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Träfflista för sökning "WFRF:(Sigal A) "

Sökning: WFRF:(Sigal A)

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1.
  • Ruilope, LM, et al. (författare)
  • Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
  • 2019
  • Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
  • 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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  • Martin, DP, et al. (författare)
  • Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
  • 2022
  • Ingår i: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.
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5.
  • Fluckiger, Christoph, et al. (författare)
  • The Reciprocal Relationship Between Alliance and Early Treatment Symptoms: A Two-Stage Individual Participant Data Meta-Analysis
  • 2020
  • Ingår i: Journal of Consulting and Clinical Psychology. - : AMER PSYCHOLOGICAL ASSOC. - 0022-006X .- 1939-2117. ; 88:9, s. 829-843
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Even though the early alliance has been shown to robustly predict posttreatment outcomes, the question whether alliance leads to symptom reduction or symptom reduction leads to a better alliance remains unresolved. To better understand the relation between alliance and symptoms early in therapy, we meta-analyzed the lagged session-by-session within-patient effects of alliance and symptoms from Sessions I to 7. Method: We applied a 2-stage individual participant data meta-analytic approach. Based on the data sets of 17 primary studies from 9 countries that comprised 5,350 participants, we first calculated standardized session-by-session within-patient coefficients. Second, we meta-analyzed these coefficients by using random-effects models to calculate omnibus effects across the studies. Results: In line with previous meta-analyses, we found that early alliance predicted posttreatment outcome. We identified significant reciprocal within-patient effects between alliance and symptoms within the first 7 sessions. Cross-level interactions indicated that higher alliances and lower symptoms positively impacted the relation between alliance and symptoms in the subsequent session. Conclusion: The findings provide empirical evidence that in the early phase of therapy. symptoms and alliance were reciprocally related to one other, often resulting in a positive upward spiral of higher alliance/lower symptoms that predicted higher alliances/lower symptoms in the subsequent sessions. Two-stage individual participant data meta-analyses have the potential to move the field forward by generating and interlinking well-replicable process-based knowledge.
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  • Bruno, Raphael Romano, et al. (författare)
  • The Clinical Frailty Scale for mortality prediction of old acutely admitted intensive care patients: a meta-analysis of individual patient-level data
  • 2023
  • Ingår i: Annals of Intensive Care. - : SPRINGER. - 2110-5820. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background This large-scale analysis pools individual data about the Clinical Frailty Scale (CFS) to predict outcome in the intensive care unit (ICU). Methods A systematic search identified all clinical trials that used the CFS in the ICU (PubMed searched until 24th June 2020). All patients who were electively admitted were excluded. The primary outcome was ICU mortality. Regression models were estimated on the complete data set, and for missing data, multiple imputations were utilised. Cox models were adjusted for age, sex, and illness acuity score (SOFA, SAPS II or APACHE II). Results 12 studies from 30 countries with anonymised individualised patient data were included (n = 23,989 patients). In the univariate analysis for all patients, being frail (CFS >= 5) was associated with an increased risk of ICU mortality, but not after adjustment. In older patients (>= 65 years) there was an independent association with ICU mortality both in the complete case analysis (HR 1.34 (95% CI 1.25-1.44), p < 0.0001) and in the multiple imputation analysis (HR 1.35 (95% CI 1.26-1.45), p < 0.0001, adjusted for SOFA). In older patients, being vulnerable (CFS 4) alone did not significantly differ from being frail. After adjustment, a CFS of 4-5, 6, and >= 7 was associated with a significantly worse outcome compared to CFS of 1-3. Conclusions Being frail is associated with a significantly increased risk for ICU mortality in older patients, while being vulnerable alone did not significantly differ. New Frailty categories might reflect its "continuum" better and predict ICU outcome more accurately.
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7.
  • Earle, K. A., et al. (författare)
  • Quantitative Imaging of Gut Microbiota Spatial Organization
  • 2015
  • Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128. ; 18:4, s. 478-488
  • Tidskriftsartikel (refereegranskat)abstract
    • Summary Genomic technologies have significantly advanced our understanding of the composition and diversity of host-associated microbial populations. However, their spatial organization and functional interactions relative to the host have been more challenging to study. Here we present a pipeline for the assessment of intestinal microbiota localization within immunofluorescence images of fixed gut cross-sections that includes a flexible software package, BacSpace, for high-throughput quantification of microbial organization. Applying this pipeline to gnotobiotic and human microbiota-colonized mice, we demonstrate that elimination of microbiota-accessible carbohydrates (MACs) from the diet results in thinner mucus in the distal colon, increased proximity of microbes to the epithelium, and heightened expression of the inflammatory marker REG3β. Measurements of microbe-microbe proximity reveal that a MAC-deficient diet alters monophyletic spatial clustering. Furthermore, we quantify the invasion of Helicobacter pylori into the glands of the mouse stomach relative to host mitotic progenitor cells, illustrating the generalizability of this approach. © 2015 Elsevier Inc.
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8.
  • Fitzpatrick, John L., et al. (författare)
  • Female promiscuity promotes the evolution of faster sperm in cichlid fishes
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:4, s. 1128-1132
  • Tidskriftsartikel (refereegranskat)abstract
    • Sperm competition, the contest among ejaculates from rival males to fertilize ova of a female, is a common and powerful evolutionary force influencing ejaculate traits. During competitive interactions between ejaculates, longer and faster spermatozoa are expected to have an edge; however, to date, there has been mixed support for this key prediction from sperm competition theory. Here, we use the spectacular radiation of cichlid fishes from Lake Tanganyika to examine sperm characteristics in 29 closely related species. We provide phylogenetically robust evidence that species experiencing greater levels of sperm competition have faster-swimming sperm. We also show that sperm competition selects for increases in the number, size, and longevity of spermatozoa in the ejaculate of a male, and, contrary to expectations from theory, we find no evidence of trade-offs among sperm traits in an interspecific analysis. Also, sperm swimming speed is positively correlated with sperm length among, but not within, species. These different responses to sperm competition at intra-and interspecific levels provide a simple, powerful explanation for equivocal results from previous studies. Using phylogenetic analyses, we also reconstructed the probable evolutionary route of trait evolution in this taxon, and show that, in response to increases in the magnitude of sperm competition, the evolution of sperm traits in this clade began with the evolution of faster (thus, more competitive) sperm.
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  • Hurley, Carolyn K., et al. (författare)
  • Common, intermediate and well-documented HLA alleles in world populations : CIWD version 3.0.0
  • 2020
  • Ingår i: HLA. - : WILEY. - 2059-2302 .- 2059-2310. ; 95:6, s. 516-531
  • Tidskriftsartikel (refereegranskat)abstract
    • A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (>= 1 in 10 000), intermediate (>= 1 in 100 000), well-documented (>= 5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.
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10.
  • Naaman, Efrat, et al. (författare)
  • The surprising nonlinear effects of S100A9 proteins in the retina
  • 2024
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 15:4, s. 735-744
  • Tidskriftsartikel (refereegranskat)abstract
    • Age-related macular degeneration (AMD) is a complex disease in which inflammation is implicated as a key factor but the precise molecular mechanisms are poorly understood. AMD lesions contain an excess of the pro-inflammatory S100A9 protein, but its retinal significance was yet unexplored. S100A9 was shown to be intrinsically amyloidogenic in vitro and in vivo. Here, we hypothesized that the retinal effects of S100A9 are related to its supramolecular conformation. ARPE-19 cultures were treated with native dimeric and fibrillar S100A9 preparations, and cell viability was determined. Wild-type rats were treated intravitreally with the S100A9 solutions in the right eye and with the vehicle in the left. Retinal function was assessed longitudinally by electroretinography (ERG), comparing the amplitudes and configurations for each intervention. Native S100A9 had no impact on cellular viability in vitro or on the retinal function in vivo. Despite dispersed intracellular uptake, fibrillar S100A9 did not decrease ARPE-19 cell viability. In contrast, S100A9 fibrils impaired retinal function in vivo following intravitreal injection in rats. Intriguingly, low-dose fibrillar S100A9 induced contrasting in vivo effects, significantly increasing the ERG responses, particularly over 14 days postinjection. The retinal effects of S100A9 were further characterized by glial and microglial cell activation. We provide the first indication for the retinal effects of S100A9, showing that its fibrils inflicted retinal dysfunction and glial activation in vivo, while low dose of the same assemblies resulted in an unpredicted enhancement of the ERG amplitudes. These nonlinear responses highlight the consequences of self-assembly of S100A9 and provide insight into its pathophysiological and possibly physiological roles in the retina.
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