Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men

This is the final version. Available from British Pharmacological Society / Wiley via the DOI in this record. The genetic and phenotypic UK Biobank data are available upon application to the UK Biobank (www.ukbiobank.ac.uk/register-apply). The derived data fields used in our analysis will be available via the UK Biobank, search for application number 14631. We are not able to share these directly.OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. METHODS AND ANALYSIS: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. RESULTS: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.National Institute for Health ResearchMinistry of National Education, Republic of TurkeyExpanding Excellence in EnglandUniversity of Exeter Medical Schoo

Cost-effectiveness of sorafenib for treatment of radioactive iodine (rai)-refractory locally advanced/metastatic differentiated thyroid cancer (dtc) in Turkey

WOS: 000354498503198OBJECTIVES: Sorafenib is the first product approved for treatment of RAI refractory locally advanced/metastatic DTC patients. This study was conducted in order to analyze cost-effectiveness of sorafenib for treatment of patients with RAI refractory locally advanced/metastatic DTC in Turkey. METHODS: A cohort partition model assigning patients to one of three health states according to the proportion of patients who are progression-free, progressed, or dead in each 28-days cycle was adapted to Turkish setting. The incremental cost-effectiveness ratios (ICER) were calculated per quality-adjusted life years (QALYs) and life-years (LYs) gained. Turkish payer’s perspective was taken and time-horizon was set as patient’s lifetime (maximum 30 years). Sorafenib was compared to the best supportive care (BSC) within the model since there are no agents for treatment of patients on this stage of the disease. Essential clinical inputs were derived from DECISION trial and local resource-utilization data were based on expert opinions through an expert panel. Sensitivity of the results was evaluated in terms of key inputs by deterministic oneway and probabilistic sensitivity analyses. All costs were calculated in Turkish Liras (TL) and converted to USD using TL/USD currency rate as 2.2 (mid-2014). RESULTS: Total cost of sorafenib-treated patients is 24,384 USD higher compared to BSC. Besides, sorafenib is associated with increments of 1.29 LYs and 0.80 QALYs compared to BSC. The ICER of sorafenib per LYs and QALYs gained compared to BSC were determined as 18,851 USD and 30,485 USD respectively. One-way sensitivity analysis demonstrated that results are not sensitive to the changes in model inputs and pharmacoeconomic analysis results were validated by probabilistic sensitivity analysis. CONCLUSIONS: Sorafenib is cost-effective for treatment of patients with RAI refractory locally advanced/metastatic DTC compared to BSC with an ICER value below the willingness-to-pay threshold (3-times GDP per capita ─ 32,346 USD) for Turkey

Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study.

This is the final version. Available from BMJ Publishing Group via the DOI in this record. Data availability statement: Data may be obtained from a third party and are not publicly available. Data are available on application to the UK Biobank ( www.ukbiobank.ac.uk/register-apply). Additional data are available from the corresponding author on reasonable request.OBJECTIVE: To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. DESIGN: Retrospective cohort analysis. SETTING: Primary care practices in the UK from January 1999 to September 2017. PARTICIPANTS: 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36-79 years at time of first clopidogrel prescription. INTERVENTIONS: Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). MAIN OUTCOME MEASURE: Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. RESULTS: 28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. CONCLUSIONS: A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.Medical Research CouncilAlzheimer’s SocietyNational Institute for Health ResearchUniversity of Exeter Medical SchoolUniversity of Connecticut School of MedicineMinistry of National Education, Republic of TurkeyTravelers Chair in Geriatrics and GerontologyNational Institute on Agin

Chemical and Microbiological Contamination in Limpet (Patella spp.) of the Portuguese Coast

Coastal production areas can be impacted by anthropogenic contamination from urban, agro-industrial and leisure activities. Some contaminants, such as chemical substances might also have a telluric origin. Non filter feeding univalve mollusks, such as limpets, which are collected in rocky shores either for sale or for auto-consumption, are very appreciated in Portugal, but have been excluded from provisions on the classification of production areas, although can present relevant contamination. Thus, the aim of this study was to assess the microbiological and toxic metal contaminations in limpets (Patella spp) of the Portuguese coast, taking into account the production area and seasonal variation, and comparing their contamination levels with those occurring in bivalve mollusk indicator species, mussel (Mytilus edulis). The risks associated to the consumption of limpet meals were also assessed. For that, microbial total and fecal levels and cadmium, lead and mercury contents in limpets and mussels samples from three coastal areas over several months were analyzed based on standard methodologies. Contents of mercury and lead in limpets from the three areas studied, were always below the limits of 0.50 mg kg-1 and 1.5 mg kg-1 allowed by the EU, respectively. Regarding cadmium, levels in limpet were always above the limit of 1.0 mg kg-1, reaching about 3.0 mg kg-1 in some samples. These values probably indicate contamination from telluric origin (soil or rocks) in the coastal studied areas. Results indicated that microbiological contamination of fecal origin was low and in general below the detection level. Contamination levels did not show a clear seasonal pattern. The two mollusk species, limpets and mussels, differed statistically in all contaminants analyzed, being cadmium the most of concern, and always higher in limpets than in mussel samples. Thus, the potential risk associated with limpet consumption, taking into account the cadmium tolerable weekly intake (TWI), was investigated, being possible to reach a reliable recommendation of less than a monthly meal of 160 g. As recreational picking of limpets is common in Portugal, official 4recommendations of maximum periodic human consumption should be published and enforcement increased in forbidden areasinfo:eu-repo/semantics/acceptedVersio

A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies

Masonry compressive strength prediction using artificial neural networks

The masonry is not only included among the oldest building materials, but it is also the most widely used material due to its simple construction and low cost compared to the other modern building materials. Nevertheless, there is not yet a robust quantitative method, available in the literature, which can reliably predict its strength, based on the geometrical and mechanical characteristics of its components. This limitation is due to the highly nonlinear relation between the compressive strength of masonry and the geometrical and mechanical properties of the components of the masonry. In this paper, the application of artificial neural networks for predicting the compressive strength of masonry has been investigated. Specifically, back-propagation neural network models have been used for predicting the compressive strength of masonry prism based on experimental data available in the literature. The comparison of the derived results with the experimental findings demonstrates the ability of artificial neural networks to approximate the compressive strength of masonry walls in a reliable and robust manner.- (undefined