Congregation leader and member discussions in a church-based family strengthening, mental health promotion and HIV prevention trial: Intervention.

Collaboration with African religious congregations can promote psychosocial well-being with greater accessibility. Effective collaboration requires studying congregations as unique intervention contexts. This study explored how an intervention in western Kenya fit within and altered congregational discussion patterns. We conducted a cluster-randomized trial of a church-based intervention to improve family relationships, mental health and sexual health. For each intervention topic covered, we describe baseline and post-intervention changes in church leaders' beliefs and communication as well as discussion frequency between leaders and members and among members. Mixed-effects logistic regression assessed pre-post change in member-reported discussion frequency. At baseline, members and leaders reported already discussing family, parenting, and emotions frequently and sexuality and finances less frequently. Leaders generally felt they should discuss all topics but were less comfortable and knowledgeable about sexuality and finances than other topics. After the intervention, leader comfort and knowledge increased and discussion frequency increased for nearly all topics, especially those discussed less initially. Good fit between the desires and activities of church members and leaders suggests the potential for further collaboration, especially on mental health and family well-being. Increased discussion of sensitive topics underscores the potential of community-level interventions to affect social norms.

Advancing genomics to improve health equity.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.

Opportunities for basic, clinical, and bioethics research at the intersection of machine learning and genomics.

The data-intensive fields of genomics and machine learning (ML) are in an early stage of convergence. Genomics researchers increasingly seek to harness the power of ML methods to extract knowledge from their data; conversely, ML scientists recognize that genomics offers a wealth of large, complex, and well-annotated datasets that can be used as a substrate for developing biologically relevant algorithms and applications. The National Human Genome Research Institute (NHGRI) inquired with researchers working in these two fields to identify common challenges and receive recommendations to better support genomic research efforts using ML approaches. Those included increasing the amount and variety of training datasets by integrating genomic with multiomics, context-specific (e.g., by cell type), and social determinants of health datasets; reducing the inherent biases of training datasets; prioritizing transparency and interpretability of ML methods; and developing privacy-preserving technologies for research participants' data.

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.

Severe polycystic liver disease in a cat.

Case summary: Ductal plate malformations (DPMs) are poorly documented in the veterinary literature, particularly those of the polycystic liver disease (PCLD) phenotype. A 13-year-old female spayed cat presented with progressive icterus, abdominal distension, weight loss and elevated liver enzymes. Initial empirical treatment consisting of amoxicillin/clavulanate, ursodiol and later prednisolone was attempted; however, clinical signs progressed. On abdominal ultrasound, numerous large hepatic cystic masses were noted, characterized by an anechoic center with a heterogeneous, hyperechoic wall. A post-mortem examination confirmed numerous hepatic cysts, the larger of which resulted in hemorrhage and subsequent hemoabdomen. Histologically, these cysts were determined to be of biliary origin, and a diagnosis of PCLD was assigned. Relevance and novel information: Herein, we present a detailed report of clinical, gross and histologic findings in a cat clinically affected by PCLD. This case demonstrates that cysts present in this congenital disease can ultimately lead to hepatobiliary malfunction and clinical decline via marked expansion of cysts, compression of the liver and hemoabdomen from cyst rupture. DPMs, specifically PCLD, should be considered in cats presenting with multifocal large hepatic cysts.

To boldly go: Unpacking the NHGRI's bold predictions for human genomics by 2030.

The 2020 strategic vision for human genomics, written by the National Human Genome Research Institute (NHGRI), was punctuated by a set of provocatively audacious "bold predictions for human genomics by 2030." Starting here, these will be unpacked and discussed in an upcoming series in the American Journal of Human Genetics.

Social Vulnerability, COVID-19, Racial Violence, and Depressive Symptoms: a Cross-sectional Study in the Southern United States.

BACKGROUND: In March 2020, the novel 2019 coronavirus disease (COVID-19) was declared a pandemic. In May 2020, George Floyd was murdered, catalyzing a national racial reckoning. In the Southern United States, these events occurred in the context of a history of racism and high rates of poverty and discrimination, especially among racially and ethnically minoritized populations. OBJECTIVES: In this study, we examine social vulnerabilities, the perceived impacts of COVID-19 and the national racial reckoning, and how these are associated with depression symptoms in the South. METHODS: Data were collected from 961 adults between June and November 2020 as part of an online survey study on family well-being during COVID-19. The sample was majority female (87.2%) and consisted of 661 White participants, 143 Black participants, and 157 other racial and ethnic minoritized participants. Existing social vulnerability, perceived impact of COVID-19 and racial violence and protests on families, and depressive symptoms were assessed. Hierarchical regression analysis was used to predict variance in depressive symptoms. RESULTS: Half of the sample (52%) reported a negative impact of COVID-19, and 66% reported a negative impact of national racial violence/protests. Depressive symptoms were common with 49.8% meeting the cutoff for significant depressive symptoms; Black participants had lower levels of depressive symptoms. Results from the hierarchical regression analysis indicate social vulnerabilities and the perceived negative impact of COVID-19 and racial violence/protests each contribute to variance in depressive symptoms. Race-specific sensitivity analysis clarified distinct patterns in predictors of depressive symptoms. CONCLUSION: People in the South report being negatively impacted by the confluence of the COVID-19 pandemic and the emergence of racial violence/protests in 2020, though patterns differ by racial group. These events, on top of pre-existing social vulnerabilities, help explain depressive symptoms in the South during 2020.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

SIGNIFICANCE STATEMENT: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. BACKGROUND: African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. METHODS: We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. RESULTS: In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. CONCLUSIONS: APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

Comparing fears about paediatric HIV disclosure to the lived experiences of parents and guardians: a prospective cohort study.

OBJECTIVE: We aimed to: (1) follow parents and guardians through the process of paediatric HIV disclosure to understand how often pre-disclosure worries are realised; and (2) estimate the effects of disclosure on child, caregiver, and family well-being. DESIGN: We conducted a 12-month prospective cohort study in Zimbabwe with 123 primary caregivers of children ages 9 to 15 years who were HIV positive but did not know their serostatus at baseline. By the end of the study period 65 caregivers reported that their child learned his or her HIV-positive status. MAIN OUTCOME MEASURES: We used three waves of data to compare caregivers' pre-disclosure worries to post-disclosure reports and to characterise associations between disclosure and well-being of the child (Strengths and Difficulties Questionnaire), caregiver (Patient Health Questionnaire-9), and family (Family Relationship Quality) over time. RESULTS: Caregivers' pre-disclosure worries and fears about how their child would react to disclosure of their HIV status largely went unrealised. Furthermore, we did not find strong evidence of clinically-important increases in problems on average following disclosure. CONCLUSION: Findings support the call to identify supportive intervention strategies that address caregiver fears at the beginning of the disclosure process.

Parenting in a conflict-affected setting: Discipline practices, parent-child interactions, and parenting stress in Liberia.

Children in conflict-affected settings are at increased risk for exposure to violence, placing particular importance on caregiving environments. This study first describes parenting in urban Liberia by evaluating parent-child interactions, the use and acceptance of harsh and nonharsh discipline, discipline preferences, and the co-occurrence of positive interactions and harsh discipline. The relationship between parenting stress and harsh discipline attitudes and behaviors is then tested. Participants included 813 parents with a child aged 3 or 4 years old. A quantitative survey battery assessed parent-child interactions; discipline practices, preferences, and attitudes; and parenting stress. Parents reported frequent use and high acceptance of nonharsh discipline, as well as frequent positive interactions with their child. Though parents reported less frequent use and low acceptance of harsh discipline, preference for harsh discipline-based on hypothetical situations rather than self-report-was common. There was co-occurrence of frequent positive interactions and frequent harsh discipline, with one third reporting high frequency of both. Regression analysis revealed greater parenting stress (ß = .15, t = 4.49, p < .001) and stronger acceptance of harsh discipline (ß = .47, t = 15.49, p < .001) were associated with more frequent harsh discipline. Acceptance of harsh discipline interacted with parenting stress to predict the use of harsh discipline (ß = -.09, t = -3.09, p < .01). Among parents with lowest average acceptance of harsh practices, stress predicted more frequent harsh discipline, but acceptance did not moderate the association for those who are most accepting of harsh practices. Building on existing parenting strengths and addressing parenting stress could promote nurturing caregiving in conflict-affected settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Development and functioning of the mobile app-based mh-GAP intervention guide in detection and treatment of people with mental health conditions in primary healthcare settings in Nepal.

This paper describes the development process of a mobile app-based version of the World Health Organization mental health Gap Action Programme Intervention Guide, testing of the app prototypes, and its functionality in the assessment and management of people with mental health conditions in Nepal. Health workers' perception of feasibility and acceptability of using mobile technology in mental health care was assessed during the inspiration phase (N = 43); the ideation phase involved the creation of prototypes; and prototype testing was conducted over multiple rounds with 15 healthcare providers. The app provides provisional diagnoses and treatment options based on reported symptoms. Participants found the app prototype useful in reminding them of the process of assessment and management of mental disorders. Some challenges were noted, these included a slow app prototype with multiple technical problems, including difficulty in navigating 'yes'/'no' options, and there were challenges reviewing detailed symptoms of a particular disorder using a "more information" icon. The initial feasibility work suggests that if the technical issues are addressed, the e-mhGAP warrants further research to understand if it is a useful method in improving the detection of people with mental health conditions and initiation of evidence-based treatment in primary healthcare facilities.

The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex.

Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by autoglucosylation, and glycogen synthase-1 (GYS1), which extends the glycogen chain. Although both enzymes are required for proper glycogen production, the nature of their interaction has been enigmatic. Here, we present the human GYS1:GYG1 complex in multiple conformations representing different functional states. We observe an asymmetric conformation of GYS1 that exposes an interface for close GYG1 association, and propose this state facilitates handoff of the GYG1-associated glycogen chain to a GYS1 subunit for elongation. Full activation of GYS1 widens the GYG1-binding groove, enabling GYG1 release concomitant with glycogen chain growth. This structural mechanism connecting chain nucleation and extension explains the apparent stepwise nature of glycogen synthesis and suggests distinct states to target for GSD-modifying therapeutics.

Utility of cardiac MRI to diagnose myocardial ischemia and fibrosis in dogs with cardiomegaly secondary to myxomatous mitral valve disease.

OBJECTIVE: To assess whether cardiac MRI or various biomarkers can be used to detect myocardial ischemia and fibrosis in dogs with cardiomegaly secondary to myxomatous mitral valve disease (MMVD). ANIMALS: 6 dogs with cardiomegaly secondary to naturally occurring stage B2 MMVD being treated only with pimobendan with or without enalapril and 6 control dogs with no cardiac disease. All dogs were ≥ 5 years old with no systemic illness. PROCEDURES: Serum cardiac troponin I and concentrations were measured, and dogs were anesthetized for cardiac MRI with ECG-triggered acquisition of native T1- and T2-weighted images. Gadolinium contrast was administered to evaluate myocardial perfusion and late gadolinium enhancement (LGE). Mean T1 and T2 values and regions of LGE were measured with dedicated software. Extracellular volume (ECV) was estimated on the basis of Hct and T1 values of myocardium and surrounding blood. Subjective analysis for myocardial perfusion deficits was performed. RESULTS: Dogs with MMVD had significantly (P = .013) higher cardiac troponin I concentrations than control dogs, but galectin-3 concentrations did not differ (P = .08) between groups. Myocardial fibrosis was detected in 4 dogs with MMVD and 3 control dogs; no dogs had obvious myocardial perfusion deficits. Native T1 and T2 values, postcontrast T1 values, and ECV values were not significantly different between groups (all P > .3). CLINICAL RELEVANCE: Results suggest that some dogs with cardiomegaly secondary to MMVD may not have clinically relevant myocardial fibrosis.

Validation of a machine learning approach to estimate expanded disability status scale scores for multiple sclerosis.

Background: Disability assessment using the Expanded Disability Status Scale (EDSS) is important to inform treatment decisions and monitor the progression of multiple sclerosis. Yet, EDSS scores are documented infrequently in electronic medical records. Objective: To validate a machine learning model to estimate EDSS scores for multiple sclerosis patients using clinical notes from neurologists. Methods: A machine learning model was developed to estimate EDSS scores on specific encounter dates using clinical notes from neurologist visits. The OM1 MS Registry data were used to create a training cohort of 2632 encounters and a separate validation cohort of 857 encounters, all with clinician-recorded EDSS scores. Model performance was assessed using the area under the receiver-operating-characteristic curve (AUC), positive predictive value (PPV), and negative predictive value (NPV), calculated using a binarized version of the outcome. The Spearman R and Pearson R values were calculated. The model was then applied to encounters without clinician-recorded EDSS scores in the MS Registry. Results: The model had a PPV of 0.85, NPV of 0.85, and AUC of 0.91. The model had a Spearman R value of 0.75 and Pearson R value of 0.74 when evaluating performance using the continuous estimated EDSS and clinician-recorded EDSS scores. Application of the model to eligible encounters resulted in the generation of eEDSS scores for an additional 190,282 encounters from 13,249 patients. Conclusion: EDSS scores can be estimated with very good performance using a machine learning model applied to clinical notes, thus increasing the utility of real-world data sources for research purposes.

A research agenda to support the development and implementation of genomics-based clinical informatics tools and resources.

OBJECTIVE: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled "Developing a Clinical Genomic Informatics Research Agenda". The meeting's goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. MATERIALS AND METHODS: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. RESULTS: Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. DISCUSSION: Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.