Depression, Anxiety and Glucose Metabolism in the General Dutch Population: The New Hoorn Study

BACKGROUND: There is a well recognized association between depression and diabetes. However, there is little empirical data about the prevalence of depressive symptoms and anxiety among different groups of glucose metabolism in population based samples. The aim of this study was to determine whether the prevalence of increased levels of depression and anxiety is different between patients with type 2 diabetes and subjects with impaired glucose metabolism (IGM) and normal glucose metabolism (NGM). METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional data from a population-based cohort study of 2667 residents, 1261 men and 1406 women aged 40-65 years from the Hoorn region, the Netherlands. Depressive symptoms and anxiety were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D, score >or=16) and the Hospital Anxiety and Depression Scale--Anxiety Subscale (HADS-A, score >or=8), respectively. Glucose metabolism status was determined by oral glucose tolerance test. In the total study population the prevalence of depressive symptoms and anxiety for the NGM, IGM and type 2 diabetes were 12.5, 12.2 and 21.0% (P = 0.004) and 15.0, 15.3 and 19.9% (p = 0.216), respectively. In men, the prevalence of depressive symptoms was 7.7, 9.5 and 19.6% (p<0.001), and in women 16.4, 15.8 and 22.6 (p = 0.318), for participants with NGM, IGM and type 2 diabetes, respectively. Anxiety was not associated with glucose metabolism when stratified for sex. Intergroup differences (NGM vs. IGM and IGM vs. type 2 diabetes) revealed that higher prevalences of depressive symptoms are mainly manifested in participants with type 2 diabetes, and not in participants with IGM. CONCLUSIONS: Depressive symptoms, but not anxiety are associated with glucose metabolism. This association is mainly determined by a higher prevalence of depressive symptoms in participants with type 2 diabetes and not in participants with IGM

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells

Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance

Logistic regression with depression (CES-D ≥16) as the outcome, inclusive of unadjusted models and models adjusted for confounding factors in the total population.

<p>Abbreviations: NGM, normal glucose metabolism; IGM, impaired glucose metabolism; DM2, type 2 diabetes (WHO 2006 criteria).</p><p>*Denotes reference category.</p

Prevalence and mean scores of depressive symptoms and anxiety by glucose metabolism status for the total study population and stratified according to sex.

<p>Data are %, means ± SD. P  =  p-values based on one-way ANOVA for continuous variables and χ²-tests for categorical variables. ^a significantly different comparing IGM vs. DM2. Abbreviations: NGM, normal glucose metabolism; IGM, impaired glucose metabolism; DM2, type 2 diabetes; SD, standard deviation; HADS-A. Hospital Anxiety and Depression Scale – Anxiety Subscale; CES-D, Center for Epidemiologic Studies Depression Scale.</p

Odds ratios for depression (CES-D score ≥16) and anxiety (HADS-A ≥16) by sex with impaired glucose metabolism or type 2 diabetes subjects compared with normal glucose metabolism subjects.

<p>Abbreviations: NGM, normal glucose metabolism; IGM, impaired glucose metabolism; DM2, type 2 diabetes (WHO 2006 criteria).</p>*<p>The unadjusted odds ratios.</p>§<p>Model 1: Adjusted for age, education and family history of diabetes.</p>¶<p>Model 2: Adjusted for Model 1 and triglycerides, HDL cholesterol, and total cholesterol.</p>†<p>Model 3. Adjusted for Model 2 and, hypertension, smoking and waist circumference.</p

What do we need to know to enhance the environmental sustainability of agricultural production?: a prioritisation of knowledge needs for the UK food system

Increasing concerns about global environmental change and food security have focused attention on the need for environmentally sustainable agriculture. This is agriculture that makes efficient use of natural resources and does not degrade the environmental systems that underpin it, or deplete natural capital stocks. We convened a group of 29 ‘practitioners’ and 17 environmental scientists with direct involvement or expertise in the environmental sustainability of agriculture. The practitioners included representatives from UK industry, non-government organizations and government agencies. We collaboratively developed a long list of 264 knowledge needs to help enhance the environmental sustainability of agriculture within the UK or for the UK market. We refined and selected the most important knowledge needs through a three-stage process of voting, discussion and scoring. Scientists and practitioners identified similar priorities. We present the 26 highest priority knowledge needs. Many of them demand integration of knowledge from different disciplines to inform policy and practice. The top five are about sustainability of livestock feed, trade-offs between ecosystem services at farm or landscape scale, phosphorus recycling and metrics to measure sustainability. The outcomes will be used to guide on-going knowledge exchange work, future science policy and funding

Toward Optimizing Risk Adjustment in the Dutch Surgical Aneurysm Audit

Background: To compare hospital outcomes of aortic aneurysm surgery, casemix correction for preoperative variables is essential. Most of these variables can be deduced from mortality risk prediction models. Our aim was to identify the optimal set of preoperative variables associated with mortality to establish a relevant and efficient casemix model. Methods: All patients prospectively registered between 2013 and 2016 in the Dutch Surgical Aneurysm Audit (DSAA) were included for the analysis. After multiple imputation for missing variables, predictors for mortality following univariable logistic regression were analyzed in a manual backward multivariable logistic regression model and compared with three standard mortality risk prediction models: Glasgow Aneurysm Score (GAS, mainly clinical parameters), Vascular Biochemical and Haematological Outcome Model (VBHOM, mainly laboratory parameters), and Dutch Aneurysm Score (DAS, both clinical and laboratory parameters). Discrimination and calibration were tested and considered good with a C-statistic > 0.8 and Hosmer-Lemeshow (H-L) P > 0.05. Results: There were 12,401 patients: 9,537 (76.9%) elective patients (EAAA), 913 (7.4%) acute symptomatic patients (SAAA), and 1,951 (15.7%) patients with acute rupture (RAAA). Overall postoperative mortality was 6.5%; 1.8% after EAAA surgery, 6.6% after SAAA, and 29.6% after RAAA surgery. The optimal set of independent variables associated with mortality was a mix of clinical and laboratory parameters: gender, age, pulmonary comorbidity, operative setting, creatinine, aneurysm size, hemoglobin, Glasgow coma scale, electrocardiography, and systolic blood pressure (C-statistic 0.871). External validation overall of VBHOM, DAS, and GAS revealed C-statistics of 0.836, 0.782, and 0.761, with an H-L of 0.028, 0.00, and 0.128, respectively. Conclusions: The optimal set of variables for casemix correction in the DSAA comprises both clinical and laboratory parameters, which can be collected easily from electronic patient files and will lead to an efficient casemix model