Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile

From Wiley via Jisc Publications RouterHistory: received 2020-07-23, rev-recd 2021-01-18, accepted 2021-01-21, pub-electronic 2021-02-11, pub-print 2021-09Article version: VoRPublication status: PublishedFunder: Diabetes UK; Id: http://dx.doi.org/10.13039/501100000361; Grant(s): 17/0005594Funder: European Research Council; Grant(s): 323195Abstract: Aims: Change in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. Methods: We involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals. Results: The ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (−0.04 mmol/L [−0.07, −0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up. There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86, 0.97]) and anti‐hypertensive medication (0.95 [0.91, 0.99]). Conclusions: In individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

First- and last-year medical students: is there a difference in the prevalence and intensity of anxiety and depressive symptoms?

Objective: Medical training is considered a significant stress factor. We sought to assess the prevalence and intensity of anxiety and depressive symptoms in medical students and compare samples of first-year and sixth-year students. Method: This was a cross-sectional study of first- and sixth-year medical students who attended classes regularly. The study instruments were a sociodemographic questionnaire, the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). Results: A total of 232 students (110 first-year, 122 sixth-year) completed the questionnaires, for a response rate of 67.4%. Overall 50.4% of respondents were male (56.4% of first-year and 45.1% of sixth-year students). Anxiety symptoms were reported by 30.8% of first-year students and 9.4% of sixth-year students (p < 0.001). Female students were more affected by anxiety. There were no significant between-group differences in depressive symptoms. Conclusion: A higher prevalence of anxiety symptoms was found in first-year medical students as compared with sixth-year students. Strategies should be developed to help medical students, particularly female students, manage these symptoms at the beginning of their medical training

Duration of anti-tuberculosis therapy and timing of antiretroviral therapy initiation: association with mortality in HIV-related tuberculosis.

Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear.We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended.Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm(3), 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti-tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007).The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated

Characteristics of the Study Population.

<p>HIV-infected persons who initiated antiretroviral therapy (ART), received rifamycin-based anti-tuberculosis therapy while on ART, and did not have tuberculosis at a site of disease that required extended therapy (e g, central nervous system, bone/joint, or pericardium).</p><p>Parentheses include percentages unless otherwise noted.</p><p>TB: tuberculosis</p><p>Baseline CD4+ lymphocyte and HIV-1 RNA measurements were at the time of ART initiation.</p><p>* The proportions of all persons at each study site with TB (the row percentages)—were as follows:</p><p>Argentina: 3%; Brazil: 7%; Chile: 4%; Honduras: 9%; Mexico: 4%; Peru: 16%</p><p>^ Median (IQR) values before tuberculosis diagnosis: 74 (34-191)</p><p># Median (IQR values before tuberculosis diagnosis: 4.4 log₁₀ (2.6-5.2)</p

Baseline and Treatment Characteristics of the 253 Tuberculosis Patients Included in the Study, According to Length of Follow-up/Survival and Duration of Anti-tuberculosis Therapy.

<p>Data are presented as number (%) except as shown.</p><p>P-values are for the comparison of all 4 groups, using the chi-squared test.</p><p>* the comparison limited to persons with > 6 months of follow-up and known TB treatment duration (the two inner columns) was not statistically significant. If not noted by * the statistical significance of the comparison between these two groups was similar to that of all 4 groups.</p><p>=Data available for 222 patients.</p><p>^ Data available for 222 patients.</p><p># Data available for 171 patients.</p><p>+ Data available for 228 patients.</p><p>a median time between TB diagnosis and ART start: 95 days (IQR: 53, 142)</p><p>b median time between ART start and TB diagnosis: 142 days (IQR: 30, 568)</p