Erratum: Congregation leader and member discussions in a church-based family strengthening, mental health promotion, and HIV prevention trial: Intervention mechanisms in a randomized trial in rural Kenya - ERRATUM.

[This corrects the article DOI: 10.1017/gmh.2024.44.].

Gene expansions contributing to human brain evolution.

Genomic drivers of human-specific neurological traits remain largely undiscovered. Duplicated genes expanded uniquely in the human lineage likely contributed to brain evolution, including the increased complexity of synaptic connections between neurons and the dramatic expansion of the neocortex. Discovering duplicate genes is challenging because the similarity of paralogs makes them prone to sequence-assembly errors. To mitigate this issue, we analyzed a complete telomere-to-telomere human genome sequence (T2T-CHM13) and identified 213 duplicated gene families likely containing human-specific paralogs (>98% identity). Positing that genes important in universal human brain features should exist with at least one copy in all modern humans and exhibit expression in the brain, we narrowed in on 362 paralogs with at least one copy across thousands of ancestrally diverse genomes and present in human brain transcriptomes. Of these, 38 paralogs co-express in gene modules enriched for autism-associated genes and potentially contribute to human language and cognition. We narrowed in on 13 duplicate gene families with human-specific paralogs that are fixed among modern humans and show convincing brain expression patterns. Using long-read DNA sequencing revealed hidden variation across 200 modern humans of diverse ancestries, uncovering signatures of selection not previously identified, including possible balancing selection of CD8B. To understand the roles of duplicated genes in brain development, we generated zebrafish CRISPR "knockout" models of nine orthologs and transiently introduced mRNA-encoding paralogs, effectively "humanizing" the larvae. Morphometric, behavioral, and single-cell RNA-seq screening highlighted, for the first time, a possible role for GPR89B in dosage-mediated brain expansion and FRMPD2B function in altered synaptic signaling, both hallmark features of the human brain. Our holistic approach provides important insights into human brain evolution as well as a resource to the community for studying additional gene expansion drivers of human brain evolution.

First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

Diagnosis and successful medical management of a renal corticomedullary abscess in a dog.

A 10-year-old spayed female mixed-breed dog was brought to the Ohio State University Veterinary Medical Center because of a suspected mass located to the right kidney. The mass was diagnosed by abdominal ultrasound following a recurrent lower urinary tract infection. Abdominal computed tomography revealed 2 isoattenuating, peripherally hypoattenuating, and centrally non-contrast-enhancing nodules in the right kidney; the larger one measured 1.9 cm. Initial attempts at fine-needle aspiration were unsuccessful. The dog was returned and the mass was aspirated using ultrasound guidance under heavy sedation. Cytology confirmed the presence of septic inflammation, consistent with a renal corticomedullary abscess. The dog was administered oral enrofloxacin (15 mg/kg, q24h) after diagnosis. Ultrasound guidance was used 2 wk later, under general anesthesia, to achieve percutaneous drainage of ~0.25 mL of fluid and instillation of 5.7 mg (0.25 mL) of enrofloxacin into the abscess capsule. Two weeks after percutaneous drainage, ultrasound examination showed complete resolution of the renal corticomedullary abscess. Urine culture confirmed resolution of the urinary tract infection. To the authors' knowledge, kidney-sparing medical management has never been successfully reported in a dog with a renal corticomedullary abscess. Key clinical message: Renal corticomedullary abscesses occur infrequently in dogs. Medical management is feasible and can result in complete resolution of clinical signs and imaging abnormalities.

Diagnostic et prise en charge médicale réussie d'un abcès corticomédullaire rénal chez un chienUne chienne croisée de 10 ans, stérilisée, a été amenée au centre médical vétérinaire de l'Ohio State University en raison d'une masse suspectée située au niveau du rein droit. La masse a été diagnostiquée par échographie abdominale à la suite d'une infection récurrente du tractus urinaire inférieur. La tomodensitométrie abdominale a révélé 2 nodules isoatténuants, hypoatténuants en périphérie et centralement sans contraste dans le rein droit; le plus grand mesurait 1,9 cm. Les premières tentatives d'aspiration à l'aiguille fine ont échoué. Le chien est revenu et la masse a été aspirée sous guidage échographique sous sédation lourde. La cytologie a confirmé la présence d'une inflammation septique, compatible avec un abcès corticomédullaire rénal. Le chien a reçu de l'enrofloxacine par voie orale (15 mg/kg, toutes les 24 heures) après le diagnostic. Le guidage échographique a été utilisé 2 semaines plus tard, sous anesthésie générale, pour obtenir un drainage percutané d'environ 0,25 mL de liquide et l'instillation de 5,7 mg (0,25 mL) d'enrofloxacine dans la capsule de l'abcès. Deux semaines après le drainage percutané, l'échographie a montré une résolution complète de l'abcès corticomédullaire rénal. La culture urinaire a confirmé la résolution de l'infection des voies urinaires. À la connaissance des auteurs, une prise en charge médicale préservant les reins n'a jamais été rapportée avec succès chez un chien présentant un abcès corticomédullaire rénal.Message clinique clé:Les abcès corticomédullaires rénaux surviennent rarement chez le chien. La prise en charge médicale est réalisable et peut aboutir à une résolution complète des signes cliniques et des anomalies d'imagerie.(Traduit par Dr Serge Messier).

Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease.

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type (WT) B6129SF1/J mice fed either regular chow or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared with GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared with WT mice, whereas GYS1 inhibition counteracted this effect. Compared with GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMP-activated protein kinase phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GSS641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation.NEW & NOTEWORTHY We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our results collectively demonstrate that the GYS1 inhibitor represents a novel approach to substrate reduction therapy for Pompe disease.

Radiotherapy in Equine Practice.

Radiotherapy is a valuable treatment option for equine tumors that have a high rate of recurrence or where complete surgical resection may damage vital structures. Teletherapy, brachytherapy, and plesiotherapy have been used successfully for the treatment of a variety of tumors and locations in the horse. Radiobiology, treatment protocols, side effects, and patient management are reviewed, with a focus on linear accelerator-based teletherapy. There is evidence of good success rates for treatment of periocular sarcoids and squamous cell carcinoma but teletherapy treatment is often limited to tumors on the head and distal extremities.

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.

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.

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.

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).

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.

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.