Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure Valsartan heart failure trial (Val-HeFT) echocardiographic data

AbstractObjectivesThe objective of this study was to test the hypothesis that the severity of left ventricular remodeling predicts the response to treatment and outcomes in chronic heart failure.BackgroundReversal of remodeling should produce the most favorable outcome in patients with the most severe remodeling.MethodsIn 5,010 heart failure patients on background therapy and randomized to valsartan and placebo, serial recordings of left ventricular internal diastolic diameter (LVIDd) and ejection fraction (EF) were read at sites that had to meet qualifying standards before participating. Baseline LVIDd and EF were pooled across treatments and retrospectively grouped by quartiles Q1 to Q4, representing best to worst. Kaplan-Meier survival curves were obtained by the log-rank test. Q1 was compared with Q4 for mortality and combined mortality and morbidity (M + M) from Cox regression risk ratios (RRs). Valsartan versus placebo changes from baseline in LVIDd and EF were analyzed by quartiles from analysis of covariance. Valsartan and placebo were compared by RRs for M + M.ResultsSurvival rates were greater in the better quartiles for LVIDd and EF (p < 0.00001). The RR for Q1 versus Q4 in events approached 0.5 for both LVIDd and EF (p < 0.0001). An LVIDd decrease and EF increase were quartile-dependent and greater with valsartan than placebo at virtually all time points. The RR for M + M outcomes favored valsartan in the worse quartiles.ConclusionsStratification by baseline severity of remodeling showed that patients with worse LVIDd and EF are at highest risk for an event, yet appear to gain the most anti-remodeling effect and clinical benefit with valsartan treatment

LDL aggregation susceptibility is higher in healthy South Asian compared with white Caucasian men

BACKGROUND: South Asians are more prone to develop atherosclerotic cardiovascular disease (ASCVD) compared with white Caucasians, which is not fully explained by classical risk factors. We recently reported that the presence of aggregation-prone low-density lipoprotein (LDL) in the circulation is associated with increased ASCVD mortality. OBJECTIVE: We hypothesized that LDL of South Asians is more prone to aggregate, which may be explained by differences in their LDL lipid composition. METHODS: In this cross-sectional hypothesis-generating study, LDL was isolated from plasma of healthy South Asians (n = 12) and age- and BMI-matched white Caucasians (n = 12), and its aggregation susceptibility and lipid composition were analyzed. RESULTS: LDL from South Asians was markedly more prone to aggregate compared with white Caucasians. Among all measured lipids, sphingomyelin 24:0 and triacylglycerol 56:8 showed the highest positive correlation with LDL aggregation. In addition, LDL from South Asians was enriched in arachidonic acid containing phosphatidylcholine 38:4 and had less phosphatidylcholines and cholesteryl esters containing monounsaturated fatty acids. Interestingly, body fat percentage, which was higher in South Asians (+26%), positively correlated with LDL aggregation and highly positively correlated with triacylglycerol 56:8, sphingomyelin 24:0, and total sphingomyelin. CONCLUSIONS: LDL aggregation susceptibility is higher in healthy young South Asians compared with white Caucasians. This may be partly explained by the higher body fat percentage of South Asians, leading to sphingomyelin enrichment of LDL. We anticipate that the presence of sphingomyelin-rich, aggregation -prone LDL particles in young South Asians may increase LDL accumulation in the arterial wall and thereby contribute to their increased risk of developing ASCVD later in life. (C) 2019 National Lipid Association. Published by Elsevier Inc.Peer reviewe

PR3-ANCA:a promising biomarker in primary sclerosing cholangitis (PSC)

BACKGROUND AND AIMS:The only recognized biomarker for primary sclerosing cholangitis (PSC) is atypical anti-neutrophil cytoplasmic antibodies (aANCA), which, in addition to having low sensitivity and specificity, is an indirect immunofluorescence (IIF) test lacking the advantages of high throughput and objectivity. Recent reports have shown that antibodies to proteinase-3 (PR3-ANCA) might add diagnostic value in inflammatory bowel disease (IBD), specifically in ulcerative colitis (UC). As PSC is associated with IBD, the objective of this study was to evaluate the frequency and clinical significance of PR3-ANCA in a large cohort of patients. METHODS:A total of 244 PSC and 254 control [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), hepatitis C viral infection (HCV), hepatitis B viral infection (HBV), and healthy controls] sera and their clinical correlations were retrospectively analyzed for PR3-ANCA determined by ELISA and a new chemiluminescence immunoassay (CIA). Testing was also performed for aANCA by IIF. RESULTS:When measured by CIA, PR3-ANCA was detected in 38.5% (94/244) of PSC patients compared to 10.6% (27/254) controls (p<0.0001). By ELISA, PR3-ANCA was detected in 23.4% (57/244) of PSC patients compared to 2.7% (6/254) controls (p<0.0001). PR3-ANCA in PSC patients was not associated with the presence or type of underlying IBD, and, in fact, it was more frequent in Crohn's disease (CD) patients with PSC than previously reported in CD alone. PR3-ANCA in PSC measured by CIA correlated with higher liver enzymes. CONCLUSION:PR3-ANCA is detected in a significant proportion of PSC patients compared to other liver diseases including PBC and AIH. PR3-ANCA is associated with higher liver enzyme levels in PSC, and is not solely related to underlying IBD

Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy

Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to a-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. Take- home message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. (C) 2022 Published by Elsevier Inc

The effect of mirabegron on energy expenditure and brown adipose tissue in healthy lean South Asian and Europid men

Aim: To compare the effects of cold exposure and the β3-adrenergic receptor agonist mirabegron on plasma lipids, energy expenditure and brown adipose tissue (BAT) activity in South Asians versus Europids. Materials and Methods: Ten lean Dutch South Asian (aged 18-30 years; body mass index [BMI] 18-25 kg/m2 ) and 10 age- and BMI-matched Europid men participated in a randomized, double-blinded, cross-over study consisting of three interventions: short-term (~ 2 hours) cold exposure, mirabegron (200 mg one dose p.o.) and placebo. Before and after each intervention, we performed lipidomic analysis in serum, assessed resting energy expenditure (REE) and skin temperature, and measured BAT fat fraction by magnetic resonance imaging. Results: In both ethnicities, cold exposure increased the levels of several serum lipid species, whereas mirabegron only increased free fatty acids. Cold exposure increased lipid oxidation in both ethnicities, while mirabegron increased lipid oxidation in Europids only. Cold exposure and mirabegron enhanced supraclavicular skin temperature in both ethnicities. Cold exposure decreased BAT fat fraction in both ethnicities. After the combination of data from both ethnicities, mirabegron decreased BAT fat fraction compared with placebo. Conclusions: In South Asians and Europids, cold exposure and mirabegron induced beneficial metabolic effects. When combining both ethnicities, cold exposure and mirabegron increased REE and lipid oxidation, coinciding with a higher supraclavicular skin temperature and lower BAT fat fraction.Diabetes Research Foundation Fellowship 2015.81.1808Netherlands CardioVascular Research Initiative: 'the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences' CVON2014-02 ENERGISE CVON2017-20 GENIUS-IIEuropean Union (EU) 602485European Research Council (NOMA-MRI) PCNR is an Established Investigator of the Netherlands Heart Foundation 2009T03

Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG) A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 mg or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomly assigned patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), odds ratio, 1.29 [95% CI, 0.73-2.30]; P=0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (odds ratio, 1.22 [95% CI, 0.72-2.05]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02352402

Geographical information system and environmental epidemiology: a cross-sectional spatial analysis of the effects of traffic-related air pollution on population respiratory health

<p>Abstract</p> <p>Background</p> <p>Traffic-related air pollution is a potential risk factor for human respiratory health. A Geographical Information System (GIS) approach was used to examine whether distance from a main road (the Tosco-Romagnola road) affected respiratory health status.</p> <p>Methods</p> <p>We used data collected during an epidemiological survey performed in the Pisa-Cascina area (central Italy) in the period 1991-93. A total of 2841 subjects participated in the survey and filled out a standardized questionnaire on health status, socio-demographic information, and personal habits. A variable proportion of subjects performed lung function and allergy tests. Highly exposed subjects were defined as those living within 100 m of the main road, moderately exposed as those living between 100 and 250 m from the road, and unexposed as those living between 250 and 800 m from the road. Statistical analyses were conducted to compare the risks for respiratory symptoms and diseases between exposed and unexposed. All analyses were stratified by gender.</p> <p>Results</p> <p>The study comprised 2062 subjects: mean age was 45.9 years for men and 48.9 years for women. Compared to subjects living between 250 m and 800 m from the main road, subjects living within 100 m of the main road had increased adjusted risks for persistent wheeze (OR = 1.76, 95% CI = 1.08-2.87), COPD diagnosis (OR = 1.80, 95% CI = 1.03-3.08), and reduced FEV₁/FVC ratio (OR = 2.07, 95% CI = 1.11-3.87) among males, and for dyspnea (OR = 1.61, 95% CI = 1.13-2.27), positivity to skin prick test (OR = 1.83, 95% CI = 1.11-3.00), asthma diagnosis (OR = 1.68, 95% CI = 0.97-2.88) and attacks of shortness of breath with wheeze (OR = 1.67, 95% CI = 0.98-2.84) among females.</p> <p>Conclusion</p> <p>This study points out the potential effects of traffic-related air pollution on respiratory health status, including lung function impairment. It also highlights the added value of GIS in environmental health research.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin