Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

<p>Background: Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.</p> <p>Methods: This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.</p> <p>Results: There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.</p> <p>Conclusions: Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.</p&gt

New, high statistics measurement of the K+ -> pi0 e+ nu (Ke3) branching ratio

E865 at the Brookhaven National Laboratory AGS collected about 70,000 K+(e3) events with the purpose of measuring the relative K+(e3) branching ratio. The pi0 in all the decays was detected using the e+e- pair from pi0 -> e+e-gamma decay and no photons were required. Using the Particle Data Group branching ratios for the normalization decays we obtain BR(K+(e3(gamma))=(5.13+/-0.02(stat)+/-0.09(sys)+/-0.04(norm))%, where $K+(e3(gamma)) includes the effect of virtual and real photons. This result is 2.3 sigma higher than the current Particle Data Group value. The implications of this result for the$V_{us}$ element of the CKM matrix, and the matrix's unitarity are discussed.Comment: 4 pages, 5 figures; final version accepted by PR

Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.

AIMS: Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies. METHODS AND RESULTS: Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α. CONCLUSIONS: Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.This work was supported by a grant from the British Heart Foundation (RG/08/014), the U.K. Medical Research Council, and the U.K. National Institute of Health Research Cambridge Biomedical Research Centre.This is the accepted manuscript. The final version is available from OUP at http://eurheartj.oxfordjournals.org/content/35/9/578

Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1

Experimental Study of the Radiative Decays K+ -> mu+ nu e+e- and K+ -> e+ nu e+e-

Experiment 865 at the Brookhaven AGS obtained 410 K+ -> e+ nu e+e- and 2679 K+ -> mu+ nu e+e- events including 10% and 19% background. The branching ratios were measured to be (2.48+-0.14(stat.)+-0.14(syst.))x10^-8 (m_ee>150 MeV) and (7.06+-0.16+-0.26)x10^-8 (m_ee>145 MeV), respectively. Results for the decay form factors are presented.Comment: 4 pages, 3 figures, RevTeX

First observation of the decay K+ -> e+ nu mu+ mu-

Experiment 865 at the Brookhaven AGS has observed the decay K^+ -> e^+ nu mu^+ mu^-. The branching ratio extracted is (1.72 +/- 0.37(stat) +/- 0.17(syst) +/- 0.19(model)) x 10^{-8} where the third term in the error results from the use of a model to extrapolate into a kinematic region dominated by background.Comment: 4 pages, 6 figures, Revtex4. Correction to figure and minor text change

Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Abstract Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship

An Improved upper limit on the decay K^+ -> pi^+ mu^+ e^-

Based on results of a search for the lepton-family-number-violating decay $K^+ \to \pi^+\mu^+ e^-$ with data collected by experiment E865 at the Alternating Gradient Synchrotron of Brookhaven National Laboratory, we place an upper limit on the branching ratio at $2.1 \times 10^{-11}$ (90% C.L.). Combining the results with earlier E865 data and those of a previous experiment, E777, an upper limit on the branching ratio of $1.3 \times 10^{-11}$ (90% C.L.) is obtained.Comment: v2: 13 pages, submitted to the Phys. Rev. D v3: 13 pages, resubmitted to Phys. Rev. D (corrections include: a more detailed overview of the combined analysis of the available experimntal data

A new measurement of K+(e4) decay and the s-wave pi-pi-scattering length a00

A sample of 400000 events from the decay K+->pi+pi-e+nu(e)(K(e4)) has been collected in experiment E865 at the Brookhaven AGS. The analysis of these data yields new measurements of the K(e4) branching ratio (4.11+-0.01+-0.11)*10**(-5)), the s-wave pi-pi scattering length a00=0.228+-0.012+-0.003, and the form factors F, G, and H of the hadronic current and their dependence on the invariant pi-pi mass