared and Student’s t tests. Results A total of 133 patients were admitted to intensive care in
7 years. Thirty-six patients had underlying malignancy. Predicted
mortality, indicated by APACHE II score, was similar in both groups
(malignancy: 17.1, nonmalignancy: 16.2). Inpatient mortality was lower
in patients with malignancy than those without (malignancy: 21.6%,
nonmalignancy: 38.1%, P <0.1) and shorter ITU stay (malignancy:
6.8 days, nonmalignancy: 12.7 days, P ≤0.0005). Cancer patients
required a shorter period of TPN or NG feeding (malignancy: 4.29 days,
nonmalignancy: 7.7 days, P <0.05), and a shorter duration of inotropic
support (malignancy: 2.54 days, nonmalignancy: 4.44 days, P <0.05). Peak infl ammatory markers are lower in patients with malignancy,
notably neutrophil count (malignancy: 21.15, nonmalignancy: 24.9,
P <0.05). y
Conclusion Certain controversy remains regarding a decrease in ARDS-
related mortality. Despite the fact that its incidence is not very high,
it is still a clinical entity with a high mortality, and with a prognosis
infl uenced not only by the degree of pulmonary involvement but by
the association with multiple organ dysfunction. References 1. Roca O, et al.: Estudio de cohortes sobre incidencia de SDRA en pacientes
ingresados en UCIy factores pronósticos de mortalidad. Med Intensiva
2006, 30:6-12 . 1. Roca O, et al.: Estudio de cohortes sobre incidencia de SDRA en pacientes
ingresados en UCIy factores pronósticos de mortalidad. Med Intensiva
2006, 30:6-12 . 2. Zambon M, Vincent JL: Mortality for patients with ALI/ARDS have
decreased over time. Chest 2008, 133:151-161 . 2. Zambon M, Vincent JL: Mortality for patients with ALI/ARDS have
decreased over time Chest 2008 133:151-161 3. Frutos-Vivar et al.: Epidemiology of ALI and ARDS. Curr Opin Crit Care 2004,
10:1-6. The mean APACHE II score was signifi cantly lower in cases who
survived, compared to those who did not (nondeaths: 15.3, deaths:
19.3, P <0.005). Mean albumin at admission was similar for patients
who survived compared to those who did not (deaths: 18.2, nondeaths:
18.6); however, minimum albumin during admission is signifi cantly
lower in patients who died than those who survived (deaths: 10.33,
nondeaths: 13.24, P <0.005). Duration of feeding support (TPN or NG
feeding) and time to commencement of feeding showed no diff erence
between patients who survived and those who did not. P397
E id Epidemiology and outcome of sepsis syndromes in Italian ICUs:
a regional multicenter observational cohort
L Laudari1, Y Sakr2, C Elia1, L Mascia1, B Barberis3, S Cardellino4, S Livigni5,
G Fiore6, C Filippini1, VM Ranieri1
1San Giovanni Battista-Molinette Hospital, University of Torino, Turin, Italy;
2Friedrich Schiller University Hospital, Jena, Germany; 3Ospedale degli Infermi,
Revoli, Italy; 4Ospedale Cardinal Massaia, Asti, Italy; 5Ospedale Giovanni
Bosco, Turin, Italy; 6Ospedale Santa Croce, Moncalieri, Italy
Critical Care 2012, 16(Suppl 1):P397 (doi: 10.1186/cc11004) P394 Patient characteristics were
recorded at transplant assessment and on the day of transplant: age,
MELD score, UKELD score, serum sodium, creatinine, bilirubin, albumin,
INR. Organ support (including ventilation, inotropic support and S142 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion Older critically ill cirrhotics (over 60 years) undergoing liver
transplantation have signifi cantly worse post-LT outcomes. MELD and
SOFA scores do not appear to predict outcome post LT in this cohort. Methods In this prospective, multicenter, observational study, all 3,902
patients (mean age ± SD: 64.3 ± 15.7 years, 63.5% male) admitted to
one of 24 medical or surgical ICUs between 3 April and 29 September
2006 were included. Results Four hundred and forty-six of the patients had sepsis, including
160 patients with severe sepsis (4.1%) and 145 patients (3.7%) with
septic shock. ICU mortality was 20% (n = 780) and median ICU length
of stay was 3 (1 to 9) days. ICU mortality was higher (41.3 vs. 17.2%,
P <0.001) and the median ICU LOS longer (15 (7 to 26) vs. 2 (1 to 7),
P <0.001) in patients with sepsis than in those without sepsis. The
mortality rate increased with the severity of sepsis (sepsis without
organ failure, severe sepsis, and septic shock: 19.9, 44.4, and 58.6%,
respectively). ICU-acquired sepsis was associated with higher ICU
mortality rates than sepsis occurring within 48 hours of ICU admission
(49.8 vs. 33.0%, P <0.001). In multivariate logistic regression analysis,
the occurrence of severe sepsis (OR, 1.70 (1.06 to 2.72); P = 0.026) and
septic shock (OR, 2.25 (1.49 to 3.49); P <0.001) were independently
associated with an increased risk of ICU death. Epidemiology and outcome of sepsis syndromes in Italian ICUs:
a regional multicenter observational cohort P399
HIV patients in the ICU: our experience
V Nunes Velloso, L Calejman, E Canedo, M Deheza
Hospital Rivadavia, Capital Federal, Argentina
Critical Care 2012, 16(Suppl 1):P399 (doi: 10.1186/cc11006) P399
HIV patients in the ICU: our experience
V Nunes Velloso, L Calejman, E Canedo, M Deheza
Hospital Rivadavia, Capital Federal, Argentina
Critical Care 2012, 16(Suppl 1):P399 (doi: 10.1186/cc11006) Critical Care 2012, 16(Suppl 1):P399 (doi: 10.1186/cc11006) Introduction The objective was to describe characteristics of HIV-
positive patients admitted to the ICU. Methods HIV-positive patients admitted between February 2000
and February 2011, and demographic data, APACHE II score, cause of
admission, days of internment, need for mechanical ventilation (MV),
previous antiretroviral therapy of high effi cacy before admission
(HAART), viral load and CD4 count. Conclusion About three-quarters of survivors of severe sepsis/septic
shock with congestive heart failure died after 1 year of hospital
discharge. Many of them (70%) died within 3 months of hospital
discharge. The majority had poor performance status and only 14%
were able to carry on normal activity at 1 year after hospital discharge. These data highlight the need for diff erent strategies to care for sepsis
survivors with congestive heart failure. (
),
Results A total of 3,568 patients were admitted; 715 patients (20.03%)
were HIV-positive, 413 patients (57.76%) were masculine and 302
patients (42.23%) feminine, and average age was 33 for men and
35 for women. The APACHE II average score was 13 versus 15.28 for
the general population. The most frequent cause of admission was
respiratory failure in 329 patients (46%), 57% due to Pneumocystis
jivoreci and bacterial pneumonias in 35%, the most frequent bacteria
isolated were Streptococcus, Staphylococcus aureus and Haemophilus
infl uenzae. There were two cases of respiratory Kaposi sarcoma and
26 cases of Mycobacterium tuberculosis. Other causes were decrease
in mental state in 157 patients (22%), with the most frequent causes
reported being toxoplasmosis, cryptococcus neoformans and brain
lymphoma, immediately post surgery in 79 patients (11%), COPD
reagudization and asthma (9%), digestive bleeding in 36 patients (5%)
and renal insuffi ciency in 50 patients (7%). From the 715 HIV-positive
patients admitted, 479 required MV (67%). Regarding nationality, 276
(38.6%) patients were Argentinean, and the other nationalities were
Bolivian, Paraguayan, Peruvian and Korean. The average length of stay
was 10.5 days and the mortality was 43%. Predictive value of N-terminal pro-brain natriuretic peptide among
critically ill patients critically ill patients
M Cubrilo-Turek, N Maric, I Mikacic, N Tolj Karaula, N Budinski, M Mackovic
Clinical Hospital Sveti Duh, Zagreb, Croatia
Critical Care 2012, 16(Suppl 1):P401 (doi: 10.1186/cc11008) M Cubrilo-Turek, N Maric, I Mikacic, N Tolj Karaula, N Budinski, M Mackovic
Clinical Hospital Sveti Duh, Zagreb, Croatia Critical Care 2012, 16(Suppl 1):P401 (doi: 10.1186/cc11008) Introduction N-terminal pro-brain natriuretic peptide (NT-proBNP)
represents a useful cardiac marker in evaluating heart failure. However,
its role in the assessment of critically ill patients is not clear. The aim of
this study was to evaluate survival of infected and noninfected patients
according to the measurements of NT-proBNP. g
Methods Serum NT-proBNP measurements were done in 89 (46
males/43 females, 68.20 ± 13.80 years) consecutive critically ill patients
within 6 hours after admission to the ICU. NT-proBNP was determined
with a sandwich immunoassay on an Elecsys 2010 (Roche Diagnostics,
Mannheim, Germany). Logarithmic transformation of data was required
because of the skewed distribution of NT-proBNP. Conclusion HIV-positive patients have a high frequency of admission
to the ICU, and they have a lower risk score in comparison with non-HIV
patients. The two main causes of admission where respiratory disease
and infectious CNS disease. Signifi cant results were the prevalence of
patients from limited countries, high mortality and prolonged stay in
the ICU, and poor adherence to antiretroviral therapy. p
Results The median NT-proBNP (pg/ml) was 2,485.1 pg/ml (range 31.5
to 12,041 pg/ml) (log NT-proBNP mean 3.34 ± 0.71 pg/ml). Mean log NT-
proBNP levels were higher at admission to the hospital in nonsurvivors
(3.73 ± 0.67 pg/ml) compared with survivors (3.12 ± 0.65 pg/ml), which
was statistically signifi cant (P <0.0001). Higher concentrations were
found in proven infection (X ± SD) (3.43 ± 0.68) than in bacteriological
negative patients (3.30 ± 0.72), but it was statistically insignifi cant
(P <0.42). From 57 survivors seven were mechanically ventilated
(12.28%) while 14 (43.75%) from 32 nonsurvivors were ventilated,
which was statistically signifi cant (P <0.001). More nonsurvivors were
taking vasoactive medications (n = 12 or 37.5%) than survivors (n = 3
or 5.26%), which was statistically signifi cant (P <0.001). NT-proBNP
showed no correlation for any analyzed parameters (age, erythrocytes,
leucocytes, body temperature, systolic and diastolic blood pressure,
C-reactive protein, fi brinogen, lactates or procalcitonin). Epidemiology and outcome of sepsis syndromes in Italian ICUs:
a regional multicenter observational cohort The viral load average was
inferior to 104 RNA/ml in just 44 known patients and the CD4 count was
determined in 75 patients, from which the average was 400/mm3. The
proportion of patients receiving HAART was just 26%. P400 Impact of congestive heart failure on severe sepsis and septic shock
survivors: outcomes and performance status after 1-year hospital
discharge
M Alkhalaf1, N Abd-Aziz2, Y Arabi3, B Tangiisuran1
1School of Pharmaceutical Sciences, Penang, Malaysia; 2University
Technology MARA, Puncak Alam, Malaysia; 3National Guard Hospithal,
Riyadh, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P400 (doi: 10.1186/cc11007) Epidemiology and outcome of sepsis syndromes in Italian ICUs:
a regional multicenter observational cohort L Laudari1, Y Sakr2, C Elia1, L Mascia1, B Barberis3, S Cardellino4, S Livigni5,
G Fiore6, C Filippini1, VM Ranieri1 Conclusion Underlying malignancy is associated with an increased
survival, shorter ITU stay, less requirement for inotropic support and
decreased infl ammatory markers potentially due to a less aggressive
infl ammatory response as a consequence of the presence of malig-
nancy. In this series, delay to introduction of nutrition and length of
nutritional support are not associated with outcome; however, low
albumin is associated with a poor outcome, although it is not clear if
this is secondary to nutrition or infl ammation. Introduction We assessed the epidemiology of sepsis syndromes in
patients admitted to ICUs of the Piedmont region in northern Italy and
investigated the impact of sepsis on ICU mortality in these patients. S143 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 congestive heart failure cases died, 70% of them dead within 3 months. Patients with CHF as compared to patients without CHF had a higher
percentage of comorbidity disease (P <0.01) and poor performance
status (P <0.05). The majority of these patients (85.7%) who were older
(P <0.001), and required a higher dose of dobutamine (P <0.0001),
had higher urine output (P <0.001) and prolonged INR (P <0.01) were
unable to care for self at 1 year of hospital discharge. Survivors with
CHF who died (OR 4.7, CI 1.52 to 14.33) had higher dose of dopamine
(P <0.045) and poor performance status pre sepsis (P <0.028). congestive heart failure cases died, 70% of them dead within 3 months. Patients with CHF as compared to patients without CHF had a higher
percentage of comorbidity disease (P <0.01) and poor performance
status (P <0.05). The majority of these patients (85.7%) who were older
(P <0.001), and required a higher dose of dobutamine (P <0.0001),
had higher urine output (P <0.001) and prolonged INR (P <0.01) were
unable to care for self at 1 year of hospital discharge. Survivors with
CHF who died (OR 4.7, CI 1.52 to 14.33) had higher dose of dopamine
(P <0.045) and poor performance status pre sepsis (P <0.028). Impact of congestive heart failure on severe sepsis and septic shock
survivors: outcomes and performance status after 1-year hospital
discharge M Alkhalaf1, N Abd-Aziz2, Y Arabi3, B Tangiisuran1
1School of Pharmaceutical Sciences, Penang, Malaysia; 2University
Technology MARA, Puncak Alam, Malaysia; 3National Guard Hospithal,
Riyadh, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P400 (doi: 10.1186/cc11007) Introduction The objective of this study was to evaluate the impact of
CHF on severe sepsis and septic shock survivor outcomes after 1 year
of hospital discharge. Conclusion Our results showed that cardiac NT-proBNP levels can be
elevated in critically ill patients and may also serve as markers of severity
and prognosis for survival. Mean baseline levels of log NT-proBNP were
diff erent in critically ill patients with proved bacteriological infection
than in patients without proven infection. p
g
Methods A retrospective cohort and cross-sectional study was
conducted at a tertiary-care hospital in Saudi Arabia. All patients
(≥18 years) with severe sepsis/septic shock admitted for more than
1 day to the medical–surgical and trauma ICU between April 2007
and March 2010 and alive at hospital discharge were included in the
study. Patients who died during admission, could not be contacted
and with multiple ICU admission within the same hospitalization
were excluded. Data were collected using the electronic ICU database,
hospital information system and systematic review of medical records
to determine hospital outcomes and performance status pre sepsis. Assessment of the vital status and performance at 1-year hospital
discharge were performed via structured telephone interviews using
the Karnofsky Performance Status Scale. Predictive value of N-terminal pro-brain natriuretic peptide among
critically ill patients The use of ROC
curve analysis reveals for serum NT-proBNP high sensitivity (75%), low
specifi city (57.9%) and low accuracy (64%) for discriminating survivors
from nonsurvivors. Correlation between APACHE II score and quality of life among
patients discharged from the ICU p
g
L Zubek1, L Szabó1, L Horváth1, A Mesterházi2, J Gál1, G Élő1
1Semmelweis University, Budapest, Hungary; 2Markusovszky Hospital,
Szombathely, Hungary p
g
L Zubek1, L Szabó1, L Horváth1, A Mesterházi2, J Gál1, G Élő1
1Semmelweis University, Budapest, Hungary; 2Markusovszky Hospital,
Szombathely, Hungary y
g
y
Critical Care 2012, 16(Suppl 1):P404 (doi: 10.1186/cc11011) Introduction The goal of intensive therapy is not only saving the
patient’s life, but also to restore their quality of life. Based on expected
quality of life improvement, a fair allocation of limited available
resources can be provided. The assessment scores for the physical
state of ICU patients, which correlate with survival, are widely known. However, it would be useful to know if these score systems also
correlate with the long-term quality of life. The aim of our study was to
investigate the correlation between the APACHE II score and the long-
term quality of life after ICU treatment. q
y
Methods We have collected data retrospectively from patients treated
in our department during the fi rst quarter of 2008. The APACHE II score
was calculated for all patients, after which we examined the correlation
between this value and the survival of the patients. One year after
ICU therapy, the Hungarian version of the EQ-5D questionnaire
(measurement consist of fi ve dimensions: mobility, self-care, usual
activities, pain/discomfort, anxiety/depression and a visual analog
scale about health state) developed by EuroQol Group was sent out by
post. The correlation between the APACHE score and quality of life was
calculated, the Spearmann rank-order correlation was used. g
Conclusion Our fi ndings suggest that low preoperative hepcidin
concentration indicates mortality but not renal endpoints in patients
undergoing cardiac surgery. Thereby, hepcidin may contribute to early
risk stratifi cation. Findings should be validated in independent patient
cohorts with a larger number of events. Results During this period, 190 patients were treated in our department. The average of the APACHE II score was 13.23 (±6.99). In total, 25.3%
of patients died during treatment; 22.1% died during the fi rst post-
treatment year; 27.9% surely survived and 24.7% of patients were
unattainable. In our cohort, every patient below 11 points survived
and none above 24. The average APACHE score of patients completing
the questionnaire was 9.30 (±3.85). They assessed their health as 66%
at VAS, although correlation between this value and the APACHE
score could not be shown. Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 a mean of 3.6 days, and 41% needed ARS for a mean of 3.8 days. See
Table 1. biomarker that early postoperatively predicts protection from acute
kidney injury (AKI). biomarker that early postoperatively predicts protection from acute
kidney injury (AKI). Conclusion CC and hospital mortality was 17% and 33% respectively. This study concurs with another which demonstrated that age is not
a good predictor of outcome post surgery [1]. These patients did not
have a signifi cant impact on RRT or ARS resources or CC LOS. Reference Methods We studied 100 adult patients at increased risk of AKI
(RIFLE) after cardiac surgery. Plasma and urine were sampled before
induction of anesthesia and hepcidin 25-isoforms were quantifi ed by
competitive enzyme-linked immunoassay. Our objective was to assess
the predictive indices of preoperatively measured urine and plasma
hepcidin for the development of postoperative AKI and other patient-
related outcomes, including the need for renal replacement therapy
(RRT) and in-hospital mortality. 1. Ford P, et al.: Determinants of outcome in critically ill octogenarians after
surgery. Br J Anaesth 2007, 99:824-829. P404 Results Preoperatively, patients not developing AKI presented with
nonsignifi cantly higher urine and plasma hepcidin concentrations
compared to patients that developed AKI which did not translate into
a good predictive value for postoperative AKI (AUC-ROC <0.70 for
both biomarkers). Also, the preoperative urine and plasma hepcidin
concentrations as well as serum creatinine concentration did not
distinguish patients requiring postoperative RRT from those who did
not require RRT (urine: AUC-ROC 0.62 (95% CI 0.38 to 0.86), plasma: AUC-
ROC 0.63 (95% CI 0.34 to 0.91), serum creatinine: AUC-ROC 0.61 (95% CI
0.22 to 0.99)). However, a low preoperative hepcidin concentration in
urine (median 5 ng/ml, 25th to 75th percentiles 4 to 15 ng/ml) and in
plasma (median 50 ng/ml, 25th to 75th percentiles 30 to 55 ng/ml) was
a good predictor for postoperative mortality with an AUC-ROC for urine
hepcidin of 0.89 (95% CI 0.73 to 0.99) (cut-off : 130 ng/ml, sensitivity
73% and specifi city 100%) and an AUC-ROC for plasma hepcidin of 0.90
(95% CI 0.80 to 0.99) (cut-off : 55 ng/ml, sensitivity 83% and specifi city
100%). Preoperative serum creatinine did not predict mortality (AUC-
ROC 0.50 (95% CI 0.10 to 0.94). Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Patients who survived the hospital stay
had a median preoperative hepcidin concentration in urine of 330 ng/
ml (25th to 75th percentiles 140 to 760 ng/ml), and plasma of 115 ng/
ml (25th to 75th percentiles 80 to 200 ng/ml).i 0
Correlation between APACHE II score and quality of life among
patients discharged from the ICU
L Zubek1, L Szabó1, L Horváth1, A Mesterházi2, J Gál1, G Élő1
1Semmelweis University, Budapest, Hungary; 2Markusovszky Hospital,
Szombathely, Hungary
Critical Care 2012, 16(Suppl 1):P404 (doi: 10.1186/cc11011) Correlation between APACHE II score and quality of life among
patients discharged from the ICU However, we found statistically signifi cant
correlation between the APACHE score and the current mobility of
the patients (P = 0.021). Based on our data, 34% of the patients had
problems with mobility, 36% with usual activity, 62% of patients
complained about pain or discomfort, 50% felt anxiety or depression
and 18% had problems with self-care. P402 P402
Low preoperative hepcidin concentration is a risk factor for
mortality but not for acute kidney injury after cardiac surgery
A Haase-Fieiltz1, P Mertens1, M Plaß2, M Westerman3, R Bellomo4, M Haase1
1Otto-von-Guericke University, Magdeburg, Germany; 2German Heart Center,
Berlin, Germany; 3IntrinsicLifeSciences, La Jolla, CA, USA; 4Austin Health,
Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P402 (doi: 10.1186/cc11009) Low preoperative hepcidin concentration is a risk factor for
mortality but not for acute kidney injury after cardiac surgery
A Haase-Fieiltz1, P Mertens1, M Plaß2, M Westerman3, R Bellomo4, M Haase1
1Otto-von-Guericke University, Magdeburg, Germany; 2German Heart Center,
Berlin, Germany; 3IntrinsicLifeSciences, La Jolla, CA, USA; 4Austin Health,
Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P402 (doi: 10.1186/cc11009) Introduction Hepcidin – expressed in renal proximal tubular cells – is a
key regulator of iron homeostasis and was recently described as a renal Results A total of 195 hospital survivors from 364 patients were included
in the fi nal analysis. More than 70% of severe sepsis/septic shock with S144 Predicting hospital mortality: comparing accuracy of SAPS II and
clinical staff prognosis Predicting hospital mortality: comparing accuracy of SAPS II and
clinical staff prognosis
I Patrício1, M Marques1, A Costa-Pereira2, O Ribeiro2, I Aragão1, T Cardoso1
1Hospital Geral de Santo António, University of Porto, Portugal; 2Faculty of
Medicine, University of Porto, Portugal
Critical Care 2012, 16(Suppl 1):P407 (doi: 10.1186/cc11014) f
p
g
I Patrício1, M Marques1, A Costa-Pereira2, O Ribeiro2, I Aragão1, T Cardoso1
1Hospital Geral de Santo António, University of Porto, Portugal; 2Faculty of
Medicine, University of Porto, Portugal
Critical Care 2012, 16(Suppl 1):P407 (doi: 10.1186/cc11014) Results The mortality rate of surgical patients was 12.29%. We detected
no statistical diff erence between the two groups according to age
(P = 0.27), heart rate (P = 0.13), temperature (P = 0.57), Na (P = 0.44), K
(P = 0.18), WBC (P = 0.56), Ht (P = 0.7), PaO2 (P = 0.28), PaCO2 (P = 0.7),
albumin (P = 0.21), glucose (P = 0.68) and GCS (P = 0.26). We detected
statistically signifi cant higher group B values according to BUN
(P = 0.015), creatinine (P = 0.005), bilirubin (P = 0.0032), APACHE II
score (P = 0.0018), LOS (P <0.0001) and VD (P <0.0001). We detected
statistically signifi cant higher group A values according to mean
arterial pressure (P = 0.0052) and PH (P = 0.0027). Introduction The purpose of this study is to compare the accuracy of
Simplifi ed Acute Physiology Score (SAPS) II with the subjective opinion
of clinical staff in predicting hospital mortality, in critically ill adult
patients. Introduction The purpose of this study is to compare the accuracy of
Simplifi ed Acute Physiology Score (SAPS) II with the subjective opinion
of clinical staff in predicting hospital mortality, in critically ill adult
patients. Methods A prospective study in a mixed ICU, at a university hospital,
using SAPS II to assess the risk of death. Patient outcome was also
predicted subjectively by the clinical staff (consultants, residents and
nurses), including the possibility of return to prior physical activity. The
subjective predictions were compared with SAPS II predictions using
logistic regression analysis and receiver operating characteristic curve
(ROC) measurement, as well as sensitivity and specifi city analysis for
each group of participants. Conclusion According to our data, surgical patients who died (group
B) had higher severity score on admission. Relationship between illness severity scores in the ICU Relationship between illness severity scores in the ICU
A Schneider1, M Lipcsey1, M Bailey2, D Pilcher3, R Bellomo1
1Austin Health, Heidelberg, Australia; 2Monash University, Melbourne,
Australia; 3ANZICS, Melbourne, Australia
Critical Care 2012, 16(Suppl 1):P406 (doi: 10.1186/cc11013) Outcomes and resource use for over 80 year olds admitted to a
UK critical care unit after an emergency laparotomy over a 3-year
period
V Banks, C Scott
Northern General Hospital, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P403 (doi: 10.1186/cc11010) Outcomes and resource use for over 80 year olds admitted to a
UK critical care unit after an emergency laparotomy over a 3-year
period
V Banks, C Scott
Northern General Hospital, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P403 (doi: 10.1186/cc11010) V Banks, C Scott V Banks, C Scott pfi
Critical Care 2012, 16(Suppl 1):P403 (doi: 10.1186/cc11010) Introduction There are few data on older people emergency surgical
critical care (CC) admissions and the potential implications for future
resource demands and service planning. Methods Retrospective data were collected from a cohort of patients
>80 years old admitted after emergency surgery between 2009 and
2011. CC and hospital information databases were used. Data included
mortality, length of stay (LOS) and duration of renal replacement
therapy (RRT) and advanced respiratory support (ARS). Conclusion ICU admission is associated with a high mortality, a poor
physical quality of life and low quality-adjusted life-years for 1 year
after discharge. We found that the APACHE II score did not show
signifi cant correlation with patient’s long-term quality of life, but we
detected signifi cant correlation between the APACHE II score and the
current mobility of the patients. py
p
y
pp
Results A total of 118 patients were admitted; 52% female: mean age
85 years, male mean age: 84 years. In total, 69% were general surgical,
22% vascular, and 9% hepatobiliary. Outcomes and resource use for over 80 year olds admitted to a
UK critical care unit after an emergency laparotomy over a 3-year
period
V Banks, C Scott
Northern General Hospital, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P403 (doi: 10.1186/cc11010) Eleven per cent required RRT for Table 1 (abstract P403)
Patient group
CC mortality, n (%)
Hospital mortality, n (%)
LOS CC (days)
LOS hospital (days)
All patients, n = 118
20 (17%)
39 (33%)
1 to 34, 4.5 mean
1 to 247, 29 mean
Age 80 to 84, n = 70
15 (21%)
29 (41%)
1 to 34, 4.9 mean
1 to 247, 28 mean
Age >85, n = 48
5 (10%)
10 (21%)
1 to 32, 4.1 mean
1 to 171, 31 mean
ARS, n = 49
15 (30%)
22 (45%)
1 to 34, 7.5 mean
1 to 79, 20 mean
No ARS, n = 69
5 (7%)
17 (25%)
1 to 24, 3.8 mean
1 to 247, 35 mean
RRT, n = 13
7 (54%)
9 (69%)
1 to 34, 8 mean
1 to 247, 35 mean
No RRT, n = 105
13 (12%)
30 (29%)
1 to 32, 4 mean
1 to 247, 30 mean S145 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 coeffi cient (SE) was 1.47 (0.001) for the whole cohort, 1.49 (0.001) after
exclusion of cardiac surgery patients and 1.55 (0.006) after exclusion
of patients with an absolute diff erence in ROD >1% between the two
scores. Finally, the correlation between the APII and SAPS II scores was
moderate (r2 = 0.63). The overall model was APII = 0.36×SAPS II + 4.4. The APII/SAPS II coeffi cient (SE) was 0.36 (0.0003) for the whole cohort,
0.37 (0.0004) after exclusion of cardiac surgery patients and 0.39 (0.002)
after exclusion of patients with an absolute diff erence in ROD >1%. coeffi cient (SE) was 1.47 (0.001) for the whole cohort, 1.49 (0.001) after
exclusion of cardiac surgery patients and 1.55 (0.006) after exclusion
of patients with an absolute diff erence in ROD >1% between the two
scores. Finally, the correlation between the APII and SAPS II scores was
moderate (r2 = 0.63). The overall model was APII = 0.36×SAPS II + 4.4. The APII/SAPS II coeffi cient (SE) was 0.36 (0.0003) for the whole cohort,
0.37 (0.0004) after exclusion of cardiac surgery patients and 0.39 (0.002)
after exclusion of patients with an absolute diff erence in ROD >1%. Conclusion Simple and robust translational formulas can be developed
to allow clinicians to compare illness severity in intensive care studies
of similar patients when such illness severity is expressed with diff erent
scoring systems. Predicting hospital mortality: comparing accuracy of SAPS II and
clinical staff prognosis Nevertheless, the main
diff erence between surgical patients who died and who survived the
ICU was hemodynamic instability, which was severe enough to cause
hypoperfusion, metabolic acidosis, early acute kidney injury and early
multiple organ dysfunction. As a result, the length of stay and the
ventilation days were higher in group B patients, assuming that early
and eff ective surgical management is important in order to avoid early
multiple organ dysfunction on ICU admission. g
p
p
p
Results Over the study period 72 patients were included, with a
mean age of 56.5 ± 16.8 years; 55% were male. The mean SAPS II was
47.3 ± 15.4. Eighteen patients died in hospital (25%). Discriminations
analysis showed the following areas under ROC: SAPS II 0.84 (95% CI:
0.741 to 0.945); consultants 0.77 (95% CI: 0.632 to 0.908); residents 0.67
(95% CI: 0.513 to 0.828); nurses 0.62 (95% CI: 0.453 to 0.777). See Figure 1. Conclusion In our study, contrary to previous descriptions of similar
studies, SAPS II was more accurate in predicting hospital mortality
than clinical staff opinion. Diff erences were also found between
diff erent groups of clinical staff , partially related to previous ICU clinical
experience. Outcomes and resource use for over 80 year olds admitted to a
UK critical care unit after an emergency laparotomy over a 3-year
period
V Banks, C Scott
Northern General Hospital, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P403 (doi: 10.1186/cc11010) coeffi cient (SE) was 1.47 (0.001) for the whole cohort, 1.49 (0.001) after
exclusion of cardiac surgery patients and 1.55 (0.006) after exclusion
of patients with an absolute diff erence in ROD >1% between the two
scores. Finally, the correlation between the APII and SAPS II scores was
moderate (r2 = 0.63). The overall model was APII = 0.36×SAPS II + 4.4. The APII/SAPS II coeffi cient (SE) was 0.36 (0.0003) for the whole cohort,
0.37 (0.0004) after exclusion of cardiac surgery patients and 0.39 (0.002)
after exclusion of patients with an absolute diff erence in ROD >1%. Parameters that aff ect outcome in surgical ICU patients
A Vakalos, M Petkopoulou, D Jannussis
Xanthi General Hospital, Xanthi, Greece
Critical Care 2012, 16(Suppl 1):P405 (doi: 10.1186/cc11012) Introduction Surgical ICU patients have a lower severity illness score on
ICU admission day. The aim of our study was to compare the length of
stay (LOS), ventilation days (VD) and parameters that aff ect the APACHE
II–III scoring system between surgical patients who died in the ICU and
surgical patients who survived and discharged from the ICU. pf
Conclusion Simple and robust translational formulas can be developed
to allow clinicians to compare illness severity in intensive care studies
of similar patients when such illness severity is expressed with diff erent
scoring systems. g
p
g
Methods During November 2005 and May 2011, 310 patients were
admitted to our medical and surgical ICU. From these, 122 were surgical
patients (39.35%) and were included retrospectively in our study. Mean age was 64 years, mean APACHE II score 14.5, actual mortality
rate 12.29%. The patients were separated into two groups. Group
A involved 107 surgical patients who survived the ICU and group
B 15 surgical patients who died in the ICU. We looked for statistical
signifi cant diff erence (two-tailed P value) between the mean APACHE
values at admission of group A and group B, using the unpaired Mann–
Whitney test (nonparametric) or the unpaired t test Welch corrected
(parametric), according to the normality test. p
References S146 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P408
Predictors of mortality in patients from a hematological ICU in
Brazil
OB Silva, L Correa, P Loureiro, E Araujo, D Teles, LA Vasconcelos,
T Salvattori, P Schwambach, GT Henriques-Filho
HEMOPE, Recife, Brazil
Critical Care 2012, 16(Suppl 1):P408 (doi: 10.1186/cc11015) Results The last 50 patients were admitted between January 2004 and
August 2011. Overall the number of admissions increased throughout
this period, with only one admission in 2004, peaking at 10 in 2009. In 2011, patients with a hematological malignancy represented 0.5%
of all the ICU admissions. The commonest malignancies were acute
myeloid leukemia (43%) and lymphoma (31%). The primary reason for
admission was sepsis (61%), with pneumonia the commonest source
(27%) and 42% admitted with neutropenic sepsis. Compared to the
2010/11 cohort the patients admitted with a hematological malignancy
had signifi cantly higher mean APACHE II scores (24 (SD 8) vs. 15 (SD 6)
P <0.0001), a longer mean ICU stay (10 days (SD 17) vs. 6 days (SD 10)
P <0.0001) and greater ICU (50% vs. 27% P <0.0001) and hospital
mortality (61% vs. 29% P <0.0001). However, the overall trend was a
considerable fall in mortality from 91% (2004 to 2007) to 36% (2008
to 2011). The mean SOFA score on admission for the hematological
patients was 9 (SD 3). Twenty patients required two levels of organ
support with only three patients receiving renal replacement therapy. No independent risk factors for outcome were identifi ed. Introduction The study was designed to analyze the factors responsible
for increased mortality in an ICU specialized in hematological patients. There are few ICUs specialized in hematological diseases, with reports
of high mortality rates (45 to 85%) [1], mostly related to severity
of patients with blood cancer [2], mechanical ventilation (MV) and
multiple organ failure [2-4]. The most prevalent disease diff ers among
studies [1-4] and acute leukemia seems to have the worst prognosis [2]. Methods A retrospective cohort was conducted at HEMOPE’s ICU. Data
were collected from the medical records of patients admitted from
January 2006 to December 2009. y
Results Of the 576 admissions, 396 (68.75%) could be analyzed. The
average age was 48.3 ± 19.4 years (11 to 88 years), 54% were female and
there was no association between mortality and age or gender. p
References 1. Scholz N, et al.: Eur J Anaesthesiol 2004, 21:606-611. 2. Sinuff T, et al.: Crit Care Med 2006, 34:878-885. 1. Scholz N, et al.: Eur J Anaesthesiol 2004, 21:606-611.f 1. Scholz N, et al.: Eur J Anaesthesiol 2004, 21:606-611. 2. Sinuff T, et al.: Crit Care Med 2006, 34:878-885. 2. Sinuff T, et al.: Crit Care Med 2006, 34:878-885. Figure 1 (abstract P407). ROC curve for SAPS II, consultants, nurses and
residents, for hospital mortality. Introduction Many diff erent illness severity scores are used to report
the estimated risk of death (ROD) of patients in clinical research. Such
variability makes mortality comparison between studies diffi cult. Accordingly, it would be desirable to establish a methodology to
translate the value obtained from one scoring system into an estimated
equivalent value for another scoring system. Methods We used the adult patient database of the Australian and
New Zealand (ANZ) Intensive Care Society to obtain simultaneous
APACHE II (APII), APACHE III (APIII) and SAPS II scores. We used linear
regression analyses to create models enabling translation of one score
into another. These analyses were performed for the whole cohort,
after exclusion of cardiac surgery patients and after matching for
similar risk of death. Results We obtained complete data for three illness severity scores
(SAPS II, APII, and APIII) in 636,431 admissions. There was a good
correlation between the APIII and APII scores (r2 = 0.76). The overall
model was APIII = 3.09×APII + 5.8. The APIII/APII coeffi cient (SE) was
3.09 (0.002) for the whole cohort, 3.1 (0.002) after exclusion of cardiac
surgery patients and 2.98 (0.01) after exclusion of patients with an
absolute diff erence in ROD >1% between the two scores. There was a
similar correlation between the APIII and the SAPS II scores (r2 = 0.76). The overall model was APIII = 1.47×SAPS II + 8.6. The APIII/SAPS II Figure 1 (abstract P407). ROC curve for SAPS II, consultants, nurses and
residents, for hospital mortality. p
References Acute
leukemia occurred in 43% (65.3% acute myeloid leukemia). Sepsis was
the major cause of admission (55.3%). The overall mortality rate was
57.5% and the specifi c one was 42.7%. The mean APACHE II score for
this population was 13.4 ± 1.0 (7 to 43) and was statistically higher in
the group that died (14.6 ± 0.7 vs. 11.8 ± 0.8; P = 0.013). Mean SOFA at
day 1 (D1) and day 3 (D3) was 2.8 ± 0.2 and 2.1 ± 0.2 respectively, also
signifi cantly higher in those that died (D1 3.9 ± 0.3 and D3 2.9 ± 0.3;
P <0.0001). Almost 60% used vasoactive drugs (VAD) on admission and
had a higher mortality rate (P <0.0001). MV was used in 86% and 69%
died (P <0.001). Of those with renal substitutive therapy (RST), 81.9%
died (OR = 3.12; 99% CI = 1.5 to 6.91). Mortality was also associated with
the completion of chemotherapy before ICU admission (P = 0.003) and
severe neutropenia (P <0.0001). In multivariate analysis, MV (RR = 13.1;
99% CI = 5.14 to 33.45) and a one-unit increase in SOFA D1 (RR = 1.26;
99% CI = 1.15 to 1.37) were associated with an increase in mortality. i
Conclusion The outcomes of patients with hematological malignancies
admitted to the ICU are improving with rates approaching that of
our general ICU population. Patients with hematological malignancy
requiring ICU admission continue to increase and admission should
be based on their physiological derangement and overall prognosis. Further prospective studies are required to investigate potential
predictors of outcomes in these patients. R f 1. Hampshire P, et al.: Admission factors associated with hospital mortality in
patients with haematological malignancy admitted to UK adult, general
critical care units: a secondary analysis of the ICNARC Case Mix
Programme Database. Crit Care 2009, 13:R137. References References
1. Shelton BK: Crit Care Clin 2010, 26:1-20. 2. Kress JP, et al.: Am J Respir Crit Care Med 1999, 160:1957-1961. 3. Taccone FS, et al.: Crit Care 2009, 13:R15. 4. Thiéry G, et al.: J Clin Oncol 2005, 23:4406-4413. Methods All patients with nonresectable lung cancer admitted to our
ICU between 1 January 2008 and 31 December 2010 were included in a
retrospective study. Postoperative patients were not included. 4. Thiéry G, et al.: J Clin Oncol 2005, 23:4406-4413. Results Twenty-two patients were included. Seventeen had nonsmall-
cell lung cancer (NSCLC). One had small cell lung cancer. Fifteen
patients (65%) had metastatic disease. Twelve patients were in
palliative therapy. The reason for ICU admission was acute respiratory
failure in 12 patients (55%), hemorrhage in fi ve patients (23%). Nine
patients (41%) had an infection. Fourteen patients (64%) needed
invasive mechanical ventilation. One-month survival was 45% (10/22). Six-month survival was 13% (3/22). One-year survival was 0%. One-
month survivors showed a nonsignifi cant trend to lower performance
status and severity of disease. All 6-month survivors had metastatic
disease. Six-month survivors had nonsignifi cantly lower performance
status (1.7 ± 0.6 vs. 2.7 ± 1.2; P = NS). IGS II, SOFA score and duration
of mechanical ventilation were signifi cantly shorter in survivors (see
Table 1). Six-month survival of patients with lung cancer admitted to a
medical ICU: a retrospective study O Keller, GL Laplatte, H Lessire y
Conclusion For this population, in univariate analysis mortality was
related to SOFA, RST, MV, use of VAD on admission, chemotherapy
before ICU admission, and severe neutropenia. Although there
was a relation between APACHE II score and mortality, this score
underestimates it. In multivariate analysis, needing MV and a high SOFA
D1 were independent predictors of death. CH Pasteur, Colmar, France
Critical Care 2012, 16(Suppl 1):P410 (doi: 10.1186/cc11017) Introduction ICU admission of patients with lung cancer remains
debated because of the poor short-term prognosis. We evaluated the
duration of survival of patients admitted to our ICU and looked for
factors associated with better survival. P409
Retrospective study of the outcomes of patients admitted to the
ICU with a hematological malignancy Retrospective study of the outcomes of patients admitted to the
ICU with a hematological malignancy
H Lewis, J Patel, N Lonsdale
Birmingham Heartlands Hospital, Birmingham, UK
Critical Care 2012, 16(Suppl 1):P409 (doi: 10.1186/cc11016) Birmingham Heartlands Hospital, Birmingham, UK g
g
Critical Care 2012, 16(Suppl 1):P409 (doi: 10.1186/cc11016) Introduction The UK prevalence of haematological malignancy is
increasing. Seven percent of these patients become critically ill, necessi-
tating ITU care [1]. The past decade has seen signifi cant advances in the
treatment and outcomes of patients with hemato logical malignancies. This has challenged the preconception that these patients are poor
candidates for ICU admission. This study evaluated the trends in
admission and outcomes of patients admitted to a general ICU with a
diagnosis of hematological malignancy. g
[ ]
p
gi
treatment and outcomes of patients with hemato logical malignancies. This has challenged the preconception that these patients are poor
candidates for ICU admission. This study evaluated the trends in
admission and outcomes of patients admitted to a general ICU with a
diagnosis of hematological malignancy. Conclusion Prognosis of patients with nonresectable lung cancer
admitted to the ICU was poor. Metastatic disease did not infl uence Table 1 (abstract P410)
Number of
IGS
SOFA
ventilation days
Nonsurvivors
53.2 ± 6.5
5.6 ± 3.8
6.1 ± 6.4
6-month survivors
36.3 ± 9.8
1.3 ± 2.3
0.7 ± 1.2
P <0.05
P <0.05
P <0.01 Table 1 (abstract P410) Methods A retrospective study of the last 50 consecutive admissions
of patients with a hematological malignancy admitted to the ICU. Patients were identifi ed from the ICNARC database. Demographic data,
APACHE II, SOFA scores on admission, baseline neutrophil count and
organ support data were collected. The primary outcome was ICU and
hospital mortality. Data were compared against the cohort of patients
admitted between April 2010 and April 2011. S147 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 total admissions). Sixty-eight percent were male, with a mean age of
60.21 ± 14.31 years and with an APACHE score of 22.21 ± 9.13. Solid
cancer was more frequent, 76.6% (urogenital 20%, lung 15.4% and
low intestinal 15.4% were the most common). In the hematologic
cancers (23.5%), the most frequent were non-Hodgkin lymphoma and
acute leukemia (both 7%). Active cancer (new diagnosis, recurrence or
progression) was presented in 75.3%. References 1. Toff art AC, et al.: Use of intensive care in patients with nonresectable lung
cancer. Chest 2011, 139:101-108. 2. Roques S, et al.: Six month prognosis of patients with lung cancer admitted
to the intensive care unit. Intensive Care Med 2009, 35:2044-2050. 2. Roques S, et al.: Six month prognosis of patients with lung cancer admitted
to the intensive care unit. Intensive Care Med 2009, 35:2044-2050. Health-related quality of life and survival of cancer patients
admitted to ICUs: results of the QALY study AB Cavalcanti1, UV Silva2, KN Normílio-Silva1, AN Silva1, R Zancani1,
MJ Giorgi1, AD Dias1, AT Simone1, PL Safra1, AC Figueiredo1,
G Tunes-da-Silva3, AC Lima3, LA Hajjar1, JO Auler1, J Eluf-Neto4, FR Galas1
1São Paulo State Cancer Institute, São Paulo, Brazil; 2Barretos Cancer Hospital,
Barretos, Brazil; 3Instituto de Matemática e Estatística – Universidade de São
Paulo, Brazil; 4Faculdade de Medicina da Universidade de São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P411 (doi: 10.1186/cc11018) Introduction Very limited data are available regarding postdischarge
health-related quality of life (HRQL) of cancer patients needing
intensive care. Our objective is to describe HRQL and survival in an
unselected population of cancer patients who were admitted to ICUs. y
Conclusion The mortality was associated with organ failure and
greater need for resources. Hematologic cancer develops more organ
failure without aff ecting resource consumption or their outcome in
our series. Septic patients have higher ICU and hospital mortality, and
neurological patients lower. Methods In this prospective cohort study conducted at two cancer
hospitals in Brazil, we enrolled a random sample of adult patients
with cancer admitted to the ICUs. We collected data at ICU admission,
including HRQL before the acute process that led to ICU admission,
and followed patients up on 15, 90 and 180 days after ICU admission
to assess HRQL and vital status. We determined HRQL with the EQ-5D
questionnaire, and the results were presented as summary measures
with values between –1 and 1, with 0 meaning HRQL similar to death
and 1 perfect HRQL. Summary measures were calculated using time-
trade-off value sets obtained from the UK population. Survival was
calculated with the Kaplan–Meier estimator. P409
Retrospective study of the outcomes of patients admitted to the
ICU with a hematological malignancy The main reason for admission
was respiratory failure (52.9%), shock (18.8%) or neurological impair-
ment (16.5%). The most common diagnoses were pulmonary sepsis
(23.5%), other sepsis (21.2%) and heart failure (8.2%). The ICU stay
was 7.20 ± 12.32 days; with a mortality of 41.2% (hospital mortality
50.6%). The mortality was higher in the active disease (91% vs. 64%),
P <0.01. Patients who died developed more respiratory (88.6% vs. 48%),
hemodynamic (91.4% vs. 44%), renal (68.6% vs. 16%) or hematologic
failure (45.7% vs. 16%), P <0.03. Septic patients were those with
higher ICU mortality (55.3% vs. 29.8%) and hospital mortality (63.2%
vs. 40.4%), P <0.05. By contrast, the patients with the longest survival
were the neurological (90% vs. 54.7%) and cardiology patients (88.9%
vs. 55.3%), P <0.05. Patients who died needed more MV (88.6% vs. 52%), vasopressors (91.4% vs. 46%) or dialysis (34.3% vs. 4%), P <0.01. The hematologic cancer had more cardiovascular (85% vs. 56.9%) or
hematologic failure (65% vs. 16.9%) and neutropenia (45% vs. 9.2%)
with P <0.03, but this is not refl ected in more consumption of resources
or mortality. survival in our survey. Patients admitted for a critical illness requiring
more than a few days of mechanical ventilation were very unlikely to
survive over 6 months. Managing critically ill oncological patients in hospital: a survey
across all ICUs in the UK p
Results We enrolled 805 patients. Mean age was 61.4 ± 14.3 and 42.5%
were female. Elective surgeries represented 52.2% of admissions,
urgent surgeries represented 5.0% and 42.8% were admitted due to
clinical reasons. Survival at 180 days was 51.2% (95% CI 47.4 to 54.9). The HRQL summary measure (median (interquartile range)) before ICU
admission was 0.64 (0.12 to 0.81), on the 15-day follow-up 0.73 (0.19 to
0.92), on the 90-day follow-up 0.73 (0.20 to 0.85) and on the 180-day
follow-up 0.70 (0.35 to 0.89). Introduction The survival rates for oncology patients admitted to the
ICU have improved signifi cantly. The prognostic infl uence of the pre-
admission oncological and treatment history is being questioned, the
most signifi cant impact being related to acute physiological status. In Figure 1 (abstract P413). (a) Hematological cancer. (b) Solid tumor. Checked bars, not proven in the literature. p
Conclusion HRQL is, on average, moderately impaired before ICU
admission and through the 180-day follow-up in cancer patients
needing intensive care. Only about one-half of the patients were alive
after 180 days. However, there is large variability on both HRQL and
length of survival; thus, methods to estimate quality-adjusted life-years
on an individual basis are necessary. Characteristics, resource consumption and outcome of cancer
patients admitted to ICUs New severity score of acute respiratory failure
S Allal, A Khedher, I Ben Saida, A Azouzi, A Farjallah, I Chouchen,
S Bouchoucha, M Boussarsar
CHU Farhat Hached Hospital, Sousse, Tunisia
Critical Care 2012, 16(Suppl 1):P415 (doi: 10.1186/cc11022) Methods We surveyed intensive care lead clinicians in December 2011
in order to establish: a profi le of the hospital and ICU they work in;
their estimate of overall ICU mortality for critically ill cancer patients;
the value of six outcome indicators in predicting mortality in two
subgroups of oncological candidates for ICU admission; and the local
management of acutely deteriorating cancer patients potentially
requiring ICU care. Introduction Acute respiratory failure (ARF), a common syndrome, is
still poorly clinically appreciated. Literature review reports only a few
attempts in neonatology (Silverman score) and in adults (Patrick score
[1]) constructed by authors in 1996 for scientifi c research purposes. Both scores have never been validated. Instead, clinicians developed
specifi c scores. We constructed a new respiratory failure score,
organized in a trimodal manner (Table 1). Items were selected on the
basis of pathophysiological and clinical expertise. Particular attention
was paid to formulation and scaling to make the score both simple,
noninvasive, inexpensive, didactic, and with interesting clinimetric
properties. The objective of this study is to validate this score already in
use for several years in our ICU. q
g
Results The ICU mortality rates estimated by survey respondents
diff ered from those reported in the literature: for solid tumor 21% (SEM
3) versus 10 to 23%, for metastatic solid tumor 38% (SEM 4) versus 23%,
hematological malignancy 45% (SEM 3) versus 33 to 43% with allograft
transplant 54.8% (SEM 5) versus 39 to 50% and autograft transplant 56%
(SEM 5) versus 44%. Regarding the management of cancer patients,
there were confl icts reported between teams (rarely 44%, occasionally
56%, commonly 0.2%). Few units had established triage policies for
the acutely ill cancer patient (5%) and it was also not common that
plans were made prior to the patient’s deterioration (never 11%, rarely
38%, occasionally 41%, commonly 9%). Figure 1 shows those outcome
indicators thought to be important by responders in forecasting ICU
prognosis. Table 1 (abstract P415). Characteristics, resource consumption and outcome of cancer
patients admitted to ICUs Characteristics, resource consumption and outcome of cancer
patients admitted to ICUs
R Garcia, L Terceros, I Saez, J Flordelis, L Colino, C Mudarra, S Temprano,
J Montejo
12 de Octubre Hospital, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P412 (doi: 10.1186/cc11019) p
R Garcia, L Terceros, I Saez, J Flordelis, L Colino, C Mudarra, S Temprano,
J Montejo
12 de Octubre Hospital, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P412 (doi: 10.1186/cc11019) Introduction The development of cancer treatment has improved the
prognosis for cancer patients and they need more support measures in
the ICU. Our objective is to evaluate the characteristics and evolution
of cancer patients admitted to a general ICU of a university hospital. Introduction The development of cancer treatment has improved the
prognosis for cancer patients and they need more support measures in
the ICU. Our objective is to evaluate the characteristics and evolution
of cancer patients admitted to a general ICU of a university hospital. Methods A retrospective study of cancer patients admitted to an ICU
from January 2008 to December 2010. We collected demographic and
cancer characteristics, reason for admission, complications, resource
consumption and mortality. We compared quantitative variables with
the Student t test and the qualitative variables with the chi-square test,
statistical signifi cance accepted as P <0.05. Methods A retrospective study of cancer patients admitted to an ICU
from January 2008 to December 2010. We collected demographic and
cancer characteristics, reason for admission, complications, resource
consumption and mortality. We compared quantitative variables with
the Student t test and the qualitative variables with the chi-square test,
statistical signifi cance accepted as P <0.05. Figure 1 (abstract P413). (a) Hematological cancer. (b) Solid tumor. Checked bars, not proven in the literature. Figure 1 (abstract P413). (a) Hematological cancer. (b) Solid tumor. Checked bars, not proven in the literature. i
Results A total of 108 patients were admitted with cancer, 23 with
cured cancer were excluded, so we selected 85 patients (4.38% of S148 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 this survey, we sought to evaluate the awareness of overall mortality
rates in critically ill cancer patients among intensivists in the UK. this survey, we sought to evaluate the awareness of overall mortality
rates in critically ill cancer patients among intensivists in the UK. References Results A total of 200 patients (age 70 ± 17 years, 65% males) were
admitted to the CCU during the study period; diagnoses included acute
coronary syndrome (65%), pulmonary edema (11.5%), congestive
heart failure (5.5%) and other (18%). The median length of CCU stay
was 5 ± 3 days and the median length of hospital stay 9 ± 7 days. The CCU mortality rate was 20% and in-hospital mortality 24.2%. Both APACHE II and SOFA scores were independently associated with
mortality (OR = 1.30; CI: 1.21 to 1.40, P <0.001 and OR = 1.82; CI: 1.53
to 2.16, P <0.001 respectively). The receiver operating characteristic
curves confi rmed both scores as equally eff ective predictors of clinical
outcome with areas under the curve of 0.92, P <0.001 and 0.91, P <0.001
for APACHE II and SOFA score respectively. 1. Patrick W, Webster K, Ludwig L, Roberts D, Wiebe P, Younes M: Non-invasive
positive pressure ventilation in acute respiratory distress without prior
chronic respiratory failure. Am J Respir Crit Care Med 1996, 153:1005-1011. p
y
p
2. Landis JR, Koch GG: The measurement of observer agreement for
categorical data. Biometrics 1977, 33:159-174. 2.
Minerva Anestesiol 2011, 77:305. P414 Methods A prospective study among 70 patients with ARF on previously
healthy lungs. ARF was rated in a randomized blinded manner respect-
ively by residents and seniors. An inter-rater reliability analysis using the
kappa statistic was performed to determine consistency among raters. P414
Role of illness severity scores in predicting mortality in the coronary
care unit
G Argyriou, J Terrovitis, G Sainis, V Papas, C Marvaki, S Nanas, C Routsi
Medical School, University of Athens, Greece
Critical Care 2012, 16(Suppl 1):P414 (doi: 10.1186/cc11021) Introduction Several illness severity scores have been developed in
order to predict outcome in multidisciplinary ICUs. However, the role
of these scores has not been thoroughly investigated in coronary care
units (CCUs) and the results are confl icting [1,2]. The aim of this study
was to evaluate the utility of two of the most widely used scores – that
is, APACHE II and Sequential Organ Failure Assessment (SOFA) – for the
prediction of mortality in patients admitted to CCUs. 2
y
Results The inter-rater reliability for the raters was found to be κ = 0.82
(P <0.001), indicating an almost perfect agreement [2]. The area under
the ROC curve was revealed very interesting (AUC = 0.88) indicating an
excellent prognostic predictive power. Conclusion This new and validated score could drive some advantages
in daily practice, allowing accurate assessment of ARF severity, more
objective monitoring of patients and easier communication between
care providers. It may accurately guide oxygen supplementation
and ventilatory support and aff ord accurate monitoring of patho-
physiological and etiological treatment of ARF. It could be a valuable
tool in randomized clinical trials or physiological studies evaluating
treatments in ARF. Finally it could be used as an educational tool. References p
y
p
Methods All patients consecutively admitted to an eight-bed CCU
from April 2010 to May 2011 were prospectively studied. Demographic,
clinical and laboratory data were recorded. Illness severity on admission
was measured using the APACHE II and SOFA scores. For the calculation
of the scores, the worst values for each variable on admission day were
used. 1.
Clin Cardiol 1999, 22:366. Validity of six prognostic scoring systems for septic shock patients
admitted to a medical ICU B Khwannimit, R Bhurayanontachai B Khwannimit, R Bhurayanontachai y
Prince of Songkla University, Hat Yai, Thailand Critical Care 2012, 16(Suppl 1):P416 (doi: 10.1186/cc11023) Conclusion The APACHE II and SOFA scores on admission are
independent predictors of mortality in patients hospitalized in a CCU. Both scores demonstrate excellent performance in discriminating
high-risk patients and thus are useful tools to predict clinical outcome
in CCUs. Introduction This study aimed to assess the validity of the APACHE
II, SAPS II, and SAPS 3, along with each of their customized scores, in
predicting hospital mortality in patients with septic shock admitted to
our ICU. 1.
Azoulay E, et al.: Ann Intensive Care 2011, 1:5. Characteristics, resource consumption and outcome of cancer
patients admitted to ICUs Score of respiratory failure
Grade
Respiratory rate
Accessory muscle use
Hypoxemia
I
<30
Intercostal
Normal
II
30 to 40
Supraclavicular and/or
Cyanosis
suprasternal
III
>40
Thoraco-abdominal
Circulatory and/or
swing/nasal fl aring
consciousness disorders
IV
Gasp
Exhaustion/ventilatory
Cardio-circulatory
arrest
arrest Table 1 (abstract P415). Score of respiratory failure Table 1 (abstract P415). Score of respiratory failure
G
d
R
i
A
l
H
i Table 1 (abstract P415). Score of respiratory failure
Grade
Respiratory rate
Accessory muscle use Conclusion The awareness of improved outcome in critically ill cancer
patients diff ers among physicians, and in general estimated mortalities
were far higher than those reported in the literature. Conclusion The awareness of improved outcome in critically ill cancer
patients diff ers among physicians, and in general estimated mortalities
were far higher than those reported in the literature. Reference 1. Azoulay E, et al.: Ann Intensive Care 2011, 1:5. References References Methods A prospective cohort study was conducted over a 6-year
period in a medical ICU of a tertiary referral university teaching hospital
in Thailand. S149 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Figure 1 (abstract P416). Calibration curves for customized APACHE II, SAPS II and SAPS 3. Figure 1 (abstract P416). Calibration curves for customized APACHE II, SAPS II and SAPS 3. Results A total of 880 patients were enrolled and a hospital mortality
rate of 57.4% was found. Community-acquired infections accounted for
57.2% and 32.8% of patients had positive blood culture. The respiratory
tract was the most common site of infection (48.7%). The predicted
mortality of all the scores was close to the observed mortality, with a
standardized mortality ratio (95% confi dence interval) of 0.94 (0.86 to
1.02) for APACHE II, 1.01 (0.92 to 1.1) for customized APACHE II, 0.93
(0.85 to 1.01) for SAPS II, 1.07 (0.98 to 1.17) for customized SAPS II, 0.97
(0.89 to 1.06) for SAPS 3 and 1.02 (0.93 to 1.11) for customized SAPS
3. All six scores were well discriminated, with areas under the receiver
operating characteristic curves of 0.82, 0.813, 0.819, 0.815, 0.817 and
0.813, respectively. The Hosmer–Lemeshow goodness-of-fi t showed
good calibration in only the customized APACHE II (H-statistic 12.4,
P = 0.26). See Figure 1. patients underwent study of endothelial vasodilating function using
the method proposed by Celermajer and colleagues [1]. Results A total of 880 patients were enrolled and a hospital mortality
rate of 57.4% was found. Community-acquired infections accounted for
57.2% and 32.8% of patients had positive blood culture. The respiratory
tract was the most common site of infection (48.7%). The predicted
mortality of all the scores was close to the observed mortality, with a
standardized mortality ratio (95% confi dence interval) of 0.94 (0.86 to
1.02) for APACHE II, 1.01 (0.92 to 1.1) for customized APACHE II, 0.93
(0.85 to 1.01) for SAPS II, 1.07 (0.98 to 1.17) for customized SAPS II, 0.97
(0.89 to 1.06) for SAPS 3 and 1.02 (0.93 to 1.11) for customized SAPS
3. All six scores were well discriminated, with areas under the receiver
operating characteristic curves of 0.82, 0.813, 0.819, 0.815, 0.817 and
0.813, respectively. The Hosmer–Lemeshow goodness-of-fi t showed
good calibration in only the customized APACHE II (H-statistic 12.4,
P = 0.26). See Figure 1. Reference Scientifi c Clinical Center of Miner’s Health Protection, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P417 (doi: 10.1186/cc11024) Scientifi c Clinical Center of Miner’s Health Protection, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P417 (doi: 10.1186/cc11024) 1. Celermajer DS, et al.: Non-invasive detection of endothelial dysfunction in
children and adults at risk of atherosclerosis. Lancet 1992, 340:1111-1115. Introduction The high risk of thromboembolic complications after knee
joint prosthetics is conditioned by the series of surgical intervention
particularities. The infl uence of intraoperative tourniquet usage on the
leg deep venous thrombosis frequency was studied. References Results On 4 to 5 days after surgery, leg deep venous thrombosis was
found in 11 patients (8.8% of all patients after prosthetics). For decrease
of intraoperative blood loss the tourniquet was applied onto the middle
third of the leg in 77 patients (60.6%). In this group DVT was found in
10.4% of cases. In the nontourniquet group (48 patients) DVT was
found in 6.25%. The diff erences in the complication frequency were not
statistically valid. The data from duplex scanning showed that 43 patients
(34.4%) before surgery had changes in the lower leg veins in view of
varicose subcutaneous veins and post-thrombophlebitic syndrome
combined with disorders of endothelial vasodilating func tion and low
venous tone. Tourniquet use in patients with venous pathology resulted
in DVT in 30% (fi ve of 15 patients). When a tourniquet was not used in
patients with venous disease, DVT was found only in one of 28 patients
(3.5%). The test showed a signifi cant diff erence in the frequency of
thromboembolic complications in these groups (P <0.001). Conclusion In this study, the customized APACHE II was found to be
accurate in predicting hospital mortality in septic shock patients
requiring ICU admission. Conclusion Therefore, using a tourniquet in patients with evident base
venous pathology in terms of varicose subcutaneous veins or post-
thrombophlebitic syndrome in total knee joint endoprosthetics is a risk
factor for venous thrombosis development. Reference Risk factors of venous thrombosis in knee joint endoprosthesis
SV Vlasov, IV Vlasovai Risk factors of venous thrombosis in knee joint endoprosthesis
SV Vlasov, IV Vlasova
Scientifi c Clinical Center of Miner’s Health Protection, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P417 (doi: 10.1186/cc11024) P418 P418
Proximal and distal deep venous thrombosis in critically ill patients:
incidence and prevalence
S Yus Teruel, J Camacho Oviedo, L Cachafeiro Fuciños,
M Hernandez Bernal, A Agrifoglio Rotaeche, M Irazábal Jaimes,
L Fernandez Rodriguez, B Civantos Martín, J Díez
Hospital Universitario La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P418 (doi: 10.1186/cc11025) P418
Proximal and distal deep venous thrombosis in critically ill patients:
incidence and prevalence
S Yus Teruel, J Camacho Oviedo, L Cachafeiro Fuciños,
M Hernandez Bernal, A Agrifoglio Rotaeche, M Irazábal Jaimes,
L Fernandez Rodriguez, B Civantos Martín, J Díez
Hospital Universitario La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P418 (doi: 10.1186/cc11025) Effi cacy and safety of enoxaparin as deep vein thrombosis
prophylaxis in critically ill patients
R Al-Hubail, N Hassan
King Fahad Specialist Hospital, Dammam, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P420 (doi: 10.1186/cc11027) Effi cacy and safety of enoxaparin as deep vein thrombosis
prophylaxis in critically ill patients
R Al-Hubail, N Hassan
King Fahad Specialist Hospital, Dammam, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P420 (doi: 10.1186/cc11027) Methods This was a prospective observational study conducted in our
medical–surgical and trauma ICU from October 2009 to September
2010. The inclusion criterion was ≥72 hours of ICU stay. Exclusion
criteria were admitting diagnosis of pulmonary embolism or DVT,
readmission, and patients with support withdrawal orders. The study
was approved by the Research Ethics Board of La Paz Hospital. Bilateral
lower extremity compression ultrasound was performed within 48
hours of admission to evaluate the prevalence, and twice weekly
until discharge to assess the incidence. We collected demographic
data, body mass index (BMI), APACHE II score, SOFA score, diagnostic
categories, classic risk factors for DVT, femoral catheter and the use of
mechanical ventilation and muscle relaxants. For the statistical analysis
chi-square and Fisher tests were used, as well as Mann–Whitney and
Student tests for data comparison. For the probability of DVT and its
relation with the associated factors, the odds ratio and confi dence
interval were used. Statistical signifi cance was P <0.05. Introduction Critically ill patients are at high risk of developing deep
vein thrombosis (DVT). DVT cannot be detected in most cases, leading
to fatal embolic manifestations [1]. The goal of this study was to review
the occurrence of DVT in patients receiving enoxaparin during their
length of stay in the ICU (ICU LOS). In addition we review the occurrence
f
j
bl
di
d th
b
t
i
d
t
i of major bleeding and thrombocytopenia secondary to enoxaparin. Methods This was a retrospective database analysis including medical
and surgical patients admitted to a tertiary hospital (King Fahad
Specialist Hospital Dammam) critical care department from 1 January
to 31 December 2010, aged 17 to 70 years, excluding patients with:
platelets <50,000/l; evidence of active bleeding; new ischemic or
haemorrhagic stroke; spinal or epidural catheter who were already
on anticoagulant when admitted to the ICU and who were previously
diagnosed with DVT or with pulmonary embolism (PE); DNR (do not
resuscitate). The APACHE II score, predicted mortality and ICU LOS were
calculated for included patients in the study. Saddle embolism is associated with the major adverse events in
patients with nonhigh-risk pulmonary embolism
H Kim, W Kim
Asan Medical Center, Seoul, South Korea
Critical Care 2012, 16(Suppl 1):P419 (doi: 10.1186/cc11026) Saddle embolism is associated with the major adverse events in
patients with nonhigh-risk pulmonary embolism
H Kim, W Kim
Asan Medical Center, Seoul, South Korea
Critical Care 2012, 16(Suppl 1):P419 (doi: 10.1186/cc11026) Introduction In some patients with acute pulmonary embolism (PE),
thrombi may lodge at the levels of bifurcation of the pulmonary trunk
and extend into both main pulmonary arteries, forming so-called
saddle embolism (SE). The aim of this study was to assess the incidence
of SE and whether it is associated with an increased risk of complicated
clinical course in patients with nonhigh-risk PE. p
g
Methods Between January 2006 and June 2010, 297 consecutive
patients with nonhigh-risk PE that was confi rmed with contrast-
enhanced spiral computed tomography (CT) in the emergency
department were studied. One experienced radiologist evaluated the
presence of SE. The clinical information, echocardiographic and CT
parameters were reviewed. Patients were divided into SE and non-
SE. Multivariate logistic regression was applied to determine factors
associated with occurrence of major adverse events (MAE). 1. Greets et al.: Chest 2003, 124:357s-363s. Proximal and distal deep venous thrombosis in critically ill patients:
incidence and prevalence Methods The study included 125 patients with gonarthrosis of degree
III who received total knee joint endoprosthesis. There were 26 men
and 99 women at the age of 36 to 77 (60.7 ± 8.03). For all patients,
spinal anesthesia in combination with long-term epidural blockade for
postsurgical pain relief was performed. The antithrombotic measures
included Klexan 40 mg, 12 to 15 hours before surgery and 8 hours after
it. Color mapping of the lower leg vessels with an Acuson 128XP/10c
scanner was performed before surgery, on 4 to 5 days after prosthetics
and before discharge from the in-patient department. In addition, all p
S Yus Teruel, J Camacho Oviedo, L Cachafeiro Fuciños,
M Hernandez Bernal, A Agrifoglio Rotaeche, M Irazábal Jaimes,
L Fernandez Rodriguez, B Civantos Martín, J Díez
Hospital Universitario La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P418 (doi: 10.1186/cc11025) Introduction The aim of this study was to detect deep venous
thrombosis (DVT) in patients admitted to a critical care unit (ICU) by S150 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P420fi compression ultrasonography, and to determine the incidence and
prevalence of proximal and distal DVT in this setting. Table 1 (abstract P420) Table 1 (abstract P420)
Predicted
Type of case
ICU LOS (days)
APACHE II
mortality (%)
Total cases on enoxaparine
5.29 ± 7.3
16.7 ± 10.5
28.4 ± 23.7
Low platelets cases
11.75 ± 9.7
23 ± 2.3
48.75 ± 11.18
Major bleeding cases
13.5 ± 13.1
22.4 ± 17.4
30 ± 17.5 Effi cacy and safety of enoxaparin as deep vein thrombosis
prophylaxis in critically ill patients
R Al-Hubail, N Hassan
King Fahad Specialist Hospital, Dammam, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P420 (doi: 10.1186/cc11027) The hospital electronic
system and critical care database were reviewed with the physician
order sheet according to the ICU protocol for DVT prophylaxis
(enoxaparin 40 mg subcutaneously once daily). i
Results We enrolled 182 patients, with male predominance (57.3%),
135 were mechanically ventilated (74.2%) and the mean APACHE II
score was 19.3 ( ± 7.8). The mortality in the ICU was 15.4% (28), and 20.9
(38) in hospital. The prevalence of proximal DVT was 29.1% (53/182),
and the incidence 24.0% (31/129). Seventy-nine percent of patients
received DVT prophylaxis. The localization of incidentally diagnosed
DVT was proximal in 29% and distal in 35%; 19 (64%) of these were
identifi ed on day 5 of admission. In four patients DVT was clinically
suspected and only in one of them was DVT confi rmed. The most
frequently involved were soleal veins (67%). Independent risk factors
for incidental DVT were: older age (62 ± 15.4 years vs. 54.5 ± 17.1;
P = 0.032); BMI (27.7 ± 5.5 kg/m2 vs. 24.9 ± 5.2 kg/m2; P = 0.014); and
mechanical ventilation: (OR: 3.3, 95% CI = 1.0 to 10.26). Patients with
incidental DVT had a higher hospital mortality (P = 0.03). g
y
y
Results Five hundred and ninety-seven patients were investigated,
from which 22 (3.5%) fulfi lled exclusion criteria, 220 (36%) were on a
sequential decompression device (SD), and 26 (4%) were not on DVT
prophylaxis (protocol violation). This gave a study population of 329
(55%) cases that were on enoxaparin thromboprophylaxis. In this
population there were no recorded cases of DVT and two cases (0.6%)
of PE. Major bleeding was recorded in seven cases (2.1%), platelets
<50,000/l in eight cases (2.4%), and Hb level <1.5 g/dl from baseline
without bleeding in 47 cases (14.2%). See Table 1. Conclusion In our study DVT was an early, asymptomatic and frequent
event (46% of the ICU patients). In the presence of risk factors, a
diagnostic ultrasound test might have a role. Effi cacy and safety of enoxaparin as deep vein thrombosis
prophylaxis in critically ill patients
R Al-Hubail, N Hassan
King Fahad Specialist Hospital, Dammam, Saudi Arabia
Critical Care 2012, 16(Suppl 1):P420 (doi: 10.1186/cc11027) Table 1 (abstract P420)
Predicted
Type of case
ICU LOS (days)
APACHE II
mortality (%)
Total cases on enoxaparine
5.29 ± 7.3
16.7 ± 10.5
28.4 ± 23.7
Low platelets cases
11.75 ± 9.7
23 ± 2.3
48.75 ± 11.18
Major bleeding cases
13.5 ± 13.1
22.4 ± 17.4
30 ± 17.5
Conclusion Using the hospital and critical care databases, we
observed that the critically ill patients receiving enoxaparin as
thromboprophylaxis did not experience DVT, and two (0.6%) had PE
during their ICU stay. However, thrombocytopenia and major bleeding
were recorded at very low frequencies (2.5%). Reference
1. Greets et al.: Chest 2003, 124:357s-363s. Table 1 (abstract P420) P423
Consequences of suspected heparin-induced thrombocytopenia in
the ICU y
y
Results All patients included in the study before surgery had detected
hypercoagulation and inhibition of fi brinolysis: increasing of MA
(maximum density of the clot, fi brin-platelet constant of the blood) to
20.7% (P <0.001) and ICD (intensity of coagulation drive (the intensity of
clot formation)) to 15.6%; reduction of IRCL (intensity of the retraction
and clot lysis) to 13.6% (P <0.05) in both groups compared to normal rates. At the fi rst day after surgery in patients treated with bemiparin (group 1)
MA and ICD decline to 12.7 (P <0.05) and 9.6% (P <0.001) respectively,
and IRCL increased by 4.6% (P <0.05) compared with preoperatively. In
group 2 there was a similar picture: the reduction of MA and ICD to 10.3
(P <0.001) and 6.6% (P <0.05) respectively, and IRCL increased by 4.4%
(P <0.001). At the fi fth day the condition of hemostasis in both groups
came almost to the same value – a moderate hypocoagulation, normal
activity of fi brinolysis. At 7 days of the postoperative period, thrombotic
complications developed in one patient of the fi rst group (2.70%). In the
second group, complications developed in four (9.52%) patients: in three
cases deep venous thrombosis, and in one case coagulopathic bleeding. Conclusion Using a combination of bemiparin and epidural anesthesia
reduces the level of postoperative thrombotic complications, such
as deep venous thrombosis, and massive bleedings in the patients
after total hysterectomy. Using hemoviscoelastography enables quick
identifi cation of disorders of hemostasis in patients after hysterectomy
before, during and after the surgery. P423
Consequences of suspected heparin-induced thrombocytopenia in
the ICU M Ostermann1, L McIntyre2, F Lauzier3, J Alhashemi4, I Qushmaq5,
S Langevin3, P Dodek6, M Albert7, K Khwaja8, J Kutsiogiannis9,
L Burry10, J Granton10, J Friedrich10, N Ferguson10, J Marshall10, S Finfer11,
D Heels-Ansdell12, N Zytaruk12, D Cook12, J Sheppard12, T Warkentin12,
M Crowther12 M Ostermann1, L McIntyre2, F Lauzier3, J Alhashemi4, I Qushmaq5,
S Langevin3, P Dodek6, M Albert7, K Khwaja8, J Kutsiogiannis9,
L Burry10, J Granton10, J Friedrich10, N Ferguson10, J Marshall10, S Finfer11,
D Heels-Ansdell12, N Zytaruk12, D Cook12, J Sheppard12, T Warkentin12,
M Crowther12 1King’s College London, UK; 2University of Ottawa, Canada; 3CHA-Hôpital de
l’Enfant-Jésus, Université Laval, Québec, Canada; 4King AbdulAziz University,
Jeddah, Saudi Arabia; 5King Faisal Hospital, Jeddah, Saudi Arabia; 6University
of British Columbia, Vancouver, Canada; 7Université de Montréal, Canada;
8Université McGill, Montréal, Canada; 9University of Alberta, Edmonton,
Canada; 10University of Toronto, Canada; 11The George Institute, Sidney,
Australia; 12McMaster University, Hamilton, Canada
Critical Care 2012, 16(Suppl 1):P423 (doi: 10.1186/cc11030) Introduction Clinical suspicion of heparin-induced thrombocytopenia
(HIT) may prompt changes in drug management and alert clinicians to
an increased risk of thrombosis. However, thrombocytopenia in the ICU
occurs in about 50% of patients, is multifactorial and is due to HIT in
<1%. We aimed to describe the consequences of suspected HIT among
medical–surgical critically ill patients in terms of drug and device
management, and thrombotic outcomes. g
Methods We enrolled 3,746 patients in the PROTECT trial comparing
prophylactic dalteparin to unfractionated heparin. We defi ned HIT as
occurring in patients with a clinical or laboratory-driven suspicion of
HIT and a positive serotonin release assay (SRA). We defi ned suspected
HIT as patients whose clinicians were suffi ciently concerned about HIT
to withhold heparin. We defi ned consequences of HIT as occurring
from 1 day before it was suspected to 30 days thereafter. P422 Cost-eff ectiveness analysis of two thromboprophylactic strategies
following major surgery
C Ebm, M Cecconi, A Rhodes, M Grounds
St George´s Healthcare Trust, London, UK
Critical Care 2012, 16(Suppl 1):P422 (doi: 10.1186/cc11029) y
p
y
Results One hundred and thirty patients (3.5%) had heparin held
due to clinical suspicion of HIT. Of these, 10 (7.7%) had a positive SRA
test. The drugs and devices used for thromboprophylaxis, as well as
thrombotic events, are outlined in Table 1. At least one new thrombotic
event developed in 23.8% of patients with suspected HIT and 40.0% of
patients with HIT. Reference Reference instrumental method – hemoviscoelastography preoperatively, intra-
operatively and every day during 10 days after surgery. Prevention
of thrombotic complications in group 1 (37 patients), conducted by
bemiparin 3,500 units: the fi rst injection 12 hours before surgery, then
at 6 hours after the operation in the future once a day for 10 days; group
2 (42 patients) received heparin 5,000 units: the fi rst injection 6 hours
before surgery, then 6 hours after the operation, then four times per
day for 10 days. 1. Roderick P, Ferris G, Wilson K, Halls H: Towards evidence-based guidelines for
the prevention of venous thromboembolism: systematic reviews of
mechanical methods, oral anticoagulants, dextran and regional anaesthesia
for thromboprophylaxis. Health Technol Assess 2005, 9(49):iii-iv, 1-78. 1. Roderick P, Ferris G, Wilson K, Halls H: Towards evidence-based guidelines for
the prevention of venous thromboembolism: systematic reviews of
mechanical methods, oral anticoagulants, dextran and regional anaesthesia
for thromboprophylaxis. Health Technol Assess 2005, 9(49):iii-iv, 1-78. Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P423
Consequences of suspected heparin-induced thrombocytopenia in
the ICU Introduction Patients recovering from major surgery are at high risk
of developing life-threatening deep venous thrombosis, which is a key
source of postoperative morbidity and mortality. Our objective was to
assess the cost-eff ectiveness of two diff erent thromboprophylactic agents
for patients admitted to the ICU after high-risk surgery: inter mittent
pneumatic compression (IPC) and anti-embolism stockings (AES). P421 P421
Reducing the level of postoperative thrombotic complications by
the combination of low molecular weight heparin and epidural
anesthesia at the patients after total hysterectomy
O Tarabrin, V Dubinina, A Turenko, S Tarasenko, S Shcherbakov,
D Gavrychenko, G Mazurenko
Odessa National Medical University, Odessa, Ukraine
Critical Care 2012, 16(Suppl 1):P421 (doi: 10.1186/cc11028) Results Twenty-seven out of 297 patients (9.1%) were found to have
a SE. Overall mortality at 1 month was 12.5% with no diff erence
between the groups (11.9% vs. 18.5%, P = 0.32), although SE patients
were more likely to receive thrombolytic therapy (8.1% vs. 29.6%,
P <0.01). SE patients had s signifi cantly higher rate of MAE (59.3% vs. 25.6%, P <0.01). Presence of SE and the ratio of right ventricular to left
ventricular diameter were associated with an odds ratio of MAE within
1 month of 2.48 (95% CI: 1.10 to 6.04, P = 0.03) and 3.34 (95% CI: 1.46
to 7.46, P <0.01). Introduction Each year in the world, cancer of the reproductive system
is diagnosed in more than 600,000 women. In 8 to 35% of patients with
cancer of the reproductive system, pulmonary embolism was the cause
of death – and in 43% the background for other fatal complications. Methods The results of surgical treatment of 79 patients after
hysterectomy under prolonged epidural anesthesia during the period
from 2008 to 2010 entered the study. The condition of hemostasis
was monitored by 12 standard biochemical tests, as well as the new Introduction Each year in the world, cancer of the reproductive system
is diagnosed in more than 600,000 women. In 8 to 35% of patients with
cancer of the reproductive system, pulmonary embolism was the cause
of death – and in 43% the background for other fatal complications. Methods The results of surgical treatment of 79 patients after
hysterectomy under prolonged epidural anesthesia during the period
from 2008 to 2010 entered the study. The condition of hemostasis
was monitored by 12 standard biochemical tests, as well as the new Conclusion SE by CT angiography was associated with PE-related
shock, intubation, mortality, thrombolysis, and thrombectomy within
1 month in patients with nonhigh-risk PE and may be a useful method
for simple risk stratifi cation. S151 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 R Riessen, M Behmenburg, G Blumenstock, D Guenon, S Enkel, M Haap
University Hospital Tübingen, Germany
l
l
(d
) Results Thirty patients were included, with a mean age of 59.6 ± 19.3,
APACHE II score 19.1 ± 7.2, SOFA at baseline 8.5 ± 4.0, and most patients
had septic shock (63.3%). Baseline iron and transferrin levels were low in
83.3% (14.0 (5.0 to 25.5)) and in 96.7% (94.1 ± 31.6) of the patients, while
ferritin was high in 63.3% (954.0 (508.4 to 5,394.0)). In the 19 patients
where a day 7 sample was available, variation between baseline and day
7 was statistically signifi cant for transferrin (97.9 ± 37.5 to 132.7 ± 48.3,
P = 0.013) and ferritin (478.0 (224.5 to 1,741.0) to 376.0 (187.0 to 886.7),
P = 0.018), while iron levels showed a trend towards increasing levels
at day 7 (17.0 (6.5 to 44.3) to 29.0 (21.0 to 54.0), P = 0.061). Baseline
SOFA score trends to be lower in hypoferrinemic patients (7.7 ± 3.8 vs. 12.4 ± 1.9, P = 0.098). The Spearman test showed a weak correlation
only between SOFA and iron levels (P = 0.008; r2 = 0.48). Introduction By introducing a blood-saving-bundle (BSB) consisting
of a closed-loop arterial blood sampling system, smaller tubes and an
attempt to reduce the number of blood samples, we aimed to reduce
blood loss caused by diagnostic blood sampling and to minimize the
development of anemia in a high-risk group of mechanically ventilated
intensive care patients. p
Methods Included were all patients from our medical ICU who were
ventilated for more than 72 hours. Exclusion criteria were acute or
chronic anemia on admission, a bleeding episode during the ICU stay
or end-of-life therapy. The BSB was introduced in 2009 with training
and educational support. Patients treated in the year 2008 before the
introduction of the BSB served as a control group and were compared
to patients treated in 2010 after introduction of the BSB (BSB group). Daily blood loss was calculated on the basis of the documentation of
blood samples and laboratory values in the patient data management
system and by using data from two representative study periods in
which the sample volumes of all diagnostic blood tests were measured. Results The control group comprised of 41 patients (614 observation
days), the BSB group of 50 patients (559 observation days). Evaluation of iron, transferrin and ferritin serum levels in patients
with severe sepsis and septic shock Evaluation of iron, transferrin and ferritin serum levels in patients
with severe sepsis and septic shock
M Missano Florido, M Assunção, B Mazza, M Jackiu, F Freitas, A Bafi ,
F Machado
UNIFESP, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P424 (doi: 10.1186/cc11031) M Missano Florido, M Assunção, B Mazza, M Jackiu, F Freitas, A Bafi ,
F Machado
UNIFESP, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P424 (doi: 10.1186/cc11031) Introduction Iron metabolism is altered in critically ill patients leading
to hypoferremia. Several studies related it to infl ammatory response
[1,2]. The present study aims to evaluate iron, transferrin and ferritin
serum levels in patients with severe sepsis and septic shock and its
association with severity of organ dysfunction. y
g
y
Methods A prospective observational cohort study, unicentric, in
a tertiary teaching hospital. From November 2010 to October 2011
patients over 18 years old with severe sepsis or septic shock with up
to 72 hours of organ dysfunction were included. Exclusion criteria were
blood transfusion or iron supplementation in the last 90 days, previous
inclusion and pregnancy. After obtaining informed consent, blood
samples were taken at baseline and on day 7. Demographic and APACHE
II and SOFA data were also collected. Patients who were transfused with
red blood cells between the two periods were excluded from the day 7
sample. Patients were followed until hospital discharge or death. Conclusion Angiogenic factors and their soluble receptors, particularly
sVEGFR1, play pivotal roles in the development of organ dysfunction in
DIC associated with severe trauma. The DIC-induced tissue hypoxia and
platelet consumption plays crucial roles in inducing sVEGFR1 and Ang2,
and in determining the prognosis of the severity of organ dysfunction. P426 P424 g
y
Results DIC patients showed higher Sequential Organ Failure Assess-
ment (SOFA) scores, soluble fi brin and lactate levels. The serum levels
of VEGF, Ang1, and the sTie2 levels were lower in the DIC patients than
the non-DIC patients. The serum levels of sVEGFR1, Ang2 and the
Ang2/Ang1 ratio in the DIC patients were higher than in those without
DIC. The sVEGFR2 levels showed no statistically signifi cant diff erence
between the patients with and without DIC. The levels of sVEGFR1,
Ang2 and the Ang2/Ang1 ratio correlated with the SOFA score. In
particular, sVEGFR1 and Ang2 were independent predictors of an
increase in the SOFA score. The lactate levels independently predicted
increases in the levels of sVEGFR1 and Ang2 and platelet consumption
also independently predicted the increase in Ang2 levels in severe
trauma patients with DIC. R Riessen, M Behmenburg, G Blumenstock, D Guenon, S Enkel, M Haap
University Hospital Tübingen, Germany
l
l
(d
) Mean blood
loss per ICU day decreased from 43.3 ml (95% CI 41.2 to 45.3 ml) in
the controls to 15.0 ml (14.3 to 15.7 ml) in the BSB group (P <0.001). The introduction of a closed-loop arterial blood sampling system
contributed most to this eff ect. Mean hemoglobin values showed
a similar decrease in both groups during the ICU stay. However,
hemoglobin values <9 g/dl were measured in 21.2% of observation
days in the controls versus 15.4% in the BSB group (P = 0.01). In the
control group 31.7% (18.1 to 48.1%) of the patients received red blood
cell transfusions in contrast to only 8.0% (2.2 to 19.2%) in the BSB group
(P = 0.006), while the hemoglobin concentration triggering transfusion
was not signifi cantly diff erent (8.2 vs. 7.8 g/dl). The mean number
of intubation days was 7.1 days (6.1 to 8.3 days) in the controls and
7.5 days (6.6 to 8.5) in the BSB group (P = NS). However, patients in the
BSB group stayed with a mean of 9.8 days (8.6 to 11.3 days) signifi cantly
shorter in the ICU than controls with 13.2 days (10.9 to 15.4 days)
(P = 0.014). Conclusion Septic patients have low iron and transferrin levels,
associated with high ferritin levels, and those levels improved during
the course of disease. Low iron levels might be associated with low
SOFA scores. References
1
Lagan AL 1. Lagan AL, et al.: Am J Physiol Lung Cell Mol Physiol 2008, 294:L161-L174. 2. Quinlan GJ, et al.: Am J Respir Crit Care Med 1997, 155:479-484. Table 1 (abstract P423) Table 1 (abstract P423)
1 day before to 30 days after
heparin held for suspect HIT
Intervention
Danaparoid
34 (26.2)
Lepirudin
8 (6.2)
Fondaparinux
11 (8.5)
Argatroban
19 (14.6)
Any of the above drugs
67 (51.5)
Anti-embolic stockings
25 (19.2)
Pneumatic compression device
37 (28.5)
Anti-embolic stockings or pneumatic
49 (37.7)
compression device
Any of the above interventions
96 (73.8)
Incident thromboses
Venous thrombosis (including PE)
30 (23.1)
Arterial thrombosis
1 (0.8)
Progression of a previous thrombus
2 (1.5)
Any of the above
31 (23.8) g
Methods A decision model (TreeAge Software 2010) was constructed
simulating the impact of AES and IPS on patient outcomes and costs
following high-risk surgery in the UK. Probabilities were assessed from
published data [1]. ICU and item costs were derived from NHS reference
costs tablets. Assessed outcomes were cost per deep vein thrombosis
(DVT) and pulmonary embolism (PE) prevented, net monetary benefi t and y
yi
incremental costs per quality-adjusted life expectancy (QALY) gained. Results Total costs for in-patients receiving AES were £923 and £1,010
for patients treated with IPC. Equipment costs and cost of initial care
were higher in patients who received IPC, but this was partly off set
by a reduction in costs related to treatment of early (DVT and PE)
and late complications (post-thrombotic syndrome and pulmonary
hypertension). IPC treatment increased QALY by approximately 0.01
years. The incremental cost-eff ectiveness of the IPC device was £12,650
per QALY gained. One-way sensitivity analysis revealed that the most
sensitive variables were probability of developing a DVT resulting from
the insignifi cant diff erence in treatment effi cacy.f iffi
Conclusion Based on UK cost-eff ectiveness guidelines, our results
indicate that IPC stockings should be used for patients at high risk of
developing DVT. IPCs decrease the incidence of developing DVT and
therefore result in cost savings related to preventive and therapeutic
actions. For patients at low risk of developing DVT, AES are favoured
due to higher utility and lower maintenance costs associated with AES. Due to the lack of reliable data on the incidence of PE as well as the
absence of reliable head-to-head studies between IPC and AES, no
generalisable conclusion to favour either strategy can be made. Conclusion Over 90% of patients with suspected HIT did not have
HIT. A simple blood-saving bundle reduces diagnostic blood loss in
mechanically ventilated patients R Riessen, M Behmenburg, G Blumenstock, D Guenon, S Enkel, M Haap
University Hospital Tübingen, Germany Table 1 (abstract P423) One-half of patients with suspected HIT were prescribed another S152 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Methods Fifty-seven patients with severe trauma were divided into
two subgroups: 30 DIC patients and 27 non-DIC patients. The serum
levels of angiogenic factors were measured on admission (day 1), day
3, and day 5. We compared serum levels of these angiogenic factors
between with and without DIC groups and evaluated their predictive
value for organ dysfunction and outcome. anticoagulant and one-third received mechanical prophylaxis. Thrombotic rates are higher in patients with HIT and suspected HIT
than other patients. The frequent suspicion of HIT in critically ill patients
and initiation of other interventions may create a greater clinical and
economic burden than HIT itself. Templating eff ect of clot structure can predict clot
development and outcome in diluted blood: a comparison with
thromboelastography g
p y
M Lawrence1, J Kaczynski2, S Stanford1, R Morris3, P Evans2
1Swansea University, Swansea, UK; 2ABMU LHB, Swansea, UK; 3UWIC, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P429 (doi: 10.1186/cc11036) g
p y
M Lawrence1, J Kaczynski2, S Stanford1, R Morris3, P Evans2
1Swansea University, Swansea, UK; 2ABMU LHB, Swansea, UK; 3UWIC, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P429 (doi: 10.1186/cc11036) Introduction Safety of patients is possible to increase applying
early detection of intraoperative and postoperative hemorrhage
using the widening array of monitoring opportunities; not only the
hemodynamic parameters, but the detection of total hemoglobin. Continuous noninvasive monitoring of total hemoglobin content is
possible due to the Masimo Rainbow SET technology, using multiwave
spectrophotometry. Introduction Treatment of major hemorrhage with colloids is known to
have an eff ect on clot outcome. However, determining both the rate and
extent of these changes is diffi cult. Development of a new biomarker
has shown that it can detect structural development earlier and
quantifi es these changes to clot outcome accurately when compared
to other methods. This study compares the fractal dimension, Df [1],
found when the clot fi rst forms to measures of mature clot fi rmness
obtained from thromboelastography. p
p
y
Methods Seventy-eight patients aged 15 to 59 (35.9 ± 1.62) with
laparoscopic gynecological operations were included in the research
after permission of the ethics committee and signing the informing
agreement. Total hemoglobin was detected by laboratory method
invasively, discretely and delayed. Total hemoglobin was detected by
another method oximetrically (SpHb) during the monitoring process
on the platform Rainbow SET technology noninvasive, continuous, and
promptly. SpHb was compared with total hemoglobin on the following
stages of the research: before the operation, during the operation and
in the early postoperative period. Statistical analysis was fulfi lled by
comparing real and tabular (critical) criteria of reliability – Student test. Results During the detection of total hemoglobin by the laboratory
method, the mean value was 121.5 ± 17.28 g/l, while oximetrically it
occurred 118.6 ± 17.41 g/l. The real criterion of reliability (tr) was 0.85,
the critical criterion of reliability (tcr) was 2.63.if y
Methods Forty healthy blood samples were obtained; each sample
was allocated a random dilution ratio (10%, 20%, 40%, 60%) and
diluted with gelofusine. These were matched with 40 healthy samples
that were undiluted. Reference 1. Evans P, et al.: Blood 2010, 116:3341-3346. 8
Use of coagulation screening in the critical care unit
A Rice, R Paterson, C Cairns
Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P428 (doi: 10.1186/cc11035) Introduction The aim of this audit is to compare the eff ectiveness of
indiscriminate coagulation testing versus selective testing based on
clinical indications within the HDU setting. Coagulation tests (PT and
APTT) are often taken as a matter of routine alongside patient’s daily
blood tests in the critical care setting. Abnormal coagulation results
rarely alter patient management while repeated testing has signifi cant
detrimental fi nancial implications. Reference Templating eff ect of clot structure can predict clot
development and outcome in diluted blood: a comparison with
thromboelastography An oscillatory shear technique was applied to the
blood using an AR-G2 measuring Df (clot structure). Additionally the clot
development in terms of fi rmness was measured using a ROTEM analyser
measuring at 5, 10, 15 minutes and its maximum (A5, A10, A15, MCF).i Results Df signifi cantly decreases with increasing dilution. The decrease
in structural complexity indicates that gelofusine even at 40% dilution
is producing poor quality clots. See Table 1. Table 1 (abstract P429). Change in Df with dilution
Dilution %
Df
0
1.74 (0.05)
10
1.72 (0.04)
20
1.70 (0.06)
40*
1.63 (0.05)
60*
1.59 (0.06)
*Signifi cant decrease from 0%. Table 1 (abstract P429). Change in Df with dilution Conclusion We did not discover statistically signifi cant diff erences
of total hemoglobin determined by two diff erent methods. Thereby,
noninvasive monitoring of total hemoglobin contention using
multiwave spectrophotometry by Masimo Rainbow SET technology
can serve as an appropriate replacement for the laboratory screening
of hemoglobin. Conclusion Df that is measured at the incipient clot is found much
sooner than the mature clot parameters, between 5 and 30 minutes
earlier. Df is signifi cantly correlated (P <0.05) with the mature clot
parameters of clot fi rmness (A5, A10, A15 and MCF) and elasticity
(G’max). This suggests that in dilution Df can determine the eventual clot
outcome very early. Measurement of Df could guide fl uid replacement
and component therapy more accurately and earlier than conventional
markers. P428 P428
Use of coagulation screening in the critical care unit
A Rice, R Paterson, C Cairns
Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P428 (doi: 10.1186/cc11035) Using angiogenic factors and their soluble receptors to predict
organ dysfunction in patients with disseminated intravascular
coagulation associated with severe trauma T Wada1, S Jesmin2, S Gando3, S Zaedi2, H Yokota1 ,
,
,
,
1Nippon Medical School, Tokyo, Japan; 2National Center for Global Health
and Medicine, Tokyo, Japan; 3Hokkaido University Graduate School of
Medicine, Sapporo, Japan
Critical Care 2012, 16(Suppl 1):P425 (doi: 10.1186/cc11032) ,
,
,
,
1Nippon Medical School, Tokyo, Japan; 2National Center for Global Health
and Medicine, Tokyo, Japan; 3Hokkaido University Graduate School of
Medicine, Sapporo, Japan
Critical Care 2012, 16(Suppl 1):P425 (doi: 10.1186/cc11032) Introduction Disseminated intravascular coagulation (DIC) is observed
after not only sepsis but also trauma. DIC is associated with concomitant
activation of coagulofi brinolytic disorder and systemic infl ammation
with endothelial dysfunction and microvascular permeability. The
angiogenic factors, including vascular endothelial growth factor
(VEGF), angiopoietin (Ang), and their receptors, play crucial roles in
angiogenesis and microvascular permeability. The aim of the study was
to assess: the relationship between angiogenic factors, their soluble
receptors and organ dysfunction associated with DIC precipitated by
severe trauma; and the eff ects of DIC-induced platelet consumption,
thrombin generation and tissue hypoxia on the expression of these
factors and receptors. Conclusion Our BSB could easily be implemented and was able to
reduce diagnostic blood loss by 65%. After introduction of the BSB
we observed less transfusions and a shorter ICU stay in mechanically
ventilated patients; this, however, has to be interpreted with caution
due to the longitudinal study design. S153 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P427
Comparative assessment of invasive and noninvasive methods for
detection of total hemoglobin in gynecological patients’ blood
AV Pyregov, SV Petrov
Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
Critical Care 2012, 16(Suppl 1):P427 (doi: 10.1186/cc11034) P427 P429 Templating eff ect of clot structure can predict clot
development and outcome in diluted blood: a comparison with
thromboelastography Templating eff ect of clot structure can predict clot
development and outcome in diluted blood: a comparison with
thromboelastography
M Lawrence1, J Kaczynski2, S Stanford1, R Morris3, P Evans2
1Swansea University, Swansea, UK; 2ABMU LHB, Swansea, UK; 3UWIC, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P429 (doi: 10.1186/cc11036) P432 3
Thromboelastography (platelet contribution to clot strength) for
the assessment of platelet residual function
D Haxhiademi1, S Parri1, A Cerillo1, P Del Sarto1, R Paniccia2, D Prisco2
1Fondazione Toscana G. Monasterio, Massa, Italy; 2Thrombosis Centre,
University of Florence, Italy
Critical Care 2012, 16(Suppl 1):P432 (doi: 10.1186/cc11039) Thromboelastography (platelet contribution to clot strength) for
the assessment of platelet residual function
D Haxhiademi1, S Parri1, A Cerillo1, P Del Sarto1, R Paniccia2, D Prisco2
1Fondazione Toscana G. Monasterio, Massa, Italy; 2Thrombosis Centre,
University of Florence, Italy
Critical Care 2012, 16(Suppl 1):P432 (doi: 10.1186/cc11039) P430 Methods Rheometry and confocal laser scanning microscopy (CLSM)
were used to monitor and image the formation of fi brin clots. Clotting
was initiated by the addition of diff erent levels of thrombin to solutions
of a fi xed concentration of fi brinogen. Each sample was divided into
two aliquots; one added to the measuring geometry of an AR-G2
rheometer and one to the microscope slide for the spinning disk CLSM
(Olympus IX71). Results The micrographs of formed clots (Figure 1) show marked
qualitative diff erences in clot architecture. Upon increasing the
available thrombin, the clot network (visually) appears more dense. Table 1 shows the value of the structural biomarker, the fractal dimen-
sion, that corresponds to the clots formed in Figure 1. Conclusion We demonstrate, for the fi rst time, that the fractal dimen-
sion obtained by rheometry is a sensitive measure of visually observed
structural diff erences within the fi brin network. Rheometrical detection
of incipient clots formed in whole blood provides the clinician with a
powerful tool for the diagnosis of thromboembolic disease. Reference
1. Scott et al.: Arterioscler Thromb Vasc Biol 2004, 2:1558-1566. P432
Thromboelastography (platelet contribution to clot strength) for
the assessment of platelet residual function
D Haxhiademi1, S Parri1, A Cerillo1, P Del Sarto1, R Paniccia2, D Prisco2
1Fondazione Toscana G. Monasterio, Massa, Italy; 2Thrombosis Centre,
University of Florence, Italy
Critical Care 2012, 16(Suppl 1):P432 (doi: 10.1186/cc11039)
Introduction In the early postoperative period after cardiac surgery,
platelet dysfunction is one of the main causes of excessive bleeding;
there is still controversy regarding the timing of antiplatelet therapy
Table 1 (abstract P431). Results of the fractal dimension obtained by
rheometry of fi brin clots
Thrombin (NIH)
Fractal dimension
0.02
1.85
0.1
1.95
0.3
2.13 Table 1 (abstract P430)
Mean Df
Mean MCF (mm)
Pre enoxaparin
1.79 ± 0.08
68.0 ± 8.0
Post enoxaparin
1.64 ± 0.10
64.3 ± 4.2
Figure 1 (abstract P430). Table 1 (abstract P430)
Mean Df
Mean MCF (mm)
Pre enoxaparin
1.79 ± 0.08
68.0 ± 8.0
Post enoxaparin
1.64 ± 0.10
64.3 ± 4.2
Figure 1 (abstract P430). Table 1 (abstract P431). Results of the fractal dimension obtained by
rheometry of fi brin clots
Thrombin (NIH)
Fractal dimension
0.02
1.85
0.1
1.95
0.3
2.13 Table 1 (abstract P431). Results of the fractal dimension obtained by
rheometry of fi brin clots Figure 1 (abstract P430). y
References 1. Evans PA, et al.: Blood 2010, 116:3341-3346. 2. Levi M, Opal SM: Crit Care 2006, 10:222. P430 architecture with several diseases including sepsis, bleeding or
acute thromboembolic disease [1]. We investigate our biomarker by
examining the relationship between thrombin generation and clot
architecture in an in vitro model. Methods Rheometry and confocal laser scanning microscopy (CLSM)
were used to monitor and image the formation of fi brin clots. Clotting
was initiated by the addition of diff erent levels of thrombin to solutions
of a fi xed concentration of fi brinogen. Each sample was divided into
two aliquots; one added to the measuring geometry of an AR-G2
rheometer and one to the microscope slide for the spinning disk CLSM
(Olympus IX71). y
p
Results The micrographs of formed clots (Figure 1) show marked
qualitative diff erences in clot architecture. Upon increasing the
available thrombin, the clot network (visually) appears more dense. Table 1 shows the value of the structural biomarker, the fractal dimen-
sion, that corresponds to the clots formed in Figure 1.i Figure 1 (abstract P430). admission, at 6 hours and 24 hours to assess pathophysiological state
and progression. Twelve patients were recruited: nine severe sepsis and
three severe DKA with metabolic disorder. Twelve healthy volunteers
were recruited as a matched control. Conclusion We demonstrate, for the fi rst time, that the fractal dimen-
sion obtained by rheometry is a sensitive measure of visually observed
structural diff erences within the fi brin network. Rheometrical detection
of incipient clots formed in whole blood provides the clinician with a
powerful tool for the diagnosis of thromboembolic disease. Reference Results Mean Df in the control group was 1.73 ± 0.03 whereas mean
Df in DKA and sepsis was found to be 1.77 ± 0.07 and 1.65 ± 0.05
respectively. Marked diff erences were observed in Df and maximum
clot fi rmness (MCF) in response to treatment intervention (Figure 1). Furthermore, patients saw a dramatic decrease in Df post enoxaparin,
but no signifi cant change in MCF was observed (Table 1). 1. Scott et al.: Arterioscler Thromb Vasc Biol 2004, 2:1558-1566. gi
g
Conclusion Df shows specifi city between severe DKA and sepsis. Df
shows sensitivity to treatment intervention and illness progression in
the critically ill. P432 P430 i
p
Methods Over a 14-day period, the blood results of HDU patients were
prospectively analysed in order to assess whether or not a coagulation
screen was conducted and whether or not this was appropriate based
on clinical indications. Following targeted education towards medical
and nursing staff , including publicising a list of clinical indications
within the unit, the audit cycle was repeated. y
p
Results Prior to education, only 37% of coagulation screens were
clinically indicated. Following implementation of the indications
this rose to 50%. Using the guidelines in the second round there was
100% identifi cation of abnormal results compared to only 81% prior
to education. On review of all these data we were able to extrapolate
that prior to targeted education there was a 2:1 ratio of appropriate
to inappropriate coagulation testing, post intervention this rose to 5:1. Conclusion With local targeted education of staff we signifi cantly
reduced the number of inappropriate coagulation tests undertaken
within our unit from 65% to 27%. Along with this we had a 100%
detection rate for abnormal results using our list of clinical indications
for testing. In our high turnover critical care unit this would indicate
potential savings of around £10,000 per annum; a signifi cant amount
in an organisation with longstanding fi nancial constraints. Introduction Recent research [1] has highlighted a novel new biomarker
of haemostasis: the fractal dimension (Df). This new biomarker relates
the kinetics of clot formation to clot outcome in whole blood and allows
us to quantify the complexity of the fi brin network microstructure
which is believed to be the template for development of the mature
clot. It is well established that abnormalities in haemostasis contribute
to the pathogenicity of critical illness [2]. This prospective study aims
to assess the eff ect of critical illness on clot structure and monitor the
sensitivity of Df to therapeutic intervention. Methods Patients with critical illness inducing SIRS were recruited on
admission to the intensive therapy unit in a large teaching hospital
in Wales. Blood was taken for routine coagulation testing, ROTEM
thromboelastometry and rheological analysis (Df and Tgel) on S154 architecture with several diseases including sepsis, bleeding or
acute thromboembolic disease [1]. We investigate our biomarker by
examining the relationship between thrombin generation and clot
architecture in an in vitro model. References 1. Kauvar DS: Impact of haemorrhage on trauma outcome: an overview of
epidemiology clinical presentation and therapeutic considerations. J Trauma 2006, 60:S3-S11. 2. WHO: Injuries and Violence: Facts. Geneva, Switzerland: WHO; 2010. f
f 3. Dawn M, Mark D, Pasquale M, Thomas W: Impact of pre-injury warfarin use
in elderly trauma patients. J Trauma 2000, 48:3. 3. Dawn M, Mark D, Pasquale M, Thomas W: Impact of pre-injury warfarin use
in elderly trauma patients. J Trauma 2000, 48:3. 3. Dawn M, Mark D, Pasquale M, Thomas W: Impact of pre-injury warfarin use
in elderly trauma patients. J Trauma 2000, 48:3. P434 Retrospective comparison study of warfarinised trauma patients
and an age-matched control group of nonwarfarinised patients
M Omar, P Stevens, T Jenkins, K Morris, H Hussain, A Evans
Morriston Hospital, Swansea, UK
Critical Care 2012, 16(Suppl 1):P434 (doi: 10.1186/cc11041) Introduction There are several studies stating the association of
mortality between trauma and anticoagulation; however, it is diffi cult
to ascertain a credible conclusion due to the small number of data
and inconclusive results. Some studies have showed a signifi cant
increased risk of morbidity and mortality. We analysed retrospective
data of 45,798 trauma patients, out of which 254 were on warfarin. The incidence of death continues to rise and there are no specifi c
strategies to reduce haemodilution and coagulopathy which maybe
the underlying cause of mortality. Results There was no signifi cant association between bleeding at
4, 6 and 12 hours and any of the preoperative tests. There was no
signifi cant association between bleeding at 4, 6 and 12 hours and any
of the standard laboratory tests. Platelet contribution to clot strength
(%pltMA) detected by TEG showed a signifi cant association with
postoperative blood loss (at 4, 6 and 12 hours, respectively P = 0.02,
P = 0.02, P = 0.01). Methods A retrospective analysis of a national database collected in
2009 and 2010, from the Trauma Audit and Research Network (TARN)
UK. The data also contain vital information including age, Glasgow
Coma Scale (GSC), Injury Severity Score (ISS), INR, blood products
given, number of days in hospital and clinical outcome. We evaluated
trauma patients who were on warfarin therapy and compared their
clinical outcome and mortality to age-matched patients with similar
injuries not on warfarin. Conclusion Our data confi rm the utility of perioperative evaluation
of platelet contribution to clot strength evaluated by TEG. It helps to
understand the mechanism behind the surgical bleeding and reduce
empirical transfusions. References
1
Hartmann References
1. Hartmann M, et al.: Transfus Med Rev 2006, 20:230-241. 2. Ferraris V, et al.: Ann Thorac Surg 2011, 91:944-982. 3. Mousa SA, et al.: Thromb Res 2001, 104:49-56. 2. Ferraris V, et al.: Ann Thorac Surg 2011, 91:944-982. Results A total of 45,780 adult patients were analysed. These were
subdivided into 32,225 young patients under 65 years with median
age 60.5, of which 59 were on warfarin; and 13,555 older patients
aged over 65 with median age 80.4, of which 195 were on warfarin. The mortality rate in warfarinised patients was signifi cantly higher
than in the nonwarfarinised age-matched group aged <65 (5/59, 8.5%
vs. 1,223/32,163, 3.8%; P <0.001; 95% CI). The group age >65 included
13,555, of which 195 were warfarinised (4.7/195, 24.1% vs. 1,501/13,360,
11.3%; P <0.001; 95% CI). 3. Mousa SA, et al.: Thromb Res 2001, 104:49-56. Fractal dimension: a biomarker for detecting acute thromboembolic
disease Introduction In the early postoperative period after cardiac surgery,
platelet dysfunction is one of the main causes of excessive bleeding;
there is still controversy regarding the timing of antiplatelet therapy
discontinuation [1]. The Clinical Practice Guidelines of the Society of
Thoracic Surgeons recommend that point-of-care (POC) testing may
help identify patients who can safely undergo urgent operations [2]. This
study was designed to test the relationship between platelet function
as revealed by POC tests and postoperative bleeding in patients that
undergo cardiac surgery without suspending thienopyridines at least
5 days prior to surgery. K Hawkins1, N Badiei1, J Weisel2, I Chernysh2, PR Williams1, MJ Lawrence1,
PA Evans1 1Swansea University, Swansea, UK; 2University of Pennsylvania, Philadelphia,
PA, USA Critical Care 2012, 16(Suppl 1):P431 (doi: 10.1186/cc11038) Introduction This study investigates the potential use of rheometry
to provide a structural biomarker for acute critical illness. Previous
studies have reported an association of altered fi brin clot network Figure 1 (abstract P431). CLSM micrographs of formed fi brin clots at thrombin levels of 0.02, 0.1 and 0.3 NIH. Figure 1 (abstract P431). CLSM micrographs of formed fi brin clots at thrombin levels of 0.02, 0.1 and 0.3 NIH. S155 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods Adult patients scheduled for cardiac operations in which
thienopyridines were not discontinued at least 5 days before surgery
were included. From November 2010 to February 2011, 20 patients
were enrolled in this pilot study. Samples were taken before induction
of anesthesia (T0) and 2 hours after arrival in the ICU (T1). Standard
laboratory tests and the following POCs were performed: multiple
electrode aggregometry (MEA), PFA 100 and thromboelastography (TEG). Functional fi brinogen level (FFL) is a recent modifi cation of TEG used to
investigate the function of fi brinogen [3]. We used the combination of
TEG and FFL to detect platelet contribution to the clot strength.i Measurement of hemoglobin in the operating room: what methods
can we trust?
B Giraud, D Frasca, O Mimoz
CHU La Milétrie Poitiers, France
Critical Care 2012, 16(Suppl 1):P433 (doi: 10.1186/cc11040) Conclusion This data analysis proves that mortality is signifi cantly
higher in warfarinised patients compared to the nonwarfarinised age-
matched group. Future research needs to focus on both developing
a practical procedure reducing risks of morbidity and mortality
by exploring coagulopathy and early correction of coagulations. Anticoagulated patients are more likely to receive aggressive i.v. fl uid resuscitations as the result of haemorrhage which leads to
haemodilution and further exacerbates coagulopathy. This cascade of
events is the underlying mechanism causative to mortality. References Introduction A noninvasive and continuous monitoring of total
hemoglobin (Hb) by spectrophotometry was recently marketed (SpHb;
Masimo, Irvine, CA, USA). The main objective of this study was to
determine the absolute and trend accuracy of SpHb compared to Hb assessment at the laboratory (HbLab) used as the reference method. Methods After obtaining ethics committee approval and informed
consent, 51 adult patients (29 men, 22 women, age 18 to 90 years)
undergoing major surgery with expected large blood loss were
enrolled in the study. Patients wore Rainbow adult resposable sensors
(R2–25, Revision E) connected to a Radical-7 Pulse CO-Oximeter,
software version 7.6.0.1. HbLab values were obtained by analyzing
arterial blood samples at the laboratory using a Sysmex XT-2100i
automated hematology analyzer (Roche Diagnostics, Paris, France). The same samples were also analyzed with a satellite laboratory CO-
Oximeter (Siemens RapidPoint 405 CO-Oximeter; Siemens, Munich,
Germany), HbSat, and a point-of-care hemoglobinometer (HemoCue,
Hb201; Ångelholm, Sweden), HcueArt. At the same time, a fourth drop
of blood after skin puncture on the ear or fi nger was taken for capillary
blood sampling tested also with the HemoCue: HcueCap. Invasive
Hb values were compared to Sphb obtained at the time of the blood
draw. An initial set was collected before surgery. Then blood samples
were taken on approximately an hourly basis or more often if clinically
indicated. Bland–Altman method plots were used to compare absolute
accuracy of test devices to laboratory values. The ability of the test
devices to follow the trend of the changes in Hb values reported by
the reference device was assessed by plotting the diff erence between
subsequent measurements reported by each device to the diff erence
in subsequent measurements reported by the reference device, and a
coeffi cient of determination (R2) was calculated. P436 Reducing ICU blood draws with artifi cial intelligence
FC Cismondi1, AS Fialho1, SM Vieira2, LA Celi1, SR Reti3, JM Sousa2,
SN Finkelstein1
1Massachusetts Institute of Technology, Cambridge, MA, USA; 2IST, Lisbon,
Portugal; 3BIDMC, Brookline, MA, USA
Critical Care 2012, 16(Suppl 1):P436 (doi: 10.1186/cc11043) Results The analysis of fi ndings showed both sepsis and pneumonia
development in an acute period of burn disease to be accompanied by
disorders of anticoagulant, fi brinolytic and procoagulant parts of the
hemostasis system typical for DIC syndrome. The changes of hemostasis
system indices were not only the characteristic of infection in burned
patients but they preceded the diagnosis of sepsis and pneumonia
in the clinic on average by 2 to 4 days. In patients with pneumonia,
relevant and statistically signifi cant were the activity changes of XIIa-
dependent fi brinolysis, from the second to sixth days. And on the
third to seventh days there was reliable pneumonia development
with decreased activity of antithrombin III. In patients with sepsis were
revealed changes of XIIa-dependent fi brinolysis activity – from the
third to seventh days – and antithrombin III activity – from the third to
the sixth days. Introduction Recent studies have demonstrated that frequent
laboratory testing does not necessarily relate to better outcomes. Our
aim is to reduce unnecessary blood draws for ICU laboratory tests by
predicting which tests are likely to return as normal or abnormal and
therefore infl uence clinical management around gastrointestinal (GI)
bleeding. Methods An artifi cial intelligence tool, namely fuzzy systems, was
applied to 1,092 GI bleed patients extracted from a large ICU database
with over 32,000 patients. A classifi cation approach for laboratory test
outcome was utilized for a total of seven outcome variables shown in
Table 1. The outcome for each test was binarized as normal or abnormal. Input variables included 10 physiological variables such as heart rate,
temperature and urine output, as well as further data on transfusions
for platelets, red blood cells and plasma.i y
Conclusion The development of both local and generalized infection in
an acute period of burn disease occurs against the background of DIC
syndrome induced by a serious heat injury. The indices of hemostasis
system can be included into a complex of clinic and laboratory studies
aimed at detecting infection and early intensive etiopathological
therapy. In medical–surgical ICU patients, major bleeding is common but
independent of heparin prophylaxis If
one could predict in advance whether a laboratory test would be normal
or abnormal then that particular laboratory test may not be ordered,
and thereby reducing potential complications and costs. In this work we
present an artifi cial intelligence method for the classifying the likelihood
of a blood test being normal or abnormal. Our results show acceptable
classifi cation accuracy both in terms of sensitivity and specifi city. Conclusion Reducing frequent laboratory testing, and potential
phlebotomy complications, is a major concern in critical care medicine. If
one could predict in advance whether a laboratory test would be normal
or abnormal then that particular laboratory test may not be ordered,
and thereby reducing potential complications and costs. In this work we
present an artifi cial intelligence method for the classifying the likelihood
of a blood test being normal or abnormal. Our results show acceptable
classifi cation accuracy both in terms of sensitivity and specifi city. site and severity of each bleeding event, which was reevaluated by two
independent blinded adjudicators. Patients with trauma, orthopedic
surgery or neurosurgery were excluded. Major bleeding was defi ned as
life threatening, occurring in critical sites, requiring ≥2 units of red blood
cells or an invasive intervention, or associated with an unexplained
decrease in systolic blood pressure (≥20 mmHg) or increase in heart
rate (≥20 beats/minute). We used Cox proportional hazard models
adjusting for age, APACHE II, reason for ICU admission, end-stage renal
disease, drugs aff ecting coagulation, coagulation parameters and life-
support interventions to identify predictors of bleeding. P437 y
Results Among 3,746 patients, 208 had major bleeding (5.6%, 95% CI
4.9 to 6.3%). The commonest bleeding sites were: gastrointestinal tract
(51.9%), surgical site (30.3%), respiratory tract (15.9%), retroperitoneal
(8.2%) and intracranial (3.4%). Independent predictors of major
bleeding (expressed as hazard ratio with 95% CI) were: prolonged
activated partial thromboplastin time (aPTT) (1.10, 1.05 to 1.14 per
10-second increase), thrombocytopenia (1.16, 1.09 to 1.24 per 50×109/l
decrease in platelet count), therapeutic heparin (3.26, 1.72 to 6.17), anti-
platelet agents (that is, acetylsalicylic acid and/or clopidogrel) (1.38,
1.02 to 1.88), renal replacement therapy (1.75, 1.20 to 2.56) and surgery
in the preceding 3 days (1.64, 1.01 to 2.65). Prophylactic dalteparin in
the preceding 3 days was not associated with bleeding. In medical–surgical ICU patients, major bleeding is common but
independent of heparin prophylaxis F Lauzier1, D Arnold2, C Rabbat2, D Heels-Ansdell2, P Dodek3, B Ashley3,
M Albert4, K Khwaja5, M Ostermann6, Y Skrobik4, R Fowler7, L McIntyre8,
J Nates9, T Karachi2, R Lopes10, N Zytaruk2, M Crowther2, D Cook2
1CHA-Hôpital de l’Enfant-Jésus, Université Laval, Québec, Canada; 2McMaster
University, Hamilton, Canada; 3University of British Columbia, Vancouver,
Canada; 4Université de Montréal, Canada; 5Université McGill, Montréal,
Canada; 6King’s College London, UK; 7University of Toronto, Canada;
8Université d’Ottawa, Canada; 9MD Anderson Hospital, Houston, TX, USA;
10Duke Clinical Research Institute, Durham, NC, USA fi
(
)
Results The study included 210 measurements. HbLab ranged between
6.8 and 16.3 g/dl. Compared to the reference method, the average bias
was 0.96 ± 2.78 g/dl for SpHb, 0.16 ± 0.45 g/dl for HcueArt, 0.5 ± 1.71
g/dl for HcueCap and 0.81 ± 1.04 g/dl for HbSat. R2 values were 0.39 for
SpHb, 0.93 for HcueArt, 0.53 for HcueCap and 0.47 for HbSat. Conclusion This study shows that HcueArt seem the most reliable
method of Hb assessment. The SpHb has a lower accuracy, but its ability
to monitor Hb continuously and noninvasively remains attractive and
development of this method should be encouraged. Critical Care 2012, 16(Suppl 1):P435 (doi: 10.1186/cc11042) Results The study included 210 measurements. HbLab ranged between
6.8 and 16.3 g/dl. Compared to the reference method, the average bias
was 0.96 ± 2.78 g/dl for SpHb, 0.16 ± 0.45 g/dl for HcueArt, 0.5 ± 1.71
g/dl for HcueCap and 0.81 ± 1.04 g/dl for HbSat. R2 values were 0.39 for
SpHb, 0.93 for HcueArt, 0.53 for HcueCap and 0.47 for HbSat. Introduction Bleeding frequently complicates critical illness. Our
objec tives were to describe the incidence, locations and predictors
of major bleeding in patients with low risk of bleeding receiving
thromboprophylaxis. Conclusion This study shows that HcueArt seem the most reliable
method of Hb assessment. The SpHb has a lower accuracy, but its ability
to monitor Hb continuously and noninvasively remains attractive and
development of this method should be encouraged. p
p y
Methods In the PROTECT trial comparing dalteparin to unfractionated
heparin for thromboprophylaxis in medical–surgical ICU patients,
research coordinators used a validated ICU-specifi c tool to describe the S156 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion Reducing frequent laboratory testing, and potential
phlebotomy complications, is a major concern in critical care medicine. Hemostasis system condition in infectious complication
development in severe burned patients Infectious septic complications were diagnosed
in the clinic on the basis of clinical and laboratory fi ndings, as well
as confi rmed by morphological studies in casualties (44 from 102
patients). Diagnosis of disseminated intravascular coagulation (DIC)
syndrome was made based on standard criteria. P436 Results Classifi cation accuracy of greater than 80% was achieved for
all of the seven outcome variables (Table 1). Sensitivity and specifi city
were satisfactory for all the outcomes. Input variables frequently
selected as most predictive of normal or abnormal results include urine
output and red blood cell transfusion. Table 1 (abstract P436). Classifi cation results
Outcome
ACC (%)
Sensitivity
Specifi city
Calcium
85 ± 2.3
0.88 ± 0.3
0.81 ± 0.1
PTT
86 ± 1.2
0.89 ± 0.1
0.82 ± 0.2
Hematocrit
82 ± 1.6
0.84 ± 0.2
0.78 ± 0.1
Fibrinogen
84 ± 2.8
0.87 ± 0.3
0.80 ± 0.4
Lactate
80 ± 2.2
0.82 ± 0.2
0.77 ± 0.4
Platelets
88 ± 1.3
0.90 ± 0.1
0.85 ± 0.2
Hemoglobin
84 ± 3.1
0.85 ± 0.3
0.81 ± 0.2
ACC, accuracy of classifi cation. Table 1 (abstract P436). Classifi cation results Table 1 (abstract P436). Classifi cation results
Outcome
ACC (%)
Sensitivity
Specifi city
Calcium
85 ± 2.3
0.88 ± 0.3
0.81 ± 0.1
PTT
86 ± 1.2
0.89 ± 0.1
0.82 ± 0.2
Hematocrit
82 ± 1.6
0.84 ± 0.2
0.78 ± 0.1
Fibrinogen
84 ± 2.8
0.87 ± 0.3
0.80 ± 0.4
Lactate
80 ± 2.2
0.82 ± 0.2
0.77 ± 0.4
Platelets
88 ± 1.3
0.90 ± 0.1
0.85 ± 0.2
Hemoglobin
84 ± 3.1
0.85 ± 0.3
0.81 ± 0.2
ACC, accuracy of classifi cation. P438
Randomized comparison of fi brinogen concentrate versus
cryoprecipitate for bleeding control in pediatric cardiac surgery
(FICCS study)
F Galas1, L Hajjar1, B Sorensen2, J Almeida1, M Sundin1, V Guimaraes1,
S Zeff erino1, L Camara1, F Maua1, M Moreira1, C Puttini1, M Carmona1,
J Auler Jr1, R Nakamura1
1Heart Institute, São Paulo, Brazil; 2Guy’s and St Thomas’ NHS Foundation
Trust & King’s College London School of Medicine, London, UK
Critical Care 2012, 16(Suppl 1):P438 (doi: 10.1186/cc11045)
Introduction We compared hemostatic outcomes after treatment with
fi brinogen concentrate or cryoprecipitate in pediatric cardiac surgery
patients with intraoperative bleeding. Hemostasis system condition in infectious complication
development in severe burned patients Introduction Over the period of the history of combustiology one of
the main problems for treatment of patients with burns is infection,
both local – bacterial pneumonia – and generalized – sepsis –
characterized by extremely severe course, complex diagnostics
and high lethality rate. However, the role of hemostasis disorders in
infectious complication development in severe burned patients is
taken into consideration insuffi ciently. The aim of the study is to reveal
the most relevant hemostasis system changes in sepsis and pneumonia
in patients with serious heat injury in an acute period of burn disease. Methods Hemostasis and biochemical blood parameters were studied
in 169 patients with over 20% of the body burned, from the fi rst to
12th days after burn. Sepsis developed in 33 patients, 69 patients had
pneumonia, and in 67 patients there were no complications of sepsis
and pneumonia. Infectious septic complications were diagnosed
in the clinic on the basis of clinical and laboratory fi ndings, as well
as confi rmed by morphological studies in casualties (44 from 102
patients). Diagnosis of disseminated intravascular coagulation (DIC)
syndrome was made based on standard criteria.i Introduction Over the period of the history of combustiology one of
the main problems for treatment of patients with burns is infection,
both local – bacterial pneumonia – and generalized – sepsis –
characterized by extremely severe course, complex diagnostics
and high lethality rate. However, the role of hemostasis disorders in
infectious complication development in severe burned patients is
taken into consideration insuffi ciently. The aim of the study is to reveal
the most relevant hemostasis system changes in sepsis and pneumonia
in patients with serious heat injury in an acute period of burn disease. Conclusion Major bleeding occurred in 5.6% of medical–surgical ICU
patients. Prolonged aPTT, thrombocytopenia, therapeutic (but not
prophylactic) heparin, anti-platelet agents and recent surgery are
potentially modifi able and independent predictors of bleeding. in patients with serious heat injury in an acute period of burn disease. Methods Hemostasis and biochemical blood parameters were studied
in 169 patients with over 20% of the body burned, from the fi rst to
12th days after burn. Sepsis developed in 33 patients, 69 patients had
pneumonia, and in 67 patients there were no complications of sepsis
and pneumonia. P440 Reduced EPO receptor expression may contribute to limited
pleiotropic eff ects of EPO during critical illness
O McCook, S Matějková, J Matallo, A Scheuerle, P Moeller, M Georgieff ,
E Calzia, P Radermacher, H Schelzig
University Medical School Ulm, Germany
Critical Care 2012, 16(Suppl 1):P440 (doi: 10.1186/cc11047) Introduction We showed neuroprotective and renoprotective eff ects
of recombinant human erythropoietin (rhEPO) after kidney and spinal
cord ischemia/reperfusion (I/R) injury [1,2], but clinical studies using
rhEPO to prevent acute kidney injury yielded equivocal results [3,4]. Increased cytokine release and/or oxidative stress can cause EPO
resistance due to receptor modifi cation and/or downregulation [5]. Since we recently failed to confi rm rhEPO-related kidney protection in
atherosclerotic swine [6], we compared kidney EPO receptor expression
in swine strains with and without pre-existing vascular disease and
kidney dysfunction. g
Results Sixty-three patients (fi brinogen concentrate: 30; cryoprecipitate:
33) completed the study. The median age was 3 years 5 months and
the median weight was 6.7 kg. Median fi brinogen doses were 504
mg (fi brinogen concentrate) and 402 mg (cryoprecipitate). Plasma
fi brinogen concentrations increased after study medication and were
similar in the two groups. No signifi cant between-group diff erences
were observed in PT, aPTT or platelet count. In both groups, all ROTEM
parameters showed signifi cant improvement after study medication,
with no clinically relevant between-group diff erences in any of the
EXTEM, INTEM or FIBTEM clotting parameters. Total avoidance of
allogeneic blood product transfusion was achieved in 70% of patients
in the fi brinogen concentrate group versus 18.2% in the cryoprecipitate
group (P <0.001). The mean bleeding mass was signifi cantly lower in
the fi brinogen concentrate group than in the cryoprecipitate group
after 30 minutes. The thorax was opened after study medication in zero
patients (0%) in the fi brinogen concentrate group and in six patients
(18.2%) in the cryoprecipitate group (P = 0.025). y y
Methods EPO receptor expression was quantifi ed with immunohisto-
chemistry (densitometric image analysis) of formalin-fi xed paraffi n
sections from pre-injury kidney biopsies taken in young and healthy
pigs (German Landrace, up to now n = 4) as well as swine (FBM strain,
up to now n = 6) with familial hypercholesteremia (11.1 (7.4; 12.3) vs. 1.4 (1.3; 1.5) mmol/l, P <0.001, n = 20 and 15, respectively, P <0.001) and
consecutive, diet-induced atherosclerosis [7]. P441 Recognition and management of haemophagocytic
lymphohistiocytosis on the ICU: a case series
R Baumber, B Agarwal, M Carrington
Royal Free Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P441 (doi: 10.1186/cc11048) Recognition and management of haemophagocytic
lymphohistiocytosis on the ICU: a case series
R Baumber, B Agarwal, M Carrington
Royal Free Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P441 (doi: 10.1186/cc11048) y
p
y
R Baumber, B Agarwal, M Carrington Methods We performed a randomized, double-blind study in 37
patients who underwent cesarean section. Patients were divided into
two groups: the fi rst group (n = 19) received preoperative (30 minutes
before operation) tranexamic acid 10 mg/kg; the second group (n = 18)
received preoperative placebo. The condition of hemostasis was
monitored by haemoviscoelastography. Introduction Haemophagocytic lymphohistiocytosis (HLH) is a rare
haematological condition, with a reported incidence of the familial
variety of the disease being 1.2 cases per 10,000 children per year. The acquired form of HLH predominantly aff ects adults and is almost
always precipitated by infection, with Epstein–Barr virus (EBV) being
the commonest trigger. This results in abnormal activation and
proliferation of histiocytes and macrophages. Widespread phagocytosis
of blood cell components leads cytopenias, a strong proinfl ammatory
response and cytokine release leading to tissue necrosis and multiple
organ failure. A large majority of these patients will present to the ICU
for organ support and the aim of this report is to provide an update on
HLH and raise awareness of this rare condition amongst the critical care
community. Results All patients included in the study before the surgery had
moderate hypercoagulation and normal fi brinolysis: increasing of the
intensity of clot formation (ICF) to 11.4% compared to normal rates;
the intensity of the retraction and clot lysis (IRCL) was 16.45 ± 1.40 in
both groups. At the start of the operation in patients (group 1) – ICF
decreased 9.7% (P <0.05), and IRCL decreased 27.6% (P <0.05) compared
with preoperatively. In group 2, ICF decreased 8.8% (P <0.05), and IRCL
increased 11.4% (P <0.05) compared with preoperatively. At the end of
the operation, the condition of hemostasis in both groups came almost
to the same value – moderate hypocoagulation, depressed fi brinolysis. In both groups there were no thrombotic complications. P440 Results Atherosclerotic swine presented with reduced glomerular
fi ltration rate (creatinine clearance 76 (60; 83) vs. 103 (79; 120) ml/
minute, n = 19 each, P = 0.004) and chronic histological kidney injury
(dilatation of Bowman’s space, swelling of Bowman’s capsule, tubular
dilatation and necrosis). EPO receptor expression was reduced by
nearly two orders of magnitude in this strain (94.6 (8.3; 112.5)×107 vs. 1.7 (0.0; 4.7) ×107 densitometric units, P = 0.010). Conclusion Fibrinogen concentrate raised fi brinogen levels and
improved coagulation measures to a similar degree as cryoprecipitate. Bleeding and transfusion of allogeneic blood products were lower in
the fi brinogen concentrate group. Fibrinogen concentrate may be a
valuable option for controlling bleeding and avoiding transfusion in
cardiac surgery. Conclusion Even pretreatment with rhEPO did not infl uence I/R-
induced acute kidney in swine with pre-existing impairment of kidney
function and histological damage. The lacking benefi cial eff ect of
rhEPO was most likely due to the reduced expression of the EPO
receptor, which may also explain contradictory results in clinical trials
due to the frequent underlying kidney disease in the patients recruited. References 1. Simon F, et al.: Crit Care Med 2008, 36:2143-2150. 2. Simon F, et al.: Intensive Care Med 2011, 37:1525-1533. 3. Song YS, et al.: Am J Nephrol 2009, 30:253-260. 4. Endre ZH, et al.: Kidney Int 2010, 77:1020-1030. 5. van der Putten K, et al.: Nat Clin Pract Nephrol 2008, 4:47-57. 6. Simon F, et al.: Shock 2011, 36(Suppl 1):S24. 7. Thim T: Dan Med Bull 2010, 57:B4161. 1. Simon F, et al.: Crit Care Med 2008, 36:2143-2150. 2. Simon F, et al.: Intensive Care Med 2011, 37:1525-1533. P439
Effi cacy of tranexamic acid in decreasing blood loss during cesarean
section
O Tarabrin, V Kaminskiy, S Galich, R Tkachenko, A Gulyaev, S Shcherbakov,
D Gavrychenko
Odessa National Medical University, Odessa, Ukraine
Critical Care 2012, 16(Suppl 1):P439 (doi: 10.1186/cc11046) 7. Thim T: Dan Med Bull 2010, 57:B4161. Introduction Despite signifi cant progress in obstetric care, the problem
of bleeding during labor remains unfi nished. Annually in the world
125,000 women die from obstetric hemorrhage. Introduction Despite signifi cant progress in obstetric care, the problem
of bleeding during labor remains unfi nished. Annually in the world
125,000 women die from obstetric hemorrhage. P438 S157 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Methods This was a single-center, randomized, open-label study. Key inclusion criteria were age <15 years, cardiac surgery involving
cardiopulmonary bypass, intraoperative bleeding after neutralization
of heparin, and hypofi brinogenemia. Patients received fi brinogen
concentrate (60 mg/kg body weight; Haemocomplettan® P) or cryo-
precipitate (10 ml/kg body weight). After study medication, allogeneic
blood products were administered as required. Blood samples taken
immediately before randomization and 1, 24 and 48 hours after study
medication were subjected to laboratory and thromboelastometry
(ROTEM) coagulation tests.i No impact of a massive transfusion protocol on coagulopathy and
mortality at a level 1 trauma center: why? C Bourassa-Fulop, J Chauny, J Paquet, R Daoust, E Notebaert
Hôpital Sacré-Coeur, Montreal, Canada
Critical Care 2012, 16(Suppl 1):P444 (doi: 10.1186/cc11051) Introduction Blood transfusion is associated with worse outcome in
critically ill patients. A restrictive strategy of blood transfusion has been
advocated in patients undergoing cardiac surgery in order to avoid clinical
complications related to exposure to blood components. Nevertheless,
the blood transfusion rate remains elevated in clinical practice. Introduction In 2010 we studied the mortality and coagulopathy of all
massively transfused patients at our hospital since 2004. We compared
those who were transfused before the implementation of our massive
transfusion protocol (MTP) (from 2004 to 2006) to those transfused
with MTP. We found that our MTP did not lower mortality (35.7%)
and our incidence of coagulopathy was high (72.6%). The aim of the
present study is to explain those results, while concentrating uniquely
on trauma patients. Methods We performed a retrospective study with 750 patients
undergoing elective coronary arterial graft bypass (CABG) surgery,
valvar surgery or combined procedure under cardiopulmonary
bypass (CPB) between October 2010 and October 2011 at a university
hospital cardiac surgery referral center in Brazil. We collected baseline
characteristics and preoperative laboratory data, EuroSCORE, type of
surgical procedure, intraoperative characteristics, blood transfusion
exposure, postoperative severe complication as bleeding, low output
cardiac syndrome, vasoplegia syndrome, myocardial ischemia, stroke,
ventricular or supraventricular tachyarrhythmia, respiratory failure,
acute renal failure, infection, ICU length of stay, hospital length of stay
and mortality in 30 days. Methods We conducted a retrospective nested case–control study
from our trauma registry. We included trauma patients who received 10
packed red blood cells (pRBC) or more in 24 hours and excluded those
who died within the very fi rst hours of massive trauma. We extracted
supplementary demographic and clinical data from the laboratory
database and the hospital fi les. Chi-square tests and multivariate logistic
regression were used to compare the eff ect of the two approaches
(MTP vs. non-MTP) on mortality and coagulopathy, defi ned as an INR
≥1.8, a PTT ≥54, a fi brinogen <1 g/l or a platelet count <50,000, while
controlling for acidosis (defi ned as a pH ≤7.1), hypothermia (defi ned as
≤35°C) and Injury Severity Score (ISS) (critically injured if ISS ≥30). y
y
Results A total of 512 patients (68.4%) was exposed to blood transfusion
components. Red blood transfusion is a predictor of poor outcome in pediatric
cardiac surgery Results Twenty-four patients were identifi ed with a diagnosis of HLH,
18 males and six females, with mean age 42.6 years. A history of prior
haematological malignancy, HIV infection and immunosuppressive
therapy was present in six, fi ve and four patients respectively; no
underlying medical condition was found in 5/24 patients. Infective
causes were identifi ed in 15/24 patients, EBV in eight out of 15. Other infective causes were Cytomegalovirus, Toxoplasma gonadii,
Mycobacterium tuberculosis and Schistosomiasis. All patients were
pancytopenic at ICU admission and had signifi cantly elevated serum
ferritin (15,771 ± 17,718) and triglyceride (3.8 ± 2.05) levels. Eleven
out of 24 patients displayed features of acute liver involvement. Mean
APACHE II score was 20.5 ± 5.1 and mean SAPS II was 51.3 ± 12.1. Ten
out of 24 survived to ICU discharge, and 6/24 (25%) were alive at the
time of hospital discharge. The survivors had lower APACHE and SAPS
scores, and were associated with a non-EBV infection and a lower
incidence of liver involvement. C Colognesi, R Maia, L Hajjar, F Galas
Heart Institute, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P443 (doi: 10.1186/cc11050) Introduction Red blood cell transfusion is associated with morbidity
and mortality among adults undergoing cardiac surgery. We aimed
to evaluate the association of transfusion with morbidity in pediatric
cardiac surgical patients. The purpose of this study was to assess
whether red blood cell transfusions result in worse outcomes after
cardiac surgery in pediatric patients. g
y
Methods We studied an observational and prospective cohort of 200
patients undergoing cardiac surgery for congenital heart disease. We recorded baseline characteristics, RACHS-1 score, intraoperative
data, cardiopulmonary bypass length, type of surgery, transfusion
requirement and postoperative complications as need for reoperation,
time of mechanical ventilation, cardiovascular complications, acute
renal failure, infection, readmission at ICU and death during 28 days. Results One hundred and twenty-four patients were exposed to blood
components. Seventy-seven percent of patients presented at least
one major complication. There was no diff erence between transfused
and nontransfused patients regarding baseline or intraoperative
characteristics. Transfused patients presented a higher incidence of
major complications than nontransfused patients (93.5% vs. 54.5%,
P = 0.002). In a multivariate analysis, red blood cell transfusion was an
independent risk factor for clinical complications including death in
28 days (OR = 2.2 (95% CI 1.4 to 23.4)). P443 variables, HLH disease characteristics, acute physiological derangement
(APACHE II and SAPS II), and outcome. 1.
Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al.:
Transfusion requirements after cardiac surgery: the TRACS randomized
controlled trial. JAMA 2010, 304:1559-1567. Red blood transfusion is a predictor of poor outcome in pediatric
cardiac surgery Conclusion HLH is a rare but fatal haematological syndrome that
in its acquired form may present to ICU clinicians for organ support. Diagnosis of HLH in the intensive care setting may be diffi cult because
sepsis may cause similar clinical and laboratory abnormalities. Presence
of more severe acute physiological derangement, EBV aetiology and
features of liver failure portend a poor prognosis in HLH. g
y
Results One hundred and twenty-four patients were exposed to blood
components. Seventy-seven percent of patients presented at least
one major complication. There was no diff erence between transfused
and nontransfused patients regarding baseline or intraoperative
characteristics. Transfused patients presented a higher incidence of
major complications than nontransfused patients (93.5% vs. 54.5%,
P = 0.002). In a multivariate analysis, red blood cell transfusion was an
independent risk factor for clinical complications including death in
28 days (OR = 2.2 (95% CI 1.4 to 23.4)). 1. Henter JI, et al.: HLH 2004: diagnostic and therapeutic guidelines for
haemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007,
48:124-131. Conclusion Blood transfusion after pediatric cardiac surgery is a risk
factor for worse outcome. Avoiding blood transfusion may reduce
mortality in this population. Blood transfusion is an independent predicting factor for poor
outcome after cardiac surgery
J Almeida, S Zeferino, F Galas, J Fukushima, L Camara, M Lima, T Santos,
M Ferreira, J Auler Jr, R Kalil Filho, L Hajjar
Heart Institute, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P442 (doi: 10.1186/cc11049) g
y
J Almeida, S Zeferino, F Galas, J Fukushima, L Camara, M Lima, T Santos,
M Ferreira, J Auler Jr, R Kalil Filho, L Hajjar
Heart Institute, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P442 (doi: 10.1186/cc11049) P441 Intraoperative
blood loss in the fi rst group was 300 ± 40.5 and in the second was
500 ± 60.6.i Methods A single-centre retrospective review of case records of all
patients admitted to our ICU, in a tertiary haematology referral centre,
in the last 5 years with a confi rmed or suspected diagnosis of HLH,
based on HLH-2004 guidelines. Data were collected on demographic Conclusion Using tranexamic acid before surgery signifi cantly reduces
intraoperative blood loss by 40%, without thrombotic complications. S158 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P442 Blood transfusion is an independent predicting factor for poor
outcome after cardiac surgery
J Almeida, S Zeferino, F Galas, J Fukushima, L Camara, M Lima, T Santos,
M Ferreira, J Auler Jr, R Kalil Filho, L Hajjar
Heart Institute, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P442 (doi: 10.1186/cc11049) P444 No impact of a massive transfusion protocol on coagulopathy and
mortality at a level 1 trauma center: why? C Bourassa-Fulop, J Chauny, J Paquet, R Daoust, E Notebaert
Hôpital Sacré-Coeur, Montreal, Canada
Critical Care 2012, 16(Suppl 1):P444 (doi: 10.1186/cc11051) Massive transfusion practice
M C
b ll G Y k
d
l
S L y
Results We enrolled 37 patients with severe sepsis/septic shock
requiring RBC transfusion. After transfusion, the mean arterial pressure
increased from 79 ± 9 to 82 ± 10 (T1a vs. T0: P <0.05) and 83 ± 10
mmHg (T1b vs. T0: P <0.001). Besides a nonstatistically signifi cant drop
in arterial partial oxygen pressure, we observed no change in arterial
blood gases and vital signs. Overall, RBC transfusion did not alter any
of the MD-assessed parameters (that is, lactate, pyruvate, glycerol and
glucose) or blood lactate, but it decreased the tissue LP ratio from (T0)
18.80 (interquartile range (IQR), 14.85 to 27.45) to (T1a) 17.80 (IQR,
14.35 to 25.20) (P <0.05) and (T1b) 17.90 (IQR, 14.45 to 22.75) (P <0.001). The post-transfusion changes in LP ratio at T1a (r = –0.42; 95% CI, –0.66
to –0.098; P = 0.01) and T1b (r = –0.68; 95% CI, –0.82 to –0.44; P <0.001)
were signifi cantly correlated with the pre-transfusion LP ratio but not
with baseline demographic characteristics, vital signs, severity scores,
hemoglobin level and blood lactate. Finally, 39.0% of the transfused
RBC units were leukoreduced and their median storage time was
16 days (IQR, 11 to 24). RBC storage time and leukocyte reduction had
no infl uence on the tissue metabolic response to transfusion. Introduction Management of massive blood loss requires a multi-
disciplinary team approach. Current guidelines are varied and generic
with a lack of adherence when it comes to management of massive
haemorrhage. The aim of our survey was to assess the transfusion
practice in the management of massive haemorrhage in a busy district
general hospital with a tertiary neurosurgical centre and the busiest
obstetric unit in London. Methods A retrospective analysis of cases requiring transfusion of
more than 6 units of red blood cells (RBC), between January 2009 and
January 2010. Sixty-eight cases of massive transfusion were identifi ed,
and data collected included causes of the haemorrhage, patient’s
demographics and past medical background, investigations (FBC,
clotting), use of blood products and patient outcome. Results There were 21 gastrointestinal, 17 vascular, 12 general surgical,
seven trauma, six obstetric, and fi ve haematology–oncology patients. Thirty-one per cent of patients were 61 to 80 years old. Overall mortality
was 35%, highest mortality among vascular patients. Average blood
products per patient: RBC 9 units, fresh frozen plasma (FFP) 4 units,
platelets (PLT) 1.2 units, cryoprecipitate 0.67 units. No impact of a massive transfusion protocol on coagulopathy and
mortality at a level 1 trauma center: why? Transfused patients presented a higher number of severe
clinical complications in the postoperative period compared to non-
trans fused patients (74 (34.1%) vs. 312 (61.9%), P <0.0001). Also, the
mor tality rate was higher in transfused patients than nontransfused
patients (1 (0.5%) vs. 18 (3.6%), P <0.016). In a multivariate analysis, age,
obesity, perioperative myocardial ischemia, valve disease, heart failure,
blood transfusion and CPB duration are independently associated with
mortality. y
y
y
Results Of the 84 trauma patients, 23 were transfused with the MTP and
61 without. The average ISS score was very high (29.2), most were male
(73.8%) and the average age was 41 years. The MTP versus non-MTP
groups were similar in regards to age, sex, pH, temperature, ISS and
Revised Trauma Score, but the MTP group received more transfusions
(40% vs. 22% when dichotomized in two groups: above 20 pRBC and
between 10 and 20 pRBC). The mortality and coagulopathy were
similar in both the MTP and non-MTP group (39% vs. 34% and 65% vs. 75% respectively). PTM did not aff ect mortality or coagulopathy, even
when controlling for all other variables. Individually, both hypothermia
(OR = 2.6, 95% CI: 1.1 to 6.8) and acidosis (OR = 4.3, 95% CI:1.6 to 13.0)
signifi cantly aff ected mortality, while the number of pRBC (OR = 3.8,
95% CI: 1.1 to 14.1) was the main determinate for coagulopathy. Conclusion Blood component exposure is associated with poor
outcome and mortality in patients undergoing cardiac surgery. Despite
the evidence that blood transfusion is associated with worse outcome,
the blood transfusion rates remain unacceptably high in clinical practice. Reference S159 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 http://ccforum.com/supplements/16/S1 data regarding its impact on tissue metabolism. The aim of this study
was to explore the eff ect of RBC transfusion on microdialysis-assessed
interstitial fl uid metabolic parameters in septic patients. Conclusion In our population of severely injured patients, the MTP was
not found to be benefi cial in regards to mortality nor coagulopathy. Hypothermia and acidosis seem to be the main determinants for
mortality and should be among the priorities in caring for trauma
patients. l
Methods We conducted an observational, clinical study in a 25-
bed, medical–surgical ICU of a university hospital. Blood transfusion after cardiac surgery increases the hospital
length of stay in adult patients Blood transfusion after cardiac surgery increases the hospital
length of stay in adult patients
L Hajjar1, JL Vincent2, J Almeida1, F Jatene1, A Rodrigues1, J Fukushima1,
R Nakamura1, C Silva1, E Osawa1, R Kalil1, F Galas1, J Auler Jr1
1Heart Institute, São Paulo, Brazil; 2Erasme Hospital, Université libre de
Bruxelles, Belgium
Critical Care 2012, 16(Suppl 1):P447 (doi: 10.1186/cc11054) L Hajjar1, JL Vincent2, J Almeida1, F Jatene1, A Rodrigues1, J Fukushima1,
R Nakamura1, C Silva1, E Osawa1, R Kalil1, F Galas1, J Auler Jr1
1Heart Institute, São Paulo, Brazil; 2Erasme Hospital, Université libre de
Bruxelles, Belgium
C
l C
(S
l ) P
(d
/
) Conclusion Blood product use varied widely irrespective of speciality,
the dependent factor being individual doctors involved in patient
management. Due to diffi culty of accessing and their complexity
in emergency situations, it was noted that hospital guidelines
were disregarded. FFP was the commonly used blood product
while cryoprecipitate and tranexamic acid were underused. Only
56% of patients had FBC and clotting screen to guide transfusion
management. In these patients the ratio of cryoprecipitate and PLTs
to RBCs was higher. This survey showed the need for revised, easily
accessible and user-friendly guidelines for the management of massive
haemorrhages. The results of this survey helped to establish point-
of-care testing (thromboelastography) to provide a target controlled
therapy and make the use of blood and blood products cost-eff ective. References Introduction Transfusion of allogeneic red blood cells (RBC) is a
recognized risk factor for adverse outcomes following cardiac surgery. A potential endpoint to assess clinical complications and incremental
use of resources is the measurement of hospital length of stay (LOS). The primary objective of this study was to evaluate the relationship
between blood transfusion and increased hospital LOS after cardiac
surgery. y
Methods A prospective observational substudy that analyzed data
from the overall 502 patients enrolled in the Transfusion Requirements
After Cardiac Surgery (TRACS) study [1]. Patients who received blood
transfusion during surgery or ICU stay were further categorized
according to the number of prescribed RBC units: nontransfusion
group, low transfusion requirement group (3 units or less), and high
transfusion requirement group (more than 4 units). 1. CRASH-2 Trial Collaborators et al.: Lancet 2010, 376:23-32. 2. Johansson PI, Stensballe J: Transfusion 2010, 50:701-710. 3. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA: Am J Surg
2009, 197:565-570. 4. Blood transfusion after cardiac surgery increases the hospital
length of stay in adult patients Enriquez LJ, Shore-Lesserson L: Br J Anaesth 2009, 103(Suppl 1):i14–i22. q
g
p
Results Patients who received any RBC unit had longer median LOS
than patients in the nontransfusion group: 15 days (95% CI, 12.66 to
17.34) in high transfusion requirement group versus 10 days (95% CI,
9.1 to 10.9) in low transfusion group versus 8 days (95% CI, 7.4 to 8.6)
in nontransfusion group (P <0.001). In a multivariate Cox proportional
hazards model the following factors were considered predictive: age
older than 65 years (hazard ratio (HR), 1.38 (95% CI, 1.11 to 1.73);
P = 0.004), EuroSCORE 3 to 5 (HR, 1.44 (95% CI, 1.12 to 1.86); P = 0.005),
EuroSCORE higher than 5 (HR, 1.7 (95% CI, 1.26 to 2.28); P <0.001),
valvular surgery (HR, 1.57 (95% CI, 1.26 to 1.95); P <0.001), combined
procedure (HR, 1.6 (95% CI, 1.03 to 2.46); P = 0.034), bypass duration
higher than 100 minutes (HR, 1.23 (95% CI, 1.01 to 1.51); P = 0.046),
LVEF lower than 40% (HR, 1.69 (95% CI, 1.24 to 2.32); P = 0.001), LVEF
40 to 59% (HR, 1.36 (95% CI, 1.1 to 1.69); P = 0.004), RBC transfusion Massive transfusion practice
M C
b ll G Y k
d
l
S L Tranexamic acid was
used in eight cases and factor VII in one case. At the time of haemorrhage,
FBC, clotting screen and fi brinogen levels were requested in 56% of
patients. In this group, FFP, PLTs and cryoprecipitate were used more
frequently with mean use of blood products: RBC 9 units, FFP 5 units,
PLT 1.5 units, and cryoprecipitate 1 unit. l
p
Conclusion Tissue oxygenation is improved by red blood cell
transfusion in critically ill septic patients. Monitoring of the tissue LP
ratio by microdialysis may represent a useful method for individual
clinical management. P447 Reference 1. Cotton BA, et al.: J Trauma 2009, 66:41-49. No impact of a massive transfusion protocol on coagulopathy and
mortality at a level 1 trauma center: why? We analyzed the
eff ect of transfusion of either 1 or 2 RBC units on interstitial fl uid
metabolic activity by means of a microdialysis (MD) catheter inserted
in the subcutaneous adipose tissue of the upper thigh. Samples were
collected before (T0) and after (T1a and T1b; spaced out by 4 hours)
transfusion. Lactate, pyruvate, glycerol and glucose concentrations
were measured with a bedside analyzer and the lactate/pyruvate (LP)
ratio was calculated automatically. Reference P446 Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients
P Kopterides, N Nikitas, M Theodorakopoulou, A Diamantakis,
D Vassiliadi, A Kaziani, S Assoti, F Drakopanagiotakis, A Antonopoulou,
P Papadopoulos, E Mavrou, C Georgiadou, A Tsantes, A Armaganidis,
I Dimopoulou
‘Attiko’ University Hospital, Haidari – Athens, Greece
Critical Care 2012, 16(Suppl 1):P446 (doi: 10.1186/cc11053) Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients
P Kopterides, N Nikitas, M Theodorakopoulou, A Diamantakis,
D Vassiliadi, A Kaziani, S Assoti, F Drakopanagiotakis, A Antonopoulou,
P Papadopoulos, E Mavrou, C Georgiadou, A Tsantes, A Armaganidis,
I Dimopoulou
‘Attiko’ University Hospital, Haidari – Athens, Greece
Critical Care 2012, 16(Suppl 1):P446 (doi: 10.1186/cc11053) Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients
P Kopterides, N Nikitas, M Theodorakopoulou, A Diamantakis,
D Vassiliadi, A Kaziani, S Assoti, F Drakopanagiotakis, A Antonopoulou,
P Papadopoulos, E Mavrou, C Georgiadou, A Tsantes, A Armaganidis,
I Dimopoulou
‘Attiko’ University Hospital, Haidari – Athens, Greece
Critical Care 2012, 16(Suppl 1):P446 (doi: 10.1186/cc11053) Impact on early trauma mortality of the adoption of the Updated
European Guidelines on the management of bleeding
C
l
1 G
d 2 G R
ld 2 C S dd 2 S R
2
C
l
2 Impact on early trauma mortality of the adoption of the Updated
European Guidelines on the management of bleeding
E Cingolani1, G Nardi2, G Ranaldi2, C Siddi2, S Rogante2, A Ciarlone2
1Azienda Ospedaliera San Camillo Forlanini, Roma, Italy; 2S.Camillo Hospital,
Roma, Italy
Critical Care 2012, 16(Suppl 1):P450 (doi: 10.1186/cc11057) Methods We conducted a cross-over randomized interventional study,
enrolling 10 healthy adults. Nine volunteers completed the study;
one volunteer could not complete the protocol because of anemia. Each volunteer received 1 unit of 40-day and 1 unit of 3-day stored
autologous leukoreduced PRBC, on diff erent study days according to
a randomization scheme. Blood withdrawal and reactive hyperemia
index (RHI) measurements were performed before and 10 minutes,
1 hour, 2 hours, and 4 hours after transfusion. E Cingolani1, G Nardi2, G Ranaldi2, C Siddi2, S Rogante2, A Ciarlone2
1Azienda Ospedaliera San Camillo Forlanini, Roma, Italy; 2S.Camillo Hospital,
Roma, Italy E Cingolani1, G Nardi2, G Ranaldi2, C Siddi2, S Rogante2, A Ciarlone2
1Azienda Ospedaliera San Camillo Forlanini, Roma, Italy; 2S.Camillo Hospital,
Roma, Italy Introduction Post-traumatic bleeding is the leading cause of potentially
preventable death among trauma patients. The Updated European
Guidelines (UEG), published at the beginning of 2010, were aimed to
provide an evidence-based multidisciplinary approach to improve the
management of the critically injured bleeding trauma patients. The aim
of this study is to evaluate the impact of the implementation of UEG
recommendations on early hospital mortality for severe trauma in a
high-fl ow trauma center. Introduction Post-traumatic bleeding is the leading cause of potentially
preventable death among trauma patients. The Updated European
Guidelines (UEG), published at the beginning of 2010, were aimed to
provide an evidence-based multidisciplinary approach to improve the
management of the critically injured bleeding trauma patients. The aim
of this study is to evaluate the impact of the implementation of UEG
recommendations on early hospital mortality for severe trauma in a
high-fl ow trauma center. Results The change of RHI after transfusion of 40-day stored PRBC
did not diff er as compared to 3-day stored PRBC (P = 0.67). Plasma
hemoglobin and bilirubin levels were higher after transfusion of 40-day
than after 3-day stored PRBC (P = 0.02 and 0.001, respectively). Plasma
levels of potassium, LDH, haptoglobin, cytokines, as well as blood
pressure, did not diff er between the two transfusions and remained
within the normal range. Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients y
y
P Kopterides, N Nikitas, M Theodorakopoulou, A Diamantakis, p
,
,
p
,
,
D Vassiliadi, A Kaziani, S Assoti, F Drakopanagiotakis, A Antonopoulou,
P Papadopoulos, E Mavrou, C Georgiadou, A Tsantes, A Armaganidis,
I Dimopoulou Introduction Even though red blood cell (RBC) transfusion is a
common intervention in the critical care setting, there is a paucity of S160 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 of 1 to 3 units (HR, 1.24 (95% CI, 1.01 to 1.53); P <0.001), and RBC
transfusion >3 units (HR, 1.96 (95% CI, 1.45 to 2.66); P <0.001). In an
adjusted model for age, EuroSCORE, type of surgical procedure, LVEF
and cardiopulmonary bypass time, the exposure to RBC transfusion
was associated with an elevated LOS. controlled trials (RCTs) and observational studies comparing the eff ect
of two or more diff erent PLT:RBC ratios in trauma resuscitation. We
excluded studies using whole blood or systematically addressing the
use of hemostatic products. Two independent reviewers selected the
studies, extracted data using a standardized form, and assessed the
risk of bias using the Newcastle–Ottawa scale and a checklist of key
methodological elements (for example, use of massive transfusion
protocol, survival bias). Disagreements were solved by consensus or a
third party. The primary outcome was mortality. Secondary outcomes
were multiple organ failure (MOF), lung injury and sepsis. A meta-
analysis using random eff ects models was planned. controlled trials (RCTs) and observational studies comparing the eff ect
of two or more diff erent PLT:RBC ratios in trauma resuscitation. We
excluded studies using whole blood or systematically addressing the
use of hemostatic products. Two independent reviewers selected the
studies, extracted data using a standardized form, and assessed the
risk of bias using the Newcastle–Ottawa scale and a checklist of key
methodological elements (for example, use of massive transfusion
protocol, survival bias). Disagreements were solved by consensus or a
third party. The primary outcome was mortality. Secondary outcomes
were multiple organ failure (MOF), lung injury and sepsis. A meta-
analysis using random eff ects models was planned. Conclusion Blood transfusion is an independent risk factor for
prolonged hospital LOS after cardiac surgery. P449 Liberal use of platelet transfusions in the acute phase of trauma
resuscitation: a systematic review
J Hallet1, F Lauzier1, O Mailloux2, V Trottier1, P Archambault2,
R Zarychanski3, AF Turgeon1
1CHA-Hôpital de l’Enfant-Jésus, Université Laval, Québec, Canada; 2Université
Laval, Québec, Canada; 3University of Manitoba, Winnipeg, Canada
Critical Care 2012, 16(Suppl 1):P449 (doi: 10.1186/cc11056) Rossaint et al.: Crit Care 2010, 14:R52. Red blood cell transfusion improves microdialysis-assessed
interstitial lactate/pyruvate ratio in critically ill septic patients This fi nding can support
the development of blood conservation strategies in order to avoid
deleterious outcomes of blood exposure. Reference
1. Hajjar LA, Vincent JL, Galas FR, et al.: Transfusion requirements after cardiac
surgery: the TRACS randomized controlled trial. JAMA 2010, 304:1559-1567. y
gf
p
Results From 6,123 citations, seven observational studies were included
(n = 4,230 patients). No RCT was identifi ed. All studies were considered
to be at low risk of bias and addressed confoundings through
multivariate regression or propensity scores. Four studies (n = 1,978)
reported a decrease in mortality with higher PLT:RBC ratios in patients
requiring massive transfusion and one study observed no mortality
diff erence (n = 1,181) in nonmassively transfused patients. Two studies
reported on the implementation of a massive transfusion protocol with
higher PLT:RBC ratios; only one revealed a survival benefi t (n = 211). Of the three studies accounting for survival bias, two demonstrated
a survival benefi t (n = 1,300). Among two studies reporting on the
secondary outcomes (n = 854), one observed an increase in MOF with
higher PLT:RBC ratios. Clinical heterogeneity between studies and
methodological limitations precluded the use of a meta-analysis.fi P448 P448
Transfusion of blood stored for longer periods of time does not alter
the reactive hyperemia index in healthy volunteers
A Coppadoro1, L Berra2, B Yu2, C Lei2, E Spagnolli2, AU Steinbicker2,
KD Bloch2, T Lin2, HS Warren2, FY Sammy2, BO Fernandez3, M Feelisch3,
WH Dzik2, CP Stowell2, WM Zapol2
1University of Milan-Bicocca, Monza, Italy; 2Massachusetts General Hospital,
Boston, MA, USA; 3University of Warwick, Coventry, UK
Critical Care 2012, 16(Suppl 1):P448 (doi: 10.1186/cc11055) Introduction The purpose of this study is to investigate the eff ects
of transfusing human packed red blood cells (PRBC) after prolonged
storage, as compared to short storage. Retrospective data suggest that
transfusion of PRBC stored for over 2 weeks is associated with increased
mortality and morbidity. During storage, PRBC progressively release
hemoglobin, which avidly binds nitric oxide (NO). We hypothesized
that the NO-mediated hyperemic response following ischemia would
be reduced after transfusion of PRBC stored for 40 days. Conclusion There is insuffi cient evidence to strongly support the use of a
specifi c PLT:RBC ratio for acute trauma resuscitation, especially considering
survival bias and nonmassively transfused patients. RCTs examining both
safety and effi cacy of liberal PLT transfusions are warranted. Impact on early trauma mortality of the adoption of the Updated
European Guidelines on the management of bleeding
C
l
1 G
d 2 G R
ld 2 C S dd 2 S R
2
C
l
2 Plasma nitrite concentrations increased after
transfusion of 40-day stored PRBC, but not after transfusion of 3-day
stored PRBC (P = 0.01). gl
Methods S. Camillo Hospital is a level 1 trauma center based in
downtown Rome, with a catchment population of 2.5 million people. UEG recommendations were formally adopted and implemented since
1 April 2010. The pre-existing hospital guidelines were modifi ed as
follows: immediate pelvic ring closure for all unstable patients with
a suspected pelvic fracture; early administration of plasma with a
higher rate of plasma/blood units; early use of thromboelastometry
to monitor bleeding patients; and early use of antifi brinolitics for all
bleeding patients. Data on trauma admissions and early hospital (6
hours) mortality before (2009) and after the adoption of the UEG were
collected using the hospital registry, and were subsequently analysed. Results A total of 1,617 patients met the criteria for full trauma team
activation (551 in 2009, 528 in 2010 and 538 during the fi rst 11 months
of 2011). There were no diff erences for gender, age, mechanism of
injury and average ISS. In 2009 21 patients died within the fi rst 6 hours
versus 17 in 2010 and 12 in 2011; P = 0.3, P for trend = 0.1 Hemorrhage
was the most important cause of death within this time-span. All early
trauma deaths occurred in the operating room or in the emergency
room during the initial stabilization. Conclusion Transfusion of 1 unit of autologous PRBC stored for longer
periods of time is associated with increased hemolysis, an unchanged
RHI and increased levels of plasma nitrite in healthy volunteers. P451
Hemodynamics in the severely injured patient with signifi cant
hemorrhage
G Nardi, D Piredda, A Cossu, E Cingolani, M Cristofani, I Ghezzi
S. Camillo Hospital, Roma, Italy
Critical Care 2012, 16(Suppl 1):P451 (doi: 10.1186/cc11058) outcome measures were in-hospital mortality and time to death. The
secondary endpoint was to identify the eff ect of chronic medication
on mortality. Categorical variables were compared by chi-squared test
and continuous variables by Student’s t/Mann–Whitney tests. Multiple
logistic regression analysis was used to predict mortality. P <0.05 was
considered statistically signifi cant. i
Results The inclusion criteria were met by 261 patients. Age average was
75.57 years (SD 5.7). Male gender was more prevalent (58.5%) for all age
groups. The median ISS was 17. The most frequent trauma mechanism
was low-energy type (58.2%). Patients with chronic ACT numbered 41
(15.7%). The mean ICU stay was 12.8 days (SD 2.8). Global mortality was
34.1%. Age >78 years and ISS >18 were predictive of mortality (P <0.05)
with a HR of 6.0 (CI 2.5 to 14.6) and 1.01 (CI 1.01 to 1.05) respectively. Furthermore, the time to death was found to be earlier in both of the
latter groups (P <0.05). GCS <4 or bilateral mydriasis was associated
with 100% mortality. About 15% of patients with low-energy trauma
(LET) underwent ENS compared to 7.8% with high-energy trauma. For
the same ISS category, ACT increases the risk with HR 2.7 (CI 1.2 to 6.3)
of ENS compared with nonanticoagulated patients. Introduction Very little is known about the hemodynamic impairments
induced by trauma and severe hemorrhage. The aim of this study is
to contribute to a better understanding of this topic. A recent paper
has shown that about 50% of the hemorrhagic patients receive
vasopressors [1] together with fl uids, blood and plasma. Fluids and
vasopressors are aimed to restore patients’ hemodynamics; however,
they might be detrimental. y
g
Methods The setting was a 10-bed trauma ICU in a level 1 trauma
center with a catchment population of over 2.5 million people. This is
a retrospective cohort study based on the data of the ICU electronic
shift. During a 24-month period (2009 and 2010), 780 patients with
major trauma (ISS >15) were admitted to the hospital; 410 of them
were subsequently admitted to the shock and trauma ICU. All patients
with ISS >15, who had received ≥5 blood units before ICU admission,
and who were submitted to semi-invasive hemodynamic monitoring
(PICCO), were entered into the study. p
g
p
Conclusion LET accounted for most of the older trauma patients
admitted to our ICU and had increased risk of death, especially with ACT. P451
Hemodynamics in the severely injured patient with signifi cant
hemorrhage
G Nardi, D Piredda, A Cossu, E Cingolani, M Cristofani, I Ghezzi
S. Camillo Hospital, Roma, Italy
Critical Care 2012, 16(Suppl 1):P451 (doi: 10.1186/cc11058) Although this is not necessarily secondary to alarming mechanisms. Referencei y
Results Thirty patients (mean age 42.7 ± 17, mean 37.5 ± 12) met the
study criteria. At the time of insertion of the PICCO catheter (T0) the 30
patients had already received an average of 8,760 ml fl uids (3,239 ml
blood, plasma and platelets, 4,870 ml crystalloids and 685 ml colloids). Systemic blood pressure, central venous pressure and heart rate at T0
were, as an average, in the normal range. Nevertheless, six patients
(20%) had a Cardiac Index lower than 2.5 l/minute, and 76% had a DO2
signifi cantly lower than the normal range. In the subsequent 24 hours
following the information of the PICCO, these patients received,
as an average, an additional 6,070 ml fl uids, blood and plasma. All
vasopressors were discontinued, but 40% of the patients received
dobutamine. Within 24 hours (T24), oxygen transport (DO2) and lactate
were back to the normal values in all patients but one. ICU mortality
and hospital mortality were respectively 13.3% and 16%. 1. Spaniolas et al.: Ground level falls are associated with signifi cant mortality
in elderly patient. J Trauma 2010, 69:821-825. Outcomes in older blunt chest wall trauma patients: a retrospective
study y
C Battle, H Hutchings, PA Evans C Battle, H Hutchings, PA Evans Swansea University, Swansea, UK y
Critical Care 2012, 16(Suppl 1):P453 (doi: 10.1186/cc11060) Introduction Blunt chest wall trauma accounts for over 15% of all
trauma admissions to emergency departments in the UK and has high
morbidity and mortality rates [1]. Reported risk factors for morbidity
and mortality in blunt chest trauma patients include patient age,
pre-existing disease and three or more rib fractures [2]. No guidelines
exist for management of this patient group unless the patient has
severe immediate life-threatening injuries. The aim of this study was
to investigate whether blunt chest wall trauma patients aged 65
years or more have higher rates of mortality, morbidity (respiratory
complications), ICU admissions and hospital length of stay (HLOS) than
patients aged less than 65 years. Conclusion A high percentage of the severely injured patients who
received ≥5 units of PRC have a low oxygen transport at the time of
ICU admission. A high percentage of them is treated with vasopressors. However, as 20% of the patients in our study had a low cardiac index
in spite of a normal blood pressure and a highly positive fl uid balance,
vasopressors might be harmful. In our experience, hemodynamic
monitoring with PICCO allowed the early recognition of inappropriate
oxygen transport and a goal-directed treatment. Our data do not
support the use of vasopressors to increase blood pressure in trauma
patients. Methods A retrospective study was completed in which the notes of
1,056 blunt chest wall trauma patients who presented in 2010 to the
emergency department of a large regional trauma centre in Wales were
examined. A total of 94 out of the 1,056 (9%) patients were admitted to
hospital in 2010 with blunt chest wall trauma. Data were recorded for
each of the admitted patients including patient age, severity of injury,
morbidity, mortality, ICU admission and HLOS. Patients were grouped
according to age; group one included all blunt chest wall trauma
patients aged 65 years or more and group two included all patients
aged less than 65 years. Pearson’s chi-square analyses were performed
to determine whether any diff erences existed between the two groups
and signifi cance set at P <0.05. Reference 1. J Trauma 2011, 71:17-19. Liberal use of platelet transfusions in the acute phase of trauma
resuscitation: a systematic review y
J Hallet1, F Lauzier1, O Mailloux2, V Trottier1, P Archambault2,
R Zarychanski3, AF Turgeon1
1CHA-Hôpital de l’Enfant-Jésus, Université Laval, Québec, Canada; 2Université
Laval, Québec, Canada; 3University of Manitoba, Winnipeg, Canada
Critical Care 2012, 16(Suppl 1):P449 (doi: 10.1186/cc11056) J Hallet1, F Lauzier1, O Mailloux2, V Trottier1, P Archambault2,
R Zarychanski3, AF Turgeon1
1CHA-Hôpital de l’Enfant-Jésus, Université Laval, Québec, Canada; 2Université
Laval, Québec, Canada; 3University of Manitoba, Winnipeg, Canada
Critical Care 2012, 16(Suppl 1):P449 (doi: 10.1186/cc11056) Introduction With the recognition of early trauma coagulopathy,
trauma resuscitation has recently shifted towards early and aggressive
transfusion of platelets (PLTs). However, the clinical benefi ts of this
strategy remain controversial. This systematic review examined the
impact of an aggressive approach (higher PLT:RBC ratios) compared to
restrictive PLT transfusions (lower PLT:RBC ratios) in the acute phase of
trauma resuscitation. Conclusion This is a retrospective cohort study based on the data of the
S. Camillo Hospital registry and the emergency department electronic
shift. With the limitations of all retrospective studies, our data suggest
that the implementation of the European Guidelines recommendations
might contribute to a relevant reduction in early trauma mortality. Reference Methods We systematically searched Medline, Embase, Web of Science,
Biosis, Cochrane Central and Scopus to identify relevant randomized Rossaint et al.: Crit Care 2010, 14:R52. S161 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P451
Hemodynamics in the severely injured patient with signifi cant
hemorrhage
G Nardi, D Piredda, A Cossu, E Cingolani, M Cristofani, I Ghezzi
S. Camillo Hospital, Roma, Italy
Critical Care 2012, 16(Suppl 1):P451 (doi: 10.1186/cc11058) P451 1.
Trauma Audit and Research Network: Blunt Chest Trauma Admissions in the UK
in 2010. TARN; 2011. (Kindly provided by Tom Jenks.)
2.
Blecher GE, Mitra B, Cameron PA, et al.: Failed emergency department
disposition to the ward of patients with thoracic injury. Injury 2008,
39:586-591. P455 Trauma patients and cervical spine protection in critical care: the
impact of a spinal checklist on clinical care and documentation
A Chick, C Scott, H Ellis, A Tipton
Sheffi eld Teaching Hospitals NHS Foundation Trust, Sheffi eld, UK
Critical Care 2012, 16(Suppl 1):P455 (doi: 10.1186/cc11062) Introduction In October 2010 a specifi c online proforma for cervical
spine (C-spine) assessment in the context of trauma was introduced in
critical care in a large UK teaching hospital. The aim of this study is to
assess the impact of the Metavision Spinal Checklist (MSC) on clinical
care and documentation. Prior to October 2010, the documentation of
C-spine status on admission to critical care was incomplete or unclear
in over 40% of these patients. Conclusion Surgical stabilization of spinal fractures avoids restrictive
spinal braces and permits mobilization. Surgical fi xation of spinal
fractures appears to decrease mortality and ITU stay and has a
benefi cial eff ect on respiratory function, with regards to degree of
ventilatory support and development of respiratory failure. Methods Patients were identifi ed from a comprehensive critical care
database. Inclusion criteria: age >16; polytrauma or traumatic brain
injury; other trauma where mechanism of injury suspicious for C-spine
injury; admission date after 1 October 2010, before 30 November 2011. Exclusion criteria: pre-existing spinal injury; mechanism of trauma not
consistent with C-spine injury. Clinical and MSC details were recorded,
including sequential forms for individual patients where the C-spine
status changed (for example, C-spine cleared and hard collar removed). Results A total of 62 patients met the inclusion criteria; 47% of these
had been transferred from a district hospital. In patients with an MSC
completed, there was 100% documentation of time, date and name of
the completing critical care consultant. Seventy-fi ve per cent of initial
MSCs indicated the name of the responsible consultant spinal surgeon. Seventy-nine per cent of patients with a completed MSC required their
C-spines to be cleared after critical care admission. When completed,
the initial MSC allowed clearance of C-spine and immediate removal
of hard collar in 67% of those patients. There were clearly documented
instructions for C-spine care from a spinal consultant in 92% of patients
with a completed MSC. Overall, an MSC was completed for only 39% of
patients, despite 53% of patients having sustained a spinal fracture at
some level (for example, lumbar, thoracic or cervical). Eff ect of instrumented spinal fi xation on outcome in polytrauma
patients in the ICU y
j
y
g
Results A total 951 patients were included (427 (30 months) before
RRTT and 524 (39 months) after RRTT). Of these, 83 patients (8.8%)
were dead after admission and analyzed for characters of mortality. The average age of mortality patients was 38.7 ± 16.3 years. Male was
the predominant gender. The most common mechanism of injury
was a motorcycle accident. Although there were no diff erences of
character and mechanism of injuries between the two periods, patients
associated with maxillofacial injury had signifi cant lower mortality
after RRTT (28.5% vs. 10.5%; P = 0.04). However, the after RRTT group
had signifi cantly higher occurrence of urinary complication and acute
renal failure. The average adjusted monthly mortality rate was lower
after RRTT (9.0 ± 6.1 vs. 6.9 ± 4.0%). Time series analysis between two
periods demonstrated a decrease trend in monthly mortality after
RRTT (coeffi cient (95% CI) = –0.61 (–1.13 to –0.23); P <0.01)). Introduction Spinal injuries in polytrauma patients carry high
morbidity and mortality often necessitating intensive care admission. A review of polytrauma patients admitted to the ICU at The Royal
Liverpool University Hospital was undertaken to investigate the eff ect
of spinal instrumentation on outcome in the ITU. Methods A retrospective review of all polytraumatized patients
admitted to the RLUH ICU over 3 years with a thoraco-lumbar spinal
fracture. Clinical records, laboratory results and radiological records
were accessed. Patients were grouped according to the use of
instrumented spinal fi xation versus conservative management and
outcomes compared. Results Fourteen polytrauma patients with spinal fractures were
admitted to the ICU over 3 years, fi ve managed conservatively with a
TLSO brace and nine managed operatively with instrumented spinal
fi xation. The degree of injury as graded by the Injury Severity Scale
(ISS) was lower in the nonoperative group (mean: 27, range: 14 to
59) compared to the operative group (mean: 36.1, range: 14 to 57). Mortality was signifi cantly higher in patients conservatively managed
(nonoperative: 60%, operative: 0%) (P <0.01). The intubation time
was lower in patients who underwent spinal instrumentation (mean:
12.3 days, range: 1 to 27 days), when compared to conservative
management (mean: 16 days, range: 11 to 27 days), and similarly the
ITU length of stay was reduced in the operative group (operative:
mean 20.6 days, nonoperative: 32.25 days). Reference Reference Introduction The Department of Surgery, Faculty of Medicine, Chiang
Mai University established a rapid response trauma team (RRTT) in July
2006. The aims of this study were to verify mortality rate alteration after
setting up the RRTT. 1. Morris CG, et al.: BMJ 2004, 329:495-499. P457 P457 P456f Methods We retrospectively collected data between January 2004 and
September 2009. The month before July 2006 was defi ned as before
RRTT and after July 2006 as after RRTT. The monthly mortality rate,
severity injury score (ISS) and demographic data were collected. Mortality trend alteration of thoracic injury after rapid response
trauma team establishment K Chittawatanarat, C Ditsatham, K Chandacham, T Jirapongchareonlap,
N Chotirosniramit P454
Mortality trend alteration of thoracic injury after rapid response
trauma team establishment
K Chittawatanarat, C Ditsatham, K Chandacham, T Jirapongchareonlap,
N Chotirosniramit
Chiang Mai University, Chiang Mai, Thailand
Critical Care 2012, 16(Suppl 1):P454 (doi: 10.1186/cc11061) Conclusion The uptake of this checklist has not been optimal, but the
MSC provides an excellent tool for clear documentation of C-spine
status. During this initial trial phase, October 2010 to December 2011,
the MSC has been consultant-only. Further action will involve rolling-
out the checklist to critical care trainee doctors to improve the rate of
documentation of C-spine status and improve patient safety in this
area of signifi cant clinical risk [1]. P455 The median time
from critical care admission to MSC completion was 36 hours (range 3
hours to 12 days, mean 48 hours). Eff ect of instrumented spinal fi xation on outcome in polytrauma
patients in the ICU Development of respiratory
failure was decreased in patients treated with instrumented fi xation
(operative 33.3%, nonoperative: 71%). Conclusion Rapid response trauma team establishment could decrease
the mortality trend. A protective eff ect was predominant in patients
associated with maxillofacial injury. Critical older trauma patients M Irazábal, S Yus, L Fernández M Irazábal, S Yus, L Fernández Introduction The aim of this study was characterize the older injured
patient in our setting and identify risk factors that might predict
mortality. Trauma is the fi fth leading cause of death over the age of
65. In Spain, it has become a major public health problem as a result
of the increase of this population. It represents 30% of the trauma
admissions to our ICU. Geriatric patients may have comorbidities,
limited physiologic reserve, may be taking chronic medication and the
injury pattern is diff erent [1]. i
Results There was no signifi cant diff erence in severity of injury between
the groups. The mortality rate and HLOS in the patients aged 65 years
or more were signifi cantly higher (P <0.05) than in the younger patient
group. There were no signifi cant diff erences between the morbidity
rates and number of ICU admissions. Conclusion Blunt chest wall trauma patients have a signifi cantly higher
rate of mortality and hospital length of stay if aged 65 years or more
when compared to those patients aged less than 65 years. Older blunt
chest wall trauma patients should be considered for a higher level of
care on admission to hospital from the emergency department. References f
Methods We retrospectively analyzed trauma patients aged 65 years
and older admitted to our ICU from January 2000 through December
2010. Three groups were formed on the basis of age: 65 to 70, 71 to 78
and older than 78 years. The Injury Severity Score (ISS) was categorized
into three ranges: >12, 12 to 18 and >18. Variables studied include:
age, gender, mechanism of injury, anticoagulant therapy (ACT), ISS,
Glasgow Coma Scale (GCS) or presence of pupillary abnormalities
and need for emergent neurosurgery (ENS) at admission. Primary 1. Trauma Audit and Research Network: Blunt Chest Trauma Admissions in the UK
in 2010. TARN; 2011. (Kindly provided by Tom Jenks.) y
y
2. Blecher GE, Mitra B, Cameron PA, et al.: Failed emergency department
disposition to the ward of patients with thoracic injury. Injury 2008,
39:586-591. S162 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P454
Mortality trend alteration of thoracic injury after rapid response
trauma team establishment
K Chittawatanarat, C Ditsatham, K Chandacham, T Jirapongchareonlap,
N Chotirosniramit
Chiang Mai University, Chiang Mai, Thailand
Critical Care 2012, 16(Suppl 1):P454 (doi: 10.1186/cc11061) Whole body computed tomography scanning for severe blunt
polytrauma: analysis of Trauma Audit and Research Network
database 2005 to 2010 PA Hunt1, F Lecky2, O Bouamra2
1James Cook University Hospital, Middlesbrough, UK; 2Hope Hospital, Salford,
UK Critical Care 2012, 16(Suppl 1):P457 (doi: 10.1186/cc11064) Introduction There is growing evidence to recommend the use of
whole body computed tomography (WBCT) scanning in the early
management of severe blunt polytrauma patients. One recent study
reported a survival advantage when using WBCT compared to a
conventional imaging approach [1]. A number of UK NHS institutions
already utilise WBCT protocols based upon either injury mechanism-
related or physiological factors, or a combination of these. However, the
UK Royal College of Radiologists is yet to provide recommendations on
the use of WBCT in polytrauma. We present the results of our analysis
of a large retrospective case series from 2005 to 2010 taken from the
Trauma Audit and Research Network (TARN) database. We believe this
is the fi rst analysis of its kind involving UK trauma cases and provides S163 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 of maximal CPK levels (15,780 to 52,600 U/l), but more severe acidosis
(lowest pH 7.0 to 7.2, maximum lactate: 7.5 to 28 mmol/l, acidosis
duration: 72 to 84 hours). This acidosis turned out to be due to intra-
abdominal complications: post-traumatic pancreatitis and mesenteric
ischemia. The vital prognosis of post-traumatic crush injury was good
but the sequelae of the compartment syndrome were major. The need
for RRT was not linked to CPK levels but rather to acidosis due to intra-
abdominal complications. of maximal CPK levels (15,780 to 52,600 U/l), but more severe acidosis
(lowest pH 7.0 to 7.2, maximum lactate: 7.5 to 28 mmol/l, acidosis
duration: 72 to 84 hours). This acidosis turned out to be due to intra-
abdominal complications: post-traumatic pancreatitis and mesenteric
ischemia. The vital prognosis of post-traumatic crush injury was good
but the sequelae of the compartment syndrome were major. The need
for RRT was not linked to CPK levels but rather to acidosis due to intra-
abdominal complications. important evidence to support the use of WBCT and guide best clinical
practice. Controlled mechanical ventilation tactics in patients with
polytrauma during interhospital transportation to the specialized
center A Shatalin1, S Kravtsov2, V Agadzhanyan2, D Skopintsev2
1Federal State Budgetary Medical Prohylactic Institution, Leninsk-Kuznetsky,
Russia; 2Federal State Budgetary Medical Prohylactic Institution ‘Scientifi c
Clinical Center of the Miners Health Protection’, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P460 (doi: 10.1186/cc11067) A Shatalin1, S Kravtsov2, V Agadzhanyan2, D Skopintsev2
1Federal State Budgetary Medical Prohylactic Institution, Leninsk-Kuznetsky,
Russia; 2Federal State Budgetary Medical Prohylactic Institution ‘Scientifi c
Clinical Center of the Miners Health Protection’, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P460 (doi: 10.1186/cc11067) Methods During 24 months, seven patients admitted to our surgical
intensive care after polytrauma (ISS >15) suff ered severe rhabdomyolysis
(CPK >5,000 U/l) treated by intensive fl uid resuscitation, bicarbonate
and furosemide. Results The following data are reported in Table 1: renal function (initial
creatinine, renal replacement therapy (RRT), rhabdomyolysis (maximal
CPK and myoglobin), acidosis (lowest pH, highest lactate (HL),
time lactate >5 mmol/l) and complications (mortality, neurological
sequelae). Introduction This study is an analysis of the infl uence of con-
trolled mechanical ventilation (CMV) with PEEP in conditions
of pneumocompression of the Chestnut antishock suit on the
hemodynamics and blood oxygenation in patients with polytrauma
during interhospital transportation. q
Conclusion Survival was 100% but neurological impairment in the
limbs is a major complication. The two RRT patients had a wide range Methods Seventy-two patients with polytrauma complicated by II and
III stage ARDS were included in the study. The mean age was 33 ± 2 years. All patients were divided into two equal groups. The control group (CG)
CMV was carried out with no PEEP. The experimental group (EG) CMV
was carried out with PEEP 8 to 10 mbar. Both groups received the CMV
regimen with Vt 7 ml/kg, Pmax 30 mbar. The injury severity according
to the ISS was 37.6 ± 1 points in the EG and 39.1 ± 1 in the CG. The
transportation time was 135 ± 7 minutes, the distance was 136 ± 10 km. Immobilization in the lower extremity fractures and pelvis fractures
was carried out using the Chestnut suit with pneumocompression over
the damaged parts of the body of 40 mmHg and over the remaining
parts of the body of 20 mmHg. Statistical analysis was performed using
Statistica 6.1. We used Student’s criterion. Table 1 (abstract P458). P460 P460
Controlled mechanical ventilation tactics in patients with
polytrauma during interhospital transportation to the specialized
center
A Shatalin1, S Kravtsov2, V Agadzhanyan2, D Skopintsev2
1Federal State Budgetary Medical Prohylactic Institution, Leninsk-Kuznetsky,
Russia; 2Federal State Budgetary Medical Prohylactic Institution ‘Scientifi c
Clinical Center of the Miners Health Protection’, Leninsk-Kuznetsky, Russia
Critical Care 2012, 16(Suppl 1):P460 (doi: 10.1186/cc11067) Whole body computed tomography scanning for severe blunt
polytrauma: analysis of Trauma Audit and Research Network
database 2005 to 2010 Methods We utilised retrospective, multicentre data of severe blunt
polytrauma (ISS >15) direct ED admissions aged >15 years recorded
in the UK TARN database to compare survival at 30 days between two
groups of patients: those who underwent WBCT scans, and those who
received a focused CT scan approach as part of their initial management
in the emergency department. A total of 12,792 cases were included in
the fi nal dataset. Post-traumatic rhabdomyolysis: an observational study in seven
patients l
Conclusion Exertional rhabdomyolysis is not rare, but rarely do such
patients present to the emergency department with acute abdominal
pain. Whilst triathlon training is popular among amateur sports
people, awareness must be raised to train appropriately under proper
conditions. M Alezrah, A Berger, P Bentzinger, C Sassot, L Profumo, B Saumande,
O Collange, A Meyer, B Calon
réanimation chirurgicale, Strasbourg, France
Critical Care 2012, 16(Suppl 1):P458 (doi: 10.1186/cc11065) Introduction In the ICU, post-traumatic rhabdomyolysis is a relatively
rare (1/5) cause of crush syndrome [1]. Early aggressive treatment
is quintessential to avoid complications such as renal failure and
death [2]. This observational study intends to assess the incidence of
complications after traumatic crush injury in a tertiary trauma center
ICU. Reference 1. Huber-Wagner S, et al.: Lancet 2009, 373:1455-1461. g
y
Results All three patients presented with abdominal pain after triathlon
training. On admission, creatinine kinase levels were over 30,000 in all
three cases and all required acute hospital admission for pain relief and
intravenous fl uids to prevent renal failure. Exertional rhabdomyolysis in female amateur triathletes
V Meighan Conclusion Despite the crude mortality rates appearing to demonstrate
a poorer outcome in the WBCT group, correcting for confounding
factors revealed an around 30% improvement in survival for the
WBCT group. However, when also correcting for the potential eff ect
of clustering, the benefi t of WBCT is less clear, with an around 20%
improvement in survival and a lower level of signifi cance (P = 0.084). This eff ect may, in part, be due to diff ering trauma systems and
logistical organisation between institutions. Overall, the results of our
investigation appear to suggest a potential survival benefi t from the
use of WBCT in severe blunt polytrauma. Exertional rhabdomyolysis in female amateur triathletes
V Meighan
Galway University Hospital, Galway, Ireland
Critical Care 2012, 16(Suppl 1):P459 (doi: 10.1186/cc11066) y
y
p
,
y,
Critical Care 2012, 16(Suppl 1):P459 (doi: 10.1186/cc11066 Introduction Multisport endurance events are becoming increasingly
popular in Ireland. Overexertion, especially in the heat, of overweight
or poorly conditioned athletes increases the risk of rhabdomyolysis. This study presents a case series of three female amateur triathletes
presenting with acute abdominal pain caused by rhabdomyolysis. Methods The medical case notes of three female athletes presenting to
the emergency department were reviewed. References 1. Bagley WH, Yang H, Shah KH: Rhabdomyolysis. Intern Emerg Med 2007,
2:210-218. 1. Bagley WH, Yang H, Shah KH: Rhabdomyolysis. Intern Emerg Med 2007,
2:210-218. i
Results A total 2,822 (22%) of 12,792 cases underwent WBCT from the
ED. The median ISS for the WBCT group was 22 (IQR 14 to 33) compared
to 16 (IQR 9 to 25) for the focused CT group. The calculated crude
mortality rate for the WBCT group was 10.1% compared to 8.7% in the
focused CT group (P = 0.0124). Multivariate analysis with adjustments
for potential confounding factors demonstrated an OR of 1.313 (95%
CI = 1.083 to 1.592, P = 0.006) in favour of survival in the WBCT group. 1. Bagley WH, Yang H, Shah KH: Rhabdomyolysis. Intern Emerg Med 2007,
2:210-218. 2. Bosch X, Poch E, Grau JM: Rhabdomyolysis and acute kidney injury. N Engl J
Med 2009, 361:62-72 2. Bosch X, Poch E, Grau JM: Rhabdomyolysis and acute kidney injury. N Engl J
Med 2009, 361:62-72 Impact of fl uid resuscitation volume on the severity of organ
failures in severely burned patients Impact of fl uid resuscitation volume on the severity of organ
failures in severely burned patients
N Depaye, G Minguet, A Magnette, D Jacquemin, D Ledoux, P Damas
University Hospital of Liege, Belgium
Critical Care 2012, 16(Suppl 1):P461 (doi: 10.1186/cc11068) N Depaye, G Minguet, A Magnette, D Jacquemin, D Ledoux, P Damas
University Hospital of Liege, Belgium
Critical Care 2012, 16(Suppl 1):P461 (doi: 10.1186/cc11068) Introduction Adequacy of fl uid resuscitation remains a cornerstone of
early burn management. The Parkland formula – that is, administration
of 4 ml/kg/% total of the body surface area (TBSA) burned with Ringer’s
lactate for the fi rst 24 hours post injury – has been used for decades. The purpose of this study was to evaluate the eff ect of adherence with
the Parkland protocol and its impact on the severity of organ failure
during the fi rst week post injury using the Sequential Organ Failure
Assessment (SOFA) score. Table 1 (abstract P462). SOFA during the resuscitation phase
Day 0
Day 1
Day 2
Day 3
SOFA
3.40 ± 2.48
4.26 ± 2.99
4.95 ± 3.04
5.25 ± 3.25
Respiratory
1.38 ± 1.12
1.32 ± 1.09
1.81 ± 1.09
1.76 ± 1.07
Cardiovascular
1.19 ± 1.76
2.06 ± 1.94
2.10 ± 1.85
2.22 ± 1.89
Conclusion In the resuscitation phase of our critical burn patients the
initial dysfunction was respiratory and cardiovascular, progressing
later to cardiovascular dysfunction and haematological dysfunction
appearing at the third day of admission. Knowing the possible evolution
of organ dysfunction may help early detection and treatment. Reference
1
Latenser B: Crit Care Med 2009 37:2819 2826 Table 1 (abstract P462). SOFA during the resuscitation phase Table 1 (abstract P462). SOFA during the resuscitation phase
Day 0
Day 1
Day 2
Day 3
SOFA
3.40 ± 2.48
4.26 ± 2.99
4.95 ± 3.04
5.25 ± 3.25
Respiratory
1.38 ± 1.12
1.32 ± 1.09
1.81 ± 1.09
1.76 ± 1.07
Cardiovascular
1.19 ± 1.76
2.06 ± 1.94
2.10 ± 1.85
2.22 ± 1.89 Methods We conducted a retrospective review of burns’ resuscitation
data, from 2000 to 2007, on 101 adult patients (aged ≥16 years)
admitted within the fi rst 24 hours following injury, with a %TBSA
burned of 20 or more. A classifi cation of patients into four groups,
according to fl uids administered, was done for comparison between
these groups. The SOFA score was calculated daily for the fi rst week
after admission. 1.
Jeff rey RS: The phenomenon of ‘fl uid creep’ in acute burn resuscitation.
J Burn Care Res 2007, 28:382-395. P463 i
Results A total of 62 patients with complete data on fl uid administration
were included in the analysis. Median age was 41 (28 to 54) years,
median TBSA burned was 35.5 (25 to 50); median ICU stay was 38 (12
to 62) days and 13 (21%) patients died. Ten patients suff ering from
inhalation injury were excluded from further analysis. Median fl uids
administered was 4.9 (4.1 to 6.2) ml/kg/%TBSA at 24 hours. Five patients
received <3. 5ml/kg/%TBSA, 15 between 3.5 and 4.5 ml/kg/%TBSA, 17
between 4.5 and 6 ml/kg/%TBSA and 15 patients >6 ml/kg/%TBSA. No
diff erences existed between groups concerning the cause and surface
of injury, age, sex, and comorbidities. Compared to others, patients
who received >6 ml/kg/%TBSA had a signifi cant increase in respiratory
failure (P = 0.03). The amount of fl uids administered had no impact on
the incidence of cardiovascular (P = 0.89), renal (P = 0.11), liver (P = 0.52)
and coagulation (P = 0.86) failure. Organ dysfunction in the resuscitation phase of critical burn
patients A Agrifoglio, M Sánchez, M Hernández, J Camacho, L Cachafeiro,
M Asensio, E Herrero, A García de Lorenzo, M Jiménez
Hospital Universitario La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P462 (doi: 10.1186/cc11069) Introduction Sequential Organ Failure Assessment (SOFA) is useful to
assess organ dysfunction in burn patients [1]. The aim of this study was
to determine the change in organ dysfunction from admission to day 3. Methods We performed a prospective observational cohort study
with critical burn patients (total body surface area (TBSA) >20% and/
or inhalation injury) admitted to our burn ICU from September 2008
to December 2010. Epidemiological data and SOFA score at admission
(day 0) and days 1, 2 and 3 were collected. Conclusion Use of CMV with PEEP in patients with polytrauma-
complicated ARDS provided more expressed improvement of the
blood oxygenation. Improvement of the blood gas exchange was
accompanied by lactate decrease in both groups: by 24% in the EG,
and by 13% in the CG. Application of the Chestnut allowed one to level
the hemodynamic disorders using CMV with PEEP by means of preload
maintenance and of the systolic output as a consequence. y
y
Results Sixty-four patients were enrolled (70% men) with mean
age of 48.2 ± 19.0 years; Abbreviated Burn Severity Index (ABSI):
8.78 ± 2.59; APACHE II score: 13.5 ± 6.5. Twenty-three patients (35.9%)
had inhalation injury and 19 patients (29.7%) died. The SOFA score
was increased from day 0 to day 3. At admission the most frequent
dysfunctions were cardiovascular and respiratory. The respiratory was
similar in the next days and the cardiovascular dysfunction worsened
(Table 1). Haematological dysfunction appeared at day 3 (1.05 ± 1.0)
and neurological, renal and hepatic dysfunction were uncommon in
the resuscitation phase. P461 Impact of fl uid resuscitation volume on the severity of organ
failures in severely burned patients The neurological component of SOFA was left out
because of the diffi culty to assess the actual Glasgow Coma Scale in
sedated patients. Organ failures were defi ned by partial SOFA ≥3. Data
are expressed as median (Q1 to Q3) and are analyzed using the chi-
square test (P <0.05 was considered statistically signifi cant).l Conclusion In the resuscitation phase of our critical burn patients the
initial dysfunction was respiratory and cardiovascular, progressing
later to cardiovascular dysfunction and haematological dysfunction
appearing at the third day of admission. Knowing the possible evolution
of organ dysfunction may help early detection and treatment. Reference 1. Latenser B: Crit Care Med 2009, 37:2819-2826. Controlled mechanical ventilation tactics in patients with
polytrauma during interhospital transportation to the specialized
center Results
Initial creatinine (μmol/l)
69 to 198
RRT
2/7
Maximal CPK (103 U/l)
11 to 144
Maximal myoglobin (103 U/l)
4 to 159
pH
7 to 7.3
Highest lactate (mmol/l)
2 to 28
Time lactate >5 mmol/l (hours)
0 to 84
Mortality
0
Neurological sequelae
6/7 Table 1 (abstract P458). Results Results In the EG there were the high values of SpO2 during all
observation periods and PaO2/FiO2 after completion of the trans-
portation in 1 and 12 hours (P <0.05). PaCO2 in the EG was lower after
completion of the transportation in 1 and 12 hours compared to the
CG (P <0.05). In the EG the value of FiO2 decreased from 0.5 ± 0.01 in S164 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 P462 the early examination to 0.4 ± 0.01 in 12 hours after transportation. In
the CG, FiO2 did not change. Hemodynamics diff erences between the
groups were not documented, except for HR (P >0.05). Tachycardia
was less expressed in the EG. The diff erence from the CG according to
this index occurred 12 hours after completion of the transportation,
83 ± 1 and 87 ± 0.7 beats/minute respectively (P <0.05). The lactate
rate was lower in the EG during all periods of observation (P <0.05). After completion of the transportation, the lactate rate in the EG was
2.2 ± 0.1 mol/l and in the CG was 2.7 ± 0.1 mol/l. Organ dysfunction in the resuscitation phase of critical burn
patients
A Agrifoglio, M Sánchez, M Hernández, J Camacho, L Cachafeiro,
M Asensio, E Herrero, A García de Lorenzo, M Jiménez
Hospital Universitario La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P462 (doi: 10.1186/cc11069) Early administration of parenteral estrogen suppresses the
deleterious local and systemic infl ammatory response in severe
burns Groups 2 and 3 had 40% TBSA third-degree
dorsal burns, early fl uid resuscitation and 0.5 mg/kg i.p. estrogen (or
placebo) 15 minutes post burn. From each group of 80, eight animals
were sequentially sacrifi ced (and burn tissue and blood sampled for
IL-6, TNFα, IL-1β) at one of 10 time points as follows: 0.5, 1, 2, 4, 6, 8, 18
and 24 hours and 7 days (7 days only for the eight shams). Introduction The purpose of this study was to examine the fl uid
resuscitation of severely burned patients admitted to our regional
centre and to review whether our practice had changed over the last 5
years in light of concerns of fl uid creep. Fluid creep is the term coined
by Pruitt used to describe fl uid resuscitation in excess of that predicted
by the Parkland formula and which is associated with abdominal
compartment syndrome (ACS) [1]. l
Methods Male rats (n = 168) were assigned randomly to one of three
groups: (1) sham (no) burn (n = 8); (2) burn given placebo (n = 80); and
(3) burn given E2 (estrogen). Groups 2 and 3 had 40% TBSA third-degree
dorsal burns, early fl uid resuscitation and 0.5 mg/kg i.p. estrogen (or
placebo) 15 minutes post burn. From each group of 80, eight animals
were sequentially sacrifi ced (and burn tissue and blood sampled for
IL-6, TNFα, IL-1β) at one of 10 time points as follows: 0.5, 1, 2, 4, 6, 8, 18
and 24 hours and 7 days (7 days only for the eight shams). Methods We completed a retrospective review in accordance with
clinical governance guidance of patient notes evaluating all admissions
in two groups (Group A: 1 May 2005 to 30 April 2006 and Group B: 1 May
2010 to 30 April 2011). The review examined the fi rst 72 hours of fl uid
resuscitation in patients with ≥15%TBSA burns who were admitted less
than 24 hours post burn injury. p
j
y
Results There were 12 patients in each group. Both groups were
comparable in both admission (Table 1) and resuscitation data. The total
fl uid (mean ± SD) given in the fi rst 24 hours post burn-centre admission
was 5.36 ± 2.22 ml/kg/%TBSA in Group A and 5.72 ± 3.00 ml/kg/%TBSA
in Group B (P = 0.817) with three patients in each group receiving
in excess of 250 ml/kg. 63
Epidemiological study of critical burn patients in an ICU
L Cachafeiro, M Sanchez, E Herrero, J Camacho, M Hernandez,
A Agrifoglio, A García de Lorenzo, M Jimenez
Hospital La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P463 (doi: 10.1186/cc11070) Introduction Burn injuries remain a signifi cant problem with high
associated morbidity and mortality, long average stays and high costs. The aim of our study is to analyze the epidemiology and mortality of
critical burn patients admitted to the ICU at a university hospital in
Madrid, Spain. Methods We performed a prospective, observational and descriptive
study in patients admitted with burns over 20% of the total body surface
area (TBSA), from October 2008 to December 2009. Demographic
data were collected, TBSA, location and mechanism of burns, severity
scores (ABSI, APACHE II, SOFA at admission, and next 3 days) length
of stay, complications and mortality. Data are presented as number
and percentage or as median and interquartile range, and they were
analyzed with the Fisher exact test and Mann–Whitney test. Conclusion This single-centre retrospective study indicates that
fl uid resuscitation volumes frequently overcome those previously
established by the Parkland protocol. This fl uid over-resuscitation
may have deleterious eff ects on patient outcome by increasing the
incidence of respiratory failure. Results During this period, 64 patients were admitted to our unit, 45
(70.3%) were men and 19 (29.7%) were women. The mean age was
48 ± 19. SOFA score at admission was 3 ± 2, APACHE II score 15 ± 6 (range
4 to 38) and ABSI 8 (range 5 to 16). The TBSA average was 40 ± 20%
and the mechanism of burn was by fl ame in 60 patients (93.8%), scald
in four (6.3%), electrical in two (3.1%) and chemical in one (1.6%). The
most frequent location was in the upper limbs in 60 patients (93.8%),
followed by thorax in 50 (78.19%), head and neck in 43 (67.2%), lower S165 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P464)
Patient data
Group A
Group B
P value
Number (n)
12
12
Age (years)
49 (18 to 69)
38.5 (21 to 77)
0.260
Weight (kg)
72 (55 to 109)
75 (60 to 99)
0.794
% TBSA
37.5 (16 to 70)
31 (18 to 60)
0.602
Inhalation injury (n)
6/12
3/12
0.206
Trauma (n)
1/12
0/12
0.307
Admission base defi cit
–5.95 (–15 to +1)
–6.55 (–11.7 to +2.5)
0.931
Admission lactate (mmol/l)
3.03 (0.98 to 5.4)
2.05 (0.5 to 4.1)
0.081
Survival (n)
6/12
9/12
0.206
Data presented as median (range). Figure 1 (abstract P463). Figure 1 (abstract P463). limbs in 43 (67.2%), and back in 29 (45.3%). Reference Reference Early administration of parenteral estrogen suppresses the
deleterious local and systemic infl ammatory response in severe
burns Conclusion In our study the most common burns were caused by fl ame
in the upper limbs, chest, neck and face. Eighty-nine percent of our
patients had complications, and they increased signifi cantly the length
of stay and mortality. Based on the SOFA score, patients had higher
scores for respiratory and cardiovascular systems. However, mortality
was lower than expected in severity scores. JG Wigginton1, PE Pepe1, JW Simpkins2, JW Gatson1, KG Wigginton1,
KR Kareem1, JP Minei1, D Maass1
1University of Texas Southwestern Medical Center, Dallas, TX, USA; 2University
of North Texas, Fort Worth, TX, USA
Critical Care 2012, 16(Suppl 1):P465 (doi: 10.1186/cc11072) JG Wigginton1, PE Pepe1, JW Simpkins2, JW Gatson1, KG Wigginton1,
KR Kareem1, JP Minei1, D Maass1
1University of Texas Southwestern Medical Center, Dallas, TX, USA; 2University
of North Texas, Fort Worth, TX, USA
Critical Care 2012, 16(Suppl 1):P465 (doi: 10.1186/cc11072) P464 Fluid creep in burn resuscitation: the tide has not yet turned
E James, M Hayes, P McCabe, G Williams, M Takata, MP Vizcaychipi
Chelsea and Westminster Hospital and Imperial College, London, UK
Critical Care 2012, 16(Suppl 1):P464 (doi: 10.1186/cc11071) Introduction Soon after severe burns, deleterious cytokines are
produced and found in the burned skin, including dead tissue in third-
degree injuries. This is followed by a systemic surge in these markers
and correlated with subsequent multiorgan failure (MOF). In animal
models, this response can be somewhat blunted by early debridement,
but such early intervention is not usually feasible in most clinical
settings. As estrogen is a powerful anti-infl ammatory/anti-apoptotic
agent, we tested parenteral 17β-estradiol (E2) as a feasible early
alternative intervention to dampen the proinfl ammatory response. Introduction Soon after severe burns, deleterious cytokines are
produced and found in the burned skin, including dead tissue in third-
degree injuries. This is followed by a systemic surge in these markers
and correlated with subsequent multiorgan failure (MOF). In animal
models, this response can be somewhat blunted by early debridement,
but such early intervention is not usually feasible in most clinical
settings. As estrogen is a powerful anti-infl ammatory/anti-apoptotic
agent, we tested parenteral 17β-estradiol (E2) as a feasible early
alternative intervention to dampen the proinfl ammatory response. Methods Male rats (n = 168) were assigned randomly to one of three
groups: (1) sham (no) burn (n = 8); (2) burn given placebo (n = 80); and
(3) burn given E2 (estrogen). 63
Epidemiological study of critical burn patients in an ICU
L Cachafeiro, M Sanchez, E Herrero, J Camacho, M Hernandez,
A Agrifoglio, A García de Lorenzo, M Jimenez
Hospital La Paz, Madrid, Spain
Critical Care 2012, 16(Suppl 1):P463 (doi: 10.1186/cc11070) Six patients had trauma
associated and 23 had inhalation injury. Thirty-two patients (50.0%)
required escharotomy at admission and 16 (25.0%) had compartment
syndrome. Forty-four patients (68.8%) needed mechanical ventilation,
and 20 (31.3%) tracheostomy. Fifty-six patients had complications. The most frequent were: shock (70.3%), ARDS (31.3%), sepsis (35.9%)
and renal failure (26.6%). All complications increased signifi cantly
the mortality (P <0.001). The length of stay was 30 days and global
mortality was 29.7% (19 patients). See Figure 1.l titration of fl uid administration to urine output and the specifi c role of
colloids in early resuscitation. Reference
1. Pruitt BA Jr: J Trauma 2000, 49:567-568. titration of fl uid administration to urine output and the specifi c role of
colloids in early resuscitation. Reducing the indication of ventilatory support in the severely
burnt patient and improving outcomes: results of a new protocol
approach within a regional burns centref Affi liation to group A correlated
with a shorter time of ventilation after admission (P <0.01); 61.1% of
these patients were extubated within 6 hours after admission (vs. 14.3%
in group B). Group A showed lower mortality rates (1 (1.4%) vs. 8 (14%),
P = 0.01), shorter total hospital stay (34.2 ± 23.9 vs. 50 ± 38.4, P = 0.014)
and lower incidence of sepsis (24 (39.3%) vs. 39 (68.4%), P <0.01). Methods A clinical observation study, approved by the local ethical
committee, was designed and executed. Criteria for early spontaneous
breathing were defi ned. These were formulated into a protocol for
the management of severely burnt patients and trialled over 2 years
in clinical practice on all admitted patients (group A). The ventilation
period, complications and fi nal outcomes were recorded and compared
with a retrospective control group of patients (group B) collated prior
to implementation of the protocol. Initial study analysis revealed high
inclusion rates of superfi cial burns in the intervention group. To achieve
comparability these were excluded and further analysis was conducted
only for patients with an abbreviated burn severity index (ABSI) ≥7. y
y
Results CPET was performed in 259 patients who subsequently
underwent an elective open AAA repair. Outcome data were available
for 185 patients from a potential 222 in whom 1-year follow-up was
available (83%). Baseline demographics included AT ≤10.9 ml/kg/
minute in 39% and >10.9 ml/kg/minute in 61% of patients with
respective median ages in these groups being 73 and 72. Regression
analysis demonstrated that AT was the only predictor of survival
at 30 days, 90 days and 1 year. Age and AT remained independent
predictors of survival at 90 days and 1 year following multivariate
analysis. Of note, 87 patients underwent elective endovascular
aneurysm repair and CPET, median age 76, during the period analysed. In particular, 26.4% were older than 80 years old, versus 14.7% in the
AAA group. See Figure 1. only for patients with an abbreviated burn severity index (ABSI) ≥7. Results In total 118 patients were included. The demographics and
injury characteristics of both groups were similar. Patients of group
A (n = 61) had fewer ventilator days in the time course of treatment
(3.9 ± 11.7 vs. 17.1 ± 19.6 days, P <0.01). Reducing the indication of ventilatory support in the severely
burnt patient and improving outcomes: results of a new protocol
approach within a regional burns centref AH Raithatha, S Smith, K Chakrabarti, A Tridente, K Kerr
Sheffi eld Teaching Hospitals NHS Trust: Northern General Hospital, Sheffi eld,
UK Introduction A reduced oxygen uptake at anaerobic threshold (AT) and
an elevated ventilatory equivalent for carbon dioxide (VE/VCO2) have
been shown to be predictors of outcome after major surgery [1]. We
report the demographic and outcome data of patients undergoing
elective open abdominal aortic aneurysm (AAA) surgery who
underwent cardiopulmonary exercise testing (CPET) testing within our
unit and examine the relationship between age, AT and VE/VCO2 on
survival outcomes. Introduction Initial management of the severely burnt patient often
includes sedation and mechanical ventilatory support as routine. Conversely it is documented in the literature that nonjudiciously
applied mechanical ventilatory support can itself lead to poorer
patient outcomes [1]. Exploring means to reduce this iatrogenic risk, a
standardised in-house fi ve-point protocol off ering clinical guidance on
the use and duration of ventilation was introduced, analysed and the
impact on outcome assessed. Methods A retrospective observational analysis of our unit’s CPET Excel
database was conducted to identify patients who underwent CPET
testing for elective open AAA repair over a 6-year period. Demographic
data and survival at 30 days, 90 days and 1 year were extracted. Logistic
regression analysis was undertaken using STATA statistical software to
determine if age, AT or VE/VCO2 were predictors of survival at 30 days,
90 days or 1 year. p
Methods A clinical observation study, approved by the local ethical
committee, was designed and executed. Criteria for early spontaneous
breathing were defi ned. These were formulated into a protocol for
the management of severely burnt patients and trialled over 2 years
in clinical practice on all admitted patients (group A). The ventilation
period, complications and fi nal outcomes were recorded and compared
with a retrospective control group of patients (group B) collated prior
to implementation of the protocol. Initial study analysis revealed high
inclusion rates of superfi cial burns in the intervention group. To achieve
comparability these were excluded and further analysis was conducted
only for patients with an abbreviated burn severity index (ABSI) ≥7. Results In total 118 patients were included. The demographics and
injury characteristics of both groups were similar. Patients of group
A (n = 61) had fewer ventilator days in the time course of treatment
(3.9 ± 11.7 vs. 17.1 ± 19.6 days, P <0.01). P467 P467
Cardiopulmonary exercise testing and elective open abdominal
aortic aneurysm surgery over a 6-year period in a UK teaching
hospital
AH Raithatha, S Smith, K Chakrabarti, A Tridente, K Kerr
Sheffi eld Teaching Hospitals NHS Trust: Northern General Hospital, Sheffi eld,
UK
Critical Care 2012, 16(Suppl 1):P467 (doi: 10.1186/cc11074) Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results In placebos, very high levels of cytokines appeared almost
immediately in the echars and circulation, persisting 7 days post burn. In the estrogen group, cytokines, including tissue and circulating IL-6,
the greatest predictor of MOF, remained suppressed at all time points,
even day 7 (Figure 1). No patients fulfi lling the inclusion criteria required re-intubation or
emergency intubation. Conclusion Extended periods of mechanical ventilatory support are
known to be associated with poorer outcomes in the severely burnt
patient. Guidance on minimising ventilator dependency through
introduction of a protocol has led to improved outcomes of such
patients within a regional burns centre. This study suggests that many
burns patients are overtreated through routine ventilation. Reference y
g
Conclusion Early single-dose parenteral estrogen can dramatically
suppress both the local and systemic massive proinfl ammatory
responses in severe burns. Based on these data, estrogen may not only
be an inexpensive, simple, adjunctive therapy in burn management, it
may obviate the need for many subsequent interventions altogether. References 1. Mackie D, Spoelder E, Paauw R, et al.: Mechanical ventilation and fl uid
retention in burn patients. J Trauma 2009, 67:1233-1238. 1. Mackie D, Spoelder E, Paauw R, et al.: Mechanical ventilation and fl uid
retention in burn patients. J Trauma 2009, 67:1233-1238. 1. Crit Care Med 2010, 38:S620-S629. 1. Crit Care Med 2010, 38:S620-S629. 2. J Neuroinfl amm 2009, 6:30-36. Early administration of parenteral estrogen suppresses the
deleterious local and systemic infl ammatory response in severe
burns Almost one-third of the fl uid administered
was colloid in each group. The hourly urine output (mean ± SD) was
1.34 ± 0.72 ml/kg/hour in Group A and 1.53 ± 1.47 ml/kg/hour in Group
B (P = 0.817). Inhalational injury was present in six patients in Group
A and three in Group B. The inhalational injury group (mean ± SD)
received 6.64 ± 2.51 ml/kg/%TBSA whilst the noninhalational injury
group received 4.88 ± 2.50 ml/kg/%TBSA (P = 0.101). There was no
reported incidence of ACS.l Figure 1 (abstract P465). Burned skin IL-6 levels at day 7. Conclusion Despite our awareness of fl uid creep, our practice has not
changed signifi cantly over the last 5 years. Fluid was administered
in excess of that predicted by the Parkland formula despite almost
one-third being given as colloid and no cases of ACS being reported. A multicentre randomised control trial is required to examine stricter S166 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Perioperative evaluation of elective surgical patients: is it possible
to plan ICU admission? p
LM Mozzoni, FR Ruggeri, MN Nastasi
Ospedale Ceccarini Riccione, Italy
Critical Care 2012, 16(Suppl 1):P468 (doi: 10.1186/cc11075) p
LM Mozzoni, FR Ruggeri, MN Nastasi
Ospedale Ceccarini Riccione, Italy
Critical Care 2012, 16(Suppl 1):P468 (doi: 10.1186/cc11075) Results There was no signifi cant diff erence between both groups
intraoperatively concerning arrhythmias, blood transfusion, and
hemodynamic support. Off -pump patients had a signifi cantly higher
mean number of constructed grafts than in the ONCAB group
(mean, 3.30 ± 0.88 vs. 2.84 ± 0.80, P = 0.02). There were no signifi cant
diff erences between off -pump and on-pump regarding postoperative
blood loss, blood transfusion, length of the ICU and the hospital
stay, the ventilation time, the use of intraaortic balloon pump, renal
complications, respiratory complications, and reopening. However,
graft occlusion, MI, raised cardiac enzymes, ventricular tachycardia,
cardiogenic shock, and disturbed conscious level were signifi cantly
higher in the OPCAB group. The postoperative mortality rate was
signifi cantly higher in the OPCAB group than in the ONCAB group
(15% vs. 0%, P = 0.046). Follow-up angiograms in 40 patients out of
65 (61.5%) who underwent 124 grafts revealed that no signifi cant
diff erence between off -pump and on-pump groups regarding the
overall rate of graft patency (83.5% vs. 84.4%, P = 0.84). No mortality
was reported in both groups at 6-month follow-up. Introduction The aim of the study is to evaluate the possibility to
predict ICU admission in elective surgical patients, studying the
perioperative period variables. Introduction The aim of the study is to evaluate the possibility to
predict ICU admission in elective surgical patients, studying the
perioperative period variables. Methods This is a prospective, nonintervention study concerning
207 patients, who have been operated on under elective conditions
from January to October 2011. The group we studied was aff ected by
thoracic (n = 78) or abdominal (n = 129) cancer. Mean age was 67.8 (SD
11.3; limits 24 to 91). ASA score III concerned 107 patients (51.7%) and
score II 98 patients (47.3%). A senior anesthetist screened all patients
before operation, assigning them to one of these three possible
groups: G0 (patient who does not need ICU admission), G1 (patients
who could need ICU admission), G2 (patients who defi nitely need ICU
admission). Scheduling of patients into groups was made considering
medical history, laboratory data, physical evaluation and type of
surgery. Patients were studied from surgical intervention to discharge. Aortic aneurysm disease versus aortic occlusive disease: diff erences
in postoperative ICU requirements after open elective abdominal
aortic surgery Aortic aneurysm disease versus aortic occlusive disease: diff erences
in postoperative ICU requirements after open elective abdominal
aortic surgery Aortic aneurysm disease versus aortic occlusive disease: diff erences
in postoperative ICU requirements after open elective abdominal
aortic surgery
J Bisgaard1, HK Jørgensen1, T Gilsaa1, E Ronholm1, P Toft2
1Littlebaelt Hospital Kolding, Denmark; 2Odense University Hospital, Odense,
Denmark
Critical Care 2012 16(Suppl 1):P470 (doi: 10 1186/cc11077) J Bisgaard1, HK Jørgensen1, T Gilsaa1, E Ronholm1, P Toft2
1Littlebaelt Hospital Kolding, Denmark; 2Odense University Hospital, Odense,
Denmark J Bisgaard1, HK Jørgensen1, T Gilsaa1, E Ronholm1, P Toft2
1Littlebaelt Hospital Kolding, Denmark; 2Odense University Hospital, Odense,
Denmark Critical Care 2012, 16(Suppl 1):P470 (doi: 10.1186/cc11077) Conclusion Preoperative evaluation does not appear to be a signifi cant
predictor for ICU admission, which is determined by intraoperative
or organizational factors. The ICU admission reduces the incidence of
postoperative complications; mortality is mainly due to the immediate
perioperative period. Introduction Open elective abdominal aortic surgery is a high-
risk procedure involving clamping of the aorta. Indications include
abdominal aortic aneurysm (AAA) or aortic occlusive disease (AOD)
causing lower limb ischaemia. These patients are often regarded as
one entity in postoperative study settings. However, previous studies
indicate that risk profi les, infl ammatory activity, and haemodynamic
capacity may diff er between these groups [1,2]. The aim of this study
was to evaluate postoperative ICU requirements after open elective
abdominal aortic surgery, hypothesising that AAA patients had longer
ICU stays and needed more mechanical ventilation or acute dialysis
than did patients with AOD. Reference Reference 1. Rhodes A, et al.: Intensive Care Med 2011, 37:1466-1472. 1. Rhodes A, et al.: Intensive Care Med 2011, 37:1466-1472. Perioperative evaluation of elective surgical patients: is it possible
to plan ICU admission? All data were analyzed using IBM SPSS statistics v19 (SPSS Inc.), using
adequate test and accepting P <0.05. Conclusion There was a higher incidence in postoperative
complications and mortality in the off -pump procedure than the on-
pump. At 6-month follow-up, no signifi cant diff erences between both
techniques were found in graft patency and mortality. Hence, longer-
term mortality from randomized trials of off -pump versus on-pump
CABG is needed. q
p
g
Results Sixty-six patients (31.9% of all patients) were in G0, 70 (33.8%)
in G1 and 71 (34.3%) in G2. The ASA score can distinguish patients in
G0 and G2, but not in G1 (P <0.05). The decision to schedule patients
in a group arises mainly from the coexistence of both cardiovascular
and respiratory diseases [1]. Ninety patients (43.5%) entered the ICU;
30 (42.8%) of these were in G1 and 34 (47.9%) in G2; 26 (39.4%) were
in G0. Distribution in the three groups of ICU-admitted patients was
similar (P = NS) and there was no signifi cant relationship between the
ASA score (and its distribution in the three groups) and ICU admission
(P = NS). Patients admitted had undergone surgery of longer duration
or had problems in the theater (low output syndrome, diffi cult
weaning at the end of procedure, bleeding) or organizational problems
(P <0.05). ICU-admitted patients show a lower number of postoperative
complications as arrythmias and wound infections (P <0.05). Four
patients died, all had been hospitalized in the ICU. The mortality rate
was 1.9% (75% were in G2). Patients with complications requiring
further surgery were 15 (7.2%), seven of which had been hospitalized
in the ICU.i Reference Reducing the indication of ventilatory support in the severely
burnt patient and improving outcomes: results of a new protocol
approach within a regional burns centref Affi liation to group A correlated
with a shorter time of ventilation after admission (P <0.01); 61.1% of
these patients were extubated within 6 hours after admission (vs. 14.3%
in group B). Group A showed lower mortality rates (1 (1.4%) vs. 8 (14%),
P = 0.01), shorter total hospital stay (34.2 ± 23.9 vs. 50 ± 38.4, P = 0.014)
and lower incidence of sepsis (24 (39.3%) vs. 39 (68.4%), P <0.01). Conclusion Our data support existing evidence that AT can be used as
a predictor of survival in open elective AAA surgery. In addition, age at Figure 1 (abstract P467). Elective AAA mortality rates by group. Figure 1 (abstract P467). Elective AAA mortality rates by group. S167 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods This nonrandomized single-centre control trial was
prospectively conducted on 65 patients who were subjected to
coronary artery bypass surgery followed by stay in the Open Heart
Intensive Care Center of the Police Authority Hospital, in the period
from July 2009 to January 2010. Patients were divided into two groups;
group A, 25 patients underwent surgery using cardiopulmonary
bypass pump (on coronary artery bypass pump (ONCAB)); and group
B, 40 patients underwent surgery without using cardiopulmonary
bypass pump (off -pump coronary artery bypass (OPCAB)). All of the
demographic, operative and postoperative data were prospectively
collected and analyzed statistically. Six months later, the patients
underwent coronary angiography. CPET also predicted 90-day and 1-year survival; however, VE/VCO2 was
not a predictor of survival in this cohort. Reference CPET also predicted 90-day and 1-year survival; however, VE/VCO2 was
not a predictor of survival in this cohort. Reference 1. Carlisle J, et al.: Mid-term survival after abdominal aortic aneurysm surgery
predicted by cardiopulmonary exercise testing. Br J Surg 2007, 94:966-969. P469 Cardiac-specifi c biomarkers and life-threatening complications of
off -pump versus on-pump coronary bypass surgery in Egyptian
patients
H Elabd1, A Alsherif2, T El Gohary2, M Hagras2, S Salah Eldin2
1Student Hospital, Cairo University, Giza, Egypt; 2Kasr Alaini Hospitals, Cairo,
Egypt
Critical Care 2012, 16(Suppl 1):P469 (doi: 10.1186/cc11076) Reference 1. Shroyer AL, Grover FL, Hattler B, et al.: On-pump versus off -pump coronary-
artery bypass surgery. N Engl J Med 2009, 361:1827-1837. P471 P471
High postoperative blood levels of macrophage migration
inhibitory factor are associated with less organ dysfunction in
patients after cardiac surgery
C Stoppe1, G Grieb1, D Simons1, R Rossaint1, J Bernhagen1, S Rex2
1University Hospital of the RWTH, Aachen, Germany; 2University Hospital
Gasthuisberg, KU Leuven, Belgium
Critical Care 2012, 16(Suppl 1):P471 (doi: 10.1186/cc11078) Introduction Macrophage migration inhibitory factor (MIF) is a
structurally unique infl ammatory cytokine [1] that exerts protective
eff ects during ischemia and reperfusion [2]. We hypothesized that
elevated MIF levels in the early postoperative time course might be
inversely associated with postoperative organ dysfunction as assessed
by SAPS II and SOFA score in patients after cardiac surgery. y
p
g
y
Methods Fifty-two cardiac surgical patients (mean age (± SD) 67 ± 10
years; EuroSCORE: 7 (2 to 11)) were enrolled in this monocenter,
prospective, observational study. Serum levels of MIF and clinical data
were obtained after induction of anesthesia, at admission to the ICU, 4
hours thereafter and at the fi rst and second postoperative day (POD). Patient outcome was assessed using the SAPS II at POD1 and SOFA
score for the fi rst 3 days of the eventual ICU stay. Conclusion Prolonged mechanical ventilation occurred in 40% of our
patients after heart transplantation. A higher creatinine level during
the fi rst 24 hours after the surgery was associated with prolonged
mechanical ventilation in this study. P472 and malignant disease (2.7 vs. 0.6%, P = 0.02). In contrast, AOD patients
had a higher prevalence of smoking (95 vs. 86%, P <0.001), and diabetes
(16 vs. 9%, P <0.001). AAA patients had larger intraoperative blood
losses (1,610 (1,000 to 2,500) vs. 1,200 (750 to 1,800) ml, P <0.001),
but duration of surgery was shorter (161 (130 to 205) vs. 194 (160 to
240) minutes, P <0.001). Postoperatively, more AAA patients had ICU
stays >24 hours (62 vs. 45%, P <0.001), tended to need mechanical
ventilation more often (16 vs. 12%, P = 0.08), and more needed acute
dialysis (3.8 vs. 0.9%, P <0.03). and malignant disease (2.7 vs. 0.6%, P = 0.02). In contrast, AOD patients
had a higher prevalence of smoking (95 vs. 86%, P <0.001), and diabetes
(16 vs. 9%, P <0.001). AAA patients had larger intraoperative blood
losses (1,610 (1,000 to 2,500) vs. 1,200 (750 to 1,800) ml, P <0.001),
but duration of surgery was shorter (161 (130 to 205) vs. 194 (160 to
240) minutes, P <0.001). Postoperatively, more AAA patients had ICU
stays >24 hours (62 vs. 45%, P <0.001), tended to need mechanical
ventilation more often (16 vs. 12%, P = 0.08), and more needed acute
dialysis (3.8 vs. 0.9%, P <0.03). 1.
Shteinberg D, et al.: Eur J Vasc Endovasc Surg 2000, 20:462-465.
2.
Johnston WE, et al.: Anesthesiology 1987, 66:386-389. f
References 1. Shteinberg D, et al.: Eur J Vasc Endovasc Surg 2000, 20:462-465. 2. Johnston WE, et al.: Anesthesiology 1987, 66:386-389. Results The mean age of the patients (71% male) was 31.5 ± 16.8
years and the incidence of prolonged mechanical ventilation was 40%. Compared with patients who did not require prolonged mechanical
ventilation, those who did had signifi cantly lower preoperative
hemoglobin levels (12.0 ± 1.5 vs. 13.7 ± 2.4 mg/dl, P = 0.03), higher
intraoperative lactate levels (7.14 ± 4.13 vs. 3.5 ± 1.82 mmol/l,
P = 0.006), higher postoperative day 1 serum creatinine levels (2.2 ± 0.9
vs. 1.2 ± 0.7 mg/dl, P = 0.002), and longer cardiopulmonary bypass
times (143.0 ± 24.2 vs. 122.8 ± 29.1 minutes, P = 0.005). Binary logistic
regression revealed that the postoperative day 1 serum creatinine level
was an independent risk factor for prolonged mechanical ventilation
after heart transplantation (OR: 5.109; 95% CI: 1.362 to 19.159, P = 0.016). Length of hospital stay was signifi cantly longer in patients with PMV
than those who did not require prolonged mechanical ventilation
(36.4 ± 30.4 vs. 21.8 ± 12.7, P = 0.049). The respective mortality rates
for patients with prolonged mechanical ventilation and those without
prolonged mechanical ventilation were 60% versus 40%, P = 0.15. Predictors of prolonged mechanical ventilation after heart
transplantation Introduction Several studies have reported that prolonged mechanical
ventilation is associated with high mortality and morbidity rates, length
of hospital stay, and costs after coronary artery and valvular surgeries. However, no study has focused on the incidence and risk factors of
prolonged mechanical ventilation after heart transplantation. The
aim of this study was to determine the incidence and predictors of
prolonged mechanical ventilation after heart transplantation. y
Conclusion Compared to the AOD group, more AAA patients had ICU
stays >24 hours and more often needed acute dialysis. Distinguishing
between these two diseases may be useful in planning and distribution
of ICU resources. Furthermore, considering these two patient groups as
diff erent pathological entities may be advised in future studies. References Methods We retrospectively analyzed the records of 38 out of 45
patients who underwent heart transplantation from February 2003 to
November 2010 at our center. Patients under 12 years of age and those
who died before extubation were excluded. We defi ned prolonged
mechanical ventilation as mechanical ventilation longer than 36
hours. Preoperative, intraoperative, and postoperative variables were
collected. Reference 1. Cislaghi F, et al.: Minerva Anestesiol 2007, 73:615-621. 1. Cislaghi F, et al.: Minerva Anestesiol 2007, 73:615-621. i
Results MIF_AUC, the computed area under the curve of MIF serum
levels from admission until POD1, was inversely correlated with SAPS
II and SOFA score on POD1 (Table 1). MIF at admission (r = 0.296;
P = 0.041) and MIF at 4 hours (r = 0.367; P = 0.012) correlated inversely
with the paO2/FiO2 ratios at POD1. Moreover, postoperative MIF values
were inversely correlated with SAPS II (r = 0.528; P = 0.044) and SOFA
scores during the early postoperative stay (Table 1). In addition, MIF
values on POD1 were related to the calculated Cardiac Power Index
(r = 0.420; P = 0.009). Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Cardiac-specifi c biomarkers and life-threatening complications of
off -pump versus on-pump coronary bypass surgery in Egyptian
patients Cardiac-specifi c biomarkers and life-threatening complications of
off -pump versus on-pump coronary bypass surgery in Egyptian
patients p
Methods This cohort study was based on prospectively registered data
from the Danish National Vascular Registry and the Danish ICU Database
between 1 January 2007 and 1 May 2010. The study population
comprised all patients (n = 1293) undergoing open elective, primary
aorto-iliac bypass, or aorto-femoral bypass procedures (n = 363) or
abdominal aortic aneurysm repair (n = 930) in the eight hospitals
performing these procedures in Denmark. The primary endpoints
were: ICU stay >24 hours, mechanical ventilation, and acute dialysis. Results Patients in the AAA group were older (70 ± 7 vs. 62 ± 9 years,
P <0.001), predominantly males (80 vs. 49%, P <0.001), with a higher
prevalence of preoperative cardiac co-morbidity (34 vs. 24%, P = 0.001), p
H Elabd1, A Alsherif2, T El Gohary2, M Hagras2, S Salah Eldin2
1Student Hospital, Cairo University, Giza, Egypt; 2Kasr Alaini Hospitals, Cairo,
Egypt
Critical Care 2012, 16(Suppl 1):P469 (doi: 10.1186/cc11076) gyp
Critical Care 2012, 16(Suppl 1):P469 (doi: 10.1186/cc11076) Introduction Coronary artery bypass grafting (CABG) has traditionally
been performed with the use of cardiopulmonary bypass (ONCAB). This study aims to compare between on-pump and off -pump surgery
concerning postoperative morbidity and mortality, and also to evaluate
6-month graft patency in Egyptian patients. Results Patients in the AAA group were older (70 ± 7 vs. 62 ± 9 years,
P <0.001), predominantly males (80 vs. 49%, P <0.001), with a higher
prevalence of preoperative cardiac co-morbidity (34 vs. 24%, P = 0.001), S168 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Oxygen delivery index during goal-directed therapy predicts
complications and hospital length of stay in patients undergoing
high-risk surgery y
M Cecconi, N Arulkumaran, R Suleman, D Shearn, M Geisen, J Mellinghoff ,
D Dawson, J Ball, M Hamilton, M Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P474 (doi: 10.1186/cc11081) Introduction National guidance for patients presenting to the emergency
department (ED) with a traumatic head injury advises that head computed
tomography (CT) should be performed and reported within 1 hour [1]. The operative intervention or injury to knife time should be within 4 hours
[2]. With more than 50% of patients requiring neurosurgical intervention
in the UK taken to hospitals without onsite neurosurgical services [3],
secondary transfer is necessary prior to defi nitive intervention. Are we
achieving timely transfers in rural England? Introduction National guidance for patients presenting to the emergency
department (ED) with a traumatic head injury advises that head computed
tomography (CT) should be performed and reported within 1 hour [1]. The operative intervention or injury to knife time should be within 4 hours
[2]. With more than 50% of patients requiring neurosurgical intervention
in the UK taken to hospitals without onsite neurosurgical services [3],
secondary transfer is necessary prior to defi nitive intervention. Are we
achieving timely transfers in rural England? Introduction The aim of this study was to evaluate the effi cacy of a
goal-directed therapy (GDT) protocol designed to augment the oxygen
delivery index (DO2I) and to assess the relationship between DO2I
measurements and postoperative complications and length of stay. Methods A single-centre retrospective cohort study assessing the data
obtained during an 8-hour post-operative GDT protocol in consecutive
major surgical patients admitted to the ICU. Introduction The aim of this study was to evaluate the effi cacy of a
goal-directed therapy (GDT) protocol designed to augment the oxygen
delivery index (DO2I) and to assess the relationship between DO2I
measurements and postoperative complications and length of stay. Methods A single-centre retrospective cohort study assessing the data
obtained during an 8-hour post-operative GDT protocol in consecutive
major surgical patients admitted to the ICU. y
Methods The Royal Cornwall Hospital is a district general hospital
serving a population of 300,000. The regional neurosurgical unit is
100 km away. All patients undergoing transfer to the neurosurgical
unit during 2009 were identifi ed. A notes review was undertaken of all
these patients transferred to the care of neurosurgeons. The operative
logs were also reviewed. Oxygen delivery index during goal-directed therapy predicts
complications and hospital length of stay in patients undergoing
high-risk surgery Time lines were created of their care from
ambulance call to neurosurgical intervention. j
g
p
Results Thirty-seven patients were included. The median DO2I increased
over the 8-hour protocol from a baseline level of 407 ml/minute/m2 to
a maximum of 537 ml/minute/m2 (P <0.0001) (Figure 1). Twenty-one
(57%) patients developed a postoperative complication. Patients who
developed zero or one complication had a higher maximum oxygen
delivery index DO2I than patients who had more than one complication
(602 vs. 477 ml/minute/m2, P = 0.018) (Table 1). The proportion of
patients with a length of stay greater than 2 weeks was less in patients
who achieved a DO2I of at least 600 ml/minute/m2 (P = 0.035). Results Ten patients in total were transferred for neurosurgical
intervention. Two of these patients required two transfers as they were
initially seen in satellite minor injury units. No patient had CT within
1 hour of arriving in the ED. The median time was 2 hours 56 minutes. The CT report was available at a median of 3 hours 17 minutes. None
of these patients arrived in the tertiary referral centre within 4 hours of
their injury. The fastest time to intervention was 8 hours 29 minutes,
median 22 hours 59 minutes after injury. 2
Conclusion Postoperative GDT was able to increase DO2I in the
postoperative period. Patients who achieved a DO2I of 600 ml/minute/
m2 were less likely to suff er postoperative complications and have a
signifi cantly reduced length of hospital stay. y
Conclusion We are not meeting targets for CT head acquisition and
transfer for neurosurgical intervention. Prompt transfer of a trauma
patient from a rural district general hospital in the UK to a tertiary
referral centre for neurosurgical intervention is a multifactorial problem. The introduction of trauma centres and of protocols for direct admission
to tertiary centres by paramedics may reduce the delays that our audit
has highlighted. Figure 1 (abstract P474). Increase in DO2I from baseline to maximum
over the 8-hour protocol. Atrial fi brillation following major noncardiac thoracic surgery:
signifi cance and impact on morbidity P475 P475
Transfer delays in patients referred for neurosurgical intervention
with traumatic brain injury
L Smith1, B Jordan2, J Paddle1
1Royal Cornwall Hospital NHS Trust, Truro, UK; 2Derriford Hospital, Plymouth, UK
Critical Care 2012, 16(Suppl 1):P475 (doi: 10.1186/cc11082) P475
Transfer delays in patients referred for neurosurgical intervention
with traumatic brain injury
L Smith1, B Jordan2, J Paddle1
1Royal Cornwall Hospital NHS Trust, Truro, UK; 2Derriford Hospital, Plymouth, UK
Critical Care 2012, 16(Suppl 1):P475 (doi: 10.1186/cc11082) P475
Transfer delays in patients referred for neurosurgical intervention
with traumatic brain injury References 1. Head Injury Triage: Assessment, Investigation and Early Management of
Head Injury in Infants, Children and Adults, Methods Evidence and
Guidance. Commissioned by the National Institute for Health and Clinical
Excellence. [http://guidance.nice.org.uk/CG56/NICEGuidance/pdf/English] p
g
g
p
g
2. Better Care for the Severely Injured. Joint Report. Royal College of Surgeons
of England and British Orthopaedic Association. [http://www.rcseng.ac.uk/
publications/docs/severely_injured.html]i p
y
j
3. Trauma: Who Cares? Report. National Confi dential Enquiry into Patient
Outcome and Death. [http://www.ncepod.org.uk/2007report2/Downloads/
SIP_report.pdf] P474 Oxygen delivery index during goal-directed therapy predicts
complications and hospital length of stay in patients undergoing
high-risk surgery
M Cecconi, N Arulkumaran, R Suleman, D Shearn, M Geisen, J Mellinghoff ,
D Dawson, J Ball, M Hamilton, M Grounds, A Rhodes
St George’s Hospital, London, UK
Critical Care 2012, 16(Suppl 1):P474 (doi: 10.1186/cc11081) Atrial fi brillation following major noncardiac thoracic surgery:
signifi cance and impact on morbidity Metaxa Hospital, Athens, Greece
Critical Care 2012, 16(Suppl 1):P473 (doi: 10.1186/cc11080) Table 1 (abstract P471)
MIF level
SOFA 1. POD
SOFA 2. POD
SOFA 3. POD
ICU admission
r = –0.2; P = 0.18
r = –0.4; P = 0.11
r = –0.6; P = 0.05
4 hours later
r = –0.4; P = 0.40
r = –0.5; P = 0.05
r = –0.8; P = 0.01
MIF_AUC
r = –0.4; P = 0.01
r = –0.2; P = 0.55
r = –0.4; P = 0.19
1. POD
r = –0.3; P = 0.08
r = –0.6; P = 0.03
r = –0.7; P = 0.02
Conclusion Elevated postoperative MIF levels are inversely correlated
with organ dysfunction in patients after cardiac surgery. References
1. Calandra T, et al.: Macrophage migration inhibitory factor: a regulator of
innate immunity. Nat Rev Immunol 2003, 3:791-800. 2. Koga K, et al.: Macrophage migration inhibitory factor provides
cardioprotection during ischemia/reperfusion by reducing oxidative
stress. Antioxid Redox Signal 2011, 14:1191-1202. Introduction Atrial fi brillation (AF) is a common complication after
noncardiac thoracic surgery. Its impact on overall mortality has not
yet been fully assessed and few data are available on the eff ects of the
noncardiac post-thoracotomy AF on clinical outcomes. Methods From July 2006 to July 2011, 226 consecutive patients
undergoing lung resection for lung cancer were studied retrospectively. Preoperative data and serial electrocardiograms were evaluated. Hypertension, dyslipidaemia, diabetes mellitus, smoking and advanced
age (>75 years) were considered as risk factors. Patients (n = 97) who
had structural heart disease or ≥2 risk factors were considered a high-
risk group whereas those with <2 risk factors constituted the low-risk
group. g
p
Results Thirty-two patients (14.16%) experienced new-onset post-
operative AF. The high-risk group had a 58% incidence of AF compared
with 23% in the low-risk group (P <0.001). Moreover, following
β-blocker administration, more of the high-risk group required
antiarrhythmic treatment with amiodarone than did the low-risk group
(67% vs. 35% respectively, P = 0.02). Patients who developed AF had 2. Koga K, et al.: Macrophage migration inhibitory factor provides
cardioprotection during ischemia/reperfusion by reducing oxidative
stress. Antioxid Redox Signal 2011, 14:1191-1202. Atrial fi brillation following major noncardiac thoracic surgery:
signifi cance and impact on morbidity S169 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 P475
Transfer delays in patients referred for neurosurgical intervention
with traumatic brain injury
L Smith1, B Jordan2, J Paddle1
1Royal Cornwall Hospital NHS Trust, Truro, UK; 2Derriford Hospital, Plymouth, UK
Critical Care 2012, 16(Suppl 1):P475 (doi: 10.1186/cc11082)
Table 1 (abstract P474). Postoperative complications by achievement of an
oxygen delivery index of 600
DO2I >600
DO2I <600
P value
Number of patients
16 (43%)
21 (57%)
–
Complications
13 (29%)
32 (71%)
P = 0.003
Mortality
0 (0%)
4 (100%)
P = 0.12 Table 1 (abstract P474). Postoperative complications by achievement of an
oxygen delivery index of 600 Table 1 (abstract P474). Postoperative complications by achievement of an
oxygen delivery index of 600 a signifi cantly longer hospital stay (P <0.01). The 30-day mortality rate
was signifi cantly higher in the high-risk group (11% vs. 2%; P = 0.03)
but AF was not an independent risk factor for death. In the multivariate
analysis, major resection (pneumonectomy) and advanced age
were identifi ed as independent risk factors for the development of
postoperative AF (P = 0.004 and P = 0.008 respectively).i a signifi cantly longer hospital stay (P <0.01). The 30-day mortality rate
was signifi cantly higher in the high-risk group (11% vs. 2%; P = 0.03)
but AF was not an independent risk factor for death. In the multivariate
analysis, major resection (pneumonectomy) and advanced age
were identifi ed as independent risk factors for the development of
postoperative AF (P = 0.004 and P = 0.008 respectively).i DO2I >600
DO2I <600
P value
Number of patients
16 (43%)
21 (57%)
–
Complications
13 (29%)
32 (71%)
P = 0.003
Mortality
0 (0%)
4 (100%)
P = 0.12 Conclusion Atrial fi brillation occurrence after lung resection does not
independently aff ect the short-term mortality but is associated with a
prolonged length of hospital stay. Performances of ventilator at simulated altitude
1
k1
l
1
l h1 Performances of ventilator at simulated altitude
E Forsans1, L Franck1, T Leclerc1, M Bensalah1, J Tourtier1, Y Auroy1,
C Bourrilhon2
1HIA Val-de-Grâce, Paris, France; 2Institut de Recherche Biomédicale des
Armées, Brétigny sur Orges, France
Critical Care 2012, 16(Suppl 1):P476 (doi: 10.1186/cc11083) E Forsans1, L Franck1, T Leclerc1, M Bensalah1, J Tourtier1, Y Auroy1,
C Bourrilhon2
1HIA Val-de-Grâce, Paris, France; 2Institut de Recherche Biomédicale des
Armées, Brétigny sur Orges, France
Critical Care 2012, 16(Suppl 1):P476 (doi: 10.1186/cc11083) E Forsans1, L Franck1, T Leclerc1, M Bensalah1, J Tourtier1, Y Auroy1,
C Bourrilhon2 C Bourrilhon
1HIA Val-de-Grâce, Paris, France; 2Institut de Recherche Biomédicale des
Armées, Brétigny sur Orges, France
Critical Care 2012, 16(Suppl 1):P476 (doi: 10.1186/cc11083) Introduction We have assessed the ability of three ventilators to deliver
to a normal lung model a set tidal volume (Vt) at diff erent simulated
cabin altitudes. We studied the performance of the LTV-1200 (Viasys
Healthcare, USA), the Elisée 350 (Resmed, Australia) and the Medumat
transport (Weinmann, Germany). Figure 1 (abstract P474). Increase in DO2I from baseline to maximum
over the 8-hour protocol. Figure 1 (abstract P474). Increase in DO2I from baseline to maximum
over the 8-hour protocol. S170 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 critical care capacity and as a consequence the surge in admissions had
a signifi cant impact on both critical care and critical care dependent
hospital services. Figure 1 (abstract P476). p
Methods Data were collected prospectively through the Critical
Care Minimum Data Set: the number of critical care admissions with
confi rmed or highly suspected infl uenza, co-morbidities, mortality rate,
level 3 bed day occupancy, number and mode of advanced respiratory
support days, numbers of nonclinical and clinical transfers, and
numbers of cancelled operations requiring critical care. p
q
g
Results In a 10-week period 128 patients in Wales required critical care
with infl uenza. A total of 1,692 level 3 bed days were required. There are
95 potential level 3 beds across Wales per day. Therefore >25% of level
3 beds over 10 weeks were occupied by infl uenza patients. Fifty percent
of patients had signifi cant comorbidities; pregnancy, COPD, morbid
obesity, immunocompromise (Figure 1). The overall mortality rate for
all aff ected critical care patients was 23.4%. Mortality was 25% in those
with comorbidities and 22% in those without. Performances of ventilator at simulated altitude
1
k1
l
1
l h1 The overall mortality rate
for all aff ected patients treated in Wales during the 2009/10 infl uenza
pandemic was 9.6%. The UK has fewer critical care beds per head of
population than comparable nations, and Wales fewer still so critical
care in Wales is more vulnerable to surges in admissions. This was
apparent in the peak in nonclinical critical care transfers seen during
this period, performed due to units exceeding their capacity, and in an
increase in cancellations of elective surgery requiring critical care. Methods We used a decompression chamber to mimic the hypobaric
environment at a range of simulated cabin altitudes of 2,438 and
3,657 m (8,000 and 12,000 feet). Ventilators were tested with a set
fraction of inspired oxygen of 50% and Vt set at 450. Respiratory rate
was 12 breaths/minute. Comparisons of preset to actual measured
values were accomplished using a t test for each altitude. The protocol
included 36 measurements for each Vt set at each simulated altitude. A
signifi cant diff erence was defi ned by P <0.05. Methods We used a decompression chamber to mimic the hypobaric
environment at a range of simulated cabin altitudes of 2,438 and
3,657 m (8,000 and 12,000 feet). Ventilators were tested with a set
fraction of inspired oxygen of 50% and Vt set at 450. Respiratory rate
was 12 breaths/minute. Comparisons of preset to actual measured
values were accomplished using a t test for each altitude. The protocol
included 36 measurements for each Vt set at each simulated altitude. A
signifi cant diff erence was defi ned by P <0.05. Conclusion The shortage of critical care capacity in Wales is made more
apparent during times of increased critical care requirement such as
the infl uenza in the winter 2010/2011. Hospital services are increasingly
dependent on critical care, and government and health boards need to
provide targeted increases in critical care bed provision to match those
levels in other similar nations to mitigate the eff ect on critical care and
dependent services due to surges in demand. Results Figure 1 summarizes the data. Comparisons of actual delivered
Vt in altitude and set Vt demonstrated a signifi cant diff erence for the
three ventilators. P478f 8
Eff ects of levels of clinical supervision during simulated ICU
scenarios on resident learning and patient care: a qualitative study
D Piquette1, M Mylopoulos2, VR LeBlanc3
1Sunnybrook Health Sciences Centre, Toronto, Canada; 2SickKids Hospital,
Toronto, Canada; 3Wilson Centre, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P478 (doi: 10.1186/cc11085) Performances of ventilator at simulated altitude
1
k1
l
1
l h1 Conclusion The LTV-1200 showed a very signifi cant increase in Vt
delivered with increasing altitude (suggesting a lack of effi cacy of
altimetric correction in hypobaric conditions), whereas the Elisée 350
and Medumat transport delivered respectively a stable and a rather
stable Vt. P479 P479
Virtual reality and live scenario simulation: options for training
medical students in mass casualty incident triage
PL Ingrassia, L Ragazzoni, L Carenzo, FL Barra, D Colombo, G Gugliotta,
F Della Corte
CRIMEDIM Research Center in Disaster and Emergency Medicine, Novara, Italy
Critical Care 2012, 16(Suppl 1):P479 (doi: 10.1186/cc11086) Introduction Multicasualty triage is the process of establishing the
priority of care among casualties in disaster management. Recent mass
casualty incidents (MCI) revealed that health personnel are unfamiliar
with the triage protocols. The objective of this study is to compare the
relative impact of two simulation-based methods for training medical
students in mass casualty triage using the Simple Triage and Rapid
Treatment (START) algorithm. Results The transportation time by ambulance was shorter for the fi rst
time since statistics were fi rst kept in 1999, the mean time was 33.7
minutes in 2009 and 33.2 minutes in April 2011. Furthermore, the new
system is expected to reduce the operational costs by 40,000,000 yen a
year. The data on the transportation time by ambulance are continually
stored in the system and analyses are continuing. Conclusion The introduction of iPad to the new 99 Saga Net has
three benefi cial points. First, the utilization of information and
communication technology is useful for a realistic emergency medical
setting. Second, the situation of a realistic emergency medical setting
is visualized in real time. Finally, both the emergency personnel and
the medical staff in the hospital share the information in an emergency
medical setting by eliminating vertically divided administrative
functions. Medical personnel will work with local governments in the
future to analyze the data from this new system. Methods A prospective randomized controlled longitudinal study. Medical students enrolled in the emergency medicine course were
randomized into two groups (A and B). On day 1, group A students
were exposed to a virtual reality (VR) scenario and group B students
were exposed to a live scenario (LS), both exercises aiming at triaging
10 victims in a limited period of time (30 seconds/victim). On day
2 all students attended a 2-hour lecture about medical disaster
management and START. On day 3 group A and B students were
exposed to a LS and to a VR scenario respectively. The vital signs and
clinical condition of the 10 victims were identical in the two scenarios. Impact of H1N1 infl uenza on critical care and dependent services in
Wales during winter 2010/2011 Introduction Closer clinical supervision of residents is often perceived
as a double-edged sword, improving patient safety but limiting
resident participation in patient care. There has been little empirical
research on the educational eff ects of closer supervision. We examined
the impact of levels of clinical supervision on clinical learning and
patient care during acute simulated resuscitation. Introduction Infl uenza H1N1 admissions to critical care from
December 2010 to January 2011 had a signifi cant impact on intensive
care bed occupancy across Wales. Wales is relatively underprovided in Methods Fifty-four ICU residents (PGY1 to 4) were randomly assigned
to complete a simulated ICU scenario in one of three levels of Figure 1 (abstract P477). Infl uenza admissions into critical care in winter 2010/2011. Figure 1 (abstract P477). Infl uenza admissions into critical care in winter 2010/2011. S171 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 supervision (physical proximity of supervising ICU fellow: distant,
immediately available, direct). In-person and telephone interactions
between participants were recorded and transcribed. We conducted an
inductive thematic analysis of anonymized transcripts using constant
comparison within and between scenarios. Distributed cognition
theory was used as a framework to guide analysis. supervision (physical proximity of supervising ICU fellow: distant,
immediately available, direct). In-person and telephone interactions
between participants were recorded and transcribed. We conducted an
inductive thematic analysis of anonymized transcripts using constant
comparison within and between scenarios. Distributed cognition
theory was used as a framework to guide analysis. prompting critical decisions in mass casualty drills. In the beginning the
average time to complete the VR scenario was higher than the LS. This
could be due to the fact that on day 1 very detailed VR victims created
a higher challenge for untaught students. However, the higher triage
accuracy recorded at the end of day 3 in VR could be explained by a
lower stress level compared to the LS, which could be creating a more
stressful environment in taught students. y
g
y
Results Both distant and direct levels of supervision resulted in
variable involvement of residents in patient care. A shift of control
over patient care from residents to fellows often occurred regardless
of the physical distance of the fellow. Direct supervision did not always
result in decreased resident contributions. Impact of H1N1 infl uenza on critical care and dependent services in
Wales during winter 2010/2011 Fellows were found to
facilitate more elaborated cognitive contributions from the residents
during direct supervision. In addition, practicing in the presence of
a supervisor was more likely to lead to timely feedback. However,
a presence at the bedside allowed fellows to infl uence the nature of
resident involvement by delegating specifi c tasks such as technical
procedures. During distant supervision, fellows had to use residents as
proxies to obtain information about patients and to deliver care, with
potentially serious consequences: when residents’ interpretations of
the clinical information were problematic, the quality of fellows’ clinical
decisions was negatively aff ected. Higher cognitive work required of
fellows during distant supervision appeared to limit their ability to
invest cognitive resources in teaching. P480 P479 Ability of the groups to manage a simulated triage scenario was then
compared (times and triage accuracy). Reference 1. Fire and Disaster Management Agency: White Paper on Fire and Disaster (2010) [in
Japanese]. [http://www.fdma.go.jp/html/hakusho/h22/h22/html/2-4-5_4.html] p
g
y
Results Groups A and B were composed of 25 and 28 students
respectively. During day 1 group A LS triage accuracy was 58%, while
the average time to assess all patients was 4 minutes 28 seconds. The
group B VR scenario triage accuracy was 52%, while the average time to
complete the assessment was 5 minutes 18 seconds. During day 3 the
triage accuracy for group A VR simulation was 92%, while the average
time was 3 minutes 53 seconds. Group B triage accuracy during the LS
was 84%, with an average time of 3 minutes 25 seconds. Triage scores
improved signifi cantly during day 3 (P <0.001) in the two groups. The
time to complete each scenario decreased signifi cantly from day 1 to
day 3. Utilization of iPad in the system of emergency demand and
acceptance Utilization of iPad in the system of emergency demand and
acceptance K Yamada1, Y Sakamoto1, Y Enjiyouji2
1Saga University, Saga, Japan; 2Saga Prefectural Government, Saga, Japan
Critical Care 2012, 16(Suppl 1):P480 (doi: 10.1186/cc11087) Introduction This study reports that the transportation time by
ambulance was shorter following the introduction of iPad (Apple,
Inc.) to the current system of emergency demand and acceptance in
Saga Prefecture, Japan. There were about over 5,000,000 ambulance
dispatches in Japan, and the time for transportation is increasing
(the national average: 36.1 minutes) [1]. The administration has made
various eff orts nationwide that did not achieve any positive results. Although the information system of medical institutions and the
emergency medical service (99 Saga Net) was established in 2003 in
Saga, it has been underutilized. The Saga prefectural government
renewed the previous system as the real-time system of emergency
demand and acceptance for the fi rst time in Japan in April 2011. Conclusion Level of clinical supervision was not the main determinant
of resident engagement in patient care. Both distantly and directly
supervised scenarios presented learning opportunities for residents. Given the observed negative eff ects of distant supervision on patient
care, strategies to optimize unique learning opportunities off ered by
direct supervision should be investigated. i
Methods Cloud computing has provided new system to facilitate
Internet access from ambulances. In addition, iPads were put into all
ambulances (about 55) and emergency medical technicians can get
the picture of acceptable hospitals in real time. Emergency personnel
who arrive on the scene select the patient’s symptoms with an iPad,
and this new system displays an up-to-date list of acceptable hospitals. The data that the emergency personnel entered into the system from
the iPad are uploaded to 99 Saga Net immediately. Therefore, both
the emergency personnel and medical staff in the hospital share the
information of where the emergency occurred, the transportation and
the medical institutes to which patients were transferred in real time. Mass evacuation of victims from emergency areas by medica
modules aboard the aircraft of EMERCOM of Russia
I Yakirevich, A Popov
EMERCOM of Russia, Zhukovsky, Moscow Region, Russia
Critical Care 2012, 16(Suppl 1):P481 (doi: 10.1186/cc11088) I Yakirevich, A Popov p
EMERCOM of Russia, Zhukovsky, Moscow Region, Russia
Critical Care 2012, 16(Suppl 1):P481 (doi: 10.1186/cc11088) Introduction During elimination of medical consequences of various
emergencies the issues concerning victims’ mass evacuation to a
specialized hospital base are constantly brought up. The physicians of
the Central Airmobile Rescue Service of EMERCOM of Russia and the
specialists of Kazan Helicopter Plant ‘Zarechye’ developed two types
of modules. The Medical Airplane Module (MMS) is used for medical Introduction During elimination of medical consequences of various
emergencies the issues concerning victims’ mass evacuation to a
specialized hospital base are constantly brought up. The physicians of
the Central Airmobile Rescue Service of EMERCOM of Russia and the
specialists of Kazan Helicopter Plant ‘Zarechye’ developed two types
of modules. The Medical Airplane Module (MMS) is used for medical Conclusion The study demonstrates that the training course generates
signifi cant improvement in triage accuracy and speed. It also reveals
that VR simulation compared to live exercises has equivalent results in S172 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Conclusion Our triage system shows a good interrater reliability and
validity in predicting resource consumption. To our knowledge, this is
the fi rst prospective Italian study that tests the relationships between
the triage category assigned by the nurses (using a four-level triage
method) and resource consumption. Conclusion Our triage system shows a good interrater reliability and
validity in predicting resource consumption. To our knowledge, this is
the fi rst prospective Italian study that tests the relationships between
the triage category assigned by the nurses (using a four-level triage
method) and resource consumption. evacuation of four victims aboard Ilyushin 76 aircraft. The Medical
Helicopter Module (MMV) is used for medical evacuation of two victims
aboard an MI 8 helicopter. MMS and MMV advantages are: mobility
– the possibility of installation in various aircraft cabins types; and
versatility – the possibility of any required equipment installation for
the treatment of victims with various trauma severity, safe fi xation of
medical equipment straight on the module, equipment operation off -
line as well as using the aircraft power supply network. g
p
pp y
Methods From December 2008 until now 28 medical evacuations
were carried out using MMS aboard Iluyshin 76 aircraft: traffi c accident
victims, terrorism act victims and manmade catastrophes. P483 Coordination of emergency resources after Lorca’s earthquakes
L Escobar1, A Ferrández2, J Jimenez1, A Peláez1, A Corbatón3, R Alvaro4
1Hospital Rafael Méndez, Lorca, Spain; 2Gerencia 061, Murcia, Spain; 3Hospital
Clínico San Carlos, Madrid, Spain; 4Área II Servicio Cantabro de Salud,
Santander, Spain
Critical Care 2012, 16(Suppl 1):P483 (doi: 10.1186/cc11090) Introduction This work’s purpose is to describe the coordination
of diff erent medical resources after Lorca’s 2011 earthquakes. They
caused 11 deaths, including two pregnant women and their babies,
many injured, moderate or severe damage to 80% of the buildings, and
more than 30,000 people without shelter.i p
p
Methods A descriptive study of the fi les of Murcia’s Emergency
Coordination Center (ECC) on the activation of resources after the
earthquakes. Results MMS and MMV application in case of mass evacuation in fl ight
ensures spare victims’ transportation, total monitoring and treatment
continuity. It enables one to carry out anesthetic and resuscitation
treatment, intensive care, monitoring and treatment of all the victims. Conclusion The quality of mass medical evacuation of extremely injured
victims has considerably improved and the time of transportation
from emergency area to specialized hospitals to render them effi cient
medical aid has reduced. Results MMS and MMV application in case of mass evacuation in fl ight
ensures spare victims’ transportation, total monitoring and treatment
continuity. It enables one to carry out anesthetic and resuscitation
treatment, intensive care, monitoring and treatment of all the victims. Results Time 17:06 hours: fi rst call. Local resources and city emergency
plan are activated. Four medical teams (UME) are pre-activated. 18:49
hours: incoming calls alert of buildings crumbling, dead among the
rubble, and hundreds of injured. 18:55 hours: seven UME from fi ve cities
are sent to Lorca. 19:00 hours: telephone communications collapse. The
ECC uses its internal network. An Advanced Command Point (ACP) is
established with a fi eld hospital. 19:10 hours: Rafael Mendez Hospital
(225 patients) has to be evacuated. Medical personnel of the hospital,
private ambulances and UMEs begin the evacuation. The emergency
service of the hospital continues to be operative in the building until
evacuation is completed and in a fi eld hospital later. 19:20 hours: the
Military Emergencies Unit is required for activation. 19:30 hours: the
military and emergency services fi eld hospitals are sent to Lorca. 19:50
hours: Virgen del Alcázar Hospital has to be evacuated (145 patients). P482 Reliability and validity of an Italian four-level emergency triage system
N Parenti1, G Rastelli2, C Ferri2, V Serventi1, R Lazzari3, L Sarli1
1University of Parma, Bologna, Italy; 2Ospedale Fidenza, Italy; 3University of
Modena, Italy
Critical Care 2012, 16(Suppl 1):P482 (doi: 10.1186/cc11089) Critical Care 2012, 16(Suppl 1):P482 (doi: 10.1186/cc11089) Introduction The goal of this study is to assess the reliability and
validity of a four-level emergency triage system (Urgency Category
(UC) 1 = immediate response; UC 2, 3 and 4 assessment within 20, 60
and 120 minutes respectively) used in an Italian large urban hospital
with 60,000 emergency department (ED) visits annually. Methods Three triage nurses, using our triage system, independently
assigned, at the same time, triage scores to each patient admitted to the
ED from June to August 2011. We collected demographic and clinical
characteristics, nurse triage category, resources used for each triage
code (for example, laboratory tests, EKG, radiographs, procedures),
admission status and site, nurse triage forms that included presenting
complaint, vital signs, and pain score. For each scenario, the most
frequent UC (the mode) has been considered as true triage. Weighted
kappa (K) was used to calculate inter-rater reliability. Validity was
evaluated by studying the relationships between the triage category
assigned by the nurses and resource consumption. Conclusion Coordination of the diff erent medical and emergency
services by the ECC made possible correct use of resources and
fast attention to the population that minimized the eff ects of the
catastrophe. Figure 1 (abstract P483). Thirty thousand people need shelter after the
earthquakes. g
y
p
Results A total of 315 patients admitted to the ED were included in the
study randomly (35 were excluded for incomplete data). Mean age was
47 years. Five patients were admitted to the ICU, 48 to nonintensive
units. Trauma was the most frequent symptom at triage (44%). The
mean time of rating was 2 minutes. The UCs assigned were: 14%
with UC 4, 60% UC 3, 25.7% UC 2, 0.3% UC 1. We found 2/315 (0.6%)
cases with a marked discordance (2 or more points), 69/315 (21.9%)
cases with partial agreement (2/3) and 244/315 (77.5%) cases with a
complete agreement (5/5) among nurses who used the triage method. Interrater reliability among the three nurses was K = 0.71 (CI: 0.58 to
0.84). Hospital admission by our triage system was as follows: 1 (100%),
2 (30%), 3 (12%), 4 (2%). Mass evacuation of victims from emergency areas by medica
modules aboard the aircraft of EMERCOM of Russia
I Yakirevich, A Popov
EMERCOM of Russia, Zhukovsky, Moscow Region, Russia
Critical Care 2012, 16(Suppl 1):P481 (doi: 10.1186/cc11088) In total,
198 patients were evacuated (including 12 children), 55 victims with
artifi cial lung ventilation (ALV). Medical evacuation of severely injured
children and adults from regional hospitals to Moscow specialized
hospitals in order to provide effi cient and modern medical aid was
carried out using MMV. In total, 27 patients were evacuated (including
fi ve children), fi ve patients with ALV. The majority of victims were in
severe and extremely severe conditions with associated multisystem
trauma. Closed craniocerebral injury was observed in 75% of victims
with mass aff ection of locomotor apparatus, mine and explosion
trauma, gunshot wounds, burn shock and burn disease. Constant
monitoring, oxygen therapy, ALV, analgesia and sedation, intensive and
anti-shock care as well as wound dressing were carried out in fl ight. The victims’ general condition was evaluated according to the Glasgow
Coma Scale, APACHE II and SOFA scales.l P483 20:25 hours: at the ACP fi eld hospital of the Red Cross, Civil Protection
and Emergency Services are being set. 20:30 hours: 11 hospitals in six
provinces are contacted to relocate evacuated patients. 20:40 hours:
all buildings in Lorca are have been evacuated. Thirty thousand people
need shelter. Ten camps with tents are set throughout Lorca by the Red
Cross, Emergency Services and Civil Protection to give shelter to 16,000
people. See Figure 1.f g
Conclusion The quality of mass medical evacuation of extremely injured
victims has considerably improved and the time of transportation
from emergency area to specialized hospitals to render them effi cient
medical aid has reduced. P484
Lightning injuries in a lightning city: a district hospital experience
in Singapore factor analysis to analyze responses with regard to factors such as face
wash, toilets, sleep, clothes, and food. p
Results The overall response rate was 59.5% (n = 47/79); the response
rate was 38.3% (n = 18/47) for medical doctors, 36.2% (n = 17/47) for
nurses, and 25.5% (n = 12/47) for logisticians. The mean length of
career was 16.5 years (standard deviation, 9.75). Descriptive statistics
revealed that the participants reported high satisfaction with regard
to the command system and consistent satisfaction with regard to
membership. However, some were unsatisfi ed with the deployment
length. Almost all participants wanted to be part of a relief team if given
an opportunity again. Factor analysis derived one factor (eigenvalue
shows 3.48 (one factor), 0.33 (two factors), 0.17 (three factors), and
0.13 (four factors)) as comfort. Face wash (–0.95) contributed the most
satisfaction compared to other factors such as toilets (–0.86), sleep
(–0.81), clothes (–0.74), and food (–0.69).i Y Mok, P Tan, R Jagadesan
Changi General Hospital, Singapore
Critical Care 2012, 16(Suppl 1):P484 (doi: 10.1186/cc11091) Introduction Tropical Singapore’s meterological profi le makes it one of
the world’s lightning capitals. This study aims to assess the profi le of
the at-risk patient, and possibly identify factors predicting the length of
hospital stay in patients with lightning injuries over a period of 11 years. Methods This is an 11-year retrospective study of patients who were
admitted to Changi General Hospital, the only hospital located in
eastern Singapore, from 2000 to 2011 with the diagnosis of lightning
injuries. j
Results There were a total of 27 subjects, with 25 (95.6%) males
and two (7.4%) females in the sample. Their age ranged from 17 to
62 years; 63% of the subjects were between 20 and 40 years old. All
except three subjects had no comorbidities, with the latter having
only hypertension or hyperlipidemia. Most of the events occurred
during two periods, March to April and October to December, which
is consistent with previously observed seasonal peaks. The length of
hospital stay ranged from 1 to 10 days for all patients, except one who
stayed for 78 days and one who was transferred to another hospital. Six
patients (22.2%) required admission to the ICU or high dependency. There were three mortalities, all found in asystole at the incident site
and also suff ered hypoxic ischemic encephalopathy (HIE). P482 The mean of resources used for each triage
code was: 4.5 (SD 2.2) for UC 2; 3.2 (SD = 1.67) for UC 3; 1.89 (SD 0.84)
for UC 4. Figure 1 (abstract P483). Thirty thousand people need shelter after the
earthquakes. S173 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 References 1. Chao TC, et al.: A study of lightning deaths in Singapore. Singapore Med J
1981, 22:150-157. 1. Chao TC, et al.: A study of lightning deaths in Singapore. Singapore Med J
1981, 22:150-157. 2. Feng Z, et al.: Lightning city. The Straits Times, 22 November 2011, B1. Nuclear disaster and the medical problems during the earthquake
in Japan, 2011 Y Haraguchi, Y Tomyasu, H Nishi, M Sakai, E Hoshino, M Hoshino,
T Takeda-Nozawa Japanese Compendium Team for Disaster Medicine, Kawasaki, Japan
Critical Care 2012, 16(Suppl 1):P486 (doi: 10.1186/cc11093) Introduction The roles of medicine including intensivists against
natural mega-disaster followed by artifi cial disaster are discussed. Methods The Higashinihon earthquake caused more than 2,000 deaths
or missing, which was followed by the Fukushima Daiichi nuclear plant
explosion. This study was mainly studied based upon on the actual
experience in and around the nuclear station.fi Results Many medical teams, rescue teams and public offi cials worked
hard. However, many serious problems are revealed, even if they are
limited to the medical fi elds, which are as follows: inappropriate basic
preparedness against the largest degree of mega-disaster; lack of
offi cial education for medical teams against special disaster, such as
nuclear disaster (that is, most members of the Japan DMAT or disaster
medical assistance team seemed to be laypersons); incorrect standard/
rules of Japan DMAT, which were thought to be excessively focused
upon the cure of the injured patients and a planned short period or
nearly 48 hours; and insuffi cient consideration for the weak people or
CWAP: children, (pregnant) women, aged people, and the poor people/
sick patients. Many CWAP seemed not to have survived. Conclusion The results of this study add to the small but increasing
literature on lightning injuries and may serve to increase physician
awareness in this medical niche. References 1. Singh G, et al.: Psychiatry Clin Neurosci 2003, 57:333-336. 2. Kondo Y, et al.: Jpn J Reanimatol 2011, 30:77-81. Satisfaction survey among medical staff involved in relief
operations following the Great East Japan Earthquake and Tsunami Satisfaction survey among medical staff involved in relief
operations following the Great East Japan Earthquake and Tsunami
Y Kondo1, T Abe2, S Deguchi3, Y Kuba4, H Mitsunaga5, H Sekiguchi1,
K Kohshi1, I Kukita1 ,
1University of the Ryukyus, Nishihara, Japan; 2Mito Kyodo General Hospital,
University of Tsukuba, Mito, Japan; 3Graduate School of Health Sciences, Meio
University, Nago, Japan; 4Medical Corporation Kariyushi Heart-Life Hospital,
Nishihara, Japan; 5Tokyo Institute of Technology, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P485 (doi: 10.1186/cc11092) 1University of the Ryukyus, Nishihara, Japan; 2Mito Kyodo General Hospital,
University of Tsukuba, Mito, Japan; 3Graduate School of Health Sciences, Meio
University, Nago, Japan; 4Medical Corporation Kariyushi Heart-Life Hospital,
Nishihara, Japan; 5Tokyo Institute of Technology, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P485 (doi: 10.1186/cc11092) P487 P485 p
y
Conclusion In order to cope with the mega-disaster, it became evident
that it is insuffi cient to take makeshift measures or use cheap tricks. Working out the systematization of disaster medicine, based upon the
academic viewpoints and philosophy/reliability, is essential to protect
the people and the nation too. P485
Satisfaction survey among medical staff involved in relief
operations following the Great East Japan Earthquake and Tsunami
Y Kondo1, T Abe2, S Deguchi3, Y Kuba4, H Mitsunaga5, H Sekiguchi1,
K Kohshi1, I Kukita1
1University of the Ryukyus, Nishihara, Japan; 2Mito Kyodo General Hospital,
University of Tsukuba, Mito, Japan; 3Graduate School of Health Sciences, Meio
University, Nago, Japan; 4Medical Corporation Kariyushi Heart-Life Hospital,
Nishihara, Japan; 5Tokyo Institute of Technology, Tokyo, Japan
Critical Care 2012, 16(Suppl 1):P485 (doi: 10.1186/cc11092) P484
Lightning injuries in a lightning city: a district hospital experience
in Singapore Seventeen
(63%) events were occupation related with all occurring either at the
airbase or open construction sites. Although there were reportedly
six mechanisms of lightning injuries (direct strike, contact injury, side
fl ash, ground current, upward streamer and blast injury) this study only
established two types of mechanisms – direct strike and contact injury
– amongst our patients. Clinical and biochemical parameters that were
studied included cardiovascular morbidity, rhabdomyolysis, otologic
injuries, burns, acute kidney injury and neurological complications. The small numbers limited a statistical analysis for any correlations
between clinical factors and prognosis as well as hospital length of
stay. Nevertheless, it is notable that all three deaths had asystole arrest
at presentation, developed HIE, and a trend towards a higher serum
creatinine on admission. Conclusion Almost all participants were satisfi ed with their level of
comfort, and the infl uence of factors responsible for this comfort in
descending order were face wash, toilets, sleep, clothes, and food. References Family meetings and end-of-life decision-making in Thai critically ill
patients P Chatrkaw1, R Champunot2, W Riyakul3
1Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;
2Buddhachinaraj Hospital, Phitsanulok, Thailand; 3Chulalongkorn Hospital,
Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P489 (doi: 10.1186/cc11096) P Chatrkaw1, R Champunot2, W Riyakul3
1Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;
2Buddhachinaraj Hospital, Phitsanulok, Thailand; 3Chulalongkorn Hospital,
Bangkok, Thailand
Critical Care 2012, 16(Suppl 1):P489 (doi: 10.1186/cc11096) p
Results All stressor categories were diff erently reported by the three
groups analysed: environmental (S = 17 (15 to 19), R = 15 (13 to 18),
P = 10 (8 to 11), P <0.01), relationships (S = 23 (21 to 25), R = 20.5 (17 to
24.5), P = 14 (11 to 17), P <0.01), emotional (S = 25.5 (23 to 28), R = 24
(20 to 26), P = 18 (15 to 22), P <0.01), and physical (S = 35 (31 to 38),
R = 33 (26.5 to 37), P = 27 (21 to 30), P <0.01). Among the staff members,
nurses overestimated more than attending physicians, while trainees
are closer to relatives’ perception (P = 0.03). Staff members used to
conscious sedation overestimate less the impact of environmental
stressors (P = 0.03). Years of experience (r = 0.24, P = 0.03) and age
(r = 0.27, P = 0.01) are related to stressor overestimation among staff
members.f Introduction Limitation of life-sustaining therapy after critical illnesses
in Thailand is uncommon. The barriers may be uncertain prognosis,
wrong sense of doctor duty, guilty feeling, confl icts on the goals of care
and fear of liability. Therefore we set a formal healthcare team meeting
followed by a family meeting to fi nd the balance between curative and
palliative intention. The objective was to determine the nature and
eff ects of family meetings in the Thai social context. f
y
g
Methods A descriptive, retrospective analysis of charts and preference
forms after family meetings in the surgical ICU during 2003 to 2005. Close family members were invited and encouraged to express their
ideas and feelings. Conclusion Members of the staff should reconsider their beliefs on
patients’ perception of stressors. We argue that such an overestimation
may bring inappropriate administration of analgesic and sedative
drugs, particularly for nurses and older members of staff . Relatives
might be useful intermediaries to have a better insight of patients’
perception. Results Thirty-one family meetings were analysed. P489 categories; higher scores refer to a higher stressfulness. The median
(IQR) was calculated for each category. Twenty-eight high-risk critically
ill at discharge, 55 relatives 48 hours after admission of their next of kin,
and a total of 125 staff members (55 attending physicians, 40 nurses
and 30 medical students/specialist trainees) were interviewed. Fifty-six
of the staff members were used to keep patients consciously sedated
as for local guidelines; the remaining used deeper levels of sedation. Nonparametric tests were used as needed. Reference Figure 1 (abstract P489). Preferences for care at the end of life after
family meetings. 1. Novaes: Intensive Care Med 1997, 23:1282. Infl uence of burnout on attitudes of ICU doctors and nurses towards
liberalization of visiting polices Results From the fi rst measurement it occurred that 66.7% of the
relatives faced severe symptoms of PTSD (scores >33) and from the
second measurement it occurred that 70% of family members were
identifi ed as cases of severe stress symptoms too. No correlation
was found between these symptoms and APACHE II score (P >0.05),
indicating that such symptoms exist in family members during the
whole patient’s stay in the ICU, regardless of the seriousness of the
patient’s condition.f A Giannini1, G Miccinesi2, E Prandi1, M Audisio3, A Bencivinni4, E Biagioni5,
E Castenetto6, I Laganà7, R Oggioni4, V Porta8, R Salcuni9, A Sarti10,
MG Visconti11, C Borreani12 A Giannini1, G Miccinesi2, E Prandi1, M Audisio3, A Bencivinni4, E Biagioni5,
E Castenetto6, I Laganà7, R Oggioni4, V Porta8, R Salcuni9, A Sarti10,
MG Visconti11, C Borreani12 1Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy;
2Istituto per lo Studio e la Prevenzione Oncologica, Florence, Italy; 3Ospedale
di Ciriè, Italy; 4Ospedale Nuovo del Mugello, Borgo San Lorenzo, Italy; 5Azienda
Ospedaliera Universitaria di Modena, Italy; 6Ospedale Civico, Chivasso, Italy;
7Azienda Ospedaliera ‘G. Salesi’, Ancona, Italy; 8Ospedale Civile, Legnano, Italy;
9Ospedale di Ivrea, Italy; 10Ospedale S. Maria Nuova, Florence, Italy; 11Ospedale
‘A. Uboldo’, Cernusco sul Naviglio, Italy; 12Istituto Nazionale per lo Studio e la
Cura dei Tumori, Milan, Italy Conclusion Relatives of ICU patients seem to suff er from symptoms of
PTSD. Nurses who work in the ICU, and have direct and longer contact
with patients and relatives too, need to recognize, evaluate and
minimize these symptoms in order that further disorders and damage
to the relatives’ mental health be prevented. y
Critical Care 2012, 16(Suppl 1):P490 (doi: 10.1186/cc11097) Introduction The staff working in the ICU have a complex and stressful
job and are at risk of burnout [1]. We conjectured that the presence
of a burnout profi le may also infl uence the views of ICU doctors and
nurses regarding the liberalization of visiting policies. We investigated P488
Role of ICU nurses in the confrontation of post-traumatic stress
disorder in relatives of ICU patients in a general hospital of Athens,
Greece
M Kourti1, T Katostaras2, G Kallergis2, E Christofi lou1, I Floros1, G Fildisis2
1Laiko General Hospital, Athens, Greece; 2University of Athens, Faculty of
Nursing, Athens, Greece
Critical Care 2012, 16(Suppl 1):P488 (doi: 10.1186/cc11095) Figure 1 (abstract P489). Preferences for care at the end of life after
family meetings. Introduction This study was planned to assess post-traumatic stress
disorder (PTSD) in relatives of ICU patients and to evaluate the role of
ICU nurses in the confrontation of these symptoms. Introduction This study was planned to assess post-traumatic stress
disorder (PTSD) in relatives of ICU patients and to evaluate the role of
ICU nurses in the confrontation of these symptoms. Conclusion Withholding intubation and withdrawal therapy are
uncommon in Thai people. However, most Thai families prefer not to
escalate therapy including CPR. All of them died peacefully and the
families were satisfi ed with the care at the end of life. Reference Methods The Impact of Event Scale – Revised (IES-R) was translated and
distributed to the family members of patients that were hospitalized in
the ICU from August 2008 to September 2010. Two measurements took
place: the fi rst one 7 to 10 days from the admission of the patient to the
ICU and the second one (to the same relative) after 15 to 20 days from
the admission. The maximum IES-R score is 88 (0 to 4 for each one of the
22 questions that constitute the scale). Scores over 33 were interpreted
as severe cases of PTSD. Patients’ health condition was evaluated with
the APACHE II score before each measurement.i 1. Truog RD, et al.: Crit Care Med 2001, 29:2332-2348. Family meetings and end-of-life decision-making in Thai critically ill
patients The mean age of
the patients was 65.5 (± 12.9) with mean SAPS II of 55.6 (± 14.9). Three
patients were post CPR. Metastatic cancer was the most common
underlying condition (45.2%). Most families requested to have full
support, except CPR. Around 20% were not ready to make a decision,
but fi nally agreed not to escalate therapy. See Figure 1. P488 P488
Role of ICU nurses in the confrontation of post-traumatic stress
disorder in relatives of ICU patients in a general hospital of Athens,
Greece
M Kourti1, T Katostaras2, G Kallergis2, E Christofi lou1, I Floros1, G Fildisis2
1Laiko General Hospital, Athens, Greece; 2University of Athens, Faculty of
Nursing, Athens, Greece
Critical Care 2012, 16(Suppl 1):P488 (doi: 10.1186/cc11095) Stressors in the ICU: diff erent perceptions of patients, relatives and
staff members Stressors in the ICU: diff erent perceptions of patients, relatives and
staff members
M Umbrello1, G Mistraletti1, B Cerri1, E Carloni1, V Mariani2, A Di Carlo1,
F Martinetti1, L D’Amato1, S Miori1, G Iapichino1
1Università degli Studi di Milano, Milan, Italy; 2AO San Paolo – Polo
Universitario, Milan, Italy
Critical Care 2012, 16(Suppl 1):P487 (doi: 10.1186/cc11094) Introduction We conducted an attitude survey regarding satisfaction
among medical staff involved in relief operations following the Great
East Japan Earthquake (magnitude 9.0) and Tsunami, which struck
Japan on 11 March 2011. The damage was enormous and a number
of medical relief teams visited the aff ected area to rescue victims. Our
Okinawa medical relief team visited Otuchi, Iwate, on 15 March and
provided medical support to the victims for 2.5 months. Introduction The high-risk critically ill are exposed to signifi cant
stressors, along with diffi culties in communicating them to relatives
and members of the staff . The aim of this study was to compare the
perception of stressors as reported by patients (P), relatives (R) and ICU
staff members (S). Methods We conducted an anonymous paper survey using self-
developed questionnaires. The 79 participants included medical
doctors, nurses, and logisticians from medical relief teams involved in
rescuing victims of the 2011 Great East Japan Earthquake and Tsunami. Data were analyzed using descriptive statistics. We also performed f
Methods A validated questionnaire [1] was used to quantitatively
assess discomforts related to the ICU stay. Items were clustered into S174 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 References
1.
Azoulay E, et al.: Am J Respir Crit Care Med 2005, 171:987-994.
2.
Azoulay E, et al.: Am J Respir Crit Care Med 2001, 163:135-139.
3
Horowitz MJ et al : Psych Med 1979 41:209 218 y ,
p
,
2.
Azoulay E, et al.: Am J Respir Crit Care Med 2001, 163:135-139. 1.
Azoulay E, et al.: Am J Respir Crit Care Med 2005, 171:987-994. A family-based satisfaction survey on the ICU
D Moult, R Breeze, A Molokhia A family based satisfaction survey on
D Moult, R Breeze, A Molokhia gi
Results A total of 364 questionnaires were evaluated, including 282
nurses and 82 ICU physicians. The prevalence of severe BOS was 51%
among ICU physicians and 42% in nursing staff . For ICU nurses, factors
independently associated with lower MBI scores were the following:
work on fi xed days (OR 0.6; 95% CI 0.3 to 0.9; P = 0.01), integrated
in-ICU working groups (OR 0.6; 95% CI 0.3 to 0.9; P = 0.02), good
relationships with physicians (OR 0.8; 95% CI 0.7 to 0.9; P = 0.008) and
good relationships with supervisors (OR 0.8; 95% CI 0.7 to 1; P = 0.05). In contrast, at least one death over the last week was associated with
higher MBI score (OR 2; 95% CI 1.2 to 3.2; P = 0.008). For ICU physicians,
not being partnered was independently associated with higher MBI
scores. Conversely, good relationships with colleagues was associated
with lower MBI scores (OR 0,5; 95% CI 0.3 to 0.8; P = 0.004). Interestingly,
this study confi rms that clinicians with severe BOS had increased
burden such as sleep disorders, libido troubles, lack of memory,
inadequate money management as well as the wish to leave the ICU. Conclusion The prevalence of severe BOS is very high among ICU
workers in Uruguay. We have identifi ed diff erent risk factors associated D Moult, R Breeze, A Molokhia D Moult, R Breeze, A Molokhia University Hospital Lewisham, London, UK University Hospital Lewisham, London, UK
Critical Care 2012, 16(Suppl 1):P493 (doi: 10.1186/cc11100) y
p
Critical Care 2012, 16(Suppl 1):P493 (doi: 10.1186/cc11100) Introduction We conducted a prospective survey to determine
satisfaction amongst relatives of patients on our ICU. Patient-reported
outcome measures have become widely used and accepted in the
pursuit of improved quality of care [1]. However, assessing patient
satisfaction is diffi cult on the ICU, an environment where we more
commonly communicate with the family of patients regarding the
care of their relative. Therefore, a more family-centred approach is
indicated, for which family satisfaction questionnaires have already
been validated [2]. Methods We utilised a 35-point questionnaire-based survey of relatives
of patients in our ICU over 10 weeks. Questionnaires were distributed
to family members when the decision to discharge from the ICU was
made. References S175 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 with the development of severe BOS. These results confi rm previous
fi ndings and highlight that strategies to decrease BOS in ICU clinicians
are urgently warranted. this issue in the course of a survey about the impact on ICU staff of
liberalization of visiting policies. this issue in the course of a survey about the impact on ICU staff of
liberalization of visiting policies. Methods We administered an anonymous closed-question question-
naire to nurses and doctors at eight ICUs that were about to increase
the daily visiting time to at least 8 hours, soliciting their views on
policy changes in their unit. The ICU staff were asked to fi ll in the same
questionnaire a year after implementation. On both occasions we also
administered the Maslach Burnout Inventory (a 22-item self-completed
questionnaire) to survey the incidence of burnout.i P492 Opening the ICU: views of ICU doctors and nurses before and after
liberalization of visiting policies Opening the ICU: views of ICU doctors and nurses before and after
liberalization of visiting policies A Giannini1, G Miccinesi2, E Prandi1, M Audisio3, A Bencivinni4, E Biagioni5,
E Castenetto6, I Laganà7, R Oggioni4, V Porta8, R Salcuni9, A Sarti10,
MG Visconti11, C Borreani12 A Giannini1, G Miccinesi2, E Prandi1, M Audisio3, A Bencivinni4, E Biagioni5,
E Castenetto6, I Laganà7, R Oggioni4, V Porta8, R Salcuni9, A Sarti10,
MG Visconti11, C Borreani12 q
y
Results The fi rst response rate was 91% (234/258), the second 76%
(197/258). Most doctors and nurses gave a favourable opinion
regarding changes to visiting policy in both the fi rst (72%) and the
second survey (71%). In both phases of the study, the percentage
of respondents presenting a profi le compatible with burnout was
36% and 41% respectively. In subjects without burnout there was
a marked predominance of a favourable opinion (80% vs. 61%),
and this favourable attitude was also maintained a year after the
implementation of policy change (79% vs. 59%).l 1Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy;
2Istituto per lo Studio e la Prevenzione Oncologica, Florence, Italy; 3Ospedale
di Ciriè, Italy; 4Ospedale Nuovo del Mugello, Borgo San Lorenzo, Italy; 5Azienda
Ospedaliera Universitaria di Modena, Italy; 6Ospedale Civico, Chivasso, Italy;
7Azienda Ospedaliera ‘G. Salesi’, Ancona, Italy; 8Ospedale Civile, Legnano, Italy;
9Ospedale di Ivrea, Italy; 10Ospedale S. Maria Nuova, Florence, Italy; 11Ospedale
‘A. Uboldo’, Cernusco sul Naviglio, Italy; 12Istituto Nazionale per lo Studio e la
Cura dei Tumori, Milan, Italy y
Critical Care 2012, 16(Suppl 1):P492 (doi: 10.1186/cc11099) y
g
Conclusion The presence of burnout has a strong infl uence on the
opinion of doctors and nurses regarding liberalization of visiting
policies in the ICU. A favourable opinion predominates among ICU staff
members without burnout symptoms. In preparing for and assisting
the opening of ICUs it is important also to be aware of this aspect and
to off er nurses and physicians appropriate support. Introduction Italian ICUs still impose restrictive visiting policies (with
a median visiting time of about 2 hours/day); however, a revision of
current policies is underway [1-3]. No data are available on the views
of Italian ICU teams following an at least partial liberalization of visiting
policies. We investigated this issue in the course of a survey about the
impact on ICU teams of the liberalization of visiting policies. Reference Methods We administered an anonymous closed-question question-
naire to nurses and doctors at eight ICUs that were about to increase
daily visiting time to at least 8 hours, soliciting their views on policy
changes in their unit. The ICU staff were asked to fi ll in the same
questionnaire a year after implementation.i 1. Embriaco N, et al.: Curr Opin Crit Care 2007, 13:482-488. References Methods A survey was conducted in 12 Uruguayan adult ICUs. The level
of BOS was evaluated on the basis of the Maslach Burnout Inventory
(MBI score). ICU, patient, and clinician characteristics were assessed for
their association with the prevalence of severe BOS (that is, highest MBI
scores). All variables with P <0.2 in univariate analysis were included
in a model of ordinal regression. P <0.05 was considered statistically
signifi cant. 1. Giannini et al.: Intensive Care Med 2008, 34:1256-1262. 2. Giannini et al.: Intensive Care Med 2011, 37:1890. 3
Giannini et al : Pediatr Crit Care Med 2011 12:e46 e50 3. Giannini et al.: Pediatr Crit Care Med 2011, 12:e46–e50. Prevalence, risk factors and impact of severe burnout syndrome in
12 Uruguayan ICUs q
y
p
Results The fi rst response rate was 91% (234/258), the second 76%
(197/258). In the fi rst instance, 83% of doctors and 67% of nurses
expressed a favourable opinion regarding the change in visiting policy. After 1 year a positive opinion was expressed by 84% of doctors and 63%
of nurses. Both phases of the study show a signifi cant predominance of
positive opinions among doctors (P = 0.032 and 0.005).f y
G Burghi1, J LAmbert2, M Chaize2, C Quiroga3, G Pittini4, M Cancela5,
H Bagnulo1, S Chevret2, E Azoulay2
1Hospital Maciel, Montevideo, Uruguay; 2Saint Louis Hospital, Paris, France;
3Hospital Español, Montevideo, Uruguay; 4CAAMEPA, Pando, Uruguay;
5Hospital de Clínicas, Montevideo, Uruguay
Critical Care 2012, 16(Suppl 1):P491 (doi: 10.1186/cc11098) Conclusion Most ICU staff members view the opening of the unit
positively, and on the whole maintain this opinion 1 year after the
policy change. Overall, the attitude of doctors is more favourable than
that of nurses. It is essential to build up a picture of the diffi culties
that liberalizing visiting could create for ICU staff (and particularly
for nurses), and to explore the causes and extent of such diffi culties,
in order to identify possible solutions and off er nurses and doctors
appropriate support. Introduction Burnout syndrome (BOS) is defi ned as a state of emotional
fatigue that leads to a loss of motivation, usually progressing towards
feelings of inadequacy and failure. Severe BOS is relevant as it leads to
loss of psychological well-being, increased absenteeism and turnover,
and deterioration in the quality of care provided to patients. The
objective was to determine the prevalence of BOS among Uruguayan
ICU clinicians. To evaluate personal or organization characteristics
associated with the development of severe BOS. Acknowledgments The study was supported by Associazione per il
Bambino Nefropatico (Milan, Italy). Opening the ICU: views of ICU doctors and nurses before and after
liberalization of visiting policies Introduction Italian ICUs still impose restrictive visiting policies (with
a median visiting time of about 2 hours/day); however, a revision of
current policies is underway [1-3]. No data are available on the views
of Italian ICU teams following an at least partial liberalization of visiting
policies. We investigated this issue in the course of a survey about the
impact on ICU teams of the liberalization of visiting policies. Acknowledgments The study was supported by Associazione per il
Bambino Nefropatico (Milan, Italy). A family-based satisfaction survey on the ICU
D Moult, R Breeze, A Molokhia We limited this to two family members per patient who were in
the ICU for more than 48 hours. S176 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results We received 29 completed questionnaires. Relatives of 24 of the
respondents had survived to ICU discharge. Responses were linearly
transformed to give percentage scores. Higher values represented a
greater degree of satisfaction. Overall care in the ICU, 88.8%. Courtesy,
respect and compassion to the patient (93.8%), to relatives (92.2%);
assessment and treatment of pain (94.4%), breathlessness (92.9%),
agitation (88.9%); emotional support (89.4%); care from nurses (92.0%),
doctors (95.5%); frequency of communication nurses (92.9%), doctors
(89.7%). Overall decision-making, 91.3%. Willingness of staff to answer
questions (90.5%); honesty (90.5%), completeness (91.4%), consistency
of information (90.5%); inclusion in decision-making, 78.7%; support
during decision-making, 78.7%; time to think about information given,
96.2%. to provide some history as a surrogate to patient interview. We think
the care we provide should encompass both the patient and their
family. This is already accepted practice in the paediatric ICU setting
[2]. Communication between family and clinical staff , ideally on a daily
basis, is clearly imperative and a systematic approach to improve this
is good practice. Increasing insight into relatives’ perceptions and
expectations will aid the delivery of high-quality care. We believe that
involving relatives in the ward round will be of benefi t for us in our
professional relationships with them and improve their understanding
during an extremely diffi cult time. to provide some history as a surrogate to patient interview. We think
the care we provide should encompass both the patient and their
family. This is already accepted practice in the paediatric ICU setting
[2]. Communication between family and clinical staff , ideally on a daily
basis, is clearly imperative and a systematic approach to improve this
is good practice. Increasing insight into relatives’ perceptions and
expectations will aid the delivery of high-quality care. We believe that
involving relatives in the ward round will be of benefi t for us in our
professional relationships with them and improve their understanding
during an extremely diffi cult time. fi
Methods This was a prospective study over 2 months formally inviting
up to four families per day to be present for that part of the ward round
involving their relative. Family satisfaction in an interdisciplinary ICU: a quality audit
UM S h
id R Al i
T Ri
CK H f Introduction Meeting the needs of family members of patients in the
ICU is an important criterion in assessment of quality of care in the ICU. Therefore this study was conducted to determine the immediate needs
and level of anxiety of families with traumatic brain injury patients
admitted to ICUs in Shiraz, Iran in 2008. Introduction The quality of intensive care medicine depends on
multiple indicators [1,2]. Meeting relatives’ needs in the challenging
situation of ICU visits is crucial. The aim of this audit was to assess next
of kin’s satisfaction and infl uencing factors. Methods In this descriptive cross-sectional study, a convenience sample
of 60 family members was recruited over a period of 4 months. On the
second day of ICU admission, one family member for each patient who
met the study criteria were asked to complete three questionnaires,
consisting of the Critical Care Family Need Inventory (CCFNI), the State-
trait Anxiety Inventory (STAI) and a demographic data sheet. Methods With institutional approval, questionnaires were distributed
to family members of ICU patients. The survey included two visual
analogue scale ratings (VAS 1: patient care, VAS 2: decision-making)
and 24 questions with four dimensions D1 to D4 (general impression,
treatment and patient care quality, professional quality) on a fi ve-point
Likert scale, transformed into values 1 to 100. Patient-specifi c and
relatives’ sociodemographic data were recorded. Data are presented
as the mean ± SD, median (Q.5), interquartile range (IQR) and range
(minimum/maximum). Subgroup analysis (relative’s and patient’s
age, sex, education, marital status, length of stay, visit frequency and
mortality) was performed using the Mann–Whitney U test. y
y
g
Results The mean ages of the subjects were 32.2 years. A total of 10
needs statements in the CCFNI were rated to be important or very
important needs by 50 of the 60 families (83.3%); seven were needs
for assurance, two were needs for information, and one of them was
needs for proximity. The mean of CCFNI satisfaction scores were
low (16.5 ± 1.5) for needs to comfort, and high for needs to support
(38.1 ± 4.7). Also the mean score of state anxiety (56.75 ± 5.7) and trait
anxiety score (52 ± 6.2) was higher than previous studies. i
References 1. Dodek et al.: Crit Care Med 2004, 32:1922-1927. 1. Dodek et al.: Crit Care Med 2004, 32:1922-1927. Conclusion In this single-centre survey we have demonstrated that
inviting families to ICU ward rounds is feasible and we believe that
this intervention could improve family satisfaction on the ICU. We
are investigating the impact of this intervention with a detailed
comparative survey, which we will present in the future. References 1. Dodek et al.: Crit Care Med 2004, 32:1922-1927. 2. Wall et al.: Crit Care Med 2007, 35:271-279. 1. Dodek et al.: Crit Care Med 2004, 32:1922-1927. 2. Wall et al.: Crit Care Med 2007, 35:271-279. 1. Dodek et al.: Crit Care Med 2004, 32:1922 1927. 2. Wall et al.: Crit Care Med 2007, 35:271-279. 2. Wall et al.: Crit Care Med 2007, 35:271-279. Family satisfaction in an interdisciplinary ICU: a quality audit
UM S h
id R Al i
T Ri
CK H f y
p
g
y
Results Questionnaires of 159 patients were analyzed (patients: age =
66.1 ± 13.0 years, 64% female, SAPS = 38.8 ± 17.5, LOS = 13.5 ± 11.8 Conclusion A needs-based education program can decrease the level
of family anxiety and increase the level of satisfaction. Table 1 (abstract P496)
Mean ± SD
Q.5/IQR
Minimum/maximum
VAS1
9.1 ± 0.9
9.3/0.9
5.5/10
VAS2
8.6 ± 1.5
9.0/1.5
3.1/10
∑Satisf
87 ± 15.1
80/20
20/100
D1
91.1 ± 15
100/20
20/100
D2
89.2 ± 13
100/20
40/100
D3
86 ± 15.4
80/20
20/100
D4
85.5 ± 15
80/40
20/100 Immediate needs and level of anxiety of families with traumatic
brain injury patients admitted to ICUsf 1. Patient Satisfaction [www.patientsatisfaction.co.uk] j
y
S Gholamzadeh, R Abdoli, F Shariff , R Gholamzadeh, 1. Patient Satisfaction [www.patientsatisfaction.co.uk]
2. Aronson et al.: Paediatrics 2009, 124:1120-1125. 1. Patient Satisfaction [www.patientsatisfaction.co.uk]
2. Aronson et al.: Paediatrics 2009, 124:1120-1125. 1. Patient Satisfaction [www.patientsatisfaction.co.uk]
2. Aronson et al.: Paediatrics 2009, 124:1120-1125. S Gholamzadeh, R Abdoli, F Shariff , R Gholamzadeh,
A Maraghian Mohammadi
Shiraz University of Medical Sciences, Shiraz, Iran
Critical Care 2012, 16(Suppl 1):P494 (doi: 10.1186/cc11101) 2. Aronson et al.: Paediatrics 2009, 124:1120-1125. A family-based satisfaction survey on the ICU
D Moult, R Breeze, A Molokhia Subsequently they were asked to complete a
questionnaire anonymously on the experience.l Conclusion Family satisfaction with our ICU is high, with satisfaction
high in both care and decision-making domains. Appropriate inclusion
with and support during the decision-making process were areas with
lower satisfaction scores. The structuring of options for answering
these questions may have been a confounding factor in this fi nding. However, this may represent genuine lower levels of satisfaction and
steps should be taken to improve this. In response to these fi ndings
we have invited families to join their relatives’ part of the consultant
ward round to improve inclusion and support in decision-making. We
are currently repeating the survey with these changes in place and will
present our fi ndings in the future. R f Results The results that refl ected 31 ward round attendances
were unanimous: every family agreed that their attendance had a
positive impact, alleviating misconceptions about the intensive care
environment and clarifying the processes involved in the care of their
relative. The survey also revealed that attendance at the ward round
provided an excellent opportunity to have their questions answered
by consultants. All those invited wished to attend and all respondents
said the experience was valuable and they would like to attend again. Comments included: ‘Explanations very helpful to deal with the
stress of the situation’ and ‘Reassuring to have information delivered
professionally and compassionately’. Incidence of post-traumatic stress, anxiety and depression
symptoms in patients and relatives during the ICU stay and after
discharge Lovell Federal Healthcare Center, North Chicago, IL, USA;
2Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
Critical Care 2012, 16(Suppl 1):P499 (doi: 10.1186/cc11106) Introduction The eff ect of the full moon (the lunar eff ect) on human
behaviour has occupied researchers for centuries. We aim to determine
such a lunar eff ect on mortality among patients admitted to the ICU. Methods We analyze the electronic medical records of patients
admitted to the ICU. The subjects were divided into two groups:
patients who died on full moon days (14th,15th, and 16th days of the
lunar month) and the patients who died on other days of the lunar
month. The mortality rates were calculated for patients in both groups. Parameters including age, gender, acute physiology and chronic health
evaluation (APACHE) III scores, predicted mortality, type of ICU, and
actual mortality were compared between the two groups. Student’s t
test was performed to determine whether there were any diff erences
between the groups. Introduction The eff ect of the full moon (the lunar eff ect) on human
behaviour has occupied researchers for centuries. We aim to determine
such a lunar eff ect on mortality among patients admitted to the ICU. Introduction The eff ect of the full moon (the lunar eff ect) on human
behaviour has occupied researchers for centuries. We aim to determine
such a lunar eff ect on mortality among patients admitted to the ICU. Methods We analyze the electronic medical records of patients
admitted to the ICU. The subjects were divided into two groups:
patients who died on full moon days (14th,15th, and 16th days of the
lunar month) and the patients who died on other days of the lunar
month. The mortality rates were calculated for patients in both groups. Parameters including age, gender, acute physiology and chronic health
evaluation (APACHE) III scores, predicted mortality, type of ICU, and
actual mortality were compared between the two groups. Student’s t
test was performed to determine whether there were any diff erences
between the groups. y
Conclusion At least one-third of family members visiting patients
in the ICU suff er from symptoms of anxiety, depression or both. The
level of post-traumatic stress symptoms in family members was high
after ICU discharge. Depression, anxiety and post-traumatic stress
symptoms were higher among family members compared to patients. Female gender and oncologic diagnosis were strongly associated
with depression and post-traumatic stress. P495 Families: the newest members of the ICU multidisciplinary team
R Santhirapala, J Lipton, T Hall, R Breeze, A Molokhia
University Hospital Lewisham, London, UK
Critical Care 2012, 16(Suppl 1):P495 (doi: 10.1186/cc11102) Families: the newest members of the ICU multidisciplinary team
R Santhirapala, J Lipton, T Hall, R Breeze, A Molokhia
University Hospital Lewisham, London, UK
Critical Care 2012, 16(Suppl 1):P495 (doi: 10.1186/cc11102) Introduction We have started inviting the relatives of our patients to
remain present during our multidisciplinary team ICU ward round. The aim is to improve their understanding of the complex activity on
an ICU and reduce inconsistencies in communication. In the UK it is
becoming expected practice that patient satisfaction is an endpoint
we should be measuring and improving [1]. Assessing this on the
ICU is often very diffi cult due to the confounding factors inherent to
critical illness. We often seek assent from families for procedures and S177 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Methods A retrospective analysis of all patients that were treated in the
medical ICU of a large German university hospital in 2009 and 2010 and
died during their hospital stay. Methods A retrospective analysis of all patients that were treated in the
medical ICU of a large German university hospital in 2009 and 2010 and
died during their hospital stay. days, mortality = 16.5%; relatives: age = 44.5 ± 26.9 years, 63.7% female,
13% medical/25.5% higher education). High satisfaction (VAS 1/2, D1
to D4) was observed (Table 1). Signifi cant diff erences within subgroups
were found: relatives with healthcare education showed higher D1 to
D4 satisfaction than the ones with a graduate degree only. Higher VAS
scorings were observed from next of kin with high visit frequency (≥5×/
week). g
p
y
Results During the observation period 3,401 patients were treated in
our ICU. The ICU mortality was 15% (n = 501), hospital mortality was 19%
(n = 658). The mean predictive mortality derived from the SAPS 2 score
was 29% for all patients (standardized mortality ratio 0.67), deceased
patients had a predictive mortality of 56%. Of all deceased, 232 (35%)
had received CPR, 170 of those (73%) outside the ICU. Of all patients
who died in the hospital, 126 (19%) had received unlimited therapy. p
References 1. Myhren H, et al.: Crit Care 2010, 14:R14. 2. Pochard F, et al.: Crit Care Med 2001, 29:1893-1897. 3. Fumis R, et al.: Intensive Care Med 2009, 35:899-902. References 1. Intensive Care Med 2007, 33:1913-1920. 2. Intensive Care Med 2009, 35:2051-2059. 1. Intensive Care Med 2007, 33:1913-1920. 2. Intensive Care Med 2009, 35:2051-2059. 1. Intensive Care Med 2007, 33:1913-1920. 2. Intensive Care Med 2009, 35:2051-2059. P498 Conclusion The full moon does not seem to aff ect the mortality of
patients admitted to the ICU. P495 Life support was withdrawn in 245 patients (37%) and life support was
withheld in 241 patients (36%). In 46 patients (7%) palliative care was
instituted right from the beginning of the ICU stay. In 104 cases (16%)
the patients themselves made the EOL decision, in 78 cases (12%) an
advance directive was present. A legally designated healthcare proxy
was involved in 8%. In 541 cases (82%) the relatives were integrated
in EOL decisions with the objective of fi nding a broad consensus;
however, in these cases the assessment of the medical indication and
the prognosis by the medical team was of particular importance. Cases
in which relatives were not involved in EOL decisions were in 76% cases
with short unsuccessful maximal therapy, for example CPR (median
ICU stay 5 hours). The rate of life support withdrawal was highest (60%)
in patients with CNS diseases. We did not experience any serious or
unsolvable confl icts with relatives. Involvement of a law court was
necessary in none of the cases. Conclusion Relatives of ICU patients were in general highly satisfi ed. The educational status and ICU visit frequency of the next of kin were
revealed to be infl uencing factors. Incidence of post-traumatic stress, anxiety and depression
symptoms in patients and relatives during the ICU stay and after
discharge Further actions might be
adopted to diminish the incidence of these disorders. Results Data from 4,387 patients who were followed for 23 months
were analyzed. Overall, 297 patients died during this period, including
31 patients on full moon days and 266 patients on the other days of
the month. Both groups were similar in terms of age (73 vs. 71 years,
P = 0.39), APACHE III scores (82.06 vs. 76.52, P = 0.28), and predicted
mortality (0.405 vs. 0.370, P = 0.48). There was no diff erence in the
frequency of death between the full moon days and the other days
(10.33 vs. 9.85, P = 0.81). See Table 1.f Incidence of post-traumatic stress, anxiety and depression
symptoms in patients and relatives during the ICU stay and after
discharge R Fumis, P Martins, G Schettino R Fumis, P Martins, G Schettino Hospital Sirio-Libanes, São Paulo, Brazil Hospital Sirio-Libanes, São Paulo, Brazil Critical Care 2012, 16(Suppl 1):P497 (doi: 10.1186/cc11104) Introduction To study the incidence and predictors of post-traumatic
stress, anxiety and depression symptoms in medical and surgical patients
and relatives during the ICU stay and at 30 and 90 days post ICU discharge. Methods A prospective study of 72 patients and 99 family members
that completed the Hospital Anxiety and Depression Scale during the
ICU stay and at 30 and 90 days after discharge. The Impact of Event
Scale at 30 and 90 days after ICU discharge was used to evaluate post-
traumatic stress disorder (PTSD). Conclusion EOL policies were applied in 81% of our intensive care
patients who died during their hospital stay. The new German law
regulations served as a practical and realizable basis for EOL policies
in our medical ICU. Results The prevalence of symptoms of anxiety, depression or both
in patients during the ICU stay was 10%, 2.8% and 6.9% respectively. Among family members prevalence was 17.3%, 6.5% and 14.4%
respectively, and was signifi cantly higher compared to patients
(P = 0.034). PTSD symptoms were present in 39.8% and 32.7% of
family members respectively at 30 and 90 days after discharge. Among patients symptoms were signifi cantly lower (P <0.001). Factors
associated with symptoms of anxiety and depression during the ICU
stay in a multivariate model included patient-related factors as SAPS 3
(OR 1.1, 95% CI 1.01 to 1.24) and length of family member stay in the
ICU (OR 1.39, 95% CI 0.89 to 2.16) and family-related factors as female
gender (OR 5.43, 95% CI 0.67 to 43.8) and oncologic diagnosis (OR 0.25,
95% CI 0.05 to 1.31). The multivariate model also identifi ed patient age
(OR 0.97, 95% CI 0.93 to 1) and oncologic diagnosis (OR 0.27, 95% CI
0.09 to 0.79) associated with symptoms of post-traumatic stress after
discharge among family members. P499
Eff ect of a full moon on mortality of patients admitted to the ICU
R Nadeem1, A Nadeem1, E Madbouly1, J Molnar2, J Morrison2
1Captain James A. Growing a positive culture in an ICU antimicrobial stewardship
program p p
y
yi
g
Results Among 720 patients, 165 were women (22.9%), 506 (70.3%)
aged <55 years old and 214 (29.7%) ≥55 years old. Overall mortality
was 31.7% and 70.2% of deaths occurring following the WLST [2]. Unadjusted mortality was 41.2% in women versus 28.8% in men
(P = 0.003). We observed similar fi ndings in patients <55 years old (30.5
vs. 21.4%, P = 0.06), but not among men and women aged ≥55 years
old (55.7 vs. 55.0%, P = 0.43). Adjusted hazard ratios (HRs) showed a
nonsignifi cantly increased risk of death in women aged <55 years old
as compared to men (1.51 (0.92 to 2.47)), and in women aged ≥55 years
old (1.53 (0.94 to 2.50)). We observed no diff erence both in the overall
unadjusted incidence of WLST between women and men (73.5 vs. 68.8%, P = 0.47) and in women and men aged <55 years old, while there
was a nonsignifi cantly increased rate of WLST in women ≥55 years old
(HR 1.53 (0.94 to 2.50)). K Walker, J Litynsky, J Powis K Walker, J Litynsky, J Powis y
y
Toronto East General Hospital, Toronto, Canada Toronto East General Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P502 (doi: 10.1186/cc11109) Toronto East General Hospital, Toronto, Canada
Critical Care 2012, 16(Suppl 1):P502 (doi: 10.1186/cc11109) p
Critical Care 2012, 16(Suppl 1):P502 (doi: 10.1186/cc11109) Introduction A 3-month pilot antimicrobial stewardship program (ASP)
was initiated in a 490-bed urban community hospital medical/surgical
ICU. The ASP continued post pilot. ASP goals are to optimize/reduce
antimicrobial (AM) usage, improve clinical outcomes and reduce
nosocomial Clostridium diffi cile rates [1,2]. Methods The pilot had one pharmacist (Ph) providing ICU clinical
service and one AMPh, both working as ICUPhs. The AMPh collected
standardized data on patients and were reviewed with the ID physician;
then the AMPh and ID physician discussed with the ICU care team for
optimal AM use. Post pilot, the ICUPh assumed the AM stewardship
role. The ASP reduced from 5 to 3 days/week. Data collection included
the ASP time required and interventions. The same metrics were
collected pre/post pilot. Conclusion There may be gender-based diff erences in outcome
among patients with severe TBI. Overall, mortality for women tended
to be higher, as were decisions for WLST. These diff erences may be due
to unmeasured confounders, biologic responses to TBI, or diff erences
in level of care decision-making. P500 P500
Potential association of gender with mortality and withdrawal of
life-sustaining therapies in patients with severe TBI: a Canadian
multicentre cohort study
AF Turgeon1, F Lauzier1, A Boutin1, N Côte1, R Zarychanski2, R Fowler3,
D Scales3, M Meade4, K Burns3, F Bernard5, D Zygun6, L Moore1,
D Fergusson7
1Laval University, Quebec, Canada; 2University of Manitoba, Winnipeg,
Canada; 3University of Toronto, Canada; 4McMaster University, Hamilton,
Canada; 5Université de Montréal, Canada; 6University of Calgary, Canada;
7Ottawa Hospital Research Institute, Ottawa, Canada
Critical Care 2012, 16(Suppl 1):P500 (doi: 10.1186/cc11107) References was to introduce advanced computerised infusion pumps with in-built
drug safety software, so-called smart pumps, in the ICU to facilitate
safer drug administration. 1. Wolbank S, Praus G, Smolle-Juettner F, et al.: The infl uence of lunar
phenomena on the incidence of emergency cases. Resuscitation 2003,
58:97-102.f Methods The working group consisted of an ICU pharmacist,
clinical nurse specialist and consultant intensivist. A drug library was
constructed by the ICU pharmacist and consultant intensivist and
loaded onto the infusion pumps. The selection of drugs and dose
limits were carefully considered to ensure that they were within the
boundaries of normal usage so as not to impede patient management
whilst maximising patient safety. Super users then provided
individualised training to 85 ICU nurses. In the UK there have been 50
system implementations to date. The national average for compliance
with the use of the software is 50%. 2. Alves DW, Allegra JR, Cochrane DG, Cable G: Eff ect of lunar cycle on
temporal association in cardiopulmonary arrest in seven emergency
departments during eleven years. Eur J Emerg Med 2003, 10:225-228. 2. Alves DW, Allegra JR, Cochrane DG, Cable G: Eff ect of lunar cycle on
temporal association in cardiopulmonary arrest in seven emergency
departments during eleven years. Eur J Emerg Med 2003, 10:225-228. Application of a new German law as a basis for end-of life decisions
in a medical ICU Table 1 (abstract P499). Characteristics of patients who died on full moon
days versus other days
Full moon
Other days
P value
Age
73.6 ± 14.59
71.07 ± 16.1
0.39
Male/female
15/16
133/133
0.86
APACHE III
82.06 ± 24.1
76.52 ± 27.4
0.28
Mortality
0.405 ± 0.249
0.370 ± 0.268
0.48 Table 1 (abstract P499). Characteristics of patients who died on full moon
days versus other days R Riessen, C Bantlin, M Haap University Hospital Tübingen, Germany University Hospital Tübingen, Germany y
y
Critical Care 2012, 16(Suppl 1):P498 (doi: 10.1186/cc11105) Introduction In 2009 a new German law came into eff ect that clarifi ed
issues regarding end-of-life decisions, especially the role of patient
autonomy and the importance of a medical indication in the course
of treating patients with terminal illness. In this study we analyzed
the end-of-life (EOL) policies in our medical ICU with a focus on the
practicability of this law. S178 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 References 1. Fowler RA, Sabur N, Li P, et al.: CMAJ 2007, 177:1513-1519. 2. Turgeon AF, Lauzier F, Simard JF, et al.; Canadian Critical Care Trials Group:
CMAJ 2011, 183:1581-1588. References 1. Upton D: 2011 Why are so few infusions smart? Hosp Pharm Eur 57:39-42. 2
Camire E, et al.: Medication errors in critical care: risk factors, prevention
and disclosure. CMAJ 2009, 180:936-943. Potential association of gender with mortality and withdrawal of
life-sustaining therapies in patients with severe TBI: a Canadian
multicentre cohort study Results Feedback following training with the new system was very
positive. In our ICU, utilisation of the drug safety software during drug
administration was 94% within the fi rst 6 months. Of 18,000 drug
infusions, only 1,000 were used outside the drug safety software. There were seven over-rides from the high limit. Of these, two were
for furosemide where there was a genuine clinical need for a higher
dose. On two other occasions the software prevented insulin being
administered at 30 units/hour and potassium at 100 mmol/hour. The
number of drug errors reduced from three to zero during the study
period. This demonstrated that the design of our package was sensitive
enough to ensure safe drug administration and suffi ciently practical to
enable consistent use of the system. 1Laval University, Quebec, Canada; 2University of Manitoba, Winnipeg,
Canada; 3University of Toronto, Canada; 4McMaster University, Hamilton,
Canada; 5Université de Montréal, Canada; 6University of Calgary, Canada;
7Ottawa Hospital Research Institute, Ottawa, Canada
Critical Care 2012, 16(Suppl 1):P500 (doi: 10.1186/cc11107) Introduction Diff erences in admission patterns, delivery of care
and outcomes between women and men admitted to the ICU have
been previously identifi ed [1]. However, these observations have not
been well described in patients with traumatic brain injury (TBI). Our
objective was to identify diff erences in outcomes between women and
men with severe TBI. y
Conclusion We have demonstrated that the introduction of an
advanced computerised infusion pump system in the ICU can provide
a safer drug administration environment if the appropriate health
professionals are selected to implement the system, the drug library is
constructed carefully and a comprehensive training package is applied. References Methods We used data from a large retrospectively cohort study in
which adults with severe TBI (GCS ≤8) admitted to six Canadian level I
trauma centres (2005 to 2006) were identifi ed through health records
using ICD-10 codes [2]. Demographic, severity of illness, and outcome
data were collected by trained abstractors. The primary outcome was
the diff erence in mortality and withdrawal of life-sustaining therapies
(WLST) between women and men; secondary outcome was the impact
of age (<55 vs. ≥55 years old) among genders. Analyses included chi-
square tests and Cox regression analyses adjusted for GCS motor and
pupillary reactivity, with stratifi cation for age. Growing a positive culture in an ICU antimicrobial stewardship
program Results The ASP total patient recommendations/100 patient-days
were 5-day mean 9.3, 3-day mean 13.5 (P = 0.030) with an increased
ICU physician acceptance (5 days = 95.9%, 3 days = 99.7%). Statistically
signifi cant was an increase in recommendations to broaden therapy (Table
1) and nonstatistically signifi cant was a reduction in recommendations
to de-escalate therapy (5-day mean 1.4 recommendations/100
patient-days, 3-day mean 1.2 recom mendations/100 patient-days;
P = 0.601). Also, there was an increase in recommendations for duration
optimization (5-day mean 4.0 recommendations/100 patient-days,
3-day mean 6.0 recommendations/100 patient-days; P = 0.055) and
discontinue AMs (5-day mean 2.7 recommendations/100 patient-days;
3-day mean 3.7 recommendations/100 patient-days; P = 0.181). The ASP
mean time required (minutes/month) was reduced (5 days 864, 3 days
771; P = 0.267). 1.
Fowler RA, Sabur N, Li P, et al.: CMAJ 2007, 177:1513-1519.
2
T
AF L
i
F Si
d JF
l C
di
C i i
l C
T i l G 2.
Alves DW, Allegra JR, Cochrane DG, Cable G: Eff ect of lunar cycle on
temporal association in cardiopulmonary arrest in seven emergency
departments during eleven years. Eur J Emerg Med 2003, 10:225-228. P503
Injectional anthrax: the infl ammatory response
M Booth, A Hart, L Donaldson
Royal Infi rmary, Glasgow, UK
Critical Care 2012, 16(Suppl 1):P503 (doi: 10.1186/cc11110) Methods This study employed a Delphi selection process involving
38 intensivist participants using a web-based survey tool. In Round
1, participants were presented with 15 interventions proposed by
investigators. Using a fi ve-item Likert scale, they responded to the
question: ‘In your opinion as an expert, how suffi cient is the evidence
that this intervention reduces the risk of ALI in eligible patients?’
Participants were also prompted to comment and submit additional
items for consideration. In Round 2, participants followed the same
approach to rate and comment on items submitted by the group. Finally, in Round 3, participants reviewed aggregated ratings and
comments for all items, and voted for or against inclusion in the draft
checklist. Inclusion was limited a priori to items with at least 70%
agreement among participants. Introduction From December 2009 to July 2010 there were 47 cases
of anthrax amongst injecting drug users in Scotland with 13 fatalities. The majority presented as severe soft tissue infection following i.v. injection or muscle popping as described by Ringertz and colleagues
[1]. At fi rst they were diagnosed as necrotising fasciitis (NF) until the
diagnosis of anthrax was made. With experience they appeared to have
a milder infl ammatory response to their infection compared to other
soft tissue infections such as NF. To investigate this the anthrax group
was compared to a cohort of confi rmed NF cases. pi
Methods Patients admitted to the ICU with NF or injectional anthrax
from 1 January 2008 to 30 June 2011 were identifi ed. The white
blood count (WBC) and C-reactive protein (CRP) at presentation were
recorded. Demographic data (sex, age, ICU and hospital LOS, APACHE
II score, predicted and actual hospital mortality and drug-injecting
history) were retrieved. All data were collected prospectively for
routine ICU management. g
g p
p
Results Following Round 1, items submitted by participants were
aggregated with minimal change into six additional items for Round
2. In Round 3, of the 21 total items, nine were endorsed by 70% of
participants for inclusion in a draft checklist. These items were grouped
conceptually into two domains: respiratory support and resuscitation. Conclusion The Delphi process of expert consensus can be employed
to develop a checklist of time-sensitive interventions, in a manner that
combines available evidence with the perspective of expert clinicians. Results There were six patients with injectional anthrax and 16 with
NF. References 1. Dellit TH, et al.: Clin Infect Dis 2007, 44:159-177. 2. Polk RE, et al.: Clin Infect Dis 2007, 44:664-670. Multicenter consensus development of a checklist for lung injury
prevention p
JM Litell1, O Gajic1, J Sevransky2, M Gong3, DJ Murphy2
1Mayo Clinic, Rochester, MN, USA; 2Emory University School of Medicine,
Atlanta, GA, USA; 3Montefi ore Medical Center, Bronx, NY, USA
Critical Care 2012, 16(Suppl 1):P504 (doi: 10.1186/cc11111) JM Litell1, O Gajic1, J Sevransky2, M Gong3, DJ Murphy2
1Mayo Clinic, Rochester, MN, USA; 2Emory University School of Medicine,
Atlanta, GA, USA; 3Montefi ore Medical Center, Bronx, NY, USA
Critical Care 2012, 16(Suppl 1):P504 (doi: 10.1186/cc11111) Introduction Acute lung injury (ALI) is linked to almost 75,000 US deaths
annually. The syndrome is defi ned clinically by criteria that identify only
patients with established ALI, at which point treatment options are
limited and largely supportive. After 40 years and more than 25 NIH-
funded trials of ALI interventions, only supportive therapy with lung
protective ventilation has been associated with a mortality benefi t. The US Critical Illness and Injuries Trials Group lung injury prevention
subgroup seeks to standardize best practices for patients at risk of ALI. The recently validated lung injury prediction score (LIPS) identifi es
patients at risk of ALI, and can prompt the early use of preventative
interventions. This may attenuate the progression to ALI. This study
seeks expert consensus about best practices in patients at risk of ALI,
as determined by their LIPS. These practices will be incorporated into
a checklist for lung injury prevention. Standardization of care may
protect patients against ALI development and provide a uniform
background for enrollment in other ALI trials. P501 P501
Making drug delivery in the ICU safer: the implementation of
advanced computerised intravenous infusion pumps
A Dimech, A Le Page, P Gruber, T Wigmore
The Royal Marsden, London, UK
Critical Care 2012, 16(Suppl 1):P501 (doi: 10.1186/cc11108) Introduction Drug administration errors account for approximately
78% of all medical errors occurring in ICUs [1,2]. The aim of this project Conclusion ASP reduction from 5 to 3 days/week was successful. Necessary skills were developed by the ICUPh. ASP reduction increased S179 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 recommendations for discontinuation and prospective duration
optimization goals of AMs. A reduction in recommendations to de-
escalate therapy and an increase in broadening therapy may refl ect
an increased acceptance goals. The 3-day ASP also demonstrated an
increase in total recommendations/100 patient-days and a reduction in
the total time required which enhanced use of resources, both fi nancial
and human. References
Table 1 (abstract P502)
ASP days
Recommendations/
100 patient-days
5-day mean
3-day mean
P value
Broaden
0.4
1.6
0.003 P504
Multicenter consensus development of a checklist for lung injury
prevention
JM Litell1, O Gajic1, J Sevransky2, M Gong3, DJ Murphy2
1Mayo Clinic, Rochester, MN, USA; 2Emory University School of Medicine,
Atlanta, GA, USA; 3Montefi ore Medical Center, Bronx, NY, USA
Critical Care 2012, 16(Suppl 1):P504 (doi: 10.1186/cc11111) P503
Injectional anthrax: the infl ammatory response
M Booth, A Hart, L Donaldson
Royal Infi rmary, Glasgow, UK
Critical Care 2012, 16(Suppl 1):P503 (doi: 10.1186/cc11110) The results are presented in Table 1. There was a marked diff erence
in the infl ammatory response between the two groups with the CRP
being highly statistically signifi cant. The anthrax group was also
younger (35.5 vs. 43.2) with a lower severity of illness, lower predicted
mortality (18.6% vs. 31.7%) but much higher actual mortality. P506 Introduction The purpose of the medical emergency team (MET) is to
fi nd and treat deteriorating ward patients. Suboptimal care and delays
on general wards before admission to intensive care have an eff ect on
mortality [1] and patients admitted from general wards have a worse
outcome than from the operating room (OR) or emergency department
(ED) [2]. MET patients have a high rate of ICU admissions but whether their
outcome diff ers from other patients admitted from the wards has not been
studied before. We evaluated characteristics and outcome of ICU patients
based on mode of admittance, via the MET versus the conventional way. Introduction The implementation of an in-hospital rapid response
system (RRS) could improve the outcome of a deteriorating patient
but could increase the medical emergency team (MET) and ICU staff
workload [1,2]. y
Methods An observational prospective study of patients admitted
from general wards to the central ICU at Karolinska University hospital,
Stockholm, Sweden in 2007 to 2009. Two groups were identifi ed:
admissions directly following a MET call or the conventional way,
usually on request from the ward physician. Patients were analyzed
for age, gender, co-morbidities, length of stay, severity scoring system
(APACHE II) and mortality. Methods A retrospective analysis of the years pre, during and post
implementation of a RRS in a 480-bed hospital with a mean of 17,500
admissions/year. Figure 2 (abstract P506). Hospital mortality predicted and observed
before, during and after the RRS implementation. Figure 1 (abstract P506). MET calls and ICU admission before, during
and after the RRS implementation. Figure 1 (abstract P506). MET calls and ICU admission before, during
and after the RRS implementation. Results Of 2,571 ICU admissions, 694 admissions in 643 patients came
from the wards. In total, 355 were admitted by the MET and 339 were
conventional admissions. Median age was 65 years in the MET group
versus 58 years in the conventional group, hospital LOS prior to ICU
admission was median 3 days versus 1 day and APACHE II score was a
mean of 26 versus 21. They did not diff er as to proportion of invasive
ventilator treatment or dialysis but MET patients more often received
noninvasive ventilation, 57.2% versus 29.2% (P <0.01). ICU mortality
was 14.5% versus 8.9% (P = 0.04) and 30-day mortality 27.0% versus
19.1% (P = 0.02). P505 The number of ICU admissions did not increase (Figure 1). During the
period of study there was a reduction of observed mortality compared to
that predicted from SAPS II score, especially in surgical patients (Figure 2). Finally, there was an increase of ICU length of stay (LOS) from 11.5 to 13.7
days and a reduction of hospital LOS from 24 to 23.1 days. Results A total of 3,629 admissions during a 4-year period pre ICON
(August 2004 to August 2008) and 1,446 admissions during 18 months
post ICON (August 2009 to February 2011) were audited. Following the
introduction of ICON the percentage of unplanned admissions fell from
36.68% to 22.9%. These patients also had a lower mortality rate (14.57%
vs. 9.36%) and the SMR decreased from 1.55 to 1.35. Results The number of MET calls initially increased from 34 to 56 and then
decreased to 39 calls/1,000 admissions/year. Most of the calls were from
the emergency department and less from medical and surgical wards. The number of ICU admissions did not increase (Figure 1). During the
period of study there was a reduction of observed mortality compared to
that predicted from SAPS II score, especially in surgical patients (Figure 2). Finally, there was an increase of ICU length of stay (LOS) from 11.5 to 13.7
days and a reduction of hospital LOS from 24 to 23.1 days. the emergency department and less from medical and surgical wards. The number of ICU admissions did not increase (Figure 1). During the
period of study there was a reduction of observed mortality compared to
that predicted from SAPS II score, especially in surgical patients (Figure 2). Finally, there was an increase of ICU length of stay (LOS) from 11.5 to 13.7
days and a reduction of hospital LOS from 24 to 23.1 days. Conclusion Our data show that the mortality rate has decreased
since the introduction of ICON although a confounding factor could
be a concurrent decreased crude mortality rate (5.5% in 2003 to 2004
vs. 4.2% 2008 to 2010) in all paediatric intensive care patients in the
UK [2]. Despite this we believe that ICON is a signifi cant contributing
factor in identifying and rescuing patients on the wards before further
signifi cant deterioration requiring intensive care. Further ongoing
audit is required. References 1. Acutely Ill Patients in Hospital: Full Guideline [http://guidance.nice.org.uk/
CG50/Guidance] 1. Acutely Ill Patients in Hospital: Full Guideline [http://guidance.nice.org.uk/
CG50/Guidance] P505 P505
Impact of the Paediatric Intensive Care Outreach Network service
on mortality within intensive care
K Sadasivam, S Skellett
Great Ormond Street Hospital for Children, London, UK
Critical Care 2012, 16(Suppl 1):P505 (doi: 10.1186/cc11112) Conclusion Anthrax releases three factors: lethal factor (LF), edema
factor (EF) and protective antigen (PA). PA and LF form lethal toxin
which kills macrophages and inhibits B-cell and T-cell function so
minimising the immune response to anthrax. This is refl ected in the
inappropriately low CRP levels at presentation. Severe soft tissue
infection in an injecting drug user associated with subjectively poor
infl ammatory response should raise the possibility of anthrax infection. Reference Introduction We audited the mortality rate by admission source in our
paediatric ICU, a paediatric tertiary referral centre, from 2004 to 2008
and found that the group of emergency unplanned internal admissions
had a higher Standardised Mortality Ratio (SMR) of 1.55 compared to
a SMR of 1.00 overall for patients admitted to the paediatric ICU. This
was in keeping with data from other large paediatric centres [1]. The
reasons for the increased mortality for this internal group were not clear
and possibly multifactorial. To help address this, a Paediatric Intensive
Care Outreach Network (ICON) team was developed and introduced in
September 2009. 1. Ringertz SH, et al.: Injectional anthrax in a heroin skin popper. Lancet 2000,
356:1574-1575. 1. Ringertz SH, et al.: Injectional anthrax in a heroin skin popper. Lancet 2000,
356:1574-1575. Table 1 (abstract P503)
Anthrax
NF
Number
6
16
APACHE II score
12.2
19.4
P <0.05
Died (%)
66.6
18.8
P <0.05
WBC
11.6
16.0
NS
CRP
71.2
287.3
P <0.001 p
Methods A before-and-after study design was used to determine
diff erences in percentage of admissions, mortality rate and SMR. Data
were collected using the PICANet database for emergency unplanned
internal admissions before (August 2004 to August 2008) and after
implementation of the ICON team (August 2009 to February 2011). PICANet is a national database that audits all paediatric intensive care
admissions in the UK [2]. S180 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Results The number of MET calls initially increased from 34 to 56 and then
decreased to 39 calls/1,000 admissions/year. Most of the calls were from
the emergency department and less from medical and surgical wards. References 1. McQuillan et al.: BMJ 1998, 316:1853-1858. 2. Goldhill et al.: Crit Care Med 1998, 26:1337-1345. 1. McQuillan et al.: BMJ 1998, 316:1853-1858. 2. Goldhill et al.: Crit Care Med 1998, 26:1337-1345. 1. McQuillan et al.: BMJ 1998, 316:1853-1858. 2. Goldhill et al.: Crit Care Med 1998, 26:1337-1345. P507
Medical emergency team admittance to intensive care versus
conventional admittance: characteristics and outcome
G Jäderling, M Bell, CR Martling, A Ekbom, M Bottai, D Konrad
Karolinska Institutet, Stockholm, Sweden
Critical Care 2012, 16(Suppl 1):P507 (doi: 10.1186/cc11114) 2. Paediatric Intensive Care Audit Network [http://www.picanet.org.uk/] Medical emergency team admittance to intensive care versus
conventional admittance: characteristics and outcome q
References 2. DeVita MA, et al.: Crit Care Med 2006, 34:2463-2478. 2. DeVita MA, et al.: Crit Care Med 2006, 34:2463-2478. 1. FO Odetola, et al.: Do outcomes vary according to the source of admission
to the PICU? Pediatr Crit Care Med 2008, 9:20-25. P505 y
p
y
Conclusion The implementation of RRS could result in a temporary
increase of MET calls but not of ICU admissions; moreover, it could lead
to a reduction of mortality and hospital LOS, but not of ICU LOS. References P506 MET patients also had a higher proportion of co-
morbidities, with a prevalence of heart failure in 17.3% versus 11.7%
(P = 0.0.4) and malignancy in 45.3% versus 35.1% (P <0.01) as well as
a higher proportion of limitation of medical treatment (LOMT), 23.0%
versus 15.7% (P = 0.02). When LOMT patients were excluded, mortality
rates were no longer signifi cantly diff erent, ICU mortality then being
5.7% versus 3.3% (P = 0.2). Figure 1 (abstract P506). MET calls and ICU admission before, during
and after the RRS implementation. Figure 2 (abstract P506). Hospital mortality predicted and observed
before, during and after the RRS implementation. Conclusion Two distinct groups of patients with intensive care needs
are found in general wards. Those admitted by the MET are older, have
more severe co-morbidities and have been in hospital longer. We fi nd
the MET to be an important tool to identify patients with multiple
problems and at high risk of an adverse outcome. R f Intensive care services in Hungary 2000 to 2010: an analysis of bed
numbers, occupancy rates, case mix and economics gold standard value. The frequency of these diff erences was analysed. Results Both computer and manual systems returned all the required
data, giving a total of 700 data variables. Diff erent values were returned
for 183 (26%) variables. The systems had good concordance in the
demographic variables, with only 4/300 (1.3%) discrepancies between
the computer and manual systems. In the organ support variables,
there were 179/400 (45%) discrepancies. Days of renal support had
most concordance, with discrepancies in 3/50 patients (6%). Days of
level 2 support had least concordance, with discrepancies in 37/50
patients (76%). Overall, the computer method returned the correct
variable for 544 (78%) variables, where the manual system returned the
correct variable on 591 (84%) variables. p
y
A Csomos1, B Fulesdi2, M Gresz3 ,
,
1Semmelweis University, Budapest, Hungary; 2University of Debrecen,
Hungary; 3National Institute for Quality and Organisational Development in
Healthcare, Budapest, Hungary ,
,
1Semmelweis University, Budapest, Hungary; 2University of Debrecen,
Hungary; 3National Institute for Quality and Organisational Development in
Healthcare, Budapest, Hungary Critical Care 2012, 16(Suppl 1):P509 (doi: 10.1186/cc11116) Critical Care 2012, 16(Suppl 1):P509 (doi: 10.1186/cc11116) Introduction The purpose of this study is to describe the changes in
pattern of intensive care (ICU) use over a 10-year period in Hungary. We attempt to analyze national data in order to improve resource use. Methods A retrospective analysis of national data provided by the
hospitals for reimbursement of care to the National Healthcare Fund of
Hungary between 2000 and 2010. Conclusion This study shows that both computer and manual data
collection methods could be improved, but at present both have
similar accuracy. This may be because the criteria for some organ
support can be subjective (for example, risk of deterioration), which
can be interpreted in diff erent ways between manual data collectors
but not by a computer. We plan to rewrite the computer program,
aiming for >95% concordance with the gold standard. g
y
Results The total number of active hospital beds decreased by 33.4%
(from 65,532 to 44,300); however, the number of ICU beds increased
by 9.8% (from 1,189 to 1,306) between 2000 and 2010. As a result,
the percentage of ICU beds to hospital beds increased from 1.89% in
2000 to 2.95% in 2010. The ICU bed occupancy rate ranged between
58.43% and 63.78%; it showed no correlation with the case mix index
(r2 = 0.2799). P510 P510
Data acquisition for the UK Critical Care Minimum Data Set:
validation of a computer model for automatic calculation from an
electronic patient record
A Clarke, M Thomas, T Gould, C Bourdeaux
Bristol Royal Infi rmary, Bristol, UK
Critical Care 2012, 16(Suppl 1):P510 (doi: 10.1186/cc11117) P510
Data acquisition for the UK Critical Care Minimum Data Set:
validation of a computer model for automatic calculation from an
electronic patient record
A Clarke, M Thomas, T Gould, C Bourdeaux
Bristol Royal Infi rmary, Bristol, UK
Critical Care 2012, 16(Suppl 1):P510 (doi: 10.1186/cc11117) P510
Data acquisition for the UK Critical Care Minimum Data Set:
validation of a computer model for automatic calculation from an
electronic patient record validation of a computer model for automatic calculation from an
electronic patient record
A Clarke, M Thomas, T Gould, C Bourdeaux
Bristol Royal Infi rmary, Bristol, UK
Critical Care 2012, 16(Suppl 1):P510 (doi: 10.1186/cc11117) Introduction This study reports the accuracy of a computer and a
manual system at collecting data for the UK Critical Care Minimum
Data Set (CCMDS). This is required by the Department of Health to
compare performance, to facilitate funding and to plan future resource
provision. There are 14 data fi elds in the mandatory dataset, and
the full compliment extends to 34 fi elds. At present this is collected
manually, which is laborious and subjective. We use an electronic
patient record (Innovian, Draeger, Germany) to store all the measured
patient observations and laboratory results. We have written a program
to interrogate Innovian for the CCMDS data, thereby reducing the
administrative time. Conclusion Our data suggest that critical care admission decisions are
made based mainly on the assessment of patients’ pre-morbid state
and functional capacity, rather than on the extent of acute physiological
derangement. This behaviour is more consistent with the application of
a prioritization model, defi ning those patients who will benefi t most
from critical care admission (Priority 1) to those who will not benefi t at
all (Priority 4) and consistent with pressured resources, rather than an
objective parameters model or a diagnostic model [1]. References Methods A stratifi ed sample of 50 patients’ data (elective and
emergency surgical and medical patients) was analysed. Both manual
and computer systems collected the mandatory 14 items of the CCMDS. P508 Factors aff ecting critical care admission to a UK university hospital
A Tridente1, A Chick1, S Keep1, S Furmanova2, S Webber1, DC Bryden1
1Sheffi eld Teaching Hospitals, Sheffi eld, UK; 2University Hospital Wales, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P508 (doi: 10.1186/cc11115) Factors aff ecting critical care admission to a UK university hospital
A Tridente1, A Chick1, S Keep1, S Furmanova2, S Webber1, DC Bryden1
1Sheffi eld Teaching Hospitals, Sheffi eld, UK; 2University Hospital Wales, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P508 (doi: 10.1186/cc11115) Factors aff ecting critical care admission to a UK university hospital
A Tridente1, A Chick1, S Keep1, S Furmanova2, S Webber1, DC Bryden1
1Sheffi eld Teaching Hospitals, Sheffi eld, UK; 2University Hospital Wales, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P508 (doi: 10.1186/cc11115) Figure 2 (abstract P506). Hospital mortality predicted and observed
before, during and after the RRS implementation. Introduction Access to critical care is limited, with disparity existing
between availability and demand. Guidance to inform triage decisions S181 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Table 1 (abstract P509). Distribution of intensive care services in 2010
Total
Total
Case mix
National data,
number
number
index
2010
of units
of beds
(mean ± SD)
P value
University hospitals (level III)
10
412
7.67 (± 4.06)
0.204
County hospitals (level II)
30
584
8.08 (± 2.89)
0.376
City hospitals (level I)
39
280
6.05 (± 1.97)
0.093 Table 1 (abstract P509). Distribution of intensive care services in 2010 has been published but may no longer refl ect current pressures [1,2]. We aimed to identify a set of criteria able to reliably predict likelihood
of admission to a critical care unit in a large UK tertiary care centre. We aimed to identify a set of criteria able to reliably predict likelihood
of admission to a critical care unit in a large UK tertiary care centre. Methods Consecutive patient referrals were prospectively enrolled in a
review cohort. Data were collected using a predefi ned case report form
(CRF). The CRF included information on the referral, acute physiological
parameters, hospital length of stay (LOS), demographic and functional
status, dependency and comorbidities. Logistic regression was
performed to identify factors predicting admission, employing STATA [3]. Intensive care services in Hungary 2000 to 2010: an analysis of bed
numbers, occupancy rates, case mix and economics
A Csomos1, B Fulesdi2, M Gresz3
1Semmelweis University, Budapest, Hungary; 2University of Debrecen,
Hungary; 3National Institute for Quality and Organisational Development in
Healthcare, Budapest, Hungary
Critical Care 2012, 16(Suppl 1):P509 (doi: 10.1186/cc11116) Intensive care services in Hungary 2000 to 2010: an analysis of bed
numbers, occupancy rates, case mix and economics
A Csomos1, B Fulesdi2, M Gresz3
1Semmelweis University, Budapest, Hungary; 2University of Debrecen,
Hungary; 3National Institute for Quality and Organisational Development in
Healthcare, Budapest, Hungary
Critical Care 2012, 16(Suppl 1):P509 (doi: 10.1186/cc11116) P508 Results Between 17 July and 27 November 2011, 201 patients were
referred to critical care, of whom 85 (42.7%) were declined. Median
age (interquartile range) was 67 (54 to 79) years, 121 (60.8%) were
male, median LOS (interquartile range) was 1 (1 to 3) day. Age, gender,
ethnic origin, LOS, referral reason, and markers of acute physiological
derangement did not impact on likelihood of admission to critical care. Odds ratios (95% CIs) for admission were 3.1 (1.72 to 5.56) for exercise
tolerance >100 yards (P <0.001), 3.03 (1.56 to 5.89) for self-caring status
(P = 0.001), 0.38 (0.2 to 0.71) for house-bound status (P = 0.003), 0.28
(0.1 to 0.76) for wheelchair-bound status (P = 0.013), 0.41 (0.23 to
0.74) for cardiovascular (P = 0.003), 0.36 (0.18 to 0.72) for renal system
(P = 0.004), 0.34 (0.14 to 0.85) for malignant (P = 0.021), and 0.49 (0.25 to
0.94) for neurological (P = 0.033) comorbidities, respectively. P510 This consists of six demographic variables (for example, admission
date, discharge date, date of birth) and eight organ support variables
(for example, duration of either advanced or basic cardiovascular,
respiratory, renal or neurological support or duration of level 2 or 3
support). Where the computer and manual systems returned diff erent
values, a blinded physician analysed the patient records and created a
gold standard value. The frequency of these diff erences was analysed. Results Both computer and manual systems returned all the required
data, giving a total of 700 data variables. Diff erent values were returned
for 183 (26%) variables. The systems had good concordance in the
demographic variables, with only 4/300 (1.3%) discrepancies between
the computer and manual systems. In the organ support variables,
there were 179/400 (45%) discrepancies. Days of renal support had
most concordance, with discrepancies in 3/50 patients (6%). Days of
level 2 support had least concordance, with discrepancies in 37/50
patients (76%). Overall, the computer method returned the correct
variable for 544 (78%) variables, where the manual system returned the
correct variable on 591 (84%) variables. 1. Guidelines for intensive care unit admission, discharge, and triage. ACCCM, SCCM. Crit Care Med 1999, 27:633-638. 2. Fair allocation of intensive care unit resources. ATS. Am J Respir Crit Care
Med 1997, 156:1282-1301. 2. Fair allocation of intensive care unit resources. ATS. Am J Respir Crit Care
Med 1997, 156:1282-1301. 3. STATA 10.1. College Station, TX: StataCorp. 3. STATA 10.1. College Station, TX: StataCorp. P511 P511
To admit or not to admit? The suitability of critical care admission
criteria
D Marriott, Z Turner, N Robin, S Singh
Countess of Chester Hospital, Chester, UK
Critical Care 2012, 16(Suppl 1):P511 (doi: 10.1186/cc11118) P509 Intensive care services in Hungary 2000 to 2010: an analysis of bed
numbers, occupancy rates, case mix and economics
A Csomos1, B Fulesdi2, M Gresz3
1Semmelweis University, Budapest, Hungary; 2University of Debrecen,
Hungary; 3National Institute for Quality and Organisational Development in
Healthcare, Budapest, Hungary
Critical Care 2012, 16(Suppl 1):P509 (doi: 10.1186/cc11116) Intensive care services in Hungary 2000 to 2010: an analysis of bed
numbers, occupancy rates, case mix and economics The number of ventilator days increased from 28.9% to
66.1%; it showed good correlation with the case mix index (r2 = 0.9125). Analysing 2010 data, we found signifi cantly lower mortality in level III
units (30 ± 18%) compared to level II (51 ± 20%) and level I (56 ± 19%)
care (P = 0.001 and 0.003), without signifi cant diff erences in case mix
index (Table 1). The mean ICU bed occupancy rate was 59.5% (SD ±12%),
and length of hospital stay was 12.3 (SD ±3.0) in 2010. Geographic
distribution of ICU beds per 100,000 population ranged between 7.3
and 27.4 (nationwide 12.9/100,000); it showed no correlation with
regional gross domestic product values (r2 = 0.4593). P511 Assessing demand for intensive care services: the role of
readmission rates Introduction Out-of-hours discharge from the ICU is associated with
increased mortality. In Scotland, approximately 15% of discharges
occur out of hours [1]. The aim of this study was to determine the
reasons behind out-of-hours discharges in our hospital and the eff ect
this has on mortality. RA O’Leary, B O’Brien Methods We carried out a retrospective analysis of all patients admitted
to our ICU over a 3-year period. Patients who died during their ICU stay,
patients <16 years, patients transferred to another ICU, and those with
missing data were excluded. Data collected: patient demographics,
APACHE II score, time of discharge from the ICU, reason for out-of-hours
discharge, and hospital mortality. The out-of-hours period was defi ned
as per the Scottish Intensive Care Society (SICS) as 20:00 to 07:59 hours,
then later re-defi ned as 17:00 to 07:59 hours. Introduction Irish ICUs typically have bed occupancy rates approaching
100%, with 75 to 80% being the recommended level [1]. Detection
of excessive demand from simple databases can thus be diffi cult:
expedited turnover and cancellations of elective surgery often ensue,
leaving occupancy rates unchanged. We hypothesised that excessive
demand would produce higher readmission rates, thus illustrating the
strain imposed on ICU resources during the H1N1 infl uenza pandemic. Methods The GICU database was examined from 1 March 2010 to 1
March 2011. The H1N1 pandemic was recognised as a period of strain
on the ICU and this period was estimated as 24 December 2010 to
21 January 2011. All ICU readmissions during the same hospital stay
were noted. Transfers between GICU, cardiac ICU and theatre recovery
were excluded as patients were still being treated by the intensive care
team. Patients readmitted after transfer for extracorporeal membrane
oxygenation (ECMO) were also excluded. i
Results A total of 766 patients were included: 607 discharged between
08:00 and 19:59 hours, 159 discharged between 20:00 and 07:59 hours. Data are expressed as mean values (SD) or percentages, ‘in hours’ versus
‘out of hours’. Both groups were similar: age 51.9 (18.1) versus 54.0
(17.7) years, males 48.9% versus 50.9%, APACHE II score 15.8 (8.7) versus
17.4 (8.0). Hospital mortality following ICU discharge was 9.9% (55/607
deaths) versus 10.0% (16/159 deaths), RR 1.11 (95% CI 0.66 to 1.88). Discharge was delayed due to a shortage of ward beds in 28.5% versus
43.4% of cases. No early discharges were recorded. P511
To admit or not to admit? The suitability of critical care admission
criteria Introduction During the 2010/2011 winter the H1N1 infl uenza
pandemic placed increased demand on critical care services,
prompting our department to devise a modifi ed triage tool for the
ICU to be implemented at a time of exceptional bed crisis [1]. Scoring
systems such as APACHE or Sequential Organ Failure Assessment Introduction During the 2010/2011 winter the H1N1 infl uenza
pandemic placed increased demand on critical care services,
prompting our department to devise a modifi ed triage tool for the
ICU to be implemented at a time of exceptional bed crisis [1]. Scoring
systems such as APACHE or Sequential Organ Failure Assessment Conclusion Our data suggest that intensive care beds are not utilized;
a progressive level of care does not function and also there are
unnecessary regional diff erences in intensive care provision in Hungary. S182 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 (SOFA) have been used to predict mortality and optimize critical care
service utilization [2]. This audit aimed to validate our triage tool for
patients admitted to the ICU. when medical staffi ng levels on the wards are highest. The SICS defi ne
the out-of-hours period based on the time of handover to nightshift. For discharges at this time, there was no increase in mortality. In our
hospital, evening ward cover is the same as overnight. For an out-
of-hours period of 17:00 to 07:59, there was a signifi cant increase in
mortality following out-of-hours discharge. Methods We retrospectively examined patient notes for all admissions
to our adult ICU during December 2010 and January 2011. Patient
admission criteria (SpO2 <90% on FiO2 >85%, respiratory acidosis
pH ≤7.2, respiratory failure or airway compromise, systolic pressure
<90 mmHg, SOFA score ≥7) or refusal criteria (SOFA score ≥12, severe
trauma, unwitnessed or non-VF arrest, severe life-limiting condition)
were recorded with outcome data. y
Conclusion Our data show increased mortality following ICU step-
down in the evening as well as at night. Discharge was most often
delayed due to a lack of ward beds. To reduce mortality, eff orts must
therefore be made to improve bed management and ensure discharge
from the ICU before 17:00. Results We analysed 27 sets of notes. Twenty-two patients (81%)
fulfi lled at least one admission and no refusal criteria. Two patients
(7%) had documented refusal criteria. Delayed discharges revisited: impact of a liaison post on patients’
transition from ICU to ward caref J Mellinghoff , P O’Shea, D Dawson, J Ball, A Rhodes, M Grounds
St George’s Healthcare NHS Trust, London, UK
Critical Care 2012, 16(Suppl 1):P513 (doi: 10.1186/cc11120) Conclusion The proposed admission criteria concurred with clinical
decision-making in 81% of admissions. The patients that met refusal
criteria required either prolonged hospital stay or had short survival
times and may not represent optimal utilization of critical care facilities
during a time of increased demand. Those patients not meeting the
admission criteria had short critical care stays illustrating that rigid
admission requirements may exclude patients who could benefi t from
critical care. A standardized set of admission criteria may supplement
decision-making during times of increased critical care demand and
strengthen documentation of those decisions. However, no set of
criteria can replace clinical judgement in critical care admission. References Introduction This audit reviewed the discharge process of patients
from an adult general ICU to the general wards before and after the
introduction of a liaison nurse post over a 3-year, 3-month time period. Methods The audit utilised routinely collected retrospective data from
a 17-bed ICU. We examined the impact of a liaison post on the length
of delays on discharge of patients from the ICU to the general wards. Introduction This audit reviewed the discharge process of patients
from an adult general ICU to the general wards before and after the
introduction of a liaison nurse post over a 3-year, 3-month time period. Methods The audit utilised routinely collected retrospective data from
a 17-bed ICU. We examined the impact of a liaison post on the length
of delays on discharge of patients from the ICU to the general wards. Results The study period was from April 2008 until June 2011 with the
start date of the liaison nurse post in January 2010. Overall, there were
4,327 patient discharges to hospital wards (before group = 2,063, after
group = 2,264). The odds of experiencing a delay in discharge >4 hours
were 3.2-fold higher in the before group compared to the after group
(95% CI = 2.808 to 3.717, P <0.0001). Accumulated discharge delays
decreased by 23% from 1,116 (before group) to 864 days (after group)
despite an increase in patient turnover of 10% (n = 201). The median
delay time was 7.2 hours (IQR 5.0 hours, 10.4 hours) in the before group
and 5.3 hours in the after group (IQR 2.7 hours, 9.0 hours). Reference 1. Scottish Intensive Care Society Audit Group: Audit of Critical Care in Scotland
2011, Reporting on 2010; 2011. Edinburgh: ISD Scotland. Out-of-hours discharge from the ICU: defi ning the out-of-hours
period and its eff ect on mortality
YL Bramma, R Allan, R Sundaram
Royal Alexandra Hospital, Paisley, UK
Critical Care 2012, 16(Suppl 1):P512 (doi: 10.1186/cc11119) YL Bramma, R Allan, R Sundaram Royal Alexandra Hospital, Paisley, UK Royal Alexandra Hospital, Paisley, UK y
y
Critical Care 2012, 16(Suppl 1):P512 (doi: 10.1186/cc11119) Delayed discharges revisited: impact of a liaison post on patients’
transition from ICU to ward caref See Figure 1. Conclusion Our analysis suggests that the introduction of a liaison
nurse post within intensive care signifi cantly reduced the length of
delays in the discharge process despite an increase in patient turnover. y
g
p
g
Results The study period was from April 2008 until June 2011 with the
start date of the liaison nurse post in January 2010. Overall, there were
4,327 patient discharges to hospital wards (before group = 2,063, after
group = 2,264). The odds of experiencing a delay in discharge >4 hours
were 3.2-fold higher in the before group compared to the after group
(95% CI = 2.808 to 3.717, P <0.0001). Accumulated discharge delays
decreased by 23% from 1,116 (before group) to 864 days (after group)
despite an increase in patient turnover of 10% (n = 201). The median
delay time was 7.2 hours (IQR 5.0 hours, 10.4 hours) in the before group
and 5.3 hours in the after group (IQR 2.7 hours, 9.0 hours). See Figure 1. Conclusion Our analysis suggests that the introduction of a liaison
nurse post within intensive care signifi cantly reduced the length of
delays in the discharge process despite an increase in patient turnover. 1. Christian MD, et al.: Development of a triage protocol for critical care
during an infl uenza pandemic. CMAJ 2006, 175:1377-1381. 1. Christian MD, et al.: Development of a triage protocol for critical care
during an infl uenza pandemic. CMAJ 2006, 175:1377-1381. 2. Ling CY, et al.: Outcome scoring systems for acute respiratory distress
syndrome. Shock 2010, 34:352-357. P511
To admit or not to admit? The suitability of critical care admission
criteria The fi rst of these had a severe
life-limiting condition, staying 29 days in the ICU and a further 65 days
in hospital. The second was admitted post non-VF arrest, dying after
2 days in the ICU. Three patients (11%) met no admission criteria. These
patients stayed between 4 and 6 days in critical care with total hospital
stays of 18 to 98 days, one requiring 30 days of rehabilitation. Assessing demand for intensive care services: the role of
readmission rates With the out-of-
hours period re-defi ned: 393 patients were discharged between 08:00
and 16:59 hours, 373 between 17:00 and 07:59 hours. Both groups were
similar: age 51.0 (18.4) versus 53.8 (17.5) years, males 49.9% versus
48.8%, APACHE II 14.9 (8.7) versus 17.4 (8.2). Hospital mortality was
7.7% (28/393 deaths) versus 11.5% (43/373 deaths), RR 1.62 (95% CI
1.03 to 2.55). Discharge was delayed due to a shortage of ward beds in
22.7% versus 41.0% of cases. ICU step-down is most safely performed y
Results The number of GICU admissions during the period was 422. There were 19 readmissions (readmission rate of 4.6%). However, this
rate increased to 8.6% during the period of high activity encompassing
the H1N1 pandemic (Figure 1). Hospital mortality was 36.8% in the
readmission group, higher than the average, 24.6%, for the whole GICU
population. This is in keeping with previous research showing up to an
11-fold increase in relative risk of mortality in patients readmitted to
the ICU [2]. S183 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Conclusion The annual readmission rate for our unit was acceptable
[3]. A clear spike was noted during the period of the H1N1 pandemic. Whilst this is a pattern we hope to address, it is a useful indicator of
increased demand. Our study suggests that readmission trends
in a single institution may be helpful when analysing the severity
of epidemics, planning staffi ng needs, and comparing periods of
P515
Management of cardiac drugs in a critical care setting
M Mallick1, J Walkington1, A Gratrix1, R Pretorius2
1Hull Royal Infi rmary, Hull, UK; 2York Teaching Hospital, York, UK
Critical Care 2012, 16(Suppl 1):P515 (doi: 10.1186/cc11122)
Figure 1 (abstract P513). Number of ward discharges and accumulated delay. Figure 1 (abstract P514). Readmissions over time. Figure 1 (abstract P513). Number of ward discharges and accumulated delay. Figure 1 (abstract P513). Number of ward discharges and accumulated delay. Figure 1 (abstract P513). Number of ward discharges and accumulated delay. Figure 1 (abstract P514). Readmissions over time. Figure 1 (abstract P514). Readmissions over time. Conclusion The annual readmission rate for our unit was acceptable
[3]. A clear spike was noted during the period of the H1N1 pandemic. Whilst this is a pattern we hope to address, it is a useful indicator of
increased demand. 2.
Rosenberg AL, et al.: Crit Care Med 2001, 2 1.
Intensive Care Society: Standards for Intensive Care Units. London: ICS; 1997. 3.
Rosenberg AL, et al.: Chest 2000, 118:492-502. 2.
Rosenberg AL, et al.: Crit Care Med 2001, 29:511-551. 1.
Intensive Care Society: Standards for Intensive Care Units. London: ICS; 1997.
2.
Rosenberg AL, et al.: Crit Care Med 2001, 29:511-551. Assessing demand for intensive care services: the role of
readmission rates Our study suggests that readmission trends
in a single institution may be helpful when analysing the severity
of epidemics, planning staffi ng needs, and comparing periods of
heightened demand. References P515
Management of cardiac drugs in a critical care setting
M Mallick1, J Walkington1, A Gratrix1, R Pretorius2
1Hull Royal Infi rmary, Hull, UK; 2York Teaching Hospital, York, UK
Critical Care 2012, 16(Suppl 1):P515 (doi: 10.1186/cc11122) Introduction ICU admissions may lead to discontinuation of
longstanding evidence-based therapies. A recent study demonstrated
how such medications have been discontinued for patients even after
their ICU stay [1]. Evidence has shown the benefi cial role of β-blockers
in the perioperative period [2], and roles for other drugs such as Pharmacists and fastidiousness improve compliance with
guidelines for stress ulcer prophylaxis
S Sanders, KC Shelley, AJ Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P516 (doi: 10.1186/cc11123) Frenchay Hospital, Bristol, UK Conclusion Although most of the ICU staff believe that the CPOE
and bar-code has the potential to improve medication safety and the
quality of care for critically ill patients, our survey showed a low level of
satisfaction 6 months after implementing the system, particularly for
physicians who consider the system unfriendly. Reference Introduction This audit assessed compliance with guidelines for the
use of stress ulcer prophylaxis (SUP) in our mixed general/neurosurgical
ICU. These patients are at increased risk of gastrointestinal bleeding
with clinically important bleeding occurring in about 3.5% of patients
ventilated for 48 hours or more [1]. SUP guidelines: all patients at risk
of stress ulceration (coagulopathy/IPPV >48 hours/nasogastric (n.g.)
feed not absorbed) or already on ant acids should receive ranitidine,
enterally where possible. Exceptions are patients on a proton pump
inhibitor (PPI) prior to ICU admission. PPIs should continue enterally if
possible as lanzoprazole, or as omeprazole i.v. Reference
1. Poon EG, et al.: N Engl J Med 2010, 362:1698-1707. 1. Poon EG, et al.: N Engl J Med 2010, 362:1698-1707. P518
Safer ICU trainee handover: a service improvement project
E Godfrey1, I Hassan1, A Carson-Stevens2, AG Saayman1
1University Hospital of Wales, Cardiff , UK; 2Cardiff University, Cardiff , UK
Critical Care 2012, 16(Suppl 1):P518 (doi: 10.1186/cc11125) Methods Data were collected from May to August 2010 (Period 1). Results from this were discussed and the following interventions
adopted prior to further data collection (Period 2: August to November
2011): prescription of SUP in all ventilated patients on admission
to the ICU; discontinuation of SUP after 48 hours if n.g. feeding
tolerated; documented daily review of SUP including consideration of
discontinuation, drug, route and dose used; and the presence of the
ICU pharmacist on ward rounds, briefed specifi cally to prompt correct
SUP use. Introduction Quality handover between team members within the ICU
is vital for patient safety. Critically ill patients are at high risk of medical
errors; these complex patients are exposed to high-risk interventions,
medical and procedural [1]. Distractions are known to be particularly
prevalent within critical care [2]. This can compromise handover
effi ciency, interrupt information-giving and may ultimately lead to
poorer patient outcomes [3]. We sought to demonstrate the capability
of junior physicians to lead change to their practices that benefi t
the quality of patient care in a large critical care unit. P517 P517
Healthcare workers’ experience when using an electronic medical
order entry and bar-code technology in an ICU
R Fumis, I Souza, V Pizzo, G Schettino
Hospital Sírio-Libanês, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P517 (doi: 10.1186/cc11124) P516 Pharmacists and fastidiousness improve compliance with
guidelines for stress ulcer prophylaxis
S Sanders, KC Shelley, AJ Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P516 (doi: 10.1186/cc11123) P517
Healthcare workers’ experience when using an electronic medical
order entry and bar-code technology in an ICU
R Fumis, I Souza, V Pizzo, G Schettino
Hospital Sírio-Libanês, São Paulo, Brazil
Critical Care 2012, 16(Suppl 1):P517 (doi: 10.1186/cc11124) Introduction Medication errors are frequent in the ICU and may occur
during medical ordering, transcription or administration of drugs. A
system consisting of a computerized physician order entry (CPOE) with
bar-code verifi cation of medications (TASY; Web Sistemas, Brazil) has
been described as a tool to improve medication safety [1], but few data
are available about the satisfaction of healthcare workers with the use
of this new technology in the ICU. Methods We conducted a survey to evaluate the satisfaction of
healthcare workers when using a CPOE with bar-code verifi cation of
medications in a tertiary 40-bed adult ICU in Sao Paolo, Brazil 6 months
after implementing the system. A satisfaction questionnaire which
consisted of items in a numeric scale type from 1 (low satisfaction) to 10
(high satisfaction) was fi lled out by physicians (n = 42), nurses (n = 58),
nurses technicians (n = 84) and other professionals (n = 66). gi
y
g
y
Conclusion The study does highlight a trend associated with patients
who are on medications who do not receive them to either develop
higher complication rates or higher mortality rates or both. Further
research involving larger numbers is required to produce validated
opinions. f p
Results Most subjects were female (66%), below 36 years of age (69%)
and used the computer daily at home (81%). On average, respondents
were satisfi ed with the CPOE system (score 5.74 ± 2.14) and believed
it improved safety (score 7.64 ± 2.42). Satisfaction was lower among
physicians (score 4.62 ± 1.79) when compared to other professionals
(score 5.97 ± 2.14; P <0.0001). The ease to place the fi rst medical order
and to copy the order form the previous day scored 5.41 ± 2.05 and
6.39 ± 1.93. The visualization of the medical order with the bar-code
verifi cation of drugs administration scored 5.95 ± 2.51 by the nurses. On average, physicians found the system less user-friendly (score
3.88 ± 1.85) than other professionals (6.40 ± 2.29; P <0.0001). p
References References 1. Bell CM: JAMA 2011, 306:840-847. 1. Bell CM: JAMA 2011, 306:840-847. 2. 2009 ACCF/AHA focused update on preoperative beta blockade: a report
of the American College of Cardiology Foundation/American Heart
Association task force on practice guidelines. Circulation 2009,
120:2123-2151. References S184 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 angiotensin-converting enzyme inhibitors (ACE-I) and statins have
been demonstrated. The aim of the current study was to examine 30-
day mortality and complication rates in the critical care population who
were on cardiac medications and did not receive these medications
during their ICU stay. angiotensin-converting enzyme inhibitors (ACE-I) and statins have
been demonstrated. The aim of the current study was to examine 30-
day mortality and complication rates in the critical care population who
were on cardiac medications and did not receive these medications
during their ICU stay. unindicated SUP use; and reduction in inappropriate i.v. administration
(23.1% vs. 0%, P = 0.0024). Conclusion Emphasis on the guidelines for SUP to all members of the
team, especially the pharmacist, improves compliance. Inclusion in
SUP prescriptions of the intended discontinuation date may further
reduce excessive duration of treatment. Re-audit will occur after
implementation of new guidelines which acknowledge the diminishing
benefi t from SUP and the not-insignifi cant risks associated with its use. Reference g
y
Methods We looked retrospectively at the last 80 patients admitted to
the ICU or HDU in York, 2011. The patients’ case notes were examined
to assess if they were on cardiac medications and if those drugs were
omitted during their admission. The cardiac medications assessed
were β-blockers, ACE-I and statins. We also reviewed any cardiac
complications incurred during their stay, alongside 30-day mortality. Results A total of 29.6% of patients on β-blockers received them,
whilst 67.8% did not. Complication and mortality rates for medications
given versus not given were 12.5% versus 68.4% and 0% versus 42.1%
(P = 0.003 and P = 0.007) respectively. A total of 17.6% of patients on
ACE-I received them, whilst 82.3% did not. Complication and mortality
rates for medications given versus not given were 0% versus 9.0%
and 0% versus 35.7% (P = 0.004 and P = 0.055) respectively. A total
of 31.6% of patients on statins received them, whilst 68.4% did not. Complication and mortality rates for medications given versus not
given were 25.0% versus 42.3% and 8.3% versus 38.5% (P = 0.256 and
P = 0.02 respectively). References The global complication and mortality rates for
medications given versus not given were 28% versus 55.2% and 11.5%
versus 51.7% (P = 0.0648 and P = 0.0039) respectively. Omission of
β-blockers resulted in signifi cantly higher complication and mortality
rates. Omission of ACE-I resulted in higher complication rates and of
statins in higher mortality rates. Omission of cardiac medications g
y
Methods We looked retrospectively at the last 80 patients admitted to
the ICU or HDU in York, 2011. The patients’ case notes were examined
to assess if they were on cardiac medications and if those drugs were
omitted during their admission. The cardiac medications assessed
were β-blockers, ACE-I and statins. We also reviewed any cardiac
complications incurred during their stay, alongside 30-day mortality. 1. Cook DJ, et al.: Crit Care 2001, 5:368-375. Results A total of 29.6% of patients on β-blockers received them,
whilst 67.8% did not. Complication and mortality rates for medications
given versus not given were 12.5% versus 68.4% and 0% versus 42.1%
(P = 0.003 and P = 0.007) respectively. A total of 17.6% of patients on
ACE-I received them, whilst 82.3% did not. Complication and mortality
rates for medications given versus not given were 0% versus 9.0%
and 0% versus 35.7% (P = 0.004 and P = 0.055) respectively. A total
of 31.6% of patients on statins received them, whilst 68.4% did not. Complication and mortality rates for medications given versus not
given were 25.0% versus 42.3% and 8.3% versus 38.5% (P = 0.256 and
P = 0.02 respectively). The global complication and mortality rates for
medications given versus not given were 28% versus 55.2% and 11.5%
versus 51.7% (P = 0.0648 and P = 0.0039) respectively. Omission of
β-blockers resulted in signifi cantly higher complication and mortality
rates. Omission of ACE-I resulted in higher complication rates and of
statins in higher mortality rates. Omission of cardiac medications
resulted in a signifi cantly higher mortality rate. Pharmacists and fastidiousness improve compliance with
guidelines for stress ulcer prophylaxis
S Sanders, KC Shelley, AJ Marsh
Frenchay Hospital, Bristol, UK
Critical Care 2012, 16(Suppl 1):P516 (doi: 10.1186/cc11123) We present an
improvement project that has transformed handover quality in our ICU. Methods Participant observation of handover practices took place
within a high-occupancy 33-bed adult ICU. Quantitative assessment
of handover criteria as per Royal College of Anaesthetists guidelines Results Period 1 (n = 86) revealed excess use of SUP, excess use of
PPIs when ranitidine was indicated, unnecessary i.v. administration
and failure to discontinue prophylaxis appropriately. Period 2 (n = 71)
demonstrated: no fall in SUP use in those with indications (93% vs. 97%, P = 0.65); increased prescription accuracy in terms of drug, dose
and administration route (40% vs. 84%, P = 0.0001); no increased S185 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 [4] was performed at baseline (handovers: n = 6, patients: n = 119)
and 3 months post-intervention (handovers: n = 4, patients: n = 108). Interventions included presentation of data at multiprofessional
departmental meetings, education of team members regarding
frequency of handover interruptions and development and utilisation
of an electronic handover tool. P519 ICU handover: are we forgetting something? A preliminary study
T Aslanidis, IL Chytas, A Kontos, I Soultati, A Efthmiou, E Geka,
V Ourailoglou, E Anastasiou, M Giannakou-Peftoulidou
G.H. AHEPA, Thessaloniki, Greece
Critical Care 2012, 16(Suppl 1):P519 (doi: 10.1186/cc11126) ICU handover: are we forgetting something? A preliminary study
T Aslanidis, IL Chytas, A Kontos, I Soultati, A Efthmiou, E Geka,
V Ourailoglou, E Anastasiou, M Giannakou-Peftoulidou
G.H. AHEPA, Thessaloniki, Greece
Critical Care 2012, 16(Suppl 1):P519 (doi: 10.1186/cc11126) Introduction The aim of this ongoing study is to review the process
of handover in a university teaching hospital ICU, highlight areas
of special interest and defi ciency during the process, and improve
current practice. Clinical handover, defi ned as a process of transferring
authority and responsibility for providing care of patients from
departing caregiver to named recipient, is a basic part of clinical
practice. Failure to exchange essential information and focus on the
important may have disastrous consequences for the patient. y
Conclusion Although only 28% of discharge summaries achieved an
acceptable or higher rating from the ICU team, GPs valued the majority
of discharge summaries issued by our ICU. Further research is needed
to explain the diff erence between ICU doctors’ perception of discharge
summary quality and the value provided by them to GPs. Reference Methods A prospective observational study was undertaken over a
22-day period to examine the quality and content of clinical handover
by nightshift doctor to the medical team. Key aspects expected to be
handed over included patient details, diagnosis, system – treatment
domains and communication with relatives. Additional data collected
also included duration of handover and frequency of interruptions. 1. National Institute for Health and Clinical Excellence: Clinical Guideline 83:
Rehabilitation after Critical Illness. London: National Institute for Health and
Clinical Excellence; 2009 [www.nice.org.uk/CG83]. P521 Results A total of 207 sets of patients were collected during the study
period. All handovers were supervised by a consultant intensivist. Clinical information handed over verbally covered reason for admission
in 12% of cases, working diagnosis in 13% and current management plan
in 29% (100% in these three in new admissions). Medical comorbidities
where also poorly covered (8%). The handover was rather focused on
special aspects of clinical information like the respiratory system (86%),
fl uid balance and laboratory fi ndings (68%), infections status (67%),
CNS (56%) and hemodynamics (54%), while nutrition and GI was poorly
covered (20%). Only 26% of handovers covered signifi cant changes in
the last shift, 21% commented on the interventions made and 32% had
a proposed plan for the forthcoming day discussed. Of the allocated
30 minutes, the duration of the handover varied from 20 to 50 minutes
(average 28 minutes). There was a total of 34 interruptions over 22 days
of the audited period. Reasons for interruption included telephone
calls and requests from visiting teams and nurses.i Volume–outcome relationship in critical care: a systematic review
DJ Wallace1, YL Nguyen2, L Trinquart2, DC Angus1, P Ravaud2, JM Kahn1
1CRISMA Center, University of Pittsburgh School of Medicine, Pittsburgh, PA,
USA; 2Centre d’épidémiologie clinique, CHU Hôtel Dieu, Paris, France
Critical Care 2012, 16(Suppl 1):P521 (doi: 10.1186/cc11128) Introduction The relationship between provider volume and patient
outcome has been demonstrated for many medical and surgical
services, including critical care. This relationship is used as one rationale
for regionalization of adult intensive care. However, the volume–
outcome relationship is not always consistent across studies, and it
has not been explicitly evaluated in a heterogeneous population. We
performed a systematic review of studies that assessed the association
between volume and outcome among critically ill adult patients. Introduction The relationship between provider volume and patient
outcome has been demonstrated for many medical and surgical
services, including critical care. This relationship is used as one rationale
for regionalization of adult intensive care. However, the volume–
outcome relationship is not always consistent across studies, and it
has not been explicitly evaluated in a heterogeneous population. We
performed a systematic review of studies that assessed the association
between volume and outcome among critically ill adult patients. P520
Quality and value of intensive care discharge summaries for general
practitioners Results Provision of patient details during handover was substandard. Utilisation of a structured handover sheet signifi cantly improved the
number of patient details provided; in particular, patient age (18%
vs. 100%), duration of stay (29% vs. 79%) and medical management
plan (53% vs. 93%). Frequent handover interruptions seen on initial
observation signifi cantly improved (100% vs. 25% of handover
periods interrupted) following our collaboration with the senior nurse,
physiotherapist and other team leads regarding the number and
nonurgent nature of interruptions; at re-audit, interruptions occurred
for clinically urgent requests only. p
F Daruwalla, FJ Lamb, CA Mearns
Surrey and Sussex Healthcare NHS Trust, Redhill, UK
Critical Care 2012, 16(Suppl 1):P520 (doi: 10.1186/cc11127) Introduction Good communication between healthcare professionals
is required to provide continuity of care for patients being discharged
from the ICU [1]. It is our unit’s practice to send a copy of a patient’s
computerized ICU discharge summary to both the hospital team with
ongoing responsibility and to their general practitioner (GP). The aim
of this study was to establish and compare the quality and value of the
summaries as judged by ICU doctors and GPs. Conclusion Simple measures instituted by junior doctors, such as team
education and use of a structured handover tool, can aid high-quality
handover within critical care. Evidence suggests that high-quality
handover within critical care will translate into improved clinical care
for patients. j
g
y
Methods Discharge summaries for patients admitted in July 2011 were
obtained from the ICU WardWatcher® database. These were scored
independently by two ICU consultants and a trainee doctor using
a predefi ned rating scale. The GPs were sent postal questionnaires
regarding their perceptions of the quality and value of the summaries. A comparison was made between the ratings made by the ICU team
and the responses to the GP questionnaires. References 1. Reader TW, et al.: Curr Opin Crit Care 2007, 13:732-736. 2. Horn J, et al.: Anaesthesia 2004, 59:658-663. 3. Nimmo G, et al.: JICS 2008, 9:240-242. 4. McQuillan P, et al.: In The Royal College of Anaesthetists. Raising the Standard: A
Compendium of Audit Recipes. 2nd edition; 2006:218-219 [http://www.rcoa. ac.uk/docs/ARB-section10.pdf]. 4. McQuillan P, et al.: In The Royal College of Anaesthetists. Raising the Standard: A
Compendium of Audit Recipes. 2nd edition; 2006:218-219 [http://www.rcoa. ac.uk/docs/ARB-section10.pdf]. Results Sixty patients were admitted during the study period. All
60 summaries were independently rated by three ICU doctors and
good inter-rater reliability was demonstrated (Cronbach’s α = 0.89). There was a strong correlation between the ratings given by the ICU
consultants and the trainee doctor (Spearman’s = 0.91). Twenty-eight
per cent achieved an acceptable score of 6 out of 10 or greater (median
score 5, interquartile range 3 to 6). Fifty-four postal questionnaires were
sent to GPs and 36 were returned (response rate 67%). Seventy-six per
cent achieved an acceptable score of 16 out of 25 or greater (median
score 18, interquartile range 16 to 25). Sixty-nine per cent of GPs found
the discharge summary helpful and 86% wanted to be sent this type of
summary in future. Correlation between the ICU team rating and the
GP score for the summaries was weakly positive (Spearman’s = 0.15). References References
1. Patterson ES, et al.: Jt Comm J Qual Patient Saf 2010, 36:52-61. 2. Brenier G, et al.: Crit Care 2011, 15:491. P523
Accuracy of height and weight estimation by critical care staff
K Dunne, S Hickey Accuracy of height and weight estimation by critical care sta
K Dunne, S Hickey
Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P523 (doi: 10.1186/cc11130) y
Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P523 (doi: 10.1186/cc11130) y
y
Results We reviewed 80 studies, of which 27 (34%) met all inclusion
criteria. Studies were excluded most commonly when the majority
of the patients did not require critical care (n = 46), the study was
presented only in abstract form (n = 4), data were duplicative (n = 2)
or an outcome measure was not assessed (n = 1). One publication
included three diff erent patient populations; these were counted
as separate studies. The fi nal 29 studies represented seven clinical
categories: respiratory (n = 9), postoperative (n = 7), cardiovascular
(n = 4), general admissions (n = 3), sepsis (n = 2), neurological (n = 2)
and gastrointestinal (n = 2). Eighteen studies (62%) demonstrated a
statistically signifi cant association between higher patient volume and
better health outcomes, although the magnitude of the relationship
varied across diagnoses. No study showed a statistically signifi cant
association between higher volume and poorer outcomes. Forth Valley Royal Hospital, Larbert, UK
Critical Care 2012, 16(Suppl 1):P523 (doi: 10.1186/cc11130) Introduction Patient’s height and weight measurements are used
regularly within the critical care setting whether for calculation of drug
doses, nutritional intake, ventilator settings or calibration of cardiac
output monitoring [1]. In sedated patients these parameters are often
obtained via estimation by critical care staff . Errors in these estimations
have the potential to cause harm either from errors in drug calculations
[2], inappropriate ventilatory settings or underfeeding or overfeeding. Methods We asked members of the critical care team (medical, nursing
staff , physiotherapists and dieticians) to anonymously estimate the
heights and weights of patients within the unit at that time. Following
this we obtained accurate measurements by measuring height with
a measuring tape and patients’ weight with the Scotweigh weighing
machine. The results were then collated and the percentage inaccuracy
of estimate compared to actual measurement was calculated. Conclusion The majority of studies evaluating the volume–outcome
relationship in critically ill patients demonstrated better outcomes with
higher clinical volumes. P521 Methods We searched the MEDLINE and EMBASE databases for articles
published between January 2001 and December 2011 using medical
subject heading terms and text words for conditions related to critical
illness in adults. Trauma studies were excluded. Two study investigators
independently reviewed titles, abstracts and articles identifi ed from
the search algorithm and abstracted study-specifi c data using a
standardized abstraction form. Variables of interest included study g
y
p
Methods We searched the MEDLINE and EMBASE databases for articles
published between January 2001 and December 2011 using medical
subject heading terms and text words for conditions related to critical
illness in adults. Trauma studies were excluded. Two study investigators
independently reviewed titles, abstracts and articles identifi ed from
the search algorithm and abstracted study-specifi c data using a
standardized abstraction form. Variables of interest included study Conclusion Our study identifi ed that the structure of the handover was
rather focused on a system-based approach. Diffi culty in concentration
due to fatigue or frequent interruptions prolongs its duration and
disturbs the right fl ow of information. The senior clinician must ensure
that handover should be a focused but educational experience for the
trainee with appropriate feedback. S186 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 characteristics, patient characteristics, study period, volume defi nition,
primary and secondary outcomes, risk-adjustment methodology,
statistical analyses, results, risk of bias and funding body. P522 Radiation doses in young ICU patients: a cause for concern? RA O’Leary, C Houlihane, P McLaughlin, M Maher, D Breen
Cork University Hospital, Cork, Ireland
Critical Care 2012, 16(Suppl 1):P522 (doi: 10.1186/cc11129) Conclusion Although height estimation was measured to within 10%
accuracy in the majority of cases, staff were considerably less reliable
at estimating an accurate patient weight and on more than one-half
of all estimates underestimated the weight by greater than 10%. We therefore strongly discourage the practice of weight estimation
in situations where clinical decisions are being based on an often
unreliable value, and alternative means of obtaining an accurate
weight measurement should be sought. Introduction The aim of this study was to quantify the radiation
dose in young ICU patients to determine if it approached a clinically
signifi cant level. Ionising radiation is a well-recognised risk factor for
development of cancer. The risk is dose-related and there is no lower
threshold at which the dose can be considered clinically irrelevant. The availability of computed tomography (CT) scanning has led to a
signifi cant increase in exposure to ionising radiation of patients over
the last decade. Children and young adults are particularly at risk. This
is partly because there is a longer lifetime in which radiation eff ects
may be manifest but also because children are up to 10 times more
sensitive to radiation than adults. In view of these issues it is important
to quantify the risk to young ICU patients. g
References 1. Wigfull J, et al.: Critical assessment of haemodynamic data. Contin Educ
Anaesth Crit Care Pain 2005, 5:84-88. 2. Mahajan RP: Medication errors: can we prevent them? Br J Anaesth 2011,
107:3-5. Figure 1 (abstract P523). Accuracy of weight estimation by critical care
staff . q
y
y
g
p
Methods The general ICU database was examined from 1 March 2010
to 1 March 2011. The overall radiation exposure was quantifi ed using
the cumulative eff ective radiation dosage (CED) in millisieverts (mSv). The CED was calculated for all of the procedures performed during
the stay in the ICU using average procedure-specifi c eff ective doses
published by the UK National Radiation Protection Board. A cohort of
patients <30 years of age were selected for subanalysis. y
g
y
Results There were 403 patients admitted to the general ICU during
the period of interest. The number of patients <30 years of age was 75
with a mean age of 19 (range 0.5 to 30 years). The mean CED was 10.84
mSv (SD = 15.08) with 10 patients receiving >30 mSv. The mean CED for
patients who did not undergo CT examination was 0.063 mSv (n = 31,
SD = 0.062). Trauma patients received a far higher dose (21.86 mSv) than
either medical (3.1 mSv) or postoperative surgical (3.96 mSv) admissions. Conclusion CT is a useful and necessary tool in our diagnostic and
therapeutic armoury. However, our results show that young patients
can potentially be exposed to signifi cant doses of ionising radiation in
an ICU setting mainly due to CT. In view of the lifetime risk of cancer to
these patients we should try to minimise radiation exposure by more
judicious utilisation of CT and by use of other imaging modalities. References Figure 1 (abstract P523). Accuracy of weight estimation by critical care
staff . P523
Accuracy of height and weight estimation by critical care staff
K Dunne, S Hickey There was variability in the association across
diagnostic categories, indicating that quality improvement eff orts
based on the volume–outcome relationship such as regionalization of
care may be more successful in specifi c patient subsets. p
Results There were 330 estimations made by 30 members of staff . Height estimation was accurate ±10% for 291 patients (88.4%). Inaccuracy in height estimation ranged from –9.5% to +25% with a
mean inaccuracy of 4.75%. Weight estimation was accurate ±10%
for 123 patients (38.4%). Inaccuracy of weight estimation ranged
from –48.9% to +40.3% with a mean inaccuracy of 16.4%. There was
a tendency to underestimate weight with only 33 estimates (10%)
greater than 10% of actual weight and 174 estimates (52.7%) less than
10% of actual weight. See Figure 1. 1.
Hart D, Wall B: Radiation Exposure of the UK Population from Medical and Dental
X-ray Examinations. Chilton: National Radiological Protection Board; 2002.
2.
Kinsella SM, et al.: Kidney Int 2010, 78:789-793.
3.
Dawson P: Br J Radiol 2004, 77(Spec No 1):S10-S13.
4.
Slovis T: Radiology 2002, 223:5-6.
5.
Cardis E, et al.: Radiat Res 2007, 167:396-416.
6.
Cascade PN, et al.: AJR Am J Roentgenol 1998, 1770:561-564. P526
A new patient mobilization scoring system in the ICU: what is the
degree of similarity in scores between assessors in daily use?
M Vogel, CW Casteleijn, P Bruins, AJ Meinders
St Antonius Ziekenhuis, Nieuwegein, the Netherlands
Critical Care 2012, 16(Suppl 1):P526 (doi: 10.1186/cc11133) P526
A new patient mobilization scoring system in the ICU: what is the
degree of similarity in scores between assessors in daily use? M Vogel, CW Casteleijn, P Bruins, AJ Meinders
St Antonius Ziekenhuis, Nieuwegein, the Netherlands
Critical Care 2012, 16(Suppl 1):P526 (doi: 10.1186/cc11133) Introduction Inactivity and immobility in ICU patients have signifi cant
deleterious physiologic eff ects, including atelectasis, pressure ulcers,
and increased susceptibility to aspiration and pneumonia. A new
trend on the ICU is early mobilization of critically ill adult patients. However, evidence of when to start mobilization is missing. Casteleijn
developed a new scoring system, the Patient Mobilization Frame (PMF),
to improve early mobilization in the ICU. The framework is based on
a multidisciplinary agreement. The aim of this study was to evaluate
interobserver agreement using the PMF. Conclusion It is very challenging to implement care bundles despite
evidence showing that they improve outcome. A recent study suggests
that doing a daily quality rounds checklist (QRC) will improve long-term
compliance, thereby reducing potential complications for intensive
care patients [1]. We have implemented QRC in our practice and will be
re-auditing in 6 months to ensure continued adherence. 1. DuBose et al.: Measurable outcomes of quality improvement in the trauma
intensive care unit: the impact of a daily quality rounding checklist. J
Trauma 2008, 64:22-29. Methods A prospective observational study in 47 critically ill
patients in the ICU was performed. The PMF categorizes patients
into one of three stages of possible training using a scoring system
based on 14 items. Various factors infl uencing individual stage are
used including circulation, respiration, infection, kidney function,
wounds and neurology. Stage A (critically ill) permits only passive
physical examination. Whereas stage B (stable) and stage C (nearly
recovered) permit (guided) active mobilization and functional training,
respectively. Two staff members and one resident obtained 47
independent observation series of the PMF. All observations were at
the same date and time and were compared. P524 P524
Implementation of evidence-based care bundles in the ICU
G Juknevicius, E Balakumar, A Gratrix
Hull Royal Infi rmary, Hull, UK
Critical Care 2012, 16(Suppl 1):P524 (doi: 10.1186/cc11131) P524
Implementation of evidence-based care bundles in the ICU
G Juknevicius, E Balakumar, A Gratrix
Hull Royal Infi rmary, Hull, UK
Critical Care 2012, 16(Suppl 1):P524 (doi: 10.1186/cc11131) 1. Hart D, Wall B: Radiation Exposure of the UK Population from Medical and Dental
X-ray Examinations. Chilton: National Radiological Protection Board; 2002. 2. Kinsella SM, et al.: Kidney Int 2010, 78:789-793. 3. Dawson P: Br J Radiol 2004, 77(Spec No 1):S10-S13. 4. Slovis T: Radiology 2002, 223:5-6. 5. Cardis E, et al.: Radiat Res 2007, 167:396-416. 6. Cascade PN, et al.: AJR Am J Roentgenol 1998, 1770:561-564. 1. Hart D, Wall B: Radiation Exposure of the UK Population from Medical and Dental
X-ray Examinations. Chilton: National Radiological Protection Board; 2002. 2. Kinsella SM, et al.: Kidney Int 2010, 78:789-793. 3. Dawson P: Br J Radiol 2004, 77(Spec No 1):S10-S13. 4. Slovis T: Radiology 2002, 223:5-6. 5. Cardis E, et al.: Radiat Res 2007, 167:396-416. 6. Cascade PN, et al.: AJR Am J Roentgenol 1998, 1770:561-564. 1. Hart D, Wall B: Radiation Exposure of the UK Population from Medical and Dental
X-ray Examinations. Chilton: National Radiological Protection Board; 2002. 2. Kinsella SM, et al.: Kidney Int 2010, 78:789-793. 3. Dawson P: Br J Radiol 2004, 77(Spec No 1):S10-S13. Introduction Implementation of an evidence-based care bundle in
critically ill patients has been shown to improve outcome. Use of care
bundles to reduce ventilator-associated pneumonia and other ICU
complications has been increasing in critical care practice. gy
5. Cardis E, et al.: Radiat Res 2007, 167:396-416. 6. Cascade PN, et al.: AJR Am J Roentgenol 1998, 1770:561-564. S187 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 Critical Care 2012, Volume 16 Suppl 1
http://ccforum.com/supplements/16/S1 confi dence in its use, a similar proportion to the original audit. Eighty
per cent would have an ODP for unplanned intubations. One hundred
per cent were airway trained. Outcomes A designated consultant
was assigned to teach diffi cult airway management at quarterly
departmental induction sessions which included equipment location
and algorithms. Trainees and consultants underwent simulation and
mannequin training, including tracheostomy and surgical airway
management. Regular updates and case-based teaching sessions were
implemented. Airway profi ciency assessments were conducted at
induction. Awareness of diffi cult airway equipment on the ICU
A W
i k A I Royal Liverpool University Hospital, Liverpool, UK
Critical Care 2012, 16(Suppl 1):P525 (doi: 10.1186/cc11132) Critical Care 2012, 16(Suppl 1):P525 (doi: 10.1186/cc11132) Introduction It is widely recognised that critically ill patients can be
diffi cult to intubate, requiring the use of advanced airway skills and
equipment. The range of airway equipment necessary for patients on the
ICU has recently been recommended [1]. Our ICU has a comprehensive
diffi cult airway trolley (DAT) which is regularly maintained. With a high
turnover of trainees, we were keen to determine if there was a training
need to be met regarding airway management in ICU patients. The
objectives were to determine awareness of the DAT, assess knowledge
of its contents and ascertain confi dence in its use. Results Interobserver reliability of observers 1, 2 and 3 proved to be
adequate. Kappa for observers 1 and 2 was 0.9. Kappa for observers 1
and 3 was 0.6. Kappa for observers 2 and 3 was 0.6. The value of kappa
can range from 0 (disagreement) to 1 (perfect agreement). Kappa
larger than 0.6 was regarded as substantial agreement. Conclusion Casteleijn’s PMF proved to be a reliable scoring system as
both resident and staff members had comparable results for staging
the physical abilities of the critically ill patient in the ICU. i
Methods We audited against previously described standards [1]
using a short questionnaire, disseminated to trainees and consultants
working on the ICU in November 2010: 100% of clinicians should be
aware of the location and contents of the DAT; 100% of anaesthetists
should have had diffi cult airway equipment training. P524 confi dence in its use, a similar proportion to the original audit. Eighty
per cent would have an ODP for unplanned intubations. One hundred
per cent were airway trained. Outcomes A designated consultant
was assigned to teach diffi cult airway management at quarterly
departmental induction sessions which included equipment location
and algorithms. Trainees and consultants underwent simulation and
mannequin training, including tracheostomy and surgical airway
management. Regular updates and case-based teaching sessions were
implemented. Airway profi ciency assessments were conducted at
induction. Methods We conducted a prospective audit on implementation of a
care bundle after audit approval. We collected data for 101 patient days
from all patients admitted to Hull Royal Infi rmary ICU during the month
of November 2011. We collected information regarding stress ulcer
prophylaxis, deep vein thrombosis (DVT) prophylaxis, ventilator care
bundle, blood glucose control, daily assessment of need for a central
line, sedation score assessment and delirium score assessment at least
twice a day. y
Results All patients received stress ulcer prophylaxis. At least 95% of
patients received DVT prophylaxis, adequate blood glucose control
and appropriate sedation need assessment. There was further scope
for improvement in areas of sedation hold practice and assessing daily
need for a central line. Poor clinical practice was identifi ed in delirium
score assessment and head elevation to reduce VAP. See Table 1. Conclusion This audit highlights our variable workforce. The
presence of junior, nonairway-trained staff on the ICU calls for regular,
compulsory airway teaching sessions for all, regardless of grade. Airway competency must be formally assessed at the start of an ICU
attachment. Airway instructions for challenging patients should be
clearly documented with advice on access to senior assistance for
emergencies. Reference Table 1 (abstract P524)
Intervention in eligible patients
Adherence, n (%)
Stress ulcer prophylaxis
101/101 (100)
DVT/PE prophylaxis
94/97 (97)
Head elevation 30% in ventilated patients
62/75 (83)
Daily sedation hold
28/32 (88)
Blood glucose control
96/101 (95)
Need for central line assessed
73/85 (86)
Sedation score assessment
98/101 (97)
CAM-ICU score at least twice a day
29/101 (28) Reference 1. Jeanrenaud P, et al.: Diffi cult airway trolleys for the critical care unit. JICS
2010, 11:98-103. P529 Methods A cross-sectional retrospective descriptive and observational
study of rehabilitation of bedridden patients in hospital from January
2010 to June 2011. The programme is implemented in Section 30 (21, 9,
and 20 rooms). The inclusion criteria for the rehabilitation programme
were patients of both sexes, without age limit, inpatient of Hospital
F.J. Muñiz coming from the ICU, in bedridden condition (limitation or
motor disability in which the patient cannot move or perform activities
of daily living and must depend on the care of others), with Barthel
scale value 0 to 35 with total or severe dependence and stability
hemodynamics. P529
Muscle strength assessment of critically ill patients is associated
with functional ability and quality of life at hospital discharge
G Sidiras, I Patsaki, M Dakoutrou, E Karatzanos, V Gerovasili, A Kouvarakos,
A Kardara, K Apostolou, S Dimopoulos, V Markaki, S Nanas
University of Athens, Greece
Critical Care 2012, 16(Suppl 1):P529 (doi: 10.1186/cc11136) Introduction Patients with critical illness after hospital discharge often
exhibit poor functional ability and quality of life as a consequence
of acquired muscle weakness. The Medical Research Council (MRC)
strength score and hand-grip dynamometry (HGD) are reliable and
valid methods to detect clinically signifi cant muscle weakness. The objective of this study is to examine the correlation of these
instruments to functional ability and quality-of-life questionnaires at
hospital discharge. Introduction Patients with critical illness after hospital discharge often
exhibit poor functional ability and quality of life as a consequence
of acquired muscle weakness. The Medical Research Council (MRC)
strength score and hand-grip dynamometry (HGD) are reliable and
valid methods to detect clinically signifi cant muscle weakness. The objective of this study is to examine the correlation of these
instruments to functional ability and quality-of-life questionnaires at
hospital discharge. Results We included patients who met the inclusion criteria. The
program presented an intensive character in terms of the frequency of
weekly sessions as the number of exercises implemented in the form
was specifi ed according to the pathology of the patient. Ninety percent
of patients were male. The median age was 41 years. The predominant
infectious pathology was pulmonary tuberculosis (90%), cerebral
toxoplasmosis (50%), spastic paraplegia (6%), bilateral pneumonia
(6%), and fumigares aspergillosis (6%). 1.
Tennilä A, et al.: Intensive Care Med 2000, 26:1360-1363.
2.
Khan J, et al.: Neurology 2006, 67:1421-1425.
3.
Latronico N, et al.: Crit Care 2007, 11:R11. P528 Severity of electrophysiological alterations correlates with severity
of illness in the early phase of critical illness polyneuropathy
R Nemes, Z Fülep, B Fülesdi
University of Debrecen, Hungary
Critical Care 2012, 16(Suppl 1):P528 (doi: 10.1186/cc11135) Conclusion The signifi cantly reduced muscle strength of critically ill
survivors could have detrimental eff ects on their mobility and quality
of life. By this study it was shown that muscle strength assessment was
well associated with functional ability. We assume that this might be a
possible signifi cant prognostic role. Introduction We aimed to investigate the early characteristics of critical
illness polyneuropathy in surgical patients in a 5-day follow-up setting. Methods Twenty critically ill patients were enrolled showing signs
of systemic infl ammatory response, sepsis or multiorgan failure
featuring APACHE II score ≥12 on admittance aged 26 to 86 years. Routine noninvasive nerve conduction study of bilateral median and
ulnar nerves was performed on a two-channel portable Keypoint
Medtronic apparatus. Nerve conduction studies were performed on
fi ve consecutive days starting within at most 2 days after admittance,
then weekly follow-up was carried out. Electrophysiological fi ndings
were compared to age-matched control group parameters.i Motor and respiratory intensive rehabilitation in bedridden
patients Motor and respiratory intensive rehabilitation in bedridde
patients
E Canedo, V Nunes Velloso, L Calejman, N Leidi
Hospital de Infecciosas F.J. Muñiz, Buenos Aires, Argentina
Critical Care 2012, 16(Suppl 1):P527 (doi: 10.1186/cc11134) E Canedo, V Nunes Velloso, L Calejman, N Leidi
Hospital de Infecciosas F.J. Muñiz, Buenos Aires, Argentina
Critical Care 2012, 16(Suppl 1):P527 (doi: 10.1186/cc11134) fi
A re-audit was conducted in June 2011 to complete the audit cycle. Results One hundred per cent of clinicians were aware of the DAT. Only
35% had read the folder detailing its contents with instructions. Ninety
per cent could confi dently name the equipment which should be readily
available for diffi cult intubations but only 70% were confi dent to use
it unaided. Fifty per cent would request the presence of an operating
department practitioner (ODP) for an unplanned intubation on the
ICU. Twenty-eight per cent were not airway trained. Re-audit showed
100% of respondents were aware of the equipment. Sixty per cent had Introduction Inability to play signifi cant social roles due to a pattern
of motor disability aff ects the quality of a person’s life, and is where
the motor and respiratory rehabilitation process takes fundamental
importance. This disability prevents one to function independently in
basic tasks such as dressing and feeding and in more complex tasks
such as handling in public and/or work. It can also be a constraint for the Introduction Inability to play signifi cant social roles due to a pattern
of motor disability aff ects the quality of a person’s life, and is where
the motor and respiratory rehabilitation process takes fundamental
importance. This disability prevents one to function independently in
basic tasks such as dressing and feeding and in more complex tasks
such as handling in public and/or work. It can also be a constraint for the S188 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 4. Mohammadi B, et al.: J Neurol 2008, 255:265-272. 5. Latronico N, et al.: Lancet Neurol 2011, 10:931-941. 6. Bolton CF, et al.: Crit Care Med 1996, 24:1408-1416. dependent patient in personal care activities. P530
Functional dependency in the direct post-ICU phase in patients
with prolonged mechanical ventilation
S Vossenberg1, I Drogt2, N Bruins2, C De Jager2, EC Boerma2, M Tijkotte1
1Zorggroep Noorderbreedte, Leeuwarden, the Netherlands; 2Medical Centre
Leeuwarden, the Netherlands
Critical Care 2012, 16(Suppl 1):P530 (doi: 10.1186/cc11137) Functional dependency in the direct post-ICU phase in patients
with prolonged mechanical ventilation
S Vossenberg1, I Drogt2, N Bruins2, C De Jager2, EC Boerma2, M Tijkotte1
1Zorggroep Noorderbreedte, Leeuwarden, the Netherlands; 2Medical Centre
Leeuwarden, the Netherlands
Critical Care 2012, 16(Suppl 1):P530 (doi: 10.1186/cc11137) P529 The profi t was 100% of kinesic
treatment adherence, 94% of cases won full independence valued
on the Barthel scale with a value of 100, and a single case achieved
independence moderated by the presence of spastic paraplegia. Methods Two hundred and sixty-six consecutive patients who had
been discharged from the ICU were evaluated and 37 of them were
eligible (inclusion criteria: in mechanical ventilation >72 hours, a
cognitive status that allows assessment) for the study (mean ± SD: age
55 ± 15; APACHE 14 ± 5; SOFA 8 ± 3; length of ICU stay 22 ± 22 days;
duration of mechanical ventilation 17 ± 19 days). Muscle strength was
evaluated with the MRC score and HGD every 7 days until discharge
from the hospital. The Functional Independence Measure (FIM) was
used to evaluate the functional ability while health-related quality of
life was assessed by the Nottingham Health Profi le (NHP).i Conclusion The intensive rehabilitation programme presented a great
benefi t for hospitalized patients; taking them from being bedridden to
total independence in the AVD, the outpatient had better social and
labor conditions. y
gi
Results At hospital discharge the MRC scale and HGD were signifi cantly
correlated with FIM (r = 0.69, P <0.001 and r = 0.58, P <0.001,
respectively). There seems to be a good correlation of the MRC scale
(r = –0.57, P <0.001) with the section of mobility of the NHP. There is
also certain association among the domain of mobility and energy
of the NHP with the FIM (r = –0.88, P <0.001 and r = –0.61, P <0.05,
respectively). Motor and respiratory intensive rehabilitation in bedridden
patients The objective of a motor
rehabilitation plan is to reduce the impact caused by this alteration of
motor ability, facilitating the restoration of functional patient capacity
so they can eff ectively engage in occupations, reaching the highest
level of functional independence possible. dependent patient in personal care activities. The objective of a motor
rehabilitation plan is to reduce the impact caused by this alteration of
motor ability, facilitating the restoration of functional patient capacity
so they can eff ectively engage in occupations, reaching the highest
level of functional independence possible. 3.
Latronico N, et al.: Crit Care 2007, 11:R11. .
Mahoney FI, Barthel DW: Functional evaluation: the Barthel Index. Md Med J
1965, 2:61-65. Functional dependency in the direct post-ICU phase in patients
with prolonged mechanical ventilation p
g
g
p p
Results On fi rst examination, within 2 days following admission 17
of 20 (85%) patients showed signs of axonal type sensory-motor
polyneuropathy. Medians of compound muscle action potential (CMAP)
and sensory nerve action potential (SNAP) amplitudes of all nerves
showed a signifi cant decrease compared to control values (P <0.001). During the 5-day study period four patients showed improvement. Sensory nerve fi bres were less severely aff ected than motor fi bers. The
consecutive measurements revealed negative correlation with the
severity of peripheral interstitial oedema determined by circumference
of the elbow. Changes in CMAP and SNAP amplitudes also showed a
negative correlation with daily rated APACHE II and SAPS II severity
scores, and thus with patients’ general condition. Introduction Prolonged mechanical ventilation and length of stay
(LOS) in the ICU is associated with long-term impaired functional
capacity. However, little is known about functional dependency in the
direct post-ICU phase. Therefore the timing and location for optimal
post-ICU rehabilitation programs remain to be established. Methods In this single-centre observational study we aimed to quantify
functional dependency at three diff erent time points: discharge from
ICU (DI), discharge from hospital (DH) and discharge from nursing home
rehabilitation unit (DR). To this end we retrospectively assed Barthel
scores (BS) for individual patients [1], with a duration of mechanical
ventilation >48 hours. Data are presented as median (IQR). Comparison
between time points was performed with nonparametric tests for
paired data and repeated measurements. P <0.05 was considered
signifi cant. p
g
Conclusion Electrophysiological alterations appear early after the
development of critical illness [1-4]. Early electrophysiological
investigations are advisory although results should be evaluated
cautiously, as it is hard to diff erentiate between defi nitive lesions and
temporary disorder caused by bioenergetic failure [3,5-6] of the nerve
which tend to improve with normalisation of patients’ condition. References i
Results Thirty-four patients were included. Baseline characteristics:
APACHE II score 20 (17 to 25), age 68 (55 to 73) years, LOS ICU 22 (8 to
36) days, mechanical ventilation 8 (2 to 17) days, LOS hospital 21 (14
to 30) days, LOS rehabilitation unit 53 (31 to 85) days. Median BS at DI
was 2 (1 to 3), indicating total functional dependency. In comparison 1. Tennilä A, et al.: Intensive Care Med 2000, 26:1360-1363. 2. Khan J, et al.: Neurology 2006, 67:1421-1425. 3. Latronico N, et al.: Crit Care 2007, 11:R11. Functional dependency in the direct post-ICU phase in patients
with prolonged mechanical ventilation S189 Critical Care 2012, Volume 16 Suppl 1
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http://ccforum.com/supplements/16/S1 to baseline, BS increased to 8 (2 to 12) at DH (P <0.001), indicating
severe dependency, and fi nally to 16 (11 to 18) at DR, indicating
independency with some disabilities (P <0.001). The absolute increase
in BS was signifi cantly greater during the stay in the rehabilitation unit,
as compared to the general hospital ward (P <0.001). p
g
p
Conclusion ICU patients with prolonged mechanical ventilation remain
severely functionally dependent after ICU discharge, but dependency
reduces signifi cantly during rehabilitation in hospital and in a nursing
home rehabilitation unit. . Mahoney FI, Barthel DW: Functional evaluation: the Barthel Index. Md Med J
1965, 2:61-65.
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https://openalex.org/W3083888421
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Automated detection of Hainan gibbon calls for passive acoustic monitoring
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bioRxiv (Cold Spring Harbor Laboratory)
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ª 2021 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Automated detection of Hainan gibbon calls for passive
acoustic monitoring Emmanuel Dufourq1,2
, Ian Durbach3,4,1
, James P. Hansford5,6
, Amanda Hoepfner7,
Heidi Ma5
, Jessica V. Bryant8
, Christina S. Stender9, Wenyong Li10, Zhiwei Liu10, Qing Chen10,
Zhaoli Zhou10 & Samuel T. Turvey5 1African Institute for Mathematical Sciences, Muizenberg, South Africa
2 1African Institute for Mathematical Sciences, Muizenberg, South Africa
2Stellenbosch University, Stellenbosch, South Africa
3Centre for Research into Ecological and Environmental Modelling, University of St Andrews, St Andrews, UK
4Centre for Statistics in Ecology, the Environment, and Conservation, University of Cape Town, Rondebosch, South Africa
5Institute of Zoology, Zoological Society of London, Regent’s Park, London NW1 4RY, UK
6Department of Biological Sciences, Northern Illinois University, DeKalb Illinois, 60115,
7School of Biological Sciences, University of Utah, Salt Lake City Utah, 84112,
8Department of Life Sciences, University of Roehampton, London SW15 4JD, UK
9Living Collections, Zoological Society of London, Regent’s Park, London NW1 4RY, UK
10Bawangling National Nature Reserve, Changjiang Li Autonomous County, Hainan, China 3Centre for Research into Ecological and Environmental Modelling, University of St Andrews, St Andrews, UK 3Centre for Research into Ecological and Environmental Modelling, University of St Andrews, St Andrews, UK
4Centre for Statistics in Ecology, the Environment, and Conservation, University of Cape Town, Rondebosch, South Africa
5Institute of Zoology, Zoological Society of London, Regent’s Park, London NW1 4RY, UK
6Department of Biological Sciences, Northern Illinois University, DeKalb Illinois, 60115,
7School of Biological Sciences, University of Utah, Salt Lake City Utah, 84112, ntre for Statistics in Ecology, the Environment, and Conservation, University of Cape Town, Rondebosch, South Africa
titute of Zoology, Zoological Society of London, Regent’s Park, London NW1 4RY, UK 6Department of Biological Sciences, Northern Illinois University, DeKalb Illinois, 60115, Living Collections, Zoological Society of London, Regent s Park, London NW1 4RY, UK
10Bawangling National Nature Reserve, Changjiang Li Autonomous County, Hainan, China Keywords Tel: +27 21 787 9320; Fax: +27 21
7879321; E-mail: edufourq@gmail.com
Editor: Nathalie Pettorelli
Associate Editor: Christos Astaras
Received: 29 October 2020; Revised: 22
January 2021; Accepted: 4 March 2021 Keywords Bioacoustics, convolutional neural networks,
deep learning, Hainan gibbons, passive
acoustic monitoring, species identification Extracting species calls from passive acoustic recordings is a common preliminary
step to ecological analysis. For many species, particularly those occupying noisy,
acoustically variable habitats, the call extraction process continues to be largely
manual, a time-consuming and increasingly unsustainable process. Deep neural
networks have been shown to offer excellent performance across a range of acous-
tic classification applications, but are relatively underused in ecology. We describe
the steps involved in developing an automated classifier for a passive acoustic
monitoring project, using the identification of calls of the Hainan gibbon Nomas-
cus hainanus, one of the world’s rarest mammal species, as a case study. This
includes preprocessing—selecting a temporal resolution, windowing and annota-
tion; data augmentation; processing—choosing and fitting appropriate neural net-
work models; and post-processing—linking model predictions to replace, or more
likely facilitate, manual labelling. Our best model converted acoustic recordings
into spectrogram images on the mel frequency scale, using these to train a convo-
lutional neural network. Model predictions were highly accurate, with per-second
false positive and false negative rates of 1.5% and 22.3%. Nearly all false negatives
were at the fringes of calls, adjacent to segments where the call was correctly iden-
tified, so that very few calls were missed altogether. A post-processing step identi-
fying intervals of repeated calling reduced an 8-h recording to, on average, 22 min
for manual processing, and did not miss any calling bouts over 72 h of test record-
ings. Gibbon calling bouts were detected regularly in multi-month recordings
from all selected survey points within Bawangling National Nature Reserve, Hai-
nan. We demonstrate that passive acoustic monitoring incorporating an auto-
mated classifier represents an effective tool for remote detection of one of the
world’s rarest and most threatened species. Our study highlights the viability of
using neural networks to automate or greatly assist the manual labelling of data
collected by passive acoustic monitoring projects. We emphasize that model
development and implementation be informed and guided by ecological objec-
tives, and increase accessibility of these tools with a series of notebooks that allow
users to build and deploy their own acoustic classifiers. Correspondence
Emmanuel Dufourq, African Institute for
Mathematical Sciences, Muizenberg, South
Africa. doi: 10.1002/rse2.201 Introduction Deep learning holds enormous promise for automating
the labelling of bioacoustic data. The number of appli-
cations
is
growing
(Christin
et
al.,
2019),
but
the
majority of datasets are still labelled manually (Fairbrass
et al., 2019; Kiskin et al., 2020; Pamula et al., 2019),
even as the rate of data collection makes this approach
increasingly unsustainable. The mismatch between the
potential of deep learning approaches and their actual
uptake among practitioners occurs because getting mod-
els to perform as well as an experienced human is dif-
ficult. Human-like
performance
usually
requires
substantial amounts of training data or relatively stable
background
environments,
conditions
that
are
often
absent in ecological applications. Model tuning and
data manipulation is often required, and while guideli-
nes are emerging (Patterson & Gibson, 2017; Stowell
et al., 2019b), these can, with some justification, appear
subjective
and
case
specific. A
lack
of
computing
resources and user-friendly software can also be a bar-
rier to entry. Case studies reporting successful applica-
tions
play
an
important
role
in
developing
and
disseminating
best
practices,
and
in
discriminating
between those tasks that current deep learning methods
are able to automate and those they cannot. Previous
applications have used convolutional neural networks
(CNNs; LeCun et al. (2015)) to identify various bird
(Grill & Schl¨uter, 2017; Kahl et al., 2017; Stowell et al.,
2019b) and whale species (Bergler et al., 2019; Bermant
et al., 2019; Jiang et al., 2019; Shiu et al., 2020), bees
(Kulyukin et al., 2018; Nolasco et al., 2019), as well as
anomalous acoustic events in soundscapes (Sethi et al.,
2020). These have shown, for example, that a generally
good approach is to represent data as spectrograms and
treat the problem as an image classification one, as well
as providing specialized approaches for data augmenta-
tion on spectrogram inputs, such as pitch and time
shifting
and
introducing
background
noise
(Bergler
et al., 2019; Sprengel et al., 2016). The Hainan gibbon is the world’s rarest primate and
one of the world’s rarest mammals, with only a single
population of about 30 individuals surviving in Bawan-
gling National Nature Reserve (BNNR), Hainan, China
(Chan et al., 2005; Liu et al., 2020; Turvey et al., 2015). Introduction Improved monitoring of this population using novel
methods, to understand factors affecting successful disper-
sal, breeding group formation and colonization of new
habitat, has been identified as an urgent short-term con-
servation goal for the species (Turvey et al., 2015; Zhang
et al., 2020). Gibbons call regularly to advertise territory
and maintain group cohesiveness against rivals, using a
complex structure consisting of short individual vocal syl-
lables or ‘notes’ of ca. 0.2–2.75 s assembled together into
longer ‘phrases’ consisting of one to six notes, which are
themselves organized into ‘songs’ of several minutes
(Deng et al., 2014). Gibbon population surveys are usu-
ally conducted by detecting this daily song using a fixed-
point count survey method, whereby researchers listen
opportunistically for
calls at elevated listening posts
(Brockelman & Srikosamatara, 1993; Kidney et al., 2016). However, this traditional monitoring approach is labour
intensive and is only conducted for discrete survey peri-
ods. Gibbons are therefore prime candidates for passive
acoustic monitoring and recent studies have used data
collected in this way to model occupancy (Vu & Tran,
2019) and to discriminate between individuals using spec-
tral features (Clink et al., 2019; Zhou et al., 2019). All of
these studies, however, have relied on an initial manual
extraction of calls. In order to develop a continuous monitoring protocol
for Hainan gibbons we conducted long-term passive
acoustic monitoring and developed an automated classi-
fier able to identify whether gibbons were calling in the
vicinity of a particular recorder, with the aim of establish-
ing whether the area proximal to the recorder was occu-
pied that day. It was therefore important to be able to
detect individual gibbon calling bouts, but not necessarily
to be able to discriminate every phrase made during the
bout. We address issues that are important to the overall
usefulness of a classifier, including deciding how much
data to manually label, data augmentation, operationally
meaningful definitions of classifier success and the devel-
opment of user-friendly software. Our study provides an
effective new monitoring method for the world’s rarest
primate, and also has wider applicability for applying
deep learning to develop passive acoustic monitoring
frameworks
for
other
conservation-priority
loud-call Despite this, no studies report the process of applying
deep learning within the scope of a typical acoustic moni-
toring project designed to answer a well-defined research
question. Correspondence Correspondence
Emmanuel Dufourq, African Institute for
Mathematical Sciences, Muizenberg, South
Africa. Tel: +27 21 787 9320; Fax: +27 21
7879321; E-mail: edufourq@gmail.com p
Emmanuel Dufourq, African Institute for
Mathematical Sciences, Muizenberg, South
Africa. Tel: +27 21 787 9320; Fax: +27 21
7879321; E-mail: edufourq@gmail.com Editor: Nathalie Pettorelli
Associate Editor: Christos Astaras Received: 29 October 2020; Revised: 22
January 2021; Accepted: 4 March 2021 doi: 10.1002/rse2.201 doi: 10.1002/rse2.201 1 1 Automated Detection of Hainan Gibbon Calls E. Dufourq et al. E. Dufourq et al. E. Dufourq et al. passive acoustic recordings collected as part of a long-
term monitoring project, with the aim of providing prac-
titioners with a realistic and relatable idea of the process,
and modelling choices, involved, as well as guidelines for
these choices. Data collection Eight Song Meter SM3 recorders (Wildlife Acoustics,
Maynard, Massachusetts) were used to collect acoustic
data from 1 March to 20 August 2016 within BNNR. Recorders were attached to trees at a height of approxi-
mately 1.5 m in tropical evergreen forest. Four recorders
were situated within the known home ranges of the four
Hainan gibbon social groups existing during the study
period (Groups A–D; see Bryant et al. (2017)), three were
situated at locations intermediate between known home
ranges, and a further recorder was placed in an area
where a solitary male gibbon was thought to occur (Bry-
ant et al., 2016). They were placed at locations that were
used as regular listening posts for monitoring gibbons by
reserve staff (Fig. 1). The peak Hainan gibbon calling per-
iod is 06:00–07:00, with calling continuing at decreasing
regularity for several hours (Chan et al., 2005). Recorders
were therefore set to record for 8 h each day from the
time of sunrise, which varied between approximately
05:00 and 06:00 during the study period. Memory cards
and batteries were changed every 40 days. Devices did not
record continuously throughout the entire survey period
due to logistical and technical issues; in total, survey days
per recorder varied between 79 and 129 days, and roughly
6000 h of recordings were collected. The majority of
recordings were made with a sampling rate of 9600 Hz
and
bit
depth
of
16,
with
isolated
recordings
at
28 800 Hz. Each recording was downsampled to 4800 Hz, so that
the Nyquist rate was higher than the maximum fre-
quency of Hainan gibbon calls (2000 Hz). No anti-alias-
ing was performed although, because we downsampled
entire recordings, we would expect any artefacts to be
unrelated to the presence of gibbon calls. This was con-
firmed by a post hoc comparison of aliased and non-
aliased versions of a 5% sample of segments. The down-
sampled inputs – each segment a time series of 48 000
sample points – used as inputs to the 1-D CNNs
described in the next section. Introduction Most applications are either smaller – using
data collected for the purpose of testing a deep learning
approach, and often written for a machine learning rather
than ecological audience (e.g. Kiskin et al., 2020; Kulyu-
kin et al., 2018); or larger – aggregating datasets across
several independent studies to investigate if models gener-
alize (Bergler et al., 2019; Shiu et al., 2020; Stowell et al.,
2019b) – than most monitoring projects. In this paper we
address this gap, describing the development of a classifier
for identifying Hainan gibbon Nomascus hainanus calls in 21 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London 2 Automated Detection of Hainan Gibbon Calls E. Dufourq et al. species such as cetaceans, elephants or other primates
(Crunchant et al., 2020). positive segments after windowing. All audio was con-
verted into mono, as done in various applications (e.g. Bergler et al., 2019; Qazi et al., 2018; Stowell et al.,
2019a). By cross-referencing the time intervals of each
segment with the logged start and end times of known
gibbon phrases, each segment was labelled as (a) a ‘pres-
ence’, if its time interval completely contained the interval
of at least one labelled phrase, (b) an ‘absence’, if its time
interval contained no part of any phrase or (c) a ‘partial
presence’, if its time interval intersected but did not com-
pletely contain the interval of at least one labelled phrase
(Fig. 2). Partial presences were excluded from further
analysis. Data collection In addition, we converted
each audio segment into a mel-scale spectrogram (Ber-
gler et al., 2019; Huang et al., 2001), to be used as an
input image to a 2-D CNN, using a Hann analysis win-
dow size of 1024 samples (213 ms), a hop size of 256
samples (53.3 ms, 75% overlap) and 128 mel frequency
bins with centres uniformly spaced between 1 and 2k Hz,
a conservative interval following Deng et al. (2014) and
our own exploratory analyses. This results in 188 time
steps by 128 frequency bands. These were computed
using the Librosa library. These values were chosen on
the basis of preliminary investigations, although the
results were not particularly sensitive to these choices. The spectrogram images had a size of 128 × 188 pixels;
larger image sizes can capture greater detail but typically
require more network parameters and computation time
to do so. Data analysis We manually labelled 32 8-h recordings by inspecting
spectrograms and listening to audio using Sonic Visu-
aliser (Cannam et al., 2010), and end times, and the
number of notes, of each observed gibbon phrase. Four
files containing no gibbon calls were discarded, as peri-
ods without gibbon calls are readily available from the
remaining 28 files. This process yielded 1246 gibbon
phrases. After processing, our dataset consisted of 5285 seg-
ments containing at least one complete phrase. While the
vast majority of segments do not contain any gibbon
calls, we restricted the number of absence segments to the
same number as presences, to avoid a large class imbal-
ance. Absence segments were initially collected by ran-
domly sampling, but we found that better results were
obtained by specifically including absence segments that
contained typical ambient noise, such as bird calls, rain
events and other background noises that could potentially
confuse the classifier (Stowell et al., 2019a). Extracting
these required additional manual processing of the audio
data. To construct the fixed-length inputs required by CNNs,
we divided each 8-h recording into segments with win-
dow length 10 s and hop length 1 s (starting times of
consecutive 10 s segments differ by 1 s, Fig. 2). This win-
dow length was chosen so that even the longest phrase
(8 s, Supplementary Material A) fits within a single seg-
ment; using a slightly longer segment length allows for
potentially longer unseen phrases, and results in more 3 Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London Automated Detection of Hainan Gibbon Calls E. Dufourq et al. Figure 1. Locations of eight Song Meter SM3 recorders (labelled 1–8) used to detect gibbons in 2016 within Bawangling National Nature
Reserve, Hainan, China, in relation to approximate distributions of four Hainan gibbon social groups (A–D). Mapped distributions of groups A–C
are based on field data collected in 2010–2011 (see Bryant et al., (2017)); the groups all changed their location slightly between 2011 and 2016,
but data on exact group locations in 2016 are unavailable. Approximate location of Group D indicated with hatching based on Bryant et al.,
(2016). Figure 1. Locations of eight Song Meter SM3 recorders (labelled 1–8) used to detect gibbons in 2016 within Bawangling National Nature
Reserve, Hainan, China, in relation to approximate distributions of four Hainan gibbon social groups (A–D). Neural networks We considered two kinds of CNN architectures: a 1-D
CNN using preprocessed amplitudes of 10 s segments as
inputs, and a 2-D CNN that had inputs consisting of
spectrogram images constructed from the preprocessed
amplitudes. A CNN with a large number of network
parameters (e.g. MobileNetV2 (Sandler et al., 2018) which
has over 3 million parameters) can result in overfitting –
due to degree of freedom given the large number of
parameters – if the network is trained on a relatively
small number of examples. This observation is often
reported in the literature and has also been reported in
applications of CNNs in ecology (Chilson et al., 2019). As
we had relatively little training data by deep learning stan-
dards, we chose these networks as they use simple archi-
tectures requiring relatively few parameters. Both 1-D and
2-D CNNs use up to three convolutional layers, each fol-
lowed by a max pooling layer that reduces the size of the
intermediate input passed to the next layer of the net-
work. We used 16 × 1 and 16 × 16 convolutional kernels
for 1-D and 2-D CNNs respectively. The stack of convo-
lutional layers was followed by one or two dense layers
(Fig. 4). The resulting model outputs a detection proba-
bility that the input segment (1-D or 2-D) contains at
least one complete gibbon phrase. After augmenting the original segments, we obtained
18 992 segments (9496 presence, 9496 absence) from 19
recordings to train the neural networks. We randomly
selected 60% of the data for training (5697 presence,
5697 absence) and used the remaining 40% for valida-
tion (3799 presence, 3799 absence). Non-augmented seg-
ments from nine separate recordings (2231 presence,
23 689 absence) were kept aside for testing. The files
which were used for training and testing were randomly We chose model hyperparameters using a grid search
over the number of convolutional (1, 2, 3) and dense (1,
2, 3) layers, nodes in each of the dense layers (8, 16, 32),
filters in each convolutional layer (8, 16, 32), kernel size
in each convolutional and max pooling layer (4, 8, 16),
and dropout rate (0, 0.2, 0.4, 0.6). Each model was
trained for 50 epochs using the Adam optimizer (Kingma Figure 3. Data analysis Mapped distributions of groups A–C
are based on field data collected in 2010–2011 (see Bryant et al., (2017)); the groups all changed their location slightly between 2011 and 2016,
but data on exact group locations in 2016 are unavailable. Approximate location of Group D indicated with hatching based on Bryant et al.,
(2016). Figure 2. Hainan gibbon calls consist of a sequence of ‘phrases’, each phrase consisting of variable (typically, 1–6) ‘notes’ and often with
relatively large intervals between phrases. Left: a two-note phrase followed by a three-note phrase. A single calling bout may last anywhere from
a few to dozens of minutes. Our model divides the recording interval into sliding 10 s windows or ‘segments’ (blue boxes), with 80% overlap
between adjacent segments. Segments are classified as contained at least one full gibbon phrase (Present; solid line), a partial phrase (Partial;
dotted line), or no part of a phrase (Absent; dashed line). Partial presences were excluded from further analysis, creating a two-class audio
classification problem. Right: a gibbon phrase partially obscured by noisy background conditions, in this case other species calling (red boxes). Figure 2. Hainan gibbon calls consist of a sequence of ‘phrases’, each phrase consisting of variable (typically, 1–6) ‘notes’ and often with
relatively large intervals between phrases. Left: a two-note phrase followed by a three-note phrase. A single calling bout may last anywhere from
a few to dozens of minutes. Our model divides the recording interval into sliding 10 s windows or ‘segments’ (blue boxes), with 80% overlap
between adjacent segments. Segments are classified as contained at least one full gibbon phrase (Present; solid line), a partial phrase (Partial;
dotted line), or no part of a phrase (Absent; dashed line). Partial presences were excluded from further analysis, creating a two-class audio
classification problem. Right: a gibbon phrase partially obscured by noisy background conditions, in this case other species calling (red boxes). ª 2021 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of Lon 4 E. Dufourq et al. Automated Detection of Hainan Gibbon Calls selected and each file contained at least one presence of
a gibbon call. Data augmentation Data augmentation – boosting sample sizes by adding
new samples artificially created by manipulating existing
ones, for example using geometric operations like transla-
tions and rotation – is commonly used to improve classi-
fier performance, particularly when the training dataset is
relatively small (Hestness et al., 2017; Sun et al., 2017). We used data augmentation to create either one or two
copies of each 10 s segment in both presence and absence
classes. For each presence segment x(pre), we randomly
selected two absence segments, x i
(abs), i = 1,2. We ran-
domly shifted the starting time of each absence segment
forward by 0 < ti<9 s, with the absence segment wrap-
ping back on itself so that it remained 10 s long (Fig. 3
C), to obtain the shifted segment x i
(shift). Presence seg-
ments were not shifted, as this already occurred during
the windowing process used to create the original seg-
ments. Segments contain amplitude values and thus allow
for arithmetic operations to be performed on them. We
blended
the
presence
segment
with
each
shifted
segment
to
create
augmented
presence
segments
x aug
ð
Þ
i
¼ αx pre
ð
Þ þ 1α
ð
Þx shift
ð
Þ
i
, where α is a mixing param-
eter, here chosen to be 0.9 (Fig. 3D). We created aug-
mented absence segments using the same approach, that
is, combining pairs of absence segments to create a mix-
ture of background scenes. Automated Detection of Hainan Gibbon Calls 2D CNN
with augmentation
2D CNN
without augmentation
with
Conv2D, 8 filters of
size 16x16, ReLU
activation
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
Dense, 32 units,
ReLU activation
Dense, 2 units,
softmax activation
Dense, 2 units,
softmax activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Dense, 32 units,
ReLU activation
Dense, 32 units,
ReLU activation
Con
s
Max
Con
s
Max
Con
s
Max
De
Re
Input spectrogram
with size
(128x188x1)
(13,28,8)
(28,43,8)
(113,173,8)
(3,7,8)
(32)
Input spectrogram
with size
(128x188x1)
Inpu
(2)
(113,173,8)
(28,43,8)
(13,28,8)
(3,7,8)
(32)
(2)
(32)
(4798
(299
(298
(18
(17
(1 2D CNN
with augmentation 1D CNN
with augmentation Input spectrogram
with size
(128x188x1) Conv2D, 8 filters of
size 16x16, ReLU
activation (2) (2) Dense, 16 units,
ReLU activation
Dense, 2 units,
softmax acitvation
(2)
(16)
(16) (2) Figure 4. Best architectures for 1-D and 2-D CNNs, for both augmented and non-augmented training datasets. Selected architectures were those
with intermediate numbers of free parameters, particularly for 2-D CNNs. The dimensions of the data after each operation is provided in
parentheses. (McFee et al., 2020). Model training and testing was done
on a machine running Ubuntu 16.04 LTS with an Intel
i7-6700K CPU, 16GB of RAM, and an Nvidia GTX 1070
8GB Graphics Processing Unit. Code and analysis scripts
are available online at https://github.com/emmanuelduf
ourq/GibbonClassifier. & Ba, 2014) a batch size of eight segments, and a learning
rate of 0.001. Models were evaluated based on test set
accuracy (proportion of all predictions that were correct),
sensitivity (recall) (proportion of true positives divided by
positive examples), specificity (proportion of true nega-
tives divided by negative examples), precision (portion of
true positives divided by true positives and false positives)
and F1-score (harmonic mean between precision and F1-
score). Optimal thresholds for converting detection prob-
abilities into binary classifications were those that mini-
mized the ratio of sensitivity and false discovery rate in
the validation dataset. Neural networks Data augmentation steps involve (a) selecting a presence segment containing a Hainan gibbon phrase, (b) randomly selecting a
segment containing only background noise, (c) shifting the starting time of the absence segment forward by a random amount, here 2 s and (d)
blending together the presence and shifted absence segments. Figure 3. Data augmentation steps involve (a) selecting a presence segment containing a Hainan gibbon phrase, (b) randomly selecting a
segment containing only background noise, (c) shifting the starting time of the absence segment forward by a random amount, here 2 s and (d)
blending together the presence and shifted absence segments. The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London 5 Automated Detection of Hainan Gibbon Calls Automated Detection of Hainan Gibbon Calls E. Dufourq et al. 2D CNN
with augmentation
2D CNN
without augmentation
1D CNN
with augmentation
1D CNN
without augmentation
Conv2D, 8 filters of
size 16x16, ReLU
activation
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
MaxPool2D, size of
4x4
Dense, 32 units,
ReLU activation
Dense, 2 units,
softmax activation
Dense, 2 units,
softmax activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Conv2D, 8 filters of
size 16x16, ReLU
activation
Dense, 32 units,
ReLU activation
Dense, 32 units,
ReLU activation
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Dense, 16 units,
ReLU activation
Dense, 16 units,
ReLU activation
Dense, 2 units,
softmax acitvation
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Conv1D, 8 filters of
size 16, ReLU
activation
MaxPool1D, size of
16
Dense, 16 units,
ReLU activation
Dense, 2 units,
softmax acitvation
Input spectrogram
with size
(128x188x1)
(13,28,8)
(28,43,8)
(113,173,8)
(3,7,8)
(32)
Input spectrogram
with size
(128x188x1)
Input amplitudes with
size (48000)
(2)
(113,173,8)
(28,43,8)
(13,28,8)
(3,7,8)
(32)
(2)
(32)
(2)
(2)
(47985,8)
(2999,8)
(2984,8)
(186,8)
(171,8)
(10,8)
(16)
(16)
Input amplitudes with
size (48000)
(47985,8)
(2999,8)
(2984,8)
(186,8)
(171,8)
(10,8)
(16)
Figure 4. Best architectures for 1-D and 2-D CNNs, for both augmented and non-augmented training datasets. Selected architectures were those
with intermediate numbers of free parameters, particularly for 2-D CNNs. The dimensions of the data after each operation is provided in
parentheses. Results Hainan gibbon calls could be detected with a high degree
of accuracy. Without post-processing, nearly 80% of seg-
ments containing gibbon calls were correctly identified,
with very few false positives (Table 1). Even with false
negative rates of 20% very few gibbon phrases were
missed altogether, because phrases occur across multiple
overlapping segments and nearly all segments incorrectly
identified as absences occurred at the beginning and end
of a phrase, abutted by several segments where the phrase
was correctly detected (Fig. 5). After post-processing,
fewer than 2% of all presence segments occurred outside
of detected call bouts (Table 1), and all 20 call bouts
across nine test set recordings were detected, with two
predicted call bouts being false positives (Supplementary
Material B). In the training set, 34 of 35 call bouts were
correctly recognised with two false positive call bouts. To do this, we formed connected components of pres-
ence segments that occur close together in time and in
sufficient numbers that, given known gibbon call charac-
teristics (i.e. song duration, inter-phrase duration), they
are likely to be part of a single calling bout (Supplemen-
tary Material A). With presence segments arranged in
temporal order, presence segment i is included in the
same component as segment i-1 if they are separated by
less than 200 s; otherwise segment i begins a new compo-
nent. This process allocates each presence segment to
exactly one component. Any component consisting of
fewer than 20 segments (equivalent to roughly four
phrases of length 5 s) are automatically removed. This
was done given our analysis of the characteristics of the
calls which revealed that the calls are typically repetitive
over a period of time and the total duration was never
less than 20 s. Additionally, any component where the
average time between consecutive presence segments in
the component was greater than 10 s, was removed (sug-
gesting a ‘chain’ of isolated presence predictions, since
calls usually persist over multiple consecutive segments). The best performing approach was a 2-D CNN with
both data augmentation and post-processing. Data aug-
mentation improved specificity by 5.6%, a relative reduc-
tion in false positives of 79% but without associated
relative reduction in sensitivity; post-processing further
improved both sensitivity (20.6%) and specificity (0.9%,
Table 1). Post-processing For
an
audio
recording
of
arbitrary
duration,
our
approach was to break that recording into overlapping
10 s segments, and to use a trained CNN to output, for
each segment starting at second s = 0, 1, 2, . . ., a detec-
tion probability indicating the likelihood that at least one
complete gibbon phrase is contained in the next 10 s. These probabilities are based only on the acoustic content Models were implemented in Python 3 using the Ten-
sorFlow (Abadi et al., 2015) library with Keras (Chollet,
2015) for the neural network component, and the Librosa
library for audio processing and spectrogram construction 6 21 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London E. Dufourq et al. Automated Detection of Hainan Gibbon Calls accuracy measures are conditional on the use of addi-
tional, error-free manual verification. of their associated segments, and can give rise to biologi-
cally unrealistic call patterns. We used a post-processing
step to remove isolated detected presence segments which
are highly likely to be false positives rather than actual
calls, and to obtain start and end times for each detected
calling bout, to facilitate manual verification and support
the main research objective of detecting and monitoring
gibbon activity. The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London Table 1. Average performance and parameter settings for the best 2-D and 1-D CNN models across 72 h of test recordings (2231 segments con-
taining gibbon phrases, 23 689 without). Gibbon calls can be identified with very high accuracy, and performance is improved by data augmenta-
tion and a post-processing heuristic. Results Segments with detected probabilities above an optimized threshold of 0.76 (red line) are classified as containing a gibbon phrase, with
misclassifications denoted by crosses. Observed and detected classes are plotted above the probabilities, using the same notation. Colour is used
to denote the observed class. Most incorrect false negative classifications are at the beginning and end of phrases, separated by segments that
correctly identify the call. In this way, nearly all phrases are clearly identified, and a practitioner can be pointed to those regions that contain calls. Automated Detection of Hainan Gibbon Calls
E. Dufourq et al. Automated Detection of Hainan Gibbon Calls E. Dufourq et al. Figure 5. Per-second detected probabilities that a gibbon phrase is contained within the next 10 s of audio, over (A) an 8-h file, (B) a 5-min
window. Segments with detected probabilities above an optimized threshold of 0.76 (red line) are classified as containing a gibbon phrase, with
misclassifications denoted by crosses. Observed and detected classes are plotted above the probabilities, using the same notation. Colour is used
to denote the observed class. Most incorrect false negative classifications are at the beginning and end of phrases, separated by segments that Figure 5. Per-second detected probabilities that a gibbon phrase is contained within the next 10 s of audio, over (A) an 8-h file, (B) a 5-min
window. Segments with detected probabilities above an optimized threshold of 0.76 (red line) are classified as containing a gibbon phrase, with
misclassifications denoted by crosses. Observed and detected classes are plotted above the probabilities, using the same notation. Colour is used
to denote the observed class. Most incorrect false negative classifications are at the beginning and end of phrases, separated by segments that
correctly identify the call. In this way, nearly all phrases are clearly identified, and a practitioner can be pointed to those regions that contain calls. gibbon calls were detected on 71% of recording days
across all locations. Gibbons were detected regularly at all
locations, with recorders situated within known group or
solitary home ranges detecting calls on 33–86% of record-
ing days, and those situated between home ranges detect-
ing calls on 46–89% of recording days. Mean durations of
calling bouts per recorder varied between 24.2 and
40.8 min (overall mean = 29.7 min), with mean starting
times of 06:16–07:56 AM and mean finishing times of
09:12–10:15 AM (Fig. 6; Table 2). Results Accuracy was substantially higher when treating
the task as an image (spectrogram) classification problem
than if the preprocessed acoustic data were directly used
as input to a 1-D CNN. Using the 2-D CNN with both
data augmentation and post-processing, an 8 h test file
took on average 6 min to process of which 3 min 10 s
were used for reading in the audio file and 2 min 42 s to
convert to spectrograms; the remaining time was used to
compute the CNN predictions. The first and last presence segment in each remaining
component give the start and end times of each predicted
gibbon calling bout. To evaluate the potential usefulness
of the post-processing step, we recalculated accuracy mea-
sures under the assumption that all detected bouts were
subsequently passed to an observer for manual processing,
and that this observer correctly identified all presence seg-
ments within the bout. This mimics the intended applica-
tion of our approach, but means that post-processing We applied the 2-D CNN with both data augmentation
and post-processing on the entire monitoring project and nd parameter settings for the best 2-D and 1-D CNN models across 72 h of test recordings (2231 segments con-
without). Gibbon calls can be identified with very high accuracy, and performance is improved by data augmenta-
tic. Table 1. Average performance and parameter settings for the best 2-D and 1-D CNN models across 72 h of test recordings (2231 segments con-
taining gibbon phrases, 23 689 without). Gibbon calls can be identified with very high accuracy, and performance is improved by data augmenta-
tion and a post-processing heuristic. CNN
2-D
2-D
2-D
1-D
1-D
1-D
+ Augmentation
Yes
Yes
No
Yes
Yes
No
+ Post-processing
Yes
No
No
Yes
No
No
Accuracy
99.37%
97.60%
92.32%
94.30%
94.76%
94.76%
Sensitivity
98.30%
77.68%
79.65%
54.21%
40.98%
25.56%
Specificity
99.42%
98.51%
92.92%
95.96%
96.91%
97.60%
Precision
85.30%
70.28%
45.78%
49.14%
41.35%
44.58%
F1-score
90.55%
72.18%
53.14%
46.36%
38.42%
27.09%
Model Parameters
23 922
23 922
24 978
2650
2650
2378
Train Duration (sec)
644
643
265
628
627
117
ª 2021 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London
7 Figure 5. Per-second detected probabilities that a gibbon phrase is contained within the next 10 s of audio, over (A) an 8-h file, (B) a 5-min
window. Results Calls were detected less
frequently during the wet season (March–April) than the
dry season (May–August), with inter-season differences
varying substantially between locations (Supplementary
Table C). saving time, funds and manpower. Our approach, applied
to Hainan gibbons, is general and easily extended to other
calling species. Our models allow new recordings to be classified on a
per-second basis, to a high degree of accuracy. Although
perhaps false negative rates of 1.7% may not be suffi-
ciently low for full automation of Hainan gibbon call
monitoring, they greatly facilitate the process of manually
annotating these datasets by ruling out large portions of
recordings that have a relatively low probability of con-
taining gibbon song. In our test datasets, this reduced the
amount of audio to be manually processed by 95%. Our
model clearly detected all calling bouts in the test data, at
the cost of two false positives. Where false negatives are
particularly costly, this is easily incorporated by lowering
the threshold required for manual verification. We expect
that with more, and more diverse, training data, error
rates would decline further. 21 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London Discussion The red line denotes, per 10 min, the proportion of recordings across all locations in which a
call was detected (e.g. 05:00–05:10, 05:10–05:20,...). The black line smooths the observed proportions using a GAM (see Supplementary Material
D for details). The bottom plot shows the number of recordings per 10-min segment, showing the survey effort from 05:00 to 14:00. Peak
activity occurs shortly after dawn, dropping rapidly but with some calling activity recorded throughout the morning. Plot inset shows the duration
of independent call bouts detected by the classifier. Call bouts are intervals of regular calling, with no detected call 200 s either side of the bout. Daily calling typically consists of a number of calling bouts. q Figure 6. Daily patterns in gibbon calling activity. The red line denotes, per 10 min, the proportion of recordings across all locations in which a
call was detected (e.g. 05:00–05:10, 05:10–05:20,...). The black line smooths the observed proportions using a GAM (see Supplementary Material
D for details). The bottom plot shows the number of recordings per 10-min segment, showing the survey effort from 05:00 to 14:00. Peak
activity occurs shortly after dawn, dropping rapidly but with some calling activity recorded throughout the morning. Plot inset shows the duration
of independent call bouts detected by the classifier. Call bouts are intervals of regular calling, with no detected call 200 s either side of the bout. Daily calling typically consists of a number of calling bouts. Figure 6. Daily patterns in gibbon calling activity. The red line denotes, per 10 min, the proportion of recordings across all locations in which a
call was detected (e.g. 05:00–05:10, 05:10–05:20,...). The black line smooths the observed proportions using a GAM (see Supplementary Material
D for details). The bottom plot shows the number of recordings per 10-min segment, showing the survey effort from 05:00 to 14:00. Peak
activity occurs shortly after dawn, dropping rapidly but with some calling activity recorded throughout the morning. Plot inset shows the duration
of independent call bouts detected by the classifier. Call bouts are intervals of regular calling, with no detected call 200 s either side of the bout. Daily calling typically consists of a number of calling bouts. Table 2. Calling behaviour across eight survey locations for the 161 day survey period March–August 2016. Discussion Location
Survey days
% days calls detected
Mean calling time per day (min)
Mean start time of first bout
Mean end time of last bout
1
87
70
24.2
07:34
09:41
2
90
46
29.9
06:58
09:12
3
103
82
31.3
07:30
10:15
4
105
86
26.5
07:44
09:52
5
79
33
29.9
07:31
09:23
6
103
79
24.4
07:56
10:15
7
129
89
30.9
06:53
09:54
8
105
65
40.8
06:16
10:01
Recorders were situated within the known home ranges of the four Hainan gibbon social groups existing during the study period, at locations
intermediate between known home ranges, and in an area where a solitary male gibbon was thought to occur. Locations of home ranges are
indicated by numbers 1, 2, 3 and 4. 6 = solitary. Table 2. Calling behaviour across eight survey locations for the 161 day survey period March–August 2016. Recorders were situated within the known home ranges of the four Hainan gibbon social groups existing during the study period, at locations
intermediate between known home ranges, and in an area where a solitary male gibbon was thought to occur. Locations of home ranges are
indicated by numbers 1, 2, 3 and 4. 6 = solitary. models; and selecting a preferred model and using it to
process the unlabelled portion of the data. Our study
illustrates how model development and implementation
are informed and guided by ecological objectives, here
primarily detecting gibbon vocalizations over time scales
of minutes or hours, and domain knowledge of Hainan
gibbon call behaviour. warrant confidence in the associated predictions, but
these results suggest that, as more training data covering
a range of environmental conditions are added, model
applications may go beyond gibbon detection, by auto-
matically extracting inputs for more detailed behavioural
analyses, for example of gibbon call syntax (Clarke et al.,
2006). Practically, developing an acoustic classifier such as
ours requires a number of steps: deciding on an appropri-
ate unit of analysis; manually labelling data; augmenting
data and allocating it between training, validation and test
sets; choosing and fitting appropriate neural network We based our classifier on phrases, rather than shorter
notes or longer calling bouts, to balance ease of identifica-
tion with data availability and computational require-
ments. Individual notes are easily confused with other
sources (see Fig. 2B). Discussion Long-term monitoring will generate thousands of hours
of recordings across multiple survey sites, and manually
labelling these recordings is typically infeasible given
logistical constraints. Our results demonstrate that passive
acoustic monitoring incorporating an automated classifier
can be an effective tool for remote detection of calling
species, potentially enabling systematic monitoring while Where environmental conditions were similar to those
used to train the model, predictions were almost perfect
and could be used to identify start and end times of call
phrases and bouts, returning almost identical values to a
human observer. It is impossible to know in advance
whether environmental conditions are similar enough to 8 ª 2021 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of Lon Automated Detection of Hainan Gibbon Calls E. Dufourq et al. warrant confidence in the associated predictions, but
these results suggest that, as more training data covering
a range of environmental conditions are added, model
applications may go beyond gibbon detection, by auto-
matically extracting inputs for more detailed behavioural
analyses, for example of gibbon call syntax (Clarke et al.,
models; and selecting a preferred model and using it to
process the unlabelled portion of the data. Our study
illustrates how model development and implementation
are informed and guided by ecological objectives, here
primarily detecting gibbon vocalizations over time scales
of minutes or hours, and domain knowledge of Hainan
Table 2. Calling behaviour across eight survey locations for the 161 day survey period March–August 2016. Location
Survey days
% days calls detected
Mean calling time per day (min)
Mean start time of first bout
Mean end time of last bout
1
87
70
24.2
07:34
09:41
2
90
46
29.9
06:58
09:12
3
103
82
31.3
07:30
10:15
4
105
86
26.5
07:44
09:52
5
79
33
29.9
07:31
09:23
6
103
79
24.4
07:56
10:15
7
129
89
30.9
06:53
09:54
8
105
65
40.8
06:16
10:01
Recorders were situated within the known home ranges of the four Hainan gibbon social groups existing during the study period, at locations
intermediate between known home ranges, and in an area where a solitary male gibbon was thought to occur. Locations of home ranges are
indicated by numbers 1, 2, 3 and 4. 6 = solitary. Figure 6. Daily patterns in gibbon calling activity. Discussion While calling bouts are highly 9 Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of London Automated Detection of Hainan Gibbon Calls E. Dufourq et al. to them, but where intermediate features (here, spectral
densities) can be provided, these speed up the learning
process and provide measurable benefits. Beyond the 2-D/
1-D distinction, we found that there was little impact on
the model performance when different configurations (i.e. changing the number of filers or units) to small networks
were explored. Large networks with a much larger num-
ber of layers did not improve the performance and we
achieved good performance using relatively small, simple
network architectures. We used few dense layers, each
with only a small number of nodes, as these are particu-
larly parameter hungry. Our basic approach was to start
with simple architectures, evaluate them, and then add
complexity in an iterative manner. distinctive, there are relatively few of them and, being
longer in duration, they require more parameters to cap-
ture the same degree of detail. Phrases are far more
numerous, less variable and require fewer parameters. Given this choice, segment duration was chosen to be
longer than the longest phrase across all training data
(8 s). The slightly longer segment length provides more
presence segments – for example, an 8 s phrase results in
three 10 s presence segments, but would only result in a
single segment if the segment length was restricted to 8 s. Preliminary runs based on shorter segments of 0.5–2 s
and partial phrases did not yield good performance, with
many false positives, probably because a small segment is
not enough to distinguish gibbons from other species
calling within the same frequency range. Traditional performance metrics such as precision and
sensitivity (recall), while important, are not the only rele-
vant measures of classifier success. Practically, classifiers
such as ours can be used to point to audio segments that
possibly contain gibbon calls, and that require manual ver-
ification. Where classification accuracy lags behind that of
human experts, or where errors are costly – that is, in
many ecological applications – attention shifts from
replacing manual annotation to facilitating it. Discussion We found that 2-D CNNs based on spectrograms per-
formed substantially better than 1-D CNNs that use
amplitude time series following some initial preprocess-
ing, mirroring Stowell et al. (2019b). Deep neural net-
works are often motivated by an argument that they learn
salient features, rather than having to have these provided Even using phrases, we have relatively few positive
examples and these occur within a highly variable back-
ground environment, which is likely to be a common sit-
uation for ecological applications. The amount of data
available to train neural networks is important, and
CNNs tend to require relatively large amounts of data to
generalize well. While preempting the exact amount of
data required to train CNNs is challenging, one approach
is simply to attempt to train a network and evaluate its
performance on a test set and iteratively add data if need
be. It may often be possible, as in our case, to collect or
label additional data, but data augmentation is a valuable
low-cost strategy for increasing sample sizes in conjunc-
tion with these other more effort-intensive approaches
(Bergler et al., 2019; Hestness et al., 2017; Kahl et al.,
2017; Sun et al., 2017). In practice the process can be an
iterative one guided by subjective judgement. We initially
annotated only 40 h across five recordings, but models
based on these were poor, even with augmentation. Model performance (on the same test set) improved as
we add more training data; we were also able to create
more
complex
neural
networks. Gains
in
accuracy
decreased with additional annotations, and we stopped
when these became marginal, but presumably further
increases are possible as novel environments are included. T
i i
lid ti
d t t d t
t
h
ld b Analysis of our multi-month dataset demonstrated that
gibbons could be detected regularly across all selected sur-
vey points, with call detection consistent with known pat-
terns
of
gibbon
behaviour
and
ecology. Calls
were
detected at expected times (Chan et al., 2005), and our
dataset provides a more precise baseline on Hainan gib-
bon call timing and duration. Hainan gibbon calling
bouts were also generally detected less frequently during
the wet season, a period when other gibbon species are
also known to sing less frequently (Cheyne, 2008; Clink
et al., 2020). Discussion Probability
cutoffs can be calibrated to balance the costs of false posi-
tives and negatives, and, even if the model is wrong by a
few seconds, the amount of time spent in manual verifica-
tion, compared to that required to processing the entire
file manually, is minimal. Our classifier reduces an 8-h
recording to on average 22 min with false positive and
negative rates under 2%. This time can be further reduced
by playing back only those 10 s segments that are pre-
dicted to contain phrases, although in our case the reduc-
tion in overall time was offset by the difficulty of manually
verifying segments that are often not contiguous in time. g
q
y
g
Even using phrases, we have relatively few positive
examples and these occur within a highly variable back-
ground environment, which is likely to be a common sit-
uation for ecological applications. The amount of data
available to train neural networks is important, and
CNNs tend to require relatively large amounts of data to
generalize well. While preempting the exact amount of
data required to train CNNs is challenging, one approach
is simply to attempt to train a network and evaluate its
performance on a test set and iteratively add data if need
be. It may often be possible, as in our case, to collect or
label additional data, but data augmentation is a valuable
low-cost strategy for increasing sample sizes in conjunc-
tion with these other more effort-intensive approaches
(Bergler et al., 2019; Hestness et al., 2017; Kahl et al.,
2017; Sun et al., 2017). In practice the process can be an
iterative one guided by subjective judgement. We initially
annotated only 40 h across five recordings, but models
based on these were poor, even with augmentation. Model performance (on the same test set) improved as
we add more training data; we were also able to create
more
complex
neural
networks. Gains
in
accuracy
decreased with additional annotations, and we stopped
when these became marginal, but presumably further
increases are possible as novel environments are included. Training, validation and test datasets should be con-
structed by allocating longer contiguous sequences of
audio to each of these, and then preprocessing each of
these, rather than randomly allocating the segments them-
selves, which are highly autocorrelated and will thus over-
state test accuracy. Wherever possible, we recommend
using entirely independent recordings in the test dataset. References Abadi, M., Agarwal, A., Barham, P., Brevdo, E., Chen, Z., Citro,
C.. et al. (2015) Large-scale machine learning on heterogeneous Abadi, M., Agarwal, A., Barham, P., Brevdo, E., Chen, Z., Citro,
C.. et al. (2015) Large-scale machine learning on heterogeneous
systems. Retrieved from https://www.tensorflow.org systems. Retrieved from https://www.tensorflow.org Augustine, B.C., Royle, J.A., Linden, D.W. & Fuller, A.K. (2020) Spatial proximity moderates genotype uncertainty in
genetic tagging studies. Proceedings of the National Academy
of Sciences, 117(30), 17903–17912. Discussion Interestingly, call bouts recorded within the
area occupied by a solitary male gibbon were among the
shortest recorded bouts, and started and finished later
than bouts from known social groups. While we cannot
exclude the possibility of detecting group calls at this
location, this finding suggests important new information
on the behavioural ecology of solitary Hainan gibbons
that
may
assist
future
monitoring
and
conservation
planning. Training, validation and test datasets should be con-
structed by allocating longer contiguous sequences of
audio to each of these, and then preprocessing each of
these, rather than randomly allocating the segments them-
selves, which are highly autocorrelated and will thus over-
state test accuracy. Wherever possible, we recommend
using entirely independent recordings in the test dataset. We found that 2-D CNNs based on spectrograms per-
formed substantially better than 1-D CNNs that use
amplitude time series following some initial preprocess-
ing, mirroring Stowell et al. (2019b). Deep neural net-
works are often motivated by an argument that they learn
salient features, rather than having to have these provided 10 ª 2021 The Authors. Remote Sensing in Ecology and Conservation published by John Wiley & Sons Ltd on behalf of Zoological Society of Lon Automated Detection of Hainan Gibbon Calls E. Dufourq et al. International
Development
Research
Centre,
Ottawa,
Canada (www.idrc.ca), and with financial support from
the Government of Canada, provided through Global
Affairs Canada (GAC; www.international.gc.ca). We also
thank the following rangers who contributed to data col-
lection: Guang Wei, Zhong Zhao, Qing Lin, Jinbing
Zhang,
Zhicheng
Zhang,
Quanjin
Li,
Xiaoliang
Fu,
Zhengchong Zhou, Lubiao Huang, Zhengkun Ye, Zheng-
hai Zou, Jinqiang Wang, Wentao Han and Zengnan Xie. It is uncertain whether within-recorder and between-
recorder variation in calling bout detections represents
variation in calling frequency between groups, and/or
variation in detection effectiveness by recorders, with the
latter possibility likely associated with specific recorder
placement, local terrain, specific gibbon movement pat-
terns across landscapes, and group home range size (cf. Bryant et al., (2017)). Future work could investigate
detection likelihood in relation to specific environmental
parameters and local weather conditions (e.g. rainfall,
wind, temperature), data on which were not available for
our survey period but are known to affect calling beha-
viour in other gibbons (Coudrat et al., 2015; Yin et al.,
2016). Data Availability Statement All code for training and testing the neural networks and
conducting additional analyses is available at https://
github.com/emmanueldufourq/GibbonClassifier
(Supple-
mentary Material E). A subset of acoustic recordings,
including training and testing labels, has been stored on
Zenodo: https://doi.org/10.5281/zenodo.3991714. The authors declare no competing interests. Where calls can be detected across multiple recording
locations, acoustic spatial capture–recapture methods pro-
vide a means of estimating animal abundance (Stevenson
et al., 2015). While our locations are too far apart for this
to be feasible, this represents an important next step in
monitoring a critically endangered population. Classifiers
capable of discriminating between groups or individuals
can be valuable inputs to this process (Augustine et al.,
2020), as well as providing insight into the behavioural
ecology of groups or individuals. We also recommend that
call detection ranges should be determined for the specific
field conditions at BNNR (e.g. slope, vegetation density),
to calibrate monitoring effectiveness of specific recorders,
and determine effective recorder placement (grid area/den-
sity) to ensure saturation of monitoring coverage. How-
ever, passive acoustic monitoring can now be introduced
as an important component of the Hainan gibbon conser-
vation toolkit, both for future use at BNNR and also to
potentially detect unknown remnant gibbon populations
elsewhere across Hainan (Turvey et al., 2017). Our classi-
fier permits rapid and potentially real-time monitoring of
Hainan gibbons, and we hope that the approach we
describe in developing this classifier can serve as a road-
map for practitioners to implement their own classifier for
other passive acoustic monitoring projects, and contribute
to the effective conservation of calling species. Authors’ Contributions ST, JB and HM conceived the passive monitoring project
and developed the study designs and protocols. ED, ID
and JH conceived the development of an automated clas-
sifier and designed the methodology. WL, ZL, QC, ZZ,
HM and JB were responsible for fieldwork and data col-
lection. ED, AH and JB annotated the data. ED con-
structed the classifier and performed the analysis. ED, ID
and ST wrote the paper. All authors contributed critically
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History of MeToo University movement in Spain
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Historia social y de la educación
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To link this article: http://doi.org/10.17583/hse.10545 To link this article: http://doi.org/10.17583/hse.10545 Instructions for authors, subscriptions and further details:
http://mcs.hipatiapress.com ‘History of MeToo University Movement in Spain p
g
1) Universitat Rovira i Virgili (Spain)
2) Universidad de Granada (Spain)
3) Universitat de Barcelona (Spain)
4) Universitat Autònoma de Barcelona (Spain) Date of publication: June 2022
Edition period: February 2022 - June 2022 To cite this article: Joanpere, M., Burgues-Freitas, A., Soler, M., & Aiello, E. (2022). ‘History of MeeToo University Movement in Spain. Social and
Education History, 11(2), 181-200. http://doi.org/10.17583/hse.10545 Instructions for authors, subscriptions and further details:
http://mcs.hipatiapress.com
‘History of MeToo University Movement in Spain
Mar Joanpere1, Ana Burgues-Freitas2, Marta Soler3, & Emilia Aiello4
1) Universitat Rovira i Virgili (Spain)
2) Universidad de Granada (Spain)
3) Universitat de Barcelona (Spain)
4) Universitat Autònoma de Barcelona (Spain)
Date of publication: June 2022
Edition period: February 2022 - June 2022
To cite this article: Joanpere, M., Burgues-Freitas, A., Soler, M., & Aiello, E.
(2022). ‘History of MeeToo University Movement in Spain. Social and
Education History, 11(2), 181-200. http://doi.org/10.17583/hse.10545
To link this article http //doi org/10 17583/hse 10545 Instructions for authors, subscriptions and further details:
http://mcs.hipatiapress.com
‘History of MeToo University Movement in Spain
Mar Joanpere1, Ana Burgues-Freitas2, Marta Soler3, & Emilia Aiello4
1) Universitat Rovira i Virgili (Spain)
2) Universidad de Granada (Spain)
3) Universitat de Barcelona (Spain)
4) Universitat Autònoma de Barcelona (Spain)
Date of publication: June 2022
Edition period: February 2022 - June 2022
To cite this article: Joanpere, M., Burgues-Freitas, A., Soler, M., & Aiello, E. (2022). ‘History of MeeToo University Movement in Spain. Social and
Education History, 11(2), 181-200. http://doi.org/10.17583/hse.10545
To link this article http //doi org/10 17583/hse 10545 PLEASE SCROLL DOWN FOR ARTICLE The terms and conditions of use are related to the Open Journal System and to
Creative Commons Attribution License(CC-BY). HSE – Social and Education History Vol. 11 No.2 June 2022 pp. 181-
200 HSE – Social and Education History Vol. 11 No.2 June 2022 pp. 181- History of MeToo University
movement in Spain Mar Joanpere
Universitat Rovira i Virgili Ana Burgues-Freitas
Universidad de Granada Marta Soler
Universitat de Barcelona Emilia Aiello
Universitat Autònoma Barcelona Keywords: MeToo University, Isolating Gender Violence, Victims,
Survivors Abstract The precedents of the MeToo University movement, both in USA and Spain,
has been led since the 1990s both by people who have taken a stand against
sexual harassment in universities. The present study reflects the history of
the MeToo University in Spain with an emphasis in the start of organized
movement in 2013, also simultaneously with the one organized in the USA. For this purpose, in-depth interviews were conducted with people who led
this transformation since its beginnings, as well as with others who have
joined recently, in order to learn about the historical scope of this movement
from a qualitative approach. Those people have suffered from isolating
gender violence for daring to break the silence, being a loudspeaker and
putting a name to a problem still silenced in Spanish universities and in the
world. The movement has achieved great advances in academic settings,
such as the obligation of all universities to have protocols for action in case
of sexual harassment or gender violence, the legislation of isolating gender
violence, and an unstoppable number of people who come out to tell their
cases. Keywords: MeToo University, Isolating Gender Violence, Victims, Keywords: MeToo University, Isolating Gender Violence, Victims,
Survivors 2021HipatiaPress
ISSN: 2014-3567
DOI: 10.17583/hse.10545 HSE – Social and Education History Vol. 11 No.2 June 2022 pp. 181-
200 HSE – Social and Education History Vol. 11 No.2 June 2022 pp. 181- Historia del movimiento MeToo
Universidad en España Mar Joanpere
Universitat Rovira i Virgili Ana Burgues-Freitas
Universidad de Granada Marta Soler
Universitat de Barcelona Emilia Aiello
Universitat Autònoma Barcelona Resumen Los precedentes del movimiento MeToo Universidad, tanto en EE.UU. como en España, han sido liderados desde la década de los 90 por personas
que se han posicionado contra el acoso sexual en las universidades. El
presente estudio refleja la historia del MeToo Universidad en España con
énfasis en el inicio del movimiento organizado en 2013, también
simultáneamente con el organizado en EE.UU. Para ello, se realizaron
entrevistas en profundidad a personas que lideraron esta transformación
desde sus inicios, así como a otras que se han incorporado recientemente,
con el fin de conocer el alcance histórico de este movimiento desde un
enfoque cualitativo. Esas personas han sufrido violencia de género aisladora
por atreverse a romper el silencio, ser altavoz y poner nombre a un problema
aún silenciado en las universidades españolas y en el mundo. El movimiento
ha conseguido grandes avances en el ámbito académico, como la obligación
de todas las universidades de disponer de protocolos de actuación en caso de
acoso sexual o violencia de género, la legislación de la violencia de género
aisladora, y un número imparable de personas que están empezando a contar
sus casos. Palabras clave: MeToo Universidad, violencia de género aisladora,
víctimas, supervivientes. 2021HipatiaPress
ISSN: 2014-3567
DOI: 10.17583/hse.10545 HSE – Social and Education History, 11(1) 185 HSE – Social and Education History, 11(1) 185 n September 1991, the Community of Researchers on
Excellence for All [CREA] was founded. The analysis made
by their creators in the previous years concluded that only
transforming the dominant feudalism in Spanish academia
could the Spanish Universitites both improve their scientific
contributions and overcome their racism and sexism, including their
omertà about sexual harassment. As Ángela clarifies: “even most
female professors publishing about gender issues looked the other way
when their students were harassed by the male professors who were in
a higher hierarchy to them and arbitrarily decided their professional
future”. Julia adds: “since the first moment, we developed Roma
studies, Gender Studies, Arab and Muslim Studies and others oriented
to scientific, policy and social impact. In several years, those studies
crystallized in several Study Groups, the one on Gender finally
decided the name of Sappho Women’s Group”. h
i
h
f
d l
f
i h
i
i i
f
l
I I At that time, the feudal structure of Spanish universities “freely”
left in the hands of hierarchically superior professors the decision and
the criteria over which precarious professors obtained a stable position
and which already stable professors were promoted. The slightest
support to a victim or the simple recognition that there was gender
violence in the university led to massively extending slander about
those who did as a previous step to expel them from the university. Given that the criteria for selection and promotion were arbitrary, such
expulsion was disguised in one of the assessments of their quality that
led to attributing zero points to an article published in a top-ranked
international scientific journal if the author had supported a victim and
attributing ten points to an article published in the journal of the
harasser catedrático (Full Professor) if the author was subdued to his
harassments. Those practices maintained a fierce omertà on sexual harassments
and also impeded the improvement of the scientific quality of the
research and publications. In 1991 university professors’ research had
to be conducted in their own departments, they could not constitute
interdisciplinary research centers among members from different
departments. HSE – Social and Education History, 11(1) 185 Those who held the power in each department had the 186 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo subjugation of its members guaranteed, because they were in the
academic committees that decided their promotion, but they could not
secure the subjugation of professors from other departments whose
promotion depended on other committees. CREA started an
interdisciplinary research center with important support from the
Research Programmes of the European Commission. Other professors
followed this example and in 1995 the University of Barcelona
approved a regulation that made the formation of interdisciplinary
research centers possible (Soler, 2017). This new situation allowed professor Ramón Flecha (founder and
at that time director of CREA) to put the first official complaint
against one professor that was harassing several students and to
propose to the Rector's team the approval of measures to overcome
sexual harassment in the university. Flecha did not receive any written
answer, only an oral response warning him that his proposal would
absolutely not be considered, affirming that there was no gender
violence at the universities and clarifying that he would not let
CREA’s ethical code include a point saying that their members
supported victims of sexual harassment in the university. Many more years had to go by to be able to break the silence for
good. Tens of organizations in Catalonia (one of them CREA’s
Sappho Women’s Group) created the “Platform against Gender
Violence” which in 2003 organized the conference: 'Against
harassment, zero tolerance'. Being the only university group of the
Platform, CREA had to break the silence inside Spanish universities
and led a scientific research project with diagnosis and solutions to
gender violence in the academia. Simultaneously, CREA approved
one new point in its ethical guidelines (Diario Feminista, 2021)
accepted by the University of Barcelona several years before: "In the
face of gender violence, all members of CREA want to contribute, to
the greatest extent possible, to its eradication. That is why we are
committed -as requested by the different organizations- to zero
tolerance to mistreatment. HSE – Social and Education History, 11(1) 185 We consider it essential (1) to always
position ourselves in favor of the victim and never in favor of the
abuser and (2) to collaborate with the victim to explain and denounce
all those cases of which we are aware, whether close and/or distant, in HSE – Social and Education History, 11(1) 187 order to improve the quality of life of all people and especially of
women victims of abuse" (Diario Feminista, 2021, see Omerta 14,
Omerta 15, Omerta 53). The Scientific Investigations on Gender Violence Transformed
Spanish Universities That attempt unleashed a very cruel Isolating Gender Violence (Vidu
et al., 2021) against CREA and against its members. The University of
Barcelona decided to eliminate CREA’s ethical guidelines (Diario
Feminista, 2021, see Omerta 15). CREA obtained a very important
international support from universities like Harvard and organizations
like the European Women’s Lobby besides the Platform against
Gender Violence. Their research proposal was approved and funded
by the Spanish National RTD Program. The preliminary results were
commented on in the dialogues between members of CREA and
members of the Spanish Parliament from diverse political parties. In
2007, the Spanish Parliament approved the legislation oblying the
Spanish universities to recognize that they had an important sexual
harassment issue inside and also oblying them to take the measures
clarified by the results of this research. In doing so, the Parliament
made the correction of a grave mistake it made three years before
when in 2004 it approved the gender violence legislation without
including that point. The CRUE (Conference of Rectors of Spanish
Universities) positioned itself against this recognition and against the
researchers, but they had to follow this legislation. The results of the research and their scientific, policy and social
impact appeared in some of the main newspapers and TV channels,
generating a profound awareness on the vision that society and
politics had of the university feudalism and of the need to transform it. That was one of the main strengths that would later lead to carry
out a meritocratic transformation of academia to overcome its
feudalism and hence improve its scientific productivity and its non- 188 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo 188 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo sexist and non-racist values (Ley Orgánica 6/2001; LOMLOU
4/2007). sexist and non-racist values (Ley Orgánica 6/2001; LOMLOU
4/2007). The previous arbitrarily in the selection and promotion of professors
was substituted by scales where an article published in a top scientific
journal at the international level had the maximum points, and an
article published in a harasser’s journal that was not in any scientific
ranking was assigned with zero points. Since that moment, in order to
obtain their selection and promotion, professors did not have to
subdue to harassers. On the contrary, they had to create knowledge
that would be published in the top scientific journals. This new situation facilitated the possibility of presenting a
complaint. On November 25 2009, Professor and member of CREA
Lidia Puigvert sent to the Dean of the Faculty of Economics and
Business of the University of Barcelona an official letter
demonstrating that the structure of the Master’s and Doctoral
Programs
promoted
practices
that
would
encourage
sexual
harassments. This letter also announced that one professor was
harassing several students a year. Sarah Rankin (Director of Harvard's
Office of Sexual Harassment Prevention) wrote these words about
CREA: "Future generations of students and faculty will undoubtedly
have a very different experience because of your work." All victims and survivors interviewed highlight that both their
support and the attacks they received came from all types of
ideologies, genders and positions. In both sides, in favor of harassers
and in favor of victims, there were people from all genders, sexual
options, ideologies and professions. As Diana explains: “every person
who has supported a victim at some point knows that there are always
men and women on both sides, women and men in favor of the victim,
and men and women in favor of the harasser. To affirm that all men
are potential aggressors, that new masculinities are “whitewash” is not
only a lie, but it means positioning oneself in favor of the harasser and
against the supports of victims, provoking their isolation and their
possibility to become survivors”. HSE – Social and Education History, 11(1) 189 On September 26 2011, student of sociology Ana Vidu asked
Professor Ramón Flecha for support after receiving a new email from
Professor JdM, who was the most known professor in Spain by those
types of harassing conducts. 188 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo Flecha presented a complaint to the
recently created Equality Committee of the Faculty of Economics and
Business of the University of Barcelona. He also sent this denounce to
Harvard’s Office of Sexual Assault Prevention and Response, because
this professor said in his email that he was linked to this institution. On October 5 the Economics and Business Faculty’s Equality
Committee at the University of Barcelona decided that there was no
case. On October 19, Harvard's Office of Sexual Assault Prevention
and Response sent an email to the Dean. On October 25 the
Economics and Business Faculty’s Equality Committee rectified its
initial position and decided to initiate a case. Asking interviewees about this position that might seem strange in
principle of the recently named Equality Committee, we obtain the
following clarification (Julia): “The Rectors were obliged from the
legislation to create Equality Commissions, but they maintained in
their power the arbitrary designation of their components and they
delegated in the Deans the designation of the members of each
Faculty’s Equality Commission. Most of them made designations that
allowed the university to maintain the omertà and therefore silence the
complicities that they had had with that situation. In fact, all female
professors who had researched the issue and had supported the victims
were either not named for those Commissions or, the few of those
who have done it and who were named, were excluded when they
showed the first support to a victim. Their objective is well expressed
by the Count of Lampedusa in The Leopard “If we want everything to
stay as it is, everything has to change”. On November 3 2011, Ana Vidu initiated the contacts with other
victims and 13 of them decided to provide their witness and emails
that they have received with harassing content. On October 5 2012,
the University of Barcelona decided it could not do anything and sent
the report to the Prosecutor's Office. The only member of the Equality 190 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo Commission that continued supporting Ana Vidu and who had
elaboratd the first protocol against sexual harassment in a Faculty of a
Spanish university, precisely for that commission, was excluded from
it. The Creation of the Firsts Networks of Victims and Survivors The Creation of the Firsts Networks of Victims and Survivors In 2013 the Solidarity Network of Victims of Gender Violence in
Universities was created in Spain, simultaneously with EROC (End
Rape On Campus) in the United States. On November 15, after
receiving the file report from the Public Prosecutor's Office, the
Network contacted the Rector, the Dean and the Equality Commission
of the University of Barcelona to request meetings. Because they did
not receive any answer, on November 28 2012 the Network decided to
go public and directly meet with the press. On December 15, one of
the five most important newspapers in Spain published a news with
the following header: "Ten UB students demand measures against a
professor for alleged sexual harassment". In her interview, Naiara clarified: “the CRUE (the Rectors)
threatened us and they justified themselves with the argument that
speaking and writing about the supposed gender violence in academia
gravely discredited the university. We always said that in the middle
and long term the discrediting came from the omertà which
maintained the silence about the very serious situation many females
had in their universities. Unfortunately, they did not believe us until
they read and saw in the newspapers and TV not only that gender
violence was a reality in universities but also that they did not even
want to talk to the victims and survivors”. In 2014, the first victory in Spanish universities was already
obtained when the University of Barcelona had to finally take an
official position with clear measures against one denounced person. He was a male student reported by harassment to three female
students of the Master's Program in Sociology. The victims asked and
obtained support from Professor Ramón Flecha and Professor Marta
Soler. At the end, their complaint process ended up winning, HSE – Social and Education History, 11(1) 191 becoming the first case in which a Spanish university explicitly
sanctioned someone due to sexual harassment misconduct at the
university. This was considered by MeToo University a great victory
that immediately diminished impunity in the face of harassment. Laura, one of those victims clarified important elements of this
process: “the Director of the Master’s Program, chosen and nominated
by the Dean, told Flecha off in an intimidating way saying that by
supporting the victims he was being disloyal to the university and that
such action would bring him consequences. The Creation of the Firsts Networks of Victims and Survivors The members of the
Equality Commission said the victims were overreacting due to
reporting that the cited student would put on the classroom table a
knife of illegal dimensions while he painted female students naked
staring at all parts of their bodies. This student was also found with a
knife inside the women’s bathroom at the school. Members of the
Equality Commission said that victims were overreacting. However,
when the Equality Commission had to interview the student, the one
responsible for the Commission asked and achieved to have security
guards at her door. The vice president of the professionals for Gender
Equality (also a student of the Master’s) wrote a public letter against
the victims and in favor of the harasser”. The Network was very active breaking the omertà and the citizens,
policymakers and media were increasingly knowing what was
happening inside the universities. More victims were becoming
survivors and they were obtaining more victories and transforming the
universities into spaces free of violence. What they were not
conscious enough about is that important powers felt increasingly
threatened by this transparency and were organizing themselves in a
lobby with members of the universities and members of the media,
planning a powerful campaign of slander in order to destroy the
Network and their members, including the very few professors that
supported them. This victory and this breaking of silence led the
harassers, and those who for years and decades had been accomplices,
to push forward a campaign, with significant institutional support in 192 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo 192 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo universities, of Isolating Gender Violence [IGV] against those who
supported the victims. On February 5 2014, the most read Spanish newspaper, El País,
published the words of the Secretary of Universities of the Catalan
government when he found out that the Dean was aware of the
compulsive sexual harassment of professor JdM since she was a
student: "The head of Universities has also referred to the case of
alleged sexual harassment at the University of Barcelona starring the
professor of Sociology... saying that it is a regrettable fact that will set
a precedent... and it is also regrettable that there are people who say
that they already knew, that the fact lasted for years and did not
denounce it and I do not say it for the victims but for those responsible
for the university. If they knew about it, why didn't they act? The
Secretary referred to the statement made by the dean of the Faculty of
Economics... before the Mossos (Catalan police body) in which she
recognized that in 1987, when she was a student, the existence of
harassment was already rumored by the faculty". On February 20 2014, students made a protest meeting in the office
of the Rectorate to register the 1000 signatures collected demanding
that the most denounced professor would no longer have teaching or
research responsibilities with students. On March 1 2014, the Student
Assembly of the Faculty of Economics organized the first assembly
against sexual harassment in the Faculty of Economics and Business. On March 3 2014, the Observatory of Gender Violence of the
Women's Foundation and funded by the Spanish Ministry of Equality
recognized the Solidarity Network of Victims of Gender Violence in
Universities as a Good Practice and included it on its website in the
"Database of Good Practices for the Prevention of Gender Violence". This was a very important position statement rejecting the slander
against the victims and their supporters that were spread through the
university hallways. That recognition was not only towards their effort
but to the quality of their reflections and their actions, qualifying them
as a good practice and including them in its official website. HSE – Social and Education History, 11(1) 193 On May 9 2014 the Solidarity Network, together with the Unitary
Platform against Gender Violence, launched the campaign "Our
daughters have the right". 192 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo On July 23 2014, the scientific jornal
Qualitative Inquiry published the article "What Students Say About
Gender Violence Within Universities: Rising Voices From the
Communicative Methodology of Research" (Vidu, A., Schubert, T.,
Muñoz, B., & Duque, E., 2014) about the voices of the victims in this
movement. The Network allowed victims to become survivors. They
maintained at the same time the continuous dialogue and collaboration
with the organizations fighting against gender violence in the whole
society and the publication of scientific articles in the top scientific
journals of this matter and from different disciplines. This dialogic
approach made them promote the criteria of social impact and co-
creation, which is now a guideline and even a requirement of the
current scientific programmes of research in all sciences in the
European Commission (European Commission, 2018). Citizens’ Reaction Against the Isolating Gender Violence
Campaign When it was known that the Rector (who recognized to the
newspaper El País that JdM was his friend) decided to let JdM teach
again, the students’ movement and the Network strengthened their
actions… but the lobby had been preparing their campaign against
them for several months. From June 3 to 5 2016 the Network was
invited to give a talk in the Feminist Conference of Barcelona. On
June 8 2016 students, in collaboration with the Network, published a
letter against the reinstatement of Professor JdM to teaching. On 13 June 2016, a very cruel campaign of Isolating Gender
Violence (hereinafter, IGV) was launched against the victims and the
few professors who supported them (including attacks on their
daughters and sons) in which several journalists collaborated, as some
confessed, looking for an audience through morbidity. In the short
term, this IGV obtained its objective and the mobilization stopped. 194 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo 194 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo 194 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo In the middle and long term, this IGV acted as a boomerang against
the ones that launched it. The cruelty of the slander ended up
discrediting especially those who launched them, whereas those who
received them, in spite of suffering a lot in the beginning, have seen
their scientific prestige greatly increase, first internationally and then
in Spain. There is almost a unanimous consideration that not only
have they been infinitely anti-sexist, solidary and brave, but that they
have also been infinitely more intelligent than the members of the
lobby of harassers. On December 19 and 20 2016, the first conference on Isolating
Gender Violence was held at the University of Barcelona, organized
by CREA. Members of the Parliament and of all political parties,
women’s movements, representatives of governments and media were
speakers in the conference. They were astonished by the cruelty of the
Isolating Gender Violence campaign during the second half of that
year against victims and supporters. They were also shocked by the
process of evaluation of that dissertation. At the beginning of 2017, Ana Vidu, who was doing a research
stay in Stanford University, defended her doctoral thesis on gender
violence in universities in the Sociology Doctorate program of the
Faculty of Economics and Business from the University of Barcelona. The doctoral committee of the Department of Sociology in charge of
evaluating the dissertation approved it by unanimity. However, the
Dean and the Equality Commission pressed for the Faculty of
Economics and Business to reject it. Even the Dean herself wrote the
many words that Vidu should include in her own dissertation. All that
was a scandal because it skipped all the university norms and did it
with a student who had received the Award Best Student at the
Bachelor’s Degree in Sociology and the Award to the Best Student in
the Master’s Degree in Sociology. Ana Vidu had to come back, ending her research stay at Stanford
earlier than planned. She and her family and friends were extremely
sad and disheartened. The director of her dissertation, Ramón Flecha,
was working in Brussels as evaluator of the European Framework HSE – Social and Education History, 11(1) 195 Programme of Research. 194 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo When he came back to Barcelona,
everything was transformed, as was explained in the webpage of the
women journalist of the main Spanish TV reproducing the following
writing by Ana Vidu with the title “The croissant and the winning
victim”: “When my director and I received the first rejection of the
dissertation, I was on a stay at Stanford; I decided to return to do what
they asked and to be able to submit the dissertation again. At the
University of Barcelona, I was waiting for an interview with the
director of the equality commission and the dean at the time. The
commission ended up presenting itself almost completely and, as on
previous occasions, the criticism came towards me and towards the
people who had always supported me. Both my family and I were
devastated and very discouraged. That day my thesis director Ramón
Flecha came back from a trip to wait for me after the meeting and
surprise me. We went to the bakery that won the award for the best
croissant in Spain. Ramón told me that we were going to celebrate
everything, every rejection, because the reason for our struggle was so
clear that those rejections were the result of injustice but also of the
lack of intelligence of the harassers and their allies, and the more they
attacked us, the more they would be exposed. We took this photo and
I sent it to my family. They were stunned to see that we were
celebrating, and they changed from sadness to celebration. I told them
that there would come a day when everything was going to work out,
and that we were going to be okay, that we were going to succeed in
the fight against gender violence at the university and in my life. Thanks to excellent people like Curro Aguilera, Enrique Pérez, Gema
Tomás, I am now very well at the University of Deusto. My family is
now very happy and the victims no longer feel so alone, we are here to
help them as they have helped me.” The dissertation was presented again including all words imposed
by the Dean, but as quotations by her, instead of assumed as the
candidate’s words. The dissertation was approved and obtained the
highest qualification by the committee. 194 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo Almost all newspapers and TV 196 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo channels published about the very brave and honest action of Ana
Vidu, the Network and CREA and about the cruelty that they received
from the harassers and their accomplices. On May 31 2017 the
documentary "Voices against silence" was released by TVE, the most
important Spanish public TV channel, which included a long
explanation of Ana Vidu’s case. On May 16 2018, “Voices against
silence” won the Golden Globe of the World Media Festival of
Hamburg. It was a great success for quality journalism and MeToo
University. The MeToo University and the Legislations Against Isolating
Gender Violence When the MeToo Movement was founded worldwide in 2017,
many movements and persons in different parts of the world felt
supported; some of them have adopted the same name and one of
these was the MeToo University as the new name of the Solidarity
Network of Victims of Gender Violence in Universities. It is obtaining
incredible victories in Spain and now also in other countries. Their
members are altruist that they proclaim to be working in favor of a
violence-free and safe university for all, including the daughters and
granddaughters of the current harassers. On January 23, 2022, the
front page of one of the most read journals in Spain, was dedicated to
a “U” occupaging the whole page and inside the pictures of 25 women
that were victims and survivors from sexual harassment in univeristies
(El Periódico, 2022). Inside, a long and excellent report elaborated by
three female journalists during six month. Their difficulties to find 25
women willing to be there expressed that the fear is present in an
institution where the harassers and their isolating gender violence are
very powerful. This report moved to talk about this issue in almost all
newspapers and TV. Those victories are the result of the outstanding scientific, policy
and social impact of both their studies and their actions. Their policy
impact includes the approval of the legislation for the first time in the HSE – Social and Education History, 11(1) 197 world against Isolating Gender Violence. On December 22 2020, the
Parliament of Catalonia was a world pioneer in incorporating Isolating
Gender Violence in its legislation by unanimously approving it in law
17/2020. On March 17 2022 the Basque Parliament incorporated
Isolating Gender Violence in its legislation, in the Law for the
Equality of Women and Men, Article 50, point 4. In this case the
approval was not by unanimity, but by the majority of votes in the
Parliament. This was not because some members of the Parliament
were against this proposal, but because there was only one voting of
the whole law and those not voting in favor did not do so because of
this point, but because they disagreed in other points of the same law. This kind of disagreement was also seen in the Catalan parliament, but
the approval of this point was by unanimity because it was voted
separately from the other points of the same law. The MeToo University and the Legislations Against Isolating
Gender Violence Other Parliaments from Spain but also from other countries are in
the process of approving legislation against Isolating Gender Violence
as well. Besides Parliaments, many diverse organizations and even
enterprises are initiating similar processes responding to the proposal
made by MeToo University. Its proposal has been also approved by
organizations like the European Sociological Association and Ana
Vidu has been nominated member of the ESA’s Research Network on
Women’s and Gender Studies. Members of Metoo University and
their supporters are teaching professionals from very different fields
about how to face Isolating Gender Violence, the only way to
overcome all kinds of gender violence; even they have been asked by
Ministers of Justice to train judges and prosecutors on this subject. This political impact is changing society in this matter, it is generating
an increasing social impact in terms of the decrease of cases in diverse
settings and institutions and breaking the silence about the existing
cases. In all, this policy and social impact is possible also because of the
scientific impact of the studies made by the members of MeToo
University and their supporters. Several articles have been published
in top-ranked scientific journals of different disciplines analyzing: the 198 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo quantitative and qualitative dimensions of gender violence in Spanish
universities (Valls, Puigvert, Melgar & Garcia-Yeste, 2016), the
concept and the name of Isolating Gender Violence (Vidu, Puigvert,
Flecha & López de Aguileta, 2021), the IGV as the first reason to do
not support victims (Melgar, Geis-Carreras, Flecha & Soler, 2021),
the consequences of IGV for the health of supporters (Aubert &
Flecha, 2021), the typology of the victims of IGV (Flecha, 2021), the
pioneer legislation on IGV (Vidu, Tomás & Flecha, 2021), the media
that take position in support of harassers (Madrid, Joanpere, De
Botton, Campdepadrós, 2020), the media working with the
professional criteria of journalism (Pulido, Villarejo, Vidu, Ramis, &
Flecha,2021), the first international conference of IGV (Vidu, Valls,
Puigvert, Melgar & Joanpere, 2017), how new alternative
masculinities respond to the demands of support of victims (Nazareno,
Vidu, Merodio & Valls, 2022), and also concrete cases that happened
during the hard lockdown imposed in Spain due to COVID-19
(Puigvert, Vidu, Melgar & Salceda, 2021). References Aubert, A. & Flecha, R. (2021). Health and Well-Being Consequences
for Gender Violence Survivors from Isolating Gender Violence. International Journal of Environmental Research and Public
Health, 18(16), 8626. https://doi.org/10.3390/ijerph18168626 Diario Feminista (2021). Omerta in Academia. The most rigorous and
detailed analysis of hypothetical situations of second order of
sexual
harassment. Retrieved
from
https://eldiariofeminista.info/wpcontent/uploads/2021/03/Omerta.p
df El Periódico (January, 23th 2022). #MeToo at the University. Retrieved from https://www.elperiodico.com/es/cuaderno/metoo-
university-spain-sh/index.html European Commission (2018). Monitoring the Impact of the EU
Framework Programmes. Publication Office of the European
Union,
Luxembourg. Retrieved
from HSE – Social and Education History, 11(1) 199 https://op.europa.eu/en/publication-detail/-/publication/cbb7ce39-
d66d-11e8-9424-01aa75ed71a1 Flecha, R. (2021). Second-Order Sexual Harassment: Violence
Against the Silence Breakers Who Support the Victims. Violence
against
women,
27(11). 1980-
1999. https://doi.org/10.1177/1077801220975495 Ley Orgánica 4/2007, de 12 de abril, por la que se modifica la Ley
Orgánica 6/2001, de 21 de diciembre, de Universidades. Madrid, A., Joanpere, M., de Botton, L., & Campdepadrós, R. (2020). Media Manipulation Against Social Justice Researchers: Second-
Order Sexual Harassment. Qualitative Inquiry. https://doi.org/10.1177/1077800420938853 Melgar, P., Geis-Carreras, G., Flecha, R., & Soler, M. (2021). Fear to
Retaliation: The Most Frequent Reason for Not Helping Victims of
Gender Violence. International and Multidisciplinary Journal of
Social Sciences, 10(2), 31-
50. https://doi.org/10.17583/rimcis.2021.8305 50. https://doi.org/10.17583/rimcis.2021.8305 Nazareno, E., Vidu, A., Merodio, G., & Valls, R. (2022). Men
Tackling Isolating Gender Violence to Fight against Sexual
Harassment. International Journal of Environmental Research and
Public
Health,
19(4),1924. http://dx.doi.org/10.3390/ijerph19041924 Puigvert, L.; Vidu, A.; Melgar, P.; Salceda, M. (2021). BraveNet
Upstander Social Network against Second Order of Sexual
Harassment. Sustainability,13,
4135. https://doi.org/10.3390/su13084135 Pulido, C.M., Villarejo-Carballido, B., Vidu, A., Ramis, M., & Flecha,
R. (2021) “Voices against Silence”: a case study of the social
impact
of
journalism. Feminist
Media
Studies. https://doi.org/10.1080/14680777.2021.1992643 Soler, M. (2017). Achieving social impact: sociology in the public
sphere. Springer. ISBN: 9783319602691. Valls R, Puigvert L, Melgar P, Garcia-Yeste, C. (2016). Breaking the
silence at the Spanish universities: the first research about violence 200 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo 200 Joanpere, Burgues-Freitas, Soler & Aiello– History of MeToo against
women. Violence
Against
Women,
22,
1519-
1539.https://doi.org/10.1177/1077801215627511 against
women. Violence
Against
Women,
22,
1519-
1539.https://doi.org/10.1177/1077801215627511 p
g
Vidu, A. (2017). Doctoral dissertation, Networks of Solidarity. Student
mobilizations against sexual violence in universities. Doctoral
program in Sociology. University of Barcelona. Retrieved from
https://www.tesisenred.net/handle/10803/402514#page=1 Vidu, A., Tomás, G. & Flecha, R. (2021). Pioneer Legislation on
Second Order of Sexual Harassment: Sociolegal Innovation in
Addressing Sexual Harassment. Sexuality Research and Social
Policy. https://doi.org/10.1007/s13178-021-00571-0 Vidu, A., Puigvert, L., Flecha, R. & López de Aguileta, G. (2021). The Concept and the Name of Isolating Gender Violence. Multidisciplinary Journal of Gender Studies, 10(2), 176-
200. https://doi.org/10.17583/generos.2021.8622 Vidu, A., Schubert, T., Muñoz, B., & Duque, E. (2014). What
Students Say About Gender Violence Within Universities: Rising
Voices From the Communicative Methodology of Research. Qualitative
Inquiry,
20(7),
883–888. https://doi.org/10.1177/1077800414537211 Vidu, A., Valls, R., Puigvert, L., Melgar, P., & Joanpere, M. (2017). Second Order of Sexual Harassment – SOSH. Multidisciplinary
Journal
of
Educational
Research,
7(1),
1-26. https://doi.org/10.17583/remie.2017.2505 HSE – Social and Education History, 11(1) 201 Mar Joanpere. Departmento de Gestión de Empresas. Universitat
Rovira i Virgili, Spain. ORCID ID: https://orcid.org/0000-0002-6006-0190
Ana Burgues-Freitas. Departamento de Sociología. Universidad
de Granada, Spain. ORCID ID: https://orcid.org/0000-0002-0167-6489
Marta Soler. Departamento de Sociología. Universitat de
Barcelona, Spain. ORCID ID: https://orcid.org/0000-0003-4494-4508
Emilia Aiello: Departamento de Sociología. Universitat
Autònoma de Barcelona. ORCID ID: https://orcid.org/0000-0002-0005-6501
Contact adress: mar.joanpere@urv.cat Mar Joanpere. Departmento de Gestión de Empresas. Universitat
Rovira i Virgili, Spain. ORCID ID: https://orcid.org/0000-0002-6006-0190 Mar Joanpere. Departmento de Gestión de Empresas. Universitat
Rovira i Virgili, Spain.
ORCID ID: https://orcid.org/0000-0002-6006-0190 Ana Burgues-Freitas. Departamento de Sociología. Universidad
de Granada, Spain. ORCID ID: https://orcid.org/0000-0002-0167-6489 Marta Soler. Departamento de Sociología. Universitat de
Barcelona, Spain. ORCID ID: https://orcid.org/0000-0003-4494-4508 Emilia Aiello: Departamento de Sociología. Universitat
Autònoma de Barcelona. ORCID ID: https://orcid.org/0000-0002-0005-6501
Contact adress: mar.joanpere@urv.cat
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Social media trends in obstetrics and gynecology residency programs on Instagram and X (Twitter)
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PLOS ONE RESEARCH ARTICLE OPEN ACCESS Citation: Gnade CM, Avery CC, Yang Z, Pickett CM,
Oshinowo AE (2024) Social media trends in
obstetrics and gynecology residency programs on
Instagram and X (Twitter). PLoS ONE 19(5):
e0296930. https://doi.org/10.1371/journal. pone.0296930 Colette M. GnadeID1¤*, Chace C. Avery2, Ziyi Yang3, Charlotte M. Pickett4, Adeoti
E. Oshinowo5 Colette M. GnadeID1¤*, Chace C. Avery2, Ziyi Yang3, Charlotte M. Pickett4, Adeoti
E. Oshinowo5 1 Department of Obstetrics and Gynecology, University of Kansas, Kansas City, Kansas, United States of
America, 2 Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio, United
States of America, 3 Department of Biostatistics and Health Data Science, Indiana University, Indianapolis,
Indiana, United States of America, 4 Department of Obstetrics and Gynecology, University of California San
Diego, La Jolla, California, United States of America, 5 Department of Obstetrics and Gynecology, Indiana
University, Indianapolis, Indiana, United States of America a1111111111
a1111111111
a1111111111
a1111111111
a1111111111 ¤ Current address: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas
City, Kansas, United States of America
* cgnade@kumc.edu Background During the COVID pandemic, residency program’s social media presence increased to aid
in residency recruitment by attempting to increase engagement and readily available infor-
mation for applicants across specialties. However, little information exists on what charac-
teristics and content on obstetrics and gynecology (OBGYN) residency program accounts
attract more followers or engagement. Editor: Kento Sonoda, Saint Louis University
School of Medicine, UNITED STATES
Received: August 23, 2023
Accepted: December 26, 2023
Published: May 6, 2024
Copyright: © 2024 Gnade et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Editor: Kento Sonoda, Saint Louis University
School of Medicine, UNITED STATES
Received: August 23, 2023
Accepted: December 26, 2023
Published: May 6, 2024 Objectives To identify social media trends in OBGYN residencies and determine which aspects of pro-
grams influence the number of followers and interaction with content posted. Copyright: © 2024 Gnade et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Data Availability Statement: Data are available at:
https://github.com/cgnade2001/
SocialMediaOBGYN. Data Availability Statement: Data are available at:
https://github.com/cgnade2001/
SocialMediaOBGYN. Funding: The author(s) received no specific
funding for this work. Methods We performed a retrospective review of ACGME accredited OBGYN programs and deter-
mined their presence on Instagram and X in the fall of 2021. Content from the thirty pro-
grams with the most followers was analyzed independently by two authors. Multivariate
analysis and a linear mixed model were used to characterize and evaluate content on Insta-
gram and X. PLOS ONE PLOS ONE Results Most programs utilized Instagram (88.5%, N = 262/296) and were managed solely by resi-
dents (84.4%, N = 108/128). Number of followers on Instagram positively correlated with
features such as program size, Instagram profile duration, and Doximity rankings (p <
0.0x01). Programs on X had more followers if their profile had a longer duration, followed Competing interests: The authors have declared
that no competing interests exist. Abbreviations: DEI, diversity, equity, and inclusion;
DITL, day in the life; Q&A, question & answer. 1 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies more individuals, or were ranked higher on Doximity. The most posted Instagram content
was biographical and social in nature. Instagram posts with the highest engagement were
awards and/or the Match. more individuals, or were ranked higher on Doximity. The most posted Instagram content
was biographical and social in nature. Instagram posts with the highest engagement were
awards and/or the Match. Conclusions Understanding what social media content attracts more followers and increases engage-
ment is crucial as it likely impacts OBGYN resident recruitment. Professional groups should
establish guidelines for social media use in recruitment for the protection of both residents
and applicants. Introduction Currently there are 4.62 billion social media users making up 58.4% of the world population. This number grew by more than 10% from 2021 to 2022 [1]. This trend in social media use is
paralleled in healthcare with up to 90% of workers having a social media account [2]. Increased
professional content on social media has been driven by the desire to stay connected to peers
in the medical community, share accurate knowledge with patients, and develop a brand [3–
5]. An increase in social media influence has transformed the experience of residency trainees
by impacting education, professional development, and academic scholarship [6]. The COVID
pandemic has further increased residency program presence on social media as it brought sig-
nificant challenges to residency recruitment, interviewing, and away rotations [5, 7–9]. The
number of programs on social media is rapidly expanding but remains variable on both Insta-
gram (40.9% neurology to 96.6% plastic surgery residency programs) and X, formerly known
as Twitter, (14% of dermatology programs to 44.1% otolaryngology residency programs) [7,
10–12]. Obstetrics and gynecology (OBGYN) residency programs have increased their pres-
ence on Instagram, specifically during the pandemic [13]. Residency applicants report that a program’s social media presence influences their applica-
tion, interview, and rank process. In studies with recruitment prior to 2020, around 12–29% of
applicants note that social media presence influenced their recruitment [8, 14, 15]. However,
after 2020, around 60%-71% of applicants reported social media impacted their perceptions of
residency programs [16–18]. These studies, which are from a wide range of specialties includ-
ing general surgery, anesthesia, and family medicine, have concluded that programs should
consider investing resources into their social media [16–18]. Social media platforms have
become, and likely will remain, an integral part of professional life and residency recruitment. However, factors to help engage applicants and create an interactive social media residency
account are relatively unknown. Our study was performed to examine social media trends in
OBGYN residencies, analyze program and social media characteristics associated with pro-
gram followers, and analyze social media content and post engagement. Materials and methods We performed a retrospective study to identify the extent of social media presence of OBGYN
programs on both Instagram and X platforms as these were those most studied prior [13, 19]. Facebook was initially inquired, however, given low numbers, difficulty searching the pro-
grams, and American College of Obstetrics and Gynecology (ACOG) only utilizing Instagram
and X for virtual residency showcase recruitment since 2020, this was deferred [20]. Institu-
tional IRB exemption (#13531) was obtained for this study from Indiana University Human 2 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Research Protection Program. We complied with both Instagram and X terms of use. An
online search was performed in the fall of 2021 for all Accreditation Council of Graduate Med-
ical Education (ACGME) approved OBGYN residency programs after initial residency recruit-
ment to capture maximal engagement. Two individual observers (AC, CG) found programs
online by searching for full and abbreviated program names in addition to the search terms
“OBGYN”, “obstetrics”, and “gynecology” as previously described in the literature [5, 8, 21]. For every social media account, the number of followers, following, and posts were obtained
(October 27, 2021 for Instagram and December 3, 2021 for X) shortly after the submission
deadline for residency applications. X posts, or formerly tweets, were not analyzed given total
number are not easily available and content differs from Instagram. Instagram stories were not
evaluated as this is temporary content for 24 hours and difficult to extract given the number of
programs. Duration of social media account existence was abstracted from the date of the pro-
gram’s first post on Instagram while X publicly posts this data. Program rank was determined
using the Doximity residency navigator tool by reputation in 2022 [22]. The FREIDA database
was queried to determine the type of residency program: academic, community, or combined. Both FREIDA and Doximity were used to obtain the number of residents in the program. If
these were not in congruence, the residency home page was visited, and number of residents
counted manually. Doximity was used to determine the location of the program, and city size
was extrapolated from the location using the U.S. Census Bureau’s statistical area [23]. Popula-
tions were defined as large metropolitan (1.5 million or more people), metropolitan (500,000
to 1.5 million people), medium-size urban (200,000–500,000 people), and small urban
(50,000–200,000 people). PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 Results Of the ACGME accredited OBGYN residency programs, 88.5% (N = 262/296) programs were
identified to have an Instagram account. Of the 34 that did not have an Instagram, 11 pro-
grams had just received their initial accreditation in 2021 and 7 were military programs. Fewer
programs, 33.7% (N = 97/296), were found to have an X account. Notably, 28.8% (N = 28/97)
X accounts and 1.5% (N = 4/262) of Instagram accounts were departmental and not specific to
the OBGYN residency program. Most programs created an Instagram (60.3%, N = 158/262) or
X (53.6%, N = 52/97) account in 2020. On Instagram, baseline characteristics were collected showing most programs had an aver-
age of 821.2 posts (Standard Deviation/SD = 370.5), were in large metropolitan areas (59.9%),
classified themselves as academic programs (46.6%), and had a highlight reel (88.2%). Approx-
imately 60% of programs had at least one post about diversity in any of their posts on Insta-
gram. Most programs were run by residents (84.4%, N = 108/128). Of the 37% (N = 97)
programs that responded, thirty-one percent of respondents identified their program as a dif-
ferent type from that listed in the FREIDA database (Table 1). On Instagram, many factors were associated with increased number of followers (Table 2). The number of followers increased with more residents, specifically 5.38 more followers per
resident (Standard Error/SE = 1.64, p = 0.001). With one more month on Instagram, programs
had 4.88 (SE = 1.34, p<0.001) more followers. Programs that followed more individuals had
more followers (β estimate = 0.53, SE = 0.06, p<0.001). More posts were associated with more
followers (β = 1.00, SE = 0.17, p<0.001). The frequency of posts, or number of posts per
month, was not associated with increased followers (p = 0.721). More followers were observed
in academic than community (β = 109.2, SE = 39.22, p = 0.006) or combined programs (β =
125.87, SE = 33.63, p = 0.001). The programs in the top quartile (or top 25%) on Doximity had
more followers than those in the lower rankings (p = 0.001). The programs with a highlight
reel (β = 146.46, SE = 36.56, p<0.001) or diversity post (β = 87.30, SE = 27.85, p = 0.002) had
more followers. On X, the average number of followers was 467.0 (+/- 549.3) and duration on the platform
was 34.1 months (+/- 33.6). Materials and methods Inquiries were also sent to each program on Instagram by direct
message by author CG to ask what type of program they identify as and who posts the content
on their Instagram account. Informed consent to participate was obtained with a written
response. If their program type direct message was incongruent with FREIDA, FREIDA was
utilized for program type given this is a nationwide database. Reply time from direct messen-
ger was recorded. The home institution of this study was excluded from this part of the analy-
sis. Instagram program pages were also searched to identify if they had a highlight reel and if
their biography indicated who posted content. Programs were recorded as having a diversity
post if there was at least one post primarily regarding any of the following: gender, social and
ethnic background, or sexual orientation. The thirty OBGYN programs with the most Instagram followers were identified. Their last
thirty Instagram posts on and prior to October 27, 2021 were analyzed independently by two
reviewers (AC, CG). The classification of these posts was adapted from Azoury et al and Abbas
et al and changed to reflect specialty differences in content [5, 24]. Posts were categorized into
educational, informational, awards/Match, social, wellness, surgical, class, research, advocacy,
diversity, and other (S1 Fig). Additionally, the top thirty program’s Instagram highlight reels
were categorized by the same two reviewers. Separate classifications were given to these posts
as they include video content: educational, research, informational, social, wellness, advocacy/
diversity, rotations, location, biography, question & answer (Q&A), day in the life (DITL), and
other (S2 Fig). Disagreements between the reviewers were resolved by consensus. Summary statistics were provided for the characteristics of programs with an Instagram
and/or X presence. Mean and standard deviation were presented for continuous variables and
frequency and percentage for categorical variables. A multivariate linear regression model was
used to evaluate the association of factors with the number of followers on both Instagram and
X. A linear mixed model was used to evaluate the association of post content with the number
of likes on Instagram with random intercept for the correlation of the repeated measures
within the program. The linear mixed model also adjusted for the program size, city size, and
type of program. Materials and methods False discovery rate was used for the adjustment of multiple comparisons and PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 3 / 13 PLOS ONE Social media trends OBGYN residencies control for a possible false positive rate in the linear mixed model. All tests were two-sided and
assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). control for a possible false positive rate in the linear mixed model. All tests were two-sided and
assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Results Most programs were in large metropolitan areas (65.0%) and clas-
sified themselves as academic programs (67.0%) (Table 1). The number of followers was signif-
icantly associated with duration in months on X since the first post, number following, and
Doximity ranking (Table 2). On average, programs had 5.31 more followers per month on X
(SE = 0.99, p<0.001). As programs followed other social media users on X, they gained more
followers (β = 1.55, SE = 0.18, p<0.001). The program in the top quartile on Doximity ranking
had more followers than those in the lowest 50% of rankings (p = 0.029). An analysis of 900 posts from the top thirty most followed programs on Instagram demon-
strated most of the content was biographical (18%) or social in nature (18%) (Figs 1 and 2). The least posted content overall was surgical (3%), research (3%), and advocacy (3%). In the
top thirty programs, social content (97%) followed by information (90%) and class (90%) were
posted at least once in their last thirty posts while surgical was the least common with only
37% of programs having a post related to surgery. Highlight reels for the top thirty programs
were evaluated (Figs 3 and 4). One program had no highlight reels. Most of the content was
information (17%) or related to DITL (15%). The least posted content overall was research
(3%), Q&A (5%), and location (5%). Of the top thirty programs, informational content (70%)
followed by DITL (60%) and social (53%) were the most common content posted by programs 4 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Table 1. Baseline program characteristics. Results Category
Instagram (N = 262)
X (Twitter) (N = 97)
% of all ACGME Programs
88.5%
33.7%
Followers (Mean, SD)
821.2 +/- 370.5
467.0 +/- 549.3
Following (Mean, SD)
251.9 +/- 195.1
155.4 +/- 195.6
Doximity Ranking (Mean, SD)
138.9 +/- 83.0
111.0 +/- 81.4
Duration (Mean months, SD)
21.7 +/- 12.9
34.1 +/- 33.6
Program Size (Mean, SD)
21.9 +/- 9.2
24.9 +/- 9.0
Posts (Mean, SD)
114.8 +/- 108.0
NA
Posts per Month (Mean, SD)
5.8 +/- 5.5
NA
City Size (%, N)
Large Metropolitan
59.9% (157)
65.0% (63)
Metropolitan
23.7% (62)
24.7% (24)
Medium-size Urban
11.5% (30)
7.2% (7)
Small Urban
4.9% (13)
3.1% (3)
Program Type (%, N)
Community
16.0% (42)
9.3% (9)
Academic
46.6% (122)
67.0% (65)
Combined
37.4% (98)
23.7% (23)
Highlight Reel (% Yes, N)
88.2% (231)
NA
Diversity Post (% Yes, N)
59.5% (156)
NA
Who runs Instagram (%, N = 128)
Residents Alone
84.4% (108)
NA
Program Director/Staff
3.9% (5)
NA
Resident + Other Staff
7.8% (10)
NA
Other Admin Staff
3.9% (5)
NA
Direct Message Response
Total Programs (%, N)
37% (97)
NA
Time (Mean days, SD)
12.0 (11.1)
NA
Incongruent program type (%, N)
30.9% (30)
NA
For Instagram and X, programs were evaluated for followers, city size, program type, etc. Instagram also was
evaluated for unique characteristics including highlight reels. *NA, not applicable https://doi.org/10.1371/journal.pone.0296930.t001 by having at least one highlight regarding this content while research, and rotations were least
common with only 23% of programs having a highlight reel dedicated to these. Type of Instagram post content was significantly associated with the number of likes after
controlling for other characteristics such as program size, program type, and city size (p<0.001)
(S1 Table). Next, content was compared to one another to identify superiority after the false dis-
covery rate adjustment for multiple comparisons between content. Advocacy posts had more
likes than informational posts (p = 0.007). More likes were observed for awards/Match posts
than advocacy, biography, class, diversity, informational, surgical, others, research, social, well-
ness, and educational (p<0.001). Biography posts had more likes than informational but less
than class, and social posts (p0.007). More likes were detected for class posts than diversity,
informational, research, and educational (p0.008). Social posts had more likes than diversity
or educational posts (p<0.005). Less likes were seen for informational post than surgical, others,
social, and wellness (p0.004) (S2 Table). PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Table 2. Factors associated with followers on Instagram and X. Instagram
X (Twitter)
Factor
Difference in Followers (SE)
P value
Difference in Followers (SE)
P value
Program Size
5.38 (1.64)
0.001
2.52 (4.86)
0.606
Duration in months
4.88 (1.34)
<0.001
5.31 (0.99)
<0.001
# Following
0.53 (0.06)
<0.001
1.55 (0.18)
<0.001
# Posts
1.00 (0.17)
<0.001
NA
NA
# Posts per Month
-0.92 (2.58)
0.721
NA
NA
City Size
-
0.587
-
0.587
Small Urban a
-
-
-
-
Large Metropolitan
30.73 (54.74)
0.575
-109.80 (115.31)
0.344
Metropolitan
16.81 (56.45)
0.766
-118.71 (120.04)
0.326
Medium-size Urban
-22.34 (60.38)
0.712
-
-
Program Type
-
<0.001
-
0.394
Community a
-
-
-
-
Academic
109.20 (39.22)
0.006
19.50 (136.29)
0.887
Combined
-16.72 (35.14)
0.635
-90.14 (132.16)
0.497
Doximity Ranking
-
0.002
-
0.012
Top Quartile ( 25%) a
-
-
-
-
Second Quartile (25%-50%)
-109.87 (33.63)
0.001
-174.29 (92.69)
0.063
Third Quartile (50%-75%)
-120.21 (36.71)
0.001
-329.43 (97.12)
0.001
Low Quartile ( 75%)
-140.49 (40.93)
0.001
-275.06 (123.55)
0.029
Highlight Reel
-
-
No a
-
-
Yes
146.46 (36.56)
<0.001
Diversity Post
-
-
No a
-
-
Yes
87.30 (27.85)
0.002
Factors including program size, city size, program type, and Doximity ranking were evaluated to identify any association with followers on Instagram and X. A
multilinear regression model was used to calculate the beta estimate, or difference in followers per factor. Significant p values are bolded. a R f Table 2. Factors associated with followers on Instagram and X. Factors including program size, city size, program type, and Doximity ranking were evaluated to identify any association with followers on Instagram and X. A
multilinear regression model was used to calculate the beta estimate, or difference in followers per factor. Significant p values are bolded. a Reference Factors including program size, city size, program type, and Doximity ranking were evaluated to identify any association with followers on Instagram and X. A
multilinear regression model was used to calculate the beta estimate, or difference in followers per factor. Significant p values are bolded. a Reference Results Overall, posts about awards and/or Match received
the most likes while informational received the least (Fig 5). 5 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 https://doi.org/10.1371/journal.pone.0296930.t002 Discussion Our study shows that most OBGYN residency programs (88.5%) have adopted Instagram
while only 33.7% of programs adopted X. Most of these programs adopted social media during
the COVID pandemic in 2020 as previously demonstrated [13]. Instagram as a social platform
may also be more popular amongst many residency specialties given increased usage of Insta-
gram by applicants as seen in other specialties and the ability to more easily engage with photo
and video content [8, 25]. This is the first study to establish that the number of followers, or popularity, on Instagram
is positively correlated with larger residency program size and academic program type. Yadav
et al is the only other published OBGYN study to evaluate popularity on Instagram and calcu-
lated Doximity ranking in relation to number of posts, followers, and likes on a program’s last
three posts [13]. Similar to our study, Doximity ranking of OBGYN programs was associated
with a higher number of followers. However, Yadav et al did not evaluate content or followers
in relation to other program traits [13]. 6 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Fig 1. Instagram post content, all. Distribution of content for the last thirty posts for the top thirty OBGYN programs. https://doi.org/10.1371/journal.pone.0296930.g001 Fig 1. Instagram post content, all. Distribution of content for the last thirty posts for the top thirty OBGYN programs. https://doi.org/10.1371/journal.pone.0296930.g001 Fig 1. Instagram post content, all. Distribution of content for the last thirty posts for the top thirty OBGYN programs. https://doi.org/10.1371/journal.pone.0296930.g001 Fig 2. Instagram post content, top 30. Distribution on the % of the top thirty OBGYN programs that posted that specific type of content in the last
thirty posts. Fig 2. Instagram post content, top 30. Distribution on the % of the top thirty OBGYN programs that posted that specific type of content in the last
thirty posts. https://doi.org/10.1371/journal.pone.0296930.g002 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 7 / 13 PLOS ONE Social media trends OBGYN residencies Fig 3. Instagram highlight reel content, all. Distribution of content for all posted highlight reels for the top thirty OBGYN programs. https://doi.org/10.1371/journal.pone.0296930.g003 Fig 3. Instagram highlight reel content, all. Distribution of content for all posted highlight reels for the top thirty OBGYN programs. https://doi.org/10.1371/journal.pone.0296930.g003 Fig 4. Instagram highlight reel content, top 30. Discussion Distribution of the % of the top thirty OBGYN programs that posted that specific type of
content in their highlight reels. https://doi.org/10.1371/journal.pone.0296930.g004 Fig 4. Instagram highlight reel content, top 30. Distribution of the % of the top thirty OBGYN programs that posted that specific type of
content in their highlight reels. PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 8 / 13 PLOS ONE Social media trends OBGYN residencies Fig 5. Instagram post content popularity. Based off the linear mixed model of content likes in A.4, content tiers were created based on
significant and insignificant p values between content types showing the most to least popular Instagram post content. https://doi.org/10.1371/journal.pone.0296930.g005 Fig 5. Instagram post content popularity. Based off the linear mixed model of content likes in A.4, content tiers were created based on
significant and insignificant p values between content types showing the most to least popular Instagram post content. Fig 5. Instagram post content popularity. Based off the linear mixed model of content likes in A.4, content tiers were created based on
significant and insignificant p values between content types showing the most to least popular Instagram post content. https://doi.org/10.1371/journal.pone.0296930.g005 https://doi.org/10.1371/journal.pone.0296930.g005 Our study sought to further explore modifiable social media factors that can be implemented
by programs to attempt to increase followers as previously mentioned factors are likely related to
reputation and accessibility to a greater population of users. Modifiable factors that are positively
correlated with followers include number of posts for Instagram, following more accounts, and
time on each platform, which is consistent with orthopedic and plastic surgery literature [5, 24]. Surprisingly, increased frequency of Instagram posts was not associated with more follow-
ers as expected given suspected mutual engagement. This is similar to plastic surgery literature
showing only a weak correlation between number of posts and engagement [11]. Likely, there
is an optimal post frequency as seen in prior social media data [26]. Further studies are needed
to see if this changes over time. Lastly, biographical and social were the two most posted content types, also consistent with
plastic surgery and orthopedic literature [24, 25, 27]. Additionally, awards and/or the Match
followed by social, class, and surgical were the most engaged content. Although not all catego-
ries were the same, our results are consistent with plastic surgery literature with social posts
and accolades (like awards/match) being of high importance [11, 28]. PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 Discussion The emphasis on social
content may be a consequence of prohibited in-person interaction because of the COVID pan-
demic and may allow applicants to determine program ‘fit’. It is important to also highlight the least popular or engaged content includes advocacy,
research, diversity, and wellness (Figs 1, 2 and 5). These items typically showcase unique pro-
gram aspects that may distinguish programs from one another for applicants, but, unfortu-
nately, are the least emphasized. Diversity, equity, and inclusion (DEI) has become integral in
promoting and celebrating an environment of diversity for residents, faculty, staff, and patients
which is promoted by ACOG DEI Excellence Workgroup [29]. Despite this, 40% of all
OBGYN programs did not have one Instagram post about diversity. This finding may reflect
resident run accounts emphasizing a social atmosphere rather than the structured content one
may expect from a content manager or faculty. In plastic surgery literature, it was shown that
posts with a greater average Fitzpatrick skin type had a greater number of likes, the opposite of
our study [11]. However, as the authors point out, this is a subjective measure and did not eval-
uate diversity in its entirety. Our study sought to identify posts including many forms of diver-
sity. Additionally, plastic surgery literature is congruent in our results showing wellness is in
the minority posted, despite the recent emphasis on combating burnout in medicine [30]. 9 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Ultimately, programs should consider including content that represents their program’s
unique aspects and core values. Post accuracy also should be of great importance to programs. A negative impact on appli-
cant’s perception of a residency program in both orthopedic and plastic surgery literature has
been secondary to a program’s social media [8, 25]. Specifically, 11% of plastic surgery appli-
cants never trusted a program’s social media information or posts [8]. In our study, 31% of
social media accounts reported a different program type than that listed on FREIDA. This
either reflects an inaccuracy in the FREIDA database or those who post the content, 90% of
which were resident run, among programs who responded. While this may reflect a poorly
updated FREIDA database, it is important to ensure that there is accuracy in what is being
posted online, especially if programs are placing this burden on residents. Discussion Unfortunately, social media training is variable and professional guidelines are lacking [31]. The American College of Surgeons released a social media statement including a review of 7
national and international organizations, most notably American Medical Association (AMA)
and ACOG, which highlights professional web page content and appropriate communication
between physicians, patients, and colleagues on social media but not in regards to residency
recruitment [32–34]. Neither AMA nor National Resident Matching Program (NRMP) have
defined appropriate social media interactions between applicants and programs. Despite this,
social media has been used to vet residency applicants. In one study on focused on general sur-
gery, 18% of program directors reported screening applicants through social media. Further-
more, 11% of program directors lowered or removed an applicant from their rank list due to
unprofessional content [35]. In another study, at least 15% of plastic surgery applicant respon-
dents were concerned that engaging with a program’s social media would attract attention to
their own [8]. Overt bias and judgement related to social media content posted by trainees per-
sonal accounts can even be found in recent academic literature [36]. A council of residency directors in Emergency Medicine was the first and only specialty to
create social media guidelines in 2014 [37]. These guidelines recommend content should be des-
ignated to a content manager, not a trainee, to ensure professional communications and accurate
content as violations can interfere with privacy, patient confidentiality, and impartial recruit-
ment, and to employ a uniform policy to screen applicants, if performed, to decrease bias [37]. Program directors should heavily consider whether screening applicants’ social media is benefi-
cial to recruitment and if residents should bear the responsibility of posting social media content
[37]. The authors believe all specialties should consider adopting social media guidelines. Our study is the first OBGYN study to evaluate residency posted content in relation to likes
to assess what content is the most engaged instead of content to solely followers. It also uniquely
examines highlight reels and diversity posts, both of which were associated with more followers. Our study has limitations. First, there was no way to distinguish a follower’s background or
which users were liking content. Thus, our findings, while reflective of general popularity and
engagement, do not necessarily reflect residency applicants’ interactions with social media. Discussion Further, some applicants may be afraid of having their own accounts discovered and change
their social media profiles during recruitment season [8]. Second, we were only able to ascer-
tain who runs half of the total social media accounts identified either by direct message or as
identified in their profile (N = 128/262). Therefore, although a majority were identified as resi-
dent run, this may not reflect all OBGYN accounts. S2 Fig. Definitions of highlight reel content.
(DOCX) S1 Table. Factors associated with likes on Instagram. Factors including program size, city
size, program type, and content were evaluated to identify any association of likes for posts on
Instagram. A multilinear regression model was used to calculate the beta estimate, or differ-
ence in likes per factor. (DOCX) S1 Table. Factors associated with likes on Instagram. Factors including program size, city
size, program type, and content were evaluated to identify any association of likes for posts on
Instagram. A multilinear regression model was used to calculate the beta estimate, or differ-
ence in likes per factor. (DOCX) S2 Table. Content linear mixed model. False discovery rate (FDR) model showing multivari-
ate comparisons between content with only significant associations included in the following
table. (DOCX)
S1 Data. (XLSX) S2 Table. Content linear mixed model. False discovery rate (FDR) model showing multivari-
ate comparisons between content with only significant associations included in the following
table. (DOCX)
S1 Data. (XLSX) Acknowledgments A special thanks Emily Jacobs, MD (University of Iowa, Department of Obstetrics and Gyne-
cology) for aid in conceptualization. A special thanks Emily Jacobs, MD (University of Iowa, Department of Obstetrics and Gyne-
cology) for aid in conceptualization. Supporting information Supporting information
S1 Fig. Definitions of post content. (DOCX)
S2 Fig. Definitions of highlight reel content. (DOCX)
S1 Table. Factors associated with likes on Instagram. Factors including program size, city
size, program type, and content were evaluated to identify any association of likes for posts on
Instagram. A multilinear regression model was used to calculate the beta estimate, or differ-
ence in likes per factor. (DOCX)
S2 Table. Content linear mixed model. False discovery rate (FDR) model showing multivari-
ate comparisons between content with only significant associations included in the following
table. (DOCX)
S1 Data. (XLSX) Conclusions Understanding what social media content attracts more followers and increases engagement is
crucial as resident recruitment may be impacted by content posted by OBGYN programs. 10 / 13 PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
May 6, 2024 PLOS ONE Social media trends OBGYN residencies Programs should consider following more profiles and posting social and awards and/or the
Match content as this may increase followers and engagement. Our findings highlight the
need for social media content that accurately reflects residency and departmental mission
statements, is pertinent to what applicants are seeking from a program and maintains profes-
sionalism. Ultimately, national bodies and residency programs should consider establishing
professional social media guidelines for the protection of both residents and applicants. PLOS ONE | https://doi.org/10.1371/journal.pone.0296930
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May 6, 2024
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Physical activity is inversely related to drug consumption in elderly patients with cardiovascular events
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European review of aging and physical activity/European review on aging and physical activity
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Physical activity is inversely related to drug consumption
in elderly patients with cardiovascular events Francesco Cacciatore & Francesca Mazzella & Luisa Viati &
Giancarlo Longobardi & Antonio Magliocca & Claudia Basile &
Livia Guadagno & Nicola Ferrara & Franco Rengo & Pasquale Abete Received: 3 July 2012 /Accepted: 20 April 2013 /Published online: 8 May 2013
# European Group for Research into Elderly and Physical Activity (EGREPA) 2013 Abstract Elderly patients with cardiovascular events are char-
acterized by high drug consumptions. Whether high drug
consumptions are related to physical activity is not known. In
order to examine whether physical activity is related to drug
consumption in the elderly, patients older than 65 years (n=
250) with a recent cardiovascular event were studied. Physical
activity was analyzed according to the Physical Activity Scale
for the Elderly (PASE) score and related to drug consumption. PASE score was 72.4±45.0 and drug consumption was 8.3±
2.2. Elderly patients with greater comorbidity took more drugs
(8.7±2.1) and are less active (PASE=64.4±50.6) than patients
with Cumulative Illness Rating Scale severity score higher
than 1.8 than those with a score lower than 1.8 (76.3±41.4, p
<0.05, and 8.0±2.0, p=0.006, respectively). Multivariate anal-
ysis correlation confirmed that PASE score is negatively asso-
ciated with drug consumption (β=−0.149, p=0.031),
independently of several variables including comorbidity. Thus, physical activity is inversely related to drug consump-
tion in elderly patients with cardiovascular events. This inverse
relationship may be attributable to the high degree of comor-
bidity observed in elderly patients in whom poor level of
physical activity and high drug consumption are predominant. Keywords Physical activity . Drug consumption . Elderly . Cardiovascular event Keywords Physical activity . Drug consumption . Elderly . Cardiovascular event Eur Rev Aging Phys Act (2013) 10:151–156
DOI 10.1007/s11556-013-0130-z Eur Rev Aging Phys Act (2013) 10:151–156
DOI 10.1007/s11556-013-0130-z ORIGINAL RESEARCH F. Cacciatore: F. Mazzella: L. Viati: G. Longobardi: N. Ferrara:
F. Rengo
Istituto Scientifico di Campoli/Telese, Fondazione Salvatore
Maugeri, IRCCS, Benevento, Italy F. Cacciatore, F. Mazzella, L. Viati, G. Longobardi, A. Magliocca, C.
Basile, L. Guadagno: Collecting data and prepare statistical data. N.
Ferrara, F. Rengo: Data interpretation. P. Abete: Perform the
manuscript. F. Cacciatore: A. Magliocca: C. Basile: L. Guadagno:
N. Ferrara: F. Rengo: P. Abete (*)
Dipartimento di Scienze Mediche Traslazionali, Università degli
Studi di Napoli “Federico II”, Naples 80131, Italy
e-mail: p.abete@unina.it F. Cacciatore: F. Mazzella: L. Viati: G. Longobardi: N. Ferrara:
F. Rengo
Istituto Scientifico di Campoli/Telese, Fondazione Salvatore
Maugeri, IRCCS, Benevento, Italy
F. Cacciatore: A. Magliocca: C. Basile: L. Guadagno:
N. Ferrara: F. Rengo: P. Abete (*)
Dipartimento di Scienze Mediche Traslazionali, Università degli
Studi di Napoli “Federico II”, Naples 80131, Italy
e-mail: p.abete@unina.it Introduction Epidemiologic studies clearly demonstrate that cardiovascu-
lar diseases are the leading cause of morbidity and mortality
in most countries [25]. Moreover, a rise in cardiovascular
disease mortality rates is expected in developing countries
over the next 25 years due to the increase of the aging
population [25]. Indeed, the vast majority of people aged
≥65 years is characterized by a condition of comorbidity and
disability [6, 32]. Both conditions lead to a frailty state and,
therefore, to high drug consumption [5, 29]. F. Cacciatore, F. Mazzella, L. Viati, G. Longobardi, A. Magliocca, C. Basile, L. Guadagno: Collecting data and prepare statistical data. N. Ferrara, F. Rengo: Data interpretation. P. Abete: Perform the
manuscript. F. Cacciatore, F. Mazzella, L. Viati, G. Longobardi, A. Magliocca, C. Basile, L. Guadagno: Collecting data and prepare statistical data. N. Ferrara, F. Rengo: Data interpretation. P. Abete: Perform the
manuscript. Elderly subjects represent 13 % of the US population, but
receive 34 % of all drug prescriptions [31]. One recent large
survey of community-dwelling subjects showed that more
than 90 % of individuals aged ≥65 years took at least one
drug weekly, more than 40 % used five or more drugs
weekly, and 12 % used ten or more drugs weekly [18]. In
the UK, elderly patients take on average two to five pre-
scription medications on a regular basis (4±1), and
polypharmacy occurs in 20–50 % of patients [19]. Electronic supplementary material The online version of this article
(doi:10.1007/s11556-013-0130-z) contains supplementary material,
which is available to authorized users. To reduce drug use in the elderly population, several types
of interventions and strategies have been tested, including
educational interventions (i.e., continuing medical education) Eur Rev Aging Phys Act (2013) 10:151–156 152 depending on his or her need for help, such as in feeding,
bathing, dressing, and walking. Total scores range from 0 to
100, with higher scores indicating a greater degree of indepen-
dence [9]. The 6-min walking test (6MWT) was performed on
the second day after hospital admission in all patients and, in
any case, within the first week after hospitalization. Patients
were instructed to walk as far as possible along a 40-m straight,
flat hospital corridor in 6 min [22]. The test was symptom-
limited, so patients who became symptomatic (e.g., angina,
severe dyspnea, dizziness, and musculoskeletal pain) were told
to stop walking and restart when possible. Introduction However, among other interventions aiming at the re-
duction of drug consumption, physical activity can be consid-
ered a good candidate. In fact, cardiorespiratory fitness (at
least 30 min or more of moderate-intensity physical activity
daily) appears as the strongest prognostic marker in persons
with and without cardiovascular diseases [16]. In addition, a
growing body of literature suggests that physical activity
improves depressive symptoms, dementia, disability, and
frailty and reduces mortality in elderly patients [17, 20]. To our knowledge, no data are available on the relation-
ship between physical activity and drug consumption in the
elderly. Thus, the aim of our study was to assess whether the
degree of physical activity was associated with the number
of drugs assumed in the elderly population undergoing a
cardiac rehabilitation program after a cardiovascular event. Introduction Of the 250 enrolled
patients, 24 (9.6 %) were not able to perform the 6-min walking
test. These patients were not excluded, but their score was
considered equal to 0. The test was supervised by a physical
therapist who encouraged the patients in a standardized fashion
at regular intervals. The total distance walked was measured to
the nearest meter and recorded. The results of the 6MWT are
given as absolute values in meters. Severity of comorbid con-
ditions was evaluated by means of the Cumulative Illness
Rating Scale (CIRS) [10]. The CIRS is accepted to be a valid
and reliable measure of multiple morbidities. The index quan-
tifies the burden of chronic illness in a patient by taking into
account the number and severity of different illnesses across 14
anatomical and physiological systems. Each condition identi-
fied was rated on a scale from 0 to 4, where 0 indicates that
there is no problem affecting that system, 1 indicates a mild
current problem or a past significant problem, 2 indicates a
moderate problem requiring first-line therapy, 3 indicates a
severe problem that may be associated with significant disabil-
ity or is hard to control, and 4 indicates an extremely severe
problem, organ failure, or severe functional impairment. Equi-
librium and risk of fall were measured with the Tinetti Scale
[33]. Social support evaluation with Social Support Assessment
was scored from 4 (subjects with the highest support) to 1
(subjects with the lowest support) [23]. Neuro-sensitive evalu-
ation with hearing impairment was scored from 1 (no hearing
problem) to 4 (total deafness) [4]. Visual impairment was
scored from 1 (no visual impairment) to 4 (blindness) [7]. Urinary and fecal incontinence was also assessed. Usual phys-
ical activity performed before cardiac surgery was assessed by
means of the Physical Activity Scale for the Elderly (PASE)
[35] on the second day after hospital admission in all patients
and, in any case, within the first week. The PASE is a brief
(5 min) and easily scored survey designed specifically to assess
physical activity in epidemiologic studies of persons aged
65 years and older. The PASE assesses physical activity over
a 1-week time frame. Participation in leisure activities, includ-
ing walking outside the home; light, moderate, and strenuous
sport and recreation; and muscle strengthening were recorded
as never, seldom (1–2 days/week), sometimes (3–4 days/week), [28]. Study population The study enrolled 250 elderly (≥65 years) consecutive pa-
tients admitted after cardiac surgery between January 2008
and July 2009 to the Division of Cardiac Rehabilitation. The
study received full ethical approval from the “Research Ethics
Committee.” All participants signed an informed consent
form, and the institutional review boards of all participating
institutions approved the study. The demographic and clinical
variables of these patients were obtained at entry in the Divi-
sion of Cardiac Rehabilitation Center. The following data
were collected: age, sex, type of cardiac surgery (coronary
artery bypass grafting—CABG or valve surgery), off-pump
CABG, presence of coronary artery disease (CAD), chronic
heart failure (CHF), previous stroke, chronic obstructive pul-
monary disease (COPD), diabetes, and renal failure (creati-
nine level≥2.0 mg/dl). The total number of drug and the type
of drug used were assessed at entry. All procedures followed were in accordance with the eth-
ical standards of the responsible committee on human exper-
imentation (institutional and national) and with the Helsinki
Declaration of 1975, as revised in 2000. Informed consent was
obtained from all patients for inclusion in the study. Comprehensive geriatric multidimensional evaluation Comprehensive geriatric multidimensional evaluation Patients underwent a comprehensive geriatric multidimensional
evaluation within the third day after admission, which included
cognitive function evaluation with the Mini Mental State Ex-
amination [24] and evaluation of depressive symptoms with the
Geriatric Depression Scale [36]. Disability was assessed by
means of the Barthel Index, which evaluates a patient’s self-
care abilities in ten areas, including bowel and bladder control. The patient is scored from 0 to 15 points in various categories Eur Rev Aging Phys Act (2013) 10:151–156 153 Table 1 Baseline characteristics of the 250 patients enrolled in the
study Table 1 Baseline characteristics of the 250 patients enrolled in the
study recorded in total hours per week. Housework (light and heavy),
lawn work/yard care, home repair, outdoor gardening, and
caring for others are recorded as yes/no. Frequency and dura-
tion of household activities were not requested. The total PASE
score was computed by multiplying the amount of time spent in
each activity (hours/week) or participation (yes/no) in an activ-
ity by the empirically derived item weights and summing over
all activities. Table 1 Baseline characteristics of the 250 patients enrolled in the
study
Age (years±SD)
73.3±4.8
Female sex, n (%)
120 (48.0)
BMI (kg/m2)
27.5±5.7
Waist circumference (cm)
103.7±11.5
CABG, n (%)
194 (77.6)
Valve surgery, n (%)
80 (32.0)
Off-pump CABG, n (%)
152 (60.8)
Geriatric multidimensional evaluation
MMSE (score)
23.3±4.9
GDS (score)
3.9 ±2.5
Tinetti score
9.3±4.3
Visual impairment, n (%)
103 (41.2)
Hearing impairment, n (%)
44 (17.6)
Social support score
5.6±2.6
PASE
72.4±45.0
Barthel Index
74.0±21.5
6-min walking test
190.9±95.5
Comorbidities
CIRS severity score
1.8±0.4
CHF, n (%)
10 (4.0)
CAD, n (%)
202 (80.8)
Stroke, n (%)
30 (12.0)
COPD, n (%)
106 (42.4)
Diabetes, n (%)
142 (56.8)
Renal failure, n (%)
34 (13.6)
Drug consumption
Total drugs used
8.3±2.2
Diuretic, n (%)
223 (89.2)
ASA, n (%)
178 (71.2)
ACE inhibitors, n (%)
144 (57.6)
Statins, n (%)
136 (54.4)
Bisoprolol, n (%)
110 (44.0)
Amiodaron, n (%)
73 (29.2)
Carvedilol, n (%)
66 (26.4)
Steroids, n (%)
66 (26.4)
Metformin, n (%)
65 (26.0)
Warfarin, n (%)
52 (20.8)
Insulin, n (%)
51 (20.4)
Nitrates, n (%)
51 (20.4)
CABG coronary artery bypass grafting, PASE Physical Activity Scale
for the Elderly, CIRS Cumulative Index Rating Scale, CAD coronary
artery disease COPD chronic obstructive pulmonary disease Statistical analysis Continuous variables are expressed as the mean±SD. Cate-
gorical data are expressed as frequencies and percentages. Univariate analysis (ANOVA) examined the differences in
drug use in patients with and without CABG, off-pump
CABG, valve surgery, heart failure, CAD, stroke, COPD,
diabetes, and renal failure. Univariate regression analysis
was used to find a correlation among the number of drugs
used and other variables such as age, female sex, MMSE and
GDS scores, CIRS score, Barthel Index, 6MWT, PASE,
CABG, Op-CABG, valve surgery, CAD, CHF, stroke, COPD,
diabetes, and renal failure. Multiple linear regressions among
the number of drugs used and variables were found significant
at univariate analysis. CIRS was also included into the multi-
variate regression model as a potential confounder. All statistical analyses were performed with SPSS soft-
ware (version 15.0, SPSS Inc., Chicago, IL). A value of p
<0.05 was considered statistically significant. CABG coronary artery bypass grafting, PASE Physical Activity Scale
for the Elderly, CIRS Cumulative Index Rating Scale, CAD coronary
artery disease, COPD chronic obstructive pulmonary disease Measure of outcomes Each active ingredient was considered as a drug; the total
number of drugs was evaluated at entry to the Division of
Cardiac Rehabilitation. We measured specifically the use of
β-blockers (bisoprolol, atenolol, sotalol), digoxin, diuretic,
ACE inhibitors, angiotensin receptor inhibitors, nitrates,
alpha-blockers, amiodaron, dihidropiridines, diltiazem, ve-
rapamil, metformin, glibenclamide, repanglide, insulin,
ASA, warfarin, steroids, theophylline, and statins. Drugs
consumed over 20 % were reported in Table 1. Other drugs
were counted and assessed as total number of drugs. Polypharmacy in the elderly Polypharmacy in the elderly Surveys of community-based elderly patients indicate that two
to nine prescription medications on average are taken per day
[15]. It has been found that 57 % of US women aged ≥65 years
took five or more prescription medications, while 12 % took ten
or more medications [18]. Similarly, a large study in Europe
found that 51 % of patients took six or more medications per
day [13]. Accordingly, in our study, the number of drugs used
was 8.3±2.2. It should also underline the types of medications
that are being consumed. A large national survey found that the
most common drugs used in non-institutionalized patients were
estrogen products, levothyroxine, hydrochlorothiazide, atorva-
statin, and lisinopril [18], while cardiovascular agents, antibi-
otics, diuretics, opioids, and antihyperlipidemics were the most
frequently used drugs in Medicare patients [14]. Similarly, in
our sample, diuretics, followed by salicylate and angiotensin-
converting enzyme inhibitors, were the drugs more commonly
used. Table 2 Univariate and multivariate linear regression on drug
consumption
Variable
Univariate
Multivariate
β
p
β
p
Age
0.176
0.005
0.163
0.031
Sex (female)
−0.021
0.739
–
–
GDS
0.301
0.000
0.254
0.000
PASE
−0.219
0.000
−0.150
0.031
Barthel Index
−0.143
0.024
0.053
0.536
6MWT
−0.153
0.016
0.041
0.636
CIRS
0.099
0.118
0.095
0.159
MMSE
−0.104
0.111
–
–
CABG
0.164
0.009
0.089
0.370
OPCABG
0.076
0.232
–
–
Valve surgery
−0.116
0.066
–
–
CHF
−0.044
0.487
–
–
CAD
0.173
0.006
0.092
0.336
Stroke
0.023
0.713
–
–
COPD
0.151
0.017
0.051
0.457
Diabetes
0.205
0.001
0.090
0.165
Renal failure
0.212
0.001
0.160
0.016
GDS Geriatric Depression Scale, PASE Physical Activity Scale for the
Elderly, 6MWT 6-min walking test, CABG coronary artery bypass
grafting, CAD coronary artery disease, COPD chronic obstructive
pulmonary disease Table 2 Univariate and multivariate linear regression on drug
consumption Many consequences may be associated with polypharmacy. Patients are at an increased risk of having an adverse drug
reaction (ADR), geriatric syndromes, and morbidity/mortality. The risk of ADRs may increase with increased number of drugs
taken and with age-related pharmacodynamic alterations [12]. ADRs, defined as noxious and unintended reactions which
occur at dosages normally used in humans for prophylaxis,
diagnosis, or therapy, have been reported to occur in 5–35 %
of outpatients and account for 12 % of hospital admissions in
older patients [14, 15, 26]. Results The sample consisted of 250 elderly patients (mean age=73.3
±4.8 years, range=65–89 years); 120 (48.0 %) were women. One hundred seventy (68 %) underwent cardiac surgery for
CABG, 24 patients (9.6 %) had CABG and valve replacement
(n=20 aorta valve, n=4 mitral valve), while 56 (22.4 %) had
valve replacement (n=38 aorta, n=16 mitral valve replace-
ment). In two patients, both valves were replaced. Off-pump
CABG was used in 152 (89.4 %) patients. Baseline measurements, geriatric multidimensional eval-
uation, comorbidities, and drug consumption are presented
in Table 1. Prevalence of comorbidity was high in this
population considering the 80.8 % prevalence of CAD,
12.0 % of stroke, 42.4 % of COPD, 56.8 % of diabetes,
4 % of CHF, and 13.6 % of renal failure. CIRS severity Eur Rev Aging Phys Act (2013) 10:151–156 154 Fig. 1 Linear correlation between physical activity (PASE score) and
number of drug consumption in elderly patients with cardiovascular
events score was 1.8±0.4, but 33.6 % had a CIRS severity score
>1.8. PASE score was 72.4±45.0 (range=0–192), Barthel
Index was 74.0±21.5 (range=0–100), while 6MWT was
190.9±95.5 m (range=0–401). Mean drug consumption
was 8.3±2.2 (range=4–14). The highest drug consumption
was diuretic (89.2 %), followed by salicylate (71.2 %) and
angiotensin-converting enzyme inhibitors (57.6 %; Table 1). Moreover, in elderly patients with CIRS severity score
higher than 1.8, the PASE score was lower (64.4±50.6)
and drug consumption higher (8.7±2.1) than those with
CIRS severity score lower than 1.8 (76.3±41.4, p<0.05;
8.0±2.0, p=0.006, respectively). Fig. 1 Linear correlation between physical activity (PASE score) and
number of drug consumption in elderly patients with cardiovascular
events Linear regression analysis demonstrates that age and
GDS score were positively while PASE, Barthel Index,
and 6MWT were negatively correlated with drug con-
sumption (Table 2). When the PASE score is plotted
with drug consumption, a significant inverse linear re-
lation was observed (y=−8.4+146.7x, r=0.38, p<0.001;
Fig. 1). Accordingly, multivariate linear regression con-
firmed that age, GDS score, and renal failure are posi-
tively associated while, more importantly, the PASE
score is negatively, and more importantly, independently
associated with drug consumption, independently of
CIRS severity (Table 2). Discussion Our study demonstrates that physical activity is inversely
related to drug consumption in elderly subjects with cardio-
vascular events undergoing cardiac surgery. These results
demonstrate that physical activity is inversely associated in-
dependently with several variables, including comorbidity. Interventions to reduce polypharmacy in the elderly Risk factors of polypharmacy have been identified and clas-
sified into three groups: demographic (increased age, white
race, and education); health status (depression, hypertension,
anemia, asthma, angina, diverticulosis, osteoarthritis, gout,
and diabetes mellitus); and access to health care (number of
health care visits, supplemental insurance, and multiple pro-
viders) [15]. In particular, pharmacodynamic and pharmaco-
kinetic alterations with advancing age have been observed
[12]. In our sample, drug consumption was inversely related
to physical activity in univariate analysis. More importantly,
an inverse relationship was confirmed at multivariate analysis
independently by several variables, including diseases highly
prevalent in the elderly (i.e., COPD and diabetes). We conclude that physical activity is inversely related to
drug consumption in elderly patients with cardiovascular
events undergoing cardiac surgery. This inverse relationship
may be attributable to the high degree of comorbidity ob-
served in elderly subjects with poor level of physical
activity. Conflict of interest
F. Cacciatore, F. Mazzella, L. Viati, G. Longo-
bardi, A. Magliocca, C. Basile, L. Guadagno, N. Ferrara, F. Rengo, P. Abete declare that they have no conflict of interest. In addition, the greater comorbidity severity observed in
our cohort was associated with elevated drug consumption
and low physical activity. The presence of a high degree of
comorbidity may surely influence poor physical activity and
the large number of drugs consumed. This scenario is wors-
ened by a superimposed aging process which is associated
with physiologic changes that naturally predispose older
adults to progressive weakening, functional decline, mor-
bidity, disability, poor quality of life, and increased mortality
[30]. In contrast, regular exercise provides many physiolog-
ic benefits, reduces risk of disease outcomes, and triggers
important psychological gains [1, 11]. There is strong evi-
dence that regular physical activity reduces the risk of
cardiovascular disease and, therefore, the increased related
drug consumption [3]. Because of the preventive effects on
cardiovascular disease, physical activity has beneficial ef-
fects on functional limitations and health-related quality of
life in older adults, such as drug consumption. Informed consent
All subjects were fully informed of the proce-
dures involved and provided written consent. Ethical statement
The study was performed in accordance with the
ethical standards laid down in the World Medical Association’s Dec-
laration of Helsinki on medical research involving human subjects. References 1. Abete P, Ferrara N, Cacciatore F, Sagnelli E, Manzi M, Carnovale
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is strongly associated with multiple comorbidities [15], as 155 Eur Rev Aging Phys Act (2013) 10:151–156 cognitive impairment [34]. In addition, regularly active per-
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