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The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8 + T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Agency - the capacity to produce an effect - is a foundational aspect of medical education. Agency is usually conceptualized at the level of the individual , with each learner charged with taking responsibility to pull themselves up by their bootstraps. This conceptualization is problematic. First, collaboration is a central component of patient care, which does not align well with an individualistic approach. Second, a growing body of literature documents how minoritized and marginalized trainees experience inequitable restrictions on their agency. Third, a myriad of structures across medicine restricts individual agency. In this guide, we present four conceptualizations of agency beyond the individual that medical researchers can incorporate to modernize and broaden their understanding of agency: (a) temporal: how individuals wrestle with their own agency across time; (b) relational: how agency is co-created dialogically with other individuals and structures; (c) cultural: how culture and cultural resources shape possibilities for agency; and (d) structural: how restrictive structures - like racism and ableism that unjustly curtail individual agency - are created, maintained, and resisted. For each dimension, we first describe it by drawing from and summarizing the work of theorists across disciplines. Next, we highlight an article from medical education that makes particularly good use of this dimension, discussing some of its relevant findings. Finally, we offer a set of questions that researchers in medical education can ask to highlight the dimension of agency in their work, and we suggest potential directions for future inquiry. We conclude by offering an example of how a researcher might understand a resident's educational experiences through each of the four proposed dimensions and further explicating the complexity of agency in medical education.

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.

Executive functioning (EF) has been linked to chronic disease risk in children. Health behaviors are thought to partially explain this association. The current cross-sectional study evaluated specific domains of EF and varied health behaviors in three pediatric life stages. Pediatric participants (early childhood n = 2074, M age  = 6.4 ± 0.9 y; middle childhood n = 3230, M age  = 9.6 ± 1.2 y; adolescence n = 1416, M age  = 15.2 ± 1.7 y) were part of the Environmental influences on Child Health Outcomes (ECHO) Program. They completed neurocognitive tasks measuring cognitive flexibility, behavioral inhibition, and working memory. Parent- and/or child-report measures of dietary intake, physical activity, sleep duration and quality, income, and positive parenting were also collected. Neighborhood crime and greenspace were calculated from publicly available census-tract level indices. After adjusting for study site, child body mass index, and demographics, working memory was related in the hypothesized direction to several dietary behaviors within all pediatric life stages. Working memory and cognitive flexibility were positively related to physical activity in middle childhood and adolescence. In adolescence, behavioral inhibition was positively related to physical activity and inversely related to sugar-sweetened beverage and total caloric intake. Associations with sleep were all non-significant. All significant associations reflected small effect sizes. Income, positive parenting, greenspace, and crime did not significantly influence any of the EF-health behavior associations. Findings highlight the need to consider EF domains, specific health behaviors, and developmental stage in creating intervention strategies that target EF to improve health behaviors. The small effect sizes reinforce the need for multi-tiered interventions to maximize health., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to report. Ethics approval: The study protocol was approved by the single ECHO institutional review board, WCG IRB. Consent to participate: Written informed consent or parent's/guardian's permission was obtained along with child assent, as appropriate, for the ECHO Cohort Data and Biospecimen Collection Protocol participation and for participation in specific study sites. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Trauma-focused evidence-based psychotherapy (EBP) is the recommended treatment for post-traumatic stress disorder (PTSD). During and after the COVID-19 pandemic, veterans began to initiate general mental health services delivered via video telehealth at high rates. Our goal in the current project was to describe the percentage as well as the demographic, military, and clinical characteristics of veterans receiving PTSD EBPs via video telehealth versus in-person., Methods: Using data from the VA electronic health record, we identified a national cohort of all-era veterans who received individual PTSD EBP between April 2022 and April 2023 ( n  = 24,447). We used multivariable hierarchical Bayesian logistic regression to model the probability of receiving at least 50% of their EBP care via video telehealth., Results: In our sample, 74.4% of veterans who received PTSD EBP used video telehealth for at least one EBP session and 66.8% of veterans received at least half of their EBP sessions by video telehealth. Female veterans, younger veterans, and veterans with fewer mental health comorbidities were more likely to have received their PTSD EBP via video telehealth. Additional strong interaction effects for Black female veterans, Hispanic female veterans, female officer veterans, and Black officer veterans., Discussion: Video telehealth delivery of PTSD EBPs was more common than in-person delivery of PTSD EBPs. Consistent with underlying trends in telehealth services, female veterans, and particularly female, racial/ethnic minority veterans were more likely to receive PTSD EBP via video telehealth. Future research designed to contextualize the observed differences in video telehealth delivery of PTSD EBPs should consider the role of social determinants of health., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Genome-wide association studies (GWAS) have detected several susceptibility variants for urinary bladder cancer, but how gene regulation affects disease development remains unclear. To extend GWAS findings, we conducted a transcriptome-wide association study (TWAS) using PrediXcan to predict gene expression levels in whole blood using genome-wide genotype data for 6180 bladder cancer cases and 5699 controls included in the database of Genotypes and Phenotypes (dbGaP). Logistic regression was used to estimate adjusted gene-level odds ratios (OR) per 1-standard deviation higher expression with 95% confidence intervals (CI) for bladder cancer risk. We further assessed associations for individual single-nucleotide polymorphisms (SNPs) used to predict expression levels and proximal loci for genes identified in gene-level analyses with false-discovery rate (FDR) correction. TWAS identified four genes for which expression levels were associated with bladder cancer risk: SLC39A3 (OR = 0.91, CI = 0.87-0.95, FDR = 0.015), ZNF737 (OR = 0.91, CI = 0.88-0.95, FDR = 0.016), FAM53A (OR = 1.09, CI = 1.05-1.14, FDR = 0.022), and PPP1R2 (OR = 1.09, CI = 1.05-1.13, FDR = 0.049). Findings from this TWAS enhance our understanding of how genetically-regulated gene expression affects bladder cancer development and point to potential prevention and treatment targets., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Health Professions Education (HPE) assessment is being increasingly impacted by Artificial Intelligence (AI), and institutions, educators, and learners are grappling with AI's ever-evolving complexities, dangers, and potential. This AMEE Guide aims to assist all HPE stakeholders by helping them navigate the assessment uncertainty before them. Although the impetus is AI, the Guide grounds its path in pedagogical theory, considers the range of human responses, and then deals with assessment types, challenges, AI roles as tutor and learner, and required competencies. It then discusses the difficult and ethical issues, before ending with considerations for faculty development and the technicalities of AI acknowledgment in assessment. Through this Guide, we aim to allay fears in the face of change and demonstrate possibilities that will allow educators and learners to harness the full potential of AI in HPE assessment.

Prevalence of autism diagnosis has historically differed by demographic factors. Using data from 8224 participants drawn from the Environmental influences on Child Health Outcomes (ECHO) Program, we examined relationships between demographic factors and parent-reported autism-related traits as captured by the Social Responsiveness Scale (SRS; T score > 65) and compared these to relations with parent-reported clinician diagnosis of ASD, in generalized linear mixed effects regression analyses. Results suggested lower odds of autism diagnosis, but not of SRS T > 65, for non-Hispanic Black children (adjusted odds ratio [OR] = 0.76, 95% CI 0.55, 1.06) relative to non-Hispanic White children. Higher maternal education was associated with reduced odds of both outcomes (OR = 0.73, 95% CI 0.51, 1.05 for ASD autism diagnosis and 0.4, 95% CI 0.29, 0.55 for SRS score). In addition, results suggested a lower likelihood of autism diagnosis but a higher likelihood of an SRS score > 65 in Black girls. Findings suggest lower diagnostic recognition of autism in non-Hispanic Black children, despite a similar degree of SRS-assessed autism-related traits falling in the clinically elevated range. Further work is needed to address this disparity., (© 2025 International Society for Autism Research and Wiley Periodicals LLC.)

It is well understood that cancer therapies including chemotherapy, tyrosine kinase inhibitors, immune checkpoint inhibitors, and radiation can increase the risk of cardiovascular disease in patients with cancer. This can manifest as a multitude of pathologies including left ventricular dysfunction, myocarditis, cardiomyopathy, accelerated atherosclerosis, and coronary vasospasm. Multimodal cardiac imaging plays a critical role in diagnosing such pathologies by relying on noninvasive tools including echocardiograms, cardiac magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, and coronary computed tomography angiography. These methods have unique considerations and in recent years have made significant progress in their diagnostic capabilities in this patient population. As the field of cardio-oncology continues to expand rapidly, guidance on the management of such toxicities and the development of imaging technologies is crucial. In this review, we present 2 complex cases of atherosclerosis and myocarditis in patients with cancer, highlighting our rationale for management and discussing the nuances of various cardiac imaging modalities.

This pilot study evaluated the feasibility of the technology specialist intervention, which assists clients in achieving mental health recovery and well-being goals via existing digital tools in a real-world community mental health setting. Thirteen adult clients with serious mental illness and their providers completed baseline, 3-, and 6-month assessments, including goal setting, self-efficacy, activation, and acceptability measures, along with weekly ecological momentary assessments. Clients selected goals and corresponding tools, used the tools steadily, and showed improvement in activation and self-efficacy. Most participating clients (82%, n = 9) and providers (80%, n = 8) found the intervention acceptable. These preliminary findings show that the technology specialist intervention is promising and warrants further testing., Competing Interests: Conflict of interest: Dr. Elwyn reports receiving royalties from Oxford University Press and Groups Radcliffe Press; owning copyright in measures of shared decision making; being the founder and director of &think L.L.C., which owns the registered trademark for Option Grids patient decision aids; consulting for EBSCO Publishing; and serving as chief clinical research scientist for Abridge AI Inc. The other authors report no financial relationships with commercial interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Contingency management (CM), an evidence-based behavioral strategy that rewards positive behavior change including tobacco cessation, is rarely offered to support people with HIV (PWH) who smoke. In this study, we explored perspectives among patients and research staff engaged in a multi-site randomized clinical trial involving clinical pharmacist-delivered CM within HIV clinics. Between February and September 2023, we conducted 1:1 interviews with 12 PWH randomized to receive CM and one focus group with 8 staff (i.e., clinical pharmacists and research coordinators). Qualitative data collection and analysis were grounded in the Promoting Action on Research Implementation in Health Services (PARIHS) implementation science framework to understand barriers and facilitators related to evidence (perspectives on CM for smoking cessation), context (HIV clinics), and facilitation (promoting effectiveness and sustainability). Regarding evidence, PWH and staff had limited prior experience with CM and supported the use of exhaled carbon monoxide to promote accountability. PWH and staff thought CM was useful in bolstering internal motivation, but differed on ideal target behaviors (i.e., cessation vs. reduction). Regarding context, clinical pharmacist-delivered tobacco treatment within HIV clinics was viewed favorably, with mixed perspectives regarding optimal visit schedules and utility of remote CM. Regarding facilitation, PWH and research staff discussed strategies to increase participant engagement and retention such as incorporating behavioral counseling services. PWH endorsed application of CM beyond smoking cessation and for people without HIV. Future efforts should consider expanding the use of CM to target smoking cessation and related health behaviors and tailoring the intervention to individual needs and goals., Competing Interests: Declarations. Competing Interests: All authors hold no conflict of interests that are relevant to the content of this paper. Ethical Approval: This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Boards at Yale University (#2000034514). Consent to Participate: Verbal consent to participate was obtained from all study participants prior to the start of data collection., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF., Methods: Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in adult CF and healthy cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies., Results: PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and reduced lung function was most prominent in patients harboring chronic Pseudomonas aeruginosa infection., Conclusions: Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high Pseudomonas aeruginosa burden suggests that pulmonary disease may contribute to renal injury in CF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Biofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. It is commonly assumed that biofilm cells are glued together by the matrix; however, how the specific biochemistry of matrix components affects the cell-matrix interactions and how these interactions vary during biofilm growth remain unclear. Here, we investigate cell-matrix interactions in Vibrio cholerae, the causative agent of cholera. We combine genetics, microscopy, simulations, and biochemical analyses to show that V. cholerae cells are not attracted to the main matrix component (Vibrio polysaccharide, VPS), but can be attached to each other and to the VPS network through surface-associated VPS and crosslinks formed by the protein Bap1. Downregulation of VPS production and surface trimming by the polysaccharide lyase RbmB cause surface remodeling as biofilms age, shifting the nature of cell-matrix interactions from attractive to repulsive and facilitating cell dispersal as aggregated groups. Our results shed light on the dynamics of diverse cell-matrix interactions as drivers of biofilm development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Importance: A wealth of research on screening for social risks in health care has emerged, but evidence is lacking on how social risk screening among physician practices has changed over time., Objectives: To evaluate trends in screening for social risks among US physician practices and examine practice characteristics associated with adoption of social risk screening., Design, Setting, and Participants: The main analysis used a repeated cross-sectional design to analyze results from US physician practices that completed the National Survey of Healthcare Organizations and Systems, a nationally representative survey of physician practices, in 2017 and 2022. Sensitivity analysis tested robustness in a cohort of practices that completed surveys in both years., Exposures: Survey year and characteristics of physician practices., Main Outcomes and Measures: Whether physician practices systematically screened patients for 5 common social risks: food, housing, utilities, interpersonal violence, and transportation., Results: In this cross-sectional study, 3442 practice survey responses were studied. Weighted results showed that in 2022, 27% (95% CI, 23%-32%) of practices reported screening for all 5 of the social risks, an increase from 15% (95% CI, 13%-18%) of practices in 2017 (P < .001). Unadjusted results showed a significant increase in the mean number of social risks screened per practice, from 1.71 (95% CI, 1.60-1.82) in 2017 to 2.34 (95% CI, 2.12-2.55) in 2022. Practice characteristics associated with screening for more social risks remained consistent between 2017 and 2022; these included being a federally qualified health center (incidence rate ratio [IRR], 1.550 [95% CI, 1.336-1.799]) and having higher innovation culture scores (IRR, 1.012 [95% CI, 1.010-1.015]), higher advanced information system scores (IRR, 1.003 [95% CI, 1.001-1.005]), and higher payment reform exposure scores (IRR, 1.002 [95% CI, 1.000-1.003])., Conclusions and Relevance: In this survey-based cross-sectional study of US physician practices, social risk screening increased substantially from 2017 to 2022, although still less than one-third of practices systematically screened for a set of 5 common social risks. What remains to be seen is whether practices use these data to help improve patient health by adjusting health care or referring patients for assistance with social needs. As policies and incentives increasingly emphasize social risk screening, it will be important to assess the association of screening and referrals with patient outcomes.

Background: Evaluations performed before the day of surgery at perioperative clinics have been shown to reduce patient mortality and hospital lengths of stay. These clinics are becoming increasingly adopted worldwide. As the number of older patients undergoing surgery continues to increase, understanding the perspectives of this patient population regarding the preoperative evaluation process is essential to tailor care to their needs and preferences., Methods: We administered a cross-sectional survey by email or telephone to 104 patient participants ages 75 and older who underwent preoperative assessment and surgery at a rural tertiary center in Northern New England in 2022. The survey aimed to elicit patient perspectives on whether or not they prefer to speak with an anesthesia provider before the day of surgery, and on the reasons for their preference., Results: Sixty-six percent of older patients indicated they prefer to engage in conversations with their anesthesia providers before the day of surgery. The most common topics patients wanted to discuss were to address what possible side effects from anesthesia could occur, the type of anesthesia they would receive, and if other anesthesia options were available. Patients also emphasized the importance of their anesthesia provider's awareness of their specific medical conditions, such as kidney, lung, or cervical spine conditions., Conclusions: Preanesthesia assessments allow for bidirectional communication between patients and anesthesia providers, alleviating patient anxiety and allowing for vital patient information to be collected to enhance overall patient safety. Our findings indicate that preoperative assessment by an anesthesia provider is desired and valued by the older patient population, contributing to the evidence in support of the implementation of anesthesia preoperative clinics. More research is needed to determine whether tailoring preanesthesia assessments to better align with patient preferences will translate into enhanced patient-centered outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 International Anesthesia Research Society.)

Problem: Aging alters immune function in women and can lead increased risk of infections, particularly in the female reproductive tract (FRT)., Method of Study: To determine how aging affects innate immune responses in the cervical stroma of the FRT, we isolated endocervical (CX) and ectocervical (ECX) stromal fibroblasts and determine if their expression of multiple pattern recognition receptors (PRRs) and responses to viral stimulation varied with menopause and age., Results: Constitutive expression of most PRRs did not vary with age or menopausal status in either cell type. However, the expression of TLR7, MDA5, and NOD2 by ECX stromal fibroblasts significantly increased in post-menopausal women, while the expression of NOD1 by CX stromal fibroblast also significantly increased in post-menopausal women. When stratified by age, the expression of TLR6 by CX stromal fibroblasts, and MDA5 and NOD2 by ECX stromal fibroblasts increased significantly with increasing age. Stimulation with the dsRNA viral mimic HMW poly (I:C), a ligand for MDA5, resulted in significantly increased expression of the Type I interferons (IFN) IFNβ and IFNε, the Type III interferon IFNλ1, and interferon-stimulated genes (ISGs) MxA, OAS2, and ISG15 in both cell populations. However, upregulation of IFNβ, IFNλ1, MxA, OAS2, and ISG15 in response to poly (I:C) significantly declined with increasing post-menopausal age in ECX stromal fibroblasts. There was no effect of age or menopause on either IFN or ISG expression in CX stromal fibroblasts., Conclusion: Overall, these studies demonstrate that ECX and CX fibroblasts are phenotypically distinct populations and that increasing post-menopausal age reduces IFN and ISG upregulation in ECX stromal fibroblasts in response to viral stimulation, potentially leading to decreased protection against incoming viral pathogens in older post-menopausal women., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Dr. Benedek has received royalties from UpToDate. Dr. Holtzheimer has received royalties from Oxford University Press and UpToDate. Dr. Schnurr has received funding from Healing Breakthrough. Dr. Stauffer was previously a psychotherapy trainer and supervisor for Lykos Therapeutics (formerly MAPS PBC); and is the PI of investigator-initiated trials funded by the Steven and Alexandra Cohen Foundation. Dr. Woolley has consulted for Alex Shulgin Research Institute, Arcadia Medicine, and Magdelana Health; and is the PI on an investigator-initiated trial supported by Filament Health. The other authors report no financial relationships with commercial interests.

Purpose: The Environmental influences on Child Health Outcomes (ECHO) Cohort has enrolled over 60,000 children to examine how early environmental factors (broadly defined) are associated with key child health outcomes. The ECHO Cohort may be well-positioned to contribute to our understanding of rural environments and contexts, which has implications for rural health disparities research. The present study examined the outcome of child obesity to not only illustrate the suitability of ECHO Cohort data for these purposes but also determine how various definitions of rural and urban populations impact the presentation of findings and their interpretation., Methods: This analysis uses data from children in the ECHO Cohort study who had residential address information between January 2010 and October 2023, including a subset who also had height and weight data. Several rural-urban classification schemes were examined with and without collapsing into binary rural/urban groupings (ie, the Rural-Urban Continuum Codes, 2010 Rural-Urban Commuting Area [RUCA] Codes, and Urban Influence Codes)., Findings: Various rural/urban definitions and classification schemes produce similar obesity prevalence (17%) when collapsed into binary categories (rural vs urban) and for urban participants in general. When all categories within a classification scheme are examined, however, the rural child obesity prevalence ranges from 5.8% to 24%., Conclusions: Collapsing rural-urban classification schemes into binary groupings erases nuance and context needed for interpreting findings, ultimately impacting health disparities research. Future work should leverage both individual- and community-level datasets to provide context, and all categories of classification schemes should be used when examining rural populations., (© 2024 National Rural Health Association.)

Deciphering the connectome, the ensemble of synaptic connections that underlie brain function, is a central goal of neuroscience research. Here we report the in vivo mapping of connections between presynaptic and postsynaptic partners in zebrafish, by adapting the trans-Tango genetic approach that was first developed for anterograde transsynaptic tracing in Drosophila. Neural connections were visualized between synaptic partners in larval retina, brain and spinal cord and followed over development. The specificity of labeling was corroborated by functional experiments in which optogenetic activation of presynaptic spinal cord interneurons elicited responses in known motor neuronal postsynaptic targets, as measured by trans-Tango-dependent expression of a genetically encoded calcium indicator or by electrophysiology. Transsynaptic signaling through trans-Tango reveals synaptic connections in the zebrafish nervous system, providing a valuable in vivo tool to monitor and interrogate neural circuits over time., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Children with HIV (CWH) are at increased risk for cognitive and developmental delays, although HIV's influence on reading development remains unclear. Research using internationally validated reading measures with control for factors known to influence literacy outcomes is needed. The Early Grade Reading Assessment (EGRA) is a tool for assessing students' progress toward reading that has been validated across countries. It was administered to a cohort of children living with and without HIV (CWH/CWOH) and data on other factors that might affect literacy were also measured., Design and Methods: 388 children [217 children without HIV (CWOH) and 171 CWH; ages 3-8] drawn from a longitudinal study in Dar es Salaam, Tanzania completed the EGRA. EGRA performance between CWH and CWOH was compared adjusting for age, socioeconomic status, years of education, English learning, and type of school (public or private)., Results: Despite the biological and environmental confounders, CWH performed significantly worse than CWOH on the Letter Name Knowledge subtest, the Syllable subtest, the Non-Word subtest, and the Reading Comprehension subtest. The difference approached significance for the Oral Reading Fluency subtest., Conclusions: CWH performed worse than CWOH on the EGRA, indicating literacy skill development in CWH needs early intervention. Longitudinal analyses, including electrophysiological and behavioral data, are needed to find the factors associated with poor reading and literacy performance in CWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Physician turnover rates are rising in the United States. The cancer workforce, which relies heavily on clinical teamwork and care coordination, may be more greatly impacted by turnover. In this study, we aimed to characterize oncologists who move to identify targets for recruitment and retention efforts., Methods: We identified medical, radiation, and surgical oncologists who treated Medicare beneficiaries diagnosed with breast, colorectal, or lung cancer in 2016-2019. We used multivariable logistic regression to identify physician-level and multivariable multinomial regression to identify region-level characteristics associated with turnover. Measures included demographic, practice, and patient-sharing network characteristics., Results: Our cohort included 25,012 medical, radiation, and surgical oncologists, of which, 1448 (5.8%) moved. Women [vs men; odds ratio (OR): 1.46; 95% CI: 1.30-1.64] and surgeons (vs medical oncologists; OR: 1.17; 95% CI; 1.04-1.33) had higher odds of moving. Compared with oncologists with moderate patient-sharing ties, those with many ties had lower odds of moving (OR: 0.55; 95% CI: 0.43-0.70). Patient-sharing networks with low efficiency (vs moderate) were more likely to have a net loss in their oncology workforce (OR: 3.06; 95% CI: 1.12-8.35), whereas those with low specialist vulnerability (vs moderate) were less likely to have a net loss (OR: 0.32; 95% CI: 0.1-0.99)., Conclusions: This study identified novel patient-sharing network characteristics associated with turnover, providing new insights into how the structural features of patient-sharing networks may be related to the recruitment and retention of oncologists., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Omalizumab was recently approved by the US Food and Drug Administration for treatment of any single food allergy or multiple food allergies in children aged 1 year and older and adults. There is currently no formal guidance regarding recommended best practices for omalizumab use in food allergy, including patient selection, anticipated goals and outcomes of therapy, procedure for monitoring patients who elect to start omalizumab therapy, and ways in which omalizumab can be incorporated into the landscape of food allergy management and daily clinical practice. This work group report was developed by the food allergy therapies subcommittee of the Adverse Reactions to Foods Committee within the American Academy of Allergy, Asthma & Immunology. Consensus, evidence-based guidance regarding experts' recommendations for using omalizumab to treat children and adults with food allergy was developed by using modified Delphi methodology. In iterative fashion, a total of 8 statements regarding how to use omalizumab to treat patients with food allergy were developed by 16 clinical experts. This guidance provides the clinician with a suggested approach to patient selection, initiation of therapy, monitoring of efficacy, and long-term follow-up care. The role of preference-sensitive care is emphasized, with most statements offering care recommendations relevant to the culture and values of a particular practice setting., Competing Interests: Disclosure statement Disclosure of potential conflict of interest: A. Anagnostou reports institutional funding from Novartis; advisory board service for of Genentech, Novartis, Bryn, and Ready, Set, Food!; and consultation/speaker fees from ALK, Adelphi, Bryn, Novartis, Genentech, Medscape, Food Allergy Research and Education (FARE), MHJ, and EPG Health. J. A. Bird reports consultancy for Allergenis, DBV Technologies, FARE, Genentech, Hanimmune Therapeutics, HAL Allergy, Infinant Health, Novartis, Nutricia, and Parexel, as well as research for Aimmune, DBV Technologies, Genentech, the National Institute of Allergy and Infectious Diseases (NIAID), Novartis, Regeneron, and Siolta. S. Chinthrajah receives grant support from the Consortium for Food Allergy Research (CoFAR), NIAID, and FARE and is an advisory board member for Alladapt, Novartis, Allergenis, IgGenix, Intrommune Therapeutics, Phylaxis, and Genentech. T. E. Dribbin has received funding and is supported by NIH (K23 AI175525). D. M. Fleischer has received research support from ARS Pharmaceuticals and DBV Technologies; serves as an unpaid advisory board member for the Food Allergy and Anaphylaxis Connection Team and the National Peanut Board; receives royalties from UpToDate; and has received personal fees as a consultant to Aquestive, ARS Pharmaceuticals, Bryn Pharma, DBV Technologies, Genentech, and Nasus outside the submitted work. E. Kim reports grants to his institution from NIAID and FARE; personal fees from ALK, Ukko, Cellergy Pharma, DBV Technologies, Genentech, Hanimumme Therapeutics, Novartis, Phylaxis, Revolo Biotherapeutics; and safety review board service for Allergy Therapeutics. A. Nowak-Wegrzyn receives research support from NIAID, DBV Technologies, and Siolta Therapeutics; speaking fees from Nestle, Danone, Medscape, and Genentech; and royalties from UpToDate. In addition, A. Nowak-Wegrzyn serves as an associate editor for the Annals of Allergy, Asthma and Immunology; as director of the AAAAI board; and as chair of the medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association. M. S. Shaker is a member and cochair of the Joint Task Force on Practice Parameters, serves on the editorial board of The Journal of Allergy and Clinical Immunology: In Practice, is an associate editor of Annals of Allergy, Asthma & Immunology, and serves on the board of directors of the AAAAI (all views expressed are his own). W. Shreffler reports grants to his institution from NIAID, the Food Allergy Science Initiative, and FARE; contract research support to his institution from Genentech, DBV, Allergy Therapeutics, Aravax, Novartis; personal consulting fees from Aimmune, DBV, Novartis, ALK, Allergy Therapeutics, FARE; and royalty payments from UpToDate. S. Sicherer reports royalty payments from UpToDate and Johns Hopkins University Press; grants to his institution from tNIAID, FARE, and Pfizer; and personal fees from the AAAAI as deputy editor of the Journal of Allergy and Clinical Immunology: In Practice outside of the submitted work. B. P. Vickery reports grants from Alladapt, AstraZeneca, Genentech, NIAID, and Siolta; personal fees from Allergenis, Aravax, Reacta Biosciences, and Sanofi Regeneron; both grants and personal fees from Aimmune, DBV, FARE, Novartis, and Regeneron; and stock options from Moonlight Therapeutics outside the submitted work. J. Wang is a member of the Joint Task Force on Practice Parameters; receives research support from NIAID, Aimmune, DBV, and Siolta; and receives consultancy fees from ALK-Abelló, DBV, and Novartis. M. Greenhawt is a consultant for Aquestive; is a member of physician/medical advisory boards for DBV Technologies, Takeda, Griffols, Nutricia, Novartis, Aquestive, Allergy Therapeutics, AstraZeneca, ALK-Abelló, Bryn, Genentech, and Prota; is a speaker for Genentech; is an unpaid member of the scientific advisory council for the National Peanut Board and medical advisory board of the International Food Protein–Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; is the senior associate editor for the Annals of Allergy, Asthma, and Immunology; and is member of the Joint Taskforce on Allergy Practice Parameters. In addition, J. Wang has received honoraria for lectures from ImSci, Red Nucleus, Medscape, Paradigm Medical Communications, Kaplan, Food Allergy Research and Education, and multiple state and local allergy societies. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Supporting clinical teams to improve care for inpatients with palliative care needs and their carers is a known priority. Patient reported experience measures (PREMs) may assist in improvement work. Evidence about how to collect and feedback PREM data for this population and context is required., Aim: To determine the feasibility of implementing a brief, validated PREM, consideRATE and appraise its acceptability as perceived by inpatients with palliative care needs, their carers and clinicians., Design: A prospective study using: 1) PREM administration, screening log and field note completion; and; 2) a focus group with clinicians., Setting/participants: Eligible participants recruited from three wards (cancer care and internal medicine) of an Australian tertiary metropolitan hospital. Participants included patients screened to have palliative care needs (using the SPICT TM criteria), their carers and multidisciplinary clinicians (including clinical managers)., Results: Feasibility : A 71% response rate was achieved ( n  = 80 from 112 eligible patients approached). Mean screening time to inform eligible patients for PREM completion was 7.5 min. More than half of eligible participants ( n  = 47, 59%) opted for electronic completion of consideRATE and mean completion time was 6.12 min. A third of participants required assistance for PREM completion ( n  = 27, 34%). Score distribution varied across response options, albeit with a positive skew towards 'very good' and 'good'. Two thirds of respondents ( n  = 50, 62.5%) provided ⩾1 free-text response. Acceptability : Clinicians valued consideRATE data noting feedback needed to be: accessible, supported by free-text and responsive to local contexts., Conclusions: It is feasible to implement consideRATE for inpatients with palliative care needs. Clinicians note consideRATE data is acceptable in informing improvement foci., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Catherine H. Saunders reports copyright but no relevant financial interest in the consideRATE questions, the measure of serious illness care experience assessed in this study. All other authors declare that there is no conflict of interest.

Photoprotection remains the foundation of treatment for all dyschromias and cosmetic camouflage as it provides concealment of pigmentation until therapeutic agents are effective. Innovations in the treatment of dyschromias encompass topical, systemic, and procedural modalities., Competing Interests: Disclosures S.C. Taylor has served as a consultant, advisory board member and/or speaker for AbbVie, Arcutis, Armis Scientific, Avita, Beiersdorf, Biorez, Bristol-Myers Squibb, Cara Therapeutics, Dior, Eli Lilly, EPI Health, Evolus, Galderma, GloGetter, Hugel America, Incyte, Johnson & Johnson, L’Oreal USA, MedScape, MJH LifeSciences, Pfizer, Piction Health, Sanofi, Scientis US, UCB and Vichy Laboratoires. She has received royalties from McGraw-Hill. She has served as an investigator for Allergan, Concert Pharmaceuticals/Sun Pharma, Croma-Pharma GmbH, Eli Lilly, and Pfizer. All other authors have no financial disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2)., Methods: In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.6 or 6.0 mg, and dose flexibility is permitted. Participants (n = 726) in SYNCHRONIZE-1 (NCT06066515) have a baseline BMI ≥ 30 kg/m 2 or ≥27 kg/m 2 with at least one obesity-related complication but without T2D; participants (n = 755) in SYNCHRONIZE-2 (NCT06066528) have a baseline BMI ≥ 27 kg/m 2 and T2D. The primary endpoints are percentage change in body weight and proportion of participants achieving ≥5% body weight reduction from baseline to week 76. Secondary endpoints include change in systolic blood pressure and measures of glycemia. A SYNCHRONIZE-1 substudy is evaluating changes in body composition and liver fat content using magnetic resonance imaging., Conclusions: These trials are designed to provide robust evaluation of the efficacy, safety, and tolerability of survodutide for the treatment of obesity in the presence or absence of T2D., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Successful cecal intubation is crucial in ensuring a complete evaluation of the colonic mucosa. Although completion of colonoscopies should be successful in close to 100% of all examinations in the hands of experienced gastroenterologists, there are some patients with colons which can be difficult to navigate. Factors such as older age, presence of diverticular disease, as well as high or low body mass index can present challenges for endoscopists. Challenges can be divided into those that are left sided and are associated with severe angulations of the colon versus those that are right sided and present as redundant colons. Both require different strategies to achieve completion. This review will cover methods, technologies as well the evolution of colonoscope insertion tubes which can help in navigating colons, especially those that are challenging. There will also be a discussion about basic principles and techniques that should be employed in all colonoscopies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: In recent years, concern has grown around the overdetection of thyroid cancer. Changes to thyroid nodule risk stratification systems and guidelines were made to improve diagnostic yield. It is not known how these advancements have affected the size of thyroid nodules reported on ultrasonography over time., Objective: To evaluate change in reported nodule size since 1990, particularly between studies of thyroid ultrasonography obtained for diagnostic vs screening purposes., Study Selection: The systematic review included original research studies that reported thyroid nodule size in adults undergoing their first thyroid ultrasonography. Excluded studies were those that included patients with known thyroid disease, prior thyroid ultrasonography, nodules identified through other imaging modalities, and/or that had constraints on nodule size and/or characteristics., Data Sources: PubMed, SCOPUS, CENTRAL, and CINAHL were reviewed from January 1990 to March 2021. Study characteristics, patient demographic characteristics, nodule size, and ultrasonography techniques were independently extracted by multiple observers., Main Outcomes and Measures: The size of thyroid nodules reported via ultrasonography over time. Mixed-effects meta-regression models were used to evaluate mean nodule size (1) overall, (2) in studies that used ultrasonography diagnostically, and (3) in studies that used ultrasonography for screening., Results: A total of 11 963 patients were included; the mean (SD) age was 47.6 (5.2) years. A total of 1097 studies were identified; of these, 395 full-text articles were assessed, and 18 studies met inclusion criteria. All were done at academic institutions. Altogether, these studies had 11 963 patients who underwent a first thyroid ultrasonography. Reported mean nodule size increased 0.52 mm each year from 1990 to 2021 (95% CI, 0.2-0.81). Diagnostic subgroup mean nodule size increased 0.57 mm each year from 1990 to 2021 (95% CI, 0.21-0.93). Screening subgroup mean nodule size decreased by 0.23 mm each year up to 2012 (95% CI, -0.40 to -0.07)., Conclusions: The results of this systematic review and meta-analysis suggest that thyroid nodule size reported on diagnostic ultrasonography has increased over time in conjunction with changes in risk stratification systems, nodule guidelines, and radiology practice patterns. Conversely, a decrease in size reported in asymptomatic, ultrasonography-screened populations was observed. Findings from screening studies show that subcentimeter nodules are prevalent and easily identified with ultrasonography, but clinical relevance is questionable. Altogether, these results may provide insight into how ultrasonography guidelines and practice patterns have changed thyroid nodule reporting over time and can inform future guidelines and policies associated with thyroid nodule management.

Background: Cigarette smoking adversely affects fracture repair, causing delayed healing or nonunion rates twice those seen in nonsmokers., Purpose: We sought to investigate if cigarette smoke differentially affects intramembranous and endochondral healing of fractures. We hypothesize that healing via endochondral ossification will be preferentially impaired compared to intramembranous ossification., Methods: We utilized a bilateral femur fracture model in Sprague Dawley rats to examine effects of cigarette smoke exposure on healing of femur fractures, treated with either locked intramedullary nail or compression plating to induce endochondral and membranous ossification, respectively. Animals were exposed to tobacco smoke 30 days before and after surgery; evaluations included radiographs, histomorphometry, and micro-CT at 10 days, 1, 3, and 6 months postoperation, and biomechanical testing at 3 and 6 months., Results: Sixty-eight animals were randomized to control or exposure (two died perioperatively); 89% of femora achieved union when harvested at 3 or 6 months. Smoke exposure delayed cartilaginous callus formation and bone maturation in nailed fractures compared to plated fractures and controls in the same animals. Plated fractures in exposed animals exhibited little cartilage callus and healed like control animals. At 3 months, plated fractures were stiffer and stronger than nailed fractures in both groups. These differences vanished by 6 months., Conclusions: Plated fractures healed more rapidly and completely than nailed fractures under both control and smoke-exposed conditions., Clinical Relevance: Using compression plating instead of IM nailing for closed long bone fractures may lead to better outcomes in patients who smoke compared to current results with nailing., (Copyright © 2025 by ASME.)

Background: Limited decision-support tools are available to help shared decision-making (SDM) regarding food oral immunotherapy (OIT) initiation. No current tool covers all foods, forms, and pediatric ages for which OIT is offered., Methods: In compliance with International Patient Decision Aid Standards criteria, this pediatric decision-aid comparing OIT versus avoidance was developed in three stages. Nested qualitative data assessing OIT decisional needs were supplemented with evidence-synthesis from the OIT literature to create the prototype decision-aid content. This underwent iterative development with food allergy experts and patient advocacy stakeholders until unanimous consensus was reached regarding content, bias, readability, and utility in making a choice. Lastly, the tool underwent validated assessment of decisional acceptability, decisional conflict, and decisional self-efficacy., Results: The decision-aid underwent 5 iterations, resulting in a 4-page written aid (Flesch-Kincaid reading level 6.1) explaining therapy choices, risks and benefits, providing self-rating for attribute importance for the options and self-assessment regarding how adequate the information was in decision-making. A total of n = 135 caregivers of food-allergic children assessed the decision-aid, noting good acceptability, high decisional self-efficacy (mean score 85.9/100) and low decisional conflict (mean score 20.9/100). Information content was rated adequate and sufficient, the therapy choices wording balanced, and presented without bias for a "best choice." Lower decisional conflict was associated with caregiver-reported anaphylaxis., Conclusions: This first pediatric OIT decision-aid, agnostic to product, allergen, and age has good acceptability, limited bias, and is associated with low decisional conflict and high decisional self-efficacy. It supports SDM in navigating the decision to start OIT or continue allergen avoidance., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Food allergy management has greatly evolved in the last several years, moving from passive approaches, such as strict food allergen avoidance, to more active treatments, including regulatory approval of the first specifically indicated immunotherapy product (for peanut) in 2020. In 2024, a second therapy, omalizumab, received regulatory approval for the treatment of 1 or more IgE-mediated food allergies, providing clinicians with multiple treatment options to offer patients and families. With this expanded armamentarium of food allergy treatment options, the practicing clinician requires detailed knowledge of benefits and risks of omalizumab, how omalizumab fits into the management landscape, and how to use shared decision-making to optimize therapy. This yardstick aims to provide the clinician with a review of data leading to omalizumab's food allergy indication and an evidence-based expert opinion approach regarding on how best to use this and other therapies available to optimize patient management., Competing Interests: Disclosures Dr Anagnostou reports receiving institutional funding from Novartis; serving as advisory board member of Genentech, Novartis, Bryn, and Ready. Set. Food!; and receiving consultation/speaker fees from ALK, Adelphi, Novartis, Genentech, Medscape, FARE, MHJ, and EPG Health. Dr Greenhawt is a consultant for Aquestive; is a member of physician/medical advisory boards for DBV Technologies, Takeda, Griffols, Nutricia, Novartis, Aquestive, Allergy Therapeutics, AstraZeneca, ALK-Abello, Bryn, Genentech, and Prota; is a speaker for Genentech; is an unpaid member of the scientific advisory council for the National Peanut Board and medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; is the senior associate editor for the Annals of Allergy, Asthma & Immunology; and is member of the Joint Taskforce on Allergy Practice Parameters. He has received honorarium for lectures from ImSci, Red Nucleus, Medscape, Paradigm Medical Communications, Kaplan, Food Allergy Research and Education, and multiple state/local allergy societies. Dr Shaker is a member and co-chair of the Joint Task Force on Practice Parameters, serves on the editorial board of The Journal of Allergy and Clinical Immunology In Practice, is an associate editor of Annals of Allergy, Asthma & Immunology, and serves on the board of directors of the American Academy of Allergy, Asthma & Immunology (views expressed are his own). Dr Vickery reports receiving grants from Alladapt, AstraZeneca, Genentech, National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), and Siolta; personal fees from Allergenis, Aravax, Reacta Biosciences, and Sanofi Regeneron; both grants and personal fees from Aimmune, DBV, FARE, Novartis, and Regeneron; and stock options from Moonlight Therapeutics outside the submitted work. Dr Wang is a member of the Joint Task Force on Practice Parameters; receives research support from NIAID, Aimmune, DBV, and Siolta; and receives consultancy fees from ALK-Abello, DBV, and Novartis., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate potential demographic bias in artificial intelligence (AI)-based simulations of otolaryngology, residency selection committee (RSC) members tasked with selecting one applicant among candidates with varied racial, gender, and sexual orientations., Methods: This study employed random sampling of simulated RSC member decisions using a novel Application Programming Interface (API) to virtually connect to OpenAI's Generative Pre-Trained Transformers (GPT-4 and GPT-4o). Simulated RSC members with diverse demographics were tasked with ranking to match 1 applicant among 10 with varied racial, gender, and sexual orientations. All applicants had identical qualifications; only demographics of the applicants and RSC members were varied for each simulation. Each RSC simulation ran 1000 times. Chi-square tests analyzed differences across categorical variables. GPT-4o simulations additionally requested a rationale for each decision., Results: Simulated RSCs consistently showed racial, gender, and sexual orientation bias. Most applicant pairwise comparisons showed statistical significance (p < 0.05). White and Black RSCs exhibited greatest preference for applicants sharing their own demographic characteristics, favoring White and Black female applicants, respectively, over others (all pairwise p < 0.001). Asian male applicants consistently received lowest selection rates. Male RSCs favored White male and female applicants, while female RSCs preferred LGBTQIA+, White and Black female applicants (all p < 0.05). High socioeconomic status (SES) RSCs favored White female and LGBTQIA+ applicants, while low SES RSCs favored Black female and LGBTQIA+ applicants over others (all p < 0.001). Results from the newest iteration of the LLM, ChatGPT-4o, indicated evolved selection preferences favoring Black female and LGBTQIA+ applicants across all RSCs, with the rationale of prioritizing inclusivity given in >95% of such decisions., Conclusion: Utilizing publicly available LLMs to aid in otolaryngology residency selection may introduce significant racial, gender, and sexual orientation bias. Potential for significant and evolving LLM bias should be appreciated and minimized to promote a diverse and representative field of future otolaryngologists in alignment with current workforce data., Level of Evidence: NA Laryngoscope, 135:87-93, 2025., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To explore the feasibility and utility of a tolerance break (T-Break) guide on young adults' cannabis use. Participants: Young adults aged 18-29 (n = 125) who were current cannabis users. Methods: Participants recruited through posters and listservs at various universities were offered the T-Break Guide-daily activities, advice, and encouragement-to help complete a 21-day cannabis break. Bivariate analyses examined associations between Guide use and follow-up measures. Results: Compared to non-Guide users, participants who used the Guide "a lot" were more likely to complete the 21-day abstinence break (84% vs. 57%), revise their personal definition of balance to mean less cannabis (84% vs. 62%), and plan a future break (32% vs. 11%). Conclusion: Use of this self-directed T-Break Guide may help young adults take a break from cannabis use and reduce future use. Further research using more rigorous designs to test the Guide's efficacy and assess longer-term maintenance of effects is needed.

Purpose: To describe the efficacy of belzutifan as a treatment for juxtapapillary retinal hemangioblastomas in patients with von Hippel-Lindau disease. Methods: A case and its findings were analyzed, and a systematic literature review was conducted using PubMed and Ovid MEDLINE. Results: At a routine follow-up, a 63-year-old woman with a history of von Hippel-Lindau disease and slowly progressive bilateral juxtapapillary retinal hemangioblastomas presented with decreased visual acuity (VA) in the right eye resulting from significant lesion growth and an increase in central macular edema and exudate. Oral belzutifan therapy was initiated. A significant bilateral regression and decrease in tumor size, improved macular thickening and edema, and improved VA were seen over a 6-month period. Conclusions: The current literature on the therapeutic effects of oral belzutifan is limited; however, recent reports have been promising. This case shows the potential efficacy of belzutifan as a first-line treatment for vision-threatening juxtapapillary retinal hemangioblastomas in patients with von Hippel-Lindau disease., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood., Methods: The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains., Results: RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2)., Conclusions: These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Teaching and learning of clinical reasoning are core principles of medical education. However, little guidance exists for faculty leaders to navigate curricular transitions between pre-clerkship and clerkship curricular phases. This study compares how educational leaders in these two phases understand clinical reasoning instruction. Previously reported cross-sectional surveys of pre-clerkship clinical skills course directors, and clerkship leaders were compared. Comparisons focused on perceived importance of a number of core clinical reasoning concepts, barriers to clinical reasoning instruction, level of familiarity across the undergraduate medical curriculum, and inclusion of clinical reasoning instruction in each area of the curriculum. Analyses were performed using the Mann Whitney U test. Both sets of leaders rated lack of curricular time as the largest barrier to teaching clinical reasoning. Clerkship leaders also noted a lack of faculty with skills to teach clinical reasoning concepts as a significant barrier ( p  < 0.02), while pre-clerkship leaders were more likely to perceive that these concepts were too advanced for their students ( p  < 0.001). Pre-clerkship leaders reported a higher level of familiarity with the clerkship curriculum than clerkship leaders reported of the pre-clerkship curriculum ( p  < 0.001). As faculty transition students from the pre-clerkship to the clerkship phase, a shared understanding of what is taught and when, accompanied by successful faculty development, may aid the development of longitudinal, milestone-based clinical reasoning instruction.

Artificial intelligence (AI) is rapidly being introduced into the clinical workflow of many specialties. Despite the need to train physicians who understand the utility and implications of AI and mitigate a growing skills gap, no established consensus exists on how to best introduce AI concepts to medical students during preclinical training. This study examined the effectiveness of a pilot Digital Health Scholars (DHS) non-credit enrichment elective that paralleled the Dartmouth Geisel School of Medicine's first-year preclinical curriculum with a focus on introducing AI algorithms and their applications in the concurrently occurring systems-blocks. From September 2022 to March 2023, ten self-selected first-year students enrolled in the elective curriculum run in parallel with four existing curricular blocks (Immunology, Hematology, Cardiology, and Pulmonology). Each DHS block consisted of a journal club, a live-coding demonstration, and an integration session led by a researcher in that field. Students' confidence in explaining the content objectives (high-level knowledge, implications, and limitations of AI) was measured before and after each block and compared using Mann-Whitney U tests. Students reported significant increases in confidence in describing the content objectives after all four blocks (Immunology: U  = 4.5, p  = 0.030; Hematology: U  = 1.0, p  = 0.009; Cardiology: U  = 4.0, p  = 0.019; Pulmonology: U  = 4.0, p  = 0.030) as well as an average overall satisfaction level of 4.29/5 in rating the curriculum content. Our study demonstrates that a digital health enrichment elective that runs in parallel to an institution's preclinical curriculum and embeds AI concepts into relevant clinical topics can enhance students' confidence in describing the content objectives that pertain to high-level algorithmic understanding, implications, and limitations of the studied models. Building on this elective curricular design, further studies with a larger enrollment can help determine the most effective approach in preparing future physicians for the AI-enhanced clinical workflow.

Background: Although total hip and total knee arthroplasty are highly successful operations, the decision of whether and when to undergo surgery is highly subjective and discretionary, and specific guidelines regarding readiness for surgery remain elusive. The nature of these decisions underscores the importance of shared decision-making, which is founded on the concept that patients substantially contribute to determining their own readiness for surgery. The OPTION survey was developed as a conversation aid to facilitate shared decision-making in the context of total joint arthroplasty., Methods: The OPTION survey was created in partnership with a panel of 10 active joint replacement patients and 15 arthroplasty surgeons, using a modified Delphi methodology that employed 3 sequential meetings by each group. The survey interrogates patient and surgeon ratings of pain, activity limitation, duration of treatment, prior treatments, and quality of life; patient-rated treatment priorities, readiness for surgery, and surgeon engagement; and surgeon-graded radiographic disease. The survey was administered as an institutional review board-approved pilot during 641 patient-clinician encounters for hip or knee arthritis at 9 U.S. sites, and was independently completed by the patient and surgeon., Results: Patient self-assessment of readiness for surgery includes consideration of existing functional impairment, outcome priorities, realistic expectations, and personal socioeconomic circumstances. Patients most commonly ranked removal of activity limitations as their top treatment priority, while alleviation of pain and avoidance of a long recovery were also ranked highly. Mild and severe pain were associated with similar radiographic disease severity, and worsening radiographic disease was associated with increasing patient-reported readiness for surgery. Patients and surgeons agreed on symptom severity in >90% of cases. When disagreement occurred, surgeons typically underestimated patient-reported symptoms; these cases were associated with lower patient-rated surgeon engagement in shared decision-making conversations., Conclusions: Shared decision-making conversations substantially contributed to the assessment of patient readiness for joint replacement surgery. When patient and surgeon assessments were not aligned, surgeons most commonly underestimated patient-perceived impairment. These observations should inform optimal surgeon-patient communications., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: No external funding was received for this work. However, several of the patients participating in this work were members of the Patient Advisory Board of the PEPPER Trial, funded by PCORI. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I350)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, targeted therapies, immunotherapies, antibody-drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor-stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor's histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly targeted therapies. For studying immunotherapies and antibody-drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer.

Introduction: Little is known about the factors associated with care-resistant behavior in community-dwelling persons living with dementia., Methods: Regression modeling was performed on 41,143 responses to a standardized questionnaire from the National Alzheimer's Coordinating Center's Uniform Data Set., Results: In the fully adjusted mixed-effects regression model, collinearity was low, with no variance inflation factor above 1.15. Moderate (adjusted odds ratio [aOR] = 1.59; 95% confidence interval [CI]: 1.50, 1.69) and severe (aOR = 1.95; 95% CI: 1.82, 2.09) dementia severity; and Black (aOR = 1.64; 95% CI: 1.47, 1.82), Hispanic ethnicity (aOR 1.13; 95% CI: 1.00, 1.28), frontotemporal (aOR 1.29; 95% CI: 1.12, 1.49) and Lewy body dementia (aOR 1.15; 95% CI: 1.02, 1.29) diagnosis type were associated with a higher odds of care-resistant behavior. Female sex (aOR 0.85; 95% CI: 0.80, 0.91) and higher education (aOR 0.9, 95% CI: 0.84, 0.97) were associated with lower odds of care-resistant behavior., Discussion: Interventions to manage care-resistant behaviors should consider sociocultural factors as well as type of dementia diagnosis to limit caregiver strain and burden., Highlights: Frontotemporal dementia, Lewy body dementia, and Black race were associated with a higher likelihood of exhibiting care-resistant behavior. Female sex and higher educational attainment were associated with a lower likelihood of exhibiting care-resistant behavior. Differences in specific presentations of care-resistant behaviors are less understood., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Explore the tip-of-the-tongue (TOT) scores from the Children's Auditory and Visual Naming Tests (cANT, cVNT) as embedded validity indicators (EVIs)., Method: A retrospective design of 98 consecutively referred youth aged 6-15 years (M = 11.28, SD = 2.80) that completed neuropsychological evaluation at a tertiary-care academic medical center., Results: Invalid performance (i.e., ≥2 failed PVTs) occurred in 12.2% of the sample, with base rates of failure on individual PVTs ranging from 1.0% to 30.6%. Area under the curve (AUC) showed statistical significance for the auditory (AUC = 0.811, p = .004) but not the visual TOT. Logistic regression indicated the combination of both TOT scores with other PVTs increased correct identification of invalid performance to 85.7% versus 75% without TOT scores., Conclusion: The utility of the TOT as a language-based EVI is one of many potential advantages of the cANT and cVNT compared to other confrontation naming tests. To confirm this, future studies with more diverse populations are warranted., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Inborn Errors of Immunity are a rapidly expanding group of monogenetic disorders affecting the immune system. Advancements in genetic testing and functional validation studies have accelerated the pace of IEI gene discovery and mechanism of disease, particularly in the past five years. To keep up with this rapid expansion, the International Union of Immunological Societies (IUIS) Expert Committee has periodically, since 1999, released updated IEI classifications with corresponding genotypic and phenotypic catalogues with its most recent update in 2022.1-5 Now there are over 485 monogenetic disorders of the immune system described among 10 main groups of classification. This article reviews recent clinical developments in IEI, including a closer look at some of the more recently described IEI disorders. In particular we highlight a few disorders with the following clinical phenotypes of IEI: severe atopy, immunodeficiency with immune dysregulation, immune dysregulation with lymphoproliferation, autoinflammation, and innate phenotype. To aid the clinician, we also provide a diagnostic approach to use when there is suspicion of IEI and a discussion of management and treatment., (Copyright © 2024. Published by Elsevier Inc.)

Background: Frailty, a syndrome of decreased resilience to physiologic stress, has been associated with increased postoperative length of stay (LOS) for specific procedures. Yet, the literature lacks large-scale analyses examining the relationship between frailty and LOS across surgical procedure., Study Design: We conducted a retrospective cohort study of patients aged 65+ undergoing inpatient surgery including emergency procedures between 2015 and 2019 using American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP®) data. Frailty, measured by the modified 5-item frailty index (mFI-5), was categorized as non-frail (mFI-5 < 2) or frail (mFI-5 ≥ 2). We modeled LOS, adjusting for demographic variables, comorbidities, and surgical factors, and conducted a subgroup analysis based on emergency surgery status and surgical procedure type., Main Results: Among 1,254,809 patients, 29.0 % were frail. A higher proportion of frail patients were Black (10 % vs. 5.5 %), Hispanic (6.1 % vs. 3.8 %), of ASA class IV/V (23.3 % vs. 9.1 %), malnourished (2.7 % vs. 1.9 %), and underwent vascular surgery (16.5 % vs. 8.3 %). They experienced longer median LOS across all surgical procedures, except bariatric surgery. Unadjusted analysis revealed that mFI-5 scores of 4 and 5 were associated with increased median LOS by 3.5 days (95 % CI 3.36-3.64) and 4.64 days (95 % CI 3.96-5.32), respectively, compared to mFI-5 scores of 0. In adjusted analysis, frailty remained a significant risk factor for increased median LOS, with an mFI-5 score of 5 associated with a 3-day longer increase (95 % CI 2.79-3.22) compared to an mFI-5 score of 0. Subgroup analysis showed that each one-point increase in mFI-5 score had the strongest association with increased median LOS in emergency surgery (0.5 days, 95 % CI 0.48-0.52) and lower extremity bypass surgery (0.53 days, 95 % CI 0.47-0.59)., Conclusions: Frailty is an independent risk factor for prolonged postoperative LOS among older surgical patients, even after adjustment for patient and procedure covariates. Other independent risk factors for increased LOS include emergent surgery, malnutrition, and higher ASA class., Competing Interests: Declaration of competing interest Stacie G. Deiner reports financial support was provided by the LeRoy Garth Endowment from the Geisel School of Medicine and the Dartmouth Hitchcock Medical Center Department of Anesthesiology. Stacie G. Deiner reports a relationship with The American Board of Anesthesiology that includes: board membership, any views expressed in this manuscript are her own and not necessarily those of the American Board of Anesthesiology. Co-author has served as an expert witness - S.G.D. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Drosophila and its parasitoids provide an ecologically relevant model for studying host-parasitoid biology, focusing on the behavioral and physiological responses involved in host defensive strategies and parasitoid countermeasures. Here, we outline a protocol for rearing Pachycrepoideus, a pupal parasitoid wasp, and a behavioral assay to assess the long-term impact of parasitoid exposure on adult Drosophila. We detail the steps for preparing and cohabiting Drosophila with the wasps, documenting egg-laying, and analyzing reproductive responses and eclosion in fruit flies. For complete details on the use and execution of this protocol, please refer to Sadanandappa et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The current FDA paradigm may not fully capture important patient-centered outcomes or measure a primary outcome that is truly meaningful to patients. Patient reported outcome measures (PROMs) are standardized tools measuring the patient's experience in food allergy clinical trials, which can help support shared decision-making (SDM) and further our understanding of treatment impact. Food allergy PROMs include quality of life (QoL), health state utility (HSU), severity, and self-efficacy measures. Currently, FDA registration trials for product approval only consider a fixed increase in allergen threshold from pre-to-post intervention as a primary outcome (vs. a more flexible "X-fold" increase not accounting for an upper and lower specific threshold), though many use QoL as a secondary outcome for patient-centered assessment of treatment impact. Currently used QoL PROMs were not designed to measure change on therapy nor measure HSU (e.g., quantitative risk a patient may be willing to take to improve their current health), which can be used to determine therapy value. While the current paradigm for primary and secondary outcomes in food allergy clinical trials was appropriate at the early stages of food allergy therapy development when conceived in the late 2000's and early 2010's, in the 2020's these outcome choices risk being stagnant and outdated. As such, the current paradigm for food allergy outcomes should evolve to incorporate more patient-centered primary outcome measures which patient data indicate are meaningful, so outcomes more realistically reflect a therapy's impact. This evolution will better support SDM discussions as patients consider their therapy options and can inform new product development., (Copyright © 2024. Published by Elsevier Inc.)

Background: Participation and inclusion of service users in health governance impact the quality of care and citizen well-being. In developing countries, such as Kosovo, disadvantaged groups are particularly important due to deep exclusionary structures and multiple systemic barriers to participation and care provision., Purpose: To investigate the effects of three interventions on social participation in decision-making in several primary healthcare sites among the population and particularly vulnerable groups, i.e. ethnic minorities of Roma, Ashkali, and Egyptian backgrounds, elderly citizens, and people with disabilities., Methods: This study uses the consolidated framework of social participation and adapts it to Kosovo's primary healthcare context. We analysed the degrees of inclusiveness, intensity, and influence across three interventions, i.e., social participation mechanisms implemented in four municipalities and related primary care networks in Kosovo. We applied an embedded multiple-case study design relying on qualitative data collection., Results: Degrees of social participation within each case study ranged from low to moderate. Patient councils serve as representative mechanisms to consider patient complaints with an informative and liaising role. The community scorecard mechanism involves community representatives in decision-making processes, with varying levels of inclusiveness and participation intensity, effectively voicing their preferences and demands. The municipal health action plans process exhibits varying inclusiveness levels where community representatives wield decision-making influence., Conclusion: The participation mechanisms examined in this study could sustain moderate social participation across inclusiveness, intensity, influence and impact domains. These shared platforms between service users and providers produce the most meaningful influence. The use of these mechanisms has a promise of increasing social participation in primary care settings in Kosovo., Competing Interests: Declarations. Ethics approval and consent to participate: This study was granted ethical approval by the Medical Chamber in Kosovo (Ref. No. 43/2023]. The study adhered to principles of the Declaration of Helsinki, and the Law Nr. 04/L-135 on Scientific Research Activities in Kosova. Informed consent to participate was obtained from all participants prior to their involvement in the research. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Gene expression is regulated by controlling distinct steps of the transcriptional cycle, including initiation, pausing, elongation, and termination. Kinases phosphorylate RNA polymerase II (RNA Pol II) and associated factors to control transitions between these steps and to act as central gene regulatory nodes. Similarly, phosphatases that dephosphorylate these components are emerging as important regulators of transcription, although their roles remain less well understood. Here, we discover that the mouse PNUTS-PP1 phosphatase complex plays an essential role in controlling transcription pause release in addition to its previously described function in transcription termination. Transcription pause release by the PNUTS complex is essential for almost all RNA Pol II-dependent gene transcription, relies on its PP1 phosphatase subunit, and controls the phosphorylation of factors required for pause release and elongation. Together, these observations reveal an essential new role for a phosphatase complex in transcription pause release and show that the PNUTS complex is essential for RNA Pol II-dependent transcription., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Circadian rhythms are ∼24-h biological oscillations that enable organisms to anticipate daily environmental cycles, so that they may designate appropriate day/night functions that align with these changes. The molecular clock in animals and fungi consists of a transcription-translation feedback loop, the plant clock is comprised of multiple interlocking feedback-loops, and the cyanobacterial clock is driven by a phosphorylation cycle involving three main proteins. Despite the divergent core clock mechanisms across these systems, all circadian clocks are able to buffer period length against changes in the ambient growth environment, such as temperature and nutrients. This defining capability, termed compensation, is critical to proper timekeeping, yet the underlying mechanism(s) remain elusive. Here we examine the known players in, and the current models for, compensation across five circadian systems. While compensation models across these systems are not yet unified, common themes exist across them, including regulation via temperature-dependent changes in post-translational modifications., (© 2024 Wiley Periodicals LLC.)

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest form is provided with the online version of the article (http://links.lww.com/JBJS/I263).