Violence prevention accelerators for children and adolescents in South Africa:A path analysis using two pooled cohorts

Background: The INSPIRE framework was developed by 10 global agencies as the first global package for preventing and responding to violence against children. The framework includes seven complementary strategies. Delivering all seven strategies is a challenge in resource limited contexts. Consequently, governments are requesting additional evidence to inform which ‘accelerator’ provisions can simultaneously reduce multiple types of violence against children. Methods and Findings: We pooled data from two prospective South African adolescent cohorts including Young Carers (2010-2012), and Mzantsi Wakho (2014-2017). The combined sample size was 5034 adolescents. Each cohort measured six self-reported violence outcomes: sexual abuse, transactional sexual exploitation, physical abuse, emotional abuse, community violence victimisation, and youth lawbreaking; and seven self-reported INSPIRE-aligned protective factors: positive parenting, parental monitoring and supervision, food security at home, basic economic security at home, free schooling, free school meals, and abuse response services. Associations between hypothesised protective factors and violence outcomes were estimated jointly in a sex-stratified multivariate path model, controlling for baseline outcomes and socio-demographics, and correcting for multiple hypothesis testing using the Benjamini-Hochberg procedure. We calculated adjusted probability estimates conditional on the presence of no, one, or all protective factors significantly associated with reduced odds of at least three forms of violence in the path model. Adjusted risk differences (ARD) and risk ratios (ARR) with 95% confidence intervals (CI) were also calculated. The sample mean age was 13.54 years and 56.62% were female. There was 4% loss to follow up. Positive parenting, parental monitoring and supervision, and food security at home, were each associated with lower odds of three or more violence outcomes (p Conclusion: In this cohort study, we found that positive and supervisory caregiving, and food security at home are associated with reduced risk of multiple forms of violence against children. The presence of all three of these factors may be linked to greater risk reduction as compared to the presence of one, or none of these factors. Policies promoting action on positive and supervisory caregiving, and food security at home are likely to support further efficiencies in the delivery of INSPIRE.</p

Improving lives by accelerating progress towards the UN Sustainable Development Goals for adolescents living with HIV: a prospective cohort study

BACKGROUND: Low-income and middle-income countries (LMICs) face major challenges in achieving the UN's Sustainable Development Goals (SDGs) for vulnerable adolescents. We aimed to test the UN Development Programme's proposed approach of development accelerators-provisions that lead to progress across multiple SDGs-and synergies between accelerators on achieving SDG-aligned targets in a highly vulnerable group of adolescents in South Africa. METHODS: We did standardised interviews and extracted longitudinal data from clinical records at baseline (2014-15) and 18-month follow-up (2016-17) for adolescents aged 10-19 years living with HIV in the Eastern Cape province of South Africa. We used standardised tools to measure 11 SDG-aligned targets-antiretroviral therapy adherence, good mental health, no substance use, HIV care retention, school enrolment, school progression, no sexual abuse, no high-risk sex, no violence perpetration, no community violence, and no emotional or physical abuse. We also assessed receipt at both baseline and follow-up of six hypothesised development accelerators-government cash transfers to households, safe schools (ie, without teacher or student violence), free schools, parenting support, free school meals, and support groups. Associations of all provisions with SDG-aligned targets were assessed jointly in a multivariate path model, controlling for baseline outcomes and sociodemographic and HIV-related covariates, and adjusted for multiple outcome testing. Cumulative effects were tested by marginal effects modelling. FINDINGS: 1063 (90%) of 1176 eligible adolescents were interviewed. Three provisions were shown to be development accelerators. Parenting support was associated with good mental health (odds ratio 2·13, 95% CI 1·43-3·15, p<0·0001), no high-risk sex (2·44, 1·45-5·03, p=0·005), no violence perpetration (2·59, 1·63-4·59, p<0·0001), no community violence (2·43, 1·65-3·86, p<0·0001), and no emotional or physical abuse (2·38, 1·65-3·76; p<0·0001). Cash transfers were associated with HIV care retention (1·87, 1·15-3·02, p=0·010), school progression (2·05, 1·33-3·24, p=0·003), and no emotional or physical abuse (1·76, 1·12-3·02, p=0·025). Safe schools were associated with good mental health (1·74, 1·30-2·34, p<0·0001), school progression (1·57, 1·17-2·13, p=0·004), no violence perpetration (2·02, 1·45-2·91, p<0·0001), no community violence (1·81, 1·30-2·55, p<0·0001), and no emotional or physical abuse (2·20, 1·58-3·17, p<0·0001). For five of 11 SDG-aligned targets, a combination of two or more accelerators showed cumulative positive associations, suggesting accelerator synergies of combination provisions. For example, the fitted probability of adolescents reporting no emotional or physical abuse (SDG 16.2) with no safe schools, cash transfers, or parenting support was 0·25 (0·16-0·34). With cash transfer alone it was 0·37 (0·33-0·42), with safe school alone 0·42 (0·30-0·55), and with parenting support alone 0·44 (0·30-0·59). With all three development accelerators combined, the probability of adolescents reporting no emotional or physical abuse was 0·76 (0·67-0·84). After correcting for multiple tests, four of the SDG-aligned targets (antiretroviral therapy adherence, no substance use, school enrolment, and no sexual abuse) were not associated with any hypothesised accelerators. INTERPRETATION: The findings suggest the UN's accelerator approach for this high-risk adolescent population has policy and potential financing usefulness. Services that simultaneously promote several SDG targets, or combine to support particular targets, might be important to meet not only health-related targets, but also to ensure that adolescents in LMICs thrive within a new development framework. FUNDING: Nuffield Foundation, UK Research and Innovation Global Challenges Research Fund, UKAID, Janssen Pharmaceutica, International AIDS Society, John Fell Fund, European Research Council, Economic and Social Research Council, Philip Leverhulme Trust, and UNICEF

MYOD1 involvement in myopathy

[Excerpt] Introduction Myogenic Differentiation 1 (MYOD1) encodes a transcription factor that plays an important role in myogenic determination into mature skeletal muscle [1]. The first loss-of-function mutation of MYOD1 in humans was described in three siblings with perinatal lethal fetal akinesia [2].[...]We thank the individual and family. Funding was provided by The Fonds de recherche du Québec - Santé (FRQS) and Canadian Institutes of Health Research (CIHR) to P.M.C., Fundação para a Ciência e Tecnologia (FCT) with the fellowship SFRH/BD/84650/2010 to F.L. and Groupe Pasteur Mutualité Foundation (GPM Foundation) to M.M.info:eu-repo/semantics/publishedVersio

DOORS syndrome and a recurrent truncating ATP6V1B2 variant

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system

Model matchmaking via the Solve-RD Rare Disease Models &amp; Mechanisms Network (RDMM-Europe)

In biomedical research, particularly for rare diseases (RDs), there is a critical need for model organisms to unravel the mechanistic basis of diseases, perform biomarker studies and develop potential therapeutic interventions. Within Solve-RD, an EU-funded research project with the aim of solving large numbers of previously unsolved RDs, the European Rare Disease Models &amp; Mechanisms Network (RDMM-Europe) has been established.</p

BAFopathies\u27 DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening