Neuromedin U pathway in the control of obesity and other hypothalamus-regulated phenotypes

This is a candidate pathway study in European children and adults. Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates metabolic phenotypes. Our preliminary analyses in European children suggested that NMU gene plays an important role in adiposity and bone health. This project aims at investigating the associations between hypothalamus-regulated phenotypes and NMU pathway genes, by: (i) investigating in children and confirming in adults possible associations between polymorphisms in NMU pathway genes and adiposity, insulin resistance, blood pressure and bone health; (ii) verifying gene-gene interaction effects; (iii) identifying specific rare loci or regions with aberrant methylation in the genes confirmed for associations. Two populations of children and adults will be used. A two-step approach will be set-up to identify and replicate associations, considering false discovery rate correction. The results will be useful to identify potential target for novel drugs and to recognize subjects at high risk for metabolic and bone diseases

A Systematic Review of Meta-Analyses on Gene Polymorphisms and Gastric Cancer Risk

BACKGROUND: Individual variations in gastric cancer risk have been associated in the last decade with specific variant alleles of different genes that are present in a significant proportion of the population. Polymorphisms may modify the effects of environmental exposures, and these gene-environment interactions could partly explain the high variation of gastric cancer incidence around the world. The aim of this report is to carry out a systematic review of the published meta-analyses of studies investigating the association between gene polymorphisms and gastric cancer risk, and describe their impact at population level. Priorities on the design of further primary studies are then provided. METHODS: A structured bibliographic search on Medline and EMBASE databases has been performed to identify meta-analyses on genetic susceptibility to gastric cancer, without restriction criteria. We report the main results of the meta-analyses and we describe the subgroup analyses performed, focusing on the detection of statistical heterogeneity. We investigated publication bias by pooling the primary studies included in the meta-analyses, and we computed the population attributable risk (PAR) for each polymorphism. RESULTS: Twelve meta-analyses and one pooled-analysis of community based genetic association studies were included, focusing on nine genes involved in inflammation (IL-1beta, IL-1RN, IL-8), detoxification of carcinogens (GSTs, CYP2E1), folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53). According to their random-Odds Ratios, individuals carrying one of the IL-1RN *2, IL-1beta -511T variant alleles or homozygotes for MTHFR 677T are significantly at higher risk of gastric cancer than those with the wild type homozygote genotypes, showing high PARs. The main sources of heterogeneity in the meta-analyses were ethnicity, quality of the primary study, and selected environmental co-exposures. Effect modification by Helicobacter pylori infection for subjects carrying the unfavourable variant of IL-1 polymorphisms and by low folate intake for individuals homozygotes for MTHFR 677T allele has been reported, while genes involved in the detoxification of carcinogens show synergistic interactions. Publication bias was observed (Egger test, p = 0.03). DISCUSSION: The published meta-analyses included in our systematic review focused on polymorphisms having a small effect in increasing gastric cancer risk per se. Nevertheless, the risk increase by interacting with environmental exposures and in combination with additional unfavourable polymorphisms. Unfortunately meta-analyses are underpowered for many subgroup analyses, so additional primary studies performed on larger population and collecting data on environmental and genetic co-exposures are demanded

Joint analysis of gravitational-wave and electromagnetic data of mergers:breaking an afterglow model degeneracy in GW170817 and in future events

On August 17, 2017, Advanced LIGO and Virgo observed GW170817, the first gravitational-wave (GW) signal from a binary neutron star merger. It was followed by a short-duration gamma-ray burst, GRB 170817A, and by a non-thermal afterglow emission. In this work, a combined simultaneous fit of the electromagnetic (EM, specifically, afterglow) and GW domains is implemented, both using the posterior distribution of a GW standalone analysis as prior distribution to separately process the EM data, and fitting the EM and GW domains simultaneously. These approaches coincide mathematically, as long as the actual posterior of the GW analysis, and not an approximation, is used as prior for the EM analysis. We treat the viewing angle, $\theta_v$, as shared parameter across the two domains. In the afterglow modelling with a Gaussian structured jet this parameter and the jet core angle, $\theta_c$, are correlated, leading to high uncertainties on their values. The joint EM+GW analysis relaxes this degeneracy, reducing the uncertainty compared to an EM-only fit. We also apply our methodology to hypothetical GW170817-like events occurring in the next GW observing run at $\sim$140 and 70 Mpc. At 70 Mpc the existing EM degeneracy is broken, thanks to the inclusion of the GW domain in the analysis. At 140 Mpc, the EM-only fit cannot constrain $\theta_v$ nor $\theta_c$ because of the lack of detections in the afterglow rising phase. Folding the GW data into the analysis leads to tighter constraints on $\theta_v$, still leaving $\theta_c$ unconstrained, requiring instruments with higher sensitivities, such as Athena.Comment: 15 pages, 10 figures. Accepted for publication in MNRA

T-wave axis deviation, metabolic syndrome and estimated cardiovascular risk in men and women of the MOLI-SANI Study

Aim: We aimed at investigating the association between T-wave axis deviation, metabolic syndrome (MetS), its components and estimated risk of cardiovascular disease (CVD) at 10 years in a adult Italian population. Methods: 11,143 women (54±11 years) and 9,742 men (55±11 years) were analysed from the Molisani cohort, randomly recruited from the general population. MetS was defined using the ATPIII criteria. T-wave axis deviation was measured from the standard 12-lead resting electrocardiogram. CVD risk in ten years was estimated by the CUORE score. Results: 29% of men and 27% of women with MetS showed borderline or abnormal T-wave as compared to 24% and 17% without MetS (p<0.0001 for both genders). Among components of MetS, elevated waist and blood pressure were strongly associated with Twave axis deviation, whereas glucose, HDL and triglycerides were only marginally. The odds of having borderline or abnormal T-wave axis deviation in multivariable regression analysis, was 1.38 (95% CI:1.25-1.53) in MetS men and 1.68 (95% CI:1.51-1.87) in MetS women compared to those without. Further adjustment for MetS components completely abolished the associations. Abnormal T-wave axis deviation was associated with an increased risk of CVD in 10 years in men (OR=4.4; 95% CI:1.10-17.9). Conclusion: T-wave axis deviation is strongly associated with components of the MetS, in particular high waist circumference and blood pressure and with an increased CVD risk, particularly in men. ECG monitoring to identify T-wave axis deviation in obese, hypertensive or MetS subjects can be an early indicator of vascular disease and help in reducing cardiac events

Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: An updated meta-analysis

BackgroundSeveral randomized clinical trials evaluated whether preoperative supplementation of omega-3 (n-3) polyunsaturated fatty acids protects against postoperative atrial fibrillation after cardiac surgery, a condition associated with increased cardiac and cerebral mortality. However, their efficacy remains still controversial. An updated meta-analysis was performed to clarify if preoperative n-3 polyunsaturated fatty acid supplementation prevents postoperative atrial fibrillation in patients undergoing cardiac surgery.MethodsArticles were retrieved until November 2012 by screening electronic databases (PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials) and cross references. Two of us independently reviewed articles and agreed to select 8 randomized clinical trials. For each study, the incidence of atrial fibrillation in both the intervention and placebo groups was extracted to calculate odd ratio and 95% confidence intervals (CIs). Weighted study-specific estimates were combined using fixed (Mantel-Haenszel method) and random-effects (DerSimonian-Laird method) models.ResultsThis meta-analysis includes 2687 patients (1337 in the intervention group) who underwent cardiac surgery. Pooled analysis using fixed-effects models showed a significant reduction (average, 16%; 95% CI, 1%-29%) in postoperative atrial fibrillation by preoperative n-3 polyunsaturated fatty acids. There was a low heterogeneity among studies (P = .07 and I2 = 46%). By using a random-effects model, the reduction averaged 25% (odds ratio, 0.75; 95% CI, 0.57-1.00; P = .05). When isolated coronary artery bypass graft surgery was only considered (7 studies), a significant protection averaging 34% was observed in a fixed model (odds ratio, 0.66; 95% CI, 0.50-0.87; P = .003; I2 = 26%, P = .23).ConclusionsA preoperative supplementation of n-3 polyunsaturated fatty acids significantly prevents the occurrence of postoperative atrial fibrillation in patients undergoing cardiac surgery, in particular coronary artery bypass surgery

The North Italian Longitudinal Study Assessing the Mental Health Effects of SARS-CoV-2 Pandemic on Health Care Workers-Part I: Study Design and Psychometric Structural Validity of the HSE Indicator Tool and Work Satisfaction Scale

Literature on the impact of the SARS-CoV-2 pandemic on the mental health of Health Care Workers (HCWs) is mostly based on cross-sectional surveys. We designed a longitudinal study to assess work-related stress and mental health before and after the pandemic onset in a university-hospital in Lombardia region, Italy. We report on sample representativeness and structural validity of questionnaires assessing work stress (HSE Indicator Tool, HSE-IT) and work satisfaction (WS), which were not validated in the HCWs population. n = 1287 HCWs from 67 hospital wards/offices were invited to an online survey in summer 2019 (pre-COVID-19 wave) and again during winter 2020 (COVID-19 wave). Selected hospital wards/offices did not differ from the remaining wards for turn-over and down-sizing rates, overload, sick leaves, and night shifts (Wilcoxon rank tests p-values &gt; 0.05). Participation rates were 70% (n = 805) and 60% (n = 431) in the pre-COVID-19 and COVID-19 waves, respectively. Socio-demographic and work-related characteristics did not impact data completeness nor participation to the COVID-19 wave. While confirming a 7-component structure for HSE-IT, we identified a new factor related to participation in work organization. A one-factor model for WS had satisfactory fit. Our longitudinal study based on a representative sample and adopting validated questionnaires is well-suited to elucidate the role of work conditions on the development of mental health disorders in HCWs

The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

Background and aims: Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children. Methods and results: From a large European multi-center study on childhood obesity, 4,528 children (2.0–9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p&lt;0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years’ time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p&lt;0.05). Conclusions: This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

Background: High dietary glycaemic index (GI) and load (GL) have been associated with increased risk of various cardiometabolic conditions. Among the molecular potential mechanisms underlying this relationship, DNA methylation has been studied, but a direct link between high GI and/or GL of diet and global DNA methylation levels has not been proved yet. We analyzed the associations between GI and GL and global DNA methylation patterns within an Italian population. Results: Genomic DNA methylation (5mC) and hydroxymethylation (5hmC) levels were measured in 1080 buffy coat samples from participants of the Moli-sani study (mean(SD) = 54.9(11.5) years; 52% women) via ELISA. A 188-item Food Frequency Questionnaire was used to assess food intake and dietary GI and GL for each participant were calculated. Multiple linear regressions were used to investigate the associations between dietary GI and GL and global 5mC and 5hmC levels, as well as the proportion of effect explained by metabolic and inflammatory markers. We found negative associations of GI with both 5mC (β (SE) = - 0.073 (0.027), p = 0.007) and 5hmC (- 0.084 (0.030), p = 0.006), and of GL with 5mC (- 0.14 (0.060), p = 0.014). Circulating biomarkers did not explain the above-mentioned associations. Gender interaction analyses revealed a significant association of the gender-x-GL interaction with 5mC levels, with men showing an inverse association three times as negative as in women (interaction β (SE) = - 0.16 (0.06), p = 0.005). Conclusions: Our findings suggest that global DNA methylation and hydroxymethylation patterns represent a biomarker of carbohydrate intake. Based on the differential association of GL with 5mC between men and women, further gender-based separate approaches are warranted

A real world analysis of COVID-19 impact on hospitalizations in older adults with chronic conditions from an Italian region

Healthcare delivery reorganization during the COVID-19 emergency may have had a significant impact on access to care for older adults with chronic conditions. We investigated such impact among all adults with chronic conditions aged >= 65 years, identified through the electronic health databases of two local health agencies-ATS Brianza and ATS Bergamo-from the Lombardy region, Italy. We considered hospitalizations for 2020 compared to the average 2017-2019 and quantified differences using rate ratios (RRs). Overall, in 2017-2019 there were a mean of 374,855 older adults with >= 1 chronic condition per year in the two ATS and 405,371 in 2020. Hospitalizations significantly decreased from 84,624 (225.8/1000) in 2017-2019 to 78,345 (193.3/1000) in 2020 (RR 0.86). Declines were reported in individuals with many chronic conditions and for most Major Diagnostic Categories, except for diseases of the respiratory system. The strongest reductions were observed in hospitalizations for individuals with active tumours, particularly for surgical ones. Hospitalization rates increased in individuals with diabetes, likely due to COVID-19-related diseases. Although determinants of the decrease in demand and supply for care among chronic older adults are to be further explored, this raises awareness on their impacts on chronic patients' health in the medium and long run