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Despite efforts to increase childhood vaccination coverage in the Democratic Republic of the Congo (DRC), approximately 20% of infants have not started their routine immunization schedule (zero-dose). The present study aims to evaluate the relative influence of geospatial access to health facilities and caregiver perceptions of vaccines on the vaccination status of children in rural DRC. Pooled data from two consecutive nationwide immunization surveys conducted in 2022 and 2023 were used. Geographic accessibility was assessed based on travel time from households to their nearest health facility using the AccessMod 5 model. Caregiver attitudes to vaccination were assessed using the survey question How good do you think vaccines are for your child? We used logistic regression to assess the relationship between geographic accessibility, caregiver attitudes toward vaccination, and their childs vaccination status. Geographic accessibility to health facilities was high in rural DRC, with 88% of the population living within an hours walk to a health facility. Responding that vaccines are Bad, Very Bad, or Dont Know relative to Very Good for children was associated with a many-fold increased odds of a zero-dose status (ORs 69.3 [95%CI: 63.4-75.8]) compared to the odds for those living 60+ min from a health facility, relative to

Recognizing the influence of social determinants on health and development, health care has increasingly advocated for interventions that target upstream factors as part of routine pediatric care delivery. In response, clinic-based social risk screening and referral programs have proliferated wherein patients are screened for health-related social needs (HRSNs, such as food and housing insecurity) and referred to community-based organizations (CBOs) and social service providers to address those needs. In recent years, an array of digital platforms, known as Social Health Access and Referral Platforms (SHARPs), have emerged to facilitate the scale and implementation of these models amidst growing system demand. Recent evidence on the effectiveness of social risk screen and refer models and SHARPs has been mixed, giving researchers pause and calling for more nuanced understanding of the limitations of such models, especially for promoting child and family health. Design thinking informed by the Life-Course Health Development (LCHD) framework provides a particularly useful lens for synthesizing emerging limitations of such models in the pediatric context, given the dynamic and developmentally-driven circumstances that shape family health and well-being in the early life course. By (1) focusing on addressing deficits-based social risks, (2) scoping to act upon narrow, downstream needs, (3) timing to react to social needs that have already caused harm rather than preventing them, and (4) limiting scale to individual-by-individual responses rather than structural and population-wide interventions, the current design of prevailing social risk screen and refer programs fundamentally limits their potential impact and misses opportunities to improve health equity over the life course. How can health care, social care, and technology partners move forward in collaboration with families and communities to better support equitable lifelong health and social development? In this narrative review, we will summarize the current design, implementation, and limitations of the predominant social risk screen and refer approach in the context of early childhood and adolescent care delivery. We then will apply LCHD principles to advance and improve on this approach from a reactionary focus towards a Family Journey Model that better supports life course health development.

IntroductionTraditional perinatal care alone cannot address the social and structural determinants that drive disparities in adverse birth outcomes. Despite the wide acceptance of partnerships between healthcare systems and social service agencies to address this challenge, there needs to be more research on the implementation factors that facilitate (or hinder) cross-sector partnerships, particularly from the perspective of community-based organizations. This study aimed to integrate the views of healthcare staff and community-based partner organizations to describe the implementation of a cross-sector partnership designed to address social and structural determinants in pregnancy.MethodsWe used a mixed methods design (in-depth interviews and social network analysis) to integrate the perspectives of healthcare clinicians and staff with those of community-based partner organizations to identify implementation factors related to cross-sector partnerships.ResultsWe identified seven implementation factors related to three overarching themes: relationship-centered care, barriers and facilitators of cross-sector partnerships, and strengths of a network approach to cross-sector collaboration. Findings emphasized establishing relationships between healthcare staff, patients, and community-based partner organizations.ConclusionThis study provides practical insights for healthcare organizations, policymakers, and community organizations that aim to improve access to social services among historically marginalized perinatal populations.

Childhood adversity and its structural causes drive lifelong and intergenerational inequities in health and well-being. Health care systems increasingly understand the influence of childhood adversity on health outcomes but cannot treat these deep and complex issues alone. Cross-sector partnerships, which integrate health care, food support, legal, housing, and financial services among others, are becoming increasingly recognized as effective approaches address health inequities. What principles should guide the design of cross-sector partnerships that address childhood adversity and promote Life Course Health Development (LCHD)? The complex effects of childhood adversity on health development are explained by LCHD concepts, which serve as the foundation for a cross-sector partnership that optimizes lifelong health. We review the evolution of cross-sector partnerships in health care to inform the development of an LCHD-informed partnership framework geared to address childhood adversity and LCHD. This framework outlines guiding principles to direct partnerships toward life course-oriented action: (1) proactive, developmental, and longitudinal investment; (2) integration and codesign of care networks; (3) collective, community and systemic impact; and (4) equity in praxis and outcomes. Additionally, the framework articulates foundational structures necessary for implementation: (1) a shared cross-sector theory of change; (2) relational structures enabling shared leadership, trust, and learning; (3) linked data and communication platforms; and (4) alternative funding models for shared savings and prospective investment. The LCHD-informed cross-sector partnership framework presented here can be a guide for the design and implementation of cross-sector partnerships that effectively address childhood adversity and advance health equity through individual-, family-, community-, and system-level intervention.

Myotonic dystrophy type I (DM1) is a multisystemic autosomal-dominant inherited human disorder that is caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of DMPK. Toxic RNAs expressed from such repetitive sequences can be eliminated using CRISPR-mediated RNA targeting, yet evidence of its in vivo efficacy and durability is lacking. Here, using adult and neonatal mouse models of DM1, we show that intramuscular or systemic injections of adeno-associated virus (AAV) vectors encoding nuclease-dead Cas9 and a single-guide RNA targeting CUG repeats results in the expression of the RNA-targeting Cas9 for up to three months, redistribution of the RNA-splicing protein muscleblind-like splicing regulator 1, elimination of foci of toxic RNA, reversal of splicing biomarkers and amelioration of myotonia. The sustained reversal of DM1 phenotypes provides further support that RNA-targeting Cas9 is a viable strategy for treating DM1 and other MRE-associated diseases.

BACKGROUND: Poverty and financial stress affect prenatal health and well-being as well as early childhood development. This study sought to examine interest in clinic-based financial services to address financial stress in low-income, Medicaid-enrolled prenatal patients and its relationship with self-reported social risks. METHODS: We conducted a cross-sectional study of patients at a large safety-net prenatal clinic. Participants completed a written survey on interest in linkage to financial services, poverty-related financial stress, difficulty affording social needs, and interest in services to address material hardships. We compared interest in financial and social needs services by level of financial stress using multivariate regression. RESULTS: Respondents (N = 108) were entirely Medicaid-enrolled, with a majority identifying as Hispanic/Latinx (57%) or Black/African American (20%). Sixty-four percent indicated interest in connection to any of the financial services surveyed. Interest was highest in employment (52%), savings and budgeting (49%), job training/adult education (49%), and financial counseling (48%) services. Individuals with high financial stress, compared to those with low financial stress, expressed a higher level of interest in financial services (aRR = 1.61 [95% CI 1.12-2.39]). Interest in financial services was associated with difficulty affording social needs (aRR = 2.24 [95% CI 1.33-4.43]) and interest in services addressing social needs (aRR = 1.45 [95% CI 1.13-1.92]). CONCLUSION: In this study of low-income, Medicaid-insured prenatal patients, there was a high degree of interest in clinic-based financial services. Integrating financial services into prenatal health care appears to be an approach that low-income patients would be interested in to directly address poverty and financial stress.

Glial cells regulate multiple aspects of synaptogenesis. In the absence of Schwann cells, a peripheral glial cell, motor neurons initially innervate muscle but then degenerate. Here, using a genetic approach, we show that neural activity-regulated negative factors produced by muscle drive neurodegeneration in Schwann cell-deficient mice. We find that thrombin, the hepatic serine protease central to the hemostatic coagulation cascade, is one such negative factor. Trancriptomic analysis shows that expression of the antithrombins serpin C1 and D1 is significantly reduced in Schwann cell-deficient mice. In the absence of peripheral neuromuscular activity, neurodegeneration is completely blocked, and expression of prothrombin in muscle is markedly reduced. In the absence of muscle-derived prothrombin, neurodegeneration is also markedly reduced. Together, these results suggest that Schwann cells regulate NMJs by opposing the effects of activity-regulated, muscle-derived negative factors and provide the first genetic evidence that thrombin plays a central role outside of the coagulation system.

BackgroundThe Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context.MethodsWe used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI).FindingsBetween 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa.InterpretationDeclines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden.FundingBill & Melinda Gates Foundation.

Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator- activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD- like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders., The PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three subtypes--termed PPAR-α, PPAR-δ and PPAR-γ--serve as lipid sensors in response to increased energy requirements [...]

Abstract Background The tissue factor (TF)-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS. Methods This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO2/FiO2 ≤ 300 mm). Eighteen patients (6 per cohort) were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters. Results Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population. Conclusions Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS. Trial registration ClinicalTrials.gov: NCT01438853

Background: There is uncertainty about the burden of hospitalization associated with respiratory syncytial virus (RSV) and influenza in children, including those with underlying medical conditions.Methods: We applied previously developed methodology to Health Care Cost and Utilization Project hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003 and 2010.Results: The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2,381 (95% CI(2252,2515)) in children <1 year of age; 710.6 (609.1, 809.2) (1 y old); 395 (327.7, 462.4) (2 y old); 211.3 (154.6, 266.8) (3 y old); 111.1 (62.4, 160.1) (4 y old); 72.3 (29.3, 116.4) (5-6 y of age); 35.6 (9.9,62.2) (7-11 y of age); and 39 (17.5, 60.6) (12-17 y of age). The corresponding rates of influenza-associated hospitalization were lower, ranging from 181 (142.5, 220.3) in <1 year old to 17.9 (11.7, 24.2) in 12-17 years of age. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups <5 y ranged between 3.1 (2.1, 4.7) (<1 y old) and 6.7 (4.2, 11.8) (2 y old; the corresponding risks for influenza-related hospitalization ranged from 2.8 (2.1, 4) (<1y old) to 4.9 (3.8, 6.4) (3 y old).Conclusion: RSV-associated hospitalization rates in young children are high and decline rapidly with age. There are additional risks for both RSV and influenza hospitalization associated with a prior diagnosis of asthma, with the rates of RSV-related hospitalization in the youngest children diagnosed with asthma being particularly high. [ABSTRACT FROM AUTHOR]