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- Dalby, M, et al.
(author)
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Characterizing mood disorders in the AFFECT study: a large, longitudinal, and phenotypically rich genetic cohort in the US
- 2022
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1, s. 121-
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Journal article (peer-reviewed)abstract
- There has recently been marked progress in identifying genetic risk factors for major depression (MD) and bipolar disorder (BD); however, few systematic efforts have been made to elucidate heterogeneity that exists within and across these diagnostic taxa. The Affective disorders, Environment, and Cognitive Trait (AFFECT) study presents an opportunity to identify and associate the structure of cognition and symptom-level domains across the mood disorder spectrum in a prospective study from a diverse US population.Participants were recruited from the 23andMe, Inc research participant database and through social media; self-reported diagnosis of MD or BD by a medical professional and medication status data were used to enrich for mood-disorder cases. Remote assessments were used to acquire an extensive range of phenotypes, including mood state, transdiagnostic symptom severity, task-based measures of cognition, environmental exposures, personality traits. In this paper we describe the study design, and the demographic and clinical characteristics of the cohort. In addition we report genetic ancestry, SNP heritability, and genetic correlations with other large cohorts of mood disorders.A total of 48,467 participants were enrolled: 14,768 with MD, 9864 with BD, and 23,835 controls. Upon enrollment, 47% of participants with MD and 27% with BD indicated being in an active mood episode. Cases reported early ages of onset (mean = 13.2 and 14.3 years for MD and BD, respectively), and high levels of recurrence (78.6% and 84.9% with >5 episodes), psychotherapy, and psychotropic medication use. SNP heritability on the liability scale for the ascertained MD participants (0.19–0.21) was consistent with the high level of disease severity in this cohort, while BD heritability estimates (0.16–0.22) were comparable to reports in other large scale genomic studies of mood disorders. Genetic correlations between the AFFECT cohort and other large-scale cohorts were high for MD but not for BD. By incorporating transdiagnostic symptom assessments, repeated measures, and genomic data, the AFFECT study represents a unique resource for dissecting the structure of mood disorders across multiple levels of analysis. In addition, the fully remote nature of the study provides valuable insights for future virtual and decentralized clinical trials within mood disorders.
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- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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- Alcorn, J, et al.
(author)
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Basic instrumentation for Hall A at Jefferson Lab
- 2004
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In: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 522:3, s. 294-346
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Journal article (peer-reviewed)abstract
- The instrumentation in Hall A at the Thomas Jefferson National Accelerator Facility was designed to study electro-and photo-induced reactions at very high luminosity and good momentum and angular resolution for at least one of the reaction products. The central components of Hall A are two identical high resolution spectrometers, which allow the vertical drift chambers in the focal plane to provide a momentum resolution of better than 2 x 10(-4). A variety of Cherenkov counters, scintillators and lead-glass calorimeters provide excellent particle identification. The facility has been operated successfully at a luminosity well in excess of 10(38) CM-2 s(-1). The research program is aimed at a variety of subjects, including nucleon structure functions, nucleon form factors and properties of the nuclear medium. (C) 2003 Elsevier B.V. All rights reserved.
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- Ge, R, et al.
(author)
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Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization
- 2023
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In: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR<0.05 indicated that the MFPR-derived sex- and region-specific models with nonlinear polynomials for age and linear effects of global measures had superior predictive accuracy; the range of the MAE of the models of regional subcortical volumes was 70-520 mm3 and the corresponding ranges for regional cortical thickness and regional cortical surface area were 0.09-0.26 mm and 24-560 mm2, respectively. The MFPR-derived models were also computationally more efficient with a CPU time below one second compared to a range of 2 seconds to 60 minutes for the other algorithms. The performance of all sex- and region-specific MFPR models plateaued at sample sizes exceeding 3,000 and showed comparable MAEs across distinct 10-year age-bins covering the human lifespan. Interpretation: These results provide an empirically benchmarked framework for normative modeling of brain morphometry that is useful for interpreting prior literature and supporting future study designs. The model and tools described here are freely available through CentileBrain (https://centilebrain.org/), a user-friendly web platform.
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- Luo, R, et al.
(author)
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Paternal DNA Methylation May Be Associated With Gestational Age at Birth
- 2020
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In: Epigenetics insights. - : SAGE Publications. - 2516-8657. ; 13, s. 2516865720930701-
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Journal article (peer-reviewed)abstract
- How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites. Methods: Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC. Results: Analysis of DNAm of fathers collected around their partner’s pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin ( PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood. Conclusions: Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.
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- Schael, S, et al.
(author)
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Precision electroweak measurements on the Z resonance
- 2006
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Research review (peer-reviewed)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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- Wang, Y, et al.
(author)
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COVID-19 outbreak-related psychological distress among healthcare trainees: a cross-sectional study in China
- 2020
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In: BMJ open. - : BMJ. - 2044-6055. ; 10:10, s. e041671-
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Journal article (peer-reviewed)abstract
- The COVID-19 outbreak has caused enormous strain on healthcare systems, and healthcare trainees, which comprise the future healthcare workforce, may be a vulnerable group. It is essential to assess the psychological distress experienced by healthcare trainees during the COVID-19 outbreak.Design, setting and participantsA cross-sectional study with 4184 healthcare trainees at Sichuan University in China was implemented during 7–13 February 2020. Participants were grouped by training programmes (medicine, medical technology and nursing) and training stages (undergraduate, postgraduate and residency).Main outcomesCOVID-19–related psychological distress and acute stress reaction (ASR) were assessed using the Kessler 6-item Psychological Distress Scale and the Impact of Event Scale–Revised, respectively. We estimated the ORs of distress by comparing trainees across programmes and training stages using multivariable logistic regression.ResultsSignificant psychological distress was found in 1150 (30.90%) participants and probable ASR in 403 (10.74%). Compared with the nursing trainees, the medical trainees (OR 1.54, 95% CI 1.22 to 1.95) reported a higher burden of psychological distress during the outbreak, while the medical technology trainees (OR 1.25, 95% CI 0.97 to 1.62) reported similar symptom scores. Postgraduates (OR 1.55, 95% CI 1.16 to 2.08) in medicine had higher levels of distress than their undergraduate counterparts did, whereas the nursing residents (OR 0.38, 95% CI 0.20 to 0.71) reported a lower burden than did nursing undergraduates. A positive association was found between having active clinical duties during the outbreak and distress (OR 1.17, 95% CI 0.98 to 1.39), particularly among the medical trainees (OR 1.85, 95% CI 1.47 to 2.33) and undergraduates (OR 4.20, 95% CI 1.61 to 11.70). No clear risk patterns of ASR symptoms were observed.ConclusionsMedical trainees, particularly postgraduates and those with active clinical duties, were at risk for psychological distress during the COVID-19 outbreak. Stress management may be considered for high-risk healthcare trainees.
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| 49. |
- Aad, G., et al.
(author)
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- 2011
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swepub:Mat__t (peer-reviewed)
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| 50. |
- Aad, G., et al.
(author)
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- 2011
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swepub:Mat__t (peer-reviewed)
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