Statins, fibrates, and venous thromboembolism: a meta-analysis.

Aims The aim is to make a systematic review of the literature to assess the effect of lipid-lowering drugs on venous thromboembolism (VTE) occurrence. Methods and results MEDLINE and EMBASE databases were searched to identify studies that evaluated the effect of lipid-lowering drugs, in particular statins and fibrates, on VTE risk until April 2009. A scoring system was used to divide studies into two quality categories. Odds ratios (ORs) and 95% confidence intervals (CIs) were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I2 statistics. Three randomized controlled trials (RCTs), three cohort, and eight case\u2013control studies were included in our systematic review, for a total of 863 805 patients. Statins use significantly reduced VTE risk [OR, 0.81; 95% CI, 0.66\u20130.99, random-effect model)]. There was a very high heterogeneity among the studies (I2 > 80%). The use of fibrates was associated with a significant increase in the risk of VTE (OR, 1.58; 95% CI, 1.23\u20132.02), without heterogeneity (I2 = 0%). Data on other lipid-lowering drugs were lacking. Conclusion This meta-analysis of available literature suggests that statins may lower the risk of VTE, whereas fibrates may increase this risk. Due to several methodological limitations, this conclusion should be considered with caution, and additional, specifically designed RCTs are warranted

Triggering of cardiovascular hospital admissions by fine particle concentrations in New York state: Before, during, and after implementation of multiple environmental policies and a recession

Background Previous studies reported triggering of acute cardiovascular events by short-term increasedPM2.5 concentrations. From 2007 to 2013, national and New York state air quality policies and economic influences resulted in reduced concentrations of PM2.5 and other pollutants across the state. We estimated the rate of cardiovascular hospital admissions associated with increased PM2.5 concentrations in the previous 1–7 days, and evaluated whether they differed before (2005–2007), during (2008–2013), and after these concentration changes (2014–2016). Methods Using the Statewide Planning and Research Cooperative System (SPARCS) database, we retained all hospital admissions with a primary diagnosis of nine cardiovascular disease (CVD) subtypes, for residents living within 15 miles of PM2.5 monitoring sites in Buffalo, Rochester, Albany, Queens, Bronx, and Manhattan from 2005 to 2016 (N = 1,922,918). We used a case-crossover design and conditional logistic regression to estimate the admission rate for total CVD, and nine specific subtypes, associated with increased PM2.5 concentrations. Results Interquartile range (IQR) increases in PM2.5 on the same and previous 6 days were associated with 0.6%–1.2% increases in CVD admission rate (2005–2016). There were similar patterns for cardiac arrhythmia, ischemic stroke, congestive heart failure, ischemic heart disease (IHD), and myocardial infarction (MI). Ambient PM2.5 concentrations and annual total CVD admission rates decreased across the period. However, the excess rate of IHD admissions associated with each IQR increase in PM2.5 in previous 2 days was larger in the after period (2.8%; 95%CI = 1.5%–4.0%) than in the during (0.6%; 95%CI = 0.0%–1.2%) or before periods (0.8%; 95%CI = 0.2%–1.3%), with similar patterns for total CVD and MI, but not other subtypes. Conclusions While pollutant concentrations and CVD admission rates decreased after emission changes, the same PM2.5 mass was associated with a higher rate of ischemic heart disease events. Future work should confirm these findings in another population, and investigate whether specific PM components and/or sources trigger IHD events

Changes in the Acute Response of Respiratory Diseases to PM2.5 in New York State from 2005 to 2016

Prior studies reported that exposure to increased concentrations of fine particulate matter (PM2.5) were associated with increased rates of hospitalization and emergency department (ED) visits for asthma and chronic obstructive pulmonary disease (COPD). In this study, rates were examined from 2005 to 2016 using a case-crossover design to ascertain if there have been changes in the rates per unit mass exposure given substantial reductions in PM2.5 concentration and changes in its composition. PM2.5 concentrations were reduced through a combination of policies designed to improve air quality and economic drivers, including the 2008 economic recession and shifts in the relative costs of coal and natural gas. The study period was split into three periods reflecting that much of the emissions changes occurred between 2008 and 2013. Thus, the three periods were defined as: BEFORE (2005 to 2007), DURING (2008–2013), and AFTER (2014–2016). In general, the number of hospitalizations and ED visits declined with the decreased concentration of PM2.5. However, the rate of COPD hospitalizations and asthma ED visits associated with each interquartile range increase in ambient PM2.5 concentration was larger in the AFTER period than the DURING and BEFORE periods. For example, each 6.8 μg/m3 increase in PM2.5 on the same day was associated with 0.4% (0.0%, 0.8%), 0.3% (−0.2%, 0.7%), and 2.7% (1.9%, 3.5) increases in the rate of asthma emergency department visits in the BEFORE, DURING, and AFTER periods, respectively, suggesting the same mass concentration of PM2.5 was more toxic in the AFTER period

The Association between Respiratory Infection and Air Pollution in the Setting of Air Quality Policy and Economic Change

Rationale: Fine particulate air pollution (≤2.5µm; PM2.5) has been associated with an increased risk of respiratory disease, but assessments of specific respiratory infections in adults are lacking. Objective: To estimate the rate of respiratory infection healthcare encounters in adults associated with acute increases in PM2.5 concentrations. Methods: Using case-crossover methods, we studied 498,118 adult New York State residents with a primary diagnosis of influenza, bacterial pneumonia, or culture negative pneumonia upon hospitalization or emergency department (ED) visit (2005-2016). We estimated the rate of healthcare encounters associated with increases in PM2.5 in the previous 1-7 days and explored differences Before (2005 to 2007), During (2008-2013), and After (2014-2016) implementation of air quality policies and economic changes. Results: Interquartile range increases in PM2.5 over the previous 7 days were associated with increased excess rates of culture negative pneumonia hospitalizations (2.5%; 95% CI 1.7%, 3.2%) and ED visits (2.5%; 95% CI 1.4%, 3.6%), and increased excess rates of influenza ED visits (3.9%; 95% CI 2.1%, 5.6%). Bacterial pneumonia hospitalizations but not ED visits were associated with increases in PM2.5 and though imprecise, were of a similar magnitude to culture negative pneumonia (Lag day 6 ER 2.3%; 95% CI: 0.3, 4.3). Increased relative rates of influenza ED visits and culture negative pneumonia hospitalizations were generally larger in the After period (p< 0.025 for both outcomes), compared to the During period, despite reductions in overall PM2.5 concentrations. Conclusion: Increased rates of culture negative pneumonia and influenza were associated with increased PM2.5 concentrations during the previous week, which persisted despite reductions in PM2.5 from air quality policies and economic changes. Though unexplained, this temporal variation may reflect altered toxicity of different PM2.5 mixtures or increased pathogen virulence

The mechanism of transglutaminase 2 externalisation in renal tubular epithelial cells

Transglutaminase type 2 (TG2) catalyses the formation of an ε-(γ-glutamyl)-lysine isopeptide bonds between adjacent peptides or proteins including those of the extracellular matrix(ECM). ECM crosslinking has been associated with both the acceleration of collagen deposition while conferring the ECM with resistance to proteolytic degradation. Subsequently the cellular secretion of TG2 has been associated with wound healing and aberrant wound healing leading to kidney, lung, liver and heart fibrosis as well as atherosclerosis. TG2 has no signal peptide and cannot be transported classically. It is unknown how TG2 is targeted to the cell surface and secreted into ECM. Understanding TG2 transport may help to develop specific mechanisms to interfere with TG2 action in the scarring process. In this study, we identified that amino acids 88-106 in N-terminal β-sandwich domain of TG2 molecule is crucial for TG2 externalisation using deletion and mutation analysis in three renal tubular epithelial cells (TEC). Of interest, this TG2 export motif (aa88-106) itself appeared to be able to target other proteins for extracellular secretion. Yeast-two-hybrid studies were then performed to identify what the TG2 export motif would bind to and thus give clues as to the downstream mechanism of trafficking. Large T antigen (LTA) and tapasin were identified as binding partners. The interaction between LTA or tapasin and TG2 was confirmed by co-immunoprecipitation using endogenous protein from wild-type cells. TG2 externalisation was significantly decreased when LTA and tapasin were knockdown using siRNA suggesting that large T antigen and tapasin is involved in TG2 externalisation process. The possible TG2 externalisation pathway was explored further using fluorescent imaging including co-localisation analysis and live cell imaging. TG2 was predominantly co-localised with endoplasmic reticulum (ER) around the cell nucleus, but not localised with Golgi apparatus and lysosomes. We observed plasma membrane blebbing in the cells transfected with wild-type TG2 but not in the cells transfected withTG2 carrying a mutation in the export motif. Plasma membrane blebbing or a direct molecular trap is the most likely mechanism for TG2 externalisation based on the data generated. In conclusion, the amino acid sequence 88-106 in β-sandwich domain of TG2 is critical to TG2 externalisation in TEC. This export motif binds to large T antigen and tapasin. Large T antigen and tapasin is involved in TG2 externalisation possibly through plasma membrane blebbing or direct molecular trap in TEC.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

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