Citations

Background: Traditional neuropathological assessment of Alzheimer's disease (AD) relies on manual, semi-quantitative scoring of amyloid-beta (Aβ) burden. This approach is limited by high inter-rater variability and often qualitative, failing to capture subtle, continuous pathology changes. While 11C-PiB PET neuroimaging provides non-invasive longitudinal monitoring, it has a limited dynamic range and lacks the sub-millimeter spatial resolution necessary to track localized microvascular and parenchymal Aβ trajectories. Methods: We introduce ViTamyloid, a generalizable modular computational pathology pipeline for high-throughput Aβ segmentation and classification in postmortem tissue. In Stage 1, a pathologist-supervised hybrid framework combining an EfficientNet-B4 encoder with a Residual U-Net decoder, complement with a localization-aware Faster R-CNN detector, to generate binary segmentation masks and isolated lesion candidates. In Stage 2, classification model powered by a frozen, high-resolution UNI2-h computational pathology foundation backbone and a ViT-Adapter, classifies candidates into a fine-grained four-class taxonomy: classic cored plaques (CCP), coarse-grained plaques (CGP), capillary cerebral amyloid angiopathy (CAA Type 1), and parenchymal/leptomeningeal CAA (CAA Type 2). We bench-marked out-of-distribution (OOD) robustness on external datasets from different brain banks, and validated clinical scalability across 1,646 whole-slide images from three brain banks. Results: The ViTamyloid classifier achieved strong feature-separation metrics, yielding area under the receiver operating characteristic curve (AUROC) and precision-recall curve (AUPRC) values of 0.994/0.958 for CCP, 0.989/0.945 for CGP, 0.992/0.977 for CAA Type 1, and 0.997/0.978 for CAA Type 2. More importantly, ViTamyloid consistently outperforms other pipelines' models and frozen features in all external datasets with different antibodies, and scanner settings, and image quality. Conclusion: By replacing empirical, from-scratch architectures with a generalizable foundation model adapter framework, ViTamyloid provides a highly sensitive scalable digital pathomics toolkit. This pipeline expose continuous microscopic neuropathological dynamics beyond the spatial and sensitivity plateaus of in vivo neuroimaging, offering objective, quantitative endpoints for Alzheimer's disease clinical trials and disease subtyping.

Abstract Background Lithium remains one of the most effective long-term treatments for bipolar disorder (BD). However, concerns about kidney function can make decisions about long-term treatment more difficult. The extent to which lithium exposure, BD, and sex contribute to changes in kidney function remains uncertain. Methods We conducted a retrospective longitudinal cohort study of 3,458 adults aged ≥18 years at their first lithium measurement and with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m², including 2,383 with BD and 1,075 without BD. Longitudinal eGFR trajectories were examined using mixed-effects models accounting for age, sex, BD status, cumulative lithium exposure, current and past lithium use, a history of serum lithium concentrations ≥1.2 mmol/L, and comorbidity burden. A secondary analysis examined change in eGFR between the first and last measurements in relation to changes in cumulative lithium exposure. Results Greater cumulative lithium exposure was consistently associated with lower eGFR across sex and BD groups. Overall, each additional year of lithium exposure was associated with a 1.14 mL/min/1.73 m² lower eGFR (95% CI, -1.29 to -1.00; p < .001). Current and past lithium use were also associated with lower eGFR compared with non-use. A history of lithium toxicity, defined as at least one serum lithium concentration ≥1.2 mmol/L, was associated with lower eGFR overall (-1.58; 95% CI, -2.19 to -0.97; p < .001), with a significant association among females but not males. In the secondary analysis, an increase in cumulative lithium exposure of >2 years was associated with greater eGFR decline across all sex and BD groups. However, interactions between lithium exposure change, sex, and BD status were not significant, providing no clear evidence that this association differed by sex or BD status. Conclusions Long-term kidney-function changes were more consistently associated with lithium exposure than with BD itself. Greater cumulative exposure and a history of lithium toxicity were associated with lower eGFR. These findings support continued monitoring of kidney function and lithium levels during long-term treatment while maintaining lithium’s important role in the management of BD.

Background Microsurgery is a critical component of plastic and reconstructive surgery. However, the high cost of training and equipment pose significant barriers, particularly in resource-limited settings. To address this challenge, the Microsurgery and Regenerative Medicine Lab within the Division of Plastic Surgery at the University of Wisconsin developed a low-cost, 3D-printed surgical microscope. This study qualitatively appraised the use of this novel microscope for microsurgery training by surveying surgeons about their experiences using this tool relative to traditional magnification methods. Methods In this prospective, multi-institutional appraisal study, surgical residents, fellows, and attending surgeons with varying microsurgical experience performed a single end-to-end microsurgical anastomosis on chicken thigh femoral arteries using the 3D-printed microscope. Participants then completed a survey assessing ease of use, adequacy for microsurgical training, educational value, and perceived impact on teaching capacity in local and global settings. Results Over 80% of participants reported that performing an end-to-end anastomosis was easier or equivalent using the 3D-printed microscope compared to surgical loupes. All respondents expressed willingness to use the device for microsurgery teaching and practice. Additionally, 91.7% (33/36) believed access to the microscope would enhance microsurgical teaching at their home institutions, and 97.1% (34/35) felt it would improve teaching capacity in globally. Qualitative feedback was overwhelmingly positive, with suggestions primarily related to ergonomics and lighting. Conclusion This study supports that this low-cost, 3D-printed microscope is an effective microsurgical training tool. Ongoing design refinements informed by user feedback may further optimize its role in expanding access to microsurgery education worldwide.

Obstructive sleep apnea (OSA) is a common, heterogeneous disorder managed through a multidisciplinary pathway that connects recognition, physiologic testing, treatment selection, specialty referral, insurance coverage, and longitudinal reassessment. This narrative review provides a clinically oriented, system-level overview of the adult OSA care ecosystem in the United States for an international clinical audience, with particular emphasis on the evolving role of otolaryngology. We describe the organization and complementary functions of sleep physicians, otolaryngologists, dentists, and allied health professionals. We also outline the roles of polysomnography and home sleep apnea testing, along with major therapeutic pathways including positive airway pressure, oral appliance therapy, weight management, upper-airway surgery, and neurostimulation. Otolaryngology provides an important interface between physiologic diagnosis and airway-specific treatment by integrating anatomic evaluation, sleep-state airway phenotyping, intervention selection, and post-treatment reassessment. Recent advances in neurostimulation, pharmacologic weight management, wearable and home-based monitoring, airflow analysis, and artificial intelligence are expanding opportunities for accessible and phenotype-informed care. Important challenges include underdiagnosis, treatment attrition, fragmented transitions, variable coverage, and reliance on the apnea–hypopnea index. Although health-care structures differ internationally, multidisciplinary coordination, individualized treatment selection, and longitudinal reassessment provide broadly applicable principles for developing patient-centered OSA programs.

Abstract Backgrounds Isolated REM sleep behaviour disorder (iRBD) is a prodromal marker of α-synucleinopathies. Although cognitive impairment is consistently reported in iRBD, its assessment varies considerably across studies. This study characterized mild cognitive impairment (MCI) patterns in iRBD using machine learning and identified the minimal neuropsychological test battery needed for accurate diagnosis. Methods Comprehensive neuropsychological data from 216 assessments (162 with MCI, 54 without) in 110 iRBD patients were analysed. Four supervised classifiers (logistic regression, support vector machine, random forest, gradient boosting) were trained across three frameworks (raw scores, raw scores plus demographics, binarized scores) to distinguish MCI status. A multi-objective hyperparameter optimization approach then identified the minimal test subset preserving diagnostic accuracy. Results Of MCI cases, 30% were single-domain and 70% multi-domain, with attention/executive functions and memory most frequently impaired. Binarized neuropsychological scores yielded the best classification performance, with support vector machine achieving 94.7% accuracy. Feature importance analyses consistently highlighted episodic memory, executive, and visuospatial measures. The optimization framework identified a mean of 8 informative tests spanning these domains, achieving comparable diagnostic accuracy to the full battery. Conclusions Cognitive impairment is common in iRBD and predominantly multidomain. Machine learning approaches applied to neuropsychological data can accurately classify MCI status and identify a concise, clinically feasible set of tests with high diagnostic value. These findings support comprehensive, multidomain neuropsychological assessment in iRBD and may inform optimized risk stratification in prodromal α-synucleinopathies.

The chemotherapeutic 5‐fluorouracil (5‐FU) is commonly used to treat solid tumors, especially colorectal cancer. Deleterious variants in DPYD, which encodes dihydropyrimidine dehydrogenase (DPD), are strongly associated with severe and potentially lethal 5‐FU toxicity. Phenotypic assays for DPD function have been proposed as alternative or complementary approaches to identify DPD deficiencies with the rationale that they may capture unrecognized causes. These assays include the direct measurement of DPD activity in peripheral blood mononuclear cell (PBMC) lysates and measuring plasma metabolites uracil (U), dihydrouracil (UH 2 ), and the dihydrouracil/uracil (UH 2 :U) ratio. We evaluated correlations between PBMC DPD activity and plasma metabolite measures in matched samples from 203 patients with available DPYD exome sequencing data. We also compared the ability of phenotypic measures to identify carriers of deleterious DPYD variants. In addition to established high‐risk variants, we identified three rare DPYD variants predicted to be deleterious: c.274C>G, c.966C>A, and c.1435G>A. Collectively, these variants were associated with impaired DPD function with effect sizes comparable to well‐studied toxicity‐associated variants. At the population level and within carriers of specific genotypes, weak but significant correlations were observed between PBMC DPD activity and either UH 2 :U ratio or U level. These findings suggest that although phenotypic assays can detect severe DPD deficiency, high variability limits their utility as standalone diagnostic tools. Integration with genetic testing may provide a more robust pretreatment risk assessment strategy.

Background & Aims: We examined treatment patterns and clinical outcomes in a contemporary cohort of children with newly diagnosed inflammatory bowel disease (IBD) in a large, commercially insured U.S. population. Methods: Using the OptumLabs® Data Warehouse, we created an inception cohort of physician-diagnosed IBD in children aged 6–17 years between 2007–23. We examined cumulative incidence of hospitalization, surgery, safety events, and medication use in patients with Crohn's disease (CD) and ulcerative colitis (UC), overall and stratified by diagnostic era, race and ethnicity, sex, and age at diagnosis. Results: Among 787 children with newly diagnosed CD (age at diagnosis, 13.4±2.9y; 57% male; 82% White, 5% Black, 7% Hispanic) followed over mean 4.6±3.0y, 5-year risk of IBD-related hospitalization and major surgery was 30% and 10%, respectively. In children diagnosed in 2019–23, 1-year cumulative use of corticosteroids and advanced therapy was 46% and 75%, respectively; advanced therapy use increased significantly over time (aHR, 3.43 [95% CI, 2.71–4.32] for 2019–23 vs. 2007–12), while corticosteroid use declined (0.67 [0.53–0.84]). Risk of IBD-related hospitalization was lower in children diagnosed between 2019–23 (0.65 [0.43–0.97]) compared with those diagnosed between 2007-12; surgical risk did not decline significantly, with confidence intervals compatible with a clinically meaningful reduction. Among 399 children with newly diagnosed UC (age at diagnosis, 14.0±3.0y; 53% male; 78% White, 5% Black, 7% Hispanic) followed over 4.5±3.0y, 5-year risk of IBD-related hospitalization and colectomy was 36% and 8%, respectively. Advanced therapy use increased significantly over time (4.46 [2.85–6.98] for 2019–23 vs. 2007–12), with no significant change in hospitalization or surgical risk across eras. No consistent racial and ethnic, age, or sex differences in advanced therapy use or clinical outcomes were identified in either CD or UC. Conclusions: In a contemporary cohort of commercially insured children with newly diagnosed IBD, early advanced therapy use has increased markedly over time. Surgical risk did not decline significantly in either disease; however, the study was not powered to exclude a clinically meaningful reduction, and these findings are hypothesis-generating rather than conclusive.

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).