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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 trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal excitatory tDCS in 48 older adults (see Table All behavioral data is reported in ref. | PMC10238397 |
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Cognitive training with concurrent tDCS | Cognitive training consisted of a letter updating task | PMC10238397 |
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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 × 3 mm³ voxel size, repetition time (TR) = 2000 ms, echo time (TE) = 30 ms, flip angle = 90°, 34 slices, descending acquisition, field of view 192 × 192 mm², 176 volumes, TA = 6.00 min). Participants were instructed to keep their eyes closed, to not think of anything in particular, and to try not to fall asleep (whether participants fell asleep or not was assessed per self-report directly after the resting-state scan; no participant reported to have fallen asleep). High-resolution anatomical images were acquired using a three-dimensional T1- weighted magnetization prepared rapid gradient echo imaging (1 mm³ isotropic voxel, TR = 2300 ms, TE = 2.96 ms, inversion time = 900 ms, flip angle = 9°, 256 × 240 × 192 mm³ matrix). Further, a diffusion-weighted spin-echo echo-planar imaging sequence was acquired (1.8 × 1.8 × 2.0 mm³ voxel size, TR = 11100 ms, TE = 107 ms, 70 slices, 64 directions ( | PMC10238397 |
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MRI data analyses | PMC10238397 |
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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 algorithm. A diffusion tensor model was fitted to the motion-corrected DTI data at each voxel to create individual 3-dimensional FA and MD maps. FSL’s BEDPOSTX was used to calculate the distribution of fiber orientations at each brain voxel. We used a seed-based probabilistic approach to track prefrontal white matter fibers.Probabilistic fiber tracking was conducted with PROBTRACKX2 implemented in FSL; this method repeatedly samples the distribution at each voxel to produce ‘streamlines’ that connect voxels from selected seed regions. The following parameters were applied: 5000 streamline samples, 0.5 mm step length, curvature threshold = 0.2. The left middle frontal gyrus from the Harvard-Oxford atlas also used for resting-state fMRI analyses (see below), transformed into individual DTI space, multiplied with diffusion maps and binarized, was used as seed regions for the tractsIndividual T1-weighted images were coregistered to the b0 images, using rigid-body transformation. These registrations were used to transform masks of the left stimulation target to the MD maps. To extract MD from the gray matter within the stimulation target, the individually segmented left middle frontal gyrus was masked by the ROI used for seed-based tractography and rsFC analyses, in line with previous studiesTo evaluate the robustness of FA results, we conducted complementary tract-based spatial statistics (TBSS) | PMC10238397 |
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Statistical analyses | To assess the statistical significance of differences in microstructural MRI markers between stimulation conditions, R | PMC10238397 |
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Reporting summary | Further information on research design is available in the | PMC10238397 |
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Supplementary information |
Supplementary InformationPeer Review FileReporting Summary | PMC10238397 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-38910-x. | PMC10238397 |
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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; collection, management, analyses, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We thank Robert Malinowski for MR imaging support. | PMC10238397 |
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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 statistical data analysis; D.A., M.M., and A.F. interpreted the results and wrote the paper; all authors reviewed the paper. | PMC10238397 |
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Peer review | PMC10238397 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10238397 |
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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 by a single sheet within the source data file ( | PMC10238397 |
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Code availability | All analyses were performed using the available toolboxes: R version 4.1.2 ( | PMC10238397 |
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Competing interests | The authors declare no competing interests. | PMC10238397 |
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References | PMC10238397 |
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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/LBW infants from a rural community-based setting of Kenya up to 18 months adjusted age. | PMC10476111 |
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Design | Cross-sectional study. | PMC10476111 |
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Setting | Migori County, Kenya. | PMC10476111 |
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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 |
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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 and Hammersmith Infant Neurological Examination. Analyses were descriptive and univariate regression models. No alterations were made to planned data collection. | PMC10476111 |
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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 reports. Overall, 22.7% of caregivers expressed concern about their child’s neurodevelopmental status. Neurodevelopmental delays were identified in 8.6% of infants based on one or more standardised tools, and 1.9% showed neurological findings indicative of cerebral palsy. | 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 underestimate true rates of neurodevelopmental delays or disability.The study design did not allow direct comparison to term, appropriate birth weight controls.It was not possible to investigate factors contributing to poor growth or neurodevelopmental outcomes through multivariate analyses due to sample size constraints. | PMC10476111 |
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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-income countries (LMIC) are not represented in current estimates.In Kenya, an estimated 12% and 10.5% of births are PT and LBW, respectively.Early interventions (eg, physio, occupational and speech therapies, family support and training) increasingly show improvements in long-term outcomes of PT and other at-risk babies, both in high-income settings and LMIC, highlighting the need for additional studies to better understand growth and neurodevelopment of PT/LBW infants across community settings. | PMC10476111 |
Materials and methods | PMC10476111 |
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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’s impact on stillbirth and neonatal survival. The protocol and primary results of this cRCT have been published elsewhere. | PMC10476111 |
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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 |
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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, 12 or 18 months±2 weeks of age was created, with age adjusted for PT status if the infant was born at less than 37 weeks’ gestation. Recruitment was sequential toward the goal sample size across combined cRCT arms, as this follow-up study was not designed to evaluate the impact of the cRCT intervention.A priori calculation of sample size using the Cochran’s method was based on the caregiver-report Ten Questions Questionnaire (TQQ) in a community-based study of PT versus term infants in Malawi. | 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.Pregnancy, birth and neonatal course data were extracted from the cRCT database and confirmed with the caregiver when possible. Assessors were blind to the child’s birth weight and gestational age, and questions regarding these variables were not asked at the study visit. The sequence of assessments was: (1) caregiver interview for sociodemographic information, medical history including growth, illness and development, and the TQQ; (2) direct neurodevelopmental assessments including the Malawi Developmental Assessment Tool (MDAT) and Hammersmith Infant Neurological Examination (HINE); and (3) physical examination including anthropometric measurements. Details of the anthropometric measurement standardised guidelines and the three neurodevelopmental assessment tools are in
All assessments were conducted in a conducive environment, when the child was settled and in relatively stable health, and complied with health and safety procedures. The research team consisted of clinical officers and nurses, all trained in study procedures and certified to conduct neurodevelopmental assessments. Two team members were present for each assessment, with one conducting the assessment and one observing and recording findings. A paediatrician trained in all study procedures provided consultation and regular supervision.After assessment, feedback on the child’s neurodevelopment and health was given to the caregiver and their concerns were addressed. Caregivers were also given information on nutrition, danger signs for common childhood illnesses and simple games to play with their child. Children identified with any significant health or developmental concern, such as hearing impairment, acute malnutrition or neurodevelopmental delay, were referred to appropriate follow-up care customised to the identified need (eg, audiology, nutrition support), with costs of up to four care visits covered by the study.Data collection was paper based, with subsequent entry into a Microsoft Access database. Double entry and verification to test for logical sequence, discrepancies and outliers was completed. Data were deidentified and stored on an encrypted server within a locked study facility. Efforts to address potential bias included sequential recruitment toward sample size goal, reporting of differences between consenting individuals and the eligible sample, similar procedures at multiple sites to reduce loss to follow-up risk that might be associated with travel to a central location, and blinding of assessors as to child’s birth weight and gestational age. | 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 roles and priorities.While caregiver participants were not involved in the design or conduct of this cross-sectional study, other than being a participant, findings specific to their child’s data were shared directly with caregivers at the visit. If health conditions or neurodevelopmental delays were identified, clinical referrals were made as well. | PMC10476111 |
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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 neurodevelopmental delay and malnutrition in infants were examined in univariate logistic regression models using the total dataset without age categorisation due to small sample size. Risk of neurodevelopmental delay or malnutrition was computed as an OR with a confidence level of 95%. All analyses were completed using STATA V.13.0 Stata/MP.Child medical experiences were summarised as past medical illnesses (since birth) or current medical status (within 2 weeks of the assessment). MDAT and HINE total and domain scores were calculated. MDAT scores were investigated using two methods. First, the MDAT was noted as failed overall if a child was unable to complete two or more items in any one domain that would be expected to be passed by 90% of the normal reference population at their age.For growth, WHO child growth standards were used in calculation of z-scores as provided in the STATA igrowup package.All available data were included in the analyses. There were few missing datapoints, and any cases of missingness for pregnancy, infant and child health characteristics are noted in Delivery and immediate postnatal period characteristics*Infants >37 weeks’ gestation were included only if birth weight was <2500 g.†Infants 2500–2999 g were included only if gestational age was <37 weeks.Child characteristics at time of visit*Normal (≥−1 for WAZ and LAZ; ≥−1 to ≤2 for WLZ), at risk (≥−2 to <−1), moderate (<−2 to ≥−3), severe (<−3). Overweight WLZ>2 to ≤3, obese WLZ>3.†Composite malnutrition includes infants who were either underweight, stunted or wasted.‡Other illnesses included abscess (1), thrush (4), scabies (8), dermatitis (3), skin infection (18), anaemia (1), convulsions (3), otitis media (1), congenital cataract (1). | 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.Study flow diagram. | PMC10476111 |
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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). Birth weight was over 2500 g for 35.6%, and more than 90% had 5 min Apgar scores ≥7. Sixteen per cent were admitted to the newborn unit, and 35.6% needed special care (ie, oxygen, phototherapy, kangaroo mother care) in the first month of life. Approximately 50.6% of mothers were aged 19–25. Most were multiparous (70.4%) and 13% of deliveries were by C-section (Compared with the eligible pool of caregivers and infants from the parent study, mothers in the current study were older on average (24.7 years vs 23.6 years, t=3.16, p<0.005), and babies were more likely female (60.2% vs 52.8%, χ | PMC10476111 |
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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 Developmental Assessment Tool; TQQ, Ten Questions Questionnaire.The most common illnesses reported as ever experienced by participants included malaria (56.7%), diarrhoeal disease (55.2%) serious febrile illness (42.3%); and in the past 2 weeks prior to assessment, respiratory tract infections (26%). | 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.†Neurodevelopmental delay defined as a fail on one or more of the three evaluation criteria, MDAT pass/fail, MDAT z-score (≤−2 SD from mean) or HINE.HINE, Hammersmith Infant Neurologic Examination; MDAT, Malawi Developmental Assessment Tool.Univariate analyses for neurodevelopmental delay***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 Developmental Assessment Tool; TQQ, Ten Questions Questionnaire.As described previously, this study recruited infants who had participated in a cRCT. The number of infants with neurodevelopmental delay were small in both control and intervention groups, and the sample was not large enough to be adequately powered to detect significant group differences if present. These data are provided for review in | PMC10476111 |
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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 settings with available NICU care. Only 27% were born at the county’s tertiary referral hospital, with the remaining born at other rural facilities. Surviving infants would thus be expected to have better outcomes than their counterparts requiring neonatal intensive care in urban settings of Africa.Rates of stunting and underweight were higher than locally reported data, suggesting a higher risk of malnutrition in the current PT/LBW sample than in the general population of young children in the local community. Direct comparison to growth data from available community-based African samples is complicated by differences in country under-5 malnutrition rates when these studies took place.This study demonstrates that standardised assessments can be locally implemented to enhance neurodevelopmental evaluation at the community level. Directly administered, standardised neurodevelopmental assessment tools identified delay or disability in 8.6% of PT/LBW infants. This proportion is lower than global estimates from settings with high NMR but NICU care available, where one might anticipate higher-risk infants surviving. It is more comparable to, but still lower than that of other cited community-based studies.The HINE was successfully used as an assessment for cerebral palsy or motor disability risk. Approximately 2% of children showed concern for being non-ambulatory by 2 years, and one additional child met clinical criteria for cerebral palsy but was not included in the sample due to acute illness at the time of visit. While these numbers are low, the percentage is not markedly different than the 3.4% of children with neonatal encephalopathy who had ‘sub-optimal’ HINE scores in a recent Ugandan study.In addition to malnutrition and neurodevelopmental risks, a high proportion of the sample were reported to have experienced acute childhood illness in their lifetime, including malaria, diarrhoeal disease and serious febrile illness. Children in the current study had higher rates of acute respiratory infection in the last 2 weeks than local averages for children under 5 years (26% vs 13%).Our data may underestimate true developmental delay/disability rates for PT/LBW infants for two reasons. First, participants were part of a larger cRCT evaluating the effect of an intrapartum and immediate postnatal intervention package on PT/LBW neonatal survival in which the control arm also received two of the four interventions. Post-hoc univariate analyses revealed no significant differences in growth or neurodevelopment between babies born at control versus intervention sites (This study has several limitations. First, the study design did not allow for direct comparison to term, normal birth weight controls and it was not possible to investigate factors contributing to poor growth or neurodevelopmental outcomes through multivariate analyses. Additionally, there were too few babies in the highest-risk PT/LBW categories to separately investigate their neurodevelopmental outcomes. There were several constraints related to recruitment for this study. The parent study was not originally designed as a longitudinal follow-up past 28 days, and this meant that we did not have recurrent contact with caregivers between the infant turning 28 days and the follow-up study recruitment call, which occurred up to 17 months later. Additionally, a national health worker strike significantly reduced recruitment into the parent study during the birth months of 18-month-olds, markedly reducing the number of potentially eligible children at this age. Although only 6.9% of those contacted declined to participate, 25.9% were unreachable and 20.4% of those scheduled for an informational recruitment visit did not attend that visit, so it was not possible to describe the study to them in detail. The analysed sample consisted of just under 50% of the identified eligible sample ( | 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 for disability. The results highlight the need for policies that support close monitoring of and early intervention for high-risk infants to assure PT/LBW infants in both rural and urban areas of LMIC are able to thrive. | PMC10476111 |
Supplementary Material | PMC10476111 |
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Reviewer comments | PMC10476111 |
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Data availability statement | Data are available upon reasonable request. | PMC10476111 |
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Ethics statements | PMC10476111 |
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Patient consent for publication | Not applicable. | PMC10476111 |
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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 Director of Health. Formal written informed consent procedures were completed in the preferred language of each caregiver. | PMC10476111 |
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References | PMC10476111 |
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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 mental health symptoms. | PMC10413600 |
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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 |
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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 FCC (PTSD: interaction β=-1.18, 95% CI: -2.10, -0.26; depression: interaction β=-0.76, 95% CI: -1.53, 0.006). Per protocol analyses of mFICare components suggested fewer PTSD and depression symptoms among mothers who had higher NICU stress scores and participated in clinical team rounds and/or group classes, compared with mothers who had high stress and did not participate in rounds or classes. | PMC10413600 |
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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 |
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Keywords | PMC10413600 |
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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 (FICare) is a parent-partnered NICU care delivery model that provides well-defined yet flexible protocols for ensuring meaningful participation of parents in all aspects of NICU caregiving, from an individual infant’s bedside to the hospital boardroom. FICare has four main pillars: NICU environment, NICU team education and support, parent education, and parent support [The United States (US) healthcare and social contexts are different than in other countries and these differences may affect NICU implementation of FCC and FICare and parental uptake of supportive services. For example, most countries provide more generous perinatal leave benefits and more generous extended leave benefits if a child is critically ill than the US [ | 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 |
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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. Parents received up to $50 in gift cards for completion of study surveys. The study was approved by the institutional review board at each site and written informed consent was obtained from all participants [ | PMC10413600 |
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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 provided elsewhere [The first cohort of enrolled parents received usual FCC. Then recruitment was paused for mFICare training of NICU staff and parent mentors. Once approximately 80% of each NICU’s staff received training, the second cohort of parent/infant dyads was enrolled and received mFICare. | PMC10413600 |
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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 potential moderators of the intervention effect on PTSD or depression symptoms: GA at birth (i.e., did the intervention effect differ based on the infant’s GA at birth?); Infant age at enrollment (i.e., did the intervention effect differ based on when it was started after the baby’s birth?); Infant discharge on respiratory or feeding devices or monitoring equipment (i.e., did the intervention effect differ based on whether the infant was discharged on a medical device); and Parent stress (i.e., did the intervention effect differ based on the parents’ perceived NICU-related stress at study enrollment). The selected moderators have been shown in prior studies to influence PTSD or depression in mothers after their infant’s discharge from the NICU [Additional sample characteristics were obtained from the infant medical record and parents surveys. Parents’ perception of the family-centeredness of NICU care they received was assessed near the time of discharge with the Digi Family-Centered Care-Parent Version (DigiFCC-P); scores range 1–7 with high scores indicating high perceived quality of FCC [ | PMC10413600 |
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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 backwards stepwise regression to identify demographic and clinical covariates that contributed p < .1 to the final model.We then tested for moderating effects on the intervention with four factors: infant gestational age at birth, infant chronological age at study enrollment (log transformed), whether the infant was discharged on a respiratory or feeding device, and NICU-related stress level at study enrollment (log-transformed), controlling for additional covariates as described above. Finally, for factors that had an interaction with the intervention group (denoted intervention moderators) with p < .05, we conducted an exploratory per protocol analysis testing for an interaction between the moderator and each of the following mFICare intervention components over the course of the NICU hospitalization: whether the parent had a mentor; participated in at least 2 clinical rounds; attended at least 1 parent class; or logged into the We3health™ app at least 4 times. We report results meeting a nominal p < .05, as none reached Bonferroni-corrected significance. | PMC10413600 |
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Results | PMC10413600 |
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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
Maternal characteristics by intervention group (n = 178)Note: Data are presented as mean (SD) or % (n). P-values are for independent t-tests or chi-square tests, as appropriate. ADI = Area Deprivation Index – national rank (1 = least deprivation, 100 = most deprivation); PSS:NICU = Parental Stressor Scale: NICU; PTSD = Post-Traumatic Stress Disorder; PPQ = Perinatal Post-Traumatic Stress Disorder Questionnaire; EPDS = Edinburgh Postnatal Depression Scale
Infant characteristics by intervention group (n = 178)Note: Data are presented as mean (SD) or % (n). P-values are for independent t-tests or chi-square tests, as appropriate | PMC10413600 |
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Measures of maternal mental health by intervention group | Measures of maternal mental health for each intervention group are shown in Table | PMC10413600 |
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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, p > .05). However, we found a nominally significant interaction association between PSS:NICU scores and intervention group for PPQ (interaction β=-1.18, 95% CI: -2.10, -0.26; p = .012; Table
Intent-to-treat analysis of the main and interaction effects of the mFICare intervention on maternal mental healthEPDS = Edinburgh Postnatal Depression Scale; FCC: family-centered care; PPQ = Perinatal Post-Traumatic Stress Disorder Questionnaire; PTSD = Post-Traumatic Stress Disorder; PSS:NICU: Parental Stressor Scale: NICU.* PTSD model adjusted for site, length of hospital stay, 5-minute Apgar score, and mother’s perception of FCC quality at enrollment.** Depression model adjusted for NICU site and infant gestational age.
Interaction effects of parent NICU stress and mFICare intervention on PTSD symptoms (a) and depression (b) after NICU discharge. Dotted lines indicate the 95% confidence interval for each group. | 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 stress, participating at least twice in clinical rounds was associated with fewer PTSD symptoms after discharge. However, for mothers who experienced low levels of NICU-related stress, there was no apparent association. This differential association (β=-1.08 [between clinical rounds and NICU-related stress]; 95% CI -1.99, -0.16; p = .022; Table
Interaction effect of parent NICU stress and attending mFICare clinical rounds on PTSD symptoms (a) and depression (b) after NICU discharge. Dotted lines indicate the 95% confidence interval for each group. Results were similar when examining if attending parental classes has a differential association with PTSD and depression symptoms after discharge. Among mothers who experienced high levels of NICU-related stress, those who attended at least one parent class experienced fewer PTSD symptoms (interaction β=-1.09, 95% CI -2.03, -0.16, p = .024) and fewer symptoms of depression (interaction β=-0.98, 95% CI -1.76, -0.20; p = .015) after discharge than similarly stressed mothers who did not attend parent classes. However, for mothers who had low levels of stress, there was no apparent association (Fig.
Per protocol analysis of the main and interaction effects of the mFICare intervention components on maternal mental healthEPDS = Edinburgh Postnatal Depression Scale; PPQ = Perinatal Post-Traumatic Stress Disorder Questionnaire; PTSD = Post-Traumatic Stress Disorder; PSS:NICU = Parental Stressor Scale: NICU.* PTSD model adjusted for site, length of hospital stay, 5-minute Apgar score, and mother’s perception of FCC quality at enrollment.** Depression model adjusted for NICU site and infant gestational age.Note: Parent mentorship and We3health™ app usage were unrelated to maternal health outcomes (data not shown).
Interaction effect of mFICare parent classes and parent NICU stress and on PTSD symptoms (3a) and depression (3b) after NICU discharge. Dotted lines indicate the 95% confidence interval for each group. | 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 health services. For example, the California Law, Assembly Bill (AB) 3032-Maternal Mental Health Conditions Education, Early Diagnosis, and Treatment Act [
Our study had several limitations in design and implementation, including selection bias because of the non-random design, unmeasured participation of families in the usual FCC group and incomplete uptake of the mFICare intervention by all mothers in that group. Selection bias may have also affected recruitment. We note that 59% of eligible FCC participants enrolled and 71% of mFICare participants enrolled; nevertheless, there were few differences in characteristics of the two groups. Timing of the intervention may be important and affected by enrollment later in the admission. Other limitations include mFICare intervention curtailment by the COVID-19 pandemic, further reducing intervention dose for some participants, and the exclusion of non-English-speaking families, limiting generalizability. Strengths of the study include increased generalizability of the findings because of the racially and ethnically diverse participant families as well as populations served by the participating NICUs and use of mobile app technology to increase intervention access.
In conclusion, the mFICare model was not associated with fewer mental health symptoms for mothers than the FCC model overall, but it was associated with fewer mental health symptoms for those experiencing higher levels of stress during the NICU stay. Further research on mFICare is urgently needed to address the prevalent and persistent mental health symptoms experienced by parents of preterm infants. | 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 |
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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 conceptualization of the study, supervised data collection, and critically reviewed the manuscript for important intellectual content. TH and CG carried out the analyses and critically reviewed the manuscript for important intellectual content. BL and YS contributed to conceptualization and intervention design and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. | PMC10413600 |
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Funding | PRETERM BIRTH | University of California, San Francisco, California Preterm Birth Initiative, funded by Marc and Lynne Benioff. | PMC10413600 |
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Data Availability | Deidentified data will be shared upon reasonable request directed to Linda S. Franck ([email protected]) from qualified investigators beginning 6 months and ending 5 years after publication. | PMC10413600 |
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Declarations | PMC10413600 |
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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 and that of their child. | PMC10413600 |
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Consent for publication | N/A. | PMC10413600 |
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Competing interests | The authors declare no competing interests. | PMC10413600 |
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References | PMC10413600 |
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Results | PMC10471167 |
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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 supernatant from RBCs exposed to hypoxia significantly improved postischemic cardiac recovery of left ventricular developed pressure (LVDP) ( | 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 the α1-subunit of sGC (GC KO mice) to hypoxia and the supernatant was administered to hearts from WT mice. The supernatant from these RBCs exposed to hypoxia failed to protect the hearts against IR injury, strongly suggesting that RBC sGC played a key role in cardioprotection (Having confirmed that RBC sGC was responsible for the observed effects, we next performed experiments to determine if cGMP, the product of sGC, is exported from the RBC. To determine the involvement of cGMP in the cardioprotective effect of the supernatant from hypoxic RBCs, the cGMP hydrolyzing enzyme phosphodiesterase 5 (PDE5) was administered to the supernatant before administration of the supernatant to the isolated heart. The cardioprotective effect in the presence of PDE5 was compared to a control group given supernatant from RBCs exposed to hypoxia without addition of PDE5 and performed during the same time period. Importantly, administration of PDE5 abolished the cardioprotective effect of the supernatant from hypoxic RBCs ( | 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 nitrate for 4 weeks were compared both with RBCs incubated with the sGC inhibitor ODQ before being administered to the isolated hearts and with RBCs from sGC-KO mice treated with nitrate. The control experiments and those with incubation with ODQ were matched in time, whereas the experiments using RBCs from sGC-KO mice were run at a separate occasion due to limitation in availability of the KO mice. Preincubation of the RBCs with ODQ blocked the protective effect induced by RBCs from nitrate-treated mice ( | PMC10471167 |
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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 cGMP-binding to PKG, Rp-8-bromoguanosine-3′,5′-cyclic monophosphorothioate (Rp-8-Br-cGMPS) ( | 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 RBCs from WT mice resulted in improved recovery of postischemic LVDP, and this effect was blocked by the sGC inhibitor ODQ and was absent when using RBCs from sGC-KO mice ( | 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 intake of nitrate ( | PMC10471167 |
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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 boosted by a dietary intervention with inorganic nitrate. The strict involvement of RBC sGC in the cardioprotective effect was demonstrated using both pharmacological and gene-targeted approaches. Finally, we demonstrate that this cardioprotective signaling by RBCs also occurs in humans following intake of dietary nitrate in amounts readily achieved through a rich intake of green leafy vegetables.It has been suggested that RBCs are capable of inducing hypoxic vasodilatation through the generation of a signal during deoxygenation of hemoglobin (We next hypothesized that dietary supplementation with inorganic nitrate — a precursor of nitrite that is further metabolized in blood (An interesting issue is how hypoxia leads to sGC activation in the RBC with downstream cGMP signaling resulting in cardioprotection. RBCs are known to be a major source of nitrite (A major strength of the present study is that we were able to translate these findings to the clinical setting with validation of the results in RBCs from patients with hypertension. RBCs collected from patients on a high nitrate diet afforded marked sGC-dependent cardioprotection compared with RBCs from the group receiving a low-nitrate diet. The cardioprotection was of comparable magnitude irrespective of whether nitrate was given in the form of nitrate pills or nitrate-rich vegetables, strongly supporting that the effect was mediated by nitrate per se. The observation that dietary nitrate induces RBC-mediated protection against cardiac IR injury in this patient group is of interest considering the importance of hypertension as a risk factor for myocardial infarction. It should be emphasized that the amount of nitrate was not more than what can readily be consumed with a normal diet. To study if this cardioprotective effect of nitrate is seen also in vivo in humans will obviously require a prospective clinical trial. Nevertheless, it is interesting that green leafy vegetables (the major dietary nitrate source) constitute a central part of diets associated with reduction in cardiovascular events (This study, along with our earlier studies (This study has certain limitations that need to be considered. First, the cardioprotective effects of the RBCs are demonstrated using RBCs ex vivo in an isolated heart model. It remains to be demonstrated to what degree NO bioactivity derived from hypoxic RBCs may mediate cardioprotection in vivo. Earlier studies have shown that oral administration of nitrite and nitrate protects the heart from IR injury (In conclusion, the present results reveal a fundamental endogenous protective mechanism mediated by RBCs when exposed to hypoxic conditions. To the best of our knowledge, this is the first demonstration of intercellular or paracrine signaling by cGMP exported from hypoxic RBCs. The abundance and ubiquitous presence of RBCs make them highly suitable for the purpose of tissue protection, suggesting that this may represent a physiological defense mechanism designed to minimize IR injury. This finding may provide an explanation to the recently observed cardioprotective effect of RBCs collected from patients with acute myocardial infarction ( | PMC10471167 |
Methods | PMC10471167 |
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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 |
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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 |
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RBC isolation. | Heparinized blood from mice and humans was centrifuged at 1,000 | PMC10471167 |
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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 |
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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 stimulation of sGC in RBC from WT and sGC-KO mice. In these experiments, the RBCs were incubated with the sGC stimulator BAY 41-2272 (10 μM; Sigma-Aldrich), the PDE5 inhibitor sildenafil (100 μM; Sigma-Aldrich) and the NO donor DEA/NO (200 μM; Sigma-Aldrich) for 20 minutes before being administered to the isolated heart. Isolated RBCs from WT mice were also incubated with the sGC stimulator vericiguat (10 μM Bayer AG) for 1 hour. After centrifugation (1,000 | 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 an investigator blinded to group allocation ( | 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 nitrogen and stored at –80°C. Protein was extracted from the heart by using radioimmunoprecipitation assay buffer (RIPA buffer, VWR International) containing protease inhibitors (Roche Diagnostics). The protocol of Western blotting was described previously (To further localize the expression of pVASP and determine the role of cGMP, additional hearts were collected for immunofluorescence using a protocol described elsewhere ( | 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-Wallis test followed by Dunn’s multiple comparison test, depending on the distribution of data. Differences between 2 groups were analyzed by unpaired or paired 2-tailed | 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 Declaration of Helsinki. The protocol was approved by the Swedish Ethical Review Authority for human studies. All participants were informed of the study’s purpose and gave their oral and written informed consent before any study-related procedures were initiated. | PMC10471167 |
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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, MC, and EW edited the manuscript, and all authors reviewed and approved the final version of the manuscript. | PMC10471167 |
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Supplementary Material | PMC10471167 |
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Supplemental data | PMC10471167 |
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09/01/2023 | Electronic publication | PMC10471167 |
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09/06/2023 | Term clarification on page 7 | PMC10471167 |
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RBCs release a cardioprotective factor during hypoxia. | ( | PMC10471167 |
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Hypoxia-induced release of cardioprotective cGMP from RBCs. | ( | PMC10471167 |
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