Recent developments on the role of epigenetics in obesity and metabolic disease

The increased prevalence of obesity and related comorbidities is a major public health problem. While genetic factors undoubtedly play a role in determining individual susceptibility to weight gain and obesity, the identified genetic variants only explain part of the variation. This has led to growing interest in understanding the potential role of epigenetics as a mediator of gene-environment interactions underlying the development of obesity and its associated comorbidities. Initial evidence in support of a role of epigenetics in obesity and type 2 diabetes mellitus (T2DM) was mainly provided by animal studies, which reported epigenetic changes in key metabolically important tissues following high-fat feeding and epigenetic differences between lean and obese animals and by human studies which showed epigenetic changes in obesity and T2DM candidate genes in obese/diabetic individuals. More recently, advances in epigenetic methodologies and the reduced cost of epigenome-wide association studies (EWAS) have led to a rapid expansion of studies in human populations. These studies have also reported epigenetic differences between obese/T2DM adults and healthy controls and epigenetic changes in association with nutritional, weight loss, and exercise interventions. There is also increasing evidence from both human and animal studies that the relationship between perinatal nutritional exposures and later risk of obesity and T2DM may be mediated by epigenetic changes in the offspring. The aim of this review is to summarize the most recent developments in this rapidly moving field, with a particular focus on human EWAS and studies investigating the impact of nutritional and lifestyle factors (both pre- and postnatal) on the epigenome and their relationship to metabolic health outcomes. The difficulties in distinguishing consequence from causality in these studies and the critical role of animal models for testing causal relationships and providing insight into underlying mechanisms are also addressed. In summary, the area of epigenetics and metabolic health has seen rapid developments in a short space of time. While the outcomes to date are promising, studies are ongoing, and the next decade promises to be a time of productive research into the complex interactions between the genome, epigenome, and environment as they relate to metabolic disease.Susan J. van Dijk, Ross L. Tellam, Janna L. Morrison, Beverly S. Muhlhausler, and Peter L. Mollo

Triangulation and child adjustment after parental divorce: Underlying mechanisms and risk factors.

Parental triangulation is a particular risk to healthy child adjustment after divorce. However, detailed knowledge is lacking on how triangulation predicts child adjustment, and whether some children are more vulnerable to triangulation’s effects. Therefore, the present study used a sample of 135 children (Mage = 11.76) and 130 parents from 77 recently divorced families to identify whether intrapersonal processes (loyalty conflicts, self-blame, and self-esteem) underlie the link between postdivorce triangulation and child adjustment over a period of 2 years. We also explored whether these direct and indirect effects were dependent on children’s environmental sensitivity and empathy. By means of path analysis in MPlus, the mediation analyses indicated that more triangulation was only indirectly associated with a relative increase in children’s internalizing problems, via experiencing more loyalty conflicts and lower self-esteem. Loyalty conflicts also explained the link between triangulation and children’s externalizing problems. Yet, there were no indirect effects via children’s self-blame attributions. Second, moderation analyses revealed that the effect of triangulation was dependent on children’s level of empathy, but not sensitivity. Children scoring high on empathy showed a stronger association between triangulation and child-reported adjustment problems, both directly and indirectly via loyalty conflicts and self-esteem. There were hardly any significant effects for parent-reported child adjustment. Overall, the present study calls for more awareness on the adversity of postdivorce triangulation for children, its working mechanisms, and the factors that make children more vulnerable to its detrimental effects

Two-year effectiveness of a stepped-care depression prevention intervention and predictors of incident depression in primary care patients with diabetes type 2 and/or coronary heart disease and subthreshold depression; data from the Step-Dep cluster randomized controlled trial

Introduction Major depressive disorders (MDD), diabetes mellitus type 2 (DM2) and coronary heart disease (CHD) are leading contributors to the global burden of disease and often co-occur. Objectives To evaluate the two-year effectiveness of a stepped-care intervention to prevent MDD compared to usual care and to develop a prediction model for incident depression in DM2 and/or CHD patients with subthreshold depression. Methods Data of 236 Dutch primary care DM2/CHD patients with subthreshold depression (Patient Health Questionnaire 9 (PHQ-9) score ≥6, no current MDD according to the Mini International Neuropsychiatric Interview (DSM-IV criteria)), who participated in the Step-Dep trial were used. A PHQ-9 score of ≥10 at minimally one measurement during follow-up (at 3, 6, 9, 12 and 24 months) was used to determine the cumulative incidence of MDD. Potential demographic and psychological predictors were measured at baseline via web-based self-reported questionnaires and evaluated using a multivariable logistic regression model. Model performance was assessed with the Hosmer–Lemeshow test, Nagelkerke’s R2 explained variance and Area Under the Receiver Operating Characteristic curve (AUC). Bootstrapping techniques were used to internally validate our model. Results 192 patients (81%) were available at two-year follow-up. The cumulative incidence of MDD was 97/192 (51%). There was no statistically significant overall treatment effect over 24 months of the intervention (OR 1.37; 95% CI 0.52; 3.55). Baseline levels of anxiety, depression, the presence of >3 chronic diseases and stressful life-events predicted the incidence of MDD (AUC 0.80 interquartile range (IQR) 0.79-0.80; Nagelkerke’s R2 0.34 IQR 0.33-0.36). Conclusion A model with four factors predicted depression incidence during two-year follow-up in patients with DM2/CHD accurately, based on the AUC. The Step-Dep intervention did not influence the incidence of MDD. Future depression prevention programs should target patients with these four predictors present, and aim to reduce both anxiety and depressive symptoms

Cortical depth dependent population receptive field attraction by spatial attention in human V1

Visual spatial attention concentrates neural resources at the attended location. Recently, we demonstrated that voluntary spatial attention attracts population receptive fields (pRFs) toward its location throughout the visual hierarchy. Theoretically, both a feed forward or feedback mechanism could underlie pRF attraction in a given cortical area. Here, we use sub-millimeter ultra-high field functional MRI to measure pRF attraction across cortical depth and assess the contribution of feed forward and feedback signals to pRF attraction. In line with previous findings, we find consistent attraction of pRFs with voluntary spatial attention in V1. When assessed as a function of cortical depth, we find pRF attraction in every cortical portion (deep, center and superficial), although the attraction is strongest in deep cortical portions (near the gray-white matter boundary). Following the organization of feed forward and feedback processing across V1, we speculate that a mixture of feed forward and feedback processing underlies pRF attraction in V1. Specifically, we propose that feedback processing contributes to the pRF attraction in deep cortical portions

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Aims: Intraperitoneal (IP) insulin administration is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R-SH) content) compared to SC insulin in subjects with T1DM.Materials and methods: Prospective, observational case-control study. Serum thiol measurements were performed at baseline and at 26 weeks in age- and gender-matched patients with T1DM. Serum-free thiols, compounds with a R-SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status.Results: A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R-SH concentration was 248 (31) μmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R-SH levels. The estimated geometric mean concentrations of R-SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI -2, 14) μmol/L.Conclusions: Based on R-SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM.</p

Diagnostic accuracy of depression questionnaires in adult patients with diabetes: a systematic review and meta-analysis

Importance Comorbid depression is common among patients with diabetes and has severe health consequences, but often remains unrecognized. Several questionnaires are used to screen for depression. A systematic review and meta-analysis regarding the diagnostic accuracy of depression questionnaires in adults with diabetes is unavailable. Objective To conduct a systematic review and meta-analysis to evaluate the diagnostic accuracy of depression questionnaires in adults with type 1 or type 2 diabetes. Data sources PubMed, Embase and PsycINFO were searched from inception to 28 February 2018. Study selection Studies were included when the diagnostic accuracy of depression questionnaires was assessed in a diabetes population and the reference standard was a clinical interview. Data extraction and synthesis Data extraction was performed by one reviewer and checked by another. Two reviewers independently conducted the quality assessment (QUADAS-2). Diagnostic accuracy was pooled in bivariate random effects models. This study is reported according to PRISMA-DTA and is registered with PROSPERO (CRD42018092950). Main Outcome(s) and measure(s) Diagnostic accuracy, expressed as sensitivity and specificity, of depression questionnaires in an adult diabetes population. Results A total 6,097 peer-reviewed articles were screened. Twenty-one studies (N= 5,703 patients) met the inclusion criteria for the systematic review. Twelve different depression questionnaires were identified, of which the CES-D (n=6 studies) and PHQ-9 (n=7 studies) were the most frequently evaluated. Risk of bias was unclear for multiple domains in the majority of studies. In the meta-analyses, five (N= 1,228) studies of the CES-D (≥16), five (N= 1,642) of the PHQ-9 (≥10) and four (N=822) of the algorithm of the PHQ-9 were included in the pooled analysis. The CES-D (≥16) had a pooled sensitivity of 85.0% (95%CI, 71.3-92.8%) and a specificity of 71.6% (95%CI, 62.5-79.2%); the PHQ-9 (≥10) had a sensitivity of 81.5% (95%CI, 57.1-93.5%) and a specificity of 79.7% (95%CI, 62.1-90.4%). The algorithm for the PHQ-9 had a sensitivity of 60.9% (95%CI, 52.3-50 90.8%) and a specificity of 64.0% (95%CI, 53.0-93.9%). Conclusions and relevance This review indicates that the CES-D had the highest sensitivity, whereas the PHQ-9 had the highest specificity, although confidence intervals were wide and overlapping. The algorithm for the PHQ-9 had the lowest sensitivity and specificity. Given the variance in results and suboptimal reporting of studies, further high quality studies are needed to confirm the diagnostic accuracy of these depression questionnaires in patients with diabetes

Mobile vaccination units to increase COVID-19 vaccination uptake in areas with lower coverage:a within-neighbourhood analysis using national registration data, the Netherlands, September-December 2021

BackgroundVaccine uptake differs between social groups. Mobile vaccination units (MV-units) were deployed in the Netherlands by municipal health services in neighbourhoods with low uptake of COVID-19 vaccines.AimWe aimed to evaluate the impact of MV-units on vaccine uptake in neighbourhoods with low vaccine uptake.MethodsWe used the Dutch national-level registry of COVID-19 vaccinations (CIMS) and MV-unit deployment registrations containing observations in 253 neighbourhoods where MV-units were deployed and 890 contiguous neighbourhoods (total observations: 88,543 neighbourhood-days). A negative binomial regression with neighbourhood-specific temporal effects using splines was used to study the effect.ResultsDuring deployment, the increase in daily vaccination rate in targeted neighbourhoods ranged from a factor 2.0 (95% confidence interval (CI): 1.8-2.2) in urbanised neighbourhoods to 14.5 (95% CI: 11.6-18.0) in rural neighbourhoods. The effects were larger in neighbourhoods with more voters for the Dutch conservative Reformed Christian party but smaller in neighbourhoods with a higher proportion of people with non-western migration backgrounds. The absolute increase in uptake over the complete intervention period ranged from 0.22 percentage points (95% CI: 0.18-0.26) in the most urbanised neighbourhoods to 0.33 percentage point (95% CI: 0.28-0.37) in rural neighbourhoods.ConclusionDeployment of MV-units increased daily vaccination rate, particularly in rural neighbourhoods, with longer travel distance to permanent vaccination locations. This public health intervention shows promise to reduce geographic and social health inequalities, but more proactive and long-term deployment is required to identify its potential to substantially contribute to overall vaccination rates at country level.</p

Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

The present study is the first intervention study in a well-established, translational mouse model for hyperlipidaemia and atherosclerosis showing that anacetrapib dose-dependently reduces atherosclerosis development and adds to the anti-atherogenic effects of atorvastatin. This effect is mainly ascribed to the reduction in non-HDL-C despite a remarkable increase in HDL-C and without affecting HDL functionality. In addition, anacetrapib improves lesion stabilit

Plasma Protein Profiling Reveals Protein Clusters Related to BMI and Insulin Levels in Middle-Aged Overweight Subjects

Biomarkers that allow detection of the onset of disease are of high interest since early detection would allow intervening with lifestyle and nutritional changes before the disease is manifested and pharmacological therapy is required. Our study aimed to improve the phenotypic characterization of overweight but apparently healthy subjects and to identify new candidate profiles for early biomarkers of obesity-related diseases such as cardiovascular disease and type 2 diabetes

Favourable serum calcification propensity with intraperitoneal as compared with subcutaneous insulin administration in type 1 diabetes

Background: Serum calcification propensity can be monitored using the maturation time of calciprotein particles in serum (T-50 test). A shorter T-50 indicates greater propensity to calcify; this is an independent determinant of cardiovascular disease. As the intraperitoneal (IP) route of insulin administration mimics the physiology more than the subcutaneous (SC) route in persons with type 1 diabetes (T1DM), we hypothesized that IP insulin influences determinants of calcium propensity and therefore result in a longer T-50 than SC insulin administration. Methods: Prospective, observational case-control study. Measurements were performed at baseline and at 26 weeks in age and gender matched persons with T1DM. Results: A total of 181 persons, 39 (21.5%) of which used IP and 142 (78.5%) SC insulin were analysed. Baseline T-50 was 356 (45) minutes. The geometric mean T-50 significantly differed between both treatment groups: 367 [95% confidence interval (CI) 357, 376] for the IP group and 352 (95% CI 347, 357) for the SC group with a difference of -15 (95% CI -25, -4) minutes, in favour of IP treatment. In multivariable analyses, the IP route of insulin administration had a positive relation on T-50 concentrations while higher age, triglycerides and phosphate concentrations had an inverse relation. Conclusion: Among persons with T1DM, IP insulin administration results in a more favourable calcification propensity time then SC insulin. It has yet to be shown if this observation translates into improved cardiovascular outcomes