Abstract Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51–2.18, P = 3.48×10 −10 ). Importantly, this signal remains despite conditioning on the lead class I and class II variants ( P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.
Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes. Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours. Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred. Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.
Cancer is one of the most complicated and prevalent diseases in the world, and its incidence is growing worldwide. Natural products containing pharmacological activity are widely used in the pharmaceutical industry, especially in anticancer drugs, due to their diverse structures and distinctive functional groups that inspire new drug results by means of synthetic chemistry. Terrestrial medicinal plants have traditionally been the primary source for developing natural products (NPs). However, over the past thirty years, marine organisms such as invertebrates, plants, algae, and bacteria have revealed many new pharmaceutical compounds known as marine NPs. This field constantly evolves as a discipline in molecular targeted drug discovery, incorporating advanced screening tools that have revolutionised and become integral to modern antitumor research. This review discusses recent studies on new natural anticancer alkaloids obtained from marine organisms. The paper illustrates the structure and origin of marine alkaloids and demonstrates the cytotoxic action of new alkaloids from several structural families and their synthetic analogs. The most recent findings about the potential or development of some of them as novel medications, together with the status of our understanding of their current mechanisms of action, are also compiled.
Background: Procalcitonin (PCT), an amino acid protein precursor of calcitonin hormone released by thyroid C cells or other body cells, can be used as a marker for diagnosing infection. PCT has a suggestive role in diagnosing diabetic foot infection alone or in combination with other markers of infection. Aim: We aimed to evaluate the roles of interleukin-6 (IL-6), CRP, and PCT levels in the differential diagnosis of the patients with infected diabetic foot ulcer (IDFU) and non-infected diabetic foot ulcer (NIDFU) and to compare those with C-reactive protein (CRP), white blood cell (WBC), and erythrocyte sedimentation rate (ESR). Methods: A total of 95 subjects with DFU and NIDFU were enrolled. WBC count, ESR, CRP, and PCT were done for all subjects at admission after obtaining informed consent. Patients over 18 years with a diagnosis of type 2 diabetes mellitus and DFU who were followed up in our hospital were included in the study. In addition to this patient group, patients with diabetes but without DFU were determined as the control group. Results: Twenty nine patients with IDFU, 29 patients with NIDFU, and 43 patients as the control group were included in the study. Fifty-six point three percent of the patients who participated in the study were males, and the mean age was 62.87 ± 10.99 years. WBC, ESR, CRP, and IL-6 levels of the cases with IDFU were determined to be significantly higher compared to the cases in NIDFU (p <0.001). The area under the ROC curve (AUROC) value was highest for CRP (p <0.001), and the best cut-off value for CRP was 36 m/L. The best cut-off values for IL-6, ESR, and WBC were 109.4 pg/mL, 53 mm/h, and 13.7 (103 μ/L), respectively. Conclusion: Serum PCT levels were not found to be effective in the discrimination of IDFU and NIDFU. Serum IL-6 level seems to be one promising inflammatory markers in the discrimination of IDFU. Based on our results, we conclude that PCT has a valuable role in diagnosing infection in DFUs.
Oxygen therapy has long become a cornerstone in the treatment of patients with chronic obstructive pulmonary diseases and other hypoxemic and hypercapnic chronic respiratory diseases. Studies have clearly shown benefits in terms of survival, improvement in dyspnea, exercise tolerance, and other associated conditions like pulmonary hypertension that arise due to the disease. However, guidelines regarding prescription of oxygen and to make choice of the delivery devices are not explicit. Furthermore, there still prevails a large unawareness and confusion among physicians to properly prescribe and advise patients about the use of oxygen for home therapy customized as per individual needs. The availability of several new oxygen delivery and conservation devices and techniques over the past few decades has provided a wide spectrum of options to be used in combinations or alone. This article retrospectively tries to review the studies, trials, and researches published so far in this field to give a broad idea based on consistent scientific evidence to help physicians frame their set of guidelines for prescribing long-term oxygen therapy.
Background: Haemodialysis (HD) patients are at an increased risk of Hepatitis C virus (HCV) infection, which is significantly associated with increased morbidity and mortality. This study was conducted to determine the prevalence of HCV infection among patients who were put on maintenance HD and its associated risk factors. Methods: A total of 145 patients (102 males and 43 females) were included in the study. The medical records were reviewed for details regarding history, age, sex, duration of dialysis, dialyzer reuse, blood transfusions, number of dialysis centers and other biochemical data. Results: Out of 145 patients 18 (12.4%) patients were found to be anti-HCV positive. The mean age of the HCV positive patients was 45.8 ± 13.9 years. There were 13 (72.2%) males in the HCV positive group and 89 (70.1%) males in the HCV negative group. The mean duration of the dialysis among HCV positive group was 36.6 ± 31.6 months, while it was 18.5 ± 21.2 months for HCV negative ones. The duration of dialysis was significantly longer in HCV positive patients (p = 0.002). Similarly, patients who had dialysis at more than one centre had a higher (55.56%) positivity, which was statistically significant (p = 0.001). Binary logistic regression analysis showed that the duration of dialysis and dialysis at more than one centre were the significant variables for increased positivity. Conclusion: The patients on HD had 12.4% positivity for antiHCV in our dialysis unit. Further, the present study demonstrated that the duration of haemodialysis and getting the dialysis done at more than one centre were the important risk factors for acquiring HCV infection in these patients.
Objective: To evaluate the usage pattern of glimepiride and metformin fixed-dose combinations (FDC) and to determine its efficacy and tolerability in Type 2 diabetes mellitus (T2DM) patients with established complications in Indian settings. Methods: This was a retrospective multi-centric ( n = 156), cross-sectional study. Patients of either sex, age above 18 years, who had developed microvascular and/or macrovascular complications receiving any strength of glimepiride and metformin FDC for the treatment of T2DM were included. Demographics, clinical characteristics, laboratory assessments, and adverse event profiles were retrieved from medical records. Results: A total of 470 patients with a mean age of 53.6 years were included. The majority of patients was obese (68.1%). Hypertension (58.7%) was the most common comorbidity, followed by dyslipidemia (36.0%). Macrovascular and microvascular complications were observed in 21.5% and 86.8% of patients, respectively. Among the available strengths, glimepiride 2 mg and metformin 500 mg FDC was most widely used in 30.2% of patients. Dosage up-titration was observed in 44.3% of patients. A significant improvement in glycemic parameters was observed posttreatment with glimepiride and metformin FDC ( P < 0.001). Physicians’ global evaluation of efficacy and tolerability showed a majority of patients on a good to excellent scale (96.0% and 93.1%). Conclusion: Glimepiride and metformin FDCs have been extensively studied and found to be safe and effective in improving glycemic control with minimal risk of hypoglycemic events and weight gain in T2DM patients with established complications in Indian settings.
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