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Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

Abstract Background and aim Digital interventions for depression and anxiety can be as effective as face-to-face therapy. One in six workers experience some form of mental health problems, making the workplace a potential avenue to deliver mental health interventions as part of a stepped care model. This study aimed to assess the acceptability, feasibility, and preliminary efficacy of a digital cognitive behavioural therapy (dCBT) on depression and anxiety for employees in the workplace. Methods A mixed-methods evaluation of employees allocated to dCBT (n=25), or a waitlist control group (n=27) was used to assess five feasibility objectives related to recruitment of employers and employees, engagement, study procedure and preliminary efficacy of the intervention. Quantitative outcome measures and qualitative interviews at 8 weeks post-randomisation were used. Quantitative outcomes were also assessed within subject at 3-, 6-, and 12-month follow-up. Qualitative data was analysed using thematic and framework analysis in Nvivo, whilst quantitative outcomes were analysed using mixed effect linear models between and within subject in R and SPSS. Results Thirty-Three businesses agreed to facilitate the delivery of three trials run by the University of Warwick in their workplaces. 52 participants consented into the REST trial. Adherence/usage of participants of the treatment platform was just over 50% across the whole sample. There was a reduction in depression and anxiety symptoms post-intervention and at follow-up timepoints across all participants and over time although there were no statistically significant between group differences. High acceptability and satisfaction of the intervention were reported by participants based on qualitative interview data at post-intervention. Conclusions Results from this feasibility study suggests that the dCBT programme (REST) was acceptable and shows improvement in depression and anxiety symptoms, albeit not over and above the treatment effects in the control group. Recruitment of participants and engagement with the intervention made the feasibility of the delivery somewhat challenging. With better recruitment promotion and engagement strategies, as well as implementing the learnings from the feasibility trial, a fully powered study can inform the efficacy of the REST intervention. Trial registration The study is registered in the BMC Springer Nature ISRCTN registry ISRCTN31161020 (registered on 08/06/2021).

Abstract Background Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient’s symptoms, opening new avenues for diagnosis and management. Case Presentation We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). Conclusion This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

Ethnic and racial sexual minority men with HIV have a disproportionately higher risk of HIV-related cardiovascular disease (CVD). There is a lack of tailored and culturally salient behavioral interventions to address HIV-related chronic illness in ethnic and racial sexual minority men, and literature on their understanding and awareness of modifiable behavioral risks is limited. The purpose of this study was to assess illness perceptions about HIV and HTN, and describe physical activity, tobacco, and e-cigarette use in Black and Latinx sexual minority men living with HIV. We used the validated Illness Perception Questionnaire-Revised (IPQ-R) to assess perceptions about two interrelated chronic diseases, HIV and CVD. To assess CVD behavioral risk, we assessed physical activity using the International Physical Activity Questionnaire. Tobacco and e-cigarette use were assessed using items from the Behavioral Risk Factor Surveillance System. Sleep difficulties were the most prevalent symptom attributed to HIV, and were statistically associated with fatigue, upset stomach, and loss of strength. Anxiety was reported to be caused by HIV (57%) and HTN (39%). Half of the participants engaged in vigorous activity for 128 min (SD = 135) daily, and 63% engaged in moderate activity for 94 min (SD = 88) daily. Over a third reported current tobacco use and 20% reported current e-cigarette use. This study provides formative data to better understand how Black and Latinx sexual minority men with HIV perceive intersecting chronic illnesses and their engagement in modifiable CVD risk behaviors. Sleep, mental health disparities, and financial hardships were commonly reported. More research is needed to address intersecting chronic illnesses and mental health conditions that are influenced by social positioning over the life course, and impact CVD risk factors. This study was not registered.

The personal, social, and academic challenges during the transition from high school to college contribute to lower retention rates and lower GPAs. These challenges are even more pronounced for historically underserved populations. In light of the COVID-19 pandemic, students face new challenges and a lack of access to the typical resources and events to assist with their transition. In response to these challenges, an online summer support program was developed that focused on building academic self-efficacy, fostering a sense of belonging and connection to faculty and peers, and connecting students to campus resources. Survey results showed greater connection and self-efficacy for participants, and a one-way between-subjects ANCOVA indicated significantly higher first-term GPAs for those who participated (over 0.3 points higher on a 4-point scale). Initial qualitative interviews indicated overall positive student perceptions of their participation and the program's benefit.

Abstract/Introduction: Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1–4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population5–9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such asFGF21, ADIPOQ, GCGandIL6showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liverPCSK9) as well as genes encoding enzymes producing metabolites (adiposePNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource asGene-DerivedCorrelationsAcrossTissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

Abstract Background The U.S. mpox outbreak in 2022 introduced new and exacerbated existing challenges that disproportionately stigmatize gay, bisexual, and other sexual minoritized men (GBSMM). This study contextualizes the perceptions, susceptibility, and lived experiences of the mpox outbreak among GBSMM in the U.S. using an intersectional framework. Methods Between September 2022 to February 2023, we conducted 33 semi-structured qualitative interviews with purposively sampled GBSMM in the Northeast and the South region of the United States on various aspects related to their experience during the mpox outbreak. Results We identified four themes: (1) understanding and conceptualizations of mpox, (2) mpox vaccine availability and accessibility, (3) mpox vaccine hesitancy and mistrust, and (4) call to action and recommendations. GBSMM collectively discussed the elevated mpox stigmatization and homophobic discourse from mainstream social media and news outlets. GBSMM also discussed the lack of availability of mpox vaccines, unclear procedures to receive the vaccine, and continued mistrust in government, non-government, and other institutions of health that were complicit in anti-LGBTQ + narratives related to mpox. However, they expressed that these challenges may be addressed through more LGTBQ + representation and leveraging ways to empower these communities. Conclusion GBSMM have mpox experiences that are distinct and multifaceted. Effectively addressing mpox and mitigating public health emergencies for GBSMM requires prioritizing destigmatizing communication channels and vaccine distribution strategies by centering their stories and lived experiences to advance health equity.

Abstract The SHiP-charm project was proposed to measure the associated charm production induced by 400 GeV/c protons in a thick target, including the contribution from cascade production. An optimisation run was performed in July 2018 at CERN SPS using a hybrid setup. The high resolution of nuclear emulsions acting as vertex detector was complemented by electronic detectors for kinematic measurements and muon identification. Here we present first results on the analysis of nuclear emulsions exposed in the 2018 run, which prove the capability of reconstructing proton interaction vertices in a harsh environment, where the signal is largely dominated by secondary particles produced in hadronic and electromagnetic showers within the lead target.

Abstract Background Family planning has significant health and social benefits, but in settings like Uganda, is underutilized due to prevalent community and religious norms promoting large family size and gender inequity. Family Health = Family Wealth (FH = FW) is a multi-level, community-based intervention that used community dialogues grounded in Campbell and Cornish’s social psychological theory of transformative communication to reshape individual endorsement of community norms that negatively affect gender equitable reproductive decision-making among couples in rural Uganda. Methods This study aimed to qualitatively evaluate the effect of FH = FW’s community dialogue approach on participants’ personal endorsement of community norms counter to family planning acceptance and gender equity. A pilot quasi-experimental controlled trial was implemented in 2021. This paper uses qualitative, post-intervention data collected from intervention arm participants (N = 70) at two time points: 3 weeks post-intervention (in-depth interviews, n = 64) and after 10-months follow-up (focus group discussions [n = 39] or semi-structured interviews [n = 27]). Data were analyzed through thematic analysis. Results The community dialogue approach helped couples to reassess community beliefs that reinforce gender inequity and disapproval of family planning. FH = FW’s inclusion of economic and relationship content served as key entry points for couples to discuss family planning. Results are presented in five central themes: (1) Community family size expectations were reconsidered through discussions on economic factors; (2) Showcasing how relationship health and gender equity are central to economic health influenced men’s acceptance of gender equity; (3) Linking relationship health and family planning helped increase positive attitudes towards family planning and the perceived importance of shared household decision-making to family wellness; (4) Program elements to strengthen relationship skills helped to translate gender equitable attitudes into changes in relationship dynamics and to facilitate equitable family planning communication; (5) FH = FW participation increased couples’ collective family planning (and overall health) decision-making and uptake of contraceptive methods. Conclusion Community dialogues may be an effective intervention approach to change individual endorsement of widespread community norms that reduce family planning acceptance. Future work should continue to explore innovative ways to use this approach to increase gender equitable reproductive decision-making among couples in settings where gender, religious, and community norms limit reproductive autonomy. Future evaluations of this work should aim to examine change in norms at the community-level. Trial registration Clinicaltrials.gov (NCT04262882).

Abstract Background Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. Methods This is a pre‐specified secondary analysis of a randomized, double‐blind, placebo‐controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once‐daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40‐week follow‐up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least‐square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. Results Among the 128 participants with follow‐up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow‐up of 36 weeks was −2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: −0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was −0.24% (95% CI, −0.41 to −0.06, P‐value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow‐up with liraglutide, but there was no change with placebo. Conclusions In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once‐daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Abstract The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been associated with worse outcomes from severe traumatic brain injury (TBI). The NLRP3 inflammasome is also strongly associated with other pro-inflammatory conditions, such as obesity. Little is known about the potential effect of mild TBI (mTBI) on the NLRP3 inflammasome and the extent to which modifying factors, such as obesity, may augment the inflammatory response to mTBI. The purpose of this study was to evaluate the association of NLRP3 inflammasome proteins with obese body mass index (BMI ≥ 30) within 24 h of mTBI after presenting to a level 1 trauma center emergency department. This is a secondary analysis of prospectively enrolled patients with mTBI who presented to the emergency department of one U.S. Level 1 trauma center from 2013 to 2018 (n = 243). A series of regression models were built to evaluate the association of NLRP3 proteins obtained from blood plasma within 24 h of injury and BMI as well as the potential interaction effect of higher BMI with NLRP3 proteins (n = 243). A logistic regression model revealed a significant association between IL-18 (p

Children on the autism spectrum often experience anxiety. Mindfulness is growing in popularity as a method to support children with anxiety; however, there is limited evidence on mindfulness for children on the autism spectrum. This study investigated the feasibility of a 10-week group-based mindfulness intervention for 14 children on the autism spectrum. A one-group pre-post design determined outcomes of anxiety (caregiver and child report), mindful attention, and wellbeing (child report). Interviews explored children's and caregivers' perceptions. There were no significant differences in outcomes post-intervention. Five themes were identified from interviews: (1) Children felt calmer; (2) Parents observed differences in anxiety; (3) Breathing and yoga helped; (4) Parents wanted more; and (5) Challenges and benefits of group intervention.

BackgroundSexual minority men with HIV are at an increased risk of cardiovascular disease (CVD) and have been underrepresented in behavioral research and clinical trials. ObjectiveThis study aims to explore perceptions of HIV-related comorbidities and assess the interest in and usability of a virtual environment for CVD prevention education in Black and Latinx sexual minority men with HIV. MethodsThis is a 3-phase pilot behavioral randomized controlled trial. We report on formative phases 1 and 2 that informed virtual environment content and features using qualitative interviews, usability testing, and beta testing with a total of 25 individuals. In phase 1, a total of 15 participants completed interviews exploring HIV-related illnesses of concern that would be used to tailor the virtual environment. In phase 2, usability testing and beta testing were conducted with 10 participants to assess interest, features, and content. ResultsIn phase 1, we found that CVD risk factors included high blood pressure, myocardial infarction, stroke, and diabetes. Cancer (prostate, colon, and others) was a common concern, as were mental health conditions. In phase 2, all participants completed the 12-item usability checklist with favorable feedback within 30 to 60 minutes. Beta-testing interviews suggested (1) mixed perceptions of health and HIV, (2) high risk for comorbid conditions, (3) virtual environment features were promising, and (4) the need for diverse avatar representations. ConclusionsWe identified several comorbid conditions of concern, and findings carry significant implications for mitigating barriers to preventive health screenings, given the shared risk factors between HIV and related comorbidities. Highly rated aspects of the virtual environment were anonymity; meeting others with HIV who identify as gay or bisexual; validating lesbian, gay, bisexual, transgender, queer, and others (LGBTQ+) images and content; and accessibility to CVD prevention education. Critical end-user feedback from beta testing suggested more options for avatar customization in skin, hair, and body representation. Our next phase will test the virtual environment as a new approach to advancing cardiovascular health equity in ethnic and racial sexual minority men with HIV. Trial RegistrationClinicalTrials.gov NCT04061915; https://clinicaltrials.gov/study/NCT05242952 International Registered Report Identifier (IRRID)RR2-10.2196/38348

BackgroundWe report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC).MethodsPatient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test.ResultsFrom September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19.ConclusionsDespite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in

Introduction: Pregnancy represents a stressful period for both women and their families. Whether the family maintains functioning during pregnancy could have significant implications on maternal and child health. In this study, we explored individual- and family-level factors associated with family functioning in adolescent and young adult mothers. Methods: This study was a secondary analysis of 295 young mothers, ages between 15 and 21 years. Multivariate logistic regression models were conducted to estimate adjusted odds ratios of exploratory factors on the risk of being in high family functioning group. The parent study was approved by the Institutional Review Boards at Yale University. Results: The mean score of family functioning was 5.14 out of 7. With the inclusion of individual-level factors (Model 1), significant associations were observed between high family functioning and having ever attended religious services (OR?=?2.22, 95% CI: 1.20?4.09), low perceived discrimination (OR?=?3.04, 95% CI: 1.60?5.75), and high perceived social support (OR?=?3.74, 95% CI: 2.01?6.95). After including both individual- and family-level factors (Model 2), results identified significant associations between high family functioning and annual household income>$15,000 (OR?=?9.82, 95% CI: 1.67?57.67, p?=?0.011) and no experience of violence from any family members (OR?=?4.94, 95% CI: 1.50?16.21, p?=?0.008). Discussion: The models of care should be structured to support the continuity of maternity care in which health care providers have the opportunity to discover and utilize each family's strengths to provide the optimal caring experience for young mothers and their families as a unit.

Patients with type 2 diabetes face an elevated risk of cardiovascular disease. This review centers on sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of drugs that, according to a growing body of evidence, may have major potential for managing cardiovascular disease in patients with type 2 diabetes. This review presents findings from multiple clinical trials suggesting that SGLT2 inhibitors can not only serve as preventive therapeutic agents but also play a role in the active management of heart failure. The discussion includes the mechanism of action of SGLT2 inhibitors, emphasizing that they enhance urinary glucose excretion, which could lead to improved glycemic control and contribute to metabolic shifts beneficial to cardiac function. Alongside these cardiometabolic effects, safety concerns and practical considerations for prescribing these agents are addressed, taking into account potential adverse effects such as genitourinary infections and diabetic ketoacidosis as well as the financial implications for patients. Despite these drawbacks, therapeutic indications for SGLT2 inhibitors continue to expand, including for kidney protection, although further research is necessary to fully understand the mechanisms driving the cardioprotective and kidney-protective effects of SGLT2 inhibitors. By synthesizing current knowledge, this review intends to inform and guide clinical decision-making, thereby enhancing cardiovascular disease outcomes in patients with type 2 diabetes.

Abstract Background Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. Methods Multidisciplinary professionals from The Association of Children’s Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Results and discussion Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. Conclusions This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

Abstract Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemically and structurally, using cryo-electron microscopy. Tpo uses opposing surfaces to recruit two copies of receptor, forming a 1:2 complex. Although it binds to the same, membrane-distal site on both receptor chains, it does so with significantly different affinities and its highly glycosylated C-terminal domain is not required. In one receptor chain, a large insertion, unique to TpoR, forms a partially structured loop that contacts cytokine. Tpo binding induces the juxtaposition of the two receptor chains adjacent to the cell membrane. The therapeutic agent romiplostim also targets the cytokine-binding site and the characterisation presented here supports the future development of improved TpoR agonists.

BackgroundWorkplace legal protections are important for perinatal health outcomes. Black birthing people are disproportionally affected by pregnancy discrimination and bias in the employment context and lack of family-friendly workplace policies, which may hinder their participation in the labor force and lead to gender and racial inequities in income and health. We aimed to explore Black pregnant women's experiences of pregnancy discrimination and bias when looking for work, working while pregnant, and returning to work postpartum. Additionally, we explored Black pregnant women's perspectives on how these experiences may influence their health.MethodsUsing an intersectional framework, where oppression is based on intersecting social identities such as race, gender, pregnancy, and socioeconomic status, we conducted an analysis of qualitative data collected for a study exploring the lived experience of pregnancy among Black pregnant women in New Haven, Connecticut, United States. Twenty-four women participated in semi-structured interviews (January 2017-August 2018). Interview transcripts were analyzed using grounded theory techniques.ResultsParticipants expressed their desire to provide a financially secure future for their family. However, many described how pregnancy discrimination and bias made it difficult to find or keep a job during pregnancy. The following three themes were identified: 1) "You're a liability"; difficulty seeking employment during pregnancy; 2) "This is not working"; experiences on the job and navigating leave and accommodations while pregnant and parenting; and 3) "It's really depressing. I wanna work"; the stressors of experiencing pregnancy discrimination and bias.ConclusionBlack pregnant women in this study anticipated and experienced pregnancy discrimination and bias, which influenced financial burden and stress. We used an intersectional framework in this study which allowed us to more fully examine how racism and economic marginalization contribute to the lived experience of Black birthing people. Promoting health equity and gender parity means addressing pregnancy discrimination and bias and the lack of family-friendly workplace policies and the harm they cause to individuals, families, and communities, particularly those of color, throughout the United States.

BackgroundA disproportionate number of people who are killed by police each year are Black. While much attention rightly remains on victims of police brutality, there is a sparse literature on police brutality and perinatal health outcomes. We aimed to explore how Black pregnant women perceive police brutality affects them during pregnancy and might affect their children.MethodsThis qualitative study involved semi-structured interviews among 24 Black pregnant women in New Haven, Connecticut (January 2017 to August 2018). Interview questions explored neighborhood factors, safety, stressors during pregnancy, and anticipated stressors while parenting. Grounded theory informed the analysis.ResultsParticipants, regardless of socioeconomic status, shared experiences with police and beliefs about anticipated police brutality, as summarized in the following themes: (1) experiences that lead to police distrust - "If this is the way that mommy's treated [by police]"; (2) anticipating police brutality - "I'm always expecting that phone call"; (3) stress and fear during pregnancy - "It's a boy, [I feel] absolutely petrified"; and (4) 'the talk' about avoiding police brutality - "How do you get prepared?" Even participants who reported positive experiences with police anticipated brutality towards their children.ConclusionsInteractions between Black people and police on a personal, familial, community, and societal level influenced how Black pregnant women understand the potential for police brutality towards their children. Anticipated police brutality is a source of stress during pregnancy, which may adversely influence maternal and infant health outcomes. Police brutality must be addressed in all communities to prevent harming the health of birthing people and their children.

Abstract Observing System Simulation Experiments (OSSEs) provide an effective way to evaluate the impact of assimilating data from a specific observing system on hindcasting, nowcasting, and forecasting of environmental systems. The NSF NCAR's Data Assimilation (DA) Research Testbed/Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model (DART/TIEGCM) tool, to be hosted at the NASA Community Coordinated Modeling Center, serves as a valuable and accessible community resource for quantitatively evaluating the impact of observations from both current and future ionosphere‐thermosphere (IT) observing systems. This study demonstrates the utility of DART/TIEGCM as an IT OSSE tool, using synthetic observations simulated using a currently planned NASA Geospace Dynamics Constellation (GDC) observing system design. Five sets of OSSEs are carried out to compare the effects of assimilating various combinations of prospective GDC observations (e.g., neutral temperature, neutral wind, neutral composition, atomic oxygen ion density, and ion and electron temperature) during a major geomagnetic storm period of the St Patrick's Day Storm on 17 March 2013. The maximum error reduction in neutral temperature and atomic ion oxygen density is 24.6% and 43.3% compared to the control experiment. These OSSEs indicate the benefits of coupled IT DA approaches implemented in DART/TIEGCM to maximize the impact of multi‐parameter IT observations, such as those expected from the GDC mission. Although more work is required to draw any definitive conclusion on the GDC data impact, the study provides an illustrative example of how the DART/TIEGCM community tool can be used to evaluate observational impacts of planned or existing missions for geospace research and applications.

Recovery capital is a framework in addiction research aiming to understand substance use disorder recovery holistically by considering individuals' access to resources across the four domains of human, physical, social, and community capital. Each domain is opposed by negative capital. The underrepresentation of women's experiences in substance use research and the limited understanding of substance use treatment's effect on recovery capital limits our understanding of how treatment programs can support women in developing and maintaining recovery capital. This secondary qualitative analysis of data collected from the RENEW study explores the experiences of n = 19 women enrolled in substance use disorder treatment in Connecticut at baseline. Interviews occurred at two time points three months apart between February 2020 and April 2021 and discussed participants' experiences with treatment and the resources they have access to early in recovery. Thematic analysis identified four main themes related to recovery capital development. First, the direct effects of treatment, defined as clinical pathways to recovery capital, promoted resource growth primarily in the domains of human and physical capital. Second, non-clinical pathways, including indirect effects of treatment, facilitated maintenance of treatment-related improvements in human, social, and community capital. Third, interactions between domains promoted recovery capital resource growth across domains. Finally, goals and expectations for treatment motivated resource development across study time points. This study's findings have important implications for operationalization of the recovery capital framework and highlight the importance of more robust integration of non-clinical interventions to improve the experiences of women in treatment for substance use disorders.

Introduction Manufacturer-supported didactic teaching programmes offer effective automated insulin delivery (AID) systems onboarding in children and young people (CYP) with type 1 diabetes (T1D). However, this approach has limited flexibility to accommodate the needs of families requiring additional support.Research design and methods Evaluate the efficacy of an inperson manufacturer-supported didactic teaching programme (Group A), in comparison to a flexible flipped learning approach delivered virtually or inperson (Group B). Retrospective analysis of CYP with T1D using continuous glucose monitoring (CGM), who were initiated on AID systems between 2021 and 2023. Compare CGM metrics from baseline to 90 days for both groups A and B. Additionally, compare the two groups for change in CGM metrics over the 90-day period (∆), patient demographics and onboarding time.Results Group A consisted of 74 CYP (53% male) with median age of 13.9 years and Group B 91 CYP (54% male) with median age of 12.7 years. From baseline to 90 days, Group A lowered mean (±SD) time above range (TAR, >10.0 mmol/L) from 47.6% (±15.0) to 33.2% (±15.0) (p

Objectives: To investigate the potential value and feasibility of creating a listing system-wide registry of patients with at-risk and established Atherosclerotic Cardiovascular Disease (ASCVD) within a large healthcare system using automated data extraction methods to systematically identify burden, determinants, and the spectrum of at-risk patients to inform population health management. Additionally, the Houston Methodist Cardiovascular Disease Learning Health System (HM CVD-LHS) registry intends to create high-quality data-driven analytical insights to assess, track, and promote cardiovascular research and care. Methods: We conducted a retrospective multi-center, cohort analysis of adult patients who were seen in the outpatient settings of a large healthcare system between June 2016 - December 2022 to create an EMR-based registry. A common framework was developed to automatically extract clinical data from the EMR and then integrate it with the social determinants of health information retrieved from external sources. Microsoft's SQL Server Management Studio was used for creating multiple Extract-Transform-Load scripts and stored procedures for collecting, cleaning, storing, monitoring, reviewing, auto-updating, validating, and reporting the data based on the registry goals. Results: A real-time, programmatically deidentified, auto-updated EMR-based HM CVD-LHS registry was developed with ∼450 variables stored in multiple tables each containing information related to patient's demographics, encounters, diagnoses, vitals, labs, medication use, and comorbidities. Out of 1,171,768 adult individuals in the registry, 113,022 (9.6%) ASCVD patients were identified between June 2016 and December 2022 (mean age was 69.2 ± 12.2 years, with 55% Men and 15% Black individuals). Further, multi-level groupings of patients with laboratory test results and medication use have been analyzed for evaluating the outcomes of interest. Conclusions: HM CVD-LHS registry database was developed successfully providing the listing registry of patients with established ASCVD and those at risk. This approach empowers knowledge inference and provides support for efforts to move away from manual patient chart abstraction by suggesting that a common registry framework with a concurrent design of data collection tools and reporting rapidly extracting useful structured clinical data from EMRs for creating patient or specialty population registries.

Background Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone.Methods and analysis E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials.Ethics and dissemination The East Midlands—Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings.Trial registration number EudraCT number 2022-002659-20; ISRCTN 10615985.

Introduction: Historical maps of racialized evaluation of mortgage lending risk (i.e., redlined neighborhoods) have been linked to adverse health outcomes. Little research has examined whether living in historically redlined neighborhoods is associated with obesity, differentially by race or gender. Methods: This is a cross-sectional study to examine whether living in historically redlined neighborhoods is associated with BMI and waist circumference among Black and White adults in 1985–1986. Participants’ addresses were linked to the 1930s Home Owners’ Loan Corporation maps that evaluated mortgage lending risk across neighborhoods. The authors used multilevel linear regression models clustered on Census tract, adjusted for confounders to estimate main effects, and stratified, and interaction models by (1) race, (2) gender, and (3) race by gender with redlining differentially for Black versus White adults and men versus women. To better understand strata differences, they compared Census tract–level median household income across race and gender groups within Home Owners’ Loan Corporation grade. Results: Black adults (n=2,103) were more likely than White adults (n=1,767) to live in historically rated hazardous areas and to have higher BMI and waist circumference. Redlining and race and redlining and gender interactions for BMI and waist circumference were statistically significant (p