Citations

Surgeons are at high risk of developing long-term Work-Related Musculoskeletal Disorders (WMSDs) due to awkward sustained postures. Passive spine-supporting exoskeletons are a potential intervention to improve posture and reduce fatigue. The NekSpine ® was evaluated by 21 surgeons (15 male) across two hospital sites within a quaternary academic hospital system. Each surgeon performed at least two comparable procedures, one with the exoskeleton and one without. Surgeons completed pre- and postoperative surveys assessing NASA-TLX workload, usability, body-part discomfort, overall fatigue, and workflow disruptions. Eighty-two cases were evaluated (43 exoskeleton cases). Compared with baseline cases, surgeons reported reduced neck and upper back discomfort and lower overall fatigue when using the exoskeleton. The NekSpine ® exoskeleton may reduce spinal discomfort and fatigue during surgery, supporting its potential as an ergonomic intervention for surgeons.

Abstract Background Evaluation of middle ear prostheses requires high-resolution imaging to assess position and structural integrity. Purpose To assess the diagnostic performance of photon-counting-detector (PCD)-CT for middle ear prosthesis imaging in cadaveric specimens. Materials and Methods Nine different middle ear prostheses were implanted in five fresh-frozen whole-head specimens, both in correct anatomic position and displaced to mimic malposition. Specimens were scanned on PCD-CT (NAEOTOM Alpha, Siemens) and energy-integrating-detector (EID)-CT (SOMATOM Force, Siemens), reconstructed at 0.2mm and 0.4mm, respectively. Eighteen cases (9 prostheses, 2 positions) per scanner were evaluated by two neuroradiologists (36 readings), blinded to scanner and position, who scored prosthesis position, reader confidence, and overall image quality. Agreement with the reference standard and between readers was compared. Results PCD-CT showed higher diagnostic confidence compared with EID-CT, while accuracy and inter-reader agreement did not demonstrate significant differences between scanners. Correct readings, PCD-CT versus EID-CT: lateral contact, 31/36 (86.1%; 95% CI: 58.3%-94.4%) vs. 29/36 (80.6%; 55.6%-91.7%), p = 0.500; medial contact, 30/36 (83.3%; 55.6%-94.4%) vs. 26/36 (72.2%; 50.0%-83.3%), p = 0.250. PCD-CT identified all cases of complete contact loss (score 3), while EID-CT missed one reading per contact. Inter-reader agreement may be higher with PCD-CT vs EID-CT (lateral: κw: 0.804 [0.578-0.941] vs. 0.571 [0.302-0.778], p = 0.250; medial: 0.684 [0.191-0.934] vs. 0.481 [0.024-0.835], p = 0.250). Reader confidence was significantly higher with PCD-CT; mean paired differences for Readers 1 and 2 were 9.4 (1.8-17.1; Holm-adjusted p = 0.019) and 23.1 points (13.4-32.7; p < 0.001) for lateral contact, and 16.4 (10.0-22.8; p < 0.001) and 17.8 points (6.8-28.8; p = 0.007) for medial contact. Readers preferred PCD-CT image quality in 16/18 (88.9%; 65.3%-98.6%) and 17/18 cases (94.4%; 72.7%-99.9%), respectively. Conclusion PCD-CT was associated with significantly higher reader confidence and preferred image quality, without significant differences in diagnostic accuracy or inter-reader agreement. These findings suggest PCD-CT is a promising modality for postoperative middle ear evaluations that warrants further investigations.

Aberrant activation of the Hippo–YAP/TAZ–TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP–TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690/36549045, AN-655/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP–TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP–TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) enhance anti‐tumour immunity by modulating immune pathways but can also trigger immune‐related adverse events. We aimed to evaluate the risk of developing coeliac disease (CeD) among patients with malignancy treated with ICIs. Methods Using the TriNetX US Collaborative Network, we identified adults (≥ 18 years) diagnosed with malignancies for which ICIs are routinely used between January 2010 and December 2024 and stratified them by exposure to immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, or avelumab). Patients with pre‐existing celiac disease (CeD) were excluded. Cohorts were propensity score matched for demographics and autoimmune comorbidities. The primary outcome was incident CeD occurring ≥ 90 days after the index event. Adjusted hazard ratios (aHRs) were calculated, with subgroup analyses by age and sex. Statistical significance was defined as p < 0.05. Results After propensity score matching, 158,208 patients were included in each cohort. CeD was diagnosed more frequently among patients exposed to ICIs than among matched controls (0.152% vs. 0.071%; aHR 3.95, 95% CI 3.11–5.03; p < 0.001), corresponding to a number needed to harm (NNH) of 1235. The increased risk persisted across sex and age subgroups, including females (aHR 3.43, 95% CI 2.55–4.62), males (aHR 5.36, 95% CI 3.53–8.12), with the risk being highest among patients older than 60 years (0.14% vs. 0.06%; aHR 4.24, 95% CI 3.17–5.67; p < 0.001). Conclusion In this large real‐world cohort, ICI exposure was associated with nearly a fourfold increase in the risk of being diagnosed with CeD compared with matched controls.

ABSTRACT The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5‐year‐old boy with classical cohesinopathy features, including DD/ID and feeding difficulties, along with non‐classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel de novo missense variant of uncertain significance (NM_005862.3:c.643G>A(p.Val215Ile)) in the STAG1 gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other STAG1 variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1‐RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1‐related cohesinopathy and advances our understanding of the disease mechanism.

Abstract Clinical syndromes of frontotemporal dementia present both distinct and overlapping neuroimaging abnormalities and, consequently, domains of impairment. The aim of this study was to determine how well covariance patterns from multiple neuroimaging modalities discriminate across clinical frontotemporal dementia syndromes. Four-hundred participants with a clinical frontotemporal dementia diagnosis, including behavioral variant of frontotemporal dementia, semantic variant of primary progressive aphasia, right temporal variant of frontotemporal dementia, primary progressive aphasia, apraxia of speech with agrammatic aphasia, primary progressive apraxia of speech, progressive supranuclear palsy and corticobasal syndrome, and 109 cognitively unimpaired participants underwent extensive neurological and neuropsychological assessments, structural MRI, flortaucipir-PET for tau and [18F] fluorodeoxyglucose-PET. Multimodal imaging covariance was investigated at the voxel-level using principal component analysis after adjusting for age and sex effects. Linear regression models were fit to investigate the relationship between principal components and clinical scores. Multinomial logistic regression models investigated the ability of imaging principal components to discriminate across syndromes. The first principal component, which describes the largest source of variability in the data, was a pattern of widespread cortical atrophy (21% variability explained) and of frontoparietal and temporal hypometabolism (21%): scores were lowest in behavioral variant of frontotemporal dementia and correlated with general cognitive impairment. On tau-PET, the first principal component (43% variability) was not significantly different among syndromes and captured a widespread cortical tau uptake, with a focus on the temporal lobe. In all three modalities, the second principal component captured temporal lobe imaging abnormalities, contrasting the motor and semantic clinical syndromes. Subsequent components described smaller variability. On cross-validation, the classifiers based on principal components from MRI (multiclass area under the receiver operating characteristic: 0.76) and [18F]fluorodeoxyglucose-PET (0.79) outperformed tau-PET (0.71), while combining all three modalities did not significantly improve the classifier performance. On cross-validation, the sensitivity of the image-based classifiers was heterogeneous across syndromes and modalities, with highest values for progressive supranuclear palsy and semantic variant of primary progressive aphasia and lowest for primary progressive aphasia and corticobasal syndrome. Our study found that the covariance components of structural and molecular neuroimaging underlying frontotemporal dementia clinical syndromes exist both as a continuum and with syndrome-specific patterns. More than one imaging model was able to correctly classify several frontotemporal dementia clinical syndromes with good specificity and sensitivity, highlighting the value of imaging in aiding patient diagnosis.

Extracorporeal membrane oxygenation (ECMO) provides life support for severe respiratory and cardiac failure, including failure from severe infection such as sepsis and acute respiratory distress syndrome. Additionally, ECMO-acquired infections are frequent and associated with prolonged hospitalization, increased healthcare utilization, and higher mortality. This review summarizes current evidence regarding the epidemiology, pathophysiology, diagnosis, prevention, and management of infectious adverse events during ECMO. Future work should aim to refine ECMO-related infectious adverse event definitions, improve harmonized multicenter data collection, and to invest in high-quality, well-designed studies.

Background: Tobacco use is a known risk factor for poor healing after rotator cuff repair (RCR), but the effects of nontobacco nicotine products remain unclear. Purpose: To compare postoperative complications among nontobacco nicotine users, tobacco users, and nonusers undergoing RCR. Study Design: Cohort study; Level of evidence, 3. Methods: Using the PearlDiver database, the authors identified patients who underwent arthroscopic RCR with ≥2 years of follow-up. Three 1:1 propensity-matched comparisons were conducted: nontobacco nicotine users versus nonusers (n = 4844), tobacco users versus nonusers (n = 19,182), and nontobacco nicotine users vs tobacco users (n = 4882). Outcomes included 90-day complications and 2-year revision surgeries. Results: Nontobacco nicotine users had mildly higher rates of lysis of adhesions than controls (0.7% vs 0.4%; OR, 1.95; P = .033) but no other significant differences. Tobacco users showed increased rates of acute kidney injury (AKI), pneumonia, infections, emergency department (ED) visits, readmissions, and revision surgery compared to controls. Compared to tobacco users, nontobacco nicotine users had moderately strong lower risks of pneumonia (0.6% vs 1.2%; OR, 0.46), ED visits (8.8% vs 13.6%; OR, 0.62), and readmissions (0.8% vs 1.5%; OR, 0.54) (all P < .01). Conclusion: While nontobacco nicotine use was associated with a modestly increased risk of lysis of adhesions after RCR, it did not significantly elevate the risk of major medical complications, infections, or revision surgery when compared to nonnicotine users. In contrast, tobacco users demonstrated consistently worse postoperative outcomes across multiple domains, including higher rates of AKI, pneumonia, surgical site infection, ED visits, readmissions, and revision procedures. Notably, when compared directly to tobacco users, nontobacco nicotine users had significantly lower rates of pneumonia, ED utilization, and readmissions. These findings suggest that although nontobacco nicotine products may not be entirely benign, their perioperative risk profile appears to be less severe than that of traditional tobacco use.

Background Diastolic dysfunction is common in patients with aortic stenosis and may influence outcomes following surgical aortic valve replacement. We aimed to examine the association of preoperative artificial intelligence (AI)‐generated diastolic function grades with early and late outcomes following aortic valve replacement and how postoperative progression influence prognosis. Methods We identified 5503 patients undergoing aortic valve replacement between 2000 and 2023. Diastolic function was assessed using a validated deep‐learning AI model applied to 12‐lead ECGs done preoperatively and on postoperative follow‐up. Diastolic grades were classified by AI into Grades 1 to 3. Longitudinal trend analyses and multivariable regression models were used to assess study end points. Results Among 5503 patients (mean age 72.4±10.8 years; 39% female), higher AI ECG diastolic grades were associated with greater comorbidity burden, including diabetes, renal disease, and heart failure. AI ECG diastolic Grade 3 was independently associated with higher in‐hospital mortality (odds ratio, 2.5; P =0.007) and other complications. At 5‐year follow‐up, patients with Grade 3 showed the least improvement in diastolic function by both ECG and echocardiography. Grades 2 and 3 diastolic function at baseline were independently associated with increased late mortality (hazard ratio, 1.3 and 2.45, respectively; both P <0.001). Additionally, lack of improvement in AI ECG diastolic grade by 1 year was also independently associated with late mortality. Conclusions AI ECG–derived diastolic function grades strongly correlates with early complications and long‐term mortality and diastolic progression after aortic valve replacement. AI ECG provides a powerful, noninvasive tool for risk stratification and longitudinal monitoring of patients with aortic stenosis.