Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

Abstract: Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability

Racial Disparities and Risk for COVID-19 Among Pregnant Patients: Results from the Michigan Statewide Collaborative

Objective: Previous studies have looked at COVID-19 outcomes in pregnancy and racial disparities among patients with COVID-19, but few have studied racial disparities among pregnant patients with COVID-19. Our goal in this study is to analyze the relationship between race and disparate COVID-19 risk in pregnancy. Study Design: A retrospective cohort analysis was performed on data collected as part of the COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative, a database of pregnant patients admitted to 14 institutions in Southern Michigan. Cases were defined as patients with a positive SARS-CoV-2 test result. Controls, those with suspicion of COVID-19 prior to universal screening or a negative PCR test, were matched to cases on the same unit within 30 days of each case. For this analysis, the two primary groups of interest were non-Hispanic Black (Black) vs. non-Hispanic White (White) patients. Potential covariates were age, body mass index (BMI), chronic hypertension, diabetes, asthma, substance use, and smoking; the dependent variable was COVID/non-COVID in a robust Poisson regression model. In addition, 18 symptoms and disease severity (mild/moderate/severe) were compared between the Black and White groups using the same statistical method. Results: Of 1,131 gravidas, 42.9%(n=485) were Black. These patients were at two-fold greater risk for COVID-19 compared with their White counterparts [35.9% vs. 18.3%, RR=1.96(1.6-2.4)]. After adjusting for obesity and diabetes, the risk of COVID-19 in Black patients remained higher compared to the risk among White patients (aRR=2.46 [1.87-3.24]). There were no differences in symptoms nor severity of disease presentation between the groups. Conclusion: In our population, Black patients are more likely to be diagnosed with COVID-19 infection during pregnancy. This finding is not explained by a range of covariates. Other factors, such as social determinants of health, may be important to understand this disparity and warrant further examination

The Distribution of Fecal Contamination in an Urbanized Tropical Lake and Incidence of Acute Diarrheal Disease

Aquatic ecosystems of tropical countries are vulnerable to fecal contamination that could cause spikes in the incidences of acute diarrheal disease (ADD) and challenge public health management systems. Vembanad lake, situated along the southwest coast of India, was monitored for one year (2018−2019). Escherichia coli, an indicator of fecal contamination, was prevalent in the lake throughout the year. Multiple antibiotic resistance among more than 50% of the E. coli isolates adds urgency to the need to control this contamination. The high abundance of E. coli and incidence of ADD were recorded during the early phase of the southwest monsoon (June−July), prior to the once-in-a-century floods that affected the region in the later phase (August). The extent of inundation in the low-lying areas peaked in August, but E. coli in the water peaked in July, suggesting that contamination occurred even prior to extreme flooding. During the COVID-19-related lockdown in March−May 2021, fecal contamination in the lake and incidence of ADD reached minimum values. These results indicate the need for improving sewage treatment facilities and city planning in flood-prone areas to avoid the mixing of septic sewage with natural waters during extreme climate events or even during the normal monsoon

COVID-19 is associated with early emergence of preeclampsia: results from a large regional collaborative

Objective: To examine the relationship between COVID-19 and preeclampsia (PreE) in a large, diverse population. Study Design: The COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative established a database of pregnant patients admitted to 14 institutions in Southern Michigan. Patients with COVID-19 (cases) were matched to 2 or 3 non-COVID patients (controls) on the same unit within 30 days of each case. Relative Risks (RR) were calculated using robust Poisson regression models with adjustment for covariates. Chi-squared test for trend was used to assess the increase in risk with the severity of disease. Results: 369 cases and 1,090 controls were delivered between March - October 2020. An increased risk of PreE (RR=1.8), driven almost entirely by an increase in preterm PreE (pretermPreE) (RR=2.85) was observed in COVID pregnancies (Table 1), with a dose-response relationship with symptomatology and severity (Table 2). The associations between COVID-19 disease and PreE or pretermPreE were independent of other risk factors, as demonstrated by the minimal changes in RR after adjustment for confounders (Table 1). However, African American (AA) COVID patients experienced pretermPreE 1.9 times more than COVID patients of other races (10.1 vs 5.3), an increase not observed in control patients. The strength of the association for COVID with PreE was comparable to the association of PreE with chronic hypertension and nulliparity (data not shown). Increasing symptoms and severity of COVID-19 were associated with an increased risk for PreE with placental lesions, even after adjustment for relevant covariates (Tables 1 & 2). Non-PreE COVID patients had an increased trend of placental lesions compared to non-COVID patients, reaching significance for intravillous thrombin. Conclusion: COVID-19 is significantly associated with early emergence of PreE, independent of known risk factors other than AA race. Our study shows that among patients predisposed to PreE, COVID-19 impacts PreE severity in that it leads to pretermPreE. Further studies on COVID-19 and PreE, with a focus on racial disparities, is warranted

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms

Dynamics of Vibrio cholerae in a Typical Tropical Lake and Estuarine System: Potential of Remote Sensing for Risk Mapping

Vibrio cholerae, the bacterium responsible for the disease cholera, is a naturally-occurring bacterium, commonly found in many natural tropical water bodies. In the context of the U.N. Sus�tainable Development Goals (SDG) targets on health (Goal 3), water quality (Goal 6), life under water (Goal 14), and clean water and sanitation (Goal 6), which aim to “ensure availability and sustain�able management of water and sanitation for all”, we investigated the environmental reservoirs of V. cholerae in Vembanad Lake, the largest lake in Kerala (India), where cholera is endemic. The response of environmental reservoirs of V. cholerae to variability in essential climate variables may play a pivotal role in determining the quality of natural water resources, and whether they might be safe for human consumption or not. The hydrodynamics of Vembanad Lake, and the man-made barrier that divides the lake, resulted in spatial and temporal variability in salinity (1–32 psu) and temperature (23 to 36 ◦C). The higher ends of this salinity and temperature ranges fall outside the preferred growth conditions for V. cholerae reported in the literature. The bacteria were associated with filtered water as well as with phyto- and zooplankton in the lake. Their association with benthic organisms and sediments was poor to nil. The prevalence of high laminarinase and chitinase enzyme expression (more than 50 µgmL−1 min−1 ) among V. cholerae could underlie their high association with phyto- and zooplankton. Furthermore, the diversity in the phytoplankton community in the lake, with dominance of genera such as Skeletonema sp., Microcystis sp., Aulacoseira sp., and Anabaena sp., which changed with location and season, and associated changes in the zooplankton community, could also have affected the dynamics of the bacteria in the lake. The probability of presence or absence of V. cholerae could be expressed as a function of chlorophyll concentration in the water, which suggests that risk maps for the entire lake can be generated using satellite-derived chlorophyll data. In situ observations and satellite-based extrapolations suggest that the risks from environmental V. cholerae in the lake can be quite high (with probability in the range of 0.5 to 1) everywhere in the lake, but higher values are encountered more frequently in the southern part of the lake. Remote sensing has an important role to play in meeting SDG goals related to health, water quality and life under water, as demonstrated in this example related to cholera

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group

Neuromuscular disease genetics in under-represented populations: increasing data diversity

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses \u27solved\u27 or \u27possibly solved\u27 ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% \u27solved\u27 and ∼13% \u27possibly solved\u27 outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally