Low-level viraemia, measured as viraemia copy-years, as a prognostic factor for medium–long-term all-cause mortality: a MASTER cohort study

n/

Role of leukocytes, gender, and symptom domains in the influence of depression on hospitalization and mortality risk: Findings from the Moli-sani study

Background: Major depressive disorder is a mental illness associated with chronic conditions like cardiovascular disease (CVD). Circulating inflammation has been proposed as a potential mechanism underlying this link, although the role of specific biomarkers, gender, and symptom domains is not well elucidated. Methods: We performed multivariable Cox regressions of first hospitalization/all-cause mortality and CVD, ischemic heart (IHD), and cerebrovascular disease (CeVD) causes vs. depression severity in an Italian population cohort (N = 13,191; age ≥ 35 years; 49.3% men; 4,856 hospitalizations and 471 deaths, median follow-up 7.28 and 8.24 years, respectively). In models adjusted for age, sex, and socioeconomic status, we estimated the proportion of association explained by C-reactive protein (CRP), platelet count, granulocyte-to-lymphocyte ratio (GLR), and white blood cell count (WBC). Gender-by-depression interaction and gender-stratified analyses were performed. Associations of polychoric factors tagging somatic and cognitive symptoms with incident clinical risks were also tested, as well as the proportion explained by a composite index of circulating inflammation (INFLA score). Results: Significant proportions of the influence of depression on clinical risks were explained by CRP (4.8% on IHD hospitalizations), GLR (11% on all-cause mortality), and WBC (24% on IHD/CeVD hospitalizations). Gender-by-depression interaction was significantly associated only with all-cause mortality (p = 0.03), with moderate depression showing a + 60% increased risk in women, but not in men. Stable associations of somatic, but not of cognitive, symptoms with increased hospitalization risk were observed (+ 16% for all causes, + 14% for CVD causes), with INFLA score explaining small but significant proportions of these associations (2.5% for all causes, 8.6% for IHD causes). Conclusions: These findings highlight the importance of cellular components of inflammation, gender, and somatic depressive symptoms in the link between depression and clinical (especially CVD) risks, pointing to the existence of additional pathways through which depression may play a detrimental effect on the cardiovascular system

ZBTB12 DNA methylation is associated with coagulation- and inflammation-related blood cell parameters: findings from the Moli-family cohort.

Background Zinc finger and BTB domain-containing protein 12 (ZBTB12) is a predicted transcription factor with potential role in hematopoietic development. Recent evidence linked low methylation level of ZBTB12 exon1 to myocardial infarction (MI) risk. However, the role of ZBTB12 in the pathogenesis of MI and cardiovascular disease in general is not yet clarified. We investigated the relation between ZBTB12 methylation and several blood parameters related to cardio-cerebrovascular risk in an Italian family-based cohort. Results ZBTB12 methylation was analyzed on white blood cells from the Moli-family cohort using the Sequenom EpiTYPER MassARRAY (Agena). A total of 13 CpG Sequenom units were analyzed in the small CpG island located in the only translated ZBTB12 exon. Principal component analysis (PCA) was performed to identify groups of CpG units with similar methylation estimates. Linear mixed effect regressions showed a positive association between methylation of ZBTB12 Factor 2 (including CpG units 8, 9–10, 16, 21) and TNF-ɑ stimulated procoagulant activity, a measure of procoagulant and inflammatory potential of blood cells. In addition, we also found a negative association between methylation of ZBTB12 Factor 1 (mainly characterized by CpG units 1, 3–4, 5, 11, and 26) and white blood cell and granulocyte counts. An in silico prediction analysis identified granulopoiesis- and hematopoiesis-specific transcription factors to potentially bind DNA sequences encompassing CpG1, CpG3–4, and CpG11. Conclusions ZBTB12 hypomethylation is linked to shorter TNF-ɑ stimulated whole blood coagulation time and increased WBC and granulocyte counts, further elucidating the possible link between ZBTB12 methylation and cardiovascular disease risk

Mortality Prediction of COVID-19 Patients Using Radiomic and Neural Network Features Extracted from a Wide Chest X-ray Sample Size: A Robust Approach for Different Medical Imbalanced Scenarios

Aim: The aim of this study was to develop robust prognostic models for mortality prediction of COVID-19 patients, applicable to different sets of real scenarios, using radiomic and neural network features extracted from chest X-rays (CXRs) with a certified and commercially available software. Methods: 1816 patients from 5 different hospitals in the Province of Reggio Emilia were included in the study. Overall, 201 radiomic features and 16 neural network features were extracted from each COVID-19 patient’s radiography. The initial dataset was balanced to train the classifiers with the same number of dead and survived patients, randomly selected. The pipeline had three main parts: balancing procedure; three-step feature selection; and mortality prediction with radiomic features through three machine learning (ML) classification models: AdaBoost (ADA), Quadratic Discriminant Analysis (QDA) and Random Forest (RF). Five evaluation metrics were computed on the test samples. The performance for death prediction was validated on both a balanced dataset (Case 1) and an imbalanced dataset (Case 2). Results: accuracy (ACC), area under the ROC-curve (AUC) and sensitivity (SENS) for the best classifier were, respectively, 0.72 ± 0.01, 0.82 ± 0.02 and 0.84 ± 0.04 for Case 1 and 0.70 ± 0.04, 0.79 ± 0.03 and 0.76 ± 0.06 for Case 2. These results show that the prediction of COVID-19 mortality is robust in a different set of scenarios. Conclusions: Our large and varied dataset made it possible to train ML algorithms to predict COVID-19 mortality using radiomic and neural network features of CXRs

Use of efavirenz or atazanavir/ritonavir is associated with better clinical outcomes of HAART compared to other protease inhibitors: routine evidence from the Italian MASTER Cohort.

Randomized trials and observational cohorts reported higher rates of virological suppression after highly active antiretroviral therapy (HAART) including efavirenz (EFV), compared with boosted protease inhibitors (PIs). Correlations with immunological and clinical outcomes are unclear. Patients of the Italian MASTER cohort who started HAART from 2000 to 2010 were selected. Outstanding outcome (composite outcome for success (COS)) was introduced. We evaluated predictors of COS (no AIDS plus CD4+ count >500/ mm3 plus HIV-RNA <500 copies/mL) and of eight single outcomes either at month 6 or at year 3. Multivariable logistic regression was conducted. There were 6259 patients selected. Patients on EFV (43%) were younger, had greater CD4+ count, presented with AIDS less frequently, and more were Italians. At year 3, 90% of patients had HIV RNA <500 copies/mL, but only 41.4% were prescribed EFV, vs. 34.1% prescribed boosted PIs achieved COS (p <0.0001). At multivariable analysis, patients on lopinavir/ritonavir had an odds ratio of 0.70 for COS at year 3 (p <0.0001). Foreign origin and positive hepatitis C virus-Ab were independently associated with worse outcome (OR 0.54, p <0.0001 and OR 0.70, p 0.01, respectively). Patients on boosted PIs developed AIDS more frequently either at month 6 (13.8% vs. 7.6%, p <0.0001) or at year 3 (17.1% vs. 13.8%, p <0.0001). At year 3, deaths of patients starting EFV were 3%, vs. 5% on boosted PIs (p 0.008). In this study, naïve patients on EFV performed better than those on boosted PIs after adjustment for imbalances at baseline. Even when virological control is achieved, COS is relatively rare. Hepatitis C virus-positive patients and those of foreign origin are at risk of not obtaining COS. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved

Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/μl Despite Effective HAART

Immunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE)

Variation of PEAR1 DNA methylation influences platelet and leukocyte function.

Background Platelet-endothelial aggregation receptor 1 (PEAR-1) is a transmembrane receptor involved in platelet activation and megakaryopoiesis whose expression is driven by DNA methylation. PEAR1 variants were associated with differential platelet response to activation and cardiovascular outcomes. We aimed at investigating the link between PEAR1 methylation and platelet and leukocyte function markers in a family-based population. Results We measured PEAR1 methylation in 605 Moli-family participants with available blood counts, plasma P-selectin and C-reactive protein, whole blood platelet P-selectin, and platelet-leukocyte mixed conjugate measurements. We performed principal component analysis (PCA) to identify groups of highly correlated CpG sites. We used linear mixed regression models (using age, gender, BMI, smoking, alcohol drinking, being a proband for family recruitment, being a member of myocardial infarction (MI) family as fixed effects, and family as a random effect) to evaluate associations between PEAR1 methylation and phenotypes. PEAR1 methylation Factor2, characterized by the previously identified megakaryocyte-specific CpG sites, was inversely associated with platelet-monocyte conjugates, P-selectin, and WBC counts, while positively associated with the platelet distribution width (PDW) and with leukocyte CD11b and L-selectin. Moreover, PEAR1 Factor2 methylation was negatively associated with INFLAscore, a low-grade inflammation score. The latter was partially mediated by the PEAR1 methylation effect on platelet variables. PEAR1 methylation association with WBC measurements and INFLAscore was confirmed in the independent cohort FLEMENGHO. Conclusions We report a significant link between epigenetic signatures in a platelet functional gene and inflammation-dependent platelet function variability measured in two independent cohorts