Sex differences in outcomes of primary prevention implantable cardioverter-defibrillator therapy: combined registry data from eleven European countries.

Aims: Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials. Methods and results: Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16-55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47-0.79; P = 0.0002). Conclusion: Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.

Bayesian estimation in random effects meta-analysis using a non-informative prior.

Pooling information from multiple, independent studies (meta-analysis) adds great value to medical research. Random effects models are widely used for this purpose. However, there are many different ways of estimating model parameters, and the choice of estimation procedure may be influential upon the conclusions of the meta-analysis. In this paper, we describe a recently proposed Bayesian estimation procedure and compare it with a profile likelihood method and with the DerSimonian-Laird and Mandel-Paule estimators including the Knapp-Hartung correction. The Bayesian procedure uses a non-informative prior for the overall mean and the between-study standard deviation that is determined by the Berger and Bernardo reference prior principle. The comparison of these procedures focuses on the frequentist properties of interval estimates for the overall mean. The results of our simulation study reveal that the Bayesian approach is a promising alternative producing more accurate interval estimates than those three conventional procedures for meta-analysis. The Bayesian procedure is also illustrated using three examples of meta-analysis involving real data. Copyright © 2016 John Wiley & Sons, Ltd.

Gender Differences in Appropriate Shocks and Mortality among Patients with Primary Prophylactic Implantable Cardioverter-Defibrillators: Systematic Review and Meta-Analysis.

BACKGROUND: Some but not all prior studies have shown that women receiving a primary prophylactic implantable cardioverter defibrillator (ICD) have a lower risk of death and appropriate shocks than men. PURPOSE: To evaluate the effect of gender on the risk of appropriate shock, all-cause mortality and inappropriate shock in contemporary studies of patients receiving a primary prophylactic ICD. DATA SOURCE: PubMed, LIVIVO, Cochrane CENTRAL between 2010 and 2016. STUDY SELECTION: Studies providing at least 1 gender-specific risk estimate for the outcomes of interest. DATA EXTRACTION: Abstracts were screened independently for potentially eligible studies for inclusion. Thereby each abstract was reviewed by at least two authors. DATA SYNTHESIS: Out of 680 abstracts retained by our search strategy, 20 studies including 46'657 patients had gender-specific information on at least one of the relevant endpoints. Mean age across the individual studies varied between 58 and 69 years. The proportion of women enrolled ranged from 10% to 30%. Across 6 available studies, women had a significantly lower risk of first appropriate shock compared with men (pooled multivariable adjusted hazard ratio 0.62 (95% CI [0.44; 0.88]). Across 14 studies reporting multivariable adjusted gender-specific hazard ratio estimates for all-cause mortality, women had a lower risk of death than men (pooled hazard ratio 0.75 (95% CI [0.66; 0.86]). There was no statistically significant difference for the incidence of first inappropriate shocks (3 studies, pooled hazard ratio 0.99 (95% CI [0.56; 1.73]). LIMITATIONS: Individual patient data were not available for most studies. CONCLUSION: In this large contemporary meta-analysis, women had a significantly lower risk of appropriate shocks and death than men, but a similar risk of inappropriate shocks. These data may help to select patients who benefit from primary prophylactic ICD implantation.

Back schools for the treatment of chronic low back pain: possibility of benefit but no convincing evidence after 47 years of research-systematic review and meta-analysis.

Back schools are interventions that comprise exercise and education components. We aimed to systematically review the randomized controlled trial evidence on back schools for the treatment of chronic low back pain. By searching MEDLINE, Embase, and Cochrane Central as well as bibliographies, we identified 31 studies for inclusion in our systematic review and 5 of these for inclusion in meta-analyses. Meta-analyses for pain scores and functional outcomes revealed statistical superiority of back schools vs no intervention for some comparisons but not others. No meta-analysis was feasible for the comparison of back schools vs other active treatments. Adverse events were poorly reported so that no reliable conclusions regarding the safety of back schools can be drawn, although some limited reassurance in this regard may be derived from the fact that few adverse events and no serious adverse events were reported in the back school groups in the studies that did report on safety. Overall, the evidence base for the use of back schools to treat chronic low back pain is weak; in nearly a half-century since back schools were first trialled, no unequivocal evidence of benefit has emerged.

Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays.

Cytotoxicity is one of the major defence mechanisms against both virus-infected and tumor cells. Radioactive (51)chromium ((51)Cr) release assay is a "gold standard" for assessment of natural killer (NK) cytolytic activity in vitro. Several disadvantages of this assay led us to design alternative tools based on flow cytometry analysis. Four different fluorescent dyes, calcein acetoxymethyl ester (CAM), carboxyfluorescein succinimidyl ester (CFSE), Vybrant DiO (DiO) and MitoTracker Green (MTG) were tested for labeling of NK target K-562 cells. Target staining stability, spontaneous release of fluorochromes and subsequent accumulation in bystander unstained cells were measured using fluorimetry and flow cytometry. Healthy donor peripheral blood mononuclear cells and affinity column purified NK cells were used as effectors coincubated with target K-562 cells at different E:T ratios for 3h and 90 min, respectively. Fluorescent probe 7-amino-actinomycin D was used for live and dead cell discrimination. Bland-Altman statistical method was applied to measure true agreement for all CAM-(51)Cr, CFSE-(51)Cr, DiO-(51)Cr and MTG-(51)Cr pairs analyzed. Based on the data, none of the four proposed methods can be stated equivalent to the standard (51)Cr release assay. Considering linear relationships between data obtained with four fluorochromes and (51)Cr release assay as well as linear regression analysis with R(2)=0.9393 value for CAM-(51)Cr pair, we found the CAM assay to be the most closely related to the (51)Cr assay.

Breath isoprene--aspects of normal physiology related to age, gender and cholesterol profile as determined in a proton transfer reaction mass spectrometry study.

BACKGROUND: This study was performed to clarify variations in breath isoprene concentrations with age, gender, body mass index (BMI) and total serum cholesterol. Our cohort consisted of 205 adult volunteers of different smoking background without health complaints. Total cholesterol in blood serum was measured in 79 of these volunteers. METHODS: Mixed expiratory exhaled breath was sampled using Tedlar bags. Concentrations of isoprene were then determined using proton transfer reaction-mass spectrometry. RESULTS: Isoprene concentrations ranged from 5.8 to 274.9 ppb, with an overall geometric mean (GM) of 99.3 ppb. There was no statistically significant difference in mean isoprene in breath between males and females (GM 105.4 and 95.5 ppb, respectively). Ageing led to a decrease in concentration in men, with an estimated slope of the regression line for log-transformed isoprene concentrations of -0.0049, but did not influence isoprene levels in women. We did not observe any significant correlation between isoprene breath content and cholesterol level in blood, even after adjusting for the possible influence of age. Similarly, no correlation was found between isoprene levels and BMI. CONCLUSIONS: Isoprene concentrations in exhaled breath showed gender-specific correlations with respect to age. Further investigations are necessary to clarify the relation between isoprene concentrations in exhaled breath and cholesterol levels and synthesis rates in blood.

Variability issues in determining the concentration of isoprene in human breath by PTR-MS.

This paper deals with variability issues connected with the proton transfer reaction-mass spectrometry (PTR-MS) measurements of isoprene concentration. We focus on isoprene as an abundant and widely studied compound in human breath. The variability caused by the measurement process is described by the within-sample distribution. Thus, based on the formula for computing isoprene concentration that reflects the principle of the PTR-MS, a theoretical model for the within-sample distribution of isoprene concentration is suggested. This model, which assumes that the distribution is proportional to a quotient of two independent Poisson-distributed random variables, is then confronted with empirical distributions obtained from 17 breath samples collected from a healthy individual within a month. (In each sample, isoprene concentration was determined 97 times.) The empirical within-sample distributions are also compared to normal and log-normal distributions. While those seem to be satisfactory approximations, the theoretical model is found suitable only in 10 out of 17 breath samples. We also comment on the stability of samples during the measurement process in the PTR-MS instrument and, for the sake of comparison, determine the within-sample and the within-subject variability of isoprene concentrations in our data. The respective geometric standard deviations are 1.01 and 1.29.