Drosophila DAxud1 Has a Repressive Transcription Activity on Hsp70 and Other Heat Shock Genes.

Drosophila melanogaster DAxud1 is a transcription factor that belongs to the Cysteine Serine Rich Nuclear Protein (CSRNP) family, conserved in metazoans, with a transcriptional transactivation activity. According to previous studies, this protein promotes apoptosis and Wnt signaling-mediated neural crest differentiation in vertebrates. However, no analysis has been conducted to determine what other genes it might control, especially in connection with cell survival and apoptosis. To partly answer this question, this work analyzes the role of Drosophila DAxud1 using Targeted-DamID-seq (TaDa-seq), which allows whole genome screening to determine in which regions it is most frequently found. This analysis confirmed the presence of DAxud1 in groups of pro-apoptotic and Wnt pathway genes, as previously described; furthermore, stress resistance genes that coding heat shock protein (HSP) family genes were found as hsp70, hsp67, and hsp26. The enrichment of DAxud1 also identified a DNA-binding motif (AYATACATAYATA) that is frequently found in the promoters of these genes. Surprisingly, the following analyses demonstrated that DAxud1 exerts a repressive role on these genes, which are necessary for cell survival. This is coupled with the pro-apoptotic and cell cycle arrest roles of DAxud1, in which repression of hsp70 complements the maintenance of tissue homeostasis through cell survival modulation.

Low-Dose ACTH Stimulation Test in Obesity: A Randomized Dose Assessment.

Background: The short cosyntropin test is widely used for adrenal insufficiency screening and diagnosis. Lower cosyntropin doses may have greater sensitivity vs. the standard dose in detecting adrenal dysfunction. Obesity and overweight are increasing, impacting the clinical presentation of some diseases. Currently more than 50% of the subjects diagnosed with autoimmune adrenal insufficiency have a BMI greater than 25, and hence individuals living with overweight and obesity are more frequently requiring evaluation of the adrenal cortical function. Fixed-dose cosyntropin stimulation may not be appropriate for individuals with obesity. Objective: The primary objective was to compare cortisol response to a weight-adapted cosyntropin dose vs. a fixed low dose (1 µg) and a more physiologically fixed dose (10 µg). Methods: Twenty individuals with obesity and 20 age-matched healthy controls underwent in a randomized sequence at least one-week apart, to the The short cosyntropin test with three different doses, 0.2 µg/kg of body weight, 1 or 10 µg fixed dose stimuli. The assessment and data analysis were blinded to the individual and the investigator. Results: Cortisol response was reduced in the group with obesity with the 1 µg fixed dose stimuli at 30 minutes (median, IQR) 649.6 µg, 567.3-738.4 µg for the control group vs. 568.6 µg, 528.4-623.13 µg, p=0.04; there was a lower cortisol peak at 60' in all the three evaluated doses, with a dose-dependent trend. A weight-adapted cosyntropin dose of 0.2 µg in obesity produces a similar response to the one observed in individuals without obesity. The 1 µg ACTH test falls short on stimulating the cortisol adrenal response in individuals with obesity.

Trends of sources of clinical research funding from 1990 to 2020: a meta-epidemiological study.

Evidence has raised concerns regarding the association between funding sources and doubtful data. Our main outcome was to analyze trends on funding sources in articles published from 1990 to 2020 in the more influential journals of internal and general medicine. In this meta-epidemiological study, we included peer-reviewed studies from the 10 highest impact journals in general and internal medicine published between January 1990 and February 2020 based on published original research according to the 2018 InCites Journal of Citation Reports, these consisted of the following: The New England Journal of Medicine, The Lancet, JAMA, BMJ, JAMA Internal Medicine, Annals of Internal Medicine, PLOS Medicine, Cachexia, BMC Medicine, and Mayo Clinic Proceedings Two reviewers working in duplicate extracted data regarding year of publication, study design, and sources of funding. In total, 496 articles were found; of these, 311 (62.7%) were observational studies, 167 (33.7%) were experimental, and 16 (3.2%) were secondary analyses. Percentages of grant sources through the years were predominantly from government (60%), industry (23.83%), and non-governmental (16.06%) organizations. The percentage of industry subsidies tended to decrease, but this was not significant in a linear regression model (r=0.02, p≥0.05). Government and non-government funding sources showed a trend to decrease in the same univariate analysis with both significant associations (r=0.21, p≤0.001 and r=0.10, p≤0.001, respectively). The main funding source in medical research has consistently been government aid. Despite previous reported data, no association was found between the source of funding and statistically significant results favoring study authors' hypothesis.

Benefits and harms of intensive glycemic control in patients with type 2 diabetes.

Diabetes is a major and costly health concern worldwide, with high morbidity, disability, mortality, and impaired quality of life. The vast majority of people living with diabetes have type 2 diabetes. Historically, the main strategy to reduce complications of type 2 diabetes has been intensive glycemic control. However, the body of evidence shows no meaningful benefit of intensive (compared with moderate) glycemic control for microvascular and macrovascular outcomes important to patients, with the exception of reduced rates of non-fatal myocardial infarction. Intensive glycemic control does, however, increase the risk of severe hypoglycemia and incurs additional burden by way of polypharmacy, side effects, and cost. Additionally, data from cardiovascular outcomes trials showed that cardiovascular, kidney, and mortality outcomes may be improved with use of specific classes of glucose lowering drugs largely independently of their glycemic effects. Therefore, delivering evidence based, patient centered care to people with type 2 diabetes requires a paradigm shift and departure from the predominantly glucocentric view of diabetes management. Instead of prioritizing intensive glycemic control, the focus needs to be on ensuring access to adequate diabetes care, aligning glycemic targets to patients' goals and situations, minimizing short term and long term complications, reducing the burden of treatment, and improving quality of life.

Endorsement of reporting guidelines and study registration by endocrine and internal medicine journals: meta-epidemiological study.

OBJECTIVES: To improve the trustworthiness of evidence, studies should be prospectively registered and research reports should adhere to existing standards. We aimed to systematically assess the degree to which endocrinology and internal medicine journals endorse study registration and reporting standards for randomised controlled trials (RCTs), systematic reviews (SRs) and observational studies (ObS). Additionally, we evaluated characteristics that predict endorsement of reporting or registration mechanism by these journals. DESIGN: Meta-epidemiological study. SETTING: Journals included in the 'Endocrinology and Metabolism' and 'General and Internal Medicine' 2017 Journal Citation Reports. PARTICIPANTS: Journals with an impact factor of ≥1.0, focused on clinical medicine, and those who publish RCTs, SRs and ObS were included. PRIMARY OUTCOMES: Requirement of adherence to reporting guideline and study registration as determined from the journals' author instructions. RESULTS: Of the 170 (82 endocrinology and 88 internal medicine) eligible journals, endorsing of reporting standards was the highest for RCTs, with 35 (43%) of endocrine journals and 55 (63%) of internal medicine journals followed by SRs, with 21 (26%) and 48 (55%), respectively, and lastly, by ObS with 41 (50%) of endocrine journals and 21 (24%) of internal medicine journals. In 78 (46%) journals RCTs were required to be registered and published in adherence to the Consolidated Standards of Reporting Trials statement. Only 11 (6%) journals required registration of SRs. Internal medicine journals were more likely to endorse reporting guidelines than endocrine journals except for Strengthening the Reporting of Observational Studies in Epidemiology. No other journal characteristic proved to be an independent predictor of reporting standard endorsement for RCTs besides trial registration. CONCLUSION: Our results highlight that study registration requirement and reporting guideline endorsement are suboptimal in internal medicine and endocrine journals. This malpractice may be further enhanced since endorsement does not imply enforcement, impairing the practice of evidence-based medicine.