| 1. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Journal article (peer-reviewed)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 2. |
- Amare, Azmeraw, et al.
(author)
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
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In: Research square. - : Research Square Platform LLC.
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Journal article (peer-reviewed)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 3. |
- Amare, Azmeraw T, et al.
(author)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Journal article (peer-reviewed)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 4. |
- Arrazuria, Rakel, et al.
(author)
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Expert workshop summary : Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections
- 2022
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In: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Journal article (peer-reviewed)abstract
- The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans. Toward this goal, in April 2021, COMBINE organized the expert workshop "Advancing toward a standardized murine model to evaluate treatments for AMR lung infections". This workshop explored the conduct and interpretation of mouse infection models, with presentations on PK/PD and efficacy studies of small molecule antibiotics, combination treatments (beta -lactam/beta -lactamase inhibitor), bacteriophage therapy, monoclonal antibodies and iron sequestering molecules, with a focus on the major Gram-negative AMR respiratory pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Here we summarize the factors of variability that we identified in murine lung infection models used for antimicrobial efficacy testing, as well as the workshop presentations, panel discussions and the survey results for the harmonization of key experimental parameters. The resulting recommendations for standard design parameters are presented in this document and will provide the basis for the development of a harmonized and bench-marked efficacy studies in preclinical murine pneumonia model.
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| 5. |
- Arrazuria, Rakel, et al.
(author)
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Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents
- 2022
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In: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Research review (peer-reviewed)abstract
- Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
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| 6. |
- Berner, Logan T., et al.
(author)
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The Arctic plant aboveground biomass synthesis dataset
- 2024
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In: Scientific Data. - : Springer Nature. - 2052-4463. ; 11:1
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Journal article (peer-reviewed)abstract
- Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m−2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.
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| 7. |
- Bull, Caroline J., et al.
(author)
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Adiposity, metabolites, and colorectal cancer risk : Mendelian randomization study
- 2020
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In: BMC Medicine. - : BMC. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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| 8. |
- Castelli Dransart, Dolores Angela, et al.
(author)
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A systematic review of older adults’ request for or attitude toward euthanasia or assisted-suicide
- 2021
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In: Aging & Mental Health. - : Informa UK Limited. - 1360-7863 .- 1364-6915. ; 25:3, s. 420-430
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Journal article (peer-reviewed)abstract
- Objectives: Prevalence rates of death by euthanasia (EUT) and physician-assisted suicide (PAS) have increased among older adults, and public debates on these practices are still taking place. In this context, it seemed important to conduct a systematic review of the predictors (demographic, physical health, psychological, social, quality of life, religious, or existential) associated with attitudes toward, wishes and requests for, as well as death by EUT/PAS among individuals aged 60years and over.Method: The search for quantitative studies in PsycINFO and MEDLINE databases was conducted three times from February 2016 until April 2018. Articles of probable relevance (n=327) were assessed for eligibility. Studies that only presented descriptive data (n=306) were excluded.Results: This review identified 21 studies with predictive analyses, but in only 4 did older adults face actual end-of-life decisions. Most studies (17) investigated attitudes toward EUT/PAS (9 through hypothetical scenarios). Younger age, lower religiosity, higher education, and higher socio-economic status were the most consistent predictors of endorsement of EUT/PAS. Findings were heterogeneous with regard to physical health, psychological, and social factors. Findings were difficult to compare across studies because of the variety of sample characteristics and outcomes measures.Conclusion: Future studies should adopt common and explicit definitions of EUT/PAS, as well as research designs (e.g. mixed longitudinal) that allow for better consideration of personal, social, and cultural factors, and their interplay, on EUT/PAS decisions.
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| 9. |
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| 10. |
- Coombes, Brandon J, et al.
(author)
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Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.
- 2021
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In: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89
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Journal article (peer-reviewed)abstract
- Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
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| 11. |
- Delrez, Laetitia, et al.
(author)
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Transit detection of the long-period volatile-rich super-Earth nu(2) Lupi d with CHEOPS
- 2021
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In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; :5, s. 775-787
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Journal article (peer-reviewed)abstract
- Exoplanets transiting bright nearby stars are key objects for advancing our knowledge of planetary formation and evolution. The wealth of photons from the host star gives detailed access to the atmospheric, interior and orbital properties of the planetary companions. nu(2) Lupi (HD 136352) is a naked-eye (V = 5.78) Sun-like star that was discovered to host three low-mass planets with orbital periods of 11.6, 27.6 and 107.6 d via radial-velocity monitoring(1). The two inner planets (b and c) were recently found to transit(2), prompting a photometric follow-up by the brand new Characterising Exoplanets Satellite (CHEOPS). Here, we report that the outer planet d is also transiting, and measure its radius and mass to be 2.56 +/- 0.09 R-circle plus and 8.82 +/- 0.94 M-circle plus, respectively. With its bright Sun-like star, long period and mild irradiation (similar to 5.7 times the irradiation of Earth), nu(2) Lupi d unlocks a completely new region in the parameter space of exoplanets amenable to detailed characterization. We refine the properties of all three planets: planet b probably has a rocky mostly dry composition, while planets c and d seem to have retained small hydrogen-helium envelopes and a possibly large water fraction. This diversity of planetary compositions makes the nu(2) Lupi system an excellent laboratory for testing formation and evolution models of low-mass planets.
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| 12. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 13. |
- Herrera-Rivero, Marisol, et al.
(author)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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In: Research square.
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Other publication (other academic/artistic)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 14. |
- Herrera-Rivero, Marisol, et al.
(author)
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Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.
- 2023
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In: Research square.
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Other publication (other academic/artistic)abstract
- The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
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| 15. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 16. |
- Ostaszewski, Marek, et al.
(author)
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COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms
- 2021
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In: Molecular Systems Biology. - : John Wiley & Sons. - 1744-4292 .- 1744-4292. ; 17:10
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Journal article (peer-reviewed)abstract
- We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
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| 17. |
- Petit, Claire, et al.
(author)
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Chemotherapy and radiotherapy in locally advanced head and neck cancer : an individual patient data network meta-analysis
- 2021
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In: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 22:5, s. 727-736
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Journal article (peer-reviewed)abstract
- BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%).INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
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| 18. |
- Subjak, Jan, et al.
(author)
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TOI-503: The First Known Brown-dwarf Am-star Binary from the TESS Mission
- 2020
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In: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 159:4
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Journal article (peer-reviewed)abstract
- We report the discovery of an intermediate-mass transiting brown dwarf (BD), TOI-503b, from the TESS mission. TOI-503b is the first BD discovered by TESS, and it has circular orbit around a metallic-line A-type star with a period of P.=.3.6772.+/-.0.0001 days. The light curve from TESS indicates that TOI-503b transits its host star in a grazing manner, which limits the precision with which we measure the BD's radius ( = R 1.34+ R b 0.150.26 J). We obtained highresolution spectroscopic observations with the FIES, Ondr.ejov, PARAS, Tautenburg, and TRES spectrographs, and measured the mass of TOI-503b to be Mb.=.53.7.+/-.1.2 MJ. The host star has a mass of Ma.=.1.80.+/-.0.06Me, a radius of Ra.=.1.70.+/-.0.05Re, an effective temperature of Teff.=.7650.+/-.160 K, and a relatively high metallicity of 0.61.+/-.0.07 dex. We used stellar isochrones to derive the age of the system to be 180 Myr, which places its age between that of RIK 72b (a 10 Myr old BD in the Upper Scorpius stellar association) and AD 3116b (a 600 Myr old BD in the Praesepe cluster). Given the difficulty in measuring the tidal interactions between BDs and their host stars, we cannot precisely say whether this BD formed in situ or has had its orbit circularized by its host star over the relatively short age of the system. Instead, we offer an examination of plausible values for the tidal quality factor for the star and BD. TOI-503b joins a growing number of known short-period, intermediate-mass BDs orbiting mainsequence stars, and is the second such BD known to transit an A star, after HATS-70b. With the growth in the population in this regime, the driest region in the BD desert (35-55MJ sin i) is reforesting.
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| 19. |
- Tchappi, Igor H., et al.
(author)
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A critical review of the use of holonic paradigm in traffic and transportation systems
- 2020
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In: Engineering applications of artificial intelligence. - : Elsevier. - 0952-1976 .- 1873-6769. ; 90
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Research review (peer-reviewed)abstract
- The paper presents a critical review of the use of holonic paradigm in order to model and simulate traffic and transportation systems. After an introduction presenting the principles of this paradigm as well as its frameworks and concepts, the paper surveys existing works using the holonic paradigm for traffic and transportation applications. This is followed by a detailed analysis of the results of the survey. In particular, the relevance, the design approaches and the holonification orientation methodologies are investigated. Finally, based on this extensive review, open issues of holonic paradigm in modeling and simulation of traffic and transportation models are highlighted.
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| 20. |
- Walsh, Roddy, et al.
(author)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Journal article (peer-reviewed)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 21. |
- Witjes, J. Alfred, et al.
(author)
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EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer – An International Collaborative Multistakeholder Effort : Under the Auspices of the EAU-ESMO Guidelines Committees
- 2020
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In: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 77:2, s. 223-250
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Journal article (peer-reviewed)abstract
- BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SETTING: Online Delphi survey and consensus conference.PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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| 22. |
- Zarafshar, Mehrdad, et al.
(author)
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The impact of stand composition and tree density on topsoil characteristics and soil microbial activities
- 2024
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In: Catena (Cremlingen. Print). - : Elsevier. - 0341-8162 .- 1872-6887. ; 234
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Journal article (peer-reviewed)abstract
- The assessment of long-term effects of forest management practices, particularly species mixing and stand density, provides valuable information for the forestry sectors. This study evaluated and compared the effect of stand composition and density on organic horizon (i.e., OL, OF, OH) and organo-mineral horizon characteristics of nine stands in the Orleans State Forest (France), seven years after the first thinning treatments. To this end, three triplets of stands of pure Quercus petraea Matt., pure Pinus sylvestris L. and a mixture of both species were selected. Each stand consisted of two plots with different tree densities: low and normal. Physicochemical variables were measured on the organic humus horizon (OH), while microbial biomass carbon (MBC) and nitrogen (MBN), and soil microbial metabolic profile were evaluated on the organo-mineral horizon; the abundance of soil microbial populations (i.e., bacteria, fungi and archaea) in each plot was also assessed by qPCR. The OH thickness consistently increased under pure pine stands (25-35 mm), while other OH characteristics showed no variation based on stand composition and tree density. Low-density plots exhibited changes in microbial biomass, with a significant decrease in both MBC and MBN. Moreover, the highest MBC was recorded under pure pine stands (1241 mg C.kg(- 1 )DW soil), and the highest MBN under pure oak stands (24-39 mg N.kg(- 1 ) DW soil). The highest C assimilation rates were recorded in the mixed stands, especially under low tree density. Bacteria and archea were similarly abundant across stand compositions and tree densities, while fungi tended to be more abundant in the mixed coniferous-broadleaf stands. Our findings should be considered by the forestry sectors of European countries where these two species are distributed, and suggest that EU forestry strategies should promote biodiversity in the context of tree plantations.
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