Citations

INTRODUCTION: The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2. METHODS: The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE. Our study included a training set of 827 patients, a testing set of 504 patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease from 6 centers, and an external validation set of 1,299 patients from 9 centers. Five algorithms were compared using area under the curve (AUC) in the test set: ElasticNet, random forest, gradient boosting machines, XGBoost, and neural networks. The top 3 (random forest, gradient boosting machines, and XGBoost) formed an ensemble model. RESULTS: In the external validation set, the ALADDIN-F2-VCTE model, using routine laboratory parameters with VCTE (AUC 0.791, 95% confidence interval [CI]: 0.764–0.819), outperformed VCTE alone (0.745, 95% CI 0.717–0.772, P < 0.0001), FibroScan-aspartate aminotransferase (0.710, 0.679–0.748, P < 0.0001), and Agile-3 model (0.740, 0.710–0.770, P < 0.0001) regarding the AUC, decision curve analysis, and calibration. The ALADDIN-F2-Lab model, using routine laboratory parameters without VCTE, achieved an AUC of 0.706 (95% CI: 0.668–0.749) and outperformed Fibrosis-4, steatosis-associated fibrosis estimator, and LiverRisk scores. DISCUSSION: Along with the steatosis-associated fibrosis estimator model developed to target significant fibrosis or higher, ALADDIN-F2-VCTE (https://aihepatology.shinyapps.io/ALADDIN1) uniquely supports a refined noninvasive approach to patient selection for resmetirom without the need for liver biopsy. In addition, ALADDIN-F2-Lab (https://aihepatology.shinyapps.io/ALADDIN2) offers an effective alternative when VCTE is unavailable.

Toxins from ingested water can significantly affect overall physical health in children and adults. In the United States, domestic water wells are not commonly tested for any heavy metal contaminants. It is well-known that chronic arsenic ingestion from water is linked to serious health effects. We surveyed patients at our academic institution via emailed questionnaires in 2023 to determine whether those with children living at home reported different patterns of behavior around well water testing as compared to those without. Survey data were collected from 8994 respondents in the U.S. Midwest who reported using residential well water. Results were used to evaluate the influence of children in the home on testing behaviors, and secondarily, whether parental demographics affected testing frequency. Respondents with children at home did not report increased testing frequency compared to those without. In parents who did report testing, having more children, being younger, and living in Wisconsin were associated with an increased frequency. Parental gender, race, and ethnicity did not correlate with testing behaviors. A total of 70% of respondents did not feel concerned about their water safety and 85% were not concerned about arsenic specifically in their water. Increased risk of toxicity to children from arsenic does not appear to influence reported well water testing behavior among parents.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

Background Flow-diverter stents (FDS) have become the standard of care for a wide range of intracranial aneurysms, but their efficacy/safety in the context of recurrent/recanalized aneurysms following stent-assisted coiling (SAC) is not well established. We evaluate the outcomes of FDS retreatment in a large multicenter cohort. Methods We retrospectively analyzed data from 118 patients across 22 institutions who underwent FDS retreatment for recurrent/persistent aneurysms after SAC (2008–22). The primary outcome was angiographic occlusion status at last follow-up, categorized as complete (100%), near-complete (90–99%), or incomplete (<90%) occlusion. Secondary outcomes included procedural complications and clinical outcomes measured by the modified Rankin Scale (mRS). Results A total of 118 patients (median age 57, 74.6% female) with median follow-up of 15.3 months were identified. Complete occlusion was achieved in 62.5% and near-complete occlusion in 25%. FDS deployment within the pre-existing stent was successful in 98.3% of cases. Major complications occurred in 3.4% of cases, including postoperative aneurysmal rupture with resultant mortality (1.6%) and thromboembolic events with long-term disability (1.6%). Favorable clinical outcomes (mRS 0–2) were observed in 95.1% of patients. Wider aneurysm neck diameter was a significant predictor of incomplete occlusion (adjusted OR (aOR) 1.23 per mm, P=0.044), with male sex trending towards association with non-occlusion (aOR 3.2, P=0.07), while baseline hypertension was associated with complete occlusion (aOR 0.32, P=0.048). Conclusions FDS treatment for recurrent/residual aneurysms after SAC represents a viable treatment option for these challenging cases with acceptable safety and reasonable occlusion rates, although lower than de novo FDS occlusion rates.

Abstract Emphysema’s significant morbidity and mortality underscore the need for reliable outcome metrics in clinical trials. However, commonly accepted chronic obstructive pulmonary disease outcome measures do not adequately capture emphysema severity or progression. Computed tomography (CT) metrics have been validated as accurate indicators of pathological emphysema and predictors of chronic obstructive pulmonary disease progression, exacerbations, and mortality. This position paper reviews the evidence supporting CT densitometry as a biomarker for emphysema, establishes implementation standards, and highlights areas for future research. A systematic literature review addressed three key questions: whether CT densitometry can be used as a diagnostic biomarker of emphysema, whether CT densitometry can be used as a prognostic biomarker, and whether longitudinal change in densitometry can be used as a disease progression monitoring biomarker. Emphysema metrics, such as the percentage of low attenuation areas below −950 Hounsfield units, are validated, highly reproducible diagnostic and prognostic biomarkers. Volume-adjusted lung density is recommended for disease monitoring. Both metrics demonstrate a scan–rescan intraclass correlation coefficient of 0.99 with proper technique. The paper also discusses relevant CT physics, techniques, and sources of variation, including technical factors, physiological changes, and software analysis. Key recommendations for clinical trials include using standardized CT techniques, proper subject selection, and longitudinal evaluation with volume-adjusted lung density.

OBJECTIVE Previous research suggests elective surgical procedures performed later in the week have worse outcomes. This study investigated whether the day of the week on which elective anterior cervical discectomy and fusion (ACDF) surgery was performed impacts clinical outcomes. METHODS Using data from the Quality Outcomes Database, a nationwide, multicenter prospective registry, this study included patients undergoing elective ACDF for cervical spondylosis. Patients were categorized into groups based on the surgery day (early week, Monday and Tuesday; late week, Thursday and Friday). Analyzed outcomes included postoperative complications, readmissions, reoperations, and patient-reported outcomes. Statistical methods included the independent t-test, Pearson’s chi-square test, and multivariable logistic regression. RESULTS The study analyzed 19,818 patients, with 41.7% undergoing surgery early in the week and 36.9% later. There were no significant differences in 30-day mortality, readmissions, or reoperations between the two groups. Early-week surgical procedures were associated with a higher incidence of postoperative dysphagia requiring nasogastric tubes (0.6% vs 0.3%, p = 0.02) and a higher incidence of vocal cord paralysis (0.5% vs 0.3%, p = 0.01). The data indicate a surgical selection bias with more complex surgical procedures and higher risk patients typically scheduled earlier in the week, which likely contributed to the increased rates of dysphagia. Conversely, patients who underwent operations on Fridays were more likely to be discharged on the same day compared to those earlier in the week (p = 0.02), without a significant difference in length of stay overall. Surgical procedures performed later in the week were more likely to be performed at ambulatory surgical centers rather than inpatient facilities (p < 0.01), indicating a strategic selection of healthier patients for end-of-week procedures. CONCLUSIONS The day of elective ACDF surgery does not affect mortality, readmissions, or reoperation rates. However, early-week surgical procedures may see slightly higher rates of postoperative dysphagia and vocal cord paralysis, likely due to the scheduling of more complex cases or higher risk patients during these days. Overall, the authors’ data confirm that day of surgery does not influence overall patient recovery significantly. This information is useful for surgical planning and for providing patient reassurance that the day of the week does not significantly impact surgical outcomes.

Abstract Context Research and scholarship are core drivers of medicine in the modern era. Evidence-based practice continues to replace expert opinion and long-held practice beliefs. Involvement in the development and writing of these guidelines is critical for Doctors of Osteopathic Medicine (DOs) to maintain a seat at the academic table. According to the American Osteopathic Association (AOA), 11 % of practicing physicians in the US are DOs. This number is growing, as nearly 25 % of current medical students attend an osteopathic medical school. Without involvement in guideline development, DOs risk giving up control of their own practice of medicine. Objectives To quantify the contribution of DOs to the body of literature guiding practice, author information was extracted from all US-based guidelines published in the years 2021, 2022, and 2023 listed in the Emergency Care Research Institute (ECRI) Guidelines Trust database. Methods Authors of US-based guidelines listed in the ECRI Trust database from the years 2021–2023 were counted and categorized into one of three groups based on terminal degree: MD holders, DO holders, and Other-degree holders. Authors whose degrees could not be identified were counted as “Unidentifiable.” Additional data including sponsoring organization, organization type, and specialty were collected. Results A total of 674 guidelines were published by US organizations in 2021, 2022, and 2023, with 604 reporting author information. A total of 9,376 authors were counted. Of that, 7,253 held an MD (77 %), 110 held a DO (1.2 %), and 1,848 held another terminal degree (19.7 %); meanwhile, 1.66 % of counted authors did not have an identifiable degree. A total of 604 guidelines published by US organizations were identified. Of these, 88 (14.6 %) contained at least one DO author in their author list. Sixty-two unique specialties were identified, along with 130 unique sponsoring organizations. Of those specialties, 28 (44.4 %) had at least one DO author of at least one guideline. Of 130 sponsoring organizations, 44 (33.8 %) developed at least one guideline with at least one DO author. No osteopathic sponsoring organizations were identified. Conclusions Based on these results, we conclude that DOs are underrepresented in the development of guidelines.

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248