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Safety, Tolerability, and Efficacy of Shorter Infusion Durations of Pegloticase Administered to Patients With Uncontrolled Gout Receiving Methotrexate: AGILE Trial.
No full textBACKGROUND/OBJECTIVE: Pegloticase is indicated to lower serum urate (SU) in patients with uncontrolled gout refractory to urate-lowering therapy. Pegloticase is infused for 120 minutes every 2 weeks, which can create logistical barriers. The phase 4, open-label AGILE trial (NCT04511702) assessed the safety and efficacy of shorter-duration pegloticase infusions in patients with uncontrolled gout.
METHODS: AGILE examined 60-, 45-, and 30-minute intravenous pegloticase infusion durations co-administered with oral methotrexate. The desirable infusion duration was determined by enrolling patients sequentially into initial cohorts and assessing them over 24 weeks. The primary endpoint was infusion reaction (IR) incidence, including anaphylaxis. Key efficacy/safety endpoints included treatment response rate; pegloticase discontinuation due to IR; anaphylaxis, or SU-lowering response loss; and time to IR that led to discontinuation, anaphylaxis, or SU-lowering response loss.
RESULTS: The 60-minute infusion cohort (n=116) was chosen and enrolled based on safety reviews. Overall, 6.0% of patients (7/116; 95% CI: 2.5%-12.0%) experienced IRs, including anaphylaxis in 1.7% (2/116) of patients. A treatment response was observed in 67.2% (78/116; 95% CI: 57.9%-75.7%) of patients (SU \u3c 6 mg/dL for ≥80% of the time during weeks 20-24). Pegloticase discontinuation due to IR, anaphylaxis, or loss of SU-lowering response occurred in 19.0% (22/116; 95% CI: 12.3%-27.3%) of patients. At least 1 adverse event occurred in 77.6% (90/116) of patients; 3.4% (4/116) of patients had serious adverse events.
CONCLUSIONS: Safety, tolerability, and efficacy results of pegloticase infused for 60 minutes were comparable to traditional infusion durations (120 min), making shorter infusion times feasible
WCN25-2620 CUMULATIVE EFFECTS OF THE ALDOSTERONE SYNTHASE INHIBITOR VICADROSTAT COMBINED WITH EMPAGLIFLOZIN ON ALBUMINURIA IN PEOPLE WITH CKD
No full textIntroduction
A phase II trial reported efficacy and safety of the aldosterone synthase inhibitor (ASi) vicadrostat (BI 690517) in chronic kidney disease (CKD), showing albuminuria reduction with or without empagliflozin in the background of up to 40%. This post hoc analysis estimates the cumulative effects of vicadrostat and empagliflozin10mg on urine albumin:creatinine ratio (UACR) with comparisons to vicadrostat alone, empagliflozin alone, and placebo (PBO). Methods
Participants receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were first randomized (R1) to an 8-week run-in period to receive empagliflozin 10 mg daily or empagliflozinPBO, followed by a second randomization (R2) to a 14-week treatment period to receive vicadrostat (3, 10, or 20 mg daily) or vicadrostatPBO. For the run-in period, empagliflozineffects were assessed by pooling participants into empagliflozin vs empagliflozinPBO groups, regardless of vicadrostat dose levels at R2. Randomized vicadrostat dose groups on top of empagliflozin/empagliflozinPBO were assessed from R2 to week 14. R2 served as the baseline reference time point, and mixed-effect model for repeated measures was used to assess change in UACR. Cumulative effects of both vicadrostat and empagliflozin were calculated by adding UACR changes from R1 to R2 and R2 to the end of treatment period. Results
UACR data were available from 249 participants randomized at R1 to receive empagliflozin 10 mg and 254 who received empagliflozinPBO. Estimated cumulative effects on UACR reduction from R1 to week 14 were larger with 10 mg vicadrostat+empagliflozin (-61%) compared to 10-mg vicadrostat alone (-40%) and vs vicadrostatPBO+empagliflozinPBO (-3%) (Figure). Download: Download high-res image (169KB) Download: Download full-size image Conclusions
Larger UACR reductions across all doses of vicadrostat were achieved in participants with CKD who received both active components (vicadrostat+empagliflozin) compared to treatment with either vicadrostat or empagliflozin alone, suggesting additive effects of the combination on UACR reduction. Combination of an ASi with an SGLT2 inhibitor is a promising, novel therapy strategy that may afford superior benefits over aldosterone synthase or SGLT2 inhibition alone and will be tested further in a phase III clinical trial (EASi-KIDNEY,NCT06531824). This abstract was also submitted to theASN 2024congress as ‘Cumulative effects of aldosterone synthase and SGLT2 inhibition on albuminuria in people with CKD’. I have potential conflict of interest to disclose. PR declares receiving consultancy and/or speakers’ fees to his institution from Astellas,AstraZeneca,Bayer,Boehringer Ingelheim, EliLilly,Gilead,MSD,Novo Nordisk,Sanofiand Vifor Pharma; and research grants fromAstraZeneca and Novo Nordisk. I did not use generative AI and AI-assisted technologies in the writing process
Epigenetic Regulation of OLIG2 in Glioblastoma: Mechanisms and Therapeutic Targets to Combat Treatment Resistance.
No full textGlioblastoma (GBM) represents one of the most aggressive brain tumors with a poor prognosis despite decades of research. Epigenetic regulation has emerged as a promising strategy for managing aggressive cancers, such as GBM, by modulating pro-tumorigenic gene expression. The role of pro-tumorigenic genes, such as oligodendrocyte transcription factor 2 (OLIG2), has been heavily associated with cancer progression and treatment resistance and is a potential target for GBM. The objective of this study is to analyze the effectiveness of various epigenetic regulators, including histone modifiers, DNA methylases, chromatin remodelers, and miRNAs, on OLIG2 expression, including the effectiveness of individual epigenetic regulators and their combinations. The effects of epigenetic regulators in GBM that are found in the literature were reviewed for their survival and co-expression with OLIG2. We found that KDM6B, BRG1, DNMT1, and HDAC2 were associated with significant co-expression with OLIG2 and decreased survival in GBM patients, reinforcing their suitability as targets. Additionally, miR-17-3p miRNAs associated with silencing OLIG2 as gene expression was downregulated in GBM. Additionally, this paper highlights the potential of combination therapies targeting multiple epigenetic pathways simultaneously. A kinase inhibitor (alisertib), together with JQ1, reduced the tumor growth of GBM cells in vivo more than either treatment alone, making combination therapies a promising solution
Age-Related Changes in the Clinical Picture of Long COVID.
No full textBACKGROUND: This study evaluated the impact of aging on the frequency and prevalent symptoms of Long COVID, also termed post-acute sequelae of SARS-CoV-2, using a previously developed Long COVID research index (LCRI) of 41 self-reported symptoms in which those with 12 or more points were classified as likely to have Long COVID.
METHODS: We analyzed community-dwelling participants ≥ 60 years old (2662 with prior infection, 461 controls) compared to participants 18-59 years (7549 infected, 728 controls) in the Researching COVID to Enhance Recovery adult (RECOVER-Adult) cohort ≥ 135 days post-onset.
RESULTS: Compared to the Age 18-39 group, the adjusted odds of LCRI ≥ 12 were higher for the Age 40-49 group (odds ratio [OR] = 1.40, 95% confidence intervals [CI] = 1.21-1.61, p \u3c 0.001) and 50-59 group (OR = 1.31, CI = 1.14-1.51, p \u3c 0.001), similar for the Age 60-69 group (OR = 1.09, CI = 0.93-1.27, p = 0.299), and lower for the ≥ 70 group (OR = 0.68, CI = 0.54-0.85, p \u3c 0.001). Participants ≥ 70 years had smaller adjusted differences between infected and uninfected symptom prevalence rates than those aged 18-39 for the following symptoms: hearing loss, fatigue, pain (including joint, back, chest pain and headache), post-exertional malaise, sleep disturbance, hair loss, palpitations, and sexual desire/capacity, making these symptoms less discriminating for Long COVID in older adults than in younger. Symptom clustering, as described in Thaweethai et al. (JAMA 2023) also exhibited age-related shifts: clusters 1 (anosmia and ageusia) and 2 (gastrointestinal, chronic cough and palpitations, without anosmia, ageusia or brain fog) were more likely, and clusters 3 (brain fog, but no loss of smell or taste) and 4 (a mix of symptoms) less likely to be found in older adults (relative risk ratios for clusters 3-4 ranging from 0.10-0.34, p \u3c 0.001 vs. 18-39 year-olds).
CONCLUSIONS: Within the limits of this observational study, we conclude that in community-dwelling older adults, aging alters the prevalence and pattern of reported Long COVID
The Philosophy of Artificial Intelligence in Healthcare: Facilitating a Human-Centred Paradigm to Optimize Healthcare Outcomes.
No full textThis article aimed to examine the philosophy of Artificial Intelligence (AI) in healthcare and present a novel framework that could bridge philosophy, ethics, and leadership to promote the responsible and human-centred integration of AI. Moving beyond efficiency and innovation, it explored the deeper philosophical, moral, and human dimensions of AI\u27s evolving role in care delivery. The proposed framework incorporated teleology, ontology, epistemology, axiology, and ethics to provide a structured foundation for guiding AI development, implementation, and governance through purpose, knowledge, values, and moral action. Grounded in these principles, it highlights the leadership approaches that foster accountability, organizational readiness, and ethical stewardship in AI adoption. These insights informed the development of a framework designed to align AI with human values and to promote compassionate, ethical, and sustainable applications that enhance healthcare outcomes while preserving the essence of human care
Randomized Controlled Trial Demonstrates Efficacy of a Culturally Adapted Behavioral Intervention Delivered in Spanish by Community Health Workers to Reduce Unhealthy Alcohol Use Among Latino/as.
No full textObjective: Latino/as comprise nearly 20% of the US population; 25% report past month binge drinking, and disparities in care persist. Culturally adapted interventions may improve outcomes and access. We tested the efficacy of a culturally adapted behavioral intervention to reduce unhealthy alcohol use, delivered in Spanish to Latino/a adults.
Method: We conducted a parallel, two-group, randomized controlled trial with 12- and 26-week follow-ups to test a 3-session intervention delivered by community health workers (CHWs) from a community-based agency in Los Angeles, California. The intervention combined culturally-adapted Motivational Enhancement Therapy and Strengths Based Case Management (CA-MET/SBCM) and was compared to the Rethinking Drinking booklet. Participants were 236 non-treatment seeking Latino/a adults who exceeded NIAAA low risk drinking limits. The primary outcome was percentage of heavy drinking days (≥ 5 drinks for men, ≥ 4 drinks for women) in the past 90 days at 26 weeks. Secondary outcomes were average number of drinks per week and alcohol-related problems.
Results: The CA-MET/SBCM group had greater reductions in heavy drinking days and average drinks per week at week 26 compared to the Rethinking Drinking group (-21.7 vs -12.9 for percent heavy drinking days; -15.9 vs -9.8 for average drinks per week). At week 12, heavy drinking days were also significantly reduced in the CA-MET/SBCM group (-18.5 vs -10.3).
Conclusions: A culturally adapted behavioral intervention, combining MET and SBCM, delivered by Spanish-speaking CHWs significantly reduced unhealthy alcohol use among Latino/as. These results are promising in addressing health disparities, though continued research is essential to further reduce unhealthy drinking and advance health equity for Latino/as
Inhaler-Related Greenhouse Gas Emissions in the US: A Serial Cross-Sectional Analysis.
No full textIMPORTANCE: Inhalers are the primary treatment modality for asthma and chronic obstructive pulmonary disease (COPD). Metered-dose inhalers contain hydrofluoroalkane propellants that contribute to substantial greenhouse gas emissions. The US federal government is facilitating a phasedown of hydrofluorocarbons over the next decade under international treaty obligations, yet current understanding of the scope and trajectory of inhaler-related emissions in the US remains incomplete.
OBJECTIVE: To quantify the magnitude, sources, and social costs of inhaler-related emissions in the US from 2014 to 2024.
DESIGN, SETTING, AND COHORT: This serial cross-sectional analysis estimated emissions from all inhalers approved for asthma or COPD using aggregated dispensing data across the US outpatient pharmaceutical market linked to estimated greenhouse gas emissions by inhaler.
EXPOSURES: All products were characterized based on their active pharmaceutical ingredients, device type, propellant type, therapeutic class, branded status, manufacturer, payer, and pharmacy benefit manager.
MAIN OUTCOMES AND MEASURES: Key end points included product utilization, greenhouse gas emissions (measured in carbon dioxide equivalents [CO2e] based on previously validated studies), and the social costs of emissions, which account for the net harms to society from greenhouse gases.
RESULTS: A total of 1.6 billion inhalers were dispensed in the US from 2014 to 2024, generating an estimated 24.9 million metric tons of CO2e (mtCO2e). Annual emissions increased by 24% from 1.9 million mtCO2e in 2014 to 2.3 million mtCO2e in 2024. Metered-dose inhalers were responsible for 98% of all emissions during the study period, and emissions were heavily concentrated among short-acting β-agonist, inhaled corticosteroid-long-acting β-agonist, and inhaled corticosteroid classes. Albuterol, budesonide-formoterol, and fluticasone propionate inhalers accounted for 87% of total emissions. The estimated social costs of emissions were 3.5 billion; upper bound, $10.0 billion).
CONCLUSIONS AND RELEVANCE: Inhaler-related emissions in the US have increased over the past decade. Policymakers and regulators seeking to reduce emissions should identify targeted solutions aimed at shifting utilization to currently marketed dry powder and soft mist inhalers while facilitating the entry of newer, affordable metered-dose products containing propellants with low global warming potential
Is the emergence of life and of agency expected?
No full textWe present an integrated and testable theory for the spontaneous emergence of life up to the prokaryote with template replication and coding. Collectively autocatalytic small-molecule sets, DNA sets, RNA sets and peptide sets have been discovered or created. Reliable theory supports the claim that such systems can emerge as a first-order phase transition. Such sets constitute Kantian wholes: the whole exists for and by means of the parts. We propose that the earliest life began with small-molecule collectively autocatalytic sets as first-order Kantian wholes. These merged with two other first-order Kantian wholes-peptide and RNA autocatalytic sets-to form a third-order Kantian whole. The autocatalytic, small-molecule set coevolved to become the metabolism of the entire system. The peptide and RNA collectively autocatalytic sets ultimately coevolved to template replication, coding and the ribosome. The same peptide-RNA coevolution may have broken chiral symmetry. Collectively autocatalytic sets achieve constraint closure. Thermodynamic work is the constrained release of energy into a few degrees of freedom. In constraint-closed systems, a set of boundary condition constraints on the release of energy, [A,B,C], constrains that release in a set of non-equilibrium processes, [1,2,3], to construct the very same set of boundary condition constraints, [A,B,C]. Cells literally construct specifically themselves. Because constraint-closed systems carry out thermodynamic work cycles, they constitute molecular autonomous agents that are able to sense, orient, decide and act in their worlds. These theories overlap and unite with the RNA world hypothesis.This article is part of the theme issue \u27Origins of life: the possible and the actual