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Background: Genome‐wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European‐ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma. Methods: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS. We validated our GWAS findings using UK Biobank data. We then used the Genotype‐Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma. Results: Variants at the 17q12‐21 locus and SNPs in CYBRD1 and TNFSF15 genes were associated with persistent childhood asthma at genome‐wide thresholds of significance. Four SNPs in the TNFSF15 gene were also associated with childhood‐onset asthma in British white participants in the UK Biobank data. The asthma‐associated rs7856856‐C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries. Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856‐CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children. Conclusions: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, and replicated associations at the 17q12‐21 childhood‐onset asthma locus. This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Methods and results Conclusions The TRANSFORM‐HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non‐adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on‐treatment analysis inclusive of all randomized patients except those confirmed non‐adherent to study diuretic.TRANSFORM‐HF was an open‐label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator‐selected dosage. This post‐hoc on‐treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non‐adherent to study diuretic. This modified on‐treatment definition was applied separately at time of hospital discharge and 30‐day follow‐up. All‐cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on‐treatment analyses at discharge and 30‐day follow‐up, respectively. There was no significant difference in all‐cause mortality between torsemide and furosemide in patients on‐treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83–1.22], p = 0.96) and at 30‐day follow‐up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81–1.27], p = 0.90). All‐cause mortality or all‐cause hospitalization was similar between torsemide and furosemide in patients who were on‐treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82–1.03]) and 30‐day follow‐up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82–1.05]). In patients who were on‐treatment at 30‐day follow‐up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86–1.14], p = 0.87).In TRANSFORM‐HF, a post‐hoc on‐treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide.Clinical Trail Registration: ClinicalTrials.gov Identifier: NCT03296813. [ABSTRACT FROM AUTHOR]

Consider the choice of outcome for overall treatment benefit in a clinical trial which measures the first time to each of several clinical events. We describe several new variants of the win ratio that incorporate the time spent in each clinical state over the common follow‐up, where clinical state means the worst clinical event that has occurred by that time. One version allows restriction so that death during follow‐up is most important, while time spent in other clinical states is still accounted for. Three other variants are described; one is based on the average pairwise win time, one creates a continuous outcome for each participant based on expected win times against a reference distribution and another that uses the estimated distributions of clinical state to compare the treatment arms. Finally, a combination testing approach is described to give robust power for detecting treatment benefit across a broad range of alternatives. These new methods are designed to be closer to the overall treatment benefit/harm from a patient's perspective, compared to the ordinary win ratio. The new methods are compared to the composite event approach and the ordinary win ratio. Simulations show that when overall treatment benefit on death is substantial, the variants based on either the participants' expected win times (EWTs) against a reference distribution or estimated clinical state distributions have substantially higher power than either the pairwise comparison or composite event methods. The methods are illustrated by re‐analysis of the trial heart failure: a controlled trial investigating outcomes of exercise training. [ABSTRACT FROM AUTHOR]

Aim: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all‐cause mortality or hospitalization. Clinicians have traditionally favoured torsemide in the setting of kidney dysfunction due to better oral bioavailability and longer half‐life, but direct supportive evidence is lacking. Methods and results: The TRANSFORM‐HF trial randomized patients hospitalized for HF to a long‐term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function (without dialysis). In this post‐hoc analysis, baseline renal function during the index hospitalization was assessed as categories of estimated glomerular filtration rate (eGFR; <30, 30–<60, ≥60 ml/min/1.73 m2). The interaction between baseline renal function and treatment effect of torsemide versus furosemide was assessed with respect to mortality and hospitalization outcomes, and the change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS). Of 2859 patients randomized, 336 (11.8%) had eGFR <30 ml/min/1.73 m2, 1138 (39.8%) had eGFR 30–<60 ml/min/1.73 m2, and 1385 (48.4%) had eGFR ≥60 ml/min/1.73 m2. Baseline eGFR did not modify treatment effects of torsemide versus furosemide on all adverse clinical outcomes including individual components or composites of all‐cause mortality and all‐cause (re)‐hospitalizations, both when assessing eGFR categorically or continuously (p‐value for interaction all >0.108). Similarly, no treatment effect modification by eGFR was found for the change in KCCQ‐CSS (p‐value for interaction all >0.052) when assessing eGFR categorically or continuously. Conclusion: Among patients discharged after hospitalization for HF, there was no significant difference in clinical and patient‐reported outcomes between torsemide and furosemide, irrespective of renal function. [ABSTRACT FROM AUTHOR]

In addition, the results of this study will be strengthened by comparing the current data with those for the microbiome of patients with Crohn's disease and CKD, and CKD patients without IBD. The causal link between inflammatory bowel disease (IBD) and chronic kidney disease (CKD) is not clear; therefore, we aimed to investigate the role of gut microbiota in decreasing renal function in patients with IBD. [Extracted from the article]

ABSTRACT Both land-cover/land-use change ( LCLUC) and greenhouse gas ( GHG) concentrations have been shown to influence regional climate, albeit at different spatial scales. In East Africa, climate changes due to changing GHG concentrations are broadly projected to be warmer and wetter. LCLUC projections include trends towards both agricultural intensification and agricultural expansion into savannas, which may result in complex climate interactions and impacts. The primary objective of this study was to examine the regional responses to future GHG, LCLUC, and their combined effects in East Africa, and to better understand how hydrometeorological mechanisms might be altered by LCLUC in future scenarios. In this study, we present high-resolution decadal simulations from a regional climate model that compare the relative and combined effects of projected LCLUC and GHG. This research suggests that taken separately, these two climate forcings may significantly alter regional precipitation patterns both temporally and spatially but in potentially different and independent ways. In combination, some portions of the region exhibit responses dominated by either LCLUC or GHG effects, but certain areas show complex effects resulting from the combined influence of these two forcings. Perhaps most importantly, the results suggest that projected precipitation changes around major population areas may be as strongly influenced by LCLUC as by GHG effects. [ABSTRACT FROM AUTHOR]