A New Cloud-Native Tool for Pharmacogenetic Analysis.

BACKGROUND: The advancement of next-generation sequencing (NGS) technologies provides opportunities for large-scale Pharmacogenetic (PGx) studies and pre-emptive PGx testing to cover a wide range of genotypes present in diverse populations. However, NGS-based PGx testing is limited by the lack of comprehensive computational tools to support genetic data analysis and clinical decisions. METHODS: Bioinformatics utilities specialized for human genomics and the latest cloud-based technologies were used to develop a bioinformatics pipeline for analyzing the genomic sequence data and reporting PGx genotypes. A database was created and integrated in the pipeline for filtering the actionable PGx variants and clinical interpretations. Strict quality verification procedures were conducted on variant calls with the whole genome sequencing (WGS) dataset of the 1000 Genomes Project (G1K). The accuracy of PGx allele identification was validated using the WGS dataset of the Pharmacogenetics Reference Materials from the Centers for Disease Control and Prevention (CDC). RESULTS: The newly created bioinformatics pipeline, Pgxtools, can analyze genomic sequence data, identify actionable variants in 13 PGx relevant genes, and generate reports annotated with specific interpretations and recommendations based on clinical practice guidelines. Verified with two independent methods, we have found that Pgxtools consistently identifies variants more accurately than the results in the G1K dataset on GRCh37 and GRCh38. CONCLUSIONS: Pgxtools provides an integrated workflow for large-scale genomic data analysis and PGx clinical decision support. Implemented with cloud-native technologies, it is highly portable in a wide variety of environments from a single laptop to High-Performance Computing (HPC) clusters and cloud platforms for different production scales and requirements.

Challenging cross couplings, in water, aided by in situ iodination of (hetero)aromatic bromides.

Palladium-catalyzed reactions that involve functionalized substrates are oftentimes problematic. Those involving aryl or heteroaryl bromides that are either resistant to, or inefficient in such couplings present challenges that are difficult to overcome and may require development of an entirely new route, or worse, no opportunity to install the desired group using a standard coupling strategy. In this report, we describe a solution that allows for the in situ conversion of such bromo educts to transient iodide derivatives that can be made and used under environmentally responsible conditions, for subsequent reactions to highly functionalized, complex targets.

Direct formation of amide/peptide bonds from carboxylic acids: no traditional coupling reagents, 1-pot, and green.

Technology for generating especially important amide and peptide bonds from carboxylic acids and amines that avoids traditional coupling reagents is described. The 1-pot processes developed rely on thioester formation, neat, using a simple dithiocarbamate, and are safe and green, and rely on Nature-inspired thioesters that are then converted to the targeted functionality.

Good survival rate, moderate overall and good respirator quality of life, near normal pulmonary functions, and good return to work despite catastrophic economic costs 6 months following recovery from Acute Respiratory Distress Syndrome.

Introduction: Long-term quality of life, return to work, economic consequences following Acute Respiratory Distress Syndrome (ARDS) are not well described in India. This study was aimed to address the question. Methods: A prospective cohort study of 109 ARDS survivors were followed up for a minimum of 6 months following discharge. Quality of life was assessed using the SF-36 questionnaire. Respiratory quality was assessed using the St Georges Respiratory Questionnaire. Time to return to work was documented. Costs-direct medical, as well as indirect were documented up to 6 months. Results: At 6 months, 6/109 (5.5%) had expired. Low energy/vitality and general heath were noted in the SF-36 scores at 6 months; overall a moderate quality of life. Pulmonary function tests had mostly normalized. Six-min walk distance was 77% of predicted. Respiratory quality of life was good. It took at the median of 111 days to go back Interquartile range (55-193.5) to work with 88% of previously employed going back to work. There were no significant differences in the severity of ARDS and any of these outcomes at 6 months. The average total cost from the societal perspective was ₹ 231,450 (standard deviation 146,430-, 387,300). There was a significant difference between the 3-ARDS severity groups and costs (P < 0.01). There were no independent predictors of return to work. Conclusion: ARDS survivors have low 6-month mortality. Pulmonary physiology and exercise capacity was mostly normal. Overall, quality of life is average was moderate, while respiratory quality of life was good. Return to work was excellent, while cost of care falls under a catastrophic heath expense.

Perceptions of farmers' and farmworkers' wives on the use and hazards of agrochemicals in rural Vellore.

Poor handling, storage, and application of agrochemicals have resulted in a steep rise in mortality and morbidity associated with their use. This study aimed at assessing the awareness of wives of farmers and farmworkers in rural Vellore on the use and health effects of agrochemicals to identify gaps in their knowledge. A cross-sectional survey among 512 wives was conducted. Nearly 75 percent of the wives (384/512) did not know that agrochemicals could pass through skin. Also, wives who owned between 1 and 5 acres of land had a higher odds of knowing that agrochemicals were harmful (OR: 1.71(1.03-2-85), p < 0.05) and need to be disposed safely (OR: 4.76 (1.47-15.36), p < 0.05), than those owning less than an acre or no land. There is a need to educate women associated with agriculture in India on the harms and proper use of agrochemicals in order to better protect and inform their households and communities.

Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients.

OBJECTIVE: Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects. METHOD: Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase. RESULTS: Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged. CONCLUSIONS: Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.