Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.

Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.

A mechanistic study on the tolerance of PAM distal end mismatch by SpCas9.

The therapeutic application of CRISPR-Cas9 is limited due to its off-target activity. To have a better understanding of this off-target effect, we focused on its mismatch-prone PAM distal end. The off-target activity of SpCas9 depends directly on the nature of mismatches, which in turn results in deviation of the active site of SpCas9 due to structural instability in the RNA-DNA duplex strand. In order to test the hypothesis, we designed an array of mismatched target sites at the PAM distal end and performed in vitro and cell line-based experiments, which showed a strong correlation for Cas9 activity. We found that target sites having multiple mismatches in the 18th to 15th position upstream of the PAM showed no to little activity. For further mechanistic validation, Molecular Dynamics simulations were performed, which revealed that certain mismatches showed elevated root mean square deviation values that can be attributed to conformational instability within the RNA-DNA duplex. Therefore, for successful prediction of the off-target effect of SpCas9, along with complementation-derived energy, the RNA-DNA duplex stability should be taken into account.

deepGraphh: AI-driven web service for graph-based quantitative structure-activity relationship analysis.

Artificial intelligence (AI)-based computational techniques allow rapid exploration of the chemical space. However, representation of the compounds into computational-compatible and detailed features is one of the crucial steps for quantitative structure-activity relationship (QSAR) analysis. Recently, graph-based methods are emerging as a powerful alternative to chemistry-restricted fingerprints or descriptors for modeling. Although graph-based modeling offers multiple advantages, its implementation demands in-depth domain knowledge and programming skills. Here we introduce deepGraphh, an end-to-end web service featuring a conglomerate of established graph-based methods for model generation for classification or regression tasks. The graphical user interface of deepGraphh supports highly configurable parameter support for model parameter tuning, model generation, cross-validation and testing of the user-supplied query molecules. deepGraphh supports four widely adopted methods for QSAR analysis, namely, graph convolution network, graph attention network, directed acyclic graph and Attentive FP. Comparative analysis revealed that deepGraphh supported methods are comparable to the descriptors-based machine learning techniques. Finally, we used deepGraphh models to predict the blood-brain barrier permeability of human and microbiome-generated metabolites. In summary, deepGraphh offers a one-stop web service for graph-based methods for chemoinformatics.

HAPNEST: efficient, large-scale generation and evaluation of synthetic datasets for genotypes and phenotypes.

MOTIVATION: Existing methods for simulating synthetic genotype and phenotype datasets have limited scalability, constraining their usability for large-scale analyses. Moreover, a systematic approach for evaluating synthetic data quality and a benchmark synthetic dataset for developing and evaluating methods for polygenic risk scores are lacking. RESULTS: We present HAPNEST, a novel approach for efficiently generating diverse individual-level genotypic and phenotypic data. In comparison to alternative methods, HAPNEST shows faster computational speed and a lower degree of relatedness with reference panels, while generating datasets that preserve key statistical properties of real data. These desirable synthetic data properties enabled us to generate 6.8 million common variants and nine phenotypes with varying degrees of heritability and polygenicity across 1 million individuals. We demonstrate how HAPNEST can facilitate biobank-scale analyses through the comparison of seven methods to generate polygenic risk scoring across multiple ancestry groups and different genetic architectures. AVAILABILITY AND IMPLEMENTATION: A synthetic dataset of 1 008 000 individuals and nine traits for 6.8 million common variants is available at https://www.ebi.ac.uk/biostudies/studies/S-BSST936. The HAPNEST software for generating synthetic datasets is available as Docker/Singularity containers and open source Julia and C code at https://github.com/intervene-EU-H2020/synthetic_data.

Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.

INTRODUCTION: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging. OBJECTIVE: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality. METHODS: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) - the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact. RESULTS: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-L-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased. CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.

Cardiovascular Outcomes of Hypogonadal Men Receiving Testosterone Replacement Therapy: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To investigate the impact of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men. METHODS: A meta-analysis of 26 randomized controlled trials involving 10 941 participants was conducted. Various clinical outcomes, including all-cause mortality, cardiovascular-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis, were assessed. RESULTS: No statistically significant differences were observed between the TRT group and the control group in terms of these clinical outcomes. Sensitivity analysis and publication bias assessment supported the robustness of the findings. Meta-regression analysis found no significant associations between clinical outcomes and potential covariates, including age, diabetes, hypertension, dyslipidemia, and smoking. DISCUSSION: Previous research on TRT and cardiovascular events, with comparisons to studies like the Testosterone Trials and the studies conducted by Vigen et al, Finkle et al, Layton et al, and Wallis et al, is provided. The significance of the systematic review and meta-analysis approach is emphasized, particularly its exclusive focus on hypogonadal patients. CONCLUSION: This study offers reassurance that TRT does not increase mortality risk or worsen cardiovascular outcomes in hypogonadal men. However, further research, especially long-term studies involving diverse populations, is essential to strengthen the evidence base and broaden the applicability of these findings.

Sequential Co-Immobilization of Enzymes on Magnetic Nanoparticles for Efficient l-Xylulose Production.

Multi-enzymatic strategies have shown improvement in bioconversion during cofactor regeneration. In this study, purified l-arabinitol 4-dehydrogenase (LAD) and nicotinamide adenine dinucleotide oxidase (Nox) were immobilized via individual, mixed, and sequential co-immobilization approaches on magnetic nanoparticles, and were evaluated to enhance the conversion of l-arabinitol to l-xylulose. Initially, the immobilization of LAD or Nox on the nanoparticles resulted in a maximum immobilization yield and relative activity of 91.4% and 98.8%, respectively. The immobilized enzymes showed better pH and temperature profiles than the corresponding free enzymes. Furthermore, co-immobilization of these enzymes via mixed and sequential methods resulted in high loadings of 114 and 122 mg/g of support, respectively. Sequential co-immobilization of these enzymes proved more beneficial for higher conversion than mixed co-immobilization because of better retaining Nox residual activity. Sequentially co-immobilized enzymes showed a high relative conversion yield with broader pH, temperature, and storage stability profiles than the controls, along with high reusability. To the best of our knowledge, this is the first report on the mixed or sequential co-immobilization of LAD and Nox on magnetic nanoparticles for l-xylulose production. This finding suggests that selecting a sequential co-immobilization strategy is more beneficial than using individual or mixed co-immobilized enzymes on magnetic nanoparticles for enhancing conversion applications.

Incidence, Predictors, and Outcomes of Venous and Arterial Thrombosis in COVID-19: A Nationwide Inpatient Analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is known to increase the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). However, the incidence, predictors, and outcomes of clinical thrombosis for inpatients with COVID-19 are not well known. This study aimed to enhance our understanding of clinical thrombosis in COVID-19, its associated factors, and mortality outcomes. METHOD: Hospitalised adult (≥18 years of age) patients with COVID-19 in 2020 were retrospectively identified from the US National Inpatient Sample database. Clinical characteristics, incident VTE, ATE, and in-hospital mortality outcomes were recorded. Multivariable logistic regression was performed to identify clinical factors associated with thrombosis and in-hospital mortality in COVID-19 inpatients. RESULTS: A total of 1,583,135 adult patients with COVID-19 in the year 2020 were identified from the National Inpatient Sample database; patients with thrombosis were 41% females with a mean age of 65.4 (65.1-65.6) years. The incidence of thrombosis was 6.1% (97,185), including VTE at 4.8% (76,125), ATE at 3.0% (47,790), and the in-hospital mortality rate was 13.4% (212,785). Patients with thrombosis were more likely to have respiratory symptoms of COVID-19 (76.7% vs 75%, p<0.001) compared with patients without thrombosis. The main factors associated with overall thrombosis, VTE, and ATE were paralysis, ventilation, solid tumours without metastasis, metastatic cancer, and acute liver failure. Although all thrombosis categories were associated with higher in-hospital mortality for COVID-19 inpatients in univariable analyses (p<0.001), they were not in multivariable analyses-thrombosis (odds ratio [OR] 1.24; 95% confidence interval [CI] 0.90-1.70; p=0.19), VTE (OR 0.70; 95% CI 0.52-1.00; p=0.05), and ATE (OR 1.07; 95% CI 0.92-1.25; p=0.36). CONCLUSIONS: The association of COVID-19 with thrombosis and VTE increases with increasing severity of the COVID-19 disease. Risk stratification of thrombosis is crucial in COVID-19 patients to determine the necessity of thromboprophylaxis.

Algorithmic Approach to Benign Prostatic Hyperplasia: An Indian Perspective.

Benign prostatic hyperplasia (BPH) is a prevalent condition affecting aging men, necessitating a comprehensive and evidence-based approach to diagnosis and management. This manuscript, through the summarization of the latest evidence, aims to establish a consensus among clinicians regarding optimal strategies for diagnosing and managing BPH, to improve patient care and outcomes in clinical practice. A panel of urologists conducted a comprehensive review of the literature by searching various databases and search engines (PubMed, Google Scholar, and Cochrane databases). They identified relevant studies on the diagnosis and management of BPH. The literature was summarized and analyzed to develop 14 statements. The panel utilized a Delphi methodology over two rounds (R1 and R2) to reach a consensus on the statements, considering both the literature evidence and expert opinions. The expert panel reached a consensus on 14 statements addressing diverse aspects of BPH, including tailored therapies for different patient profiles and the necessity for a unified diagnosis and management algorithm to enhance patient outcomes. In conclusion, a unified approach to diagnosing and managing BPH promotes consistent and effective patient care. Proper drug selection, considering factors like efficacy and patient-specific characteristics, is crucial for managing BPH. This approach optimizes treatment outcomes and improves the quality of life for BPH patients.

Minimally Invasive Open Cystogastrostomy for Giant Pancreatic Pseudocyst in Pediatric Patients.

Open cystogastrostomy is the standard treatment for the operative management of pancreatic pseudocysts. We describe our technique of minimally invasive open cystogastrostomy for giant pediatric pancreatic pseudocyst. Preoperative incision marking on the most prominent part of the pseudocyst was done by ultrasound guidance. A transverse incision of approximately 3-4 cm was made, and a minilaparotomy was performed. Stay sutures were applied on the anterior wall of the stomach. The anterior wall was exteriorized; transverse gastrotomy was performed, and superior and inferior flaps were made. Deaver's retractor was placed inside the lumen, and cystogastrostomy was completed. We employed this technique in five male patients without any complications. All patients were allowed clear liquids on postoperative day 4 or 5; and gradually shifted to a soft diet. The mean duration of postoperative stay was 7 days. The size of the scar ranged from 3 to 5 cm. All patients were doing well on follow-up. Our technique of minimally invasive open cystogastrostomy is a viable option for pancreatic pseudocyst in pediatric patients.

Glycopyrrolate as an Adjunct in the Management of Anastomotic Leak Following Repair of Esophageal Atresia: A Clinicoradiological Perspective.

Context: Anastomotic leak after primary repair of esophageal atresia (EA) with tracheoesophageal fistula (TEF) is a well-known complication and can represent a challenging clinical scenario. Aims: The present study aimed to evaluate the role of glycopyrrolate as an adjunct in the treatment of anastomotic leak after primary repair of EA Vogt type 3b. Settings and Design: A retrospective study was carried out in our tertiary care teaching institute from January 2015 to December 2022. Materials and Methods: Neonates with EA with distal TEF with primary repair who had developed anastomotic leak, managed by the author(s), were studied. The study included patients with major, minor, and radiological leaks. Glycopyrrolate was administered in the dose of 4 µg/kg 8 hourly. The outcomes of the study were either resolution or progression of the leak. Results: There were 21 patients who were managed with glycopyrrolate in addition to the classical treatment of the anastomotic leak following repair of EA with distal TEF. The male: female ratio was 1:1.1. All the cases had anastomotic leaks with either clinically detectable in the chest tube (15) or radiological leak (6). The leaks were detected early in patients with major leak (mean = 3.2 ± 0.84 days) compared to minor leak (mean =4.9 ± 1.29 days). Radiological leaks were detected in all the neonates on postoperative day 7. In five patients with major leak, there was a negligible reduction in the amount of chest tube output, and were subjected to diversion procedures. There were a total of three deaths out of five in this group. In 10 patients with minor leak, there was complete resolution of anastomotic leak in eight patients (80%); there was one patient each with mortality and diversion procedure. The patients with a radiological leak (6) did not show any deterioration, and they were fed 1-5 days after the esophagogram. Conclusions: Glycopyrrolate may be an advantageous postoperative adjunct in the management of minor and radiological leak after tracheoesophageal repair.

Nonsterile Process for Biohydrogen Production: Recent Updates, Challenges, and Opportunities.

Hydrogen (H2), a clean and versatile energy carrier, has recently gained significant attention as a potential solution for reducing carbon emissions and promoting sustainable energy systems. The yield and efficiency of the biological H2 production process primarily depend on sterilization conditions. Various strategies, such as heat inactivation and membrane-based sterilization, have been used to achieve desirable yields via microbial fermentation. Almost every failed biotransformation process is linked to nonsterile conditions at any reaction stage. Therefore, the production of renewable biofuels as alternatives to fossil fuels is more attractive. Pure sugars have been widely documented as a costly feedstock for H2 production under sterile conditions. Biotransformation under nonsterile conditions is more desirable for stable and sustainable operation. Low-cost feeds, such as biowaste, are considered suitable alternatives, but they require appropriate sterilization to overcome the limitations of inherited or contaminating microbes during H2 production. This article describes the status of microbial fermentative processes for H2 production under nonsterile conditions and discusses strategies to improve such processes for sustainable, cleaner production.

Clinical outcomes and the impact of valve morphology for transcatheter aortic valve replacement in bicuspid aortic valves: A systematic review and meta-analysis.

BACKGROUND: Bicuspid aortic valve (BAV) is present in approximately 0.5%-2% of the general population, causing significant aortic stenosis (AS) in 12%-37% of affected individuals. Transcatheter aortic valve replacement (TAVR) is being considered the treatment of choice in patients with symptomatic AS across all risk spectra. AIM: Aim Our study aims to compare TAVR outcomes in patients with BAV versus tricuspid aortic valves (TAV). METHODS: A comprehensive literature search was performed in PubMed, Web of Science, and Cochrane trials. Studies were included if they included BAV and TAV patients undergoing TAVR with quantitative data available for at least one of our predefined outcomes. Meta-analysis was performed by the random-effects model using Stata software. RESULTS: Fifty studies of 203,288 patients were included. BAV patients had increased 30-day all-cause mortality (odds ratio [OR] = 1.23 [1.00-1.50], p = 0.05), in-hospital stroke (OR = 1.39 [1.01-1.93], p = 0.05), in-hospital and 30-day PPI (OR = 1.13 [1.00-1.27], p = 0.04; OR = 1.16 [1.04-1.13], p = 0.01) and in-hospital, 30-day and 1-year aortic regurgitation (AR) (OR = 1.48 [1.19-1.83], p < 0.01; OR = 1.79 [1.26-2.52], p < 0.01; OR = 1.64 [1.03-2.60], p = 0.04). Subgroup analysis on new-generation valves showed a reduced 1-year all-cause mortality (OR = 0.86 [CI = 0.75-0.98], p = 0.03), despite higher in-hospital and 30-day PPI (OR = 0.1.21 [1.04-1.41], p = 0.01; OR = 1.17 [1.05-1.31], p = 0.01) and in-hospital AR (OR = 1.62 [1.14-2.31], p = 0.01) in the BAV group. The quality of included studies was moderate-to-high, and only three analyses presented high heterogeneity. CONCLUSION: TAVR is associated with comparable outcomes in patients with BAV and TAV. Careful selection of BAV cases by preprocedural assessment of valve anatomy and burden of calcification, pre- and post-procedural dilation, and implementing newer generations of valves may improve the safety and efficacy of TAVR in BAV patients.

Meta-analysis of outcomes following intravenous thrombolysis in patients with ischemic stroke on direct oral anticoagulants.

BACKGROUND: There has been debate on the use of intravenous thrombolysis (IVT) in patients with ischemic stroke and the recent use of direct oral anticoagulants (DOACs). Studies have compared these patients with non-DOAC groups in terms of outcomes. Herein, we aimed to systematically investigate the association between DOAC use and IVT's efficacy and safety outcomes. RESULTS: A comprehensive systematic search was performed in PubMed, Embase, Scopus, and the Web of Science for the identification of relevant studies. After screening and data extraction, a random-effect meta-analysis was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) for comparison of outcomes between patients on DOAC and controls. Six studies were included in the final review. They investigated a total of 254,742 patients, among which 3,499 had recent use of DOACs. The most commonly used DOACs were rivaroxaban and apixaban. The patients on DOAC had significantly higher rates of atrial fibrillation, hypertension, diabetes, and smoking. Good functional outcome defined by modified Rankin Scale (mRS) 0-2 was significantly lower in patients who received DOACs (OR 0.71, 95% CI 0.62 to 0.81, P < 0.01). However, in the subgroup analysis of 90-day mRS 0-2, there was no significant difference between groups (OR 0.71, 95% 0.46 to 1.11, P = 0.14). All-cause mortality was not different between the groups (OR 1.02, 95% CI 0.68 to 1.52, P = 0.93). Similarly, there was no significant difference in either of the in-hospital and 90-day mortality subgroups. Regarding symptomatic intracranial hemorrhage (sICH), the previous DOAC use was not associated with an increased risk of bleeding (OR 0.98, 95% CI 0.69 to 1.39, P = 0.92). A similar finding was observed for the meta-analysis of any ICH (OR 1.15, 95% CI 0.94 to 1.40, P = 0.18). CONCLUSIONS: Based on our findings, IVT could be considered as a treatment option in ischemic stroke patients with recent use of DOACs since it was not associated with an increased risk of sICH, as suggested by earlier studies. Further larger studies are needed to confirm these findings and establish the safety of IVT in patients on DOAC.

Comparative Safety and Effectiveness of Loading Doses of P2Y12 Inhibitors in Patients Undergoing Elective PCI: a Network Meta-analysis.

PURPOSE: Effective platelet inhibition prior to elective percutaneous coronary intervention (PCI) reduces the risk of ischemic complications. Newer P2Y12 inhibitors are preferred agents over clopidogrel for patients presenting with the acute coronary syndrome. However, the comparative efficacy and safety of them over clopidogrel in elective PCI is unclear. We performed a network meta-analysis to compare the safety and efficacy of loading strategies of P2Y12 inhibitors in patients undergoing elective PCI. METHODS: We conducted a systematic review of randomized controlled trials (RCT) up to June 2021 to compare the safety and effectiveness of different loading strategies of P2Y12 inhibitors before elective PCI. The endpoints of interest were overall mortality, rates of myocardial infarction (MI), stroke, revascularization, and major bleeding. Random effects model using the frequentist approach was used to perform a network meta-analysis using R software. RESULTS: Five trials with a total of 5194 patients were included in our analysis. For ischemic outcomes, including MI, stroke, and revascularization, prasugrel had the most favorable trend. However, clopidogrel had the highest probability of being most effective for major bleeding and all-cause mortality. None of these trends was statistically significant due to lack of power for each outcome. CONCLUSION: Although prasugrel and ticagrelor are known as more potent antiplatelet agents, their effects in preventing MI and stroke are marginal and do not translate into improved overall mortality and bleeding compared with clopidogrel.

Ameliorative effect of ellagic acid and Vitamin C against malathion-induced toxicity in testis of adult Wistar rats.

The pesticide malathion (MT), an organophosphate, is highly neurotoxic and causes cholinergic disorders as well as cytotoxicity, genotoxicity, mutagenicity, carcinogenicity and reproductive toxicity. Our purpose was to study the effect of ellagic acid (EA) and Vitamin C on the testis against MT-induced toxicity in the rats. Thirty-six adult Wistar rats were employed, separated into six groups and were given treatment for 14 days. The toxicity of MT on the testis was evaluated using a variety of physical parameters, such as mortality rate and body weight, as well as biochemical parameters, such as total protein, total cholesterol, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase, and haematological parameters, such as counts of red blood cells, haemoglobin (Hb) and white blood cells, as well as mean corpuscular volume, mean corpuscular Hb, and mean corpuscular Hb concentration. At the end of the experiment, rats were killed and a histological examination of the testis was performed. A sperm count technique and an analysis of sperm motility were used to determine the sperm quality. Biochemical indicators, sperm count, motility, viability and morphology were significantly decreased with MT. When compared with MT and the control group, EA and Vitamin C administration significantly increased sperm motility and count (p < 0.05). After receiving EA and Vitamin C, biochemical indicators and histological characteristics are also intensified. The results of the current investigation show that EA and Vitamin C can both reduce increased levels of biochemical markers and improve pathological alterations in the testis brought on by MT treatment.

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.

The NSW Emergency Psychiatry Network.

Emergency Psychiatry is evolving. In an environment that lacks a clear evidence base, and where a constellation of factors is driving up Emergency Department presentation rates and lengths of stay, several stakeholders are working towards and clamouring for change. With the goal of collaborating with such parties, we believe Emergency Psychiatrists should position themselves to establish and advocate for best-practice change in culture, research, clinical care and training, and funding in the provision of mental health crisis care. To this end, we have formed the NSW Emergency Psychiatry Network, a group of Emergency Psychiatrists with a broad experience in a range of settings, from tertiary metropolitan emergency facilities with access to subspecialty psychiatric services, to rural and remote emergency settings with sporadic in-reach from local mental health services and telehealth. We unanimously recognise the need to upskill both Emergency Department and Mental Health clinicians in crisis care, and the need for committed, evidence-based Mental Health resourcing within Emergency Departments.

Incidence and risk factors for dysglycaemia in Asian-Indians: a 10-year population-based prospective cohort study.

BACKGROUND: Diabetes prevalence estimates suggest an increasing trend in South-East Asia region, but studies on its incidence are limited. The current study aims to estimate the incidence of type 2 diabetes and pre-diabetes in a population-based cohort from India. METHODS: A subset of Chandigarh Urban Diabetes Study cohort (n=1878) with normoglycaemia or pre-diabetes at baseline was prospectively followed after a median of 11 (0.5-11) years. Diabetes and pre-diabetes were diagnosed as per WHO guidelines. The incidence with 95% CI was calculated in 1000 person-years and Cox proportional hazard model was used to find the association between the risk factors and progression to pre-diabetes and diabetes. RESULTS: The incidence of diabetes, pre-diabetes and dysglycaemia (either pre-diabetes or diabetes) was 21.6 (17.8-26.1), 18.8 (14.8-23.4) and 31.7 (26.5-37.6) per 1000 person-years, respectively. Age (HR 1.02, 95% CI 1.01 to 1.04), family history of diabetes (HR 1.56, 95% CI 1.09 to 2.25) and sedentary lifestyle (HR 1.51, 95% CI 1.05 to 2.17) predicted conversion from normoglycaemia to dysglycaemia, while obesity (HR 2.43, 95% CI 1.21 to 4.89) predicted conversion from pre-diabetes to diabetes. CONCLUSION: A high incidence of diabetes and pre-diabetes in Asian-Indians suggests a faster conversion rate to dysglycaemia, which is partly explained by sedentary lifestyle and consequent obesity in these individuals. The high incidence rates call for a pressing need for public health interventions targeting modifiable risk factors.