Citations

ABSTRACT BACKGROUND Platelet factor 4-polyanion enzyme-linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin-induced thrombocytopenia (HIT), such that current practice guidelines recommend use of ELISA-negative results to exclude HIT. Once HIT is ruled out, alternative, non-heparin-based anticoagulant treatments are ceased, and heparin reintroduction frequently occurs. METHODS Antigen-based and PF4-dependent functional testing were used to study PF4/polyvinyl sulfonate ELISA-negative platelet-activating antibodies in HIT-suspected patients and mice immunized with PF4/heparin. RESULTS Three patients with clinical presentations consistent with HIT tested negative in an ELISA using PF4-polyvinylsulfonate (PF4/PVS), an antigenic target very commonly used for HIT antibody detection. All three patients demonstrated PF4-dependent platelet activation in functional testing that was sensitive to blockade of platelet FcγRIIa receptors and inhibited by high concentrations of heparin, consistent with pathogenic HIT antibodies. Functional testing-based screening of 500 ELISA-negative patients identified three patients whose sera activated platelets in a PF4- and FcγRIIa-dependent manner, and had clinical histories consistent with HIT. Five of the six ELISA-negative HIT patients were re-exposed to heparin, which precipitated a decrease in platelet counts in all re-exposed patients, and one patient developed a new thrombus. To advance the study of ELISA-negative HIT antibodies, mice were immunized with PF4/heparin, and functional and antigenic assays were simultaneously used to successfully identify an ELISA-negative, PF4-dependent platelet-activating murine monoclonal antibody that recapitulated the serological characteristics of ELISA-negative HIT patients. CONCLUSIONS Recognition of ELISA-negative HIT is critical to avoid harm due to the cessation of alternative anticoagulation therapy and re-exposure of these patients to heparin.

Background: Internalized HIV stigma (IHS) is associated with reductions in antiretroviral therapy (ART) adherence and HIV viremia mediated through depression. However, there is still a need to quantify the direct impact of IHS on ART adherence to inform interventions to improve medication adherence. Methods: The Center for AIDS Research Network of Integrated Clinical Systems is a longitudinal, US-based, multisite cohort of people with HIV who complete patient-reported outcome assessments as part of HIV-care visits. Patient-reported outcome data include IHS items, ART adherence, depression assessments, substance use, and other outcomes. We examined associations between IHS and ART adherence using generalized linear latent and mixed models with a nonparametric random effects intercept to accommodate repeated measures. Results were compared with analyses using generalized estimating equations and marginal structural models. Results: Among 13,119 people with HIV, the mean age was 47.4 years, 17.6% were women, and 59.3% were non-White. Across 33,139 observations, controlled for repeated measures on individuals, HIV medication adherence was reduced by 1.07% for every point increase in IHS after controlling for age, sex, ethnicity, geographic location, and substance use, and 0.58% when additionally adjusted for depression score. Marginal structural models and generalized estimating equations provided similar results. Conclusions: Our study demonstrates that IHS has a direct association with reductions in ART adherence, which could affect other comorbid health outcomes that are influenced by unsuppressed viremia over time. Developing a thorough understanding of the mechanisms through which IHS affects ART adherence is critical for developing interventions to mitigate IHS and improve health outcomes across the lifespan.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

Abstract The addition of pembrolizumab to preoperative radiotherapy (RT) improved disease-free survival (DFS) for patients with stage III undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS) in the randomized SU2C-SARC032 trial. To precisely identify patients who benefit from pembrolizumab and RT, we performed comprehensive multi-omics profiling of pre- and post-treatment tumor and blood samples, including bulk RNA-seq, flow cytometry, and cytometry by time of flight. Additionally, we built a single-cell RNA-seq atlas spanning 65,786 cells from UPS and LPS to recover single-cell states in bulk tumor samples using digital cytometry. Two opposing tumor microenvironments (TMEs), immune-cold sarcoma ecotype 1 (SE1) and immune-hot sarcoma immune class E (SIC E), benefited from pembrolizumab. Pembrolizumab combined with RT caused an overall increase in activated CD8 + T cells, CD56 low NK cells, and T cell receptor diversity, while diminishing matrix-remodeling stromal cells and sarcoma cells. Our findings identify different mechanisms of response to pembrolizumab in localized, high-risk UPS/LPS and suggest that sarcoma TME signatures may identify patients most likely to benefit from adding pembrolizumab to preoperative RT.

BACKGROUND Predictive biomarkers to guide chemotherapy decisions for metastatic castration–resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS The CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA 50 response rate were assessed. RESULTS High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52–3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01–2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSION This preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION ClinicalTrials.gov number NCT02485691. FUNDING Funded by Sanofi and Epic Sciences.

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (&amp;lt;5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (&amp;gt;70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P &amp;lt; .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

Background: Atrial fibrillation (AF) significantly impacts quality of life (QoL) and is often observed in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis achieves near-complete (≥90%) transthyretin (TTR) stabilization and is approved in the USA, the UK, Europe and Japan for the treatment of ATTR-CM in adults. In the phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment significantly reduced the time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) at Month 30, and resulted in improved 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to placebo. The clinical efficacy of acoramidis has not yet been reported in patients with ATTR-CM and with an AF or atrial flutter (AFL) diagnosis at baseline. Research Question: How does acoramidis treatment affect ACM or first CVH, 6MWD, KCCQ-OS scores, and NT-proBNP levels at Month 30 in participants with ATTR-CM with or without AF/AFL diagnosis at baseline? Methods: The ATTRibute-CM study design has been previously published. This post hoc analysis included participants in the modified intention-to-treat population (N=611) grouped by AF/AFL diagnosis at baseline (defined as recorded AF medical history or the presence of AF or AFL on an ECG at enrollment). The rate of ACM or first CVH at Month 30 was compared between groups using a stratified Cox proportional hazards model. Changes from baseline to Month 30 in 6MWD, KCCQ-OS scores and NT-proBNP levels were summarized descriptively. Results: Overall, 62.8% (384/611) of participants had an AF/AFL diagnosis at baseline (acoramidis: 255/409, placebo: 129/202). These participants had lower mean 6MWD and KCCQ-OS scores and higher median NT-proBNP levels than those without AF/AFL diagnosis at baseline. Treatment with acoramidis reduced ACM or first CVH, slowed the decline in 6MWD and KCCQ-OS scores and blunted the rise in NT-proBNP compared with placebo, regardless of AF/AFL diagnosis at baseline ( Table ). Conclusions: Acoramidis improved clinical outcomes (ACM, CVH), functional status, QoL and NT-proBNP levels relative to placebo in participants with ATTR-CM, regardless of AF/AFL diagnosis at baseline.