Abstract Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly ...understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.
Estrogen receptor alpha (ERalpha) is a transcription factor that regulates expression of target genes in a ligand-dependent manner. Activation of gene expression is mediated by two transcription ...activation functions AF-1 and AF-2, which act in a promoter- and cell-specific manner. Whilst AF-2 activity is regulated by estrogen (E2) binding, the activity of AF-1 is additionally modulated by phosphorylation at several sites. One of these phosphorylation sites, serine 118 (S118) is of particular interest as its mutation significantly reduces ERalpha activity. Previous studies have shown that S118 can be phosphorylated by the ERK1/2 mitogen activated protein kinases (MAPK) and by the cyclin-dependent protein kinase Cdk7. In this study we use antisera that specifically recognize ERalpha phosphorylated at S118 to demonstrate that MAPK phosphorylates S118 in a ligand-independent manner, whereas Cdk7 mediates E2-induced phosphorylation of S118. E2 stimulation of S118 phosphorylation was observed within 10 min of its addition and was maximal at 10(-7) M E2. S118 phosphorylation was maximal at 30 min but then declined, such that by 180 min following E2 addition little S118 phosphorylation was evident. S118 phosphorylation was also induced by the partial estrogen antagonist 4-hydroxytamoxifen, but not by the complete antagonist ICI 182, 780. S118 phosphorylation upon addition of the MAPK inducers EGF or PMA followed the expected time courses. Finally, we show that ERalpha is phosphorylated at S118 in vivo using immunoblotting of extracts prepared from a series of ERalpha-positive breast tumours.
An analysis of the direct soft photon production rate as a function of the parent jet characteristics is presented, based on hadronic events collected by the DELPHI experiment at LEP1. The ...dependences of the photon rates on the jet kinematic characteristics (momentum, mass, etc.) and on the jet charged, neutral and total hadron multiplicities are reported. Up to a scale factor of about four, which characterizes the overall value of the soft photon excess, a similarity of the observed soft photon behavior to that of the inner hadronic bremsstrahlung predictions is found for the momentum, mass, and jet charged multiplicity dependences. However for the dependence of the soft photon rate on the jet neutral and total hadron multiplicities a prominent difference is found for the observed soft photon signal as compared to the expected bremsstrahlung from final state hadrons. The observed linear increase of the soft photon production rate with the jet total hadron multiplicity and its strong dependence on the jet neutral multiplicity suggest that the rate is proportional to the number of quark pairs produced in the fragmentation process, with the neutral pairs being more effectively radiating than the charged ones.
IMPORTANCE: A meta-analysis of outcomes during the 6 months after intensive care unit (ICU) discharge indicate a prevalence for clinically important posttraumatic stress disorder (PTSD) symptoms of ...25%. OBJECTIVE: To determine whether a nurse-led preventive, complex psychological intervention, initiated in the ICU, reduces patient-reported PTSD symptom severity at 6 months. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, parallel-group, cluster-randomized clinical trial with integrated economic and process evaluations conducted in 24 ICUs in the United Kingdom. Participants were critically ill patients who regained mental capacity following receipt of level 3 (intensive) care. A total of 2961 eligible patients were identified from September 2015 to January 2017. A total of 2048 were approached for participation in the ICU, of which 1458 provided informed consent. Follow-up was completed December 2017. INTERVENTIONS: Twenty four ICUs were randomized 1:1 to the intervention or control group. Intervention ICUs (n = 12; 669 participants) delivered usual care during a baseline period followed by an intervention period. The preventive, complex psychological intervention comprised promotion of a therapeutic ICU environment plus 3 stress support sessions and a relaxation and recovery program delivered by trained ICU nurses to high-risk (acutely stressed) patients. Control ICUs (n = 12; 789 participants) delivered usual care in both baseline and intervention periods. MAIN OUTCOMES AND MEASURES: The primary clinical outcome was PTSD symptom severity among survivors at 6 months measured using the PTSD Symptom Scale–Self-Report questionnaire (score range, 0-51, with higher scores indicating greater symptom severity; the minimal clinically important difference was considered to be 4.2 points). RESULTS: Among 1458 enrolled patients (mean SD age, 58 16 years; 599 women 41%), 1353 (93%) completed the study and were included in the final analysis. At 6 months, the mean PTSD Symptom Scale–Self-Report questionnaire score in intervention ICUs was 11.8 (baseline period) compared with 11.5 (intervention period) (difference, −0.40 95% CI, −2.46 to 1.67) and in control ICUs, 10.1 (baseline period) compared with 10.2 (intervention period) (difference, 0.06 95% CI, −1.74 to 1.85) between periods. There was no significant difference in PTSD symptom severity at 6 months (treatment effect estimate difference in differences of −0.03 95% CI, −2.58 to 2.52; P = .98). CONCLUSIONS AND RELEVANCE: Among critically ill patients in the ICU, a nurse-led preventive, complex psychological intervention did not significantly reduce patient-reported PTSD symptom severity at 6 months. These findings do not support the use of this psychological intervention. TRIAL REGISTRATION: ISRCTN53448131
A measurement of the W boson mass and width has been performed by the DELPHI collaboration using the data collected during the full LEP2 programme (1996-2000). The data sample has an integrated ...luminosity of 660 pb(-1) and was collected over a range of centre-of-mass energies from 161 to 209 GeV. Results are obtained by applying the method of direct reconstruction of the mass of the W from its decay products in both the W+W- -> l (nu) over bar (l) and W+W- -> q (q) over bar'(q) over barq'channels. The W mass result for the combined data set is M-W = 80.336 +/- 0.055(Stat.) +/- 0.028(Syst.) +/- 0.025(FSI) +/- 0.009(LEP) GeV/c(2) , where FSI represents the uncertainty due to final state interaction effects in the q (q) over bar'(q) over barq' channel, and LEP represents that arising from the knowledge of the collision energy of the accelerator. The combined value for the W width is Gamma(W) = 2.404 +/- 0.140(Stat.) +/- 0.077(Syst.) +/- 0.065(FSI) GeV/c(2). These results supersede all values previously published by the DELPHI collaboration.
This paper presents the application of a decision‐support tool, SimBiopharma, for assessing different manufacturing strategies under uncertainty for the production of biopharmaceuticals. SimBiopharma ...captures both the technical and business aspects of biopharmaceutical manufacture within a single tool that permits manufacturing alternatives to be evaluated in terms of cost, time, yield, project throughput, resource utilization, and risk. Its use for risk analysis is demonstrated through a hypothetical case study that uses the Monte Carlo simulation technique to imitate the randomness inherent in manufacturing subject to technical and market uncertainties. The case study addresses whether start‐up companies should invest in a stainless steel pilot plant or use disposable equipment for the production of early phase clinical trial material. The effects of fluctuating product demands and titers on the performance of a biopharmaceutical company manufacturing clinical trial material are analyzed. The analysis highlights the impact of different manufacturing options on the range in possible outcomes for the project throughput and cost of goods and the likelihood that these metrics exceed a critical threshold. The simulation studies highlight the benefits of incorporating uncertainties when evaluating manufacturing strategies. Methods of presenting and analyzing information generated by the simulations are suggested. These are used to help determine the ranking of alternatives under different scenarios. The example illustrates the benefits to companies of using such a tool to improve management of their R&D portfolios so as to control the cost of goods.
We develop a random effects discrete choice model for the analysis of households' choice of neighborhood over time. The model is parameterized in a way that exploits longitudinal data to separate the ...influence of neighborhood characteristics on the decision to move out of the current area ("push" effects) and on the choice of one destination over another ("pull" effects). Random effects are included to allow for unobserved heterogeneity between households in their propensity to move, and in the importance placed on area characteristics. The model also includes area-level random effects. The combination of a large choice set, large sample size, and repeated observations mean that existing estimation approaches are often infeasible. We, therefore, propose an efficient MCMC algorithm for the analysis of large-scale datasets. The model is applied in an analysis of residential choice in England using data from the British Household Panel Survey linked to neighborhood-level census data. We consider how effects of area deprivation and distance from the current area depend on household characteristics and life course transitions in the previous year. We find substantial differences between households in the effects of deprivation on out-mobility and selection of destination, with evidence of severely constrained choices among less-advantaged households. web URL: http://www.tandfonline.com/doi/full/10.1080/01621459.2016.1180984
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