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Rationale Immunoglobulin A (IgA) deficiency, a rare, highly heritable trait, is associated with frequent pulmonary infections, emphysema, airway changes and low lung function; however, it is unclear if reduced IgA levels may affect lung structure and function. Methods Serum IgA, IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were measured in the population-based Multi-Ethnic Study on Atherosclerosis (MESA). The MESA Lung Study measured percent emphysema on cardiac CT and airway dimensions on chest CT, and performed spirometry. Regression models were evaluated after adjustment for demographic and CT factors. Mendelian randomisation (MR) analyses were conducted using genetic variants from the Trans-Omics for Precision Medicine (TOPMed) programme. A replication analysis was performed in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS). Measurements and main results Among 5497 participants, lower log-normalised serum IgA levels were associated with greater percent emphysema (β=−0.084; 95% CI −0.14 to –0.026; p=0.005), which was confirmed on MR (β=−0.79; 95% CI −1.4 to –0.18; p=0.011). Greater log-normalised serum Gd-IgA1 levels were associated with airway wall thickness (β=0.0079; 95% CI 0.0017 to 0.014; p=0.012; n=2580) and decline in the forced expiratory volume in one second (FEV1) (β=−0.012; 95% CI −0.021 to –0.0036; p=0.0055; n=2778) and FEV1/forced vital capacity (FVC) ratio (β=−0.0028; 95% CI −0.0048 to –0.00084; p=0.0054; n=2778). Conclusion Lower serum IgA levels were associated with greater percent emphysema. Additionally, higher Gd-IgA1 levels were associated with airway wall thickness and lung function decline. These findings support a protective role of IgA in emphysema pathogenesis and possible deleterious role of Gd-IgA1 in airway diseases.

Abstract Objective: Electronic Health Record (EHR) data are critical for advancing translational research and AI technologies. The ENACT network offers access to structured EHR data across 57 CTSA hubs. However, substantial information is contained in clinical narratives, requiring natural language processing (NLP) for research. The ENACT NLP Working Group was formed to make NLP-derived clinical information accessible and queryable across the network. Methods: We established the ENACT NLP Working Group with 13 sites selected based on criteria including clinical notes access, IT infrastructure, NLP expertise, and institutional support. We divided sites into five focus groups targeting clinical tasks within disease contexts. Each focus group consisted of two development sites and two validation sites. We extended the ENACT ontology to standardize NLP-derived data and conducted multisite evaluations using the Open Health Natural Language Processing (OHNLP) Toolkit. Results: The working group achieved 100% site retention and deployed NLP infrastructure across all sites. We developed and validated NLP algorithms for rare disease phenotyping, social determinants of health, opioid use disorder, sleep phenotyping, and delirium phenotyping. Performance varied across sites (F1 scores 0.53–0.96), highlighting data heterogeneity impacts. We extended the ENACT common data model and ontology to incorporate NLP-derived data while maintaining Shared Health Research Informatics NEtwork (SHRINE) compatibility. Conclusion: This demonstrates feasibility of deploying NLP infrastructure across large, federated networks. The focus group approach proved more practical than general-purpose approaches. Key lessons include the challenge of data heterogeneity and importance of collaborative governance. This work also provides a foundation that other networks can build on to implement NLP capabilities for translational research.

ABSTRACTBackgroundErenumab‐induced medication overuse headache (MOH) remission in participants with chronic migraine (CM) in a prospective, Phase 4, randomized, placebo‐controlled trial with an open‐label treatment period (OLTP). We present 1‐year results from the combined double‐blind treatment period (DBTP) and OLTP for the stratified nonopioid cohort.MethodsParticipants with CM‐MOH were randomized 1:1:1 to subcutaneous 70 or 140 mg erenumab every 4 weeks (QM) or placebo for the initial 24 weeks (DBTP). Those successfully completing DBTP could continue the 28‐week OLTP, maintaining the same erenumab dose received during DBTP or, if receiving placebo, randomly assigned 1:1 to erenumab 70 or 140 mg QM. OLTP endpoints were exploratory.ResultsOverall, 552 participants received erenumab (70 mg, n = 274; 140 mg, n = 278); 95.3% completed OLTP. One‐year MOH relapse in participants who achieved MOH remission at DBTP Month 6 was 2.7% (3/111) and 2.4% (3/124) with erenumab 70 and 140 mg, respectively; absence of MOH at study end was observed in 69.0% (189/274) and 75.5% (210/278) of participants. Sustained MOH absence over 1 year was reported in 60.5% (107/177) and 68.8% (119/173) of participants, respectively. Sustained improvements in measures of headache days, medication days, and function were observed in both groups. No new safety concerns were identified (grade ≥ 3, 35 [6.3%]; serious, 17 [3.1%]; adverse events leading to treatment discontinuation, 5 [0.9%]).ConclusionsErenumab was effective in inducing and sustaining MOH remission and improving function over 1 year. Treatment compliance remained high, with safety events consistent with erenumab's known safety profile.Trial RegistrationNCT03971071

Abstract INTRODUCTION We investigated associations of plasma proteins with blood‐based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD). METHODS Plasma proteomics and clinical data from the Indiana AD Research Center ( N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort ( N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk. RESULTS We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker‐specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930). CONCLUSION Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD. Highlights Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker‐specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

Abstract The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

Background Delirium is a state of acute brain failure causing confusion, reduced focus, and changes in alertness. It is common in older patients, occurring in 6-38% of older emergency department (ED) patients. Evidence suggests that systematic screening improves detection rates and early detection, management and reporting are critical. However, examples of operationalizing this in clinical non-research care are scarce. Objective To describe and disseminate examples of best practices for delirium screening, management, and monitoring within the ED. Methods A group of emergency physicians interested in geriatric emergency medicine (GEM) and evidence-based medicine gathered monthly to discuss ways of implementing delirium care. Members were asked to submit any electronic health record (EHR)-based interventions for delirium in current use at their institutions. One group member categorized the EHR tools by their use for screening, prevention, management, and monitoring of delirium. As a group, categorizations were reviewed and agreed upon and similarities, differences and themes were identified. Results Current EHR interventions from 5 EDs were included. We found that: 1) Screening for delirium in EDs is challenging due to the nature of the environment and the variety of tools available. 2) Prevention tools included order sets. 3) Management was accomplished with best practice alerts and order sets to help screen, prevent, address underlying causes, and manage agitation. Delirium prevention order sets emphasize optimizing patient mobility, comfort, and communication. Assessment order sets include routine labs and consultations, while management order sets for agitation provide safe medication options considering older adults’ unique physiology. 4) Utilizing dashboards for compliance monitoring offers real-time feedback, and provides an overview of adherence to clinical guidelines, regulatory standards, and patient safety protocols. Conclusion These real-world examples can be used in EDs implementing delirium programs. Further studies on how EHR interventions impact screening, diagnosis, and treatment of delirium in the ED are needed.

Background Non-acute or chronic subdural hematoma (cSDH) is commonly treated with surgical evacuation followed by middle meningeal artery embolization (MMAe). This two step approach increases procedural complexity and redundancy, hospitalization duration, and patient risk. We hypothesized that cSDH could be managed through a single session endovascular procedure and conducted a multimodal preclinical study to evaluate feasibility. Methods We performed three-dimensional heat mapping of hematoma distribution from preoperative CT scans (n=69) and analyzed middle meningeal artery (MMA) and superior sagittal sinus (SSS) anatomy and perforation trajectories using imaging from 107 patients. Rheological properties of 41 SDH samples were assessed using hybrid rheometry and modeled with the Carreau equation. Aspiration feasibility was tested using a 0.027 inch microcatheter (n=16), and dura perforation forces were quantified with a 28 G needle in fresh cadaveric dura (n=10). Results Heat mapping localized cSDH to the parietal convexities (>80% probability) under the branches of the MMA, with limited midline involvement and proximity to the SSS (<10%). The posterior division of the MMA (diameter 1.23±0.23 mm) accommodated a 0.027 inch microcatheter in >90% of cases, with perforation trajectories targeting high probability hematoma zones in 105 of 107 cases. SDH samples exhibited shear thinning viscosity ( η ₀ =172 mPa×s, η ∞ =2.78 mPa×s), with mean aspiration times of 1.21±0.54 min per 10 mL. Perforation forces averaged 0.68±0.24 N in normal and 1.29±0.48 N in calcified dura (P=0.05). Conclusion Anatomical, rheological, and biomechanical data from this study support the feasibility of endovascular drainage of cSDH through the MMA.

BACKGROUND AND OBJECTIVES Recent changes in European diagnostic criteria allow for serologic diagnosis of celiac disease in children. Those guidelines have not been adopted in North America; hence, we aim to assess the positive predictive value (PPV) of tissue transglutaminase (tTG) immunoglobulin A (IgA) assays used in North America in identifying histologic findings of celiac disease. METHODS Multicenter retrospective cohort study of children (&lt;18 years) with an elevated tTG IgA within 6 months of an esophagogastroduodenoscopy between January 2016 and December 2021. Biopsy-confirmed celiac disease was determined by the presence of intraepithelial lymphocytosis and villous atrophy. The primary outcomes were the PPV of an elevated tTG IgA and tTG IgA greater than or equal to 10 times the upper limit of normal (10× ULN). RESULTS Overall, 4019 children (63.3% female; 9% type 1 diabetes, 2% Down syndrome) were included. Histologic findings were consistent with celiac disease for 3321 children (PPV = 82.6% [95% CI, 81.4–83.8]). Among the 1739/4019 (43.2%) children with tTG IgA greater than or equal to 10× ULN, 1651 had biopsy-confirmed celiac disease (PPV10× = 94.9% [95% CI, 93.8–95.9]). Five percent (88/1739) of children did not have histologic findings of celiac disease, including 41/1739 (2%) with normal histology. Diagnostic accuracy of tTG IgA varied widely among assays used in North America (PPV range: 71.5%–88.8%; PPV10× range: 89.3%–97.3%). Assays performed worse in children with type 1 diabetes (PPV10× 89% [95% CI, 83.5–92.8]). CONCLUSIONS Elevated tTG IgA in isolation is insufficient to confidently diagnose celiac disease. As tTG assay performance varied widely, diagnostic confirmation by a specialist prior to dietary changes is essential.

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.