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Methods
In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed
PMC10533414
Findings
ADVERSE EVENTS, ADVERSE EVENT
Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4–22) in patients treated with dihydroartemisinin–piperaquine alone versus 21% (11–34) in...
PMC10533414
Interpretation
Although tafenoquine plus dihydroartemisinin–piperaquine was statistically superior to dihydroartemisinin–piperaquine alone for the radical cure of
PMC10533414
Funding
MALARIA
ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK.
PMC10533414
Translation
For the Indonesian translation of the abstract see Supplementary Materials section.
PMC10533414
Research in context
RELAPSE
The efficacy of a single 300-mg dose of tafenoquine co-administered with chloroquine for the radical cure of This is the first clinical study to evaluate the efficacy and safety of a single 300-mg dose of tafenoquine co-administered with dihydroartemisinin–piperaquine for the radical cure of This study does not supp...
PMC10533414
Methods
PMC10533414
Study design and participants
infection
INFECTION, SECONDARY
This double-blind, double-dummy, randomised, parallel group study enrolled soldiers from two battalions based in East Java (battalion 1 at Malang; battalion 2 at Madiun; Patients were eligible for enrolment if they were male, aged at least 18 years, had microscopically confirmed The main exclusion criteria were severe ...
PMC10533414
Randomisation and masking
Eligible patients were randomly assigned in a 1:1:1 ratio to dihydroartemisinin–piperaquine alone, dihydroartemisinin–piperaquine plus tafenoquine, or dihydroartemisinin–piperaquine plus primaquine. All patients received open-label dihydroartemisinin–piperaquine for 3 days plus masked treatment as follows: tafenoquine ...
PMC10533414
Procedures
malaria
MALARIA, BLOOD, RELAPSE
Study treatments were supplied by the sponsor as eurartesim tablets containing dihydroartemisinin 40 mg and piperaquine 320 mg (Alfasigma, Bologna, Italy), tafenoquine 150-mg tablets (GSK, London, UK), and primaquine formulated as over-encapsulated 15-mg tablets (Sanofi-Aventis, Bridgewater, NJ, USA). All patients rece...
PMC10533414
Outcomes
infection, recrudescence, infections, fever
RECURRENCE, ADVERSE EVENTS, INFECTIONS, INFECTION, CYP2D6 POLYMORPHISM
The primary outcome was relapse-free efficacy over 6 months, defined as clearance of initial infection without subsequent microscopically confirmed recurrence or receipt of other antimalarial treatment. Secondary outcomes were relapse-free efficacy over 4 months, time to fever clearance, time to parasite clearance, and...
PMC10533414
Statistical methods
The primary comparison of interest was relapse-free efficacy over 6 months for tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin–piperaquine alone. By means of the log-rank test for the primary comparison to detect a clinically meaningful difference of 35% in relapse-free survival rates over 6 m...
PMC10533414
Role of the funding source
The study sponsor (GSK) was responsible for study monitoring, data management, data analysis, and writing of the clinical report.
PMC10533414
Results
REGRESSION, DRUG-INDUCED LIVER INJURY, ADVERSE EVENT, ADVERSE EVENTS
Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned to masked study treatment; 50 per treatment group (battalion 1 n=69; battalion 2 n=81; Trial profileALT=alanine aminotransferase. DP=dihydroartemisinin–piperaquine. mITT=microbiological intention-to-treat. PP=pe...
PMC10533414
Discussion
malaria, deaths
MALARIA, ADVERSE EVENT
This is the first study to evaluate the efficacy and safety of a single 300-mg dose of tafenoquine co-administered with an artemisinin-based combination therapy for the radical cure of The reasons for the lack of clinically relevant efficacy with tafenoquine plus dihydroartemisinin–piperaquine are unknown. Although no ...
PMC10533414
Data sharing
Within 6 months of this publication, anonymised individual patient data, the annotated case report form, protocol, reporting and analysis plan, dataset specifications, raw dataset, analysis-ready dataset, and clinical study report will be available for research proposals approved by an independent review committee. Pro...
PMC10533414
Declaration of interests
IS reports grants or contracts from Menzies School of Health Research, Darwin and the National Health and Medical Research Council
PMC10533414
References
PMC10533414
Supplementary Materials
PMC10533414
Indonesian translation of the abstract
PMC10533414
Supplementary appendix 2
PMC10533414
Acknowledgments
The trial was designed and funded by MMV and supported by the sponsor GSK. The protocol was drafted by GSK with input from MMV and the Indonesian study team. MMV was funded by various donors for this trial including ExxonMobil and the Bill & Melinda Gates Foundation (grant number INV-007155/19-BMGF-006), Newcrest Minin...
PMC10533414
Contributors
SD
IS was the principal investigator and JKB was responsible for study conceptualisation. JKB, IS, AS, LLE, RN, AWS, WB, SL, IE, JAG, J-PK, SD, EC, SJ, MT, and NG contributed to the study design and protocol development. SD and LKT were responsible for funding acquisition. LKT, SD, HS, AM, and EC were responsible for the ...
PMC10533414
Background
HAT
AFRICAN TRYPANOSOMIASIS
Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference l...
PMC10026442
Method
The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero-
PMC10026442
Results
The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95%
PMC10026442
Graphical Abstract
PMC10026442
Keywords
PMC10026442
Background
Infection
EBOLA, INFECTION
Infection with the parasite Despite considerable challenges, Guinea implements an efficacious HAT control program based on medical interventions supplemented with vector control. Even during the Ebola epidemic outbreak in 2014–2016, the national HAT control program managed to deploy insecticide impregnated targets in B...
PMC10026442
Methods
PMC10026442
Study setting
AFRICAN TRYPANOSOMIASIS
In Guinea, clinical suspects were prospectively recruited for the Diagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2 (DiTECT-HAT-WP2) study between January 2017 and January 2020 in 14 hospitals and health posts in the prefectures of Boffa, Dubreka and Forecariah. In these ...
PMC10026442
Study protocol
The study protocol is summarized in Fig. DiTECT-HAT-WP2 study conduct and test results in Guinea.
PMC10026442
Inclusion criteria
confusion, itching, convulsions, aggressiveness, abnormal movements, amenorrhea, motor disorders, psychiatric, coma, insomnia, headache, abortion, weight loss, apathy
STERILITY, SPEECH DISORDERS, MOTOR DISORDERS, RECURRENT FEVER, COMA
Individuals consulting the study SSS or CDT could be consecutively included if they had visited or resided in a HAT endemic area and presented with clinical suspicion for HAT. Clinical suspicion was defined as presence of at least one of the following clinical signs or symptoms: Recurrent fever not responding to anti-m...
PMC10026442
Serological screening and parasitological confirmation
Finger prick blood was tested with 3 RDTs, HAT Sero-
PMC10026442
Dried blood spot preparation
LYSED, ALDRICH
For every serological suspect two types of DBS were prepared. On a Whatman grade 4 filter paper, 16 drops of 30 µl of heparinized blood were deposited and left to dry. In parallel, 180 µl of heparinized blood were lysed for 5 min with 20 µl of 5% SDS solution (Sigma Aldrich, Saint Louis, MO, USA), and 2 drops of 40 µl ...
PMC10026442
Patient management
A lumbar puncture was carried out on parasitologically confirmed HAT patients, or if the clinician considered it appropriate, based on strong clinical suspicion. The cerebrospinal fluid (CSF) was examined for the number of white blood cells, and for presence of trypanosomes using the modified single centrifugation [
PMC10026442
Study participants with missing data
sleeping sickness
SLEEPING SICKNESS
Serological suspects that could not be confirmed at the first microscopic examination, were invited for re-examination at the CDT or were re-examined by the national program. A number of RDT seropositives detected at SSS level and who did not show up at CDT were offered microscopic examination through the national slee...
PMC10026442
Reference laboratory tests
The DBS were sent to the Centre International de Recherche-Développement sur l’Elevage en zone Subhumide (Bobo-Dioulasso, Burkina Faso), where reference laboratory tests were performed. Test performers were not informed about the clinical and reference standard results. On DBS collected on Whatman grade 4 paper, trypan...
PMC10026442
Data analysis
REGRESSION, REGRESSION
Results obtained at the CDT were immediately entered in a digital case report form [Regression analysis and evaluation of the diagnostic performance were based on the participants HAT status (Fig. Regression analysis using Stata Statistical Software (Release 14, College Station, TX: StataCorp LP) was performed to asses...
PMC10026442
Results
PMC10026442
Descriptive statistics of field results
HAT, headache
RECURRENT FEVER, REGRESSION, AFRICAN TRYPANOSOMIASIS
In total, 2353 clinical suspects were included: 707 in the prefecture of Boffa, 705 in Dubreka, and 941 in Forecariah. Of these clinical suspects, 1320 (56.1%) were female and 1033 (43.9%) male. Their median age was 30 years (range: 4–89). The most frequently observed clinical presentations were recurrent fever not res...
PMC10026442
HAT status of study participants
For further analysis of the results, study participants were considered as true HAT positives if they were confirmed as HAT patients based on trypanosome observation during microscopy performed on blood, lymph, or CSF specimens (
PMC10026442
Clinical symptoms and signs associated with HAT, regression analysis
motor disorders, HAT, coma, Coma
MOTOR DISORDERS, AFRICAN TRYPANOSOMIASIS, COMA, COMA
The frequency of the different inclusion clinical symptoms and signs, in HAT (Frequency of 13 clinical symptoms and signs in human African trypanosomiasis (HAT) and non-HAT affected study participants. The figure contains data for 48 HAT and 2297 non-HAT participants with the exception of * only 19 HAT and 1294 non-HAT...
PMC10026442
Diagnostic performance of clinical presentation
HAT, itching, weight loss, weight loss and motor disorders
MOTOR DISORDERS, AFRICAN TRYPANOSOMIASIS
The diagnostic performance of (co-)occurrence of the 4 clinical symptoms and signs that were associated singly or in combination with HAT, namely enlarged lymph nodes in the neck, severe itching, important weight loss and motor disorders, was studied in function of the HAT status in 48 HAT and 2297 non-HAT affected stu...
PMC10026442
Diagnostic performance of rapid diagnostic tests
HAT
AFRICAN TRYPANOSOMIASIS
For estimation of the RDT diagnostic performance in 48 HAT and 2297 non-HAT clinical suspects, a few participants had partially missing RDT results (Table The diagnostic performance of 3 rapid diagnostic tests for diagnosis of human African trypanosomiasis (HAT)The individual diagnostic sensitivity, specificity, positi...
PMC10026442
Diagnostic performance of reference laboratory tests on dried blood spots
Among the 48 HAT patients, 34/48 had a DBS and all 4 DBS test results were available for 33/34, while 1/34 HAT patient missed a LAMP result. Among the 66 RDT positive HAT negatives (Fig. Reference laboratory test results on dried blood spots. The Venn diagram shows the results of trypanolysis, ELISA/Table The diagnosti...
PMC10026442
Discussion
The HAT prevalence observed among the study participants during the 3 years of passive screening was 2.0%. The overall HAT prevalence reported by the national program in passive screening in the same prefectures in 2017 and 2018 was respectively 0.98 and 0.39% [Although there may be geographical and stage specific vari...
PMC10026442
Conclusions
In passive case detection, we can propose to health workers and clinicians in Guinean HAT endemic areas a relatively simple set of criteria with high sensitivity for selecting individuals to be further tested using HAT RDTs, which would result in a reduction of almost 70% of the HAT RDTs to be carried out. Performance ...
PMC10026442
Abbreviations
AFRICAN TRYPANOSOMIASIS
Centre for diagnosis and treatmentCerebrospinal fluidDried blood spotDiagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2, passive case detectionEnzyme-linked immunoassayHuman African trypanosomiasisLoopamp Mini anion exchange centrifugation technique on buffy coatNegative p...
PMC10026442
Acknowledgements
We acknowledge staff members of the Guinean HAT National Elimination Program, and the HAT team of the Centre International de Recherche-Développement sur l’Elevage en Zone Subhumide in Bobo-Dioulasso (Burkina Faso). We also acknowledge the health staff members from the health facilities involved in the study.
PMC10026442
Author contributions
All authors participated in writing, reviewing and editing of the draft. VL was responsible for conceptualization, formal analysis, data curation, funding acquisition, methodology, project administration and original draft preparation. OC participated in investigation and methodology. MC was involved in conceptualizati...
PMC10026442
Funding
This study was funded by the EDCTP2 programme supported by the Horizon 2020 European Union funding for Research and Innovation (Grant Number DRIA-2014-306-DiTECT-HAT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PMC10026442
Availability of data and materials
AFRICAN TRYPANOSOMIASIS
The public sharing of personal health data is subject to the General Data Protection Regulation. The health data underlying the findings described in the manuscript can therefore not be made public. Metadata are available via Lejon V, Camara O, Camara M, Ilboudo H, Kaboré J, Compaoré CFA, Buscher P, Bucheton B, 2022, "...
PMC10026442
Declarations
PMC10026442
Ethics approval and consent to participate
MINOR, AFRICAN TRYPANOSOMIASIS
The study in Guinea was part of the multi-country diagnostic clinical trial “Diagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2, passive case detection” (DiTECT-HAT-WP2), registered on ClinicalTrials.Gov under identifier NCT03356665. Before initiation of the study, DiTECT-...
PMC10026442
Consent for publication
Not applicable.
PMC10026442
Competing interests
The authors declare that they have no competing interests.
PMC10026442
References
PMC10026442
Background and Purpose
hearing skills
Use of unilateral cochlear implant (UCI) is associated with limited spatial hearing skills. Evidence that training these abilities in UCI user is possible remains limited. In this study, we assessed whether a Spatial training based on hand-reaching to sounds performed in virtual reality improves spatial hearing abiliti...
PMC10313844
Methods
Using a crossover randomized clinical trial, we compared the effects of a Spatial training protocol with those of a Non-Spatial control training. We tested 17 UCI users in a head-pointing to sound task and in an audio-visual attention orienting task, before and after each training. <br>Study is recorded in clinicaltria...
PMC10313844
Results
During the Spatial VR training, sound localization errors in azimuth decreased. Moreover, when comparing head-pointing to sounds before vs. after training, localization errors decreased after the Spatial more than the control training. No training effects emerged in the audio-visual attention orienting task.
PMC10313844
Conclusions
Our results showed that sound localization in UCI users improves during a Spatial training, with benefits that extend also to a non-trained sound localization task (generalization). These findings have potentials for novel rehabilitation procedures in clinical contexts.
PMC10313844
Supplementary Information
The online version contains supplementary material available at 10.1007/s00405-023-07886-1.
PMC10313844
Keywords
Open access funding provided by Università degli Studi di Trento within the CRUI-CARE Agreement.
PMC10313844
Introduction
BILATERAL HEARING LOSS, NEUROSENSORY DEAFNESS
In case of neurosensory deafness, standard interventions often comprise the application of cochlear implants (CI). Although this surgery is indicated for people with bilateral hearing loss, many patients receive only one CI [In this context of impoverished auditory cues, can CI users improve their sound localization sk...
PMC10313844
Methods
PMC10313844
Participants
neurological or psychiatric, HEH, vestibular deficit
Twenty UCI participants were recruited to participate in the study. Sample size was based on two previous experiments addressing a similar research question with an identical experimental design, but with different populations (normal hearing: [All participants were recruited at the ORL department of the civil hospital...
PMC10313844
Study design
head posture, HMD
The entire experiment was conducted inside VR environment. Participants wore a HMD (resolution: 1080 × 1200 px, Field Of View (FOV): 110°, Refresh rate: 90 Hz) that produced an immersive VR experience: participants always saw a reproduction of the room in which they were located. Importantly, the VR also allowed contin...
PMC10313844
Procedures
PMC10313844
Testing phases
PMC10313844
Head-pointing sound localization task
 In each trial, a single auditory target (3 s white noise burst) was presented from 8 possible pre-determined positions (5 repetitions each, resulting in 40 trials in each testing phase). The 8 positions were placed at 55 cm from the center of the subject’s head and they varied along the azimuth dimension (± 22.5° and ...
PMC10313844
Audio-visual cueing task
 This task aimed to assess to what extent lateralized sound could capture the participant’s audio-visual attention. The task was performed outside VR in the same room of the sound localization task, with participants sat at a desk in front of a computer monitor flanked by speakers. In each trial, a visual disk appeared...
PMC10313844
VR training tasks
Participants were immersed in the same virtual room as the head-pointing sound localization task, but saw 13 virtual loudspeakers spanning ± 72° in front space (see Fig. 
PMC10313844
Spatial VR training
Participants were instructed to reach the speaker emitting the sound using the VR controller they held in their right hand. The sound lasted until the participant reached and ‘touched’ the correct speaker. If they reached the wrong speaker, the correct loudspeaker started to display concentric red beams that expanded f...
PMC10313844
Non-Spatial VR training
Participants were instructed to identify the amplitude modulation in the target sound, and indicate their discrimination through a reaching movement using VR controller. For fast amplitude-modulated sounds, participants reached in front of them, aiming to touch the invisible virtual button placed above the central spea...
PMC10313844
Statistical analysis
head movements
Linear mixed-effect modeling was used for all statistical analyses. Statistical analyses were run using R (version 1.0.143). For the linear mixed-effect (LME) model, we used the R-packages emmean, lme4, lmerTest in R Studio [To study head movements, we extracted three dependent variables: number of head rotations, head...
PMC10313844
Results
PMC10313844
VR training
PMC10313844
Performance
hearing asymmetries, SD
The spatial discrepancy between the stimulated and the reached speaker (i.e., absolute localization error in azimuth, calculated as difference in absolute value between speaker and response position in azimuth in degrees) was on average 24.0 degrees (SD = 14.0), with a numerical (but not-significant) bias toward the si...
PMC10313844
Head movements
head movements
Head rotations were overall more frequent in the Spatial (6.51 ± 3.15) compared to the Non-Spatial VR training (1.5 ± 1.0, During the Spatial VR training, we observed that UCI users adapted their spontaneous head movements as a function of sound eccentricity as training trials progressed. Specifically, number of head r...
PMC10313844
Effects beyond the trained task
PMC10313844
Head-pointing to sounds
PMC10313844
Performance
The Spatial VR training improved performance (i.e., decreased absolute error in azimuth) more than the Non-Spatial training, irrespective of the session in which it was completed (Spatial—pre: 52.6° ± 26.2°; post: 39.3° ± 23.5°; Non-Spatial training—pre: 43.8° ± 27.4°; post: 42.0° ± 27.6°, As documented above, individu...
PMC10313844
Head movements
head movements
In order to describe changes in head movement after training, we measured number of head rotations, head-rotation extent, head-rotation bias and direction of the first head movements during the sound (see Analysis for a description of these variables). We report here the main findings, but see Supplementary Materials f...
PMC10313844
Audio-visual attention orienting task
When people with normal hearing are asked to make a visual discrimination (here on the elevation of the visual target, up vs. down), they are faster when the visual target is preceded by a sound located in the same (congruent) vs. opposite side of the space (incongruent) [
PMC10313844
Discussion
hearing threshold, head movements, head movements’ behavior, head-movement behaviors, hearing asymmetry, hearing in monaural listening conditions [
UNILATERAL HEARING LOSS
We observed that UCI users can improve their sound localization abilities, despite the substantial impoverishment of the available auditory cues. Thus, acoustic space perception improvement is possible also for people using a single CI, at least in the experimental context we have examined. Specifically, we showed that...
PMC10313844
Conclusion
Using a novel VR training based on reaching to sounds, audio-visual feedback and free head movements during listening, we documented that training sound localization ability in UCI users is possible. While these observations emerged in laboratory setting, they have direct translational implications for the clinical con...
PMC10313844
Acknowledgements
P.
BLIND, FOUNDER
We are grateful to all the participants who accepted to participate in this study. C. V. was supported by a grant of the Università Italo-Francese/Université Franco-Italienne, the Zegna Founder’s Scholarship and Associazione Amici di Claudio Demattè. F. P. , A.F. and V.G. were supported by a grant of the Agence Nationa...
PMC10313844
Author contributions
RS, FM
CV, FP, and AF conceptualized and designed the experiment and managed funding acquisition and project administration. CV, SB, SG, and FM performed the experiment. CV and FP analyzed data and wrote the paper. GV and RS worked on software. FP, AF and ET supervised the project and managed funding. LR, JG, AC, and VG helpe...
PMC10313844
Funding
Open access funding provided by Università degli Studi di Trento within the CRUI-CARE Agreement.
PMC10313844
Data availability
Data can be retrieved osf.io/mbshq.
PMC10313844
Declarations
PMC10313844
Conflict of interest
The authors have no conflicts of interest to declare.
PMC10313844
References
PMC10313844
Abstract
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
PMC10640691
Background
coronavirus disease 2019
CORONAVIRUS DISEASE 2019
There is growing consensus that coronavirus disease 2019 booster vaccines may be coadministered with other age-appropriate vaccines. Adding to the limited available data supporting coadministration, especially with adjuvanted vaccines, could enhance vaccine coverage in adults.
PMC10640691
Methods
zoster
ZOSTER, SECONDARY
In this phase 3, randomized, open-label study, eligible adults aged ≥50 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and a first dose of recombinant zoster vaccine (RZV1) 2 weeks apart (Seq group) or concomitantly (Coad group). The second RZV dose (RZV2) was administered 2 months ...
PMC10640691
Results
myalgia, mild/moderate, pain
ADVERSE EVENTS
In total, 273 participants were randomized to the Seq group and 272 to the Coad group. Protocol-specified noninferiority criteria were met. The adjusted geometric mean concentration ratio (Seq/Coad) was 1.01 (95% confidence interval [CI], .89–1.13) for anti-gE antibodies 1 month post-RZV2, and 1.09 (95% CI, .90–1.32) f...
PMC10640691
Conclusions
zoster
ZOSTER
Coadministration of mRNA-1273 booster vaccine with RZV in adults aged ≥50 years was immunologically noninferior to sequential administration and had a safety and reactogenicity profile consistent with both vaccines administered sequentially. When coadministered, mRNA-1273 COVID-19 booster vaccine and recombinant zoster...
PMC10640691
Graphical Abstract
zoster, varicella zoster, coronavirus disease 2019
ZOSTER, VARICELLA ZOSTER, VIRUS, CORONAVIRUS DISEASE 2019, DISEASE, CORONAVIRUS, DISEASE, SEVERE ACUTE RESPIRATORY SYNDROME, INFLUENZA
Accumulating real-world data substantiate the protective benefits of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines and the need for additional doses beyond the primary series due to waning immunity and/or emergence of new variants [Numerous health agencies including the United States (US) Centers f...
PMC10640691