Citations

Abstract Background The isocitrate dehydrogenase (IDH) mutation status is a key molecular marker in diagnosing and treating brain tumors. Currently, it is determined via invasive tissue biopsy. Recent advances in deep learning (DL) have offered promising non-invasive alternatives for determining IDH status. However, their clinical translation is hindered by a significant gap between DL predictions and their clinical applicability. The limited transparency of many DL-networks and inadequate evaluation metrics hinders trust and adoption, as clinicians require clear and validated insights for determining IDH status. These challenges highlight the need for robust validation and measures of predictive reliability to make DL-predictions clinically actionable. Methods We developed a unique approach for non-invasive prediction of IDH status using MRI. We combine a voxel-wise-segmentation network(MC-net) with Bayesian logistic regression (BLR) to provide an IDH status and estimate confidence scores. We utilized a comprehensive dataset of 2,481 glioma cases from eight institutions. Results Our framework(MC-net + BLR) demonstrated robust performance achieving 96.4% and 95.1% classification accuracies on diverse databases, with an AUC of 0.98. The BLR was implemented exclusively on held-out test data, ensuring that the derived confidence scores are independent of the training or validation phases. The derived confidence scores showed a low Brier score of 0.0125, highlighting its superior calibration and uncertainty quantification. Conclusion The developed framework provides an IDH status and a confidence score, offering clinicians an additional layer of assurance in prediction reliability. It bridges the gap between high-performing DL models and their clinical applicability by addressing the challenges in prediction reliability. Our framework is a significant advancement in non-invasive determination of IDH-status and confidence-informed therapeutic decision-making in neuro-oncology.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, contributing to significant morbidity and mortality worldwide. The relationship between physical exercise and AF is complex, with studies showing both beneficial and potentially adverse effects. Moreover, evidence suggests a U-shaped association between exercise intensity and AF risk. Moderate exercise has been shown to reduce AF burden by improving cardiovascular risk factors, enhancing autonomic regulation, and mitigating atrial fibrosis. In contrast, excessively high-intensity endurance exercise may increase AF risk, particularly in young athletes, due to atrial stretching, dilation, fibrosis, autonomic imbalances, and heightened inflammation. The current guidelines emphasize exercise as a core lifestyle intervention for AF management, recommending moderate-intensity aerobic activity for optimal outcomes. This review examines the current evidence on the effects of exercise on AF, identifies knowledge gaps, and proposes potential future research directions.

ABSTRACT Background Functional lumen imaging probe (FLIP) utility is established in treatment‐naïve achalasia but less clear following lower esophageal sphincter (LES) directed therapy. Methods Achalasia patients with LES directed therapy across three tertiary care centers between 2017 and 2024 with post‐treatment FLIP and timed barium esophagram (TBE) were retrospectively identified. Reduced esophagogastric junction (EGJ) opening was defined by distensibility index (DI) < 2 mm 2 /mmHg and diameter < 12 mm. Abnormal emptying on TBE was defined as column height ≥ 5 cm at 5 min and/or retained tablet. Eckardt scores ≤ 3 defined clinical response. Key Results The study included 222 patients (46% peroral endoscopic myotomy, 46% laparoscopic Heller myotomy, 8% pneumatic dilation) with a median of 1.4 years to post‐treatment TBE/FLIP. Abnormal emptying on TBE was associated with a narrower median EGJ diameter (13.2 vs. 14.8 mm, p = 0.008), a greater frequency of EGJ diameter < 12 mm (36% vs. 21%, p = 0.012), and a smaller change in EGJ diameter (+4.6 vs. +8.6 mm, p = 0.002). Abnormal emptying on TBE occurred more frequently in patients with EGJ DI < 2 mm 2 /mmHg (8.5% vs. 2.6%, p = 0.052), but was not associated with median EGJ DI (4.5 vs. 5.1 mm 2 /mmHg, p = 0.29) nor median change in EGJ DI (+2.9 vs. +3.9 mm 2 /mmHg, p = 0.25). Patients with reduced EGJ DI or EGJ diameter more often had abnormal TBE (37% vs. 22%, p = 0.012). Only the change in DI (+3.8 vs. +1.5 mm 2 /mmHg, p = 0.012) and diameter (+8.2 vs. +1.6 mm, p = 0.002) on FLIP was associated with a clinical response based on Eckardt ≤ 3. Conclusions and Inferences FLIP following achalasia therapy generally correlates with TBE, although discrepant findings are not uncommon. In particular, FLIP EGJ‐diameter has a strong association with esophageal emptying on TBE. Both TBE and FLIP have limited association with clinical response based on Eckardt, with change in DI and diameter on FLIP most strongly associated. Consequently, FLIP as part of multimodal assessment appears useful in the longitudinal follow‐up of treated achalasia.

ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-&amp;lt;25; overweight, 25-&amp;lt;30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P &amp;lt; .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

ABSTRACT Orbitrap (OT) -based mass spectrometer platforms are a gold standard in high-resolution mass spectrometry, where their primary disadvantage is slower-scanning speed in comparison to time-of-flight or linear ion trap mass analyzers. In this study, we utilize long OT transients to extend the precursor dynamic range by modifying the selected ion monitoring method to multiplex several precursor m/z ranges from 400 to 1000 m/z into a single scan called “ M ultiple A ccumulation P recursor M ass S pectrometry” (MAP-MS). Our approach requires no software or hardware modifications and hides the additional ion accumulation steps during the time it takes to make other Orbitrap measurements, producing precursor spectra with nearly 2× dynamic range and essentially no consequences. We collected data using both data-dependent acquisition (DDA) and data-independent acquisition (DIA) methods to evaluate a range of approaches. With DDA, MAP-MS precursor quantification improves with higher quality measurements. At the same time, DIA detection is enhanced by up to 11% when combining precursor and tandem mass spectra for peptide detection.

OBJECTIVES: The goal of this scoping review was to review some of the challenges hospitals faced in dealing with the shortage of ventilators during the COVID-19 pandemic and the solutions they were able to implement or suggested. By highlighting these problems and solutions, we hope this review can catalyze further discussions about how to better prepare for future pandemics and medical supply shortages. DATA SOURCES: A comprehensive search strategy using identifying key words was applied to several different databases to procure relevant literature. STUDY SELECTION: Four thousand two hundred fifty-nine studies were found in the initial search. Inclusion and exclusion criteria were created and applied to screen studies. Included studies focused on the supply and distribution of ventilators during the COVID-19 pandemic. In the case where reviewers disagreed about whether a study should be included, a third reviewer acted as a tie-breaker. DATA EXTRACTION: Thirty-three studies were included for final data extraction. Two independent reviewers collected various data points from these studies, including the main challenges discussed by the authors, the level of ventilator shortage being addressed, whether ventilator sharing was discussed, and the limitations of the study. DATA SYNTHESIS: A third reviewer compared the collected data and decided on the results. CONCLUSIONS: Some of the common solutions for the ventilator shortage discussed included augmenting overall ventilator supply through increased production, transporting ventilators between hospitals, ventilator sharing, designing new ventilators, and repurposing other resources to help address shortages of supplies.

Objectives There is substantial practice variation in the management strategies for atrial fibrillation (AF) with rapid ventricular rate (RVR) and hemodynamic instability in critically ill patients. This study aimed to evaluate the use and effectiveness of direct current cardioversion (DCCV) for unstable AF RVR in the intensive care unit (ICU). Design Multicenter retrospective cohort study. Setting Non-cardiac/cardiovascular surgery ICUs of the Mayo Clinic Hospitals in Minnesota, Wisconsin, Florida, and Arizona. Patients Adult patients who developed paroxysmal AF RVR with hemodynamic instability (heart rate ≥ 130 beats per minute and a documented SBP ≤ 90 mmHg or the need for vasopressors) during ICU stay. Interventions Emergency DCCV. Measurements and Main Results Primary outcomes were in-hospital mortality, hospital-, ICU-, and organ support-free days. Secondary outcomes were return to sinus rhythm rate before and after discharge. Among 691 patients eligible for inclusion, 47 (6.8%) received emergent DCCV in the ICU. The frequency of DCCV was higher for patients located in surgical ICUs (14.5% vs 6.1%, P = .04). Patients were 1:2 propensity-score matched. The comparative analyses were conducted on 141 patients. Those who underwent DCCV were more likely to restore sinus rhythm (odds ratio [95% confidence interval], 5.2 [1.30 20.8]). However, DCCV was not associated with increased odds of having sinus rhythm at discharge, lower mortality, or higher number of ICU-, or hospital-free days. The number of organ support-free days was significantly lower in the DCCV group (estimate ± standard error, −5.0 ± 2.0, P = .012). Conclusions Emergency DCCV is rarely used to treat unstable AF in non-cardiac ICUs. Despite increased likelihood of immediate sinus rhythm restoration, DCCV was not associated with improvement in patient-centered outcomes. Prospective studies are warranted to evaluate harms and benefits of DCCV in non-cardiac critically ill patients with unstable AF where the driver of hemodynamic instability is often an underlying condition rather than arrhythmia per se.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine &lt;1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

DEK::AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK::AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK::AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK::AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK::AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK::AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK::AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, impacting approximately 6.1 million adults in the United States, with projections to increase two-fold by 2030. AF significantly increases the risk of stroke and other adverse cardiovascular events, leading to increased morbidity and mortality. The 2023 ACC/AHA/ACCP/HRS guidelines present a paradigm shift in AF management, moving from a duration-based classification to a more comprehensive, patient-centered approach. This includes a novel AF classification system that emphasizes early detection and intervention, including risk factors and lifestyle modification tailored to each patient’s risk profile. Moreover, the recommendations advocate for a multidisciplinary care model, ensuring coordinated management involving primary care providers and specialists. Primary care providers play a crucial role in initiating risk factor management and lifestyle interventions, even before the development of AF. This review aims to thoroughly examine the guidelines for the diagnosis and management of AF and equip general internists with the necessary insights to navigate the evolving landscape of AF care effectively.