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.

Importance The long-term outcomes of surgery for pediatric traumatic cataract are not well described; understanding these outcomes would inform parental expectations. Objective To report visual acuity (VA) outcomes and cumulative incidence of ocular complications by 5 years following lensectomy for pediatric traumatic cataract. Design, Setting, and Participants This prospective cohort study was conducted across 32 sites in the US and Canada among 75 children undergoing lensectomy from birth to less than 13 years of age for unilateral traumatic cataract. Of 75 children, 60 had primary intraocular lens (IOL) placement; 15 were left aphakic. Data were collected from August 2012 to February 2020. Data analysis was performed from October 2022 to May 2025. Exposure Lensectomy. Main Outcomes and Measures The primary outcomes were best-corrected VA 5 years after lensectomy; period prevalence of strabismus and glaucoma (including cases diagnosed before lensectomy); surgery for visual axis opacification (VAO); and cumulative incidence of ocular complications by 5 years. Annual data collection was from medical record reviews through 5 years following lensectomy. Results Among 75 participants, 28 (37%) were female, and median (range) age at lensectomy was 7.4 years (0.1-13 years). Median (IQR) best-corrected VA at 5 years (available for 37 participants [49%]) was 20/63 (20/35-20/159) in pseudophakic eyes (n = 29; mean [SD] age at surgery, 7.2 [3.0] years) and 20/258 (20/56-<20/800) in aphakic eyes (n = 8; mean [SD] age at surgery, 5.5 [4.3] years). Age-normal VA was achieved by 6 pseudophakic eyes (21%; 95% CI, 10%-38%) and 1 aphakic eye (13%; 95% CI, 2%-47%). The 5-year period prevalence of glaucoma was 9% in pseudophakic eyes (95% CI, 1%-16%) and 9% in aphakic eyes (95% CI, 0%-24%). The 5-year cumulative incidence of surgery for VAO was 47% in pseudophakic eyes (95% CI, 31%-60%) and 13% in aphakic eyes (95% CI, 0%-28%). The risk was greater in eyes that did not undergo an anterior vitrectomy (84%; 95% CI, 55%-94%) vs eyes that did (15%; 95% CI, 2%-26%) (age-adjusted hazard ratio, 11.4; 95% CI, 4.6-33.1; P < .001). Conclusions and Relevance In this cohort study, while only half of the study participants had a 5-year follow-up visit, achieving age-normal VA was uncommon among the cohort in whom a best-corrected VA was determined. The prevalence of glaucoma at 5 years was low among those with 5-year follow-up, while nearly half of the pseudophakic eyes needed surgery for VAO supporting the need to monitor these children.

Importance Metabolic dysfunction–associated steatohepatitis (MASH) represents a high, underprioritized burden among noncommunicable diseases (NCDs) and people living with type 2 diabetes (T2D). Objective To identify cost-effective management approaches to prevent, detect, and treat MASH and liver fibrosis in people living with T2D. Design, Setting, and Participants This economic evaluation consisted of a generalized cost-effectiveness analysis (GCEA) that was conducted for 12 countries (Brazil, Chile, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, Sweden, Tanzania, Thailand, and the United States), across all 6 World Health Organization (WHO) regions. A cohort state-transition model simulated liver disease development and its impact on a synthetic cohort, aged 19 years and older and living with T2D, over their lifespan across 10 liver health states. Exposures Using an 80% coverage level, 14 management approaches were compared, including screening via the Fibrosis-4 (FIB-4) test and Enhanced Liver Fibrosis (ELF) test or vibration-controlled transient elastography (VCTE) as well as treatment with pharmacological and nonpharmacological interventions. Main Outcomes and Measures The main outcomes were the average cost-effectiveness ratios (ACERs) and the incremental cost-effectiveness ratios (ICERs), which were used to construct care expansion paths by ranking the management approaches in order of cost-effectiveness. The main measures were the total incremental costs and the total incremental quality-adjusted life-years (QALYs) of each intervention. Results In this GCEA, the outcomes were evaluated with respect to country-specific willingness-to-pay thresholds. The standard of care had the lowest ACERs in 8 countries (not in Chile, Germany, Saudi Arabia, or the United States). Treatment with intensive lifestyle interventions (ILIs), after screening via ELF or VCTE, was cost-effective in all countries. ILIs and treatment with semaglutide was cost-effective in 11 countries (not in Tanzania); ILIs and treatment with resmetirom was cost-effective in 8 countries (not in Brazil, South Africa, Tanzania, or Thailand). Conclusion and Relevance In this economic evaluation, screening followed by ILIs was found to be a cost-effective management approach for MASH and liver fibrosis among people living with T2D in all countries. Screening followed by pharmacological treatment was cost-effective in most countries. These results can inform health policy decision-making and further the development of WHO recommended interventions to address NCDs.

BACKGROUND AND OBJECTIVES: Meningiomas are the most common primary central nervous system tumors, with cavernous sinus meningiomas (CSMs) making up a small fraction (1% of intracranial tumors). CSMs are challenging to treat due to their location and potential invasion. Therapy methods have shifted from aggressive resections to less invasive techniques such as stereotactic radiosurgery, reducing morbidity and improving survival. This study reviews the effectiveness and safety of radiosurgery for CSMs, blending historical and contemporary approaches to guide future treatments. METHODS: A search was performed in MEDlINE, Embase, and Cochrane databases, following Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies included randomized or observational studies with ≥4 patients reporting on radiosurgery for CSM. The random-effects model was used to calculate a single proportion analysis with 95% CIs. Statistical analyses were performed using RStudio. RESULTS: Twenty seven studies, encompassing 1851 patients, were included in this analysis, with a population median age of 27 years. Outcomes were assessed as follows: the 10-year progression-free survival rate was 87% (323 patients; 95% CI: 73%-100%; I 2 = 89.6%), clinical deterioration occurred in 6% of cases (957 patients; 95% CI: 3%-8%; I 2 = 71.3%), clinical improvement was observed in 35% of patients (1106 patients; 95% CI: 27%-43%; I 2 = 86.6%), major complications rate was 4% (688 patients; 95% CI: 1%-6%; I 2 = 71.8%), and minor complications was 2% (653 patients; 95% CI: 0%-3%; I 2 = 68.6%). CONCLUSION: This study reveals stereotactic radiosurgery as an effective treatment of CSMs, showing high long-term progression-free survival and significant tumor control with few complications.

BACKGROUND AND OBJECTIVES: The Patient-Generated Subjective Global Assessment (PG-SGA) is a standardized tool for assessing malnutrition in patients with cancer. The primary aim of this study was to assess the impact of preoperative nutritional status as measured by PG-SGA on survival in patients requiring surgical intervention and/or radiotherapy for spinal metastases. METHODS: Patients with spinal metastases who underwent surgery and/or radiation therapy for symptomatic spinal metastases were enrolled in the AO Spine Metastatic Tumor Research and Outcomes Network, a prospective international multicenter research registry, between September 2017 and August 2022. Using the PG-SGA, nutritional status was classified into 3 categories: A, well nourished; B, moderately malnourished; and C, severely malnourished. RESULTS: A total of 589 patients met the inclusion criteria; 362 were classified as well nourished (61%), 159 were moderately malnourished (27%), and 68 were severely malnourished (12%). The median survival was 491 days, 328 days, and 117 days for well-nourished, moderately malnourished, and severely malnourished patients, respectively. In the multivariate analyses, severe malnourishment (HR 2.5 95% CI 1.4-4.3, P < .01) and an ECOG performance status of 3 or 4 (HR 2.7 95% CI 1.2-6.0) remained associated with significantly worse survival. CONCLUSION: Malnutrition as measured by the PG-SGA demonstrated to be significantly and independently associated with postoperative survival. The PG-SGA is a simple and useful tool to identify spinal metastases patients at risk of early postoperative mortality, and inclusion in the preoperative evaluation of these patients should be considered.

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.

Lay Summary In this study we evaluated the effectiveness of vedolizumab (anti-integrin) vs ustekinumab/risankizumab (anti-interleukin) therapy for isolated small-bowel Crohn’s disease using a real-world, multicenter national database. We found that anti-interleukin therapy was more effective for inducing steroid-free remission and reducing hospitalizations.

ABSTRACT Pulmonary hypertension (PH) is a common complication in interstitial lung disease (ILD), but the additional burden it imposes on patients and healthcare systems is not well characterized. This retrospective analysis of claims data from the US Merative MarketScan database assessed hospitalization rates and costs over 2 years in patients with connective tissue disease‐related ILD (CTD‐ILD) and non‐CTD‐ILD with or without PH (between January 2017 and December 2019). Index was the date of first ILD claim; baseline was the 12‐month preindex period. In total, 16,129 patients with non‐CTD‐ILD (1502 [9%] with PH) and 4545 patients with CTD‐ILD (663 [15%] with PH) were identified. A higher proportion of patients with non‐CTD‐ILD with PH, compared with patients without PH, had all‐cause and heart failure (HF)‐related hospitalizations during baseline (all‐cause, 37.0% vs. 22.3%; HF‐related, 14.2% vs. 3.1%), 0–12 months (62.4% vs. 43.0%; 29.0% vs. 7.0%), and 13–24 months (44.7% vs. 18.3%; 21.5% vs. 3.2%) follow‐up ( p < 0.0001 for all). A significantly higher proportion of patients with CTD‐ILD with PH, compared with patients without PH, had all‐cause and HF‐related hospitalizations during baseline (all‐cause: 30.0% vs. 20.6%; HF‐related: 9.1% vs. 1.9%), 0–12 months (41.9% vs. 29.1%; 15.5% vs. 3.9%), and 13–24 months (37.9% vs. 18.9%; 13.9% vs. 2.5%) follow‐up ( p < 0.0001 for all). In both cohorts, total all‐cause and HF‐related costs were significantly higher in patients with PH at baseline, 0–12 months, and 13–24 months follow‐up ( p < 0.05 for all). PH substantially increased hospitalization risks and costs in both types of ILD, underscoring the importance of improving outcomes in patients with ILD‐PH.

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 Background Adolescent and young adult (AYA) patients remain underrepresented in neuro-oncology research. Despite being the second most common primary brain tumor in this population, meningiomas have not been studied using age-specific molecular analyses. DNA methylation-based classification and prognostic tools have transformed meningioma care. This study aimed to evaluate the performance of these tools across age groups. Methods We analyzed 1,568 meningiomas with DNA methylation and clinical data, including 18 pediatric patients (&lt;15 years), 195 AYA patients (15-39 years), and 1,355 adult patients (&gt;39 years). Pediatric and AYA (P/AYA) tumors were combined and compared with adult tumors. The performance of established molecular classifiers and recurrence predictors, as well as differences in chromosomal copy number alterations were compared across age groups. Results While histologic grading was comparable between cohorts, P/AYA tumors displayed significantly fewer aggressive molecular groups and lower frequencies of chromosomal arm losses, including 1p, 6q, and 14q. The adult-trained recurrence predictor failed in the P/AYA population (AUC 0.57), despite similar score distributions. Retraining the model on an age-specific cohort using an identical analytic framework improved performance (AUC 0.79) and enabled effective stratification of progression-free survival (P = 0.00054). Importantly, 1p loss retained prognostic significance within the P/AYA group, supporting its clinical utility. Conclusions Molecular tools developed in adult-dominant cohorts do not generalize to younger patients due to both biological divergence and exclusion from model development. These findings underscore the need for age-specific molecular frameworks and highlight the imperative of including P/AYA populations in precision neuro-oncology research to ensure lifespan-equitable care.