Dietary Glycemic Load and Glycemic Index and Risk of Coronary Heart Disease and Stroke in Dutch Men and Women: The EPIC-MORGEN Study

BACKGROUND: The associations of glycemic load (GL) and glycemic index (GI) with the risk of cardiovascular diseases (CVD) are not well-established, particularly in men, and may be modified by gender. OBJECTIVE: To assess whether high dietary GL and GI increase the risk of CVD in men and women. METHODS: A large prospective cohort study (EPIC-MORGEN) was conducted within the general Dutch population among 8,855 men and 10,753 women, aged 21-64 years at baseline (1993-1997) and free of diabetes and CVD. Dietary intake was assessed with a validated food-frequency questionnaire and GI and GL were calculated using Foster-Powell's international table of GI. Information on morbidity and mortality was obtained through linkage with national registries. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) for incident coronary heart disease (CHD) and stroke, while adjusting for age, CVD risk factors, and dietary factors. RESULTS: During a mean follow-up of 11.9 years, 581 CHD cases and 120 stroke cases occurred among men, and 300 CHD cases and 109 stroke cases occurred among women. In men, GL was associated with an increased CHD risk (adjusted HR per SD increase, 1.17 [95% CI, 1.02-1.35]), while no significant association was found in women (1.09 [0.89-1.33]). GI was not associated with CHD risk in both genders, while it was associated with increased stroke risk in men (1.27 [1.02-1.58]) but not in women (0.96 [0.75-1.22]). Similarly, total carbohydrate intake and starch intake were associated with a higher CHD risk in men (1.23 [1.04-1.46]; and 1.24 [1.07-1.45]), but not in women. CONCLUSION: Among men, high GL and GI, and high carbohydrate and starch intake, were associated with increased risk of CVD

Cognitive Behavioral Therapy Versus Usual Care Before Bariatric Surgery:One-Year Follow-Up Results of a Randomized Controlled Trial

Background Although early results of bariatric surgery are beneficial for most patients, some patients regain weight later. Cognitive behavioral therapy (CBT) has been suggested as a way to improve patients' psychological health and maintaining weight loss in the longer term. The added value of preoperative CBT to bariatric surgery was examined. Pre- and posttreatment and 1-year follow-up data are presented. Methods In a multi-center randomized controlled trial, CBT was compared to a treatment-as-usual (TAU) control group. Measurements were conducted pre- and posttreatment/pre-surgery (T0 and T1) and at 1-year post-surgery (T2). Patients in the intervention group received 10 individual, weekly sessions of preoperative CBT focused on modifying thoughts and behaviors regarding eating behavior, physical exercise, and postoperative life style. Outcome measures included weight change, eating behavior, eating disorders, depression, quality of life, and overall psychological health. Results Though no significant differences between conditions were found per time point, in the CBT, condition scores on external eating, emotional eating, depressive symptoms, and psychological distress decreased significantly more over time between pre- (T0) and posttreatment (T1) pre-surgery compared to TAU. No significant time x condition differences were found at 1-year post-surgery (T2). Conclusions Compared to TAU, preoperative CBT showed beneficial effects on eating behavior and psychological symptoms only from pretreatment to posttreatment/pre-surgery, but not from pre-surgery to 1-year post-surgery. Preoperative CBT does not seem to contribute to better long-term outcomes post-surgery. Recent studies suggest that the optimal time to initiate psychological treatment may be early in the postoperative period, before significant weight regain has occurred

Liver function tests and risk prediction of incident type 2 diabetes:evaluation in two independent cohorts

BACKGROUND: Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking. METHODS AND FINDINGS: We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by~0.020; NRI by~9.0%; P<0.001). In the EPIC-NL case-cohort study, addition to clinical model1 resulted in statistically significant improvement in the overall population (C-statistic = +0.009; P<0.001; NRI = 8.8%; P<0.001), while addition to clinical model 2 yielded marginal improvement limited to men (C-statistic = +0.007; P = 0.06; NRI = 3.3%; P = 0.04). In the PREVEND cohort study, addition to clinical model 1 resulted in significant improvement in the overall population (C-statistic change = 0.008; P = 0.003; NRI = 3.6%; P = 0.03), with largest improvement in men (C-statistic change = 0.013; P = 0.01; NRI = 5.4%; P = 0.04). In PREVEND, improvement compared to clinical model 2 could not be tested because of lack of HbA1c data. CONCLUSIONS: Liver function tests modestly improve prediction for medium-term risk of incident diabetes above basic and extended clinical prediction models, only if no HbA1c is incorporated. If data on HbA1c are available, Liver function tests have little incremental predictive value, although a small benefit may be present in men

Tumor-specific mutations in low-frequency genes affect their functional properties

Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole-genome sequencing identified a total of 55 coding mutations (range 8–32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type

Catecholamine-mediated increases in neural gain improve the precision of cortical representations

Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations

Rapid and Sustained Effect of Dupilumab on Work Productivity in Patients with Difficult-to-treat Atopic Dermatitis:Results from the Dutch BioDay Registry

Dupilumab treatment improves signs, symptoms, and quality of life in patients with moderate-to-severe atopic dermatitis. This study evaluated the impact of dupilumab treatment on absenteeism, presenteeism, and related costs in a large multi-centre cohort of adult patients with difficult-to-treat atopic dermatitis in daily practice. Patients treated with dupilumab participating in the Dutch BioDay Registry reporting employment were included. Absenteeism, presenteeism, and related costs at baseline and during follow-up were calculated using the Work Productivity and Activity Impairment questionnaire. A total of 218 adult patients with moderate-to-severe atopic dermatitis were included. Total work impairment reduced significantly from baseline (35.5%) to week 52 (11.5%), p &lt; 0.001. Median weekly productivity losses reduced significantly from baseline (€379.8 (140.7-780.8)) to week 52 (€0.0 (0.0-211.0), p &lt; 0.001). In this study, dupilumab treatment demonstrated a significant improvement in work productivity and reduction in associated costs in a large cohort of patients with difficult-to-treat atopic dermatitis in daily practice.</p

Trend in Obesity Prevalence in European Adult Cohort Populations during Follow-up since 1996 and Their Predictions to 2015

To investigate trends in obesity prevalence in recent years and to predict the obesity prevalence in 2015 in European populations.Data of 97,942 participants from seven cohorts involved in the European Prospective Investigation into Cancer and Nutrition (EPIC) study participating in the Diogenes project (named as "Diogenes cohort" in the following) with weight measurements at baseline and follow-up were used to predict future obesity prevalence with logistic linear and non-linear (leveling off) regression models. In addition, linear and leveling off models were fitted to the EPIC-Potsdam dataset with five weight measures during the observation period to find out which of these two models might provide the more realistic prediction.During a mean follow-up period of 6 years, the obesity prevalence in the Diogenes cohort increased from 13% to 17%. The linear prediction model predicted an overall obesity prevalence of about 30% in 2015, whereas the leveling off model predicted a prevalence of about 20%. In the EPIC-Potsdam cohort, the shape of obesity trend favors a leveling off model among men (R²  = 0.98), and a linear model among women (R² = 0.99).Our data show an increase in obesity prevalence since the 1990ies, and predictions by 2015 suggests a sizeable further increase in European populations. However, the estimates from the leveling off model were considerably lower

Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay