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Participants
SECONDARY
We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in ...
PMC10238397
Cognitive training with concurrent tDCS
Cognitive training consisted of a letter updating task
PMC10238397
MRI data acquisition
MR images were acquired at the Baltic Imaging Center (Center for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald) on a 3-T Siemens verio scanner (SIEMENS MAGNETOM Verio syngo MR B17) using a 32-channel head coil. Resting-state fMRI scans were acquired using an echo-planar-imaging sequence (3 × 3...
PMC10238397
MRI data analyses
PMC10238397
Structural T1-weighted images and DTI analysis
T1 and DTI data were processed by Freesurfer version 6 (Regional volumes were extracted for the ROI corresponding to the stimulation target (i.e., left middle frontal gyri from the Desikan-Killiani atlasDTI data preprocessing included eddy current and head motion correction using an automated affine registration algori...
PMC10238397
Statistical analyses
To assess the statistical significance of differences in microstructural MRI markers between stimulation conditions, R
PMC10238397
Reporting summary
Further information on research design is available in the 
PMC10238397
Supplementary information
Supplementary InformationPeer Review FileReporting Summary
PMC10238397
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-023-38910-x.
PMC10238397
Acknowledgements
Research reported in this publication was supported by the Bundesministerium für Bildung und Forschung, Grant/Award Number: 01GQ1424A (AF); the Deutsche Forschungsgemeinschaft, Grant/Award Numbers: 327654276 - SFB1315 (A.F.) and INST 292/155-1 FUGG. The funders had no role in the design and conduct of the study; collec...
PMC10238397
Author contributions
D.A. and A.F. conceived the study and designed the experiments; F.T. performed the experiments and collected the MR data; D.A. supervised data collection; D.A., F.T., and A.E.F. processed the MR data; D.A. and A.E.F. analyzed the data and prepared the figures; D.A. prepared the brain images. D.A. and U.G. performed sta...
PMC10238397
Peer review
PMC10238397
Funding
Open Access funding enabled and organized by Projekt DEAL.
PMC10238397
Data availability
The processed data of this study are available upon request from the corresponding author. The raw data are not publicly available due to potential identifying information that could compromise participant privacy. Source data are provided with the paper, where the relevant data from each figure or table is represented...
PMC10238397
Code availability
All analyses were performed using the available toolboxes: R version 4.1.2 (
PMC10238397
Competing interests
The authors declare no competing interests.
PMC10238397
References
PMC10238397
Objective
PT/LBW, LBW, stunting
SPM-H and PO are joint first authors.Data on long-term outcomes of preterm (PT) and low birth weight (LBW) infants in countries with high rates of neonatal mortality and childhood stunting are limited, especially from community settings. The current study sought to explore growth and neurodevelopmental outcomes of PT/L...
PMC10476111
Design
Cross-sectional study.
PMC10476111
Setting
Migori County, Kenya.
PMC10476111
Participants
PT/LBW
Three hundred and eighty-two PT/LBW infants (50.2% of those identified as eligible) from a cluster randomised control trial evaluating a package of facility-based intrapartum quality of care interventions for newborn survival consented for follow-up.
PMC10476111
Outcome measures
REGRESSION
Caregiver interviews and infant health, growth and neurodevelopmental assessments were completed at 6, 12 or 18 months±2 weeks. Data included sociodemographic information, medical history, growth measurements and neurodevelopmental assessment using the Ten Questions Questionnaire, Malawi Developmental Assessment Tool a...
PMC10476111
Results
Neurodevelopmental delays
MALNOURISHED, CEREBRAL PALSY
The final sample included 362 PT/LBW infants, of which 56.6% were moderate to late PT infants and 64.4% were LBW. Fewer than 2% of parents identified their child as currently malnourished, but direct measurement revealed higher proportions of stunting and underweight than in national demographic and health survey repor...
PMC10476111
Conclusions
Malnutrition, PT/LBW, neurodevelopmental delays
MALNUTRITION
Malnutrition and neurodevelopmental delays are common among PT/LBW infants in this setting. Close monitoring and access to early intervention programmes are needed to help these vulnerable infants thrive.
PMC10476111
STRENGTHS AND LIMITATIONS OF THIS STUDY
LBW, disability, neurodevelopmental delays
This study used directly administered, standardised neurodevelopmental assessment tools to enhance evaluation at the community-level.The sample included largely moderate to late preterm (PT) infants, with predominately normal or low birth weight (LBW), as opposed to very or extremely PT/LBW infants and, therefore, may ...
PMC10476111
Introduction
deaths, PT/LBW, LBW
COMPLICATIONS
Complications associated with preterm (PT) birth and low birth weight (LBW) contribute to 25%–50% of all neonatal deaths and 12% of under-5 mortality worldwide.Data from community-based PT/LBW samples in areas without NICUs are extremely limited, meaning outcomes of the majority of PT/LBW infants born in low- or middle...
PMC10476111
Materials and methods
PMC10476111
Design
MAY
This cross-sectional study was conducted between October 2018 and May 2019 among a subset of mothers and babies previously enrolled in PTBi-K, a cluster randomised control trial (cRCT) of a package of interventions to improve quality of care during labour and the immediate postnatal period and evaluate the intervention...
PMC10476111
Setting
The current study was conducted in Migori County, Kenya. The county is mostly rural, has poor access to healthcare and has higher infant and under-5 mortality than national statistics (50 vs 39 per 1000 live births, and 82 vs 52 per 1000 live births, respectively).
PMC10476111
Study participants and sampling strategy
LBW
RECRUITMENT
Participants in the parent cRCT were identified from maternity registers. Eligible participants were LBW (<2500 g at birth) or PT (gestational age <37 weeks with birth weight <3000 g) infants delivered at one of 17 facilities across the county. A list of potentially eligible infants, alive at 28 days and approaching 6,...
PMC10476111
Procedures
illnesses and simple games, malnutrition
HEARING IMPAIRMENT, RECRUITMENT, BLIND, MALNUTRITION
Caregivers of eligible infants were contacted via phone, and a standard participation invitation script was used to explain the study. Appointments were scheduled at a study facility nearest the family’s home. All consent forms and questionnaires were translated and back translated from English to Kiswahili and Dholuo....
PMC10476111
Patient and public involvement
neurodevelopmental delays
For the larger parent study in which participants were involved, national and community advisory boards provided input on intervention priorities. Health facility providers, managers and local authorities were involved in implementation activities and influenced the focus and content of those activities based on their ...
PMC10476111
Statistical analysis
anaemia, scabies, convulsions, congenital cataract, abscess, skin infection, Overweight WLZ>2, thrush, malnutrition, dermatitis
ANAEMIA, SCABIES, OBESE, ABSCESS, SKIN INFECTION, OTITIS MEDIA, THRUSH, MALNUTRITION, REGRESSION, DERMATITIS
Analyses involved the use of descriptive statistics, as well as univariate regression models. Descriptive statistics involved the use of frequencies and proportions for categorical variables, and mean, median, range, IQR and SD for continuous variables. Sociodemographic and clinical factors associated with neurodevelop...
PMC10476111
Results
death
Of 761 eligible infants, 564 (74.1%) of caregivers were located. A total of 28 infants (3.7% of eligible) had died after 28 days of life and prior to study contact. While the specific causes of death for these infants are not known, a larger verbal and social autopsy study of the full parent study sample was conducted....
PMC10476111
Characteristics at delivery and immediate postnatal period
Most babies were female (60.2%) and moderate to late PT (56.6%, >32 weeks’ gestation; median gestational age and range=36.3 weeks (22.0–41.7)). Of infants born PT, 66.1% were late PT (34 to <37 weeks), 17.6% were moderate PT (32 to <34 weeks), 13.9% were very PT (28 to <32) and only 2.5% were extremely PT (22 to <28). ...
PMC10476111
Growth and health
malaria, febrile illness
MALARIA, RESPIRATORY TRACT INFECTIONS, FEBRILE ILLNESS
Anthropometric measurement and caregiver-reported health findings are in Univariate analyses for malnutrition***P value <0.001.**P value <0.01.*P value <0.05.PF: no variability due to low numbers causes the model to perfectly predict failure or success.HINE, Hammersmith Infant Neurological Examination; MDAT, Malawi Dev...
PMC10476111
Neurodevelopment
Neurodevelopmental
Delays on one or more of the standardised neurodevelopmental assessment tools were identified in 8.6% of infants (Neurodevelopmental outcomes*A fail score on the total MDAT can occur with a fail in any one or more subscales, thus this number does not represent the sum of children failing on the domain scores.†Neurodeve...
PMC10476111
Discussion
illness, malaria, PT/LBW, motor disability, acute illness, cerebral palsy, malnutrition, disability
MALARIA, RECRUITMENT, FEBRILE ILLNESS, NEONATAL ENCEPHALOPATHY, CEREBRAL PALSY, MALNUTRITION
This study describes growth and neurodevelopmental outcomes for a rural community sample of PT/LBW survivors. Infants were similar in gestational age to other community-based samples from countries with NMR>5 and constituted a relatively low-risk sample of PT/LBW infants compared with high-resource contexts or LMIC set...
PMC10476111
Conclusion
wasting, disability
WASTING
The current study adds to very limited community-based literature on PT/LBW infants born in countries with high NMR and suggests higher than background rates of wasting and underweight, high rates of parental concern for development, and a clinically impactful number of children with neurodevelopmental delay or risk fo...
PMC10476111
Supplementary Material
PMC10476111
Reviewer comments
PMC10476111
Data availability statement
Data are available upon reasonable request.
PMC10476111
Ethics statements
PMC10476111
Patient consent for publication
Not applicable.
PMC10476111
Ethics approval
This study involves human participants and was approved by University of California San Francisco Institutional Review Board (IRB #: 18-25555) and Scientific and Ethics Review Unit (SERU) of the Kenya Medical Research Institute (KEMRI) #KEMRI/SERU/CCR/0104/3668. Written authorisation was obtained from the Migori County...
PMC10476111
References
PMC10476111
Background
Involvement in caregiving and tailored support services may reduce the risk of mental health symptoms for mothers after their preterm infant’s neonatal intensive care unit (NICU) discharge. We aimed to compare Family-Centered Care (FCC) with mobile-enhanced Family-Integrated Care (mFICare) on post-discharge maternal me...
PMC10413600
Method
depression, PTSD, perinatal post-traumatic stress disorder
This quasi-experimental study enrolled preterm infant (≤ 33 weeks)/parent dyads from three NICUs into sequential cohorts: FCC or mFICare. We analyzed post-discharge symptoms of perinatal post-traumatic stress disorder (PTSD) and depression using intention-to-treat and per protocol approaches.
PMC10413600
Results
depression, NICU stress, PTSD
178 mothers (89 FCC; 89 mFICare) completed measures. We found no main effect of group assignment. We found an interaction between group and stress, indicating fewer PTSD and depression symptoms among mothers who had higher NICU-related stress and received mFICare, compared with mothers who had high stress and received ...
PMC10413600
Conclusion
depression, PTSD
Overall, post-discharge maternal mental health symptoms did not differ between the mFICare and FCC groups. However, for mothers with high levels of stress during the NICU stay, mFICare was associated with fewer post-discharge PTSD and depression symptoms.
PMC10413600
Keywords
PMC10413600
Introduction
critically ill, pain
CRITICALLY ILL
Parents provide essential caregiving support for preterm infants admitted to neonatal intensive care units (NICU) to promote infant growth and development, including breastfeeding, skin-to-skin contact, developmentally supportive care, positive sensory stimulation, pain management and massage [Family-Integrated Care (F...
PMC10413600
Methods
SECONDARY
This analysis of pre-defined secondary aims was part of a larger quasi-experimental, time-lagged non-randomized intervention trial of the mFICare intervention compared with FCC (NCT03418870; 01/02/2018) [
PMC10413600
Participants
congenital anomaly
Parents/primary caregivers of infants born ≤ 33 weeks gestation were invited to participate. Participants were excluded if: (1) the parent was not English literate, < 18 years of age, or had no smart phone or tablet access; or (2) the infant had a life-threatening congenital anomaly or was receiving palliative care. Pa...
PMC10413600
Intervention
RECRUITMENT
Parents of current and former NICU patients and NICU healthcare professionals were extensively involved in the design of the trial and the adaptation of the FICare intervention to the local settings. Parents also co-designed and pilot-tested a mobile app for parents. Details of the FCC and mFICare interventions are pro...
PMC10413600
Measures
depression, Depression, PTSD
The primary outcomes for this analysis were maternal symptoms of perinatal PTSD and depression measured at least three months after the infant’s NICU discharge. The Perinatal PTSD Questionnaire (PPQ) [Maternal depression was assessed by self-report using the Edinburgh Postnatal Depression Scale (EPDS) [We examined four...
PMC10413600
Statistical analysis
REGRESSION
Analyses were performed using R v4.1 [We tested for associations between PPQ and EPDS scores (log-transformed) and intervention group using a linear regression model. We first tested for main effects of the intervention. We adjusted for additional covariates using a hybrid approach, forcing in site, and then using a ba...
PMC10413600
Results
PMC10413600
Sample characteristics
Stress Disorder, Depression, PTSD
Of the 237 mothers enrolled in the study between April, 2017 and June, 2020, 178 (75%; 89 FCC, 89 mFICare) completed PPQ and EPDS measures a mean of 4.2 (SD 1.9) months after their infant’s NICU discharge and were included in this analysis (Fig. Maternal characteristics are summarized in Table  Participant flow diagram...
PMC10413600
Measures of maternal mental health by intervention group
Measures of maternal mental health for each intervention group are shown in Table 
PMC10413600
Main intervention effects and moderators
Stress Disorder, depression, Depression, PTSD
INTERACTION
As shown in Table Of the four potential moderators evaluated, there was no evidence that the intervention was differentially associated with the infant’s gestational age, infant age when mFICare was started, or whether the infant was discharged on a feeding and/or respiratory device (tested with an interaction effect, ...
PMC10413600
Per protocol analyses
β=-1.09, PTSD, Stress Disorder, depression, Depression
INTERACTION
Per protocol analyses were conducted to determine whether specific intervention components were differentially associated with maternal mental symptoms based on the mother’s level of NICU-related stress (i.e., an interaction effect with NICU-related stress). For mothers who experienced high levels of NICU-related stres...
PMC10413600
Discussion
PTSD
RECRUITMENT
Worldwide, approximately 25% of NICU parents report clinically significant PTSD symptoms [Previous studies have tended to focus on specific parent-focused therapies, for example trauma-focused therapy for PTSD [ It is now widely recognized that comprehensive perinatal care must include preventative parental mental heal...
PMC10413600
Acknowledgements
PRETERM BIRTH
The authors are grateful for the support of the research team from each site, all the staff and parents who participated in the research and for the valuable partnership of the UCSF California Preterm Birth Initiative Parent Clinician Advisory Board.
PMC10413600
Authors’ contributions
LF conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. RK coordinated data acquisition, conducted data curation and provided project administration and critically reviewed the manuscript for important intellectual content. CD, PJ, RB contributed to conceptual...
PMC10413600
Funding
PRETERM BIRTH
University of California, San Francisco, California Preterm Birth Initiative, funded by Marc and Lynne Benioff.
PMC10413600
Data Availability
Deidentified data will be shared upon reasonable request directed to Linda S. Franck (linda.franck@ucsf.edu) from qualified investigators beginning 6 months and ending 5 years after publication.
PMC10413600
Declarations
PMC10413600
Ethics approval and consent to participate
All study procedures were performed in accordance with the Declaration of Helsinki and were approved by the Institutional Review Boards at the University of California, San Francisco (16-19542) and participating hospitals. Written informed consent was obtained from all parents/legal guardians for their participation a...
PMC10413600
Consent for publication
N/A.
PMC10413600
Competing interests
The authors declare no competing interests.
PMC10413600
References
PMC10413600
Results
PMC10471167
RBCs release a cardioprotective factor during hypoxia.
hypoxia, ischemia
HYPOXIA, ISCHEMIA
First, we investigated whether RBCs exposed to hypoxia release a cardioprotective mediator by administration of RBC supernatant to an isolated heart subjected to global IR. To this end, the supernatant collected from mouse RBCs exposed to normoxia or hypoxia was given to mouse hearts at the onset of ischemia. The super...
PMC10471167
The cardioprotective effect of hypoxia is mediated by RBC sGC and export of cGMP.
hypoxia, IR injury
HYPOXIC, HYPOXIA
Having determined that a cardioprotective factor was released from RBCs during hypoxia, we next sought to determine the nature of this compound. The focus was directed toward sGC-cGMP as this pathway has been shown to be present in RBCs. To determine the involvement of sGC, we exposed RBCs collected from mice lacking t...
PMC10471167
Dietary nitrate augments RBC-induced hypoxic cardioprotection.
Inorganic nitrate can be reduced to nitrite and deoxygenated hemoglobin can further reduce nitrite to NO (To identify the mechanism by which nitrate induces protection via RBCs, we again focused on the sGC-cGMP pathway. In these experiments, control RBCs collected from mice given normal drinking water (vehicle) or nitr...
PMC10471167
Cardiac protection of RBCs is PKG-dependent.
hypoxia
HYPOXIA
After having established the signaling pathway in RBCs under hypoxia and following nitrate administration, we investigated the downstream signaling in the heart focusing on protein PKG, the major target of cGMP. In these experiments we used 2 distinct inhibitors of PKG. In a first set of experiments, the inhibitor of c...
PMC10471167
Pharmacological sGC stimulation in RBCs also induces cardioprotection and cGMP release.
hypoxia
HYPOXIA
To verify that pharmacological activation of RBC sGC produce effects similar to those of hypoxia, RBCs from WT and sGC-KO mice were preincubated with the sGC stimulator BAY 41-2272 in combination with the NO donor DEA/NO and the PDE5 inhibitor sildenafil before administration to the isolated heart. Preincubation of RBC...
PMC10471167
RBCs from nitrate-treated humans induce cardioprotection.
To translate the beneficial effect of nitrate administration in mice to the clinical situation, RBCs were collected from 3 groups of subjects randomized to a 5-week dietary intervention: 2 groups with high nitrate in the form of a potassium nitrate pill or nitrate-rich vegetables and 1 group receiving a low dietary int...
PMC10471167
Discussion
cardiac IR injury, hypoxia, hypertension, IR injury
ACUTE MYOCARDIAL INFARCTION, MYOCARDIAL INFARCTION, HYPOXIA, HYPOXIC, VASODILATATION, EVENTS, HYPERTENSION
Here, we show that RBCs under hypoxic conditions induce cardioprotection through a mechanism that is dependent on sGC in the RBC and associated with export of cGMP that, via a paracrine effect, is involved as a mediator of the cardioprotection through activation of PKG in the heart. This cardioprotective effect is boos...
PMC10471167
Methods
PMC10471167
Animals.
Wistar rats were purchased from Charles River and used for experiments at 12 to 14 weeks of age. C57Bl/6J mice were purchased from Janvier and used for experiments at 8 to 15 weeks of age. Mice lacking the α1-subunit of sGC — and thus α1β1-sGC (α1-GC KO mice) — were generated and genotyped as described previously (
PMC10471167
Heart isolation and perfusion.
Isolated hearts from rats (for human RBCs) or mice (for mouse RBCs) were perfused in a Langendorff system as described previously in detail (
PMC10471167
RBC isolation.
Heparinized blood from mice and humans was centrifuged at 1,000
PMC10471167
Supernatant of RBCs.
hypoxia
HYPOXIA
The RBCs suspension was exposed to hypoxia (1% O
PMC10471167
Nitrate treatment in mice.
C57Bl/6J mice at age of 8 weeks were housed under standard environmental conditions (room temperature at 22
PMC10471167
Experimental protocol.
ischemia
ISCHEMIA
After the start of perfusion, all hearts were allowed to stabilize for at least 30 minutes and baseline LVDP was registered. The duration of global ischemia, induced by clamping the inflow tubing, was 40 minutes for mouse hearts and 25 minutes for rat hearts (Additional experiments were performed using pharmacological ...
PMC10471167
Clinical study protocol.
hypertension
HYPERTENSION
Patients were recruited as a substudy of a double-blinded clinical trial investigating the effect of dietary nitrate on blood pressure in patients with mild hypertension (clinicaltrials.gov NCT02916615). The clinical trial was described in detail previously (
PMC10471167
Determination of heart infarct size.
Necrotic
NECROTIC
At the end of reperfusion, hearts were frozen at –20°C and sectioned into 1 mm–thick slices from the apex to the base, stained with triphenyltetrazolium chloride for 15 minutes, and fixed in 1% formaldehyde for 18 hours. Necrotic negatively stained myocardium was measured using Adobe Photoshop Elements 2019 Edition by ...
PMC10471167
Expression of cardiac vasodilator specific phosphoprotein.
ischemia
HYPOXIC, ISCHEMIA
In separate experiments, isolated and perfused mouse hearts were subjected to 5 minutes of ischemia following 30 minutes of stabilization. The supernatant from hypoxic or normoxic mouse RBCs was given to the isolated heart at the start of ischemia. After 1 minute reperfusion, the hearts were harvested using liquid nitr...
PMC10471167
Cyclic GMP detection in supernatant of RBCs.
hypoxia
HYPOXIA
Mouse RBC suspension (hematocrit about 70%) was exposed to hypoxia (1% O
PMC10471167
Statistics.
infarct
INFARCT
LVDP during reperfusion is expressed as a percentage of the preischemic values. The differences in functional cardiac parameters were analyzed by 2-way ANOVA followed by Tukey’s multiple comparison test. Differences in infarct size were analyzed using 1-way ANOVA followed by Tukey’s multiple comparison test or Kruskal-...
PMC10471167
Study approval.
All animal experiment protocols were approved by the Ethical Committee of Stockholm and conform to the Guide for the Care and Use of Laboratory Animals published by the United States National Institute of Health (NIH publication No. 85-23, revised 1996). All procedures involving humans were conducted according to the D...
PMC10471167
Author contributions
JP
JY, EW, JOL, and JP conceived and designed the study. JY and TJ performed and collected research data. JY and JP analyzed research data and performed statistical analysis. MLS, EW, JOL, and JP recruited patients and collected samples. JY, JOL, and JP wrote the manuscript. XZ, TJ, AC, YT, AM, JT, EM, SBC, ZZ, MMCK, TA, ...
PMC10471167
Supplementary Material
PMC10471167
Supplemental data
PMC10471167
09/01/2023
Electronic publication
PMC10471167
09/06/2023
Term clarification on page 7
PMC10471167
RBCs release a cardioprotective factor during hypoxia.
(
PMC10471167
Hypoxia-induced release of cardioprotective cGMP from RBCs.
(
PMC10471167