Effect of atorvastatin on glycaemia progression in patients with diabetes:an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS)

AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. METHODS: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA(1c) data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA(1c) of ≥0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA(1c) as a continuous endpoint. RESULTS: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA(1c) was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA(1c) predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA(1c) change (interaction p value 0.229). CONCLUSIONS/INTERPRETATION: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3802-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Transition of plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein pumilio

Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials

The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98).In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials

The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98).In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not

How Chromatin Is Remodelled during DNA Repair of UV-Induced DNA Damage in Saccharomyces cerevisiae

Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation–induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides important insight into how GG-NER operates in chromatin

A method to design job rotation schedules to prevent work-related musculoskeletal disorders in repetitive work

This is an Accepted Manuscript of an article published by Taylor & Francis Group in International Journal of Production Research in 2012, available online: http://www.tandfonline.com/10.1080/00207543.2011.653452.Job rotation is an organisational strategy widely used in human-based production lines with the aim of preventing work-related musculoskeletal disorders (WMSDs). These work environments are characterised by the presence of a high repetition of movements, which is a major risk factor associated with WMSDs. This article presents a genetic algorithm to obtain rotation schedules aimed at preventing WMSDs in such environments. To do this, it combines the effectiveness of genetic algorithms optimisation with the ability to evaluate the presence of risk by repeated movements by following the OCRA ergonomic assessment method. The proposed algorithm can design solutions in which workers will switch jobs with high repeatability of movements with other less demanding jobs that support their recovery. In addition, these solutions are able to diversify the tasks performed by workers during the day, consider their disabilities and comply with restrictions arising from the work organisation.The authors wish to thank the Universitat Politecnica de Valencia which supported this research through its Program for the Support of Research and Development 2009 and its financing through the project PAID-06-09/2902.Asensio Cuesta, S.; Diego-Mas, JA.; Cremades Oliver, L.; González-Cruz, M. (2012). A method to design job rotation schedules to prevent work-related musculoskeletal disorders in repetitive work. International Journal of Production Research. 50(24):7467-7478. https://doi.org/10.1080/00207543.2011.653452S74677478502

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C