LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

Study of the association of the known prognostic variables with EGFR expression in head and neck squamous cell carcinomas.

Context: : Head and neck squamous cell carcinomas (HNSCCs) are the sixth most frequent malignancy in the world. Epidermal growth factor receptors (EGFRs) are members of Erb B family of receptors. EGFR is known to act as a driver of tumorigenesis in various carcinomas. Over expression of EGFR in HNSCC is associated with poor prognosis and resistance to radiotherapy. It is a useful prognostic marker, marker for response to therapy, and also a therapeutic target. Aim: To study the association of the known prognostic variables with EGFR expression in HNSCCs and to correlate it with the clinical outcome. Settings and Design: Cross-sectional observational study. Materials and Methods: A total of 170 patients of HNSCC were evaluated for EGFR expression and followed up for at least two years, with correlation of EGFR expression with various histopathological factors and their clinical outcome. Statistical Analysis Used: : Chi-square test. Results: The expression of EGFR in HNSCC in this study population was 88.82%. Statistical significance was noted between EGFR reactivity and age of the patient, its histological grade and perineural invasion. Statistical significance was also noted between EGFR reactivity and recurrence of malignancy as well as the site of recurrence. Conclusion: EGFR expression in patients with HNSCC is a poor prognostic biomarker and has a comparatively lower survival outcome as compared to non-EGFR expressing HNSCC cases. Hence, it will be helpful for all those patients diagnosed with HNSCC to ideally undergo an additional EGFR immunohistochemical evaluation, which, in turn, will help the oncologists in management of the tumor with anti-EGFR therapy combined with radiotherapy, to obtain a better response and a survival outcome.

Two short approaches to the COVID-19 drug ß-D-N4-hydroxycytidine and its prodrug molnupiravir.

Molnupiravir, the prodrug for ß-D-N4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio™ against mild-moderate COVID-19, under FDA emergency use authorization. It is the first oral drug against the disease. This work describes two synthetic approaches to NHC and molnupiravir by amide activation in uridine with a peptide-coupling agent and with a 4-chloropyrimidinone nucleoside intermediate.

A conserved nutrient responsive axis mediates autophagic degradation of miRNA-mRNA hybrids in blood cell progenitors.

In animals, microRNAs are amongst the primary non-coding RNAs involved in regulating the gene expression of a cell. Most mRNAs in a cell are targeted by one or many miRNAs. Although several mechanisms can be attributed to the degradation of miRNA and mRNA within a cell, but the involvement of autophagy in the clearance of miRNA and its target mRNA is not known. We discover a leucine-responsive axis in blood cell progenitors that can mediate an autophagy-directed degradation of miRNA-bound mRNA in Drosophila melanogaster and Homo sapiens. This previously unknown miRNA clearance axis is activated upon amino acid deprivation that can traffic miRNA-mRNA-loaded Argonaute for autophagic degradation in a p62-dependent manner. Thus, our research not only reports a novel axis that can address the turnover of a catalytically active miRISC but also elucidates a slicer-independent mechanism through which autophagy can selectively initiate the clearance of target mRNA.

Awareness Regarding Antimicrobial Resistance and Antibiotic Prescribing Behavior among Physicians: Results from a Nationwide Cross-Sectional Survey in India.

(1) Background: Understanding the physicians' knowledge, attitudes, and antimicrobial prescribing behavior is a crucial step towards designing strategies for the optimal use of these agents. (2) Methods: A cross-sectional online survey was conducted among clinicians across India between May and July 2022 using a self-administered questionnaire in English comprising 35 questions pertaining to demographic characteristics, knowledge, attitude, and practices domains. (3) Results: A total of 544 responses were received from 710 physicians contacted. Sixty percent of participants were males, with mean age of 34.7 years. Mean ± Standard Deviation scores for knowledge, attitude, and practices domains were 8 ± 1.6, 20.2 ± 3.5, and 15.3 ± 2.1, respectively. Higher scores were associated with basic [odds ratio (95% Confidence Interval), p value: 2.95 (1.21, 7.2), 0.02], medical and allied sciences [2.71 (1.09, 6.67), 0.03], and central zone [3.75 (1.39, 10.12), 0.009]. A substantial proportion of dissatisfactory responses were found regarding hospital antibiograms, antibiotics effective against anaerobes, WHO AWaRe (access, watch, and reserve) classification of antibiotics, and the role of infection prevention and control (IPC) measures in the containment of antimicrobial resistance (AMR). (4) Conclusions: There is a need to sensitize and educate clinicians on various issues related to antimicrobial use, such as antibiograms, double anaerobic cover, IPC practices, and guideline-based recommendations, to curb the AMR pandemic.

Phenothiazine-Based Cu(II)-Selective Fluorescent Sensor: GHK-Cu Sensing Applications.

Sensing important metals in different environments is an important area and involves the development of a wide variety of metal-sensing materials. The employment of fluorescent sensors in metal sensing has been one of the most widely applied methodologies, and the identification of selective metal sensors is important. We herein report a phenothiazine-based Cu(II) fluorescent sensor that is highly selective to Cu(II) ions compared with other transition metal salts. The Lewis acidity of the Cu(II) salt certainly was found to be a factor for obtaining an enhanced sensing response in MeOH as the solvent, while a ratio of 1:1 was calculated to be the most optimum for getting the desired response.

An overview on androgen-mediated actions in skeletal muscle and adipose tissue.

Androgens are a class of steroid hormones primarily associated with male sexual development and physiology, but exert pleiotropic effects in either sex. They have a crucial role in various physiological processes, including the regulation of skeletal muscle and adipose tissue homeostasis. The effects of androgens are mainly mediated through the androgen receptor (AR), a ligand-activated nuclear receptor expressed in both tissues. In skeletal muscle, androgens via AR exert a multitude of effects, ranging from increased muscle mass and strength, to the regulation of muscle fiber type composition, contraction and metabolic functions. In adipose tissue, androgens influence several processes including proliferation, fat distribution, and metabolism but they display depot-specific and organism-specific effects which differ in certain context. This review further explores the potential mechanisms underlying androgen-AR signaling in skeletal muscle and adipose tissue. Understanding the roles of androgens and their receptor in skeletal muscle and adipose tissue is essential for elucidating their contributions to physiological processes, disease conditions, and potential therapeutic interventions.

Anxiety, depression and harmful use of alcohol in severe chronic plaque psoriasis: A cross-sectional study.

Background: Psoriasis is a common, chronic T cell-mediated disease characterised by erythematous, scaly plaques. Psoriasis is associated with depression, anxiety, poor quality of life, harmful use of alcohol and suicidal ideation. We performed this study to find out prevalence of psychological morbidity in our patients with severe psoriasis and to know clinical variables associated with higher risk of psychological morbidity. Method: This study is a cross-sectional, observational study conducted in a dermatology outpatient department (OPD) of a tertiary care centre. Study population included patients with severe psoriasis area severity index (PASI>10). Clinical and epidemiological data, Patient health questionnaire-9, Generalised anxiety disorder-7, Dermatology life quality index (DLQI) and Alcohol Use Disorders Identification Test questionnaires were recorded. Data were analysed using SPSS, version 24. Chi-square test and Spearman's rank correlation test (ρ) were performed, and p value of <0.05 was considered statistically significant. Result: A total of 140 patients were included in the study and consisted of 67 men and 73 women. The median age was 44 years, median duration of disease was 10 years and median PASI was 13.6. Scoring revealed moderate-to-severe depression in 69 (49.3%) patients, moderate-to-severe anxiety in 40 (28.6%), severe impairment in quality of life in 98 (70%), harmful use of alcohol in 23 (16.4%) and suicidal ideation in 11 (7.8%) patients. Young age, recent onset, higher PASI and facial involvement show significant association with depression, anxiety and poor quality of life. Conclusion: Screening for psychological morbidity should be performed in patients with severe psoriasis especially younger patients with recent onset disease. Higher DLQI points to concomitant psychological morbidity and it should be performed in all the patients.

DNA-encoded libraries via late-stage functionalization strategies: a review.

The hit finding strategy in drug discovery has undergone a tremendous change in the past decade with the advent of DNA-encoded libraries with diverse chemical libraries. The miniaturization of the assays has enabled high-throughput screening on diverse targets to identify binders as a starting point for medicinal chemistry campaign. The diverse chemical space that can be accessed through DEL provides a unique opportunity to explore new chemistries on DNA. This review highlights the metal-mediated synthetic pathways that allow late-stage functionalisation of DNA strands to access such DEL libraries. Critical analysis of the literature and the methods employed has been done to allow readers to understand the usefulness, as well as the limitations of these protocols.

Epidemiological investigation of viral hepatitis E outbreak in two colocated training centers.

Background: A high number of jaundice cases were reported from two colocated training centers in North India. This outbreak was investigated to describe the epidemiology, identify risk factors, and recommend preventive and control measures. Methods: Initial line list was prepared, and case definition was defined as "the presence of icterus or passage of yellow-colored urine with fever/anorexia/vomiting/abdominal pain in a resident of Military Station A between 03/04/2016 to 06/06/2016". Case search was conducted through surveillance. An unmatched 1:1 case-control study was conducted to evaluate the associated risk factors. All cases were tested for hepatitis markers. Environmental investigation of food and water sources was conducted to identify the source of infection. Results: Of 172 cases, all were males from two co-located military training centers (attack rate, 4.7%). Clinical features included icterus (100%), yellowish discoloration of urine (98.9%), anorexia (97.22%), fever (80%), nausea/vomiting (56%), and abdominal pain (52.77%). Only one case (0.6%) had complication of fulminant hepatitis, and there were no deaths (CFR = 0%). Consumption of juice with ice from juice shops was significantly associated with illness (Odds Ratio-14.3 [95%CI 7.4-27.6]). Of 172 cases, 167 (97.1%) tested anti-HEV-IgM positive. Juice shops in training centers were using ice made from contaminated water with positive coliform test. All other water samples tested satisfactory. No cross-contamination of water pipelines with sewage was observed. Conclusion: Epidemiological evidence concludes that a large viral hepatitis E outbreak was likely caused by consumption of juice with contaminated ice. Early stoppage of contaminated ice usage led to timely control of the outbreak.

Sweetness and positivity together aren't a happy ending: Case controlled study amongst severe COVID-19 for impact of diabetes mellitus on survival.

Background: India is the epicenter of diabetes mellitus (DM). The relationship between COVID and DM in age/gender-matched non-diabetics has not been studied yet. The role of DM in predicting the disease severity and outcome in COVID patients might provide new insight for effective management. Methods: We conducted a prospective comparative study at a COVID care center from 25th April-31st May 2021. Among 357 severe-COVID patients screened, all consecutive diabetes (n-113) and age/gender-matched non-diabetes (n-113) patients were recruited. All diabetics and non-diabetics at admission were subjected to high resolution computed tomography (HRCT) chest and inflammatory markers (C-reactive protein (CRP), D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase (LDH), Neutrophil-Lymphocyte Ratio (NLR)) before starting anti- COVID therapy. Statistical analysis was done using JMP 15·0 ver·3·0·0. Results: The prevalence of DM among the screened population (n-357) was 38·37%. The mean age of the study population was 61y with male preponderance (57%). There was no statistical difference in the HRCT-score or inflammatory markers in the two groups except for higher NLR (p-0·0283) in diabetics. Diabetics had significantly inferior overall survival (OS) (p-0·0251) with a 15d-OS of diabetics vs. non-diabetics being 58·87%, 72·67%, and 30d-OS of diabetics vs. non-diabetics being 46·76%, 64·61%, respectively. The duration of the hospital stay was not statistically different in the two groups (p-0·2). Conclusion: The mortality is significantly higher in severe-COVID patients with DM when compared to age/gender-matched non-diabetics. There was no significant difference in most inflammatory markers/CT at admission between the two groups.

Do extraglomerular microvasculature and mesenchymal interstitial cell proliferation indicate a stable course of lupus nephritis?

Background: Lupus Nephritis (LN) is a major and frequent manifestation of Systemic Lupus Erythematosus (SLE), an autoimmune disease. Renal biopsy has a pivotal role in the diagnosis, prognosis, and management of the LN. The aim of this study was to count the mesenchymal interstitial cells utilizing CD34 immunohistochemistry (IHC) and morphometric analysis, correlate them with clinical parameters, class, activity, and chronicity indices and see if it can predict the course of the disease. Methods: A total of 32 renal biopsy blocks were analyzed by H&E stain, special stains, and CD34 IHC. Microvasculature density and interstitial stem cells were highlighted by CD34. These were then counted using a previously standardized computerized digital photomicrograph system (Dewinter Optical Inc) and manual count, respectively. Results: Out of the 32 cases, Lupus class 3 comprised of 11 (34.38%) cases, class 4 comprised of 16 (50%) cases, and mixed class 4 + 5 had 5 (15.62%) cases. It was found that CD34 expression in the microvasculature (for both microvascular density and mean vascular lumen diameter) decreased in patients of Lupus Nephritis with higher disease activity (p < 0.05). Although not statistically significant, the number of interstitial stem cells increased with lower disease activity. A statistical significance was found between serum total protein, serum albumin, and serum creatinine among the three groups of LN. Conclusion: Immunohistochemical staining of renal biopsy with CD34 may be used as a surrogate marker of disease activity in Lupus Nephritis patients.

Strategies for the Synthesis of Fluorinated Nucleosides, Nucleotides and Oligonucleotides.

Fluorinated nucleosides and oligonucleotides are of specific interest as probes for studying nucleic acids interaction, structures, biological transformations, and its biomedical applications. Among various modifications of oligonucleotides, fluorination of preformed nucleoside and/or nucleotides have recently gained attention owing to the unique properties of fluorine atoms imparting medicinal properties with respect to the small size, electronegativity, lipophilicity, and ability for stereochemical control. This review deals with synthetic protocols for selective fluorination either at sugar or base moiety in a preformed nucleosides, nucleotides and nucleic acids using specific fluorinating reagents.

Evaluation of point of entry surveillance for COVID-19 at Mumbai international airport, India, July 2020.

India started Point of entry (PoE) surveillance at Mumbai International Airport, screening passengers returning from coronavirus disease (COVID-19)-affected countries using infrared thermometers. We evaluated in July 2020 for March 1-22 with the Centers for Disease Control and Prevention evaluation framework. We conducted key informant interviews, reviewed passenger self-reporting forms (SRFs) (randomly selected) and relevant Airport Health Organization and Integrated Disease Surveillance Programme (IDSP) records. Of screened 165,882 passengers, three suspects were detected and all were reverse transcription-polymerase chain reaction negative. Passengers under-quarantine line-listing not available in paper-based PoE system, eight written complaints: 6/8 SRF filling inconvenience, 3/8 no SRF filling inflight announcements, and standing in long queues for their submission. Outside staff deployed 128/150 (85.3%), and staff: passenger ratio was 1:300. IDSP reported 59 COVID-19 confirmed cases against zero detected at PoE. It was simple, timely, flexible, and useful in providing information to IDSP but missed cases at PoE and had poor stability. We recommended dedicated workforce and data integration with IDSP.

Headache of Wearing PPE; A Survey for Neurological Symptoms with PPE amongst Health Care Workers.

Background: The COVID-19 pandemic has put the entire medical fraternity into a very challenging and demanding situation. Along with always being at the risk of COVID infection, healthcare workers (HCWs) are also facing neurological problems due to long working hours in personal protective equipment (PPE). These symptoms and their characteristics need to be observed and studied in-depth to understand the problems experienced by HCWs and to design new solutions to overcome such problems. Objectives: This study intends to evaluate the various neurological manifestations among the HCWs wearing PPE for prolonged periods. Materials and Methods: We conducted a questionnaire-based cross-sectional study at a Covid care center from western India from April 20 to June 01, 2021 by using a self-administered web-based questionnaire. A total of 256 HCWs were surveyed. The de-identified data were analyzed using JMP 15.0.0. Results: Among a total of 256 HCWs surveyed for this study, the majority (58.6%) were aged 24-35 years, with a male preponderance (65.62%, n = 168). Participants included doctors (41%), nurses (35%), paramedical staff (22%), and housekeeping staff (1%). The symptoms encountered among the HCWs wearing the PPE were headache, classified further as donning headache in 112 (44.98%), doffing headache in 56 (26.24%), slowed mentation in 48 (21.05%), and excessive sleepiness in 86 (38.74%), which affected their work performance. The age of the HCWs had a significant correlation with all the symptoms. Conclusion: Headache, slowed mentation, and excessive sleepiness was encountered among the HCWs wearing PPE, which depended upon the duration of PPE usage. The most common symptom was headache, which was of moderate to severe intensity.

Effectiveness of ChAdOx1 nCOV-19 Vaccine: Experience of a tertiary care institute.

BACKGROUND: The first dose of the ChAdOx1 nCoV- 19 Corona Virus Vaccine (Covishield) was administered to the eligible beneficiaries of tertiary care institute of Western Maharashtra on 16 Jan 21 and in the past three months almost 97% of the staff has been vaccinated. The present study analyses the incidence of COVID cases in the unvaccinated and vaccinated population of the institute. METHODS: All Covid 19 infections (RT-PCR positive) from 01 February 21 to 25 April 21 were included in the study and analyzed as per their vaccination status. To assess the COVID 19 transmission in contacts, Secondary Attack Rates (SAR) of the pre-vaccination period (Jun-Oct 20) was compared with the present SAR. RESULTS: A total of 113 cases occurred in the study period (01 Feb to 25 Apr 21). Lower number of infections were observed among the fully vaccinated as compared to partially vaccinated and non-vaccinated. The overall vaccine effectiveness was found to be 88.6% (81.55-92.37) and 44.1% (4.55-67.3) in completely and partially vaccinated individuals respectively. Hazard Ratios for getting infected dropped significantly after 28 days of the second dose. The SAR in high risk contacts (HRCs) was found to be 4.25%, which was lower than SAR (20.6%) of pre-vaccination period. CONCLUSION: This is one of the earliest studies in India to report the impact of COVID-19 vaccination. The results indicate that the vaccine provides effective protection against COVID-19 infection. However, given the complex dynamics of vaccination, the role of NPIs and implementation of COVID appropriate behavior cannot be undermined.

Seroconversion among COVID-19 patients admitted in a dedicated COVID hospital: A longitudinal prospective study of 1000 patients.

BACKGROUND: The immune response after SARS-CoV-2 is complex and may be affected by severity of the disease, race, etc. The present study was conducted to assess the serial antibody response among the COVID-19 patients admitted in the hospital. METHODS: The study was conducted between July and October 2020 in a dedicated COVID-19 hospital. All consented patients underwent serial testing of antibodies using a rapid chromatographic immunoassay-based qualitative IgG/IgM kit every third day until their discharge or death. The data about age, sex, severity of disease, length of stay, onset of symptoms, date of molecular testing were also collected. Appropriate statistical tests were used. RESULTS: The mean age of 1000 COVID-19 patients was 47.5 ± 17.9 years. Out of the total, 687 (68.7%) were males. With respect to severity, 682 (68.2%) were asymptomatic/mild, 200 (20%) were moderate and 118 (11.8%) were severe cases. The seroconversion percentage increased from 12.8% to 97.9% and 16.3% to 80.9% for IgG and IgM respectively in 21 days. The median time for seroconversion was 10 days (IQR:6-12 days) for IgG and eight days (IQR: 6-11 days) for IgM. At the time of discharge (median nine days), detectable IgG and IgM antibodies were present in 502 (52.46%) and 414 (43.26%) participants respectively. Seroconversion was associated with days after the symptoms, increasing severity of the disease and the presence of co-morbidity. CONCLUSION: Seroconversion increased during the period of observation. The severe/moderate cases of COVID-19 tend to have an early seroconversion as compared to the asymptomatic/mild cases. Only half of the patients were seroconverted at discharge.

Precision medicine: Concept and tools.

Precision medicine is the new age medicine and refers to tailoring treatments to a subpopulation who have a common susceptibility to a particular disease or similar response to a particular drug. Although the concept existed even during the times of Sir William Osler, it was given a shot in the arm with the Precision Medicine Initiative launched by Barack Obama in 2015. The main tools of precision medicine are Big data, artificial intelligence, the various omics, pharmaco-omics, environmental and social factors and the integration of these with preventive and population medicine. Big data can be acquired from electronic health records of patients and includes various biomarkers (clinical and omics based), laboratory and radiological investigations and these can be analysed through machine learning by various complex flowcharts setting up an algorithm for the management of specific subpopulations. So, there is a move away from the traditional "one size fits all" treatment to precision-based medicine. Research in "omics" has increased in leaps and bounds and advancements have included the fields of genomics, epigenomics, proteomics, transcriptomics, metabolomics and microbiomics. Pharmaco-omics has also come to the forefront with development of new drugs and suiting a particular drug to a particular subpopulation, thus avoiding their prescription to non-responders, preventing unwanted adverse effects and proving economical in the long run. Environmental, social and behavioural factors are as important or in fact more important than genetic factors in most complex diseases and managing these factors form an important part of precision medicine. Finally integrating precision with preventive and public health makes "precision medicine" a complete final product which will change the way medicine will be practised in future.

Development and Validation of Chromatographic Method for the Standardization of Homeopathic Formulation of Syzygium Cumini.

BACKGROUND: Syzygium cumini (Lam.), family Myrtaceae, has a long history of use in folk and traditional systems of indigenous medicine. Many homeopathic formulations of Jamun seeds are available in the market for their crucial usage as an anti-diabetic. Despite the popularity of homeopathic products, a lack of standard quality is a significant impediment in their acceptance. The present study aimed to develop and validate a chromatographic method for the standardization of the homeopathic formulation of Syzygium cumini. METHODS: The seeds of Syzygium cumini were studied for physicochemical evaluation and preliminary phytochemical screening. Also, the in-house standard and marketed homeopathic formulations of Syzigium cumini were standardized for pH, total fatty content, total phenolic and flavonoid content, with quantitative high-performance liquid chromatography- photodiode array detector (HPLC-PDA) analysis by using ellagic acid as a marker. RESULTS: The physicochemical characteristics of crude material were found to be within pharmacopeial limits. The phytochemical screening showed the presence of various secondary metabolites. The total phenolic and flavonoid content was higher in the in-house standard than in marketed formulations. A validated quantitative HPLC-PDA analysis showed variations of ellagic acid content in different homeopathic formulations. CONCLUSION: Physicochemical analysis and the HPLC method for quantitative estimation of ellagic acid can be used to standardize a homeopathic formulation of Syzygium cumini.