Idiopathic or genetic adult-onset epilepsy is a common neurological disorder in domestic dogs. Genetic association has been reported only with ADAM23 on CFA 37 in few breeds. To identify novel ...epilepsy genes, we performed genome-wide association (GWA) analyses in four new breeds, and investigated the association of the previously reported ADAM23 haplotype with the epilepsy phenotype in eight breeds.
GWA analysis did not reveal new epilepsy loci. ADAM23 association (p < 0.05) was identified in five breeds. Combined analysis of all eight breeds showed significant association (p = 4.6e
, OR 1.9).
Our results further support the role of ADAM23 in multiple breeds as a common risk gene for epilepsy with low penetrance. The lack of findings in the GWA analyses points towards inefficient capture of genetic variation by the current SNP arrays, causal variant(s) with low penetrance and possible phenocopies. Future work will include studies on ADAM23 function and expression in canine neurons, as well as whole-genome sequencing in order to identify additional IE genes.
Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among ...employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression.
We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol.
We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13 and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32).
Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.
Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a ...post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.
We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed.
From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years SD 6·4, 5225 85·3% men, 903 14·7% women, 2046 33·4% with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029–2052) and median on-treatment follow-up was 1324 days (IQR 870–1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients 1·72 events per 100 patient-years) was non-inferior to allopurinol (241 patients 2·05 events per 100 patient-years; adjusted HR 0·85 95% CI 0·70–1·03, p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 0·6% patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five 0·2% patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group.
Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
Menarini, Ipsen, and Teijin Pharma Ltd.
Context.
Several observational and theoretical results indicate that the atmospheric temperature of the ultra-hot Jupiter KELT-9b in the main line formation region is a few thousand degrees higher ...than predicted by self-consistent models.
Aims.
Our aim was to test whether non-local thermodynamic equilibrium (NLTE) effects are responsible for the presumably higher temperature.
Methods.
We employed the Cloudy NLTE radiative transfer code to self-consistently compute the upper atmospheric temperature-pressure (TP) profile of KELT-9b, assuming solar metallicity and accounting for Roche potential. In the lower atmosphere, we used an updated version of the HELIOS radiative-convective equilibrium code to constrain the Cloudy model.
Results.
The Cloudy NLTE TP profile is ≈2000 K hotter than that obtained with previous models assuming LTE. In particular, in the 1–10
−7
bar range the temperature increases from ≈4000 to ≈8500 K, remaining roughly constant at lower pressures. We find that the high temperature in the upper atmosphere of KELT-9b is driven principally by NLTE effects modifying the Fe and Mg level populations, which strongly influence the atmospheric thermal balance. We employed Cloudy to compute LTE and NLTE synthetic transmission spectra on the basis of the TP profiles computed in LTE and NLTE, respectively, finding that the NLTE model generally produces stronger absorption lines, particularly in the ultraviolet, than the LTE model (up to 30%). We compared the NLTE synthetic transmission spectrum with the observed H
α
and H
β
line profiles obtaining an excellent match, thus supporting our results.
Conclusions.
The NLTE synthetic transmission spectrum can be used to guide future observations aiming at detecting features in the KELT-9b transmission spectrum. Metals, such as Mg and Fe, and NLTE effects shape the upper atmospheric temperature structure of KELT-9b, and thus affect the mass-loss rates derived from it. Finally, our results call for checking whether this is the case also for cooler planets.
Rapidly declining biodiversity may be a contributing factor to another global megatrend—the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations ...worldwide. According to the "biodiversity hypothesis," reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity. Analyzing atopic sensitization (i.e., allergic disposition) in a random sample of adolescents living in a heterogeneous region of 100 x 150 km, we show that environmental biodiversity in the surroundings of the study subjects’ homes influenced the composition of the bacterial classes on their skin. Compared with healthy individuals, atopic individuals had lower environmental biodiversity in the surroundings of their homes and significantly lower generic diversity of gammaproteobacteria on their skin. The functional role of the Gram-negative gammaproteobacteria is supported by in vitro measurements of expression of IL-10, a key anti-inflammatory cytokine in immunologic tolerance, in peripheral blood mononuclear cells. In healthy, but not in atopic, individuals, IL-10 expression was positively correlated with the abundance of the gammaproteobacterial genus Acinetobacter on the skin. These results raise fundamental questions about the consequences of biodiversity loss for both allergic conditions and public health in general.
Extremely irradiated, close-in planets to early-type stars might be prone to strong atmospheric escape. We review the literature showing that X-ray-to-optical measurements indicate that for ...intermediate-mass stars (IMSs) cooler than 8250 K, the X-ray and extreme-ultraviolet (XUV) fluxes are on average significantly higher than those of solar-like stars, while for hotter IMSs, because of the lack of surface convection, it is the opposite. We construct spectral energy distributions for prototypical IMSs, comparing them to solar. The XUV fluxes relevant for upper-planet atmospheric heating are highest for the cooler IMSs and lowest for the hotter IMSs, while the ultraviolet (UV) fluxes increase with increasing stellar temperature. We quantify the influence of this characteristic of the stellar fluxes on the mass loss of close-in planets by simulating the atmospheres of planets orbiting EUV-bright (WASP-33) and EUV-faint (KELT-9) A-type stars. For KELT-9b, we find that atmospheric expansion caused by heating due to absorption of the stellar UV and optical light drives mass-loss rates of 1011 g s−1, while heating caused by absorption of the stellar XUV radiation leads to mass-loss rates of 1010 g s−1, thus underestimating mass loss. For WASP-33b, the high XUV stellar fluxes lead to mass-loss rates of 1011 g s−1. Even higher mass-loss rates are possible for less massive planets orbiting EUV-bright IMSs. We argue that it is the weak XUV stellar emission, combined with a relatively high planetary mass, which limit planetary mass-loss rates, to allow the prolonged existence of KELT-9-like systems.
Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a ...comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual's subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.
Summary Background Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We ...analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. Methods We used individual records from 13 European cohort studies (1985–2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. Findings 30 214 (15%) of 197 473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years SD 1·7), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10–1·37). This effect estimate was higher in published (1·43, 1·15–1·77) than unpublished (1·16, 1·02–1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15–1·48) and 5 years (1·30, 1·13–1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. Interpretation Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. Funding Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.
Context.
Observationally constraining the atmospheric temperature-pressure (TP) profile of exoplanets is an important step forward for improving planetary atmosphere models, thus further enabling one ...to place the detection of spectral features and the measurement of atomic and molecular abundances through transmission and emission spectroscopy on solid ground.
Aims.
The aim is to constrain the TP profile of the ultra-hot Jupiter KELT-9b by fitting synthetic spectra to the observed H
α
and H
β
lines and identify why self-consistent planetary TP models are unable to fit the observations.
Methods.
We constructed 126 one-dimensional TP profiles varying the lower and upper atmospheric temperatures, as well as the location and gradient of the temperature rise. For each TP profile, we computed the transmission spectra of the H
α
and H
β
lines employing the Cloudy radiative transfer code, which self-consistently accounts for non-local thermodynamic equilibrium (NLTE) effects.
Results.
The TP profiles, leading to best fit the observations, are characterised by an upper atmospheric temperature of 10 000–11 000 K and by an inverted temperature profile at pressures higher than 10
−4
bar. We find that the assumption of local thermodynamic equilibrium (LTE) leads one to overestimate the level population of excited hydrogen by several orders of magnitude and hence to significantly overestimate the strength of the Balmer lines. The chemical composition of the best fitting models indicate that the high upper atmospheric temperature is most likely driven by metal photoionisation and that Fe
II
and Fe
III
have comparable abundances at pressures lower than 10
−6
bar, possibly making the latter detectable.
Conclusions.
Modelling the atmospheres of ultra-hot Jupiters requires one to account for metal photoionisation. The high atmospheric mass-loss rate (>10
11
g s
−1
), caused by the high temperature, may have consequences on the planetary atmospheric evolution. Other ultra-hot Jupiters orbiting early-type stars may be characterised by similarly high upper atmospheric temperatures and hence high mass-loss rates. This may have consequences on the basic properties of the observed planets orbiting hot stars.
The relationship of magnetic clouds (MCs) to interplanetary coronal mass ejections (ICMEs) is still an open issue in space research. The view that all ICMEs would originate as magnetic flux ropes has ...received increasing attention, although near the orbit of the Earth only about one-third of ICMEs show clear MC signatures and often the MC occupies only a portion of the more extended region showing ICME signatures. In this work we analyze 79 events between 1996 and 2009 reported in existing ICME/MC catalogs (Wind magnetic cloud list and the Richardson and Cane ICME list) using near-Earth observations by ACE (Advanced Composition Explorer) and Wind. We perform a systematic comparison of cases where ICME and MC signatures coincided and where ICME signatures extended significantly beyond the MC boundaries. We find clear differences in the characteristics of these two event types. In particular, the events where ICME signatures continued more than 6 h past the MC rear boundary had 2.7 times larger speed difference between the ICME's leading edge and the preceding solar wind, 1.4 times higher magnetic fields, 2.1 times larger widths and they experienced three times more often strong expansion than the events for which the rear boundaries coincided. The events with significant mismatch in MC and ICME boundary times were also embedded in a faster solar wind and the majority of them were observed close to the solar maximum. Our analysis shows that the sheath, the MC and the regions of ICME-related plasma in front and behind the MC have different magnetic field, plasma and charge state characteristics, thus suggesting that these regions separate already close to the Sun. Our study shows that the geometrical effect (the encounter through the CME leg and/or far from the flux rope center) does not contribute much to the observed mismatch in the MC and ICME boundary times.
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