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BackgroundThe BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting.Materials and methodsPatients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts.ResultsA total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real-world cohort, and 6-month PFS was 54.6% versus 40.1%, respectively.ConclusionMatched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment.Implications for practiceApproximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

Natural history studies (NHS) can support regulatory decision-making at different stages of the drug product life cycle and are especially important in the context of rare diseases, which are associated with not only delayed or erroneous diagnoses but also a lack of approved treatments. Real-world evidence can fill knowledge gaps and support treatment decision-making, thereby benefiting affected patients. In this context, there are three important options for NHS design: retrospective, prospective, and cross-sectional. Each of these has been successfully used to support regulatory approval as external comparator arms (ECAs) for clinical studies, especially single-arm trials (SATs). While longitudinal data obtained from retrospective or prospective designs have been more commonly used and have been the focus of regulatory guidance documents, hybrid designs that combine retrospective and prospective data collection are particularly powerful for rare disease studies. This is due, in part, to the smaller number of patients impacted by each rare disease. In these settings, retrospective or prospective data collection alone may not be sufficient or fit-for-purpose for an external comparator. Rather, a strategic combination of all available data, regardless of timing, can deliver the right information of the desired quality and completeness to answer these important questions and support regulatory evidentiary needs. For instance, patients included in retrospective studies may differ from recently treated patients in terms of disease severity, disease variants, clinical management, or other important aspects of the disease that may impact patient outcomes. Further, retrospectively collected data may lack specific data elements required to achieve adequate comparison with the treated group in single-arm studies. In the context of prospective designs, the recruitment of sufficient new patients for prospective follow-up may not be feasible or may be prolonged due to the rarity of the disease. Further, the potential for premature truncation of patient follow-up may result in insufficient longitudinal data, or prospectively collected data alone may not provide insights into the disease course for specific groups of patients. In these situations, primary data collection in a prospective study may be supplemented with retrospectively collected data from chart reviews, registries, or electronic medical record databases, either for the same patients, in an ambispective design, or for a different set of patients. These hybrid designs allow for broader and more robust contextual information on the patient journey and the natural course of the disease to be obtained, which can improve the suitability of the data as an external comparator for SATs or studies that lack internal control in situations where a prospective design alone might not be sufficient. Because retrospective and prospective data, or any two data sources that are being combined, may differ in availability and quality, there are unique challenges alongside the strengths of these designs. In this paper, we discuss considerations for the design, analysis, and conduct of hybrid NHS intended as ECAs for single-arm studies in clinical development programs for rare diseases. [ABSTRACT FROM AUTHOR]

BackgroundSurveys of patients with cardiovascular disease have suggested that "home-time"-being alive and out of any health care institution-is a prioritized outcome. This novel measure has not been studied among patients with heart failure (HF).ObjectivesThis study sought to characterize home-time following hospitalization for HF and assess its relationship with patient characteristics and traditionally reported clinical outcomes.MethodsUsing GWTG-HF (Get With The Guidelines-Heart Failure) registry data, patients discharged alive from an HF hospitalization between 2011 and 2014 and ≥65 years of age were identified. Using Medicare claims, post-discharge home-time over 30-day and 1-year follow-up was calculated for each patient as the number of days alive and spent outside of a hospital, skilled nursing facility (SNF), or rehabilitation facility.ResultsAmong 59,736 patients, 57,992 (97.1%) and 42,153 (70.6%) had complete follow-up for home-time calculation through 30 days and 1 year, respectively. The mean home-time was 21.6 ± 11.7 days at 30 days and 243.9 ± 137.6 days at 1 year. Contributions to reduced home-time varied by follow-up period, with days spent in SNF being the largest contributor though 30 days and death being the largest contributor through 1 year. Over 1 year, 2,044 (4.8%) patients had no home-time following index hospitalization discharge, whereas 8,194 (19.4%) had 365 days of home-time. In regression models, several conditions were associated with substantially reduced home-time, including chronic obstructive pulmonary disease, renal insufficiency, and dementia. Through 1 year, home-time was highly correlated with time-to-event endpoints of death (tau = 0.72) and the composite of death or HF readmission (tau = 0.59).ConclusionsHome-time, which can be readily calculated from administrative claims data, is substantially reduced for many patients following hospitalization for HF and is highly correlated with traditional time-to-event mortality and hospitalization outcomes. Home-time represents a novel, easily measured, patient-centered endpoint that may reflect effectiveness of interventions in future HF studies.

Background and Aims Current guidelines recommend 6 h of solid food and 2 h of clear liquid fasting for patients undergoing cardiac procedures with conscious sedation. There are no data to support this practice, and previous single-centre studies support the safety of removing fasting requirements. The objective of this study was to determine the non-inferiority of a no-fasting strategy to fasting prior to cardiac catheterization procedures which require conscious sedation. Methods This is a multicentre, investigator-initiated, non-inferiority, randomized trial conducted in Australia with a prospective open-label, blinded endpoint design. Patients referred for coronary angiography, percutaneous coronary intervention, or cardiac implantable electronic device (CIED)-related procedures were enrolled. Patients were randomized 1:1 to fasting as normal (6 h solid food and 2 h clear liquid) or no-fasting requirements (encouraged to have regular meals but not mandated to do so). Recruitment occurred from 2022 to 2023. The primary outcome was a composite of aspiration pneumonia, hypotension, hyperglycaemia, and hypoglycaemia assessed with a Bayesian approach. Secondary outcomes included patient satisfaction score, new ventilation requirement (non-invasive and invasive), new intensive care unit admission, 30-day readmission, 30-day mortality, 30-day pneumonia. Results A total of 716 patients were randomized with 358 in each group. Those in the fasting arm had significantly longer solid food fasting (13.2 vs. 3.0 h, Bayes factor >100, indicating extreme evidence of difference) and clear liquid fasting times (7.0 vs. 2.4 h, Bayes factor >100). The primary composite outcome occurred in 19.1% of patients in the fasting arm and 12.0% of patients in the no-fasting arm. The estimate of the mean posterior difference in proportions with credibility interval (CI) in the primary composite outcome was −5.2% (95% CI −9.6 to −.9), favouring no fasting. This result confirms the non-inferiority (posterior probability >99.5%) and superiority (posterior probability 99.1%) of no fasting for the primary composite outcome. The no-fasting arm had improved patient satisfaction scores with a posterior mean difference of 4.02 points (95% CI 3.36–4.67, Bayes factor >100). Secondary outcome events were observed to be similar. Conclusions In patients undergoing cardiac catheterization and CIED-related procedures, no fasting was non-inferior and superior to fasting for the primary composite outcome of aspiration pneumonia, hypotension, hyperglycaemia, and hypoglycaemia. Patient satisfaction scores were significantly better with no fasting. This supports removing fasting requirements for patients undergoing cardiac catheterization laboratory procedures that require conscious sedation. [ABSTRACT FROM AUTHOR]

This paper presents evidence that refugee status decision makers make assumptions about how humans think and act that are contrary to decades of scientific evidence about human behaviour and cognition (e.g. memory, risk assessment) – including studies and reviews of studies specifically focused on the RSD context. This evidence is not made available to decision makers. In contrast, decision makers regularly benefit from systems and procedures providing relevant, up to date, methodologically sound, impartial, independent, balanced expert evidence pertaining to country of origin information (COI). This paper proposes similar processes for the collation, assessment, and presentation of psychological evidence in order to ensure fairer, more sustainable refugee status decisions. [ABSTRACT FROM AUTHOR]

Hydrogen plays an essential role during the in situ assembly of tailored catalytic materials, and serves as key ingredient in multifarious chemical reactions promoted by these catalysts. Despite intensive debate for several decades, the existence and nature of hydrogen-involved mechanisms - such as hydrogen-spillover, surface migration - have not been unambiguously proven and elucidated up to date. Here, Pt-Ga alloy formation is used as a probe reaction to study the behavior and atomic transport of H and Ga, starting from Pt nanoparticles on hydrotalcite-derived Mg(Ga)(Al)Ox supports. In situ XANES spectroscopy, time-resolved TAP kinetic experiments, HAADF-STEM imaging and EDX mapping are combined to probe Pt, Ga and H in a series of H2 reduction experiments up to 650 °C. Mg(Ga)(Al)Ox by itself dissociates hydrogen, but these dissociated hydrogen species do not induce significant reduction of Ga(3+) cations in the support. Only in the presence of Pt, partial reduction of Ga(3+) into Ga(δ+) is observed, suggesting that different reaction mechanisms dominate for Pt- and Mg(Ga)(Al)Ox-dissociated hydrogen species. This partial reduction of Ga(3+) is made possible by Pt-dissociated H species which spillover onto non-reducible Mg(Al)Ox or partially reducible Mg(Ga)(Al)Ox and undergo long-range transport over the support surface. Moderately mobile Ga(δ+)Ox migrates towards Pt clusters, where Ga(δ+) is only fully reduced to Ga(0) on condition of immediate stabilization inside Pt-Ga alloyed nanoparticles.

BackgroundIt remains unclear whether the quality of acute asthma care in US emergency departments (EDs) has improved over time.ObjectivesWe investigated changes in concordance of ED asthma care with 2007 National Institutes of Health guidelines, identified ED characteristics predictive of concordance, and tested whether higher concordance was associated with lower risk of hospitalization.MethodsWe performed chart reviews in ED patients aged 18 to 54 years with asthma exacerbations in 48 EDs during 2 time periods: 1997-2001 (2 prior studies) and 2011-2012 (new study). Concordance with guideline recommendations was evaluated by using item-by-item quality measures and composite concordance scores at the patient and ED levels; these scores ranged from 0 to 100.ResultsThe analytic cohort comprised 4039 patients (2119 from 1997-2001 vs 1920 from 2011-2012). Over these 16 years, emergency asthma care became more concordant with level A recommendations at both the patient and ED levels (both P < .001). By contrast, concordance with non-level A recommendations (peak expiratory flow measurement and timeliness) decreased at both the patient (median score, 75 [interquartile range, 50-100] to 50 [interquartile range, 33-75], P < .001) and ED (mean score, 67 [SD, 7] to 50 [SD, 16], P < .001) levels. Multivariable analysis demonstrated ED concordance was lower in Southern and Western EDs compared with Midwestern EDs. After adjusting for severity, guideline-concordant care was associated with lower risk of hospitalization (odds ratio, 0.37; 95% CI, 0.26-0.53).ConclusionsBetween 1997 and 2012, we observed changes in the quality of emergency asthma care that differed by level of guideline recommendation and substantial interhospital and geographic variations. Greater concordance with guideline-recommended management might reduce unnecessary hospitalizations.

BackgroundDespite the substantial burden of asthma-related emergency department (ED) visits, there have been no recent multicenter efforts to characterize this high-risk population.ObjectiveWe aimed to characterize patients with asthma according to their frequency of ED visits and to identify factors associated with frequent ED visits.MethodsA multicenter chart review study of 48 EDs across 23 US states. We identified ED patients ages 18 to 54 years with acute asthma during 2011 and 2012. Primary outcome was frequency of ED visits for acute asthma in the past year, excluding the index ED visit.ResultsOf the 1890 enrolled patients, 863 patients (46%) had 1 or more (frequent) ED visits in the past year. Specifically, 28% had 1 to 2 visits, 11% had 3 to 5 visits, and 7% had 6 or more visits. Among frequent ED users, guideline-recommended management was suboptimal. For example, of patients with 6 or more ED visits, 85% lacked evidence of prior evaluation by an asthma specialist, and 43% were not treated with inhaled corticosteroids. In a multivariable model, significant predictors of frequent ED visits were public insurance, no insurance, and markers for chronic asthma severity (all P < .05). Stronger associations were found among those with a higher frequency of asthma-related ED visits (eg, 6 or more ED visits).ConclusionThis multicenter study of US adults with acute asthma demonstrated many frequent ED users and suboptimal preventive management in this high-risk population. Future reductions in asthma morbidity and associated health care utilization will require continued efforts to bridge these major gaps in asthma care.