Virtual Neuromuscular Training Among Physically Active Young Adults: A Feasibility Study.

CONTEXT: Evidence indicates a 2 to 3 times increased risk of musculoskeletal injury after return to play from concussion. Undetected neuromuscular control deficits at return to play may relate to increased musculoskeletal injury risk. Rehabilitation to improve neuromuscular control may benefit patients with concussion, but access to rehabilitation professionals and/or poor adherence may limit efficacy. Our purpose was to determine the feasibility of an 8-week virtual neuromuscular training (NMT) program administered through a novel smartphone application among physically active, uninjured adults. DESIGN: Feasibility trial. METHODS: Participants were instructed to complete an NMT program administered via a smartphone application and returned for follow-up questionnaires 8 weeks later. They were instructed to complete 3 asynchronous self-guided workouts per week during the 8-week intervention period. Workouts included balance, plyometrics, strengthening, and dual-task exercises. The application provided instructions for each exercise using video, text, and audio descriptions. Our primary feasibility measure was participant adherence, calculated as the percentage of workouts completed out of the total possible 24 workouts. We recorded the average duration of each workout using start/stop/advance features within the application. RESULTS: Twenty participants were enrolled, of which 15 (age = 26.3 [2.7] y, 67% female) returned for follow-up (75% retention). Participant adherence was 57.2% (25.0%; range: 16.7%-91.7%). Participants spent 17.3 (8.0) minutes per workout (range: 7.4-37.9 min). There were no adverse reactions or injuries. Most participants (60%) reported time availability as a primary barrier to intervention completion. CONCLUSIONS: Participants were moderately (>50%) adherent to a virtual NMT program, without any reported injuries. We identified several barriers to participation and pathways for improved adherence in the future. The virtual NMT program completed by uninjured adults provides evidence of its feasibility and future scalability to those with a recent concussion to address neuromuscular control deficits and reduce future injury risk.

High TNF and NF-ĸB pathway dependency are associated with AZD5582 sensitivity in OSCC via CASP8-dependent apoptosis.

Drug repurposing can accelerate the development of novel therapeutic strategies. Oral squamous cell carcinoma (OSCC) is prevalent in Asians and is associated with a poor prognosis. Here, we integrate newly generated sensitivity data for 339 anticancer drugs with genome-wide CRISPR‒Cas9 gene essentiality data for 21 cell lines mostly derived from Asian OSCC patients to identify drug repurposing candidates. We observe potent activity of AZD5582 (an antagonist of the inhibitor of apoptosis (IAP) family of proteins) in a subset of OSCC cells, which was associated with dependency on NF-ĸB pathway genes (RNF31, MAP3K7 and IKBKG). We confirm the on-target specificity and potency of AZD5582 in vitro and its ability to suppress cell growth in xenograft models. Furthermore, we identify tumor necrosis factor (TNF) as a key mediator of AZD5582 sensitivity in OSCC. CASP8-dependent apoptotic and CASP8-independent necroptotic cellular programs mediate AZD5582-induced cell death. In summary, through the systematic integration of pharmacological and CRISPR data, we identified a subset of OSCC with potent sensitivity to AZD5582 mediated through the NF-κB and TNF signalling pathways.

Serotype-specific clinical features and spatial distribution of dengue in northern Kerala, India.

Background: Collection and compilation of spatial, meteorological, entomological, and virological data are critical in mitigating climate-sensitive emerging infections like dengue. This study was a holistic attempt to understand the dengue situation in the Kasaragod district of Kerala, India. Methods: This cross-sectional study was conducted in 13 health institutions from June to July 2021. Adult patients presenting with fever and testing positive for NS1 ELISA were subjected to Dengue RT-PCR and serotyping. The spatial and clinical features of the RT-PCR-positive patients, the district's meteorological data, and the vector indices were studied. Results: The pre-epidemic months were marked by intermittent rainfall, peak ambient temperature and high larval indices. Among the 136 dengue RT-PCR patients studied, 41.2% had DENV2 followed by DENV1 (22.8%), DENV3 (5.9%) and DENV4 (4.4%); with 25% mixed infections. DENV1 showed a higher risk of gastrointestinal manifestations (80.6%, p=0.019) and musculoskeletal symptoms (77.4%, p=0.026) compared with other serotypes. Conclusions: In the context of dengue hyperendemicity, the possibility of an emerging serotype's dominance coupled with the mixing up of strains should warn the health system regarding future outbreaks. Furthermore, the study emphasizes the importance of monitoring larval indices and the window of opportunity to intervene between environmental predictors and dengue outbreaks.

Fun with electricity: A novel ballistics gelatin model with LED tracking for ultrasound needle guidance.

Background: Use of ultrasound (US) for procedural needle guidance can improve success rates, safety, and accuracy. Often, training is performed on task trainers, which can be prohibitively expensive. Determining undesired needle placement is difficult when the needle is poorly visualized with US. Currently available simulation phantoms cannot provide real-time feedback on the location of needle placement. Objectives: The primary objective was to develop and determine feasibility of a low-cost simulation phantom with an internal circuit and LED light system to determine when a needle contacts internal structures. We also aimed to determine whether its use was associated with increased comfort level. Methods: Emergency medicine (EM) residents (PGY-1 to PGY-3) performed in-plane and out-of-plane US needle guidance using homemade phantoms. Comfort levels were assessed by pre- and post intervention survey. Outcomes were measured on Likert scale (minimum = 1, maximum = 5). The primary outcome was change in confidence markers before and after the simulation task. Secondary outcomes were survey results of comparisons of these models to prior training experiences on simulators and humans. Results: All EM residents (30) in our program were invited to participate. Twenty participants enrolled and completed the study. In the primary outcome, median comfort with out-of-plane and in-plane guidance increased after using the model but was more pronounced for out-of-plane guidance. On a posttest survey, residents rated the models overall very similar to prior experience on simulators (median 5/5 [IQR 4.0-5.0]) and moderately similar to humans (median 3/5 [IQR 3.0-4.0]). Conclusions: We created a low-cost ballistic gelatin phantom with an internal electric needle guidance system. Use of the phantom for training was associated with increased learner comfort with the procedure. Learners rated the characteristics of the phantom as similar to higher-cost commercial equipment and humans.

Parasiticide use and obesity in dogs with sudden acquired retinal degeneration syndrome.

OBJECTIVE: To investigate parasiticide use and describe signalment features in patients with sudden acquired retinal degeneration syndrome (SARDS). ANIMALS: Retrospective case-control study of dogs with (n = 71) and without (136) SARDS. METHODS: Parasiticide use, presentation season, weight, body condition, and signalment were compared between dogs diagnosed with SARDS and the reference population by use of descriptive statistics and logistic regression. RESULTS: Animals with SARDS were at a 5.99 times higher odds of having previously used imidacloprid (95% CI, 1.6 to 22.2; P = .003). However, time of last imidocloprid administration was > 6 years prior to diagnosis in 6 SARDS-affected individuals and 15, 26, or 42 months before diagnosis (n = 1 each). No other class of parasiticide had a significant association with SARDS. Seasonal variation was observed with a negative association identified between incidence of SARDS and tick season (October to January; P < .001). Overweight and obese dogs were 4.42 (95% CI, 1.9 to 10.4) and 4.96 (95% CI, 2.1 to 11.6) times more likely to have SARDS (P ≤ .001). History of polyphagia or weight gain was not associated with an increased likelihood of being overweight or obese within the SARDS-affected population (P > .108). CLINICAL RELEVANCE: While a statistically significant association was found between imidacloprid use and SARDS, this is unlikely to be clinically significant given the lack of a temporal association, sparse exposure numbers, and low point estimate of the OR. A positive association between being overweight or obese and a diagnosis of SARDS was found independent of polyphagia and weight gain, suggesting that it may be a risk factor for the development of SARDS.

Cluster Buster: A Machine Learning Algorithm for Genotyping SNPs from Raw Data.

Genotyping single nucleotide polymorphisms (SNPs) is fundamental to disease research, as researchers seek to establish links between genetic variation and disease. Although significant advances in genome technology have been made with the development of bead-based SNP genotyping and Genome Studio software, some SNPs still fail to be genotyped, resulting in "no-calls" that impede downstream analyses. To recover these genotypes, we introduce Cluster Buster, a genotyping neural network and visual inspection system designed to improve the quality of neurodegenerative disease (NDD) research. Concordance analysis with whole genome sequencing (WGS) and imputed genotypes validated the reliability of predicted genotypes, with dozens of high-performing SNPs across LRRK2, APOE, and GBA loci achieving at least 90% concordance per SNP location. Further analysis of concordance between Genome Studio genotypes and imputed and WGS genotypes revealed discrepancies between the genotyping technologies, highlighting the need for selective application of Cluster Buster on SNP locations based on concordance rates. Cluster Buster's implementation significantly reduces manual labor for recovering no-call SNPs, refining genotype quality for the Global Parkinson's Genetics Program (GP2). This system facilitates better imputation and GWAS outcomes, ultimately contributing to a deeper understanding of genetic factors in NDDs.

NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations.

BACKGROUND: Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations. OBJECTIVE: We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies. METHODS: We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples. This novel platform includes approximately 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease-related genome-wide association study loci across diverse populations. RESULTS: In this article, we describe NBA's potential as an efficient means for researchers to assess known and novel disease genetic associations in a multi-ancestry framework. The NBA can identify rare genetic variants and accurately impute more than 15 million common variants across populations. Apart from enabling sample prioritization for further whole-genome sequencing studies, we envisage that NBA will play a pivotal role in recruitment for interventional studies in the precision medicine space. CONCLUSIONS: From a broader perspective, the NBA serves as a promising means to foster collaborative research endeavors in the field of neurological disorders worldwide. Ultimately, this carefully designed tool is poised to make a substantial contribution to uncovering the genetic etiology underlying these debilitating conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Upfront surgery for intrahepatic cholangiocarcinoma: Prediction of futility using artificial intelligence.

OBJECTIVE: We sought to identify patients at risk of "futile" surgery for intrahepatic cholangiocarcinoma using an artificial intelligence (AI)-based model based on preoperative variables. METHODS: Intrahepatic cholangiocarcinoma patients who underwent resection between 1990 and 2020 were identified from a multi-institutional database. Futility was defined either as mortality or recurrence within 12 months of surgery. Various machine learning and deep learning techniques were used to develop prediction models for futile surgery. RESULTS: Overall, 827 intrahepatic cholangiocarcinoma patients were included. Among 378 patients (45.7%) who had futile surgery, 297 patients (78.6%) developed intrahepatic cholangiocarcinoma recurrence and 81 patients (21.4%) died within 12 months of surgical resection. An ensemble model consisting of multilayer perceptron and gradient boosting classifiers that used 10 preoperative factors demonstrated the highest accuracy, with areas under receiver operating characteristic curves of 0.830 (95% confidence interval 0.798-0.861) and 0.781 (95% confidence interval 0.707-0.853) in the training and testing cohorts, respectively. The model displayed sensitivity and specificity of 64.5% and 80.0%, respectively, with positive and negative predictive values of 73.1% and 72.7%, respectively. Radiologic tumor burden score, serum carbohydrate antigen 19-9, and direct bilirubin levels were the factors most strongly predictive of futile surgery. The artificial intelligence-based model was made available online for ease of use and clinical applicability (https://altaf-pawlik-icc-futilityofsurgery-calculator.streamlit.app/). CONCLUSION: The artificial intelligence ensemble model demonstrated high accuracy to identify patients preoperatively at high risk of undergoing futile surgery for intrahepatic cholangiocarcinoma. Artificial intelligence-based prediction models can provide clinicians with reliable preoperative guidance and aid in avoiding futile surgical procedures that are unlikely to provide patients long-term benefits.

Outpatient Follow-Up Visits to Reduce 30-Day All-Cause Readmissions for Heart Failure, COPD, Myocardial Infarction, and Stroke: A Systematic Review and Meta-Analysis.

Introduction: Hospital readmissions is an important public health problem that US hospitals are responsible for reducing. One strategy for preventing readmissions is to schedule an outpatient follow-up visit before discharge. The objective of this study was to determine whether outpatient follow-up visits are an effective method to reduce 30-day all-cause readmissions for patients discharged from US hospitals with heart failure, chronic obstructive pulmonary disease (COPD), acute myocardial infarction (AMI), or stroke. Methods: We conducted a systematic review and meta-analysis to identify relevant articles published from 2013 through 2023. We searched PubMed, CINAHL, and Cochrane. Eligible studies were those that assessed the effect of postdischarge outpatient follow-up visits on 30-day all-cause readmission. We used random effect meta-analyses to generate pooled adjusted effect estimates and 95% CIs. Results: We initially identified 2,256 articles. Of these, 32 articles underwent full-text review and 15 met inclusion criteria. Seven studies addressed heart failure, 3 COPD, 2 AMI, and 3 stroke. Ten articles provided sufficient information for meta-analysis. The pooled adjusted effect measure was 0.79 (95% CI, 0.69-0.91), indicating that outpatient follow-up visits were associated with a 21% lower risk of readmission. However, we found a high degree of between-study heterogeneity (Q = 122.78; P < .001; I2 = 92.7%). Subgroup analyses indicated that study quality, disease condition, and particularly whether a time-dependent analysis method was used, explained much of the heterogeneity. Conclusion: Outpatient follow-up visits are a potentially effective way to reduce 30-day all-cause readmissions for patients discharged with heart failure or stroke, but evidence of benefit was lacking for COPD and we found no studies for assessing AMI. Our results emphasize the importance of study quality.

Surgical treatment of anterior glenohumeral instability: a historical review.

BACKGROUND: Glenohumeral instability is a common pathology, particularly in young, active patients. METHODS: A narrative review was performed to describe the history of surgical treatments for anterior shoulder instability. RESULTS: Open surgical techniques were first described by Bankart in 1923. Techniques include both anatomic soft tissue repairs and nonanatomic procedures to provide constraint to motion and dislocation. Osseous techniques to address glenoid bone loss include both autograft techniques, such as the Latarjet procedure, and the use of various allografts. Technologic advances, particularly arthroscopy, have continued to drive the evolution of treatments. The concept of the glenoid track has furthered our understanding of this pathology to guide appropriate treatment to reduce recurrence. CONCLUSIONS: Surgical treatment for anterior shoulder instability continues to evolve in an effort to restore function and prevent additional injury.

Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.

The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication.

Are Child Access Prevention Laws Associated With Fewer Pediatric Firearm Injuries?

OBJECTIVE: Firearm injuries are the leading cause of death for children in the United States. Child access prevention (CAP) laws have been passed in some states. This study examines characteristics of children with firearm injuries in states with different types of CAP laws. METHODS: The Pediatric Health Information System database was reviewed to identify all pediatric firearm injury patients between 2016 and 2021. Hospital data were categorized based on state laws as (1) no CAP laws (2) some CAP laws or (3) strict CAP laws. CAP laws that specifically outlined criminal liability for the negligent storage of firearms were considered a strict restriction, whereas any other form of CAP law was considered some restriction. χ-squared and independent-samples median testing were performed to compare restriction levels. RESULTS: Between 2016 and 2021, 12 853 firearm injuries were recorded in the Pediatric Health Information System database. In states with strict CAP laws, patients were significantly older (P < .001) and had a significantly higher household income (P < .001) compared with patients in states with no CAP laws. Gender, race, and the number of firearm injuries differed between the 3 restriction levels. There were less firearm injuries observed than expected in cities with strict CAP laws. CONCLUSIONS: CAP laws are associated with a higher age and household income of pediatric firearm injury patients. Given the disparities seen between cities, a federal CAP law may best protect children nationwide.

Immune signature of patients with cardiovascular disease predicts increased risk for a severe course of COVID-19.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. So far, however, there are hardly any strategies for predicting the course of SARS-CoV-2 infection in CVD patients at hospital admission. Thus, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 nonvaccinated participants, including uninfected and acutely SARS-CoV-2-infected CVD patients and healthy donors, using a 36-colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T-cell subsets. Moreover, we identified an immune signature characterised by CD161+ T cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID-19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.

Resolving Conflicting Mechanisms for Photoredox Allylic sp3-CH Arylation Using Deuterium-Labeling and Isotope Effects.

Two conflicting mechanisms have emerged for the direct arylation of allylic C-H bonds enabled by the combined use of thiol and photoredox catalysis. In the original report (Nature, 2015, 519, 74-77), a radical coupling step-between a radical anion of an arene and an allylic radical-is proposed to be the key C-C bond-forming step. A recent mechanistic study (J. Org. Chem. 2022, 87, 223-230) has suggested that the C-C bond formation occurs via radical anion capture by the olefin followed by an H atom transfer (HAT) event to deliver the allylic C-H arylation product. Utilizing cyclohexene-4,4,5,5-d 4 as a mechanistic probe to distinguish between otherwise indistinguishable regioisomeric allylic C-H arylation products in the reaction of cyclohexene and dicyanobenzene, we establish that the radical anion capture-HAT mechanism is not operative. Furthermore, experimental k H/k D studies and DFT calculations lend strong support to the radical coupling mechanism proceeding via irreversible HAT to form the allylic radical of cyclohexene, followed by regioselectivity-determining radical coupling (for unsymmetrical olefins) and facile decyanation.

Multi-source connectivity as the driver of solar wind variability in the heliosphere.

The ambient solar wind that fills the heliosphere originates from multiple sources in the solar corona and is highly structured. It is often described as high-speed, relatively homogeneous, plasma streams from coronal holes and slow-speed, highly variable, streams whose source regions are under debate. A key goal of ESA/NASA's Solar Orbiter mission is to identify solar wind sources and understand what drives the complexity seen in the heliosphere. By combining magnetic field modelling and spectroscopic techniques with high-resolution observations and measurements, we show that the solar wind variability detected in situ by Solar Orbiter in March 2022 is driven by spatio-temporal changes in the magnetic connectivity to multiple sources in the solar atmosphere. The magnetic field footpoints connected to the spacecraft moved from the boundaries of a coronal hole to one active region (12961) and then across to another region (12957). This is reflected in the in situ measurements, which show the transition from fast to highly Alfvénic then to slow solar wind that is disrupted by the arrival of a coronal mass ejection. Our results describe solar wind variability at 0.5 au but are applicable to near-Earth observatories.

Neural canal ridges: A novel osteological correlate of postcranial neuroanatomy in dinosaurs.

In this article, we document the widespread presence of bony ridges in the neural canals of non-avian dinosaurs, including a wide diversity of sauropods, two theropods, a thyreophoran, and a hadrosaur. These structures are present only in the caudal vertebrae. They are anteroposteriorly elongate, found on the lateral walls of the canal, and vary in size and position both taxonomically and serially. Similar bony projections into the neural canal have been identified in extant teleosts, dipnoans, and urodelans, in which they are recognized as bony spinal cord supports. In most non-mammals, the dura mater that surrounds the spinal cord is fused to the periosteum of the neural canal, and the denticulate ligaments that support the spinal cord can pass through the dura and periosteum to anchor directly to bone. The function of these structures in dinosaurs remains uncertain, but in sauropods they might have stabilized the spinal cord during bilateral movement of the tail and use of the tail as a weapon. Of broader significance, this study emphasizes that important new discoveries at the gross anatomical level can continue to be made in part by closely examining previously overlooked features of known specimens.

Expectations and Preferences for Digital Cessation Treatment: Multimethods Study Among Older Adults Who Smoke Cigarettes.

BACKGROUND: To address enduring age-related tobacco disparities, it is critical to promote cessation treatment among older adults (aged 65+ years). Digital health platforms offer opportunities for wide dissemination of evidence-based behavioral cessation support. However, existing digital cessation treatments are not tailored to unique aging-related needs and preferences, resulting in low uptake. Detailed information is needed about how to best adapt these treatments for this age group. OBJECTIVE: We aimed to collect detailed, hypothesis-generating information about expectations and preferences for cessation digital treatment among older adults who smoke cigarettes. METHODS: Semistructured interviews were conducted with adults aged 65+ years currently smoking or who had quit within the past month. Interviews included open-ended questions regarding prior experiences with digital health platforms and expectations and preferences for cessation treatment via various modalities (app-delivered, texting-based, or videoconferencing counseling). Interviews also elicited questions regarding digital modalities that integrated social components (app-delivered social forums and group videoconferencing counseling). Using an iterative, team-based approach, the thematic analysis identified meaningful themes. Interviews were supplemented with quantitative measures assessing sociodemographics, digital literacy, and physical health symptoms. RESULTS: Participants (12/20, 60% men; 15/20, 75% White; 4/20, 20% Black or African American; 1/20, 5% Asian) were currently smoking (17/20, 85%) or had recently quit (3/20, 15%). Thematic analysis identified 3 meaningful themes across all digital modalities: convenience, accessibility, and personalization. Expected benefits of digital platforms included convenient treatment access, without reliance on transportation. Participants preferred treatments to be personalized and deliver content or strategies beyond standard education. Most (17/20, 85%) were unfamiliar with cessation apps but found them appealing given the potential for offering a novel quitting strategy. App ease of use (eg, easy navigation) was preferred. Half (10/20, 50%) would try a texting-based intervention, with many preferring texting with a counselor rather than automated messaging. Most (17/20, 85%) would use videoconferencing and expected this modality to deliver better quality counseling than via telephone. Expected videoconferencing challenges included looking presentable onscreen, technological difficulties, and privacy or security. Videoconferencing was regarded as the most personalized digital treatment, yet benefits unique to app-delivered and texting-based treatments included anonymity and access to treatment 24/7. Participants expected integrating social components into digital treatment to be useful for quit success and social connection, yet were concerned about possible interpersonal challenges. CONCLUSIONS: Because a long history of quit attempts and familiarity with standard quitting advice is common among older adults who smoke cigarettes, digital platforms might offer appealing and novel strategies for cessation that are accessible and convenient. Overall, this population was open to trying digital cessation treatments and would prefer that these platforms prioritize ease of use and personalized content. These findings challenge the bias that older adults are uninterested or unwilling to engage with digital treatments for behavioral health.

A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level.

Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce "efficacious combination benefit" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.

Development of an artificial intelligence-based model to predict early recurrence of neuroendocrine liver metastasis after resection.

PURPOSE: We sought to develop an artificial intelligence (AI)-based model to predict early recurrence (ER) after curative-intent resection of neuroendocrine liver metastases (NELMs). METHODS: Patients with NELM who underwent resection were identified from a multi-institutional database. ER was defined as recurrence within 12 months of surgery. Different AI-based models were developed to predict ER using 10 clinicopathologic factors. RESULTS: Overall, 473 patients with NELM were included. Among 284 patients with recurrence (60.0%), 118 patients (41.5%) developed an ER. An ensemble AI model demonstrated the highest area under receiver operating characteristic curves of 0.763 and 0.716 in the training and testing cohorts, respectively. Maximum diameter of the primary neuroendocrine tumor, NELM radiologic tumor burden score, and bilateral liver involvement were the factors most strongly associated with risk of NELM ER. Patients predicted to develop ER had worse 5-year recurrence-free survival and overall survival (21.4% vs 37.1% [P = .002] and 61.6% vs 90.3% [P = .03], respectively) than patients not predicted to recur. An easy-to-use tool was made available online: (https://altaf-pawlik-nelm-earlyrecurrence-calculator.streamlit.app/). CONCLUSION: An AI-based model demonstrated excellent discrimination to predict ER of NELM after resection. The model may help identify patients who can benefit the most from curative-intent resection, risk stratify patients according to prognosis, as well as guide tailored surveillance and treatment decisions including consideration of nonsurgical treatment options.