Yale New Haven Health System

Alzheimer disease (AD) disproportionately affects racial and ethnic populations underrepresented in US clinical research, raising concerns about the generalizability of AD trial findings and the evaluation of treatment safety and efficacy for populations most affected by AD. To examine patterns and trends in the reporting and representation of patient race and ethnicity in US-based phase 3 AD clinical trials. This systematic review examined US-based phase 3 AD drug trials identified through the Trialtrove trial database between 1997 and 2023. Trials were cross-referenced with peer-reviewed publications, ClinicalTrials.gov, pharmaceutical company reports, and conference abstracts. Completed trials were eligible for inclusion if they were designated as phase 3 drug trials targeting AD and recruited patients exclusively in the US. Primary outcomes included reporting of race and ethnicity, the number of racial and ethnic groups reported, and their representation among trial populations. Secondary outcomes included terminology used, reporting of safety or efficacy differences by race and ethnicity, and discussion of racial and ethnic representation in trial reports. Temporal trends in reporting and representation were assessed. Methodologic quality was evaluated using the Quality Rating Scheme for Studies and Other Evidence. Data collection was completed May 2024. Among 88 US-based phase 3 AD clinical trials conducted between 1997 and 2023, 71 (80.7%) had publicly available results, including 52 (59.1%) published in peer-reviewed journals. Nearly half of published trials (35 [49.3%]) did not report patient race or ethnicity. Among published trials, reporting was inconsistent and focused predominantly on White (36 [50.7%]) patients, with substantially fewer trials reporting data on Asian or Pacific Islander (11 [15.5%]), Black (20 [28.2%]), Hispanic (13 [18.3%]), or Native American (2 [2.8%]) patients. Median (IQR) enrollment of White patients was 91.3% (87.3%-93.6%), whereas enrollment of underrepresented patient populations was markedly lower, with median (IQR) enrollment of 0.9% (0.6%-1.6%) for Asian or Pacific Islander, 4.5% (3.6%-6.6%) for Black (ethnicity unspecified), 7.2% (3.7%-9.1%) for Black (non-Hispanic), 5.2% (3.1%-6.6%) for Hispanic, and 0.4% (0%-0.8%) for Native American patients. Few trials (3 of 71 [4.2%]) conducted subgroup analyses by race or ethnicity, and none reported detailed subgroup characteristics or safety or efficacy outcomes by patient race and ethnicity. Reporting practices and representation showed little improvement over time. US-based phase 3 AD trials showed substantial gaps in racial and ethnic reporting and representation from 1997 to 2023, limiting the evaluation of treatment safety and efficacy across diverse populations. These findings suggest that stronger reporting standards and more inclusive trial design and recruitment strategies are needed to improve the equity and generalizability of AD trials.

Gene copy number (CN) amplifications and protein overexpression are common drug targets and detection relies on various methodologies, including NGS-based CN, IHC, and ISH. We investigated the pan-tumor landscape of amplifications and developed AmpRatio, a novel method of CN quantitation. Pan-tumor tissue (N=486,340) and liquid (N=85,635) samples underwent hybrid capture-based comprehensive genomic profiling. A genome-wide CN model for each sample was generated to estimate the purity, ploidy, and segment-level CN. AmpRatio was calculated by dividing gene CN/sample ploidy. A US-based de-identified clinico-genomic database was utilized to assess the relationship between ERBB2 AmpRatio and HER2 IHC/FISH and outcomes on anti-HER2 therapies. Amplifications with varying degrees of gain were reported in 38.6% of pan-tumor tissue samples, most frequently MYC (5.6%), 11q13 (5.2%), ERBB2 (5.2%), and CCNE1 (3.2%). ERBB2 AmpRatio was associated with HER2 positivity by IHC/FISH in gastroesophageal (overall percent agreement [OPA] 90%) and breast (OPA 95%) cancers. Among patients treated with anti-HER2 therapies, ERBB2 AmpRatio significantly stratified outcomes within the ERBB2-amplified and IHC-defined HER2+ and HER2-low/ultralow populations. High concordance (sensitivity 88%) of amplification detection in liquid biopsy vs tissue was associated with higher AmpRatio and ctDNA tumor fraction ≥20%. CN amplifications are prevalent and diverse biomarkers and AmpRatio is variable across genes and tumor types. ERBB2 AmpRatio is associated with outcomes to HER2-directed therapies and may have utility alongside IHC for clinical decision making. With the increasing number of therapies targeting amplifications/overexpression, it will be important to define harmonized methods for CN quantification for optimal patient selection.

Semaglutide, a glucagon-like peptide-1 receptor agonist, and resmetirom, a thyroid hormone receptor-β agonist, are approved therapies for noncirrhotic metabolic dysfunction–associated steatohepatitis (MASH) with moderate to advanced fibrosis. Their comparative economic value has not been established. To evaluate the cost-effectiveness of semaglutide and resmetirom compared with standard of care (SOC) in patients with noncirrhotic MASH and F2–F3 fibrosis. A state-transition model simulated disease progression in a hypothetical cohort with F2–F3 fibrosis over 5- and 10-year horizons from a U.S. healthcare payer perspective. Clinical efficacy inputs were derived from phase 3 trials (ESSENCE and MAESTRO-NASH), with costs and utilities obtained from published sources. Scenario analyses incorporated semaglutide’s cardiovascular mortality benefit. Deterministic and probabilistic sensitivity analyses assessed uncertainty. Semaglutide was cost-effective versus SOC at 5 years (ICER, $42,200/QALY) and 10 years (ICER, $44,138/QALY). Resmetirom produced higher ICERs ($95,981/QALY at 5 years; $107,002/QALY at 10 years) but remained below a $150,000/QALY threshold. Inclusion of cardiovascular mortality benefits improved semaglutide’s ICER to $38,324/QALY. Probabilistic analyses showed semaglutide had the highest probability of cost-effectiveness across willingness-to-pay thresholds. Over a 10-year horizon, treatment of 100,000 patients with F2–F3 MASH was projected to prevent 270 cases of decompensated cirrhosis, 10 cases of hepatocellular carcinoma, and 1,040 liver-related deaths with semaglutide, compared with 310 cases of decompensated cirrhosis, 10 cases of hepatocellular carcinoma, and 1,180 liver-related deaths with Resmetirom. Semaglutide demonstrated superior cost-effectiveness compared with SOC and resmetirom, with cardiovascular benefits further strengthening its economic value. Not applicable.

Antiphospholipid antibodies (aPL) are directed against phospholipids and phospholipid-binding proteins. Laboratory assays used to detect aPL include serological tests for aPL against β2-glycoprotein 1, cardiolipin and other molecules, as well as functional assays for lupus anticoagulant. The presence of aPL can lead to endothelial dysfunction or a hypercoagulable state through prothrombotic and antifibrinolytic mechanisms. These processes, often in conjunction with a 'second hit', such as trauma, surgery, or other causes of hypercoagulability or stasis, can lead to venous or arterial thrombosis. The thrombotic risk associated with aPL is best recognized in thrombotic antiphospholipid syndrome, characterized by a persistently positive test for lupus anticoagulant or seropositivity for aPL associated with venous, arterial or microvascular thrombosis. However, aPL seropositivity and its clinical effect on thrombotic events have been increasingly recognized in a broader group of individuals who do not meet traditional research criteria for thrombotic antiphospholipid syndrome. In this Review, we provide an overview of the evidence related to aPL seropositivity in individuals with or without previous thrombosis and the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events. We discuss potential management strategies and identify key knowledge gaps that warrant further research.

The COVID-19 pandemic caused widespread social disruption, with stigma emerging as a significant challenge for individuals who survived infection. This qualitative study explored the forms, drivers, and impacts of COVID-19-related stigma among survivors in Eastern Nepal. In-depth interviews were conducted with 15 COVID-19 survivors who had reported stigma in a preceding cross-sectional survey. Due to pandemic-related restrictions, interviews were conducted over the phone. Data were analysed thematically following the process outlined by Braun and Clarke. COVID-19 stigma was multifaceted, including social rejection, internalized stigma, and discriminatory practices by community members. Key drivers of stigma included self-directed fear of infection and death, misinformation and limited awareness about COVID-19 transmission and prevention, and a fragile health system and policy responses. Although COVID-19-related stigma may have declined as the pandemic evolved, the findings illustrate how stigma can emerge rapidly during health emergencies that can have social consequences related to trust, disclosure, and help-seeking behavior in future crisis. The study highlights the importance of outbreak preparedness strategies that integrate clear communication, strengthened health system capacity, and social protection measures to mitigate stigma and its harms during future public health crises.

We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, retrieving data from PubMed, Elsevier, Web of Science, and Cochrane Central Register of Controlled Trials . Primary outcomes included changes from baseline in acute headache medication days and monthly migraine days (MMD). Secondary outcomes comprised the incidence of adverse events (AEs), common AEs, and the proportion of patients achieving a ≥ 50% reduction in MMDs. Five randomized controlled trials including 875 patients (mean age of 42.7 years) were analyzed. Erenumab treatment was associated with significant reductions in acute headache medication days (mean difference = -1.72; 95% confidence interval [CI]: -2.81 to -0.62; p = 0.002) and MMDs (mean difference = -1.88; 95% CI: -2.68 to -1.07; p < 0.001). Whereas erenumab increased the risk of common AEs such as constipation (risk ratio [RR] = 1.43; 95% CI: 1.17 to 1.76; I2 = 14%), the overall incidence of AEs was not significantly different compared to placebo (RR = 1.02; 95% CI: 0.92 to 1.14; I2 = 57%). A higher proportion of patients achieved a ≥50% reduction in MMDs after 3 months in the erenumab group (RR = 1.49; 95% CI: 1.26 to 1.77; I2 = 22%). Erenumab appears effective in reducing migraine frequency and symptomatic medication use among patients with chronic migraine MOH, with an acceptable tolerability profile.