Impact of frailty on mortality and hospitalization in chronic heart failure: A systematic review and meta-analysis

© 2018 The Authors. Background-—Although frailty has been associated with increased risks for hospitalization and mortality in chronic heart failure, the precise average effect remains uncertain. We performed a systematic review and meta-analysis to summarize the hazards for mortality and incident hospitalization in patients with heart failure and frailty compared with those without frailty and explored the heterogeneity underlying the effect size estimates. Methods and Results-—MEDLINE, EMBASE, and Cochrane databases were queried for articles published between January 1966 and March 2018. Predefined selection criteria were used. Hazard ratios (HRs) were pooled for meta-analyses, and where odds ratios were used previously, original data were recalculated for HR. Overlapping data were consolidated, and only unique data points were used. Study quality and bias were assessed. Eight studies were included for mortality (2645 patients), and 6 studies were included for incident hospitalization (2541 patients) during a median follow-up of 1.82 and 1.12 years, respectively. Frailty was significantly associated with an increased hazard for mortality (HR, 1.54; 95% confidence interval, 1.34–1.75; P<0.001) and incident hospitalization (HR, 1.56; 95% confidence interval, 1.36–1.78; P<0.001) in chronic heart failure. The Fried phenotype estimated a 16.9% larger effect size than the combined Fried/non-Fried frailty assessment for the end point of mortality (HR, 1.80; 95% confidence interval, 1.41–2.28; P<0.001), but not for hospitalization (HR, 1.57; 95% confidence interval, 1.30–1.89; P<0.001). Study heterogeneity was found to be low (I 2 =0%), and high quality of studies was verified by the Newcastle-Ottawa scale. Conclusions-—Overall, the presence of frailty in chronic heart failure is associated with an increased hazard for death and hospitalization by ≈1.5-fold

Residual Expression of the Reprogramming Factors Prevents Differentiation of iPSC Generated from Human Fibroblasts and Cord Blood CD34+ Progenitors

Human induced pluripotent stem cells (hiPSC) have been generated from different tissues, with the age of the donor, tissue source and specific cell type influencing the reprogramming process. Reprogramming hematopoietic progenitors to hiPSC may provide a very useful cellular system for modelling blood diseases. We report the generation and complete characterization of hiPSCs from human neonatal fibroblasts and cord blood (CB)-derived CD34+ hematopoietic progenitors using a single polycistronic lentiviral vector containing an excisable cassette encoding the four reprogramming factors Oct4, Klf4, Sox2 and c-myc (OKSM). The ectopic expression of OKSM was fully silenced upon reprogramming in some hiPSC clones and was not reactivated upon differentiation, whereas other hiPSC clones failed to silence the transgene expression, independently of the cell type/tissue origin. When hiPSC were induced to differentiate towards hematopoietic and neural lineages those hiPSC which had silenced OKSM ectopic expression displayed good hematopoietic and early neuroectoderm differentiation potential. In contrast, those hiPSC which failed to switch off OKSM expression were unable to differentiate towards either lineage, suggesting that the residual expression of the reprogramming factors functions as a developmental brake impairing hiPSC differentiation. Successful adenovirus-based Cre-mediated excision of the provirus OKSM cassette in CB-derived CD34+ hiPSC with residual transgene expression resulted in transgene-free hiPSC clones with significantly improved differentiation capacity. Overall, our findings confirm that residual expression of reprogramming factors impairs hiPSC differentiation

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors

BACKGROUND: Genetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of two TLR9 polymorphisms between clinical severity variables in MM survivors. METHODS: We used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies of TLR9 -1237 and TLR9 +2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children. RESULTS: The TLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture for Neisseria (N.) meningitidis (p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). The TLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture for N. meningitidis (p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying the TLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower in TLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying the TLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952). CONCLUSIONS: We identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense

Welding and lung cancer in a pooled analysis of case-control studies.

Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer

Independent and combined influence of healthy lifestyle factors on academic performance in adolescents: DADOS Study

BACKGROUND. Few studies have analyzed the combined effect of lifestyle factors on academic performance (AP) in adolescents. The aim of this study was to analyze the independent and combined effects of weight status, screen time, sleep quality, daily meal frequency, cardiorespiratory fitness and physical activity (PA) on AP in adolescents. METHODS. A total of 262 adolescents (13.9±0.3 years) from the DADOS study were included in the analysis. Weight status was assessed through body mass index (kg/m 2 ). Participants completed questionnaires to evaluate screen time, sleep quality and daily meal frequency. Cardiorespiratory fitness was assessed by the 20-m shuttle run test. PA was evaluated by a wrist-worn GENEActiv accelerometer. AP was assessed through the final academic grades and a validated questionnaire. RESULTS. Non-overweight status, low screen time, good sleep quality and proper meal frequency showed independent, positive influence on AP. Moreover, adolescents achieving at least 3 healthy lifestyles were more likely to be in the high-performance group for academic grades than those achieving ≤ 1 (math OR: 3.02-9.51, language OR: 3.51-6.76 and grade point average OR: 4.22-9.36). CONCLUSIONS. Although individual healthy lifestyles are independently and positively associated with AP, the cumulative effect of multiple healthy lifestyles have a stronger impact

BNP controls early load-dependent regulation of SERCA through calcineurin

Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A