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Introduction Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India’s distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants.Research design and methods We mined 1029 Indian whole genomes for PGx variants, drug–drug interaction (DDI) and drug–drug–gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher’s exact test.Results Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs).Conclusions Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population.

Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.

Background and Aims: Results of randomized clinical trials are often first presented as conference abstracts but these abstracts may be difficult to find, and trial results included in the abstract may not be followed by subsequent journal publications. In a review of abstracts submitted to 8 major medical and surgical conferences in 2017, we identified 237 abstracts reporting primary results of randomized clinical trials accepted for presentation at 3 major gastroenterology and hepatology conferences. The aims of this new analysis were to determine the publication rate for these abstracts and the proportion of publications that included trial registration numbers in the publication abstract. Methods: Clinical trial registries, PubMed, Europe PMC, and Google Scholar were searched through November 1, 2021 for publications reporting trial results for the selected abstracts. Publications were reviewed to determine if they included a trial registration number and if the registration number was in the abstract. Results: Publications were found for 157 abstracts (66%) within 4 years of the conference. Publications were found more frequently for the 194 abstracts reporting results of registered trials (144, 74%) than for the 43 abstracts reporting unregistered trials (13, 30%), but only 67% of these 144 publications included the registration number in the publication abstract. Ten unpublished trials had summary results posted on ClinicalTrials.gov. Conclusion: Clinical trial results could be more accessible if all trials were registered, authors included registration numbers in both conference and journal abstracts, and journal editors required the inclusion of registration numbers in publication abstracts for registered clinical trials.

Introduction: Children with special health care exhibit behavioral and physical conditions that predispose them to oxidative stress and this plays a vital role in etiopathogenesis of autistic spectrum disorder (ASD), which promotes neuronal damage in genetically predisposed individuals. Any inflammatory process initiates lipid peroxidation reaction that leads to the production of malondialdehyde (MDA), which in turn alters the immunological mediators such as salivary peroxidase system. Thus, leading to initiation and progression of bacterial infections such as dental caries. Materials and Methods: Fifteen children with ASD between the age groups of 6 and 14 years, who reported to the Nitte Special Child Care Centre (N-SPECC), Department of Pediatric and Preventive Dentistry, were selected for the study. Baseline salivary samples were collected to evaluate the salivary MDA, pH, viscosity, and buffering capacity. The patients were recalled after a period of 2 months where oral health education and saliva samples were collected and evaluated for the above parameters post-treatment and the data were subjected to statistical analysis using the Shapiro-Wilk test and Wilcoxon signed-rank test. Results: There was a statistically significant difference seen for the values between the time intervals (2 months) (P < 0.01) for salivary MDA, pH, viscosity, and buffering capacity levels in children with ASD with dental caries post-treatment. Conclusion: The levels of salivary MDA, pH, and viscosity decreased significantly and furthermore, the levels of buffering capacity increased significantly post-treatment in children with ASD. Evaluation of these biomarkers can be good adjuncts in caries risk assessment in children with ASD.

Introduction: Urinary Tract Infections (UTIs) are one of the most common infections, with a predominance in females. To overcome the menace of antibiotic resistance in UTIs, it is important to delineate and follow the local antibiotic resistance patterns of these pathogens. This helps in formulating institutional infection control policies and providing guidance for antibiotic therapy. Knowledge of risk factors for UTIs in hospitalised patients is used to formulate preventive measures for admitted patients. Aim: To study the microbiological patterns and antimicrobial sensitivity of UTIs in female patients admitted to a tertiary care centre. Materials and Methods: A cross-sectional study was conducted collaboratively between the Department of Microbiology and the Department of Obstetrics and Gynaecology at RKDF Medical College Hospital and Research Centre, Bhopal, Madhya Pradesh, India. Urine samples were collected from all admitted female patients who were prescribed culture and sensitivity testing by the treating clinicians from November 2020 to October 2022. Demographic and clinical data of patients were collected, and urine samples were sent for culture-sensitivity testing. Identification and antimicrobial susceptibility testing were done using the VITEK2-compact system. Results were analysed using Statistical Packages for the Social Sciences (SPSS) version 23.0. Results: Out of 508 urine samples sent for culture-sensitivity testing, a culture positivity rate of 16.31% was observed. Diabetes was associated with 25 out of 83 patients. Among all UTI cases, 57.8% (n=48) had a urinary catheter. In catheterised patients, the predominant associated conditions were pregnancy, cardiovascular failure, followed by respiratory issues. Gram-negative isolates constituted 77.1% of the total bacterial isolates, Gram-positive isolates formed 12%, and fungal isolates comprised 10.8% of the total cultures. E. coli was the most frequently encountered species, comprising 55.4% of the isolates. The study found carbapenems to be the most effective against E. coli. In the present study, Extended Spectrum Beta-Lactamase (ESBL) production was similar in uropathogenic E. coli and K. pneumoniae, 65.9% and 64.7%, respectively. The present study study showed that aminoglycosides and nitrofurantoin are the optimal drugs for ESBL-producing organisms. Conclusion: UTIs prevalent in hospitalised women are associated with prolonged catheterisation and co-morbidities such as diabetes and cardiovascular conditions. Gram-negative bacteria are the predominant species, and their susceptibility pattern is increasingly shifting towards higher antibiotics.

Abstract Background The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. Results We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. Conclusion A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9–1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account.

Abstract Ethnic differences in pharmacogenomic (PGx) variants have been well documented in literature and could significantly impact variability in response and adverse events to therapeutics. India is a large country with diverse ethnic populations of distinct genetic architecture. India’s national genome sequencing initiative (IndiGen) provides a unique opportunity to explore the landscape of PGx variants using population‐scale whole genome sequences. We have analyzed the IndiGen variation dataset (N = 1029 genomes) along with global population scale databases to map the most prevalent clinically actionable and potentially deleterious PGx variants among Indians. Differential frequencies for the known and novel variants were studied and interaction of the disrupted PGx genes affecting drug responses were analyzed by performing a pathway analysis. We have highlighted significant differences in the allele frequencies of clinically actionable PGx variants in Indians when compared to the global populations. We identified 134 mostly common (allele frequency [AF] > 0.1) potentially deleterious PGx variants that could alter or inhibit the function of 102 pharmacogenes in Indians. We also estimate that on, an average, each Indian individual carried eight PGx variants (single nucleotide variants) that have a direct impact on the choice of treatment or drug dosing. We have also highlighted clinically actionable PGx variants and genes for which preemptive genotyping is most recommended for the Indian population. The study has put forward the most comprehensive PGx landscape of the Indian population from whole genomes that could enable optimized drug selection and genotype‐guided prescriptions for improved therapeutic outcomes and minimizing adverse events.

Abstract Background Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient’s ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India. Results We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported. Conclusion With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India.

The recently developed lipoprotein insulin resistance index (LP‐IR) incorporates lipoprotein particle numbers and sizes and is considered to reflect both hepatic and peripheral IR. As tissue IR is a strong component of nonalcoholic fatty liver disease (NAFLD) pathogenesis, we aimed to assess the degree by which LP‐IR associates with hepatic fat content. This was a single‐center retrospective analysis of patients with NAFLD. LP‐IR, the homeostasis model assessment of insulin resistance (HOMA‐IR), and adipose tissue IR (Adipo‐IR) were measured simultaneously. Liver fat content was estimated by FibroScan controlled attenuated parameter. Associations were assessed using Spearman’s correlation and multivariate linear regression. The study included 61 patients. LP‐IR was correlated with HOMA‐IR (ρ = 0.30; P = 0.02), typically thought to reflect hepatic IR, but not with Adipo‐IR (ρ = 0.15; P = 0.25). Liver fat content was significantly associated with Adipo‐IR (ρ = 0.48; P

India confines more than 17% of the world’s population and has a diverse genetic makeup with several clinically relevant rare mutations belonging to many sub-group which are undervalued in global sequencing datasets like the 1000 Genome data (1KG) containing limited samples for Indian ethnicity. Such databases are critical for the pharmaceutical and drug development industry where diversity plays a crucial role in identifying genetic disposition towards adverse drug reactions. A qualitative and comparative sequence and structural study utilizing variant information present in the recently published, largest curated Indian genome database (IndiGen) and the 1000 Genome data was performed for variants belonging to the kinase coding genes, the second most targeted group of drug targets. The sequence-level analysis identified similarities and differences among different populations based on the nsSNVs and amino acid exchange frequencies whereas a comparative structural analysis of IndiGen variants was performed with pathogenic variants reported in UniProtKB Humsavar data. The influence of these variations on structural features of the protein, such as structural stability, solvent accessibility, hydrophobicity, and the hydrogen-bond network was investigated. In-silico screening of the known drugs to these Indian variation-containing proteins reveals critical differences imparted in the strength of binding due to the variations present in the Indian population. In conclusion, this study constitutes a comprehensive investigation into the understanding of common variations present in the second largest population in the world and investigating its implications in the sequence, structural and pharmacogenomic landscape. The preliminary investigation reported in this paper, supporting the screening and detection of ADRs specific to the Indian population could aid in the development of techniques for pre-clinical and post-market screening of drug-related adverse events in the Indian population.

Perception and preferences for food and beverages determine dietary behaviour and health outcomes. Inherent differences in chemosensory genes, ethnicity, geo-climatic conditions, and sociocultural practices are other determinants. We aimed to study the variation landscape of chemosensory genes involved in perception of taste, texture, odour, temperature and burning sensations through analysis of 1,029 genomes of the IndiGen project and diverse continental populations. SNPs from 80 chemosensory genes were studied in whole genomes of 1,029 IndiGen samples and 2054 from the 1000 Genomes project. Population genetics approaches were used to infer ancestry of IndiGen individuals, gene divergence and extent of differentiation among studied populations. 137,760 SNPs including common and rare variants were identified in IndiGenomes with 62,950 novel (46%) and 48% shared with the 1,000 Genomes. Genes associated with olfaction harbored most SNPs followed by those associated with differences in perception of salt and pungent tastes. Across species, receptors for bitter taste were the most diverse compared to others. Three predominant ancestry groups within IndiGen were identified based on population structure analysis. We also identified 1,184 variants that exhibit differences in frequency of derived alleles and high population differentiation (FST ≥0.3) in Indian populations compared to European, East Asian and African populations. Examples include ADCY10, TRPV1, RGS6, OR7D4, ITPR3, OPRM1, TCF7L2, and RUNX1. This is a first of its kind of study on baseline variations in genes that could govern cuisine designs, dietary preferences and health outcomes. This would be of enormous utility in dietary recommendations for precision nutrition both at population and individual level.

Coronavirus disease 2019 (COVID-19) rapidly spread from a city in China to almost every country in the world, affecting millions of individuals. The rapid increase in the COVID-19 cases in the state of Kerala in India has necessitated the understanding of SARS-CoV-2 genetic epidemiology. We sequenced 200 samples from patients in Kerala using COVIDSeq protocol amplicon-based sequencing. The analysis identified 166 high-quality single-nucleotide variants encompassing four novel variants and 89 new variants in the Indian isolated SARS-CoV-2. Phylogenetic and haplotype analysis revealed that the virus was dominated by three distinct introductions followed by local spread suggesting recent outbreaks and that it belongs to the A2a clade. Further analysis of the functional variants revealed that two variants in the S gene associated with increased infectivity and five variants mapped in primer binding sites affect the efficacy of RT-PCR. To the best of our knowledge, this is the first and most comprehensive report of SARS-CoV-2 genetic epidemiology from Kerala.

The rapid emergence of coronavirus disease 2019 (COVID-19) as a global pandemic affecting millions of individuals globally has necessitated sensitive and high-throughput approaches for the diagnosis, surveillance, and determining the genetic epidemiology of SARS-CoV-2. In the present study, we used the COVIDSeq protocol, which involves multiplex-PCR, barcoding, and sequencing of samples for high-throughput detection and deciphering the genetic epidemiology of SARS-CoV-2. We used the approach on 752 clinical samples in duplicates, amounting to a total of 1536 samples which could be sequenced on a single S4 sequencing flow cell on NovaSeq 6000. Our analysis suggests a high concordance between technical duplicates and a high concordance of detection of SARS-CoV-2 between the COVIDSeq as well as RT-PCR approaches. An in-depth analysis revealed a total of six samples in which COVIDSeq detected SARS-CoV-2 in high confidence which were negative in RT-PCR. Additionally, the assay could detect SARS-CoV-2 in 21 samples and 16 samples which were classified inconclusive and pan-sarbeco positive respectively suggesting that COVIDSeq could be used as a confirmatory test. The sequencing approach also enabled insights into the evolution and genetic epidemiology of the SARS-CoV-2 samples. The samples were classified into a total of 3 clades. This study reports two lineages B.1.112 and B.1.99 for the first time in India. This study also revealed 1,143 unique single nucleotide variants and added a total of 73 novel variants identified for the first time. To the best of our knowledge, this is the first report of the COVIDSeq approach for detection and genetic epidemiology of SARS-CoV-2. Our analysis suggests that COVIDSeq could be a potential high sensitivity assay for the detection of SARS-CoV-2, with an additional advantage of enabling the genetic epidemiology of SARS-CoV-2.

Pulmonary diseases have known to exert significant human sufferings with high death toll globally. The association between periodontitis and pulmonary diseases is still in its infancy and needs attention. Poor oral health has shown to influence pulmonary health as well as the course of the diseases associated with this system. Numerous studies have emphasized that resident microorganisms of lungs are primarily the habitants of oral cavity. It could be due to the aspiration of oral periodontopathic bacteria into the lungs, thereby initiating the inflammatory process. Added to this, the inflammatory mediators elaborated from the inflamed periodontium in case of periodontal diseases may spread via blood to other organs such as lungs causing infections. Numerous studies have highlighted the beneficial role of periodontal therapy in improving lung function with a decreased frequency of exacerbations, reduced risk of adverse respiratory events, and morbidity, especially in chronic obstructive pulmonary disease patients. Medically compromised dentate patients admitted in intensive care units owing to their inability to maintain oral hygiene properly have increased propensity of acquiring respiratory infections. The present review focuses on emphasizing the relationship between periodontitis and pulmonary diseases with the available published literature utilizing PubMed and Google Scholar databases in the last four decades.

Novel Schiff base ligand (E)-2-((3-(benzyloxypyridinylimino) methyl)-4-bromophenol (HL) was synthesized. Using this Schiff base ligand, two new copper(II) complexes, C1 and C2 were prepared. Analytical techniques such as IR, 1H NMR, 13C NMR, mass, UV–visible spectroscopy, molar conductivity, magnetic measurement, ESR and TGA-DTA were used to characterize the ligand HL and its copper complexes. From the ESR spectra, square planar geometry was proposed for C1 and C2. The synthesized ligand, HL along with its copper(II) complexes were subjected to test their in vitro biological efficacies against four bacterial strains Escherichia coli, Salmonella typhi, Bacillus subtilis and Staphylococcus aureus and two antifungal strains Candida albicans and Aspergillus niger. The results obtained from this work suggest that the studied metal complexes are very effective in biological activities than its ligand. The anthelmintic test of the ligand HL and copper complexes against earthworms, Pheretima posthuma are also investigated. DOI: http://dx.doi.org/10.17807/orbital.v10i7.1168

Acute esophageal perforations are potentially life-threatening events that carry high morbidity and mortality rates. There has been a paradigm shift in the standard treatment of acute esophageal perforations from surgery to esophageal stents over the last two decades. We report a case of a 62-year-old male, managed successfully with fully covered esophageal stent for foreign body (denture)-induced acute esophageal perforation. The report also highlights the failure of routine radiological investigation to detect and localize denture (as dentures are made of radiolucent material).

Circular RNAs are a new addition to the growing list of diverse species of RNAs that are formed by covalent linked 3' and 5' end forming a closed loop structure. Circular RNAs are characteristically resistant to exonuclease treatment and are relatively stable to linear transcripts. Circular RNAs are formed by alternate splicing mechanism but do not follow the canonical order of exons. Backsplice junctions are unique to circRNAs. CircRNAs are shown to possess potential to act as miRNA sponges and control transcription of mRNAs. CircRNAs are also reported as biomarkers for the disease like Alzheimer's, Parkinson's and cancer. A huge number of circRNA transcripts have been identified in model organisms including C.elegans, mouse, Drosophila as well as human. But there are no circular RNAs reported in zebrafish that is a very good model to study developmental stages, cardiovascular and blood-related disorders. In order to use zebrafish as a model organism and study the role of circRNAs in disease, we have used in-house generated RNA-sequencing data for five tissues including blood, brain, muscle, gills and heart. We discarded the reads mapped contiguously and full length over reference genome and identified back-splice junctions for putative circRNA transcripts. We identified a total of 3428 circRNA junctions out of which 78% were tissue specific. We validated 22 selected candidates for 5 tissues based on literature significance. We quantitatively analysed 5 tissue-enriched candidates using Real-time PCR. We also observed that major proportion of circRNAs is originating from protein coding loci. These circRNAs could be used to further study their role in hematopoietic and cardiovascular diseases.

Hydrocephalus is a known complication of tuberculous meningitis (TBM). It is almost always present in patients who have had the disease for four to six weeks. However, hydrocephalus can also develop later in the disease course as seen in our 3 patients. All 3 patients had multi-drug resistant (MDR) tuberculosis (TB) and developed hydrocephalus after variable time after starting second line anti-tuberculous therapy (ATT). A 7 years old girl had hydrocephalus at onset of TBM and was shunted but the hydrocephalus increased in size after 6 months of being on second line ATT in spite of a patent ventricular peritoneal (VP) shunt. Hydrocephalus responded to oral acetazolamide. Other 2 patients, a 2 years old girl and 3½ years old boy developed hydrocephalus after being on treatment for 14 months. Both required insertion of VP shunt. Thus, in patients with MDR-TB, hydrocephalus may develop as late onset phenomenon and a neurological examination would be essential in each visit to the hospital.