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- Ruilope, LM, et al.
(författare)
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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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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)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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- Jia, TY, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:8, s. 3884-3895
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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- Rootes-Murdy, K, et al.
(författare)
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Clinical and cortical similarities identified between bipolar disorder I and schizophrenia: A multivariate approach
- 2022
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Ingår i: Frontiers in human neuroscience. - : Frontiers Media SA. - 1662-5161. ; 16, s. 1001692-
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Tidskriftsartikel (refereegranskat)abstract
- Structural neuroimaging studies have identified similarities in the brains of individuals diagnosed with schizophrenia (SZ) and bipolar I disorder (BP), with overlap in regions of gray matter (GM) deficits between the two disorders. Recent studies have also shown that the symptom phenotypes associated with SZ and BP may allow for a more precise categorization than the current diagnostic criteria. In this study, we sought to identify GM alterations that were unique to each disorder and whether those alterations were also related to unique symptom profiles.Materials and methodsWe analyzed the GM patterns and clinical symptom presentations using independent component analysis (ICA), hierarchical clustering, and n-way biclustering in a large (N ∼ 3,000), merged dataset of neuroimaging data from healthy volunteers (HV), and individuals with either SZ or BP.ResultsComponent A showed a SZ and BP < HV GM pattern in the bilateral insula and cingulate gyrus. Component B showed a SZ and BP < HV GM pattern in the cerebellum and vermis. There were no significant differences between diagnostic groups in these components. Component C showed a SZ < HV and BP GM pattern bilaterally in the temporal poles. Hierarchical clustering of the PANSS scores and the ICA components did not yield new subgroups. N-way biclustering identified three unique subgroups of individuals within the sample that mapped onto different combinations of ICA components and symptom profiles categorized by the PANSS but no distinct diagnostic group differences.ConclusionThese multivariate results show that diagnostic boundaries are not clearly related to structural differences or distinct symptom profiles. Our findings add support that (1) BP tend to have less severe symptom profiles when compared to SZ on the PANSS without a clear distinction, and (2) all the gray matter alterations follow the pattern of SZ < BP < HV without a clear distinction between SZ and BP.
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- Zhang, JR, et al.
(författare)
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Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour
- 2018
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 8:9, s. e017240-
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Tidskriftsartikel (refereegranskat)abstract
- Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments.DesignLiterature review, pooling analysis and correlation analysis.Data sourcesPubMed, from 1 January 2010 to 30 June 2017.Eligibility criteria for selecting studiesEligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments.ResultsOf 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29).ConclusionsNo systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.
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