Endocrinology in the time of covid-19: A rapid evolution of knowledge and care

American singer-writer and visual artist Bob Dylan produced the song "The Times They Are a-Changin" in the 1960s, which became a rallying cry for the civil rights and anti-war movements in that decade [...]

Non-alcoholic fatty liver disease: relationship with cardiovascular risk markers and clinical endpoints

Non-alcoholic fatty liver disease (NAFLD) is a common diagnosis and is increasing in prevalence worldwide. NAFLD is usually asymptomatic at presentation; progression of the disease is unpredictable, leading to the development of a variety of techniques for screening, diagnosis and risk stratification. Clinical methods in current use include serum biomarker panels, hepatic ultrasound, magnetic resonance imaging, and liver biopsy. NAFLD is strongly associated with the metabolic syndrome, and the most common cause of death for people with the condition is cardiovascular disease. Whether NAFLD is an independent cardiovascular risk factor needs exploration. NAFLD has been associated with surrogate markers of cardiovascular disease such as carotid intima-media thickness, the presence of carotid plaque, brachial artery vasodilatory responsiveness and CT coronary artery calcification score. There is no effective medical treatment for NAFLD and evidence is lacking regarding the efficacy of interventions in mitigating cardiovascular risk. Health care professionals managing patients with NAFLD should tackle the issue with early identification of risk factors and aggressive modification. Current management strategies therefore comprise lifestyle change,with close attention to known cardiovascular risk factors

Secondary analyses of global datasets: do obesity and physical activity explain variation in diabetes risk across populations?

Copyright © 2021 The Author(s). Type 2 diabetes rates vary significantly across geographic regions. These differences are sometimes assumed to be entirely driven by differential distribution of environmental triggers, including obesity and insufficient physical activity (IPA). In this review, we discuss data which conflicts with this supposition. We carried out a secondary analysis of publicly available data to unravel the relative contribution of obesity and IPA towards diabetes risk across different populations. We used sex-specific, age-standardized estimates from Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) on diabetes (1980–2014) and obesity (1975–2016) rates, in 200 countries, and from WHO on IPA rates in 168 countries in the year 2016. NCD-RisC and WHO organized countries into nine super-regions. All analyses were region- and sex-specific. Although obesity has been increasing since 1975 in every part of the world, this was not reflected in a proportional increase in diabetes rates in several regions, including Central and Eastern Europe, and High-income western countries region. Similarly, the association of physical inactivity with diabetes is not homogeneous across regions. Countries from different regions across the world could have very similar rates of diabetes, despite falling on opposite ends of IPA rate spectrum. The combined effect of obesity and IPA on diabetes risk was analyzed at the worldwide and country level. The overall findings highlighted the larger impact of obesity on disease risk; low IPA rates do not seem to be protective of diabetes, when obesity rates are high. Despite that, some countries deviate from this overall observation. Sex differences were observed across all our analyses. Overall, data presented in this review indicate that different populations, while experiencing similar environmental shifts, are apparently differentially subject to diabetes risk. Sex-related differences observed suggest that males and females are either subject to different risk factor exposures or have different responses to them.The work presented in this paper is part of a PhD project by the first author (Budour Alkaf); internal funding by Imperial College London Diabetes Centre is gratefully acknowledged. The authors are also grateful for The Medical Research Council, UK (grant numbers: MR/M013138/1, MRC/BBSRC MR/S03658X/1 (JPI HDHL H2020)) for their financial support during the authors time when conducting this piece of work and writing this paper

Oligogenic inheritance in severe adult obesity

Background/objective The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance. Methods Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service. Results We identified an oligogenic mode of inheritance of obesity in the proband’s family—this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance. Conclusion Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found

Ramadan fasting and changes in thyroid function in hypothyroidism: identifying patients at risk

Background: Ramadan fasting (RF) is associated with major changes in meal times. This can affect thyroxine absorption and thyroid function (TF) in patients with hypothyroidism. We aimed to examine the short- and long-term impact of RF on TF in patients with primary hypothyroidism on levothyroxine. Methods: TF tests in patients with primary hypothyroidism attending an endocrine center in the United Arab Emirates were retrospectively analyzed. The impact of RF on TF, namely serum thyrotropin (TSH) TSH, free thyroxine (fT4) and free triiodothyronine (fT3), was investigated in 481 patients within 3 months before Ramadan (BR), 1–2 weeks (PR1), and 3–6 months (PR2) post-Ramadan. Controlled TF was defined as TSH between 0.45 and 4.5 μIU/mL. Inadequate control was defined as TSH >4.5 μIU/mL. Loss of control was defined as having controlled TF at BR and inadequate control at PR1. Multivariable regression analyses were used to assess the association of baseline TSH, baseline levothyroxine dose, and medication use with loss of thyroid control in Ramadan. Results: TSH increased significantly from a median of 2.0 (0.8–3.7) μIU/mL at BR to 2.9 (1.4–5.6) μIU/mL at PR1 (p < 0.001). This was accompanied by a fall in fT4 and fT3 at PR1 (p < 0.001). 25.5% of patients with previously controlled TF at BR had deterioration in TF at PR1. Sixty-one percent of patients with previously uncontrolled TF at BR remained uncontrolled at PR1. Baseline TSH was significantly associated with loss of thyroid control in Ramadan with an odds ratio (95% confidence interval) of 1.5 (1.17–1.92) (p < 0.001), whereas other variables, including medications known to affect levothyroxine absorption were not associated with loss of control. TSH, fT4, and fT3 levels returned to normal at PR2. Conclusions: RF can negatively affect TF of patients on levothyroxine replacement. Although this effect is modest and transitory in most patients, a significant minority exhibit more pronounced, and clinically relevant changes. The latter includes those with higher TSH BR, and a smaller group whose thyroid disease appears to be particularly affected by the mealtime and lifestyle changes of Ramadan

Risk factors for delayed graft function in deceased donor kidney transplantation; A potential preventive role for intraoperative thymoglobulin

Introduction: Delayed graft function (DGF) is associated with significant adverse outcomes in deceased donor kidney transplantation (KT) including lower graft survival. However, risk factors and potential preventive strategies like intraoperative rabbit antithymocyte globulin (rATG; thymoglobulin) have not yet been fully evaluated. Objectives: The aim of this study was to investigate DGF risk factors and determine the association of intraoperative rATG with the risk of DGF in deceased donor kidney recipients. Patients and Methods: We retrospectively examined medical records of 163 first time deceased donor kidney transplant recipients at two major kidney transplant centers from 2014 to 2016. All the donors were standard heart-beating, brain death donors. Risk factors for DGF in recipients were evaluated using multivariate logistic regression analysis. Results: The mean recipients' age was 43±13 years and the majority of participants were male (64). The overall rate of DGF was 27. Intraoperative rATG was significantly associated with a lower rate of DGF (adjusted odds ratio AOR, 0.33, 95% CI, 0.11-0.95). Intraoperative transfusion (AOR, 3.7, 95% CI, 1.4-9.9) and diabetes mellitus (AOR, 3.7, 95% CI, 1.5-8.9) were significantly associated with higher risk of DGF. Conclusion: This study showed that intraoperative blood transfusion and diabetes mellitus were associated with increased risk of DGF. Meanwhile, administration of intraoperative rATG was associated with reduced odds ratio of DGF. Future studies are needed to evaluate the potential role of rATG in DGF-related renal outcomes. © 2019 The Author(s)

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of α6 integrin, without any change in the expression of αv, β1 and β4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of α6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of α6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against α6 and β1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas

Energy expenditure and obesity across the economic spectrum.

Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development

Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20–60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested