Simulating Non-Adiabatic Dynamics of Photoexcited Phenyl Azide: Investigating Electronic and Structural Relaxation en Route to the Formation of Phenyl Nitrene.

Excited state molecular dynamics simulations of the photoexcited phenyl azide have been performed. The semi-classical surface hopping approximation has enabled an unconstrained analysis of the electronic and nuclear degrees of freedom which contribute to the molecular dissociation of phenyl azide into phenyl nitrene and molecular nitrogen. The significance of the second singlet excited state in leading the photodissociation has been established through electronic structure calculations, based on multi-configurational schemes, and state population dynamics. The investigations on the structural dynamics have revealed the N-N bond separation to be accompanied by synchronous changes in the azide N-N-N bond angle. The 100 fs simulation results in a nitrene fragment that is electronically excited in the singlet manifold.

MiMiC: A high-performance framework for multiscale molecular dynamics simulations.

MiMiC is a framework for performing multiscale simulations in which loosely coupled external programs describe individual subsystems at different resolutions and levels of theory. To make it highly efficient and flexible, we adopt an interoperable approach based on a multiple-program multiple-data (MPMD) paradigm, serving as an intermediary responsible for fast data exchange and interactions between the subsystems. The main goal of MiMiC is to avoid interfering with the underlying parallelization of the external programs, including the operability on hybrid architectures (e.g., CPU/GPU), and keep their setup and execution as close as possible to the original. At the moment, MiMiC offers an efficient implementation of electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) that has demonstrated unprecedented parallel scaling in simulations of large biomolecules using CPMD and GROMACS as QM and MM engines, respectively. However, as it is designed for high flexibility with general multiscale models in mind, it can be straightforwardly extended beyond QM/MM. In this article, we illustrate the software design and the features of the framework, which make it a compelling choice for multiscale simulations in the upcoming era of exascale high-performance computing.

SGLT2i as a First-line Antihyperglycemic in the Management of Type 2 Diabetes in the Context of Indians: A Systematic Review and Consensus.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been used for almost a decade and have proven to be effective not only in managing Type 2 diabetes (T2D), but their cardio and renal protective features make them very useful in managing patients with risk of multiple comorbidities. This systematic review was undertaken by the authors because there is no evidence currently available in India that has studied the suitability of SGLT2i as a first-line agent in patients newly diagnosed with T2D in India. MATERIALS AND METHODS: First, literature was searched to identify features that are considered important when deciding on a first-line agent for managing T2D. A total of 5 broad topics were identified-glycemic control, extra glycemic effects, antihyperglycemic combination therapy, safety, and cost-effectiveness. These domains had further subheadings, and a total of 16 domains were identified. Metformin is the drug of choice as a first-line agent in such situations and has been considered the gold standard for evaluating the effects of SGLT2i across these domains. A systematic literature review on each domain was conducted to compare SGLT2i with the gold standard in Indian patients newly diagnosed with T2D. Evidence was graded (levels of evidence (LoE)-A, B, and C), and recommendations (class of recommendation (CoR)-I, II, and III) were classified by the expert group as defined in the methodology. RESULTS: According to the systematic reviews conducted, 11 domains had Level A evidence, 2 domains (impact on lipids and gut microbiome) had Level B, and 3 domains had Level C (ß-cell function, renal protection, and glycemic variability) evidence. Based on evidence and expert opinion, the authors recommend SGLT2i as a first-line agent for managing newly diagnosed patients with T2D with a Class I recommendation for 13 domains and Class II for the remaining 3 (impact on lipids, gut microbiome, and ß-cell function). Although a poorer level of evidence (Level C) was available for the glycemic variability domain, the authors still reported this as Class I recommendations according to their expert opinion and consensus. CONCLUSION: This article advocates adopting SGLT2 inhibitors as the primary treatment choice for treating patients with newly diagnosed T2D in India.

An Expert Group Consensus Statement on "Approach and Management of Prediabetes in India".

The prevalence of prediabetes, a forerunner of diabetes is very high, and its conversion to diabetes is also more rapid among Asian Indians. Prediabetes also predisposes to the development of macrovascular and to a lesser extent of microvascular complications of diabetes. In a large community-based epidemiological study, the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB), data reported an overall prevalence of prediabetes of 10.3%, derived from 15 Indian states. This shows that the diabetes epidemic is far from over as many of them may soon convert to diabetes. Prediabetes, however, should not be considered a path to diabetes rather it should be a window of opportunity for the prevention of diabetes. This early screening, detection, and treatment of prediabetes should be made a national priority. Several countries have introduced lifestyle programs to prevent diabetes and, when indicated, pharmacological intervention with metformin as well. This consensus statement outlines the approaches to screening and lifestyle and pharmacological management of prediabetes in Asian Indians.

Critical benchmarking of popular composite thermochemistry models and density functional approximations on a probabilistically pruned benchmark dataset of formation enthalpies.

First-principles calculation of the standard formation enthalpy, ΔHf° (298 K), in such a large scale as required by chemical space explorations, is amenable only with density functional approximations (DFAs) and certain composite wave function theories (cWFTs). Unfortunately, the accuracies of popular range-separated hybrid, "rung-4" DFAs, and cWFTs that offer the best accuracy-vs-cost trade-off have until now been established only for datasets predominantly comprising small molecules; their transferability to larger systems remains vague. In this study, we present an extended benchmark dataset of ΔHf° for structurally and electronically diverse molecules. We apply quartile-ranking based on boundary-corrected kernel density estimation to filter outliers and arrive at probabilistically pruned enthalpies of 1694 compounds (PPE1694). For this dataset, we rank the prediction accuracies of G4, G4(MP2), ccCA, CBS-QB3, and 23 popular DFAs using conventional and probabilistic error metrics. We discuss systematic prediction errors and highlight the role an empirical higher-level correction plays in the G4(MP2) model. Furthermore, we comment on uncertainties associated with the reference empirical data for atoms and the systematic errors stemming from these that grow with the molecular size. We believe that these findings will aid in identifying meaningful application domains for quantum thermochemical methods.

Isolation and Identification of Cronobacter spp. from Fish and Shellfish Sold in Retail Markets.

In this study, we investigated the incidence of Cronobacter spp. in seafood collected from retail fish markets of Mumbai, India. A total of 50 samples comprising fresh finfish (n = 32), shellfish (n = 6), dried fish (n = 9) and water (n = 3) were analyzed for Cronobacter spp. by selective enrichment, isolation and biochemical tests. Of 145 isolates presumptively identified as Cronobacter spp. by biochemical tests, 37 were confirmed as Cronobacter spp. by Polymerase Chain Reaction (PCR) specific to the internal transcribed spacer (ITS) regions. Based on the partial ITS gene sequence analysis, 35 isolates were identified as Cronobacter malonaticus and two as Cronobacter sakazakii. The highest incidence of Cronobacter spp. was in dried fish (55.6%), followed by shellfish (33.3%). The virulence gene ompA was detected in two Cronobacter sakazakii isolates. This is the first report of the incidence of Cronobacter spp. in fresh and dried seafood from India, which highlights the need to focus on this emerging pathogen in tropical seafood.

Indian Expert Review on Use of Teneligliptin in patients with Diabetes and its Safety and Efficacy (INTENSE).

INTRODUCTION: Management of diabetes in India remains less than satisfactory despite a huge prevalence of type 2 diabetes (T2D). Associated obesity, inadequate lifestyle modifications and burden of treatment costs are certain major issues contributing to inadequate management of diabetes in India. AIM: To evaluate the use of Teneligliptin in patients with diabetes and its safety, efficacy and cost effectiveness especially in Indian patients with T2D. METHODS: A detailed analysis of the best available scientific evidence (clinical trials, meta-analyses and real-world experience) was performed to create an evidence driven understanding of teneligliptin's efficacy, safety and cost effectiveness. Fourteen leading endocrinologists contributed as experts and the modified Delphi process was followed. Evidences and clinical questions were discussed over a series of web and in a live meeting. Final draft was created based on the opinions endorsed by the experts. RESULTS: Teneligliptin is the most commonly used gliptin in India and exhibits pharmacokinetic and pharmacodynamic advantages as well as greater cost effectiveness compared to other gliptins. It has been recognized as an efficacious and well tolerated antidiabetic agent both as monotherapy and in combination based on multiple clinical trials, meta-analyses and real world studies. Teneligliptin as add on therapy to other antidiabetic drugs (OADs) or insulin has provided significant reductions in HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels and is generally well tolerated with low risk of hypoglycemia both in short term and long term. Studies have also proven its efficacy in ameliorating glucose fluctuations, reducing post prandial insulin requirement, increasing active incretin levels and improving pancreatic ß cells function. Efficacy and safety has also been proven in all age groups, all stages of renal disease and mild to moderate hepatic disease. QT prolongation is not seen even with maximum recommended dose of 40 mg/day. CONCLUSION: Teneligliptin has firmly positioned itself as a very important drug in the armamentarium for managing T2D. It offers efficacy, safety and cost-effective therapeutic choice in Indian patients with T2D.

Endocrine Fatigue Syndrome.

This review on endocrine fatigue syndrome (EFS) describes the various clinical presentations of fatigue in endocrinopathy. It enumerates the various endocrine and non-endocrine causes of fatigue in endocrinopathy, and shares pragmatic clinical tips to help in differential diagnosis.

Culinary happiness.

Nutritional and dietary advice is the foundation of diabetes management. Unfortunately, such advice is seen in terms of intrusion and restriction of lifestyle, rather than as a health promoting intervention. This can be corrected by incorporating happiness into dietary modification. Culinary happiness can be defined as the process of sharing dietary, nutritional, and cooking advice, while ensuring the happiness associated with eating remains intact. The concept of culinary happiness includes all domains of culinary science: the procurement, preparation, plating and preservation of food.

A Prospective Validation Survey to Assess Usage of Premix Insulins in Management of Diabetes with Respect to the Recommendations Enlisted in Indian Guidelines.

OBJECTIVE: Widely used in the management of diabetes, the premix insulin therapy is influenced by several patient preferences and physician choices. The present survey aims to provide specific recommendations based on published data for appropriate management of T2DM with premix insulins. METHODS: We administered an online questionnaire where the respondent physicians were requested to go-through the published India specific and international guidelines before the survey. The respondents were requested to answer the electronic survey based on their clinical experiences with patients having diabetes. RESULTS: Overall, 1408 doctors participated in the survey. Majority of physicians preferred a premix insulin regimen for initiation. Short-term therapy with premix insulins in insulin-naive T2DM patients with symptomatic hyperglycemia and/ or glucotoxicity was strongly recommended by 40.7% physicians. Initiation of insulin early in the course of T2DM was recommended by 58.7% of physicians in cases where glycemic goals were not achieved by non-insulin drugs. Premix insulin analogues were preferred over human premix insulins by more than half of participating physicians (52.2%). Premix insulin analogues were preferred over basal insulins by 49.8% of physicians. Nearly half (44.5%) of the physicians recommended initiation of twice daily premix analogues over once daily basal insulins to achieve recommended glycemic targets. Around forty two percent (41.9%) physicians strongly believed that twice daily/thrice daily premix insulin analogues provide comparable glycemic control and safety to basal plus regimen with additional benefit of simplicity. During Ramadan premix insulin analogues were recommended over human premix by 46.5% physicians in view of improved safety and flexibility of dosing. SUMMARY: Majority of Indian physicians concur with the recommendations of INCG 2017 guidelines. Premix insulins were preferred for insulin initiation. IDegAsp was preferred over other premix insulins by majority of physicians. Twice daily premix insulins were recommended for intensification.

The SECURE model: A comprehensive approach for obesity management.

With rapidly increasing prevalence of obesity worldwide, it has become imperative to generate a comprehensive and easy to use clinical model for its management. We propose a simplified yet systematic approach to an obese patient, for a personalised patient centric obesity management. The SECURE model encompasses three domains in evaluation of the patient (Severity assessment, Etiological evaluation and Comorbidity workup) and the other three pillars for obesity treatment (Urge life style changes, Role of medications and surgery and Expected goal setting). This provides a clinical action checklist that may be useful even in other chronic non communicable disorders.

Tucker Tensor Approach for Accelerating Fock Exchange Computations in a Real-Space Finite-Element Discretization of Generalized Kohn-Sham Density Functional Theory.

The evaluation of Fock exchange is often the computationally most expensive part of hybrid functional density functional theory calculations in a systematically improvable, complete basis. In this work, we employ a Tucker tensor based approach that substantially accelerates the evaluation of the action of Fock exchange by transforming three-dimensional convolutional integrals into a tensor product of one-dimensional convolution integrals. Our numerical implementation uses a parallelization strategy that balances the memory and communication bottlenecks, alongside overlapping compute and communication operations to enhance computational efficiency and parallel scalability. The accuracy and computational efficiency are demonstrated on various systems, including Pt clusters of various sizes and a TiO2 cluster with 3684 electrons.

Vitamin D-dependent Rickets Type 1A Mimicking Pseudohypoparathyroidism in Presence of Active Tuberculosis.

Vitamin D-dependent rickets type 1A is caused by pathogenic variants of CYP27B1 gene, which is inherited in autosomal recessive pattern. These variants lead to defective 1α-hydroxylase enzymatic activity, leading to impaired renal formation of 1,25(OH)2 vitamin D. We report a case of a 16-year-old Asian male patient, with short stature and progressive bone deformity, whose biochemical parameters revealed low levels of 1,25(OH)2 vitamin D, low serum calcium levels, along with high phosphorus and raised levels of intact parathyroid hormone. These biochemical parameters suggested the diagnosis of pseudohypoparathyroidism. The patient also had concurrent extrapulmonary tuberculosis during the time of presentation to our endocrine unit. However, on molecular testing, it was revealed that the patient was harboring pathogenic variants of the CYP27B1 gene, in a compound heterozygous manner, with a novel missense mutation in exon 6 of the CYP27B1 gene, c.1136G > C (p.Arg379Thr), suggesting the diagnosis of vitamin D-dependent rickets type 1A. The cause of high phosphorus at the time of presentation, which led to a diagnostic dilemma of pseudohypoparathyroidism, was later explained by presence of active extra pulmonary tuberculosis. This report describes a case of vitamin D-dependent rickets type 1A, mimicking pseudohypoparathyroidism owing to presence of concurrent illness like extrapulmonary tuberculosis.

An Unusual Case of Hypoglycemia in a Non-diabetic Individual due to Hirata Disease.

Hypoglycemia is common in diabetic populations using insulin or insulin secretagogues, but rare in non-diabetics. A 60-year-old non-diabetic male presented with repeated episodes of abnormal behavior persisting for 10-15 minutes for seven days, associated with sweating, intense hunger, and relief on food intake, with no history of insulin or secretagogue intake, with stable vitals and normal systemic examination. Laboratory tests during attacks revealed low blood sugar, high serum insulin, and normal C-peptide levels, with no evidence of pancreatic or extrapancreatic hyperinsulinism, and serum anti-insulin antibody levels >100 U/ml. Based on these results, he was diagnosed with autoimmune insulin syndrome (AIS). Treatment with low-carb meals, oral prednisolone, and acarbose led to the resolution of symptoms. Hirata syndrome, though rare in India, requires consideration as a differential diagnosis to avoid unnecessary invasive procedures.

Electronic Fingerprint of the Protonated Imidazole Dimer Probed by X-ray Absorption Spectroscopy.

Protons in low-barrier superstrong hydrogen bonds are typically delocalized between two electronegative atoms. Conventional methods to characterize such superstrong hydrogen bonds are vibrational spectroscopy and diffraction techniques. We introduce soft X-ray spectroscopy to uncover the electronic fingerprints for proton sharing in the protonated imidazole dimer, a prototypical building block enabling effective proton transport in biology and high-temperature fuel cells. Using nitrogen core excitations as a sensitive probe for the protonation status, we identify the X-ray signature of a shared proton in the solvated imidazole dimer in a combined experimental and theoretical approach. The degree of proton sharing is examined as a function of structural variations that modify the shape of the low-barrier potential in the superstrong hydrogen bond. We conclude by showing how the sensitivity to the quantum distribution of proton motion in the double-well potential is reflected in the spectral signature of the shared proton.

Expert Consensus on Dipeptidyl Peptidase-4 Inhibitor-Based Therapies in the Modern Era of Type 2 Diabetes Mellitus Management in India.

India has a high prevalence of type 2 diabetes mellitus (T2DM) with unique clinical characteristics compared to other populations. Despite advancements in diabetes therapy, a significant number of patients in India still experience poor glycemic control and complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors continue to be an important component of T2DM treatment due to their favorable efficacy and tolerability profile. Given the current scenario, there is a need to revisit the role of DPP-4 inhibitors in T2DM management in Indian patients. This consensus paper aims to provide guidance on the utilization of DPP-4 inhibitors in T2DM management from an Indian perspective. A consensus group of 100 experts developed recommendations based on an extensive literature review and discussions. The expert group emphasized the importance of timely glycemic control, combination therapy, and targeting the underlying pathophysiology of T2DM. The combinations of DPP-4 inhibitors with metformin and/or sodium-glucose transport protein-2 inhibitors are rationalized in this paper, considering their complementary mechanisms of action. This paper provides valuable insights for clinicians in optimizing the management of T2DM in the Indian population with the use of DPP-4 inhibitors and proposes an algorithm for selecting DPP-4 inhibitor-based therapies.

Defining and Diagnosing Obesity in India: A Call for Advocacy and Action.

The prevalence of overweight and obesity has more than doubled since 1980, and it is predicted that around two-thirds of the global burden of the disease will be attributed to chronic non-communicable diseases. Developing countries are experiencing a more dramatic rise in the prevalence of obesity in recent years. As per National Family Health Survey-5 (NFHS-5), one in every four Indians is now having obesity. It has been reported that being overweight and obese is a significant problem among different socioeconomic spectrums of men and women in India, especially among the elderly, people residing in urban regions, and diverse socioeconomic strata. There is an urgent need to identify obesity as a chronic disease requiring immediate attention, mandating timely screening, timely treatment, and economical ways of achieving and managing weight loss across the country. In this review, the authors have discussed various aspects of overweight and obesity and critically appraised the current status of obesity in India, its public health implications, the significance of screening, the role of BMI and other parameters in diagnosing obesity, and the need for treatment and cost-effective prescriptions.

Discharge Planning for People with Inpatient Hyperglycaemia: A Review on Pharmacological Management.

Inadequate glycaemic control post-discharge is the root cause of readmission in people with diabetes mellitus (DM) and is often linked to improper discharge planning (DP). A structured DP plays a crucial role in ensuring continuing home care and avoiding readmissions. DP should help patients in self-care and provide appropriate guidance to maintain optimal glycaemic control. There is a scarcity of reports and recommendations on the proper DP for people with DM on insulin therapy. The present review provides important consideration based on experts' opinions from the National Insulin and Incretin summit (NIIS), focusing on the effective treatment strategies at the time of discharge, especially for insulin therapy. A review of literature from PubMed and Embase was conducted. The consensus was derived, and recommendations were made on effective DP for patients with DM. Recommendations were drawn at the NIIS for post-discharge treatment for medical and surgical cases, stress-induced hyperglycaemia, elderly, pregnant women, and coronavirus disease 2019 (COVID-19) cases. The committee also recommended a comprehensive checklist to assist the physicians during discharge.

Bempedoic Acid for Lipid Management in the Indian Population: An Expert Opinion.

Lipid-lowering is a central theme in the management of patients with atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH), with statins being currently used as the first-line lipid-lowering agent (LLAs). Bempedoic acid (BA) has been recently approved for lipid management in ASCVD/HeFH patients. This expert opinion paper brings out the essential concept to assess the current place of BA in the Indian population. Here we highlight that the majority of the patients with clinical ASCVD may not be receiving the optimal dose of statin, thereby failing to achieve their lipid targets. The addition of BA to statin results in a significant reduction in low-density lipoprotein cholesterol (LDL-C) along with substantial reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) levels. For patients who do not achieve LDL-C targets, BA can be an effective add-on alternative to choose among non-statin LLAs. BA is a good choice for statin-intolerant cases, especially in combination with ezetimibe. Given the lack of effect of worsening hyperglycemia or any increase in the occurrence of new-onset diabetes, BA can be used without hesitation in patients with diabetes. The small risk of hyperuricemia could be mitigated with appropriate patient selection and monitoring of serum uric acid levels in patients at high risk of hyperuricemia. We believe BA is an excellent non-statin therapy that is efficacious, well-tolerated, and cost-effective for lipid management in ASCVD, HeFH, and statin-intolerant patients in India.

Weight homeostasis & its modulators in hyperthyroidism before & after treatment with carbimazole.

BACKGROUND & OBJECTIVES: Hyperthyroidism is associated with increased food intake, energy expenditure and altered body composition. This study was aimed to evaluate the role of adipocytokines in weight homeostasis in patients with hyperthyroidism. METHODS: Patients (n=27, 11men) with hyperthyroidism (20 Graves' disease, 7 toxic multinodular goiter) with mean age of 31.3±4.2 yr and 28 healthy age and body mass index (BMI) matched controls were studied. They underwent assessment of lean body mass (LBM) and total body fat (TBF) by dual energy X-ray absorptiometer (DXA) and blood sample was taken in the fasting state for measurement of leptin, adiponectin, ghrelin, insulin, glucose and lipids. Patients were re-evaluated after 3 months of treatment as by that time all of them achieved euthyroid state with carbimazole therapy. RESULTS: The LBM was higher (P<0.001) in healthy controls as compared to hyperthyroid patients even after adjustment for body weight (BW), whereas total body fat was comparable between the two groups. Serum leptin levels were higher in patients with hyperthyroidism than controls (22.3±3.7 and 4.1±0.34 ng/ml, P<0.001), whereas adiponectin levels were comparable. Plasma acylated ghrelin was higher in patients than in controls (209.8±13.3 vs 106.2±8.2 pg/ml, P<0.05). Achievement of euthyroidism was associated with significant weight gain (P<0.001) and significant increase in lean body mass (P<0.001). The total body fat also increased but insignificantly from 18.4±1.8 to 19.9±1.8 kg. There was significant decrease (P<0.05) in serum leptin and acylated ghrelin but adiponectin levels remained unaltered after treatment. Serum leptin positively correlated with TBF and this correlation persisted even after adjustment for BW, BMI, gender and age (r=0.62, P=0.001). However, serum leptin and acylated ghrelin did not correlate with the presence or absence of hyperphagia. INTERPRETATION & CONCLUSION: Patients with hyperthyroidism predominantly had decreased lean body mass which increased after achievement of euthyroidism with carbimazole. The hyperphagia and the alterations in weight homeostasis associated with hyperthyroidism were independent of circulating leptin and ghrelin levels.