Deep learning for the PSIPRED Protein Analysis Workbench.

The PSIRED Workbench is a long established and popular bioinformatics web service offering a wide range of machine learning based analyses for characterizing protein structure and function. In this paper we provide an update of the recent additions and developments to the webserver, with a focus on new Deep Learning based methods. We briefly discuss some trends in server usage since the publication of AlphaFold2 and we give an overview of some upcoming developments for the service. The PSIPRED Workbench is available at http://bioinf.cs.ucl.ac.uk/psipred.

Long term clinical outcomes and cost-effectiveness of catheter vs thoracoscopic surgical ablation in long-standing persistent atrial fibrillation using continuous cardiac monitoring: CASA-AF randomised controlled trial.

BACKGROUND: Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known. OBJECTIVES: To compare long-term (36-months) clinical efficacy, quality of life and cost-effectiveness of SA and CA in LSPAF. METHODS: Participants were followed up for 3 years using implantable loop recorder (ILR) and questionnaires to assess change in quality of life. Intention-to-treat analyses were used to report the findings. RESULTS: Of 115 LSPAF patients treated, 104 (90.4%) completed 36-months follow-up (CA=57, SA=47). Following a single procedure without anti-arrhythmic drugs (AAD) 7 (12%) patients in the CA arm and 5 (11%) in the SA arm (HR 1.22, 95% CI 0.81 to 1.83, p = 0.41) were free from AF/AT ≥30 sec at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (HR 1.04, 95% CI 0.57 to 1.88, p = 0.91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean QALY estimates of 2.45 (95% CI 2.31 to 2.59) for CA and 2.32 (2.13 to 2.52) for SA. Estimated costs were higher for SA (mean £24,682, 95% CI £21,746 to £27,618) than for CA (mean £18,002, 95% CI £15,422 to £20,581). CONCLUSION: In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30s and ≥75% burden reduction) following a single-procedure without AADs. However, SA is significantly more costly than catheter ablation.

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid-Liquid Phase Separation for Poorly Water-Soluble Drugs.

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.

Impact of Maternal Exercise on Mice Offspring Development, Pulmonary Hypertension, and Vascular Remodeling in Chronic Hypoxia.

PURPOSE: Chronic, high-altitude hypoxic exposure increases the risk of high-altitude pulmonary hypertension (PH). Emerging evidence shows maternal exercise may improve offspring resistance to disease throughout life. The purpose of this study is to determine if maternal exercise mitigates chronic hypoxic-induced changes in the offspring indicative of high-altitude pulmonary hypertension development. METHODS: Female adult C57BL/6 J mice were randomly allocated to nonexercise or exercise conditions. Exercise consisted of voluntary running wheel exercise for four weeks during the perinatal period. Three days after birth, the pups remained at low altitude (normoxia) or were exposed to hypobaric hypoxia of 450 mmHg to simulate ~4500 m altitude exposure until 8 weeks of age. The study consisted of 4 groups: Hypoxia + Nonexercise pregnancy, Hypoxia + Exercise, or the respective, normoxia conditions (Normoxia + Nonexercise or Normoxia + Exercise). Offspring body size, motor function, right ventricular systolic pressure (RVSP), and cardiopulmonary morphology were assessed after 8 weeks in normoxia or hypoxia. RESULTS: Both hypoxic groups had smaller body sizes, reduced motor function, increased hematocrit, RVSP, muscularization in medium-sized pulmonary arteries, as well as right ventricular hypertrophy and contractility compared to the normoxic groups (p < 0.05). CONCLUSIONS: Chronic hypoxia simulating 4500 m attenuated growth, lowered motor function, and elicited PH development. Voluntary maternal exercise did not significantly decrease RVSP in the offspring, which aligned with a lack of effect to attenuate abnormal body size and cardiopulmonary development due to chronic hypoxia. These findings are preliminary in nature and more powered studies through larger group sizes are required to generalize the results to the population.

Remote monitoring of atrial fibrillation recurrence using mHealth technology (REMOTE-AF).

Aims: This proof-of-concept study sought to evaluate changes in heart rate (HR) obtained from a consumer wearable device and compare against implantable loop recorder (ILR)-detected recurrence of atrial fibrillation (AF) and atrial tachycardia (AT) after AF ablation. Methods and results: REMOTE-AF (NCT05037136) was a prospectively designed sub-study of the CASA-AF randomized controlled trial (NCT04280042). Participants without a permanent pacemaker had an ILR implanted at their index ablation procedure for longstanding persistent AF. Heart rate and step count were continuously monitored using photoplethysmography (PPG) from a commercially available wrist-worn wearable. Photoplethysmography-recorded HR data were pre-processed with noise filtration and episodes at 1-min interval over 30 min of HR elevations (Z-score = 2) were compared with corresponding ILR data. Thirty-five patients were enrolled, with mean age 70.3 ± 6.8 years and median follow-up 10 months (interquartile range 8-12 months). Implantable loop recorder analysis revealed 17 out of 35 patients (49%) had recurrence of AF/AT. Compared with ILR recurrence, wearable-derived elevations in HR ≥ 110 beats per minute had a sensitivity of 95.3%, specificity 54.1%, positive predictive value (PPV) 15.8%, negative predictive value (NPV) 99.2%, and overall accuracy 57.4%. With PPG-recorded HR elevation spikes (non-exercise related), the sensitivity was 87.5%, specificity 62.2%, PPV 39.2%, NPV 92.3%, and overall accuracy 64.0% in the entire patient cohort. In the AF/AT recurrence only group, sensitivity was 87.6%, specificity 68.3%, PPV 53.6%, NPV 93.0%, and overall accuracy 75.0%. Conclusion: Consumer wearable devices have the potential to contribute to arrhythmia detection after AF ablation. Study Registration: ClinicalTrials.gov Identifier: NCT05037136 https://clinicaltrials.gov/ct2/show/NCT05037136.

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and three additional alcohol-related signatures indicating synergism between the two exposures. Tobacco smoking was associated with differences in the mutational spectra and repertoire of driver mutations in cancer genes, and in patterns of copy number change. Together, the results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

Phylogenomics and genetic analysis of solvent-producing Clostridium species.

The genus Clostridium is a large and diverse group within the Bacillota (formerly Firmicutes), whose members can encode useful complex traits such as solvent production, gas-fermentation, and lignocellulose breakdown. We describe 270 genome sequences of solventogenic clostridia from a comprehensive industrial strain collection assembled by Professor David Jones that includes 194 C. beijerinckii, 57 C. saccharobutylicum, 4 C. saccharoperbutylacetonicum, 5 C. butyricum, 7 C. acetobutylicum, and 3 C. tetanomorphum genomes. We report methods, analyses and characterization for phylogeny, key attributes, core biosynthetic genes, secondary metabolites, plasmids, prophage/CRISPR diversity, cellulosomes and quorum sensing for the 6 species. The expanded genomic data described here will facilitate engineering of solvent-producing clostridia as well as non-model microorganisms with innately desirable traits. Sequences could be applied in conventional platform biocatalysts such as yeast or Escherichia coli for enhanced chemical production. Recently, gene sequences from this collection were used to engineer Clostridium autoethanogenum, a gas-fermenting autotrophic acetogen, for continuous acetone or isopropanol production, as well as butanol, butanoic acid, hexanol and hexanoic acid production.

Interpersonal Coordination between Female Soccer Players: Leader-Follower Roles within a Collision-Avoidance Task.

Background/Purpose: Return to sport decision-making may be improved by assessing an athlete's ability to coordinate movement with opponents in sport. The purpose was to investigate whether previous injuries associated with female soccer players' interpersonal coordination during a collision avoidance task. The authors hypothesized that external perturbations would disrupt the strength and stability of coordinated movement, and that individuals with a history of injury would be less likely to recover coordinated movement. Study Design: Cross-Sectional. Methods: Nine female athletes with a history of lower extremity injuries and nine without injuries were paired into dyads. Each dyad completed twenty trials of an externally paced collision-avoidance agility task with an unanticipated perturbation. Participant trajectories were digitized and analyzed using cross-recurrence quantification analysis (CRQA) to determine the strength and stability of interpersonal coordination dynamics. Trials in which participants with injury history assumed leader or follower roles within each dyad were then used to study how dyadic coordination varied across task stages (early, perturbation, and late) using linear mixed effect models. Cohen's d effect sizes were calculated to demonstrate magnitude of differences. In exploratory analysis, psychological readiness (i.e., self-reported knee functioning, fear of injury, and risk-taking propensity) was evaluated for their association with leader-follower status. Results: Perturbation disrupted the strength (R2=0.65, p<0.001, early=49.7±1.7, perturbation=41.1±1.7, d=0.39) and stability (R2=0.71, p < 0.001, early=65.0±1.6, perturbation=58.0±1.7, d=0.38) of interpersonal coordination regardless of leader-follower status. Individuals with injury history failed to restore coordination after the perturbation compared to control participants (injury=44.2.0±2.1, control=50.8±2.6, d=0.39). Neither demographic nor psychological measures were associated with leader-follower roles (B=0.039, p=0.224). Conclusion: Individuals with a history of lower extremity injury may have a diminished ability to adapt interpersonal coordination to perturbations, possibly contributing to a higher risk of re-injury. Level of Evidence: 3.

Case report: pre-symptomatic clinical and metabolic profile in posterior cortical atrophy and dementia with Lewy bodies.

A research participant was monitored over nearly two decades at Mayo Clinic, undergoing annual neurologic assessments, neuropsychological tests, and multimodal imaging. Initially, he was cognitively normal but developed symptoms consistent with Posterior Cortical Atrophy (PCA) during the study. Early tests indicated mild, yet normal-range declines in language and visuospatial skills. FDG-PET scans revealed increased metabolism in posterior brain regions long before symptoms appeared. Advanced analysis using a novel in-house machine-learning tool predicted concurrent Alzheimer's disease and dementia with Lewy bodies. Autopsy confirmed a mixed neurodegenerative condition with significant Alzheimer's pathology and dense neocortical Lewy bodies. This case underscores the value of longitudinal imaging in predicting complex neurodegenerative diseases, offering vital insights into the early neurocognitive changes associated with PCA and dementia with Lewy bodies.

Implications of Large Language Models for Quality and Efficiency of Neurologic Care: Emerging Issues in Neurology.

Large language models (LLMs) are advanced artificial intelligence (AI) systems that excel in recognizing and generating human-like language, possibly serving as valuable tools for neurology-related information tasks. Although LLMs have shown remarkable potential in various areas, their performance in the dynamic environment of daily clinical practice remains uncertain. This article outlines multiple limitations and challenges of using LLMs in clinical settings that need to be addressed, including limited clinical reasoning, variable reliability and accuracy, reproducibility bias, self-serving bias, sponsorship bias, and potential for exacerbating health care disparities. These challenges are further compounded by practical business considerations and infrastructure requirements, including associated costs. To overcome these hurdles and harness the potential of LLMs effectively, this article includes considerations for health care organizations, researchers, and neurologists contemplating the use of LLMs in clinical practice. It is essential for health care organizations to cultivate a culture that welcomes AI solutions and aligns them seamlessly with health care operations. Clear objectives and business plans should guide the selection of AI solutions, ensuring they meet organizational needs and budget considerations. Engaging both clinical and nonclinical stakeholders can help secure necessary resources, foster trust, and ensure the long-term sustainability of AI implementations. Testing, validation, training, and ongoing monitoring are pivotal for successful integration. For neurologists, safeguarding patient data privacy is paramount. Seeking guidance from institutional information technology resources for informed, compliant decisions, and remaining vigilant against biases in LLM outputs are essential practices in responsible and unbiased utilization of AI tools. In research, obtaining institutional review board approval is crucial when dealing with patient data, even if deidentified, to ensure ethical use. Compliance with established guidelines like SPIRIT-AI, MI-CLAIM, and CONSORT-AI is necessary to maintain consistency and mitigate biases in AI research. In summary, the integration of LLMs into clinical neurology offers immense promise while presenting formidable challenges. Awareness of these considerations is vital for harnessing the potential of AI in neurologic care effectively and enhancing patient care quality and safety. The article serves as a guide for health care organizations, researchers, and neurologists navigating this transformative landscape.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.

A real-world assessment of stage I lung cancer through electronic nose technology.

INTRODUCTION: Electronic nose (E-nose) technology has demonstrated excellent sensitivity and specificity in the setting of lung cancer screening. However, the performance of E-nose specifically for early-stage tumors remains unclear. Therefore, the aim of our study was to assess the diagnostic performance of E-nose technology in clinical stage I lung cancer. METHODS: This Phase-IIc trial (NCT04734145) included patients diagnosed with a single ≥50% solid stage I nodule. Exhalates were prospectively collected from January 2020 to August 2023. Blinded bioengineers analyzed the exhalates, using E-nose technology to determine the probability of malignancy. Patients were stratified into 3 risk groups (low-risk, <0.2; moderate-risk, ≥0.2 to 0.7; high-risk, ≥0.7). The primary outcome was the diagnostic performance of E-nose versus histopathology (accuracy and F1 score). The secondary outcome was the clinical performance of the E-nose versus clinicoradiological prediction models. RESULTS: Based on the predefined cut-off (<0.20), E-nose agreed with histopathological results in 86% of cases, achieving an F1 score of 92.5%, based on 86 true positives, 2 false negatives, and 12 false positives (n=100). Compared with Swensen and Brock models, E-nose would refer fewer patients with malignant nodules to observation (Low-risk: 2 vs. 9 and 11; respectively; p=0.028 and p=0.011) and more patients with malignant nodules to treatment without biopsy (High-risk: 27 vs. 19 and 6; respectively; p=0.057 and p<0.001). CONCLUSIONS: In the setting of clinical stage I lung cancer, E-nose has good agreement with histopathology. Accordingly, E-nose technology can be used in addition to imaging or as part of a "multiomics" platform.

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

A New Functional Threshold for Minimally Invasive Lobectomy.

OBJECTIVE: To assess the performance of a lower predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for carbon monoxide (DLCO) (ppoFEV1/ppoDLCO) threshold to predict cardiopulmonary complications after minimally invasive surgery (MIS) lobectomy. SUMMARY BACKGROUND DATA: Although MIS is associated with better postoperative outcomes than open surgery, MIS uses risk-assessment algorithms developed for open surgery. Moreover, several different definitions of cardiopulmonary complications are used for assessment. METHODS: All patients who underwent MIS lobectomy for clinical stage I-II lung cancer from 2018 to 2022 at our institution were considered. The performance of a ppoFEV1/ppoDLCO threshold of <45% was compared against that of the current guideline threshold of <60%. Three different definitions of cardiopulmonary complications were compared: Society of Thoracic Surgeons (STS), European Society of Thoracic Surgeons (ESTS), and Berry et al. RESULTS: In 946 patients, the ppoFEV1/ppoDLCO threshold of <45% was associated with a higher proportion correctly classified (79% [95% CI, 76%-81%] vs. 65% [95% CI, 62%-68%]; P<0.001). The complication with the biggest difference in incidence between ppoFEV1/ppoDLCO of 45%-60% and >60% was prolonged air leak (33 [13%] vs. 34 [6%]; P<0.001). The predicted probability curves for cardiopulmonary complications were higher for the STS definition than for the ESTS or Berry definitions across ppoFEV1 and ppoDLCO values. CONCLUSIONS: The ppoFEV1/ppoDLCO threshold of <45% more accurately classified patients for cardiopulmonary complications after MIS lobectomy, emphasizing the need for updated risk-assessment guidelines for MIS lobectomy to optimize additional cardiopulmonary function evaluation.

A 2D video-based assessment is associated with 3D biomechanical contributors to dynamic knee valgus in the coronal plane.

Introduction: Adolescent athletes involved in sports that involve cutting and landing maneuvers have an increased risk of anterior cruciate ligament (ACL) tears, highlighting the importance of identifying risky movement patterns such as dynamic knee valgus (DKV). Qualitative movement screenings have explored two-dimensional (2D) scoring criteria for DKV, however, there remains limited data on the validity of these screening tools. Determining a 2D scoring criterion for DKV that closely aligns with three-dimensional (3D) biomechanical measures will allow for the identification of poor knee position in adolescent athletes on a broad scale. The purpose of this study was to establish a 2D scoring criterion that corresponds to 3D biomechanical measures of DKV. Methods: A total of 41 adolescent female club volleyball athletes performed a three-task movement screen consisting of a single-leg squat (SLS), single-leg drop landing (SLDL), and double-leg vertical jump (DLVJ). A single rater scored 2D videos of each task using four criteria for poor knee position. A motion capture system was used to calculate 3D joint angles, including pelvic obliquity, hip adduction, knee abduction, ankle eversion, and foot progression angle. Receiver operating characteristic curves were created for each 2D scoring criterion to determine cut points for the presence of movement faults, and areas under the curve (AUC) were computed to describe the accuracy of each 2D criterion compared to 3D biomechanical data. Results: 3D measures indicated knee abduction angles between 2.4°-4.6° (SD 4.1°-4.3°) at the time point when the center of the knee joint was most medial during the three tasks. AUCs were between 0.62 and 0.93 across scoring items. The MEDIAL scoring item, defined as the knee joint positioned inside the medial border of the shoe, demonstrated the greatest association to components of DKV, with AUCs ranging from 0.67 to 0.93. Conclusion: The MEDIAL scoring criterion demonstrated the best performance in distinguishing components of DKV, specifically pelvic obliquity, hip adduction, ankle eversion, and foot progression. Along with the previously published scoring definitions for trunk-specific risk factors, the authors suggest that the MEDIAL criterion may be the most indicative of DKV, given an association with 3D biomechanical risk factors.

Treatment of esophageal adenocarcinoma in patients with a history of bariatric surgery.

BACKGROUND: The relationship among obesity, bariatric surgery, and esophageal adenocarcinoma (EAC) is complex, given that some bariatric procedures are thought to be associated with increased incidence of reflux and Barrett's esophagus. Previous bariatric surgery may complicate the use of the stomach as a conduit for esophagectomy. In this study, we presented our experience with patients who developed EAC after bariatric surgery and described the challenges encountered and the techniques used. METHODS: We conducted a retrospective review of our institutional database to identify all patients at our institution who were treated for EAC after previously undergoing bariatric surgery. RESULTS: In total, 19 patients underwent resection with curative intent for EAC after bariatric surgery, including 10 patients who underwent sleeve gastrectomy. The median age at diagnosis of EAC was 63 years; patients who underwent sleeve gastrectomy were younger (median age, 56 years). The median time from bariatric surgery to EAC was 7 years. Most patients had a body mass index (BMI) score of >30 kg/m2 at the time of diagnosis of EAC; approximately 40% had class III obesity (BMI score > 40 kg/m2). Six patients (32%) had known Barrett's esophagus before undergoing a reflux-increasing bariatric procedure. Sleeve gastrectomy patients underwent esophagectomy with gastric conduit, colonic interposition, or esophagojejunostomy. Only 1 patient had an anastomotic leak (after esophagojejunostomy). CONCLUSION: Endoscopy should be required both before (for treatment selection) and after all bariatric surgical procedures. Resection of EAC after bariatric surgery requires a highly individualized approach but is safe and feasible.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.