Drug metabolizing enzymes pharmacogenetic variation-informed antidepressant therapy approach for common mental disorders: A systematic review and meta-analysis.

IMPORTANCE: Currently, 30-50 % of individuals with depression and 40 % with anxiety-collectively referred to as common mental disorders (CMDs), exhibit inadequate responses to antidepressant treatments. OBJECTIVE: To assess the effectiveness and safety of drug-metabolizing enzyme pharmacogenetic variation informed treatment (PGxIT) versus usual antidepressant treatment (UT) in patients with CMDs. DATA SOURCES: A literature search was conducted in the MEDLINE, Scopus, and Cochrane Library databases from inception until January 30, 2024. STUDY SELECTION: Studies were selected based on CMD diagnoses, reporting on the genetic variations of drug-metabolizing enzyme (DME) genes in relation to antidepressants, involving PGxIT and UT groups with human subjects, and published in English. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment were performed independently by two authors. A pooled risk ratio (RR) with 95 % CI was estimated using both random and fixed-effect models, and heterogeneity was assessed using Cochran's Q test and the I2 statistic. The publication bias of eligible studies was assessed using post hoc Doi plots and the LFK index. RESULTS: This systematic review included 18 studies (n = 7021). The PGxIT demonstrated greater efficacy in the remission of symptoms of depressive disorder at 8 weeks (RR 1.523 [95 % CI: 1.255-1.843]; I2 = 48 %) and 12 weeks (RR 1.631 [95 % CI: 1.001-2.657]; I2 = 86 %; p < 0.01), and symptoms of anxiety disorder compared to UT. Additionally, the risk of adverse drug events (ADEs) was significantly lower in the PGxIT group (RR = 0.65 [95 % CI: 0.52-0.82]; I2 = 0 %) than in the UT group. The certainty of evidence for both outcomes was moderate. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis suggest that pharmacogenetically guided antidepressant treatment, based on genetic variation in drug-metabolizing enzymes, is associated with superior efficacy in the remission of symptoms for patients with depressive disorders and a reduction in ADEs compared to usual treatment and the findings of the systematic review for remission in anxiety disorders indicate that, PGx guided treatment is also associated with increased remission of symptoms in anxiety disorders compared to usual treatment.

Evaluation of ivabradine plus beta-blocker versus beta-blocker alone in addition to standard care in reducing hospitalization and major adverse cardiovascular event in patients with chronic heart failure: a prospective observational study in tertiary care hospital in central India.

BACKGROUND: In recent years, there has been an increase in cases of heart failure, ultimately leading to an increase in hospitalization for heart failure (HF) and cardiovascular mortality. The aim of our study was to evaluate ivabradine combined with beta-blocker versus beta-blocker alone in addition to standard care for chronic heart failure, followed for a period of 6 months for the rate of hospitalization and major adverse cardiovascular event (MACE) in patients with reduced left ventricular ejection fraction (LVEF < 35%). RESULTS: A total of 64 patients were included in this observational study with 30 patients in the ivabradine + beta-blocker (IVA + BB) group and 34 in the beta-blocker (BB) group. The median (IQR) age of the study sample was 57 (50-62) and 58.5 (55-67) in IVA + BB and BB groups, respectively, with LVEF < 35%. The incidence of the primary endpoint of composite MACE (MI, stroke, death, worsening of HF) was 5 in both groups. The mean heart rate was significantly decreased (p < 0.001) at 3-month and 6-month follow-up from baseline in the ivabradine + beta-blocker group as compared to the beta-blocker group alone, while it significantly increased in the beta-blocker group at 3 months (p < 0.01) and also at sixth months (p < 0.05). Parameters such as the New York Heart Association (NYHA) class and the Minnesota Living with Heart Failure questionnaire (MLWHFQ) were also assessed but did not show significant change. CONCLUSION: Overall, observations from the study results show that IVA + BB seems to be overall well tolerated in the study sample, with a somewhat smaller decrease in hospitalization and a delay in MACE events in the sample population enrolled in a tertiary care hospital in India. Further exploration in a larger sample is required concerning the Indian population.

Expression and functional analysis of a recombinant aquaporin Z from Antarctic Pseudomonas sp. AMS3.

Aquaporin (AQP) is a water channel protein from the family of transmembrane proteins which facilitates the movement of water across the cell membrane. It is ubiquitous in nature, however the understanding of the water transport mechanism, especially for AQPs in microbes adapted to low temperatures, remains limited. AQP also has been recognized for its ability to be used for water filtration, but knowledge of the biochemical features necessary for its potential applications in industrial processes has been lacking. Therefore, this research was conducted to express, extract, solubilize, purify, and study the functional adaptations of the aquaporin Z family from Pseudomonas sp. AMS3 via molecular approaches. In this study, AqpZ1 AMS3 was successfully subcloned and expressed in E. coli BL21 (DE3) as a recombinant protein. The AqpZ1 AMS3 gene was expressed under optimized conditions and the best optimized condition for the AQP was in 0.5 mM IPTG incubated at 25°C for 20 h induction time. A zwitterionic mild detergent [(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate was the suitable surfactant for the protein solubilization. The protein was then purified via affinity chromatography. Liposome and proteoliposome was reconstituted to determine the particle size using dynamic light scattering. This information obtained from this psychrophilic AQP identified provides new insights into the structural adaptation of this protein at low temperatures and could be useful for low temperature application and molecular engineering purposes in the future.

Two-qubit entangling operators as chaos control in a discrete dynamic Cournot duopoly game.

The current trend in economics research is to incorporate quantum mechanical concepts to increase the security of business models. This interdisciplinary field of study represents real-world market dynamics more closely than do its classical counterparts. In this paper, we shed light on the significance of the two-qubit entangling operators in controlling chaos. We introduce a modified Eisert-Wilkens-Lewenstein scheme in a nonlinear Cournot duopoly game with complete and incomplete information. By doing so, the following interesting results are obtained: To begin, monopoly in a duopoly game can be avoided with the use of special perfect entanglers. Also, the stability analysis shows that there exists a class of entangling operators which can stabilize an unstable system and vice versa. Second, numerical analysis highlights the two-qubit entangling operators which can stabilize a chaotic system or at least delay chaos. Finally, we show that with an appropriate choice of initial state and speed of adjustments, entangling operators can decrease the sensitivity of the system. In short, while we know the importance of entangling operators in quantum game theory, in this paper we indicate the significance of operators in the context of a chaotic system.

Immunogenicity, clinical efficacy and safety of additional second COVID-19 booster vaccines against Omicron and its subvariants: A systematic review.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 is a new variant of concern (VOC) and an emerging subvariant that exhibits heightened infectivity, transmissibility, and immune evasion, escalating the incidence of moderate to severe coronavirus disease 2019 (COVID-19). It resists monoclonal antibodies and diminishes vaccine efficacy. Notably, new sublineages have outpaced earlier predominant sublineages. Although the primary vaccination series and initial boosters were robust against previous VOCs, their efficacy waned against Omicron and its subvariants. In this systematic review, we assessed real-world evidence on the immunogenicity, clinical efficacy, and safety of a second booster or fourth COVID-19 vaccine dose against the Omicron VOC and its subvariants. A comprehensive literature search was conducted in Medline/PubMed, Google Scholar, bioRxiv, and medRxiv, and relevant studies published between 2022 and 30 May 2023 were reviewed. We found a total of 40 relevant articles focusing on a second booster dose for COVID-19, including clinical trials and observational studies, involving 3,972,856 patients. The results consistently revealed that an additional second booster dose restored and prolonged waning immunity, activating both humoral and cellular responses against Omicron and its subvariants. A second booster treatment correlated with enduring protection against COVID-19, notably preventing substantial symptomatic disease and mortality associated with severe Omicron infection. Both monovalent messenger RNA (mRNA) and nonmRNA vaccines demonstrated similar efficacy and safety, with bivalent mRNA vaccines exhibiting broader protection against emerging subvariants of Omicron. The safety profiles of second booster were favourable with only mild systemic and local symptoms reported in some recipients. In conclusion, this systematic review underscores the additional COVID-19 vaccine boosters, particularly with bivalent or multivalent mRNA vaccines, for countering the highly infectious emerging subvariants of Omicron.

The usage of Gellhorn pessary in pelvic organ prolapse and in regards to success, continuity of use and effect on symptoms: a retrospective study of 2 years.

INTRODUCTION: Pelvic organ prolapse (POP) is a condition involving weakened pelvic floor muscles causing organs to protrude. Conservative POP treatment comprises pelvic floor exercises and vaginal pessaries. Besides conservative care, surgery is offered. However, surgery is invasive, risky and unsuitable for those with serious medical conditions. This study aims to assess the acceptance, success and outcomes of the Gellhorn pessary for POP treatment, especially in advanced cases. MATERIALS AND METHODS: The present study is a retrospective cohort study using hospital medical records (patient files) from October 2019 to November 2021 (for 2 years). This study was performed in Malaysian women (n=53) suffering from advanced stages of POP, in which Gellhorn pessaries of diameter (44-76mm) were inserted by trained personnel. Pelvic Floor Distress Inventory-20 (PFDI-20) and Pelvic Floor Impact Questionnaire-7 (PFIQ-7) were used to measure patients' symptoms and quality of life before and after Gellhorn pessary fitting. Patients were reassessed every three months for two years and their satisfaction scores were recorded. RESULTS: We observed a significant difference in pre-test (pre-fitting) and post-test (three months post-fitting) scores on all three subscales and the PFIQ-7 total score. Twentyeight (52.83%) patients continued the use of Gellhorn pessary for at least 24 months, whereas 25 (47.20%) patients discontinued during this period. A retrospective analysis of the patients who discontinued Gellhorn pessary showed that 13 (24.52%) patients gave up the use of pessary for definitive surgery. It is noteworthy to mention here that only one out of the 13 patients who were awaiting surgery, chose surgery and the remaining 12 changed their mind after being fitted with the Gellhorn pessary. Seven (13.20%) patients declined reinsertion due to discomfort and voiding difficulties and refused further intervention, whereas three (5.66%) patients requested a ring pessary. Two (3.77%) patients, requested the removal of pessary due to vesicovaginal fistula and rectovaginal fistula (caused by an impacted pessary). The rate of continued use was 79.24% (42 patients) after 1st year and 52.83% (28 patients) at the end of two years. CONCLUSION: In the current study, the Gellhorn pessary was used to treat stage 3 and 4 POP with significant symptom reduction post-fitting. More than half of the patients continued to use the pessary after 24 months of fitting. Therefore, the Gellhorn pessary can be used as a treatment strategy for stage 3 and 4 POP with reasonable acceptance in the Malaysian population.

Nitrite and Nitric Oxide Interconversion at Mononuclear Copper(II): Insight into the Role of the Red Copper Site in Denitrification.

Nitrite (NO2 - ) and nitric oxide (NO) interconversion is crucial for maintaining optimum NO flux in mammalian physiology. Herein we demonstrate that [L2 CuII (nitrite)]+ moieties (in 2 a and 2 b; where, L = Me2 PzPy and Me2 PzQu) with distorted octahedral geometry undergo facile reduction to provide tetrahedral [L2 CuI ]+ (in 3 a and 3 b) and NO in the presence of biologically relevant reductants, such as 4-methoxy-2,6-di-tert-butylphenol (4-MeO-2,6-DTBP, a tyrosine model) and N-benzyl-1,4-dihydronicotinamide (BNAH, a NAD(P)H model). Interestingly, the reaction of excess NO gas with [L2 CuII (MeCN)2 ]2+ (in 1 a) provides a putative {CuNO}10 species, which is effective in mediating the nitrosation of various nucleophiles, such as thiol and amine. Generation of the transient {CuNO}10 species in wet acetonitrile leads to NO2 - as assessed by Griess assay and 14 N/15 N-FTIR analyses. A detailed study reveals that the bidirectional NOx -reactivity, namely, nitrite reductase (NIR) and NO oxidase (NOO), at a common CuII site, is governed by the geometric-preference-driven facile CuII /CuI redox process. Of broader interest, this study not only highlights potential strategies for the design of copper-based catalysts for nitrite reduction, but also strengthens the previous postulates regarding the involvement of red copper proteins in denitrification.

Long-term safety and effectiveness of azathioprine in the management of inflammatory bowel disease: A real-world experience.

Background and Aim: Azathioprine (AZA) forms the cornerstone for maintenance of sustained remission in inflammatory bowel disease (IBD). There is apprehension regarding the long-term effectiveness and safety of AZA in IBD. We present our experience with AZA use and outcomes in a cohort of IBD patients followed up over a long period of time. Methods: Records of 507 IBD patients under treatment at a single, tertiary care center in south India between 2013 and 2022 were evaluated retrospectively. Long-term compliance, tolerance, clinical outcome at the point of last follow-up, type and duration to the onset of adverse events, and subsequent amendment to treatment with regard to AZA were analyzed. Results: Of 507 patients with IBD, 320 patients (207 Crohn's disease [CD], 113 ulcerative colitis [UC]) who received AZA were included. The median follow-up was 41 months (interquartile range 15.5-77.5). Total duration of exposure was 1359 patient-years with median usage of 33 months. Of the patients, 26.9% received AZA for >5 years. Mean initiation and maximum doses of AZA were 0.97 and 1.72 mg/kg/day. Among the participants, 20.6% experienced side effects, including myelotoxicity (7.2%) and gastrointestinal intolerance (5.6%). Six patients developed malignancy. Among the side effects, 39.4% of side effects were dose-dependent. Among the patients, 38.1% had relapses requiring pulse corticosteroid therapy, and 16.2% had more than one relapse after commencement of AZA. AZA was continued till the last follow-up in 76.5%. Among the patients, 49.7% (UC 51.3, CD 48.8) attained durable remission without biologics, and 5.3% continued to have active disease. Conclusion: AZA is safe and effective in the long-term in IBD. Effectiveness, tolerance, and compliance with AZA are well sustained beyond 5 years of usage and comparable between UC and CD.

Securing health care data through blockchain enabled collaborative machine learning.

Transferring of data in machine learning from one party to another party is one of the issues that has been in existence since the development of technology. Health care data collection using machine learning techniques can lead to privacy issues which cause disturbances among the parties and reduces the possibility to work with either of the parties. Since centralized way of information transfer between two parties can be limited and risky as they are connected using machine learning, this factor motivated us to use the decentralized way where there is no connection but model transfer between both parties will be in process through a federated way. The purpose of this research is to investigate a model transfer between a user and the client(s) in an organization using federated learning techniques and reward the client(s) for their efforts with tokens accordingly using blockchain technology. In this research, the user shares a model to organizations that are willing to volunteer their service to provide help to the user. The model is trained and transferred among the user and the clients in the organizations in a privacy preserving way. In this research, we found that the process of model transfer between user and the volunteered organizations works completely fine with the help of federated learning techniques and the client(s) is/are rewarded with tokens for their efforts. We used the COVID-19 dataset to test the federation process, which yielded individual results of 88% for contributor a, 85% for contributor b, and 74% for contributor c. When using the FedAvg algorithm, we were able to achieve a total accuracy of 82%.

Binding by calmodulin is coupled to transient unfolding of the third FF domain of Prp40A.

Human pre-mRNA processing protein 40 homolog A (hPrp40A) is a splicing factor that interacts with the Huntington's disease protein huntingtin (Htt). Evidence has accumulated that both Htt and hPrp40A are modulated by the intracellular Ca2+ sensor calmodulin (CaM). Here we report characterization of the interaction of human CM with the third FF domain (FF3 ) of hPrp40A using calorimetric, fluorescence and structural approaches. Homology modeling, differential scanning calorimetry and small angle X-ray scattering (SAXS) data show FF3 forms a folded globular domain. CaM was found to bind FF3 in a Ca2+ -dependent manner with a 1:1 stoichiometry and a dissociation constant (Kd ) of 25 ± 3 µM at 25°C. NMR studies showed that both domains of CaM are engaged in binding and SAXS analysis of the FF3 -CaM complex revealed CaM occupies an extended configuration. Analysis of the FF3 sequence showed that the anchors for CaM binding must be buried in its hydrophobic core, suggesting that binding to CaM requires unfolding of FF3 . Trp anchors were proposed based on sequence analysis and confirmed by intrinsic Trp fluorescence of FF3 upon binding of CaM and substantial reductions in affinity for Trp-Ala FF3 mutants. The consensus model of the complex showed that binding to CaM binding occurs to an extended, non-globular state of the FF3 , consistent with coupling to transient unfolding of the domain. The implications of these results are discussed in the context of the complex interplay of Ca2+ signaling and Ca2+ sensor proteins in modulating Prp40A-Htt function.

Molecular dynamics simulation and structural analysis of aquaporin Z from an Antarctic Pseudomonas sp. strain AMS3.

Aquaporin is a water channel protein that facilitates the movement of water across the cell membrane. Aquaporin from the Antarctic region has been noted for its psychrophilic properties and its ability to perform at a lower temperature but there remains limited understanding of the water mechanism of Antarctic Pseudomonas sp. strain AMS3 However, studies regarding aquaporin isolated from psychrophilic Pseudomonas sp. are still scattered. Recently, the genome sequence of an Antarctic Pseudomonas sp. strain AMS3 revealed a gene sequence encoding for a putative aquaporin designated as AqpZ1 AMS3. In this study, structure analysis and a molecular dynamics (MD) simulation of a predicted model of a fully hydrated aquaporin tetramer embedded in a lipid bilayer was performed at different temperatures for structural flexibility and stability analysis. The MD simulation results revealed that the structures were able to remain stable at low to medium temperatures. The protein was observed to have high flexibility in the loop region as compared to the helices region throughout the simulated temperatures. The selectivity filter and NPA motifs play a major role in solute selectivity and the pore radius of the protein. The structural and functional characterization of this psychrophilic aquaporin provides new insights for the future applications of this protein.Communicated by Ramaswamy H. Sarma.

Antibiotic-associated Gut Dysbiosis.

The human gut microbiota plays a crucial role in maintaining overall health. However, the widespread use of antibiotics has raised concerns about its impact on the microbial ecosystem. This review explores the multifaceted relationship between antibiotics and gut dysbiosis, highlighting the mechanisms underlying these interactions and their implications for human health. Antibiotics, while invaluable in treating infections, disrupt the gut microbiota by indiscriminately targeting both harmful and beneficial microorganisms. This disturbance leads to a reduction in microbial diversity, altered metabolite production, and compromised immune responses, resulting in a state referred to as dysbiosis. Broad-spectrum antibiotics tend to induce more severe dysbiosis compared to narrow-spectrum agents. Antibiotic-induced dysbiosis has been linked to the onset and progression of these disorders, emphasizing the far-reaching consequences of microbial imbalance. The review highlights various strategies to mitigate the adverse effects of antibiotics on gut health, like probiotics, fecal microbiota transplantation (FMT), and phage therapy, as promising approaches to restore and maintain a balanced gut microbiota. How to cite this article: Ramakrishna BS, Patankar R. Antibiotic-associated Gut Dysbiosis. J Assoc Physicians India 2023;71(11):62-68.

Assessment of prescribing pattern of drugs and completeness of prescriptions as per the World Health Organization prescribing indicators in various Indian tertiary care centers: A multicentric study by Rational Use of Medicines Centers-Indian Council of Medical Research network under National Virtual Centre Clinical Pharmacology activity.

OBJECTIVE: The rational use of medicines as per the World Health Organization (WHO) should be practiced globally. However, data regarding the completeness of the prescriptions and their rational use is lacking from developing countries like India. Thus, the aim of this study was to assess the prescribing patterns of drugs and completeness of prescriptions as per WHO core drug use and complementary indicators to provide real-life examples for the Indian Council of Medical Research (ICMR) online prescribing skill course for medical graduates. METHODS: Prescriptions of the patients, fulfilling inclusion criteria, attending Outpatient Departments of various specialties of tertiary care hospitals, were collected by thirteen ICMR Rational use of medicines centers located in tertiary care hospitals, throughout India. Prescriptions were evaluated for rational use of medicines according to the WHO guidelines and for appropriateness as per standard treatment guidelines using a common protocol approved by local Ethics committees. RESULTS: Among 4838 prescriptions, an average of about three drugs (3.34) was prescribed to the patients per prescription. Polypharmacy was noted in 83.05% of prescriptions. Generic drugs were prescribed in 47.58% of the prescriptions. Further, antimicrobials were prescribed in 17.63% of the prescriptions and only 4.98% of prescriptions were with injectables. During the prescription evaluation, 38.65% of the prescriptions were incomplete due to multiple omissions such as dose, duration, and formulation. CONCLUSION: Most of the parameters in the present study were out of the range of WHO-recommended prescribing indicators. Therefore, effective intervention program, like training, for the promotion of rational drug use practice was recommended to improve the prescribing pattern of drugs and the quality of prescriptions all over the country.

Distribution of celiac disease predisposing genes HLA-DQ2 and HLA-DQ8 in the native population of southern India.

BACKGROUND: Celiac disease (CD) is an intestinal inflammatory condition caused by the ingestion of gluten peptides in wheat and related grains in individuals carrying HLA-DQ2 and/or HLA-DQ8 genes. In comparison to HLA-DQ8, a higher HLA-DQ2 prevalence is reported in European population where wheat has been the staple food for thousands of years. In non-European population, this pattern of HLA-DQ CD-predisposing gene distribution has not always been found. The aim of this study was to evaluate the HLA-DQ2 and HLA-DQ8 distribution in the native low-gluten consuming southern Indian population. METHODS: Overall, 211 dried blood spots (DBS) were collected from native southern Indian individuals. HLA-DQ characterization and the determination of homozygous/heterozygous status were performed using commercially available HLA-DQ typing kits. RESULTS: Of 211 collected DBS, 88 (42%, 95% CI: 36-48) were positive for HLA-DQ2 and/or HLA-DQ8 heterodimers. Overall, 40 (19%, 95% CI: 14-24) samples typed positive for HLA-DQ2 and 48 (23%, 95% CI: 18-28) typed positive for HLA-DQ8 genotypes. Of 40 HLA-DQ2-positive individuals, only one subject tested homozygous for the DQB1*02 allele. CONCLUSIONS: In the southern Indian native general population, the prevalence of HLA-DQ8 is higher in comparison to HLA-DQ2 prevalence. This finding could be related to the delayed introduction of wheat in the diet of the southern Indian population.

3D visualization of perianal fistulas using parametric models.

BACKGROUND: Magnetic resonance imaging (MRI) is used as a standard for assessment of complex perianal fistulas. Apart from textual description of the case, 3D reconstructed models from MRI further aid in understanding the entire anatomy of the fistula tract and its relation to the pelvic floor. This information is crucial as it helps surgeons to understand the extent and complexity of the disease before surgical treatment. However, 3D model generation from MRI is a time-consuming step for a radiologist as it requires tedious manual delineations to be performed on every slice of the images. The aim of this study was to develop a method that could enable radiologists to present enhanced information to surgeons for treatment of complex perianal fistulas while simultaneously reducing the manual efforts and time required to generate the information. METHODS: A method was proposed to depict relevant anatomies of complex perianal fistula as parametric models in three-dimensional (3D) space. A plugin inside 3D Slicer software was developed for the generation of the parametric models from MRI. The levator ani muscle, internal sphincter, and external sphincter are represented as tubular structures, whereas fistula tracks and abscess are presented as splines. RESULTS: Parametric models were generated to depict three cases of complex perianal fistulas and similarity measures were computed for ten cases. Visual comparison of the parametric models was made with the 3D models generated by the standard approach. The parametric models took less time to create and were able to visually present enriched information as compared to the 3D models generated by the standard approach. CONCLUSIONS: The proposed method, using parametric models, shows potential for faster generation and better visualization of the 3D information required for the treatment of complex perianal fistula cases.

Endoscopic Stone Extraction followed by Laparoscopic Cholecystectomy in Tandem for Concomitant Cholelithiasis and Choledocholithiasis: A Prospective Study.

BACKGROUND: Single-session endoscopic stone extraction (ESE) and laparoscopic cholecystectomy (LC) has the best outcome in managing concomitant cholelithiasis (gallstone disease [GSD]) and choledocholithiasis (common bile duct stone [CBDS]). Traditional rendezvous technique with an intraoperative cholangiogram is associated with various technical (bowel distention, frozen Calot's triangle, limitation of intraoperative cholangiogram and so on) and logistical difficulties (lack of trained personnel and equipment for ESE in the operating room). We modified our approach of ESE-LC (tandem ESE-LC) to study the safety of the approach and overcome these disadvantages of the traditional rendezvous approach. METHODS: A prospective study of patients with GSD and suspected CBDS from January 2017 to December 2019 was conducted. Tandem ESE-LC involves ESE and LC under the same general anaesthesia in a single day, while ESE is performed in the endoscopic suite using carbon dioxide insufflation, a balloon/basket was used for achieving bile duct clearance and the same was confirmed with an occlusion cholangiogram. Patients were then shifted to the operating room for LC. The primary outcome included bile duct clearance and safety of the procedure. RESULTS: Of 56 patients assessed for eligibility, 42 were included in the study (median age: 53 years, 25 [60%] women). Biliary colic was the most common presenting symptom (n = 24, 57%), followed by acute cholecystitis (n = 11, 26%). The median number of stones and stone size was 1 (1-6) and 4 mm (3-10), respectively. All patients had successful bile duct clearance. Stenting was performed in 5 (12%) patients. Intraoperatively, Calot's dissection was difficult and frozen in 10 and 11 patients respectively. The cystic duct was short and wide in 13 (31%) patients. Subtotal cholecystectomy was performed in 6 (14%) patients. The median duration of postprocedural hospital stay was 1 (0-13) day. Three patients had tandem ESE-LC on a day-care basis. One patient had post-endoscopic retrograde cholangiopancretography pancreatitis, and another required percutaneous drainage for gall bladder fossa collection. No patient had retained CBDS at a median follow-up of 18 (3-28) months. CONCLUSION: Tandem ESE-LC is safe and effective method in managing concomitant GSD and CBDS.

Factors causing variability in formation of coronary collaterals during coronary artery disease.

Coronary artery disease (CAD) is one of the major causes of death worldwide. CAD is narrowing of coronary arteries that prevents adequate blood supply to the heart muscle and results in acute coronary syndrome which includes unstable angina and myocardial infarction. The only remedy for it is to restore the perfusion through percutaneous intervention and grafting which may sometime cause reperfusion injury and other complications. Coronary collaterals are small inter-arterial connections that act as natural bypass which provide blood flow to the vascular territory, when the artery supplying to it gets obstructed. Acute collateral recruitment can occurs as a remedy for these adverse cardiac events. Various methods of therapies considered for the promotion and sustenance of functional coronary collaterals. The determinants of human coronary collaterals give clear evidence for prognosis in CAD and a new insight for further therapeutic promotion of coronary collaterals. This review mainly focuses on various studies done on coronary collaterals and the effect of various demographic, morphological and cardiovascular risk factors on the formation of coronary collaterals during obstructive CAD. Many studies have proven that various independent variables such as morphology of coronary artery, location of the lesion, duration of the occlusion, coronary dominance, biochemical factors, and cardiac risk factors, such as diabetes, hypertension, also affect collateral formation. The current update review gives a holistic view on coronary collaterals and findings of various authors on the effect of these independent variables on collateral formation.

Human Leukocyte Antigen DQ (HLA-DQ) genotypes and haplotypes and their association with phenotype in patients with celiac disease in India.

BACKGROUND AND AIM: Human Leukocyte Antigen DQ (HLA-DQ) genotypes play a permissive role in the genesis of celiac disease (CeD). In this case-control study, we used next-generation sequencing to determine HLA-DQA1 and ~DQB1 genotypes and haplotypes associated with CeD in Indian patients. METHODS: HLA-DQA1 and ~DQB1 loci were amplified, using long-range polymerase chain reaction (PCR), from DNA of 259 patients with symptomatic CeD (160 typical and 99 atypical), 45 asymptomatic CeD, 96 potential CeD, and 300 healthy adults. Amplicons were fragmented and sequenced on the Illumina platform, and alleles and haplotypes were assigned by matching against the HLA-international ImMunoGeneTics (IMGT) database. RESULTS: HLA-DQA1*05:01 (odds ratio [OR] 8.39, 95% confidence interval [CI] 5.64-12.47) and HLA-DQB1*02:01 (OR 8.59, 95% CI 5.75-12.83) were the genotypes that showed a risk association with symptomatic CeD. Among the haplotypes, HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (OR 8.56, 95% CI 5.67-13.19) showed a strong risk association with symptomatic CeD. When comparing symptomatic CeD with subclinical forms (asymptomatic and potential) CeD, HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (OR 2.34, 95% CI 1.61-3.43) was significantly associated with risk of symptomatic disease. The strength of association between the HLA-DQA1*05:01 ~ HLA-DQB1*02:01 haplotype and the CeD phenotype showed a gradient in the order typical > atypical > asymptomatic > potential CeD. Genotypes consistent with expression of HLA DQ2 and/or 8 were noted in 128 (80%) typical, 73 atypical (74%), 27 (60%) asymptomatic, and 52 (54%) potential CeD participants. CONCLUSION: HLA-DQA1*05:01 ~ HLA-DQB1*02:01 (haplotype DQ2.5) showed a very strong risk association with symptomatic CeD in Indian patients. The strength of association showed a gradient of increase from potential to typical CeD, coinciding with a phenotypic change in the celiac iceberg.

Metal-free Transformations of Nitrogen-Oxyanions to Ammonia via Oxoammonium Salt.

Transformations of nitrogen-oxyanions (NOx- ) to ammonia impart pivotal roles in sustainable biogeochemical processes. While metal-mediated reductions of NOx- are relatively well known, this report illustrates proton-assisted transformations of NOx- anions in the presence of electron-rich aromatics such as 1,3,5-trimethoxybenzene (TMB-H, 1 a) leading to the formation of diaryl oxoammonium salt [(TMB)2 N+ =O][NO3- ] (2 a) via the intermediacy of nitrosonium cation (NO+ ). Detailed characterizations including UV/Vis, multinuclear NMR, FT-IR, HRMS, X-ray analyses on a set of closely related metastable diaryl oxoammonium [Ar2 N+ =O] species disclose unambiguous structural and spectroscopic signatures. Oxoammonium salt 2 a exhibits 2 e- oxidative reactivity in the presence of oxidizable substrates such as benzylamine, thiol, and ferrocene. Intriguingly, reaction of 2 a with water affords ammonia. Perhaps of broader significance, this work reveals a new metal-free route germane to the conversion of NOx  to NH3 .

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis.

BACKGROUND & OBJECTIVES: Hydroxychloroquine (HCQ), reported to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in in vitro studies, has been recommended for prophylaxis of COVID-19 in healthcare workers (HCWs). The objective of this study was to assess short-term adverse events (AEs) of HCQ in HCWs. METHODS: This cross-sectional study among consenting HCWs taking prophylaxis and working in hospitals with COVID-19 patients used online forms to collect details of HCWs, comorbidities, prophylactic drugs used and AEs after the first dose of HCQ. Verification of dose and AEs was done by personal contact. Multivariate logistic regression analysis was done to determine the effect of age, gender and dose of HCQ on AE. RESULTS: Of the 1303 HCWs included, 98.4 per cent (n=1282) took HCQ and 66 per cent (n=861) took 800 mg as first day's dose. Among the 19.9 per cent (n=259) reporting AEs, 1.5 per cent (n=20) took treatment for AE, none were hospitalized and three discontinued HCQ. Gastrointestinal AEs were the most common (172, 13.2%), with less in older [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.89], with more in females (OR 2.46, 95% CI 1.78-3.38) and in those taking a total dose of 800 mg on day one compared to a lower dose. Hypoglycaemia (1.1%, n=14), cardiovascular events (0.7%, n=9) and other AEs were minimal. INTERPRETATION & CONCLUSIONS: HCQ prophylaxis first dose was well tolerated among HCWs as evidenced by a low discontinuation. For adverse effects, a small number required treatment, and none required hospitalization. The study had limitations of convenience sampling and lack of laboratory and electrocardiography confirmation of AEs.