Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank

BACKGROUND: High circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways. METHODS: We conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank (n = 378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69 years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, APOB, APOC3, and LDLR) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ≥60 years) only. Several sensitivity analyses were also conducted. FINDINGS: On average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR-, APOC3-, NPC1L1-, and LDLR-specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB. All sensitivity analyses produced similar findings. INTERPRETATION: A genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits

The mass discrepancy in intermediate- and high-mass eclipsing binaries: The need for higher convective core masses

Context. Eclipsing, spectroscopic double-lined binary star systems are excellent laboratories for calibrating theories of stellar interior structure and evolution. Their precise and accurate masses and radii measured from binary dynamics offer model-independent constraints and challenge current theories of stellar evolution. Aims. We aim to investigate the mass discrepancy in binary stars. This is the significant difference between stellar components’ masses measured from binary dynamics and those inferred from models of stellar evolution via positions of the components in the Teff − log g Kiel diagram. We study the effect of near-core mixing on the mass of the convective core of the stars and interpret the results in the context of the mass discrepancy. Methods. We fitted stellar isochrones computed from a grid of MESA stellar evolution models to a homogeneous sample of eleven high-mass binary systems. Two scenarios are considered where individual stellar components of a binary system are treated independent of each other and where they are forced to have the same age and initial chemical composition. We also study the effect of the microturbulent velocity and turbulent pressure on the atmosphere model structure and stellar spectral lines, and its link with the mass discrepancy. Results. We find that the mass discrepancy is present in our sample and that it is anti-correlated with the surface gravity of the star. No correlations are found with other fundamental and atmospheric parameters, including the stellar mass. The mass discrepancy can be partially accounted for by increasing the amount of near-core mixing in stellar evolution models. We also find that ignoring the microturbulent velocity and turbulent pressure in stellar atmosphere models of hot evolved stars results in the overestimation of their effective temperature by up to 8%. Together with enhanced near-core mixing, this can almost entirely account for the ∼30% mass discrepancy found for the evolved primary component of V380 Cyg. Conclusions. We find a strong link between the mass discrepancy and the convective core mass. The mass discrepancy can be solved by considering the combined effect of extra near-core boundary mixing and the consistent treatment in the spectrum analysis of hot evolved stars. Our binary modelling results in convective core masses between 17 and 35% of the stellar mass, which is in excellent agreement with the results from gravity-mode asteroseismology of single stars. This implies larger helium core masses near the end of the main sequence than have been anticipated so far

Incidence of Atrial Fibrillation in Patients with either Heart Failure or Acute Myocardial Infarction and Left Ventricular Dysfunction: A Cohort Study

<p>Abstract</p> <p>Background</p> <p>We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months.</p> <p>Methods</p> <p>The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo.</p> <p>Results</p> <p>The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group.</p> <p>Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89).</p> <p>In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86).</p> <p>In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24).</p> <p>Conclusion</p> <p>In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).</p

Selection Bias in a Study of Implantable Defibrillator Patients: The Role of Type D Personality

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Selection bias constitutes a major issue in research using volunteers as study participants. Purpose We examined whether research in partners may affect participation rates of implantable cardioverterdefibrillator (ICD) patients with a Type D personality (joint presence of negative affectivity and social inhibition). Method Patients who underwent ICD implantation between May 2003 and November 2007, and who had a partner, were included (n=440). In September 2005, a substudy on partners of ICD patients was added (n=276 patients). Results The proportion Type D patients after the start of the partner substudy was significantly lower as compared to the proportion before this substudy (17.5 % versus 28.8%; p= 0.006). Patients who participated following the start of the partner substudy were less likely to have a Type D personality (OR=0.44; p=0.002), adjusting for possible confounders. In the partner substudy, nonparticipation was more prevalent among partners of Type D patients as compared to partners of non-Type D patients (20.4 % versus 10.1%; p=0.044). Partner nonparticipation was marginally significantly associated with Type D personality of the patient (OR=2.13; p=0.083), adjusting for confounders. Conclusions The addition of a partner substudy may be related to a decreased proportion of participants with a Type D personality. Nonparticipation was more prevalent among partners of Type D patients. These observations may influence results of studies, as Type Ds tend to be less healthy

Extremely high He isotope ratios in MORB-source mantle from the proto-Iceland plume

The high &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He ratios yet recorded. A strong correlation between &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He and &lt;sup&gt;87&lt;/sup&gt;Sr/&lt;sup&gt;86&lt;/sup&gt;Sr, &lt;sup&gt;143&lt;/sup&gt;Nd/&lt;sup&gt;144&lt;/sup&gt;Nd and trace element ratios demonstrate that the &lt;sup&gt;3&lt;/sup&gt;He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a &lt;sup&gt;3&lt;/sup&gt;He-recharged depleted mantle (HRDM) reservoir may be the principal source of high &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure

Comparison of Short-Term Estrogenicity Tests for Identification of Hormone-Disrupting Chemicals

The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17β-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17β-Estradiol, 17α-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds—tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p′-DDT, p,p′-DDE, endosulfan, chlomequat chloride, and ethanol—varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods

The impact of albendazole treatment on the incidence of viral- and bacterial-induced diarrhea in school children in southern Vietnam: study protocol for a randomized controlled trial

Anthelmintics are one of the more commonly available classes of drugs to treat infections by parasitic helminths (especially nematodes) in the human intestinal tract. As a result of their cost-effectiveness, mass school-based deworming programs are becoming routine practice in developing countries. However, experimental and clinical evidence suggests that anthelmintic treatments may increase susceptibility to other gastrointestinal infections caused by bacteria, viruses, or protozoa. Hypothesizing that anthelmintics may increase diarrheal infections in treated children, we aim to evaluate the impact of anthelmintics on the incidence of diarrheal disease caused by viral and bacterial pathogens in school children in southern Vietnam.This is a randomized, double-blinded, placebo-controlled trial to investigate the effects of albendazole treatment versus placebo on the incidence of viral- and bacterial-induced diarrhea in 350 helminth-infected and 350 helminth-uninfected Vietnamese school children aged 6-15 years. Four hundred milligrams of albendazole, or placebo treatment will be administered once every 3 months for 12 months. At the end of 12 months, all participants will receive albendazole treatment. The primary endpoint of this study is the incidence of diarrheal disease assessed by 12 months of weekly active and passive case surveillance. Secondary endpoints include the prevalence and intensities of helminth, viral, and bacterial infections, alterations in host immunity and the gut microbiota with helminth and pathogen clearance, changes in mean z scores of body weight indices over time, and the number and severity of adverse events.In order to reduce helminth burdens, anthelmintics are being routinely administered to children in developing countries. However, the effects of anthelmintic treatment on susceptibility to other diseases, including diarrheal pathogens, remain unknown. It is important to monitor for unintended consequences of drug treatments in co-infected populations. In this trial, we will examine how anthelmintic treatment impacts host susceptibility to diarrheal infections, with the aim of informing deworming programs of any indirect effects of mass anthelmintic administrations on co-infecting enteric pathogens.ClinicalTrials.gov: NCT02597556 . Registered on 3 November 2015

Nitrogen uptake and internal recycling in Zostera marina exposed to oyster farming: eelgrass potential as a natural biofilter

Oyster farming in estuaries and coastal lagoons frequently overlaps with the distribution of seagrass meadows, yet there are few studies on how this aquaculture practice affects seagrass physiology. We compared in situ nitrogen uptake and the productivity of Zostera marina shoots growing near off-bottom longlines and at a site not affected by oyster farming in San Quintin Bay, a coastal lagoon in Baja California, Mexico. We used benthic chambers to measure leaf NH4 (+) uptake capacities by pulse labeling with (NH4)-N-15 (+) and plant photosynthesis and respiration. The internal N-15 resorption/recycling was measured in shoots 2 weeks after incubations. The natural isotopic composition of eelgrass tissues and vegetative descriptors were also examined. Plants growing at the oyster farming site showed a higher leaf NH4 (+) uptake rate (33.1 mmol NH4 (+) m(-2) day(-1)) relative to those not exposed to oyster cultures (25.6 mmol NH4 (+) m(-2) day(-1)). We calculated that an eelgrass meadow of 15-16 ha (which represents only about 3-4 % of the subtidal eelgrass meadow cover in the western arm of the lagoon) can potentially incorporate the total amount of NH4 (+) excreted by oysters (similar to 5.2 x 10(6) mmol NH4 (+) day(-1)). This highlights the potential of eelgrass to act as a natural biofilter for the NH4 (+) produced by oyster farming. Shoots exposed to oysters were more efficient in re-utilizing the internal N-15 into the growth of new leaf tissues or to translocate it to belowground tissues. Photosynthetic rates were greater in shoots exposed to oysters, which is consistent with higher NH4 (+) uptake and less negative delta C-13 values. Vegetative production (shoot size, leaf growth) was also higher in these shoots. Aboveground/belowground biomass ratio was lower in eelgrass beds not directly influenced by oyster farms, likely related to the higher investment in belowground biomass to incorporate sedimentary nutrients