Citations

Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

Importance Hypopigmented mycosis fungoides (HMF) is uncommon in adults, and data on clinicopathologic features and long-term outcomes remain sparse. Objective To investigate the clinicopathologic features and outcomes of adults with HMF in a large multicenter cohort. Design, Setting, and Participants This retrospective multicenter cohort study conducted from January 2011 to October 2023 at 6 US tertiary referral centers and included adults (18 years or older at diagnosis) with biopsy-confirmed HMF and hypopigmentation documented at diagnosis, with a median (range) follow-up of 39 (1-347) months. Data were analyzed from February to December 2025. Exposures Clinical variant, immunophenotype predominance, and polymerase chain reaction–based T-cell receptor ( TCR ) gene rearrangement in peripheral blood and/or skin. Main Outcomes and Measures Best overall response, defined as complete response, partial response, stable disease, or progressive disease, and progression to a higher stage. Results The cohort included 224 adults with HMF (median [range] age, 44 [18-74] years), of whom 164 (73%) were women (60 men [27%]), 5 (2%) were Asian individuals, 1 (0.4%) was a Hispanic/Latino individual, 1 (0.4%) was a Middle Eastern individual, 19 (8%) were White individuals, and 186 (83%) were Black individuals; 219 (98%) presented with early-stage disease. Most had hypopigmented lesions only (159 [71%]), whereas 65 (29%) exhibited mixed-variant mycosis fungoides; outcomes were similar between groups. Among 141 patients with available immunophenotyping, 88 (63%) had CD8-positive predominance. Among 207 treated patients, most (179 [90%]) received skin-directed therapy alone. Among 198 evaluable patients, the best overall response was complete response for 52 (26%), partial response for 101 (51%), stable disease for 34 (17%), and progressive disease for 11 (6%). Over a median (range) follow-up of 39 (1-347) months, 14 of 224 patients (6%) experienced progression to a higher stage, including 5 of 219 patients (2%) with early-stage disease at baseline who experienced progression to advanced-stage disease. Peripheral blood TCR monoclonality was detected in 23 of 85 tested patients (27%) and was associated with poorer treatment response but not with disease progression. Conclusions and Relevance The finding of this cohort study suggest that adult HMF demonstrated a generally indolent course, with favorable response to skin-directed therapy, irrespective of immunophenotype or mixed-variant presentation. Peripheral blood TCR monoclonality was associated with lower treatment response but not disease progression.

Purpose of review A substantial proportion of esophageal adenocarcinoma (EAC) and high-grade dysplasia (HGD) cases in Barrett's esophagus (BE) are diagnosed after a dysplasia-negative endoscopy before the next recommended surveillance interval. These are classified as postendoscopy esophageal carcinoma (PEEC) or postendoscopy esophageal neoplasia (PEEN) and represent critical failures of BE surveillance. This review summarizes current definitions, epidemiology, potential etiologies, and evolving strategies to reduce PEEC/PEEN and improve the quality of BE surveillance. Recent findings High-quality endoscopic examination using high-definition white-light endoscopy (HD-WLE) and virtual chromoendoscopy (CE), adherence to the Seattle biopsy protocol, adequate inspection time, and training in the recognition of visible lesions harboring prevalent dysplasia/EAC, are critical in reducing PEEC/PEEN. Initial data on the use of adjunctive tools (wide-area transepithelial sampling) and molecular biomarkers (p53, DNA methylation panels, and Tissue Systems Pathology tests) demonstrate promising results for detecting prevalent dysplasia and for reducing PEEC and PEEN. BE surveillance quality metrics, such as cancer and neoplasia detection rates, have been shown to be inversely associated with PEEN. Summary PEEC and PEEN reflect critical gaps in the effectiveness of BE surveillance. Improving the quality of endoscopic surveillance is essential, including meticulous mucosal inspection, appropriate use of advanced imaging techniques, and adherence to systematic biopsy protocols, to minimize missed neoplasia.

Background: Acetabular overcoverage (pincer morphology) has been suggested to be both a source of pain and dysfunction and potentially protective against osteoarthritic change. Purpose: To compare the minimum 5-year clinical outcomes of patients undergoing primary hip arthroscopic labral repair with a lateral center edge angle (LCEA) of ≥40° as compared with nondysplastic controls with an LCEA of 25° to 40°. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review was performed to identify all patients who underwent primary hip arthroscopic labral repair between 2009 and 2019 at a single academic institution. Patients with an LCEA of ≥40° (pincer) were propensity-matched to nondysplastic controls with an LCEA of 25° to 40° on a 1-to-2 basis by sex, age, body mass index, and surgery year. Patient-reported outcome measures (PROMs)—including visual analog scale, Tegner activity score, modified Harris Hip Score, International Hip Outcome Tool (iHOT-12), and Hip Outcome Score were analyzed—as were reoperations and conversions to total hip arthroplasty (THA). Results: A total of 55 patients with pincer morphology (preoperative LCEA: 41.9°± 2.1°) were matched to 110 nondysplastic controls (LCEA: 31.2°± 4.1°), resulting in a total of 165 hips in 163 patients (67% women, mean age: 37.7 ± 9 years). Pincer patients were corrected to a mean postoperative LCEA of 38.7°± 4.1º ( P < .001), with 22 pincer patients having residual overcoverage; namely, a postoperative LCEA ≥40° (range, 40°-45.8°). There were no differences between cohorts regarding intraoperative characteristics—including femoral and acetabular Outerbridge grade—as well as capsulotomy type and the presence of capsular repair ( P ≥ .210). At a mean 8-year follow-up (range, 5.1-13.2), there was no difference in any postoperative PROMs between pincers and controls ( P ≥ .215) and no difference in PROMs between patients with residual overcoverage and pincer patients with a postoperatively normalized LCEA ( P ≥ .291). At final follow-up, 4 patients in the pincer cohort (7%) and 21 controls (19%) converted to THA ( P = .046). Conclusion: Patients with lateral acetabular overcoverage demonstrated similar and satisfactory postoperative PROMs at a minimum 5-year follow-up compared with propensity-matched nondysplastic controls, regardless of whether the LCEA was corrected to <40°. Of note, nondysplastic controls demonstrated a higher rate of conversion to THA, suggesting a potentially chondroprotective role for acetabular overcoverage.

Abstract Pain assessment plays a critical role in clinical decision-making, yet conventional methods rely heavily on subjective self-reports such as the Visual Analog Scale (VAS) or the Numeric Rating Scale (NRS). These approaches fail in scenarios involving infants, sedated patients, unconscious individuals, or those with cognitive or communication impairments. To address this gap, this research proposes PainNet, an AI-driven, real-time facial pain recognition system that integrates deep learning-based object detection with Action Unit (AU)–based pain intensity scoring. The system uses YOLOv8 for rapid facial expression detection and incorporates Py-Feat to extract pain-relevant AUs, enabling computation of the Prkachin and Solomon Pain Intensity (PSPI) score. A balanced dataset comprising 500 images sourced from Delaware, BioVid, and RaFD was curated, annotated, and preprocessed for training. The YOLOv8-based binary pain vs. no-pain classifier achieved a mean Average Precision (mAP) of 0.89 and an F1-score of 0.80 on the test dataset, demonstrating strong performance in diverse environments and facial variations. The design emphasizes computational efficiency by activating AU analysis only when YOLOv8 detects probable pain, making PainNet suitable for continuous monitoring in ICUs, elder-care facilities, and telemedicine systems. This study demonstrates that the fusion of real-time object detection and clinically validated AU scoring can significantly advance automated, objective, and scalable pain assessment.

Abstract Interstitial lung disease (ILD) is a chronic, irreversible condition that is challenging to diagnose due to subtle symptoms and limitations of conventional tools. Noninvasive lung sound analysis using phonopulmography offers a promising alternative. This study evaluated the feasibility of a deep learning model for distinguishing normal and pathological lung sounds in ILD. Lung sound recordings were collected from 12 subjects (6 healthy, 6 ILD) and segmented beat-to-beat using simultaneously acquired ECG and phonopulmography, yielding 2,280 segments. Mel-frequency cepstral coefficients (MFCCs; 13 per segment) were extracted, and a one-dimensional CNN-based You Only Listen Once (YOLO) model was trained for segment classification. Evaluation used Leave-One-Out Cross-Validation, with patient-level classification by aggregating segment predictions via majority vote. On the test set (190 segments per class), the model achieved an average segment-level accuracy of 0.738 ± 0.087 and mean AUC of 0.850 ± 0.062. Precision, recall, and F1-score were 0.775 ± 0.148, 0.755 ± 0.183, and 0.738 ± 0.089, respectively. These preliminary results suggest that beat-level MFCCs with a 1D CNN-based YOLO model enable accurate segment- and patient-level classification. This feasibility study highlights the potential of AI-assisted auscultation for noninvasive monitoring and clinical decision support in ILD management, pending further validation in larger cohorts.

Abstract Accurate assessment of left-ventricular ejection fraction (EF) is a critical metric in diagnosing and managing heart failure; however, methods of assessment remain resource intensive, not widely available in low-acuity or remote settings and are intermittent in nature. This study explores the potential of a novel framework, cardiac electromechanical fingerprinting (cEMF) using synchronized electrocardiography (ECG) and seismocardiography (SCG) collected from a wearable sensing patch as a low-cost, non-invasive, continuous estimate of EF that can be used for rapid point of care screening. A machine learning pipeline was developed to process raw ECG and SCG data to derive EF. Signals were cleaned using band-pass filtering, NeuroKit2-based ECG cleaning and fiducial detection of critical electromechanical events. We extracted an ECG-SCG feature space consisting of heart-rate variability metrics, ECG morphological characterization, SCG timing intervals, spectral and entropy-based features. The top thirty most important features for EF were used to train and evaluate several regressor models. The best performing model was the Gaussian Process Regressor with an MAE of 5.43. Our findings demonstrate the promise of producing clinically relevant cardiac function measures, such as EF, from wearable electromechanical signals. Future work using larger datasets and complementary physiological signals such as phonocardiogram (PCG) may significantly strengthen EF% estimation and other cardiac functions for clinical applicability.

Background: Despite the growing clinical relevance of obesity in the context of multiligament knee injuries, there remains a paucity of data evaluating patient-reported outcomes in this population. Purpose: To compare clinical and functional outcomes, including postoperative patient-reported outcome measures (PROMs) and complication/revision rates, of multiligament knee reconstruction (MLKR) in individuals with a body mass index (BMI) >30 kg/m 2 versus <30 kg/m 2 at a minimum 2-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was performed to identify all patients who underwent MLKR between 2001 and 2022 at a single institution. Patients with a BMI >30 kg/m 2 were propensity-matched to patients with a BMI <30 kg/m 2 on a 1:1 basis by age, sex, laterality, and Schenck classification (knee dislocation). Medical records were reviewed for patient characteristics, time to surgery, year of surgery, number and type of ligament interventions, graft choice, single versus staged reconstruction, and concomitant injuries. Postoperative clinical examination findings and PROMs for each cohort, including visual analog scale score, Tegner activity scale score, Lysholm score, and International Knee Documentation Committee (IKDC) subjective score, were analyzed and compared. Postoperative complication and revision rates were evaluated and compared. Results: Of 158 patients, 79 patients with a BMI <30 kg/m 2 (mean age, 31.0 ± 11.5 years; mean BMI, 25.8 ± 3.0 kg/m 2 ) were matched to 79 patients with a BMI >30 kg/m 2 (mean age, 32.8 ± 9.5 years; mean BMI, 37.1 ± 5.8 kg/m 2 ). There were no significant differences between cohorts regarding age, sex, laterality, and Schenck classification ( P ≥ .100); however, patients in the BMI >30 kg/m 2 group had greater numbers of posterior cruciate ligament reconstruction. The mean follow-up was 7.5 ± 4.8 years for the BMI <30 kg/m 2 cohort and 7.2 ± 4.8 years for the BMI >30 kg/m 2 cohort ( P = .229). Patients with a lower BMI (<30 kg/m 2 ) had significantly better postoperative mean IKDC (79.3 ± 18.7 vs 67.9 ± 21.2; P = .004), Lysholm (85.1 ± 17.1 vs 75.7 ± 21.0; P = .007), and Tegner (5.1 ± 2.0 vs 4.4 ± 1.7; P = .041) scores. The BMI >30 kg/m 2 group also had significantly more postoperative complications ( P = .028). However, there was no significant difference between the 2 cohorts in terms of reoperation rate or conversion to total knee arthroplasty ( P ≥ .189). Conclusion: Patients who undergo MLKR and have a BMI >30 kg/m 2 demonstrate significantly decreased postoperative PROMs when compared to patients with a BMI <30 kg/m 2 . Increasing BMI significantly increased the incidence of complication rates after MLKR.