Associations between adverse childhood experiences, viral suppression, and quality of life among persons living with HIV in Washington state.

Adverse childhood experiences (ACEs) have been linked to numerous negative health outcomes in adulthood and have been recognized as a hurdle to participating in HIV care. However, few studies have examined the cumulative impact that different types of childhood trauma have on HIV care engagement and HIV outcomes. This study characterized the relationship between ACEs, viral suppression, and health-related quality of life (HRQOL) among persons living with HIV (PLWH). We used HIV surveillance data and self-reported information on ACEs and HRQOL from PLWH in Washington State from 2018-2020. Logistic regression was used to assess the relationship between the quantity and type of ACEs and viral suppression. We used Poisson regression to examine the relationship between ACEs and HRQOL as measured by unhealthy days. The majority of PLWH experienced ≥1 ACE (86.8%). ACEs were not significantly associated with the likelihood of viral suppression (OR ≥4 vs 0 ACEs: 0.49, 95% CI: 0.12-2.09), but ACEs were associated with more unhealthy days experienced in a 30-day period (RR ≥4 vs 0 ACEs: 3.19, 95% CI: 1.59-6.40). These findings provide support that trauma is common among PLWH, and efforts to address the impact of childhood trauma may work to improve quality of life.

PAX Genes in Cardiovascular Development.

The mammalian heart is a four-chambered organ with systemic and pulmonary circulations to deliver oxygenated blood to the body, and a tightly regulated genetic network exists to shape normal development of the heart and its associated major arteries. A key process during cardiovascular morphogenesis is the septation of the outflow tract which initially forms as a single vessel before separating into the aorta and pulmonary trunk. The outflow tract connects to the aortic arch arteries which are derived from the pharyngeal arch arteries. Congenital heart defects are a major cause of death and morbidity and are frequently associated with a failure to deliver oxygenated blood to the body. The Pax transcription factor family is characterised through their highly conserved paired box and DNA binding domains and are crucial in organogenesis, regulating the development of a wide range of cells, organs and tissues including the cardiovascular system. Studies altering the expression of these genes in murine models, notably Pax3 and Pax9, have found a range of cardiovascular patterning abnormalities such as interruption of the aortic arch and common arterial trunk. This suggests that these Pax genes play a crucial role in the regulatory networks governing cardiovascular development.

Healthy for Two/Healthy for You: Design and methods for a pragmatic randomized clinical trial to limit gestational weight gain and prevent obesity in the prenatal care setting.

OBJECTIVE: To compare the effect of Healthy for Two/Healthy for You (H42/H4U), a health coaching program, in prenatal care clinics that serve a racially and economically diverse population, on total gestational weight gain (GWG) (vs. usual care). We hypothesize that compared to usual prenatal care, intervention participants will have lower GWG and lower rates of gestational diabetes mellitus (GDM). METHODS: We report the rationale and design of a pragmatic, parallel arm randomized clinical trial with 380 pregnant patients ≤15 weeks gestation with overweight or obesity from one of 6 academic and community-based obstetrics practices, randomized to either H42/H4U or usual prenatal care in a 1:1 ratio. The study duration is early pregnancy to 6 months postpartum. The primary outcome is total GWG, calculated as the difference between first clinic-assessed pregnancy weight and the weight at 37 weeks gestation. Key maternal and infant secondary outcomes include GDM incidence, weight retention at 6 months postpartum, infant weight, maternal health behaviors and wellness. CONCLUSIONS: This pragmatic clinical trial embeds a pregnancy health coaching program into prenatal care to allow parallel testing compared to usual prenatal care on the outcome of total GWG. The real-world design provides an approach to enhance its sustainability beyond the trial to ultimately improve maternal/child health outcomes and reduce future obesity. TRIAL REGISTRATION: The study was first registered at clinicaltrials.gov on 1/26/21 (NCT04724330).

Cost and impact of scaling up female genital mutilation prevention and care programs: Estimated resource requirements and impact on incidence and prevalence.

PURPOSE: SDG 5.3 targets include eliminating harmful practices such as Female Genital Mutilation (FGM). Limited information is available about levels of investment needed and realistic estimates of potential incidence change. In this work, we estimate the cost and impact of FGM programs in 31 high burden countries. METHODS: This analysis combines program data, secondary data analysis, and population-level costing methods to estimate cost and impact of high and moderate scaleup of FGM programs between 2020 and 2030. Cost per person or community reached was multiplied by populations to estimate costs, and regression analysis was used to estimate new incidence rates, which were applied to populations to estimate cases averted. RESULTS: Reaching the high-coverage targets for 31 countries by 2030 would require an investment of US$ 3.3 billion. This scenario would avert more than 24 million cases of FGM, at an average cost of US$ 134 per case averted. A moderate-coverage scenario would cost US$ 1.6 billion and avert more than 12 million cases of FGM. However, average cost per case averted hides substantial variation based on country dynamics. The most cost-effective investment would be in countries with limited historic change in FGM incidence, with the average cost per case averted between US$ 3 and US$ 90. The next most effective would be those with high approval for FGM, but a preexisting trend downward, where cost per case averted is estimated at around US$ 240. INTERPRETATION: This analysis shows that although data on FGM is limited, we can draw useful findings from population-level surveys and program data to guide resource mobilization and program planning.

The Influence of the LINC00961/SPAAR Locus Loss on Murine Development, Myocardial Dynamics, and Cardiac Response to Myocardial Infarction.

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR (small regulatory polypeptide of amino acid response) locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression, we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line. We investigated post-natal growth and development, basal cardiac function, the cardiac functional response, and tissue-specific response to myocardial infarction. To investigate the influence of the LINC00961/SPAAR locus on longitudinal growth, cardiac function, and response to myocardial infarction, we used a novel CRISPR/Cas9 locus knockout mouse line. Data mining suggested that SPAAR is predominantly expressed in human cardiac endothelial cells and fibroblasts, while murine LINC00961 expression is hypoxia-responsive in mouse endothelial cells. LINC00961-/- mice displayed a sex-specific delay in longitudinal growth and development, smaller left ventricular systolic and diastolic areas and volumes, and greater risk area following myocardial infarction compared with wildtype littermates. These data suggest the LINC00961/SPAAR locus contributes to cardiac endothelial cell and fibroblast function and hypoxic response, growth and development, and basal cardiovascular function in adulthood.

The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function.

AIMS: Long non-coding RNAs (lncRNAs) play functional roles in physiology and disease, yet understanding of their contribution to endothelial cell (EC) function is incomplete. We identified lncRNAs regulated during EC differentiation and investigated the role of LINC00961 and its encoded micropeptide, small regulatory polypeptide of amino acid response (SPAAR), in EC function. METHODS AND RESULTS: Deep sequencing of human embryonic stem cell differentiation to ECs was combined with Encyclopedia of DNA Elements (ENCODE) RNA-seq data from vascular cells, identifying 278 endothelial enriched genes, including 6 lncRNAs. Expression of LINC00961, first annotated as an lncRNA but reassigned as a protein-coding gene for the SPAAR micropeptide, was increased during the differentiation and was EC enriched. LINC00961 transcript depletion significantly reduced EC adhesion, tube formation, migration, proliferation, and barrier integrity in primary ECs. Overexpression of the SPAAR open reading frame increased tubule formation; however, overexpression of the full-length transcript did not, despite production of SPAAR. Furthermore, overexpression of an ATG mutant of the full-length transcript reduced network formation, suggesting a bona fide non-coding RNA function of the transcript with opposing effects to SPAAR. As the LINC00961 locus is conserved in mouse, we generated an LINC00961 locus knockout (KO) mouse that underwent hind limb ischaemia (HLI) to investigate the angiogenic role of this locus in vivo. In agreement with in vitro data, KO animals had a reduced capillary density in the ischaemic adductor muscle after 7 days. Finally, to characterize LINC00961 and SPAAR independent functions in ECs, we performed pull-downs of both molecules and identified protein-binding partners. LINC00961 RNA binds the G-actin sequestering protein thymosin beta-4x (Tß4) and Tß4 depletion phenocopied the overexpression of the ATG mutant. SPAAR binding partners included the actin-binding protein, SYNE1. CONCLUSION: The LINC00961 locus regulates EC function in vitro and in vivo. The gene produces two molecules with opposing effects on angiogenesis: SPAAR and LINC00961.

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1-Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

Pediatric Emergency Department Staff Preferences for a Critical Incident Stress Debriefing.

INTRODUCTION: There are significant and negative psychological effects that can occur in nursing staff caring for pediatric patients experiencing critical incidents. Debriefings can provide relief from the stressors caused by critical incidents. Adapting a pre-existing critical incident stress debriefing (CISD) process to ED staff is 1 way to provide staff debriefing. METHODS: This qualitative study used an emerging, descriptive design. Focus groups, (n = 3, total participant n = 19), consisting of pediatric emergency nurses and a nursing assistant, met for a minimum of 63 to a maximum of 83 minutes. Participants provided feedback on current debriefing strategies and suggestions for adapting a currently existing critical incident stress- debriefing process. Focus group questions included "Have you participated in a structured debriefing process? If so, tell us about it" and "What would you like to see in a structured debriefing process?" RESULTS: A theoretical orientation content analysis revealed 1 main theme-Clearing the Air and Finding Answers-and 6 subthemes: Current Debriefing Strategies; Positive Reinforcement; Constructive Critique; Clinical, Not Emotional; I've already moved on; and CISD Structure. DISCUSSION: Pediatric ED staff de-stress in a variety of ways, and a nonmandatory, formalized CISD process-open to staff involved and facilitated by an emergency nurse-could provide additional relief from stress. This debriefing process should include positive feedback and critiques to help improve care processes, information about mechanism of injury, and should occur before the end of shift or within 12 to 24 hours of the incident. Staff may deal with personal feelings outside of debriefing.

Pushing the envelope through the Global Financing Facility: potential impact of mobilising additional support to scale-up life-saving interventions for women, children and adolescents in 50 high-burden countries.

INTRODUCTION: The Global Financing Facility (GFF) was launched to accelerate progress towards the Sustainable Development Goals (SDGs) through scaled and sustainable financing for Reproductive, Maternal, Newborn, Child and Adolescent Health and Nutrition (RMNCAH-N) outcomes. Our objective was to estimate the potential impact of increased resources available to improve RMNCAH-N outcomes, from expanding and scaling up GFF support in 50 high-burden countries. METHODS: The potential impact of GFF was estimated for the period 2017-2030. First, two scenarios were constructed to reflect conservative and ambitious assumptions around resources that could be mobilised by the GFF model, based on GFF Trust Fund resources of US$2.6 billion. Next, GFF impact was estimated by scaling up coverage of prioritised RMNCAH-N interventions under these resource scenarios. Resource availability was projected using an Excel-based model and health impacts and costs were estimated using the Lives Saved Tool (V.5.69 b9). RESULTS: We estimate that the GFF partnership could collectively mobilise US$50-75 billion of additional funds for expanding delivery of life-saving health and nutrition interventions to reach coverage of at least 70% for most interventions by 2030. This could avert 34.7 million deaths-including preventable deaths of mothers, newborns, children and stillbirths-compared with flatlined coverage, or 12.4 million deaths compared with continuation of historic trends. Under-five and neonatal mortality rates are estimated to decrease by 35% and 34%, respectively, and stillbirths by 33%. CONCLUSION: The GFF partnership through country- contextualised prioritisation and innovative financing could go a long way in increasing spending on RMNCAH-N and closing the existing resource gap. Although not all countries will reach the SDGs by relying on gains from the GFF platform alone, the GFF provides countries with an opportunity to significantly improve RMNCAH-N outcomes through achievable, well-directed changes in resource allocation.

Anti-Müllerian hormone overexpression restricts preantral ovarian follicle survival.

Anti-Müllerian hormone (AMH) is an ovarian regulator that affects folliculogenesis. AMH inhibits the developmental activation of the dormant primordial follicles and the oocyte within. In more mature follicles, AMH reduces granulosa cell sensitivity to follicle-stimulating hormone (FSH). We examined the effects of AMH overexpression on the stages of ovarian folliculogenesis, and the development of embryos, with a transgenic mouse that overexpresses human AMH in central nervous system neurons under the control of the mouse Thy1.2 promoter (Thy1.2-AMHTg mice). These mice are severely sub-fertile, despite relatively normal ovulation rates. The embryos of Thy1.2-AMHTg females exhibited delayed preimplantation development and extensive mid-gestation fetal resorption. Young Thy1.2-AMHTg mouse ovaries exhibited only a slight reduction in the rate of primordial follicle activation but large declines in the number of developing follicles surviving past the primary stage. It was expected that Thy1.2-AMHTg mice would retain more primordial follicles as they aged, but at 5 months, their number was significantly reduced relative to wild-type females. These data indicate that moderate elevations in AMH levels can severely restrict reproductive output and the number of developing follicles in the ovary. This evidence suggests that early antral follicles are a target for AMH signaling, which may regulate early follicle survival.

Lives Saved Tool (LiST) costing: a module to examine costs and prioritize interventions.

BACKGROUND: Achieving the Sustainable Development Goals will require careful allocation of resources in order to achieve the highest impact. The Lives Saved Tool (LiST) has been used widely to calculate the impact of maternal, neonatal and child health (MNCH) interventions for program planning and multi-country estimation in several Lancet Series commissions. As use of the LiST model increases, many have expressed a desire to cost interventions within the model, in order to support budgeting and prioritization of interventions by countries. A limited LiST costing module was introduced several years ago, but with gaps in cost types. Updates to inputs have now been added to make the module fully functional for a range of uses. METHODS: This paper builds on previous work that developed an initial version of the LiST costing module to provide costs for MNCH interventions using an ingredients-based costing approach. Here, we update in 2016 the previous econometric estimates from 2013 with newly-available data and also include above-facility level costs such as program management. The updated econometric estimates inform percentages of intervention-level costs for some direct costs and indirect costs. These estimates add to existing values for direct cost requirements for items such as drugs and supplies and required provider time which were already available in LiST Costing. RESULTS: Results generated by the LiST costing module include costs for each intervention, as well as disaggregated costs by intervention including drug and supply costs, labor costs, other recurrent costs, capital costs, and above-service delivery costs. These results can be combined with mortality estimates to support prioritization of interventions by countries. CONCLUSIONS: The LiST costing module provides an option for countries to identify resource requirements for scaling up a maternal, neonatal, and child health program, and to examine the financial impact of different resource allocation strategies. It can be a useful tool for countries as they seek to identify the best investments for scarce resources. The purpose of the LiST model is to provide a tool to make resource allocation decisions in a strategic planning process through prioritizing interventions based on resulting impact on maternal and child mortality and morbidity.

Impact of malaria interventions on child mortality in endemic African settings: comparison and alignment between LiST and Spectrum-Malaria model.

BACKGROUND: In malaria-endemic countries, malaria prevention and treatment are critical for child health. In the context of intervention scale-up and rapid changes in endemicity, projections of intervention impact and optimized program scale-up strategies need to take into account the consequent dynamics of transmission and immunity. METHODS: The new Spectrum-Malaria program planning tool was used to project health impacts of Insecticide-Treated mosquito Nets (ITNs) and effective management of uncomplicated malaria cases (CMU), among other interventions, on malaria infection prevalence, case incidence and mortality in children 0-4 years, 5-14 years of age and adults. Spectrum-Malaria uses statistical models fitted to simulations of the dynamic effects of increasing intervention coverage on these burdens as a function of baseline malaria endemicity, seasonality in transmission and malaria intervention coverage levels (estimated for years 2000 to 2015 by the World Health Organization and Malaria Atlas Project). Spectrum-Malaria projections of proportional reductions in under-five malaria mortality were compared with those of the Lives Saved Tool (LiST) for the Democratic Republic of the Congo and Zambia, for given (standardized) scenarios of ITN and/or CMU scale-up over 2016-2030. RESULTS: Proportional mortality reductions over the first two years following scale-up of ITNs from near-zero baselines to moderately higher coverages align well between LiST and Spectrum-Malaria -as expected since both models were fitted to cluster-randomized ITN trials in moderate-to-high-endemic settings with 2-year durations. For further scale-up from moderately high ITN coverage to near-universal coverage (as currently relevant for strategic planning for many countries), Spectrum-Malaria predicts smaller additional ITN impacts than LiST, reflecting progressive saturation. For CMU, especially in the longer term (over 2022-2030) and for lower-endemic settings (like Zambia), Spectrum-Malaria projects larger proportional impacts, reflecting onward dynamic effects not fully captured by LiST. CONCLUSIONS: Spectrum-Malaria complements LiST by extending the scope of malaria interventions, program packages and health outcomes that can be evaluated for policy making and strategic planning within and beyond the perspective of child survival.

Financing transformative health systems towards achievement of the health Sustainable Development Goals: a model for projected resource needs in 67 low-income and middle-income countries.

BACKGROUND: The ambitious development agenda of the Sustainable Development Goals (SDGs) requires substantial investments across several sectors, including for SDG 3 (healthy lives and wellbeing). No estimates of the additional resources needed to strengthen comprehensive health service delivery towards the attainment of SDG 3 and universal health coverage in low-income and middle-income countries have been published. METHODS: We developed a framework for health systems strengthening, within which population-level and individual-level health service coverage is gradually scaled up over time. We developed projections for 67 low-income and middle-income countries from 2016 to 2030, representing 95% of the total population in low-income and middle-income countries. We considered four service delivery platforms, and modelled two scenarios with differing levels of ambition: a progress scenario, in which countries' advancement towards global targets is constrained by their health system's assumed absorptive capacity, and an ambitious scenario, in which most countries attain the global targets. We estimated the associated costs and health effects, including reduced prevalence of illness, lives saved, and increases in life expectancy. We projected available funding by country and year, taking into account economic growth and anticipated allocation towards the health sector, to allow for an analysis of affordability and financial sustainability. FINDINGS: We estimate that an additional $274 billion spending on health is needed per year by 2030 to make progress towards the SDG 3 targets (progress scenario), whereas US$371 billion would be needed to reach health system targets in the ambitious scenario-the equivalent of an additional $41 (range 15-102) or $58 (22-167) per person, respectively, by the final years of scale-up. In the ambitious scenario, total health-care spending would increase to a population-weighted mean of $271 per person (range 74-984) across country contexts, and the share of gross domestic product spent on health would increase to a mean of 7·5% (2·1-20·5). Around 75% of costs are for health systems, with health workforce and infrastructure (including medical equipment) as the main cost drivers. Despite projected increases in health spending, a financing gap of $20-54 billion per year is projected. Should funds be made available and used as planned, the ambitious scenario would save 97 million lives and significantly increase life expectancy by 3·1-8·4 years, depending on the country profile. INTERPRETATION: All countries will need to strengthen investments in health systems to expand service provision in order to reach SDG 3 health targets, but even the poorest can reach some level of universality. In view of anticipated resource constraints, each country will need to prioritise equitably, plan strategically, and cost realistically its own path towards SDG 3 and universal health coverage. FUNDING: WHO.

Spectrum-Malaria: a user-friendly projection tool for health impact assessment and strategic planning by malaria control programmes in sub-Saharan Africa.

BACKGROUND: Scale-up of malaria prevention and treatment needs to continue but national strategies and budget allocations are not always evidence-based. This article presents a new modelling tool projecting malaria infection, cases and deaths to support impact evaluation, target setting and strategic planning. METHODS: Nested in the Spectrum suite of programme planning tools, the model includes historic estimates of case incidence and deaths in groups aged up to 4, 5-14, and 15+ years, and prevalence of Plasmodium falciparum infection (PfPR) among children 2-9 years, for 43 sub-Saharan African countries and their 602 provinces, from the WHO and malaria atlas project. Impacts over 2016-2030 are projected for insecticide-treated nets (ITNs), indoor residual spraying (IRS), seasonal malaria chemoprevention (SMC), and effective management of uncomplicated cases (CMU) and severe cases (CMS), using statistical functions fitted to proportional burden reductions simulated in the P. falciparum dynamic transmission model OpenMalaria. RESULTS: In projections for Nigeria, ITNs, IRS, CMU, and CMS scale-up reduced health burdens in all age groups, with largest proportional and especially absolute reductions in children up to 4 years old. Impacts increased from 8 to 10 years following scale-up, reflecting dynamic effects. For scale-up of each intervention to 80% effective coverage, CMU had the largest impacts across all health outcomes, followed by ITNs and IRS; CMS and SMC conferred additional small but rapid mortality impacts. DISCUSSION: Spectrum-Malaria's user-friendly interface and intuitive display of baseline data and scenario projections holds promise to facilitate capacity building and policy dialogue in malaria programme prioritization. The module's linking to the OneHealth Tool for costing will support use of the software for strategic budget allocation. In settings with moderately low coverage levels, such as Nigeria, improving case management and achieving universal coverage with ITNs could achieve considerable burden reductions. Projections remain to be refined and validated with local expert input data and actual policy scenarios.

Modeling the impact of HIV chemoprophylaxis strategies among men who have sex with men in the United States: HIV infections prevented and cost-effectiveness.

BACKGROUND AND OBJECTIVE: HIV chemoprophylaxis may be a future prevention strategy to help control the global epidemic of HIV/AIDS. Safety and efficacy trials of two agents are currently underway. We assess the expected number of HIV cases prevented and cost-effectiveness of a hypothetical HIV chemoprophylaxis program among men who have sex with men in a large US city. DESIGN AND METHODS: We developed a stochastic compartmental mathematical model using HIV/AIDS surveillance data to simulate the HIV epidemic and the impact of a 5-year chemoprophylaxis program under varying assumptions for epidemiological, behavioral, programmatic and cost parameters. We estimated program effectiveness and costs from the perspective of the US healthcare system compared with current HIV prevention practices. The main outcome measures were number of HIV infections prevented and incremental cost per quality-adjusted life-years saved. RESULTS: A chemoprophylaxis program targeting 25% of high-risk men who have sex with men in New York City could prevent 780 (4%) to 4510 (23%) of the 19 510 HIV infections predicted to occur among all men who have sex with men in New York City in 5 years. More than half of prevented infections would be among those not taking chemoprophylaxis but who benefit from reduced HIV prevalence in the community. Under base-case assumptions, incremental cost was US$ 31 970 per quality-adjusted life-years saved. The program was cost-effective under most variations in efficacy, mechanism of protection and adherence. CONCLUSION: HIV chemoprophylaxis among high-risk men who have sex with men in a major US city could prevent a significant number of HIV infections and be cost-effective.