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Basic resuscitation practices, particularly bag-mask ventilation, reduce newborn deaths from respiratory depression. There is strong scientific premise for improving bag-mask ventilation with feedback strategies, but there are significant barriers to bedside feedback in low-resource settings. To address these barriers, we developed LIVEBORN, a mobile health application to support feedback for newborn resuscitations. LIVEBORN uses data on provider actions and the newborn’s condition entered in real-time by an observer to provide real-time guidance during resuscitation and support debriefing after resuscitation. In a pilot study, we designed and then evaluated strategies to incorporate LIVEBORN Feedback into clinical practice at two health facilities in the Democratic Republic of the Congo, with one facility allocated to real-time guidance and one to debriefing. Providers at each facility used a participatory research methodology called Trials of Improved Practices to design and refine their strategy prior to pilot testing. The primary outcome of the pilot study was the feasibility of observing resuscitation care with LIVEBORN, defined as the percentage of births observed using LIVEBORN with a threshold of at least 50% of births observed to achieve feasibility. We also evaluated usability with the System Usability Scale and explored midwives’ perceptions of LIVEBORN Feedback in focus group discussions. During the pilot test, we found both strategies to be feasible with 74% of births observed with LIVEBORN at the real-time guidance facility and 67% at the debriefing facility. The strategy was also sufficiently usable with a System Usability Scale median score of 68 (Q1 65, Q3 78). Midwives perceived LIVEBORN Feedback to be helpful and believed it could save lives, but sometimes disagreed with LIVEBORN Feedback’s guidance to ventilate. In conclusion, we identified context-specific, feasible strategies for incorporating LIVEBORN Feedback into clinical care. We are now evaluating the effectiveness of LIVEBORN Feedback in a randomized control trial.

Basic resuscitation practices, particularly bag-mask ventilation, reduce newborn deaths from respiratory depression. There is strong scientific premise for improving bag-mask ventilation with feedback strategies, but there are significant barriers to bedside feedback in low-resource settings. To address these barriers, we developed LIVEBORN, a mobile health application to support feedback for newborn resuscitations. LIVEBORN uses data on provider actions and the newborn's condition entered in real-time by an observer to provide real-time guidance during resuscitation and support debriefing after resuscitation. In a pilot study, we designed and then evaluated strategies to incorporate LIVEBORN Feedback into clinical practice at two health facilities in the Democratic Republic of the Congo, with one facility allocated to real-time guidance and one to debriefing. Providers at each facility used a participatory research methodology called Trials of Improved Practices to design and refine their strategy prior to pilot testing. The primary outcome of the pilot study was the feasibility of observing resuscitation care with LIVEBORN, defined as the percentage of births observed using LIVEBORN with a threshold of at least 50% of births observed to achieve feasibility. We also evaluated usability with the System Usability Scale and explored midwives' perceptions of LIVEBORN Feedback in focus group discussions. During the pilot test, we found both strategies to be feasible with 74% of births observed with LIVEBORN at the real-time guidance facility and 67% at the debriefing facility. The strategy was also sufficiently usable with a System Usability Scale median score of 68 (Q1 65, Q3 78). Midwives perceived LIVEBORN Feedback to be helpful and believed it could save lives, but sometimes disagreed with LIVEBORN Feedback's guidance to ventilate. In conclusion, we identified context-specific, feasible strategies for incorporating LIVEBORN Feedback into clinical care. We are now evaluating the effectiveness of LIVEBORN Feedback in a randomized control trial.

Background Interprofessional education (IPE), defined as when students from two or more professions learn about, from, and with each other, has been widely espoused as a way to promote collaborative and high-quality patient care. IPE initiatives are now commonplace in undergraduate medical education, but it is unclear whether the principles of IPE are reinforced during clinical rotations. Specifically, little is known about whether, when, and how interprofessional providers (IPPs), including nurses (RN), pharmacists (PharmD), and respiratory therapists (RT), participate in teaching medical students. This study aimed to elucidate the perspective of medical students about how IPPs impacted their education during clinical rotations in the intensive care unit (ICU). Methods Surveys were distributed to medical students who rotated in the medical ICUs at three academic medical centers over a 12-month period. Survey questions focused on three major domains: IPP roles during daily rounds, interprofessional teaching (IPT) outside of rounds, and students’ attitudes about IPT. Survey data were analyzed with descriptive and comparative statistics. Free text comments were analyzed using qualitative thematic analysis. Results Twenty five out of 53 medical students completed the survey (47%). Students reported that IPPs were commonly present on ICU rounds. Students’ reports of IPP teaching varied across professions. On a 5-point Likert scale, pharmacists were perceived to teach most frequently (mean 3.58, SD 0.81), compared to RTs (mean 2.88, SD 1.01) and nurses (mean 2.17, SD 0.80) (one-way ANOVA, F(2, 69) = [14.89], p  < 0.005). On a 7-point Likert scale, IPPs were described as teaching a moderate amount outside of rounds [RN (mean 3.46, SD 1.71), PharmD (mean 4.04, SD 1.49), RT (mean 4.00, SD 1.35)], with the majority of RN and RT teaching occurring at the bedside. Students reported generally positive attitudes about IPT, with most endorsing confidence in IPP knowledge base (92%) and teaching abilities (88%); 67% would have a positive reaction if attending physicians invited more IPT on rounds. Conclusions Medical students report variable levels of teaching from IPPs on ICU rounds, but similar levels of teaching outside of rounds. Students endorsed positive attitudes toward the idea of enhancing interprofessional teaching in the ICU.

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas ( n  = 2325), malignant rhabdoid tumors ( n  = 229) and pediatric high-grade gliomas ( n  = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy. Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour.

Acetylation of histones triggers association with bromodomain-containing proteins that regulate diverse chromatin-related processes. Although acetylation of transcription factors has been appreciated for some time, the mechanistic consequences are less well understood. The hematopoietic transcription factor GATA1 is acetylated at conserved lysines that are required for its stable association with chromatin. We show that the BET family protein Brd3 binds via its first bromodomain (BD1) to GATA1 in an acetylation-dependent manner in vitro and in vivo. Mutation of a single residue in BD1 that is involved in acetyl-lysine binding abrogated recruitment of Brd3 by GATA1, demonstrating that acetylation of GATA1 is essential for Brd3 association with chromatin. Notably, Brd3 is recruited by GATA1 to both active and repressed target genes in a fashion seemingly independent of histone acetylation. Anti-Brd3 ChIP followed by massively parallel sequencing in GATA1-deficient erythroid precursor cells and those that are GATA1 replete revealed that GATA1 is a major determinant of Brd3 recruitment to genomic targets within chromatin. A pharmacologic compound that occupies the acetyl-lysine binding pockets of Brd3 bromodomains disrupts the Brd3-GATA1 interaction, diminishes the chromatin occupancy of both proteins, and inhibits erythroid maturation. Together these findings provide a mechanism for GATA1 acetylation and suggest that Brd3 \"reads\" acetyl marks on nuclear factors to promote their stable association with chromatin.

Background DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. Results For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. Conclusions In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease.

Improving neonatal resuscitation practices reduces neonatal mortality. In low- and middle-income countries (LMICs), granular details about provider actions during resuscitation are largely unknown; therefore, identifying targets for improvement is difficult. The International Liaison Committee on Resuscitation (ILCOR) recognizes the importance of uniform reporting of clinical neonatal resuscitation studies and published a guideline recommending specific variables to include. We established an open cohort study for newborn resuscitation in the Democratic Republic of the Congo (DRC) as a platform for developing and evaluating novel strategies to improve newborn resuscitation. We included all in-born neonates at two health facilities in Kinshasa, DRC. We gathered data on all enrollees via delivery registry and medical record abstraction. Using the Liveborn Observation app, we directly observed care at birth for a convenience sample. We collected heart rate data when providers used NeoBeat, a battery-operated heart rate meter. From September 2022 to August 2023, we abstracted delivery registry and medical record data for 6,414 newborns and gathered observational data on the infant’s breathing status and provider actions for 3,166 (49%). Our dataset includes 85% of ILCOR’s recommended core variables applicable to this setting, and 50% of ILCOR’s applicable supplemental variables. Our registry also contains variables beyond those recommended by ILCOR that are contextually important for evaluating resuscitation care in LMICs such as duration of suctioning, pauses in positive pressure ventilation and fresh stillbirth. Our experience establishing a resuscitation registry with novel tools in the DRC serves as a model for resuscitation research in low-resource settings. Our cohort study provides important insight to inform subsequent versions of ILCOR’s guideline on uniform reporting of neonatal resuscitations studies globally.

Birth asphyxia, defined by the World Health Organization as the failure to initiate and sustain breathing at birth, is the second cause of neonatal mortality and leads to about 25% of neonatal deaths or about 600,000 deaths per year.\" Death from prematurity, the most common cause of neonatal mortality overall and during the rest of the first week, accounts for another 900,000 deaths per year. [...]effective resuscitation at birth can be one of the most effective interventions to reduce neonatal mortality as it targets 1.5 million neonatal deaths per year due to birth asphyxia and/or prematurity. The National Institutes of Child Health and Human Development Global Network for Maternal and Child Health Research simplified versions of the World Health Organization Essential Newborn Care (ENC) program, which included basic resuscitation, and the American Academy of Pediatrics Neonatal Resuscitation Program (NRP). [...]training in a simplified NRP resulted in an additional one-third reduction in early neonatal mortality. Because most neonatal deaths occur in the lowest resource settings, a second trial was conducted in Africa, Southeast Asia, Central America, and South America with most births occurring at home and attended by traditional birth attendants or nurses.

Diabetes-related lower limb amputation (LLA) is a leading cause of disability globally, impacting individuals' physical and mental health, and ultimately their quality of life. Physical activity can reduce risk of chronic disease and mortality while improving quality of life. However, people with LLA often have reduced balance and walking ability resulting in sedentary behaviour. We co-created a physical activity intervention, IMproving Physical Activity through Coaching and Technology following Lower Limb Loss (IMPACT-L3), to support physical activity behaviour change in people with dysvasular LLA. To date, no studies have assessed a peer-led physical activity behaviour change intervention for people with LLA. Prior to launching a large trial, a pilot study is required to assess feasibility and optimize design of a future trial. This pilot study is a parallel group randomized controlled trial (RCT) with an embedded qualitative component. The intervention group will have access to once-weekly virtual peer coaching sessions with a peer trained in brief action planning; web-based physical activity modules; and a wearable activity monitor for 8 weeks. The control group will continue usual care and be offered the intervention at the end of the follow-up period. Data on feasibility will be collected including assessment of process, resource, management and treatment indicators. The proposed primary outcomes will be measured at baseline, post-intervention and one month later: total physical activity counts per day measured by the ActiGraphTM activity monitor and self-efficacy measured by the Self-efficacy for Exercise scale. Secondary measures include patient reported outcome measures of physical activity, mobility, depression, social participation, balance confidence and quality of life. Semi-structured interviews will explore feasibility and acceptability of the intervention to participants and peers. This study will inform the design of a definitive RCT to determine the effectiveness of a peer-led physical activity intervention for people with dysvascular LLA.

Background Age-related cognitive decline is a worldwide challenge, highlighting the need for safe, effective interventions that benefit cognition in older adults. Harnessing the immediate and long-term pleiotropic effects of aerobic exercise is one approach that has gained increasing interest. Objective The aim of this review is to provide knowledge on the immediate effects of acute aerobic exercise on cognitive function of healthy older adults and to assess the methodological quality of studies investigating these effects. Methods A database search in PubMed, CINAHL, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, Web of Science, ClinicalTrials.gov and Google Scholar was conducted using a systematic search strategy. Results Fifteen studies were identified and cognitive domains investigated included executive function and visual perception. Results from 14 of 15 studies showed that an acute bout of aerobic exercise can enhance at least one subsequent cognitive performance of healthy older adults when measured within 15 min post-exercise. Conclusion The small number of studies available, the limited domains of cognition investigated, the great variability between research protocols, and the low overall quality rating limits the conclusions that can be drawn. More comprehensive randomised controlled trials are needed to address these limitations and verify the potential benefits of acute aerobic exercise.