Association of genetic and epigenetic modification in MTHFR gene with coronary artery disease patients in North Indian population

Background: Methylene tetra hydro folate reductase (MTHFR) gene polymorphism C677T (rs180113) and DNA methylation in promoter region of MTHFR gene may contribute to the development of coronary artery disease however the results have been inconsistent across studies with different populations, so the aim of our study is to explore the association of polymorphism in MTHFR gene and methylation in promoter region with coronary artery disease (CAD) and other risk factor (lipid profile, homocysteine, vitamin B12 and folic acid levels)  leading to CAD in of north Indian population. Methods: Total 100 CAD patients and 100 healthy controls were enrolled in the study. Genotyping of rs1801133 SNP (C677T) is done by PCR-RFLP and DNA methylation study in promoter region by methylation specific PCR. Lipid profile analysis by automated chemistry analyzers, serum homocysteine, folic acid and vitamin B12 was assayed by ELISA. Results: As per our finding the T allele (OR=3.03, 95% CI=1.74-5.27) and hyper methylation in promoter region of MTHFR increases the odds of coronary artery disease, (OR=3.05, 95% CI=1.7-5.6). Study participants with CT and TT genotype had significantly higher homocysteine (Hcy) (p=0.001), lower folic acid level (p=0.0), and HDL levels (p<0.0001) than those with CC genotype. The study subjects with hyper methylated promoter region have a significantly high homocystenemia levels (p=0.001). Conclusions: The TT genotype of the MTHFR C677T gene polymorphism and hyper methylation in promoter region of MTHFR, is associated with CAD and can be useful in identification of new biomarkers, development of preventive and therapeutic strategies for CAD.

A survey on the knowledge and perception of computer assisted learning among undergraduate medical students in a tertiary care teaching institute of North India

Background: Computer assisted learning (CAL) in the classroom as well as laboratory in the medical profession has been rising in the present scenario worldwide. CAL can replace laboratory based animal experiments to a large extent and prevent the unnecessary harm or killing of animals. In India, only few studies have been conducted on CAL till date. Aims and objective of the study was to evaluate the knowledge and perception on CAL among undergraduate medical students.Methods: This cross sectional study was carried out on the medical students (MBBS-Second Professional) in the department of pharmacology at Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India. Feedback was obtained from 105 students who had already performed animal experiments in CAL laboratory.Results: It was seen that Computer simulated models (CSMs) are useful for undergraduate teaching (by 98.1%), CAL enrich learning experience about drug effects (by 97.1%), CSMs in CAL is user friendly (by 97.1%) and use of CSMs in teaching is ethical (by 97.1%).Conclusions: CAL is an innovative teaching and learning technique for the medical students. This is an effective mode of teaching pharmacology to the students and it also helps the students to apply their theoretical knowledge of drugs to the practical aspects (without use of animal) on computer simulated models

Comparison of drug information in package inserts with standard medical textbook of pharmacology

Background: Accurate and reliable drug product information is important for the safe and effective use of medicines. But there are variations in the quantity and quality of information mentioned in different drug information sources and a single credible benchmark is lacking. This study was carried out to compare the presentation and completeness of clinical information in package inserts (PIs) marketed by pharmaceutical companies in India with standard medical textbook of pharmacology.Methods: Out of eighty five PIs of different drugs, only 55 were found eligible to be included in this study after applying inclusion and exclusion criteria. These PIs and medical textbook were analysed for quantitative and qualitative drug information and were compared using Chi square test of two proportions. The p value of 0.05 was used as cut off to evaluate statistical significance.Results: Quantitatively medical textbook was significantly better statistically in context of treatment of overdose and references. No statistically significant difference was observed in relation to information related to mechanism of action (MOA) and pharmacokinetics (Pk). After qualitative analysis, medical textbook was significantly better statistically in context of size and readability, references related to adverse drug reactions (ADRs) and indications and pictures. No statistically significant difference was observed in context of dosing interval, frequency of doses and pharmacokinetic parameters.Conclusions: PIs can be used as a reliable source of drug information by health care professionals in addition to other sources like medical textbooks

Exposing and Addressing Cross-Task Inconsistency in Unified Vision-Language Models

As general purpose vision models get increasingly effective at a wide set of tasks, it is imperative that they be consistent across the tasks they support. Inconsistent AI models are considered brittle and untrustworthy by human users and are more challenging to incorporate into larger systems that take dependencies on their outputs. Measuring consistency between very heterogeneous tasks that might include outputs in different modalities is challenging since it is difficult to determine if the predictions are consistent with one another. As a solution, we introduce a benchmark dataset, COCOCON, where we use contrast sets created by modifying test instances for multiple tasks in small but semantically meaningful ways to change the gold label, and outline metrics for measuring if a model is consistent by ranking the original and perturbed instances across tasks. We find that state-of-the-art systems suffer from a surprisingly high degree of inconsistent behavior across tasks, especially for more heterogeneous tasks. Finally, we propose using a rank correlation-based auxiliary objective computed over large automatically created cross-task contrast sets to improve the multi-task consistency of large unified models, while retaining their original accuracy on downstream tasks. Project website available at https://adymaharana.github.io/cococon/Comment: Project Website: https://adymaharana.github.io/cococon

Role of Spectral Peaks in Autocoorelation Domain for Robust Speech Recognition

This paper presents a new front-end for robust speech recognition. This new front-end scenario focuses on the spectral features of the filtered speech signals in the autocorrelation domain. The autocorrelation domain is well known for its pole preserving and noise separation properties. In this paper we will use the autocorrelation domain as an appropriate candidate for robust feature extraction. The proposed method introduces a novel representation of speech for the cases where the speech signal is corrupted by additive noises. In this method, the speech features are computed by reducing additive noise effects via an initial filtering stage, followed by the extraction of autocorrelation spectrum peaks. Robust features based on theses peaks are derived by assuming that the corrupting noise is stationary in nature. A task of speaker-independent isolated-word recognition is used to demonstrate the efficiency of these robust features. The cases of white noise and colored noise such as factory, babble and F16 are tested. Experimental results show significant improvement in comparison to the results obtained using traditional front end methods. Further enhancement has been done by applying cepstral mean normalization (CMN) on the above extracted features

A Study on the Expression of BCR-ABL Transcript in Mixed Phenotype Acute Leukemia (MPAL) Cases Using the Reverse Transcriptase Polymerase Reaction Assay (RT-PCR) and its Correlation with Hematological Remission Status Post Initial Induction Therapy

<p><strong>Introduction</strong>: The MPAL comprise 2-5% of all acute leukemia. The present WHO 2008 classification has separated two groups in MPAL based on t(9;22) positivity and MLL rearrangement. <strong>Aims & Objectives</strong>: The aim of the present pilot study is to note the incidence of BCR-ABL transcript in MPAL cases using the RT-PCR assay and to correlate the status with hematological remission post induction. <strong>Materials & Methods</strong>: A total of 10 MPAL cases classified on Flow-cytometry based on the current WHO 2008 criteria were enrolled. In all the cases Bone marrow or peripheral blood sample in EDTA was processed for molecular studies and the RT-PCR reaction carried out using primers specific to the t (9;22) and t(4;11) translocation. The post induction check marrow slides were also reviewed. <strong>Results</strong>: Out of the total 10 MPAL cases, 7/10 (70%) were adult and 3/10 (30%) pediatric cases. A total of 4/10 (40%) cases showed positivity for the t(9;22) transcript and none for t (4;11). Of the 4 positive cases, 3/10(30%) were adult cases and 1/10(10%) pediatric case. The BCR-ABL transcript type in adult cases was b3a2 (p210) in 2/3 (66%) and e1a2 (p190) in 1/3 (33.3%) case. The single pediatric case was positive for b3a2 transcript. <strong>Discussion & Conclusion</strong>: All the 4 positive MPAL cases presented with high TLC and low platelet count (p<0.05). The positive cases also showed hematological remission at post induction check marrow (blasts<5%). This could partly be explained due to good response to the imatinib added to the treatment protocol.</p&gt

Bushfires and Mothers’ Mental Health in Pregnancy and Recent Post-Partum

Background: The compounding effects of climate change catastrophes such as bushfires and pandemics impose significant burden on individuals, societies, and their economies. The enduring effects of such syndemics on mental health remain poorly understood, particularly for at-risk populations (e.g., pregnant women and newborns). The aim of this study was to investigate the impact of direct and indirect exposure to the 2019/20 Australian Capital Territory and South-Eastern New South Wales bushfires followed by COVID-19 on the mental health and wellbeing of pregnant women and mothers with newborn babies. Methods: All women who were pregnant, had given birth, or were within three months of conceiving during the 2019/2020 bushfires, lived within the catchment area, and provided consent were invited to participate. Those who consented were asked to complete three online surveys. Mental health was assessed with the DASS-21 and the WHO-5. Bushfire, smoke, and COVID-19 exposures were assessed by self-report. Cross-sectional associations between exposures and mental health measures were tested with hierarchical regression models. Results: Of the women who participated, and had minimum data (n = 919), most (&gt;75%) reported at least one acute bushfire exposure and 63% reported severe smoke exposure. Compared to Australian norms, participants had higher depression (+12%), anxiety (+35%), and stress (+43%) scores. Women with greater exposure to bushfires/smoke but not COVID-19 had poorer scores on all mental health measures. Conclusions: These findings provide novel evidence that the mental health of pregnant women and mothers of newborn babies is vulnerable to major climate catastrophes such as bushfires.</p

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. METHODS: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). RESULTS: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). CONCLUSIONS: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. TRIAL REGISTRATION: NCT02145234, NCT02515669, NCT03039686

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI