DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.

Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1. Our spatially resolved interaction maps reveal rich network intricacies, identify shared and bait-specific interaction modules, and implicate previously concealed regulators in this process. We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins, RINN1 (CTC-534A2.2), RINN2 (FAM35A), and RINN3 (C20ORF196). Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis, promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres. Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection and in sensitizing BRCA1-deficient cells to PARP inhibitors. These findings have implications for understanding cancer-associated PARPi resistance and the evolution of antibody CSR in higher vertebrates.

A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression.

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone.

Dysfunction of protein quality control contributes to the cellular pathology of polyglutamine (polyQ) expansion diseases and other neurodegenerative disorders associated with aggregate deposition. Here we analyzed how polyQ aggregation interferes with the clearance of misfolded proteins by the ubiquitin-proteasome system (UPS). We show in a yeast model that polyQ-expanded proteins inhibit the UPS-mediated degradation of misfolded cytosolic carboxypeptidase Y(∗) fused to green fluorescent protein (GFP) (CG(∗)) without blocking ubiquitylation or proteasome function. Quantitative proteomic analysis reveals that the polyQ aggregates sequester the low-abundant and essential Hsp40 chaperone Sis1p. Overexpression of Sis1p restores CG(∗) degradation. Surprisingly, we find that Sis1p, and its homolog DnaJB1 in mammalian cells, mediates the delivery of misfolded proteins into the nucleus for proteasomal degradation. Sis1p shuttles between cytosol and nucleus, and its cellular level limits the capacity of this quality control pathway. Upon depletion of Sis1p by polyQ aggregation, misfolded proteins are barred from entering the nucleus and form cytoplasmic inclusions.

Equilibrium between nascent and parental MCM proteins protects replicating genomes.

Minichromosome maintenance proteins (MCMs) are DNA-dependent ATPases that bind to replication origins and license them to support a single round of DNA replication. A large excess of MCM2-7 assembles on chromatin in G1 phase as pre-replication complexes (pre-RCs), of which only a fraction become the productive CDC45-MCM-GINS (CMG) helicases that are required for genome duplication1-4. It remains unclear why cells generate this surplus of MCMs, how they manage to sustain it across multiple generations, and why even a mild reduction in the MCM pool compromises the integrity of replicating genomes5,6. Here we show that, for daughter cells to sustain error-free DNA replication, their mother cells build up a nuclear pool of MCMs both by recycling chromatin-bound (parental) MCMs and by synthesizing new (nascent) MCMs. Although all MCMs can form pre-RCs, it is the parental pool that is inherently stable and preferentially matures into CMGs. By contrast, nascent MCM3-7 (but not MCM2) undergo rapid proteolysis in the cytoplasm, and their stabilization and nuclear translocation require interaction with minichromosome-maintenance complex-binding protein (MCMBP), a distant MCM paralogue7,8. By chaperoning nascent MCMs, MCMBP safeguards replicating genomes by increasing chromatin coverage with pre-RCs that do not participate on replication origins but adjust the pace of replisome movement to minimize errors during DNA replication. Consequently, although the paucity of pre-RCs in MCMBP-deficient cells does not alter DNA synthesis overall, it increases the speed and asymmetry of individual replisomes, which leads to DNA damage. The surplus of MCMs therefore increases the robustness of genome duplication by restraining the speed at which eukaryotic cells replicate their DNA. Alterations in physiological fork speed might thus explain why even a minor reduction in MCM levels destabilizes the genome and predisposes to increased incidence of tumour formation.

The Role of Endothelial Cells in Atherosclerosis: Insights from Genetic Association Studies.

Endothelial cells (ECs) mediate several biological functions that are relevant to atherosclerosis and coronary artery disease (CAD), regulating an array of vital processes including vascular tone, wound healing, reactive oxygen species, shear stress response, and inflammation. Although which of these functions is linked causally with CAD development and/or progression is not yet known, genome-wide association studies have implicated more than 400 loci associated with CAD risk, among which several have shown EC-relevant functions. Given the arduous process of mechanistically interrogating single loci to CAD, high-throughput variant characterization methods, including pooled Clustered Regularly Interspaced Short Palindromic Repeats screens, offer exciting potential to rapidly accelerate the discovery of bona fide EC-relevant genetic loci. These discoveries in turn will broaden the therapeutic avenues for CAD beyond lipid lowering and behavioral risk modification to include EC-centric modalities of risk prevention and treatment.

Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics?

As a result of metabolic reprogramming, cancer cells display high rates of glycolysis, causing an excess production of lactate along with an increase in extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) are crucial in the maintenance of this metabolic phenotype, by mediating the proton-coupled lactate flux across cell membranes, also contributing to cancer cell pH regulation. Among the proteins codified by the SLC16 gene family, MCT1 and MCT4 isoforms are the most explored in cancers, being overexpressed in many cancer types, from solid tumours to haematological malignancies. Similarly to what occurs in particular physiological settings, MCT1 and MCT4 are able to mediate lactate shuttles among cancer cells, and also between cancer and stromal cells in the tumour microenvironment. This form of metabolic cooperation is responsible for important cancer aggressiveness features, such as cell proliferation, survival, angiogenesis, migration, invasion, metastasis, immune tolerance and therapy resistance. The growing understanding of MCT functions and regulation is offering a new path to the design of novel inhibitors that can be foreseen in clinical practices. This review provides an overview of the role of MCT isoforms in cancer and summarizes the recent advances in their pharmacological targeting, highlighting the potential of new potent and selective MCT1 and/or MCT4 inhibitors in cancer therapeutics, and anticipating its inclusion in clinical practice.

Multiomic Analysis and CRISPR Perturbation Screens Identify Endothelial Cell Programs and Novel Therapeutic Targets for Coronary Artery Disease.

Endothelial cells (EC) are an important mediator of atherosclerosis and vascular disease. Their exposure to atherogenic risk factors such as hypertension and serum cholesterol leads to endothelial dysfunction and many disease-associated processes. Identifying which of these multiple EC functions is causally related to disease risk has been challenging. There is evidence from in vivo models and human sequencing studies that dysregulation of nitric oxide production directly affects risk of coronary artery disease. Human genetics can help prioritize the other EC functions with causal relationships because germline mutations are acquired at birth and serve as a randomized test of which pathways affect disease risk. Though several coronary artery disease risk variants have been linked to EC function, this process has been slow and laborious. Unbiased analyses of EC dysfunction using multiomic approaches promise to identify the causal genetic mechanisms responsible for vascular disease. Here, we review the data from genomic, epigenomic, and transcriptomic studies that prioritize EC-specific causal pathways. New methods that CRISPR (clustered regularly interspaced short palindromic repeats) perturbation technology with genomic, epigenomic, and transcriptomic analysis promise to speed up the characterization of disease-associated genetic variation. We summarize several recent studies in ECs which use high-throughput genetic perturbation to identify disease-relevant pathways and novel mechanisms of disease. These genetically validated pathways can accelerate the identification of drug targets for the prevention and treatment of atherosclerosis.

Subchronic inhalation exposure to ultrafine particulate matter alters the intestinal microbiome in various mouse models.

Exposure to ultrafine particles (UFPs) has been associated with multiple adverse health effects. Inhaled UFPs could reach the gastrointestinal tract and influence the composition of the gut microbiome. We have previously shown that oral ingestion of UFPs alters the gut microbiome and promotes intestinal inflammation in hyperlipidemic Ldlr-/- mice. Particulate matter (PM)2.5 inhalation studies have also demonstrated microbiome shifts in normolipidemic C57BL/6 mice. However, it is not known whether changes in microbiome precede or follow inflammatory effects in the intestinal mucosa. We hypothesized that inhaled UFPs modulate the gut microbiome prior to the development of intestinal inflammation. We studied the effects of UFP inhalation on the gut microbiome and intestinal mucosa in two hyperlipidemic mouse models (ApoE-/- mice and Ldlr-/- mice) and normolipidemic C57BL/6 mice. Mice were exposed to PM in the ultrafine-size range by inhalation for 6 h a day, 3 times a week for 10 weeks at a concentration of 300-350 µg/m3.16S rRNA gene sequencing was performed to characterize sequential changes in the fecal microbiome during exposures, and changes in the intestinal microbiome at the end. PM exposure led to progressive differentiation of the microbiota over time, associated with increased fecal microbial richness and evenness, altered microbial composition, and differentially abundant microbes by week 10 depending on the mouse model. Cross-sectional analysis of the small intestinal microbiome at week 10 showed significant changes in α-diversity, ß-diversity, and abundances of individual microbial taxa in the two hyperlipidemic models. These alterations of the intestinal microbiome were not accompanied, and therefore could not be caused, by increased intestinal inflammation as determined by histological analysis of small and large intestine, cytokine gene expression, and levels of fecal lipocalin. In conclusion, 10-week inhalation exposures to UFPs induced taxonomic changes in the microbiome of various animal models in the absence of intestinal inflammation.

Assessment of Epidemiology and Clinical Profile of Psoriatic Arthritis Patients in India.

BACKGROUND: Psoriasis is an inflammatory skin disease associated with significant comorbidity. However, the characteristics of patients with psoriasis are not well documented in India, and a more detailed understanding is needed to delineate the epidemiologic profile at the regional level for better management of psoriasis. Herein, we reported the clinical profile and demographic pattern of psoriasis to further understand its burden in the Indian setting. METHODS: We conducted a retrospective observational study of patients diagnosed with psoriasis who fulfilled the classification criteria for psoriatic arthritis (CASPAR) criteria. Patients were included from the rheumatology outpatient department of Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute in Mumbai, India. The outcomes included demographic and clinical profiles, patterns of joint involvement, and comorbidities associated with psoriasis. A p-value of <0.05 was considered significant. RESULTS: We enrolled 60 patients, with a mean age of 50.87 years and a higher proportion of females (62%). The majority of patients with less than five joints had associated comorbidities (40 out of 60). Psoriatic arthritis (PsA) occurred in 41 patients [mean ± standard deviation (SD) age of onset-38.88 ± 13.24 years], with the highest occurrence in the 30-50 years (53.3%). The majority of patients with PsA developed it within 2 to ≥5 years of psoriasis occurrence. We did not find any significant correlation between the occurrence of PsA and comorbidities, as well as the duration of PsA and the number of joints (p = 0.152). Pitting and enthesitis were the most common morphological changes noted in almost half of the patients. CONCLUSION: Our study provides an overview of the epidemiologic and clinical characteristics of psoriasis patients in India. These findings could be useful for early diagnosis of PsA and help clinicians in assessing the progression of psoriasis into PsA.

Dynamic human liver proteome atlas reveals functional insights into disease pathways.

Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time course of primary cell cultures, and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serve as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of hepatic stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactive exploration of our resource (www.liverproteome.org).

Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers.

[Figure: see text].

Socio-demographic predictors of obesity among 12,975 adult ever married Egyptian women of reproductive age group: evidence from nationwide survey.

AIM: We aimed to explore the predictors associated with obesity among adult ever-married Egyptian women aged 20-49 years based on the Egyptian Demographic and Health Survey (EDHS). METHOD: We included adult ever married women from the EDHS conducted in 2014 that initially recruited 21,903 women. Univariate and multivariable analysis was conducted to identify socio-demographic predictors of women's obesity. RESULT: We included 12,975 Egyptian women. Among them, 76% of the total respondents were obese where as 24% were with normal body mass index (BMI). In multivariable analysis, the results revealed that increasing age, higher wealth index, listening to radio at least once a week and women with primary and secondary education were at significant odds of developing obesity (p < 0.05). However, we found no association between residence of participants and the frequency of watching television upon the development of obesity (p > 0.05). CONCLUSION: Appropriate and targeted interventions should be implemented among the Egyptian reproductive age women to reduce the obesity as well as non-communicable diseases load associated with obesity. National Health Service policy makers should take multilevel approach targeting high risk sub-groups to raise awareness and to provide prevention against obesity and the subsequent complications.

Prevalence and determinants of hypertension among urban slum dwellers in Bangladesh.

BACKGROUND: In low- and middle- income countries such as Bangladesh, urban slum dwellers are particualry vulnerable to hypertension due to inadequate facilities for screening and management, as well as inadequate health literacy among them. However, there is scarcity of evidence on hypertension among the urban slum dwellers in Bangladesh. The present study aimed to determine the prevalence and factors associated with hypertension among urban slum dwellers in Bangladesh. METHODS: Data were collected as part of a large-scale cross-sectional survey conducted by Building Resources Across Communities (BRAC) between October 2015 and January 2016. The present analysis was performed among 1155 urban slum dwellers aged 35 years or above. A structured questionnaire was adminstered to collect data electronically and blood pressure measurements were taken using standardised procedures. Binary logistic regression with generalized estimating equation modelling was performed to estimate the factors associated with hypertension. RESULTS: The prevalence of hypertension was 28.3% among urban slum dwellers aged 35 years and above. In adjusted analysis, urban slum dwellers aged 45-54 years (AOR: 1.64, 95% CI: 1.17-2.28), 55-64 years (AOR: 2.47, 95% CI: 1.73-3.53) and ≥ 65 years (AOR: 2.34, 95% CI: 1.47-3.72), from wealthier households (AOR: 1.94, 95% CI: 1.18-3.20), sleeping < 7 h per day (AOR: 1.87, 95% CI: 1.39-2.51), who were overweight (AOR: 1.53, 95% CI: 1.09-2.14) or obese (AOR: 2.34, 95% CI: 1.71-3.20), and having self-reported diabetes (AOR: 3.08, 95% CI: 1.88-5.04) had an increased risk of hypertension. Moreover, 51.0% of the participants were taking anti-hypertensive medications and 26.4% of them had their hypertension in control. CONCLUSIONS: The findings highlight a high burden of hypertension and poor management of it among the slum dwellers in Bangladesh requiring a novel approach to improve care. It is integral to effectively implement the available national non-communicable disease (NCD) control guidelines and redesign the current urban primary health care system to have better coordination.

Inhaled iloprost as an add-on therapy for advanced pulmonary arterial hypertension: An Indian perspective.

Background Pulmonary arterial hypertension (PAH) is a progressive disease with high morbidity and mortality. Risk stratification and initiation of dual or triple combination therapy has a better clinical response, especially in high-risk patients. Unfortunately, prostacyclin analogues are not marketed in India; hence, the use of these medications is limited. We report the benefits and difficulties of using iloprost inhalation in patients with advanced PAH in India. Methods In this prospective observational study, we included patients with group 1 PAH. Inhaled iloprost was initiated as an add-on therapy for patients who had clinical, echocardiographic or laboratory deterioration on dual oral medications. Patients with clinical instability were excluded. All patients underwent thorough clinical evaluation, detailed echocardiogram and laboratory investigations. Patients were started on inhaled iloprost 2.5 µg six times daily and closely followed up. The dose was escalated if necessary. On follow-up, clinical echocardiographic and laboratory evaluation was done on all patients. Results Fourteen patients (11 women) with a median age of 32 years (2-66 years) with group 1 PAH were started on inhaled iloprost as an add-on therapy. Improvement in clinical parameters, WHO functional class, echocardiographic-derived right ventricular function, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were observed in 10 of 14 patients. A median increase of 31% (4.2, 106%) in the distance travelled during 6-minute walk test, a median increase of 45% (-20, 120%) in right ventricular fractional area change, a median increase of 27% (-16.7, 60%) in tricuspid annular peak systolic excursion and a median decrease of 36.7% (-69.6, 17.2%) in NT-pro-BNP levels were observed after initiation of medication. Three patients had progression of symptoms and were then referred for lung/heart-lung transplant. One patient developed progression of symptoms after an excellent initial response and transitioned to subcutaneous treprostinil. Improvement in clinical, echocardiographic and laboratory features allowed us to successfully perform surgical Potts shunt in 2 patients. The medications were well tolerated with minimal and transient side-effects. There were no deaths. Conclusion Inhaled iloprost can be used with acceptable benefits and minimal side-effects in patients with PAH.

Achieving Correct Axis and Good Depth in Gender Affirming Vaginoplasties by Penile-Perineoscrotal Flap Vaginoplasty.

Objectives Vaginoplasty as a part of feminizing genitoplasty (FG) in transwomen helps alleviate gender dysphoria and improves mental health, sexual and psychosocial functioning, and quality of life in these individuals. Penile inversion technique (PSFV) remains the gold standard procedure for FG with least morbidity but has inherent limitations often resulting in inadequate depth and incorrect (posteroinferior) vaginal axis, precluding sexual intercourse. Material and Methods Over the past 27 years, the senior author has refined his technique considerably incorporating several modifications penile perineo-scrotal flap vaginoplasty (PPSFV) to overcome the limitations in PSFV. Most of these modifications were in place by March 2015. Out of 630 primary FGs, retrospective review of all PPSFV with minimum 6 months follow-up operated during the period March 2015 to July 2020 was done for intra and postoperative complications. Results There were 183 patients who underwent PPSFV during the study period. Average follow-up was 31 (6-62) months. There were no cases of injury to bladder, rectum, urethral stenosis, or neovaginal prolapse. Average operative time was 4 hours and eight (4.37%) patients required blood transfusion. The vaginal depth was 13 to 14 cm or more in 159 (86.88%), 10 to 12 cm in 17 (9.29%), and 7.5 to 9 cm in seven (3.82%) patients. Ten (5.46%) patients complained of intravaginal hair growth. Touch up procedures in the form of anterior commissure and labia plasty were required in 13 (7.10%) patients. All (100%) patients had good clitoral sensitivity and preserved posterosuperior vaginal axis. One-hundred thirty nine (75.96%) patients were able to have satisfactory penetrative sexual intercourse, while 39 (21.31%) had not attempted intercourse and five (2.73%) complained of poor sexual experience on account of inadequate vaginal dimensions. Conclusion PPSFV addresses the limitations in PSFV and results in good vaginal depth and posterosuperior axis, which facilitates penetrative sexual intercourse, at the same time, avoiding potential complications of procedures such as intestinal vaginoplasties.

A Comparative Study of Urinary Complication Rates before and after the Incorporation of a Urethral Lengthening Technique during Masculinizing Genital Gender Affirmation Surgery.

Objectives Masculinizing genital gender affirmation surgery (MgGAS) consists of operative procedures designed to help the transition of transmen in their journey toward male gender role. Phalloplasty and urethral lengthening remain the most challenging of these surgeries, as the female urethra (4 cm long) must be lengthened to male dimensions (15-29 cm) with anastomosis at two sites, the native urethra/pars fixa urethra and the pars fixa urethra-penile urethra. As a result, there is a high incidence of urinary complications such as strictures and fistulae. Authors incorporated a urethral lengthening technique to reduce urinary complications in MgGAS. They compare the rates of urinary complications rates in cohorts before and after the introduction of this technique. Materials and Methods Authors have been performing phalloplasty since past 27 years, utilizing mainly free radial artery forearm flap (fRAFFp 431 cases) and pedicled anterolateral thigh flap (pALTp 120 cases). A retrospective review and comparison of urinary complications were performed before and after the introduction of their new technique since March 2017. Results There was a statistically significant reduction in the incidence of stricture with and without fistulae (25.94% with conventional and 4.17% with urethral lengthening technique p = 0.001) and fistulae alone (12.81% with conventional and 2.78% with urethral lengthening technique p = 0.011) in fRAFFp cases. In pALTp cases, the respective reductions were 43.08 to 17.07%, p = 0.006 (significant), and 13.85 to 4.88%, p = 0.197 (not statistically significant). Conclusion Over years, the rates of urinary complications in MgGAS have remained constant, varying from 25 to 58% for strictures and 17 to 75% for fistulae as noted by many authors. Authors noted that in most of their cases, strictures occurred at distal pars fixa urethra (DPFU)-penile urethra anastomosis and incorporated a urethral lengthening technique, which lengthens the DPFU by 3 to 5 cm at this anastomotic site, thus significantly reducing the anastomotic tension and the rate of urinary complications.

Expanded phenotype of AARS1-related white matter disease.

PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

Association of household wealth and education level with hypertension and diabetes among adults in Bangladesh: a propensity score-based analysis.

OBJECTIVE: To determine the association of household wealth and education level with hypertension and diabetes in Bangladesh using propensity score (PS) analyses. METHODS: A nationally representative sample of the Bangladesh Demographic and Health Survey 2017-18 was analysed to explore the research question. A weighted sample of 11 320 individuals was considered. Hypertension and diabetes were the outcomes of interest, and household wealth status (non-poor and poor) and education level (secondary/higher education and no secondary/higher education) were the exposure variables of interest. A person was defined as hypertensive if their average blood pressure was ≥140/90 mmHg or self-reported history of taking antihypertensive medications. Individuals were classified as diabetic if they had a Fasting Blood Glucose level of ≥7 mmol/l or reported taking prescribed medication for reducing high blood glucose or diabetes. We used the 1:1 nearest neighbour PS matching without replacement and PS weighting approaches to assess the association between the exposures and the outcome variables. RESULTS: Wealth status was significantly associated with diabetes but not with hypertension, while education status was significantly associated with neither diabetes nor hypertension. We also observed a significant interaction effect between household wealth status and education level with diabetes. The odds of diabetes were approximately 60% higher among adults from non-poor households and those without secondary/higher education. CONCLUSION: Diabetes prevention and control programs should focus on non-poor individuals, while hypertension prevention programs should target populations irrespective of educational attainment and wealth status.

Determinants of hypertension in Nepal using odds ratios and prevalence ratios: an analysis of the Demographic and Health Survey 2016.

This cross-sectional study investigated the factors associated with hypertension among Nepalese adults aged 18 years or above using data from the Nepal Demographic and Health Survey 2016. Prevalence ratios (PRs) and odds ratios (ORs) were obtained using log-binomial regression and logistic regression, respectively. Initially, unadjusted PRs and ORs were obtained. The variables that yielded a significance level below 0.2 in unadjusted analyses were included in the multivariable analysis. The overall prevalence of hypertension among the 13,393 participants (58% male and 61.2% urban) was 21.1% (n = 2827). In the adjusted analysis, those aged 30-49 years (adjusted PR [APR]: 3.1, 95% Confidence Interval (CI): 2.6, 3.7; adjusted OR [AOR]: 3.6, 95% CI: 2.9, 4.5), 50-69 years (APR: 5.3, 95% CI: 4.4, 6.6; AOR: 8.2, 95% CI: 6.4, 10.4) and ≥70 years (APR: 7.3, 95% CI: 5.8, 9.2; AOR: 13.6, 95% CI: 10.1, 18.3) were more likely to be hypertensive than younger participants aged 18-29 years. Males (APR: 1.3, 95% CI: 1.2, 1.4; AOR: 1.5, 95% CI: 1.3, 1.7), overweight/obese participants (APR: 1.8, 95% CI: 1.7, 2.0; AOR: 2.4, 95% CI: 2.2, 2.8) and those in the richest wealth quintile (APR: 1.3, 95% CI: 1.1, 1.5; AOR: 1.5, 95% CI: 1.1, 1.9) had higher prevalences and odds of hypertension than their female, normal weight/underweight and poorest wealth quintile counterparts, respectively. Those residing in Province 4 (APR: 1.2, 95% CI: 1.0, 1.5; AOR: 1.4, 95% CI: 1.1, 1.8) and Province 5 (APR: 1.2, 95% CI: 1.0, 1.4; AOR: 1.3, 95% CI: 1.1, 1.7) were more likely to be hypertensive than those residing in Province 1. The point estimate was inflated more in magnitude by ORs than by PRs, but the direction of association remained the same. Public health programmes in Nepal aimed at preventing hypertension should raise awareness among the elderly, males, individuals in the richest wealth quintile and the residents of Provinces 4 and 5.