Sleepiness in retired male boxers: daytime sleepiness and its relationship with impulsiveness and depression symptomatology in retired professional male boxers.

BACKGROUND: Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. METHODS: 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. RESULTS: Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77-1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11-1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. CONCLUSIONS: EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression).Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Identifying Effective Strategies for Improving Engagement in HIV Prevention and Care Among Transgender Persons in the United States: A Systematic Review.

This systematic review synthesized published literature (2000 - 2023) to identify HIV interventions specifically designed for transgender persons in the United States (PROSPERO registration number: CRD42021256460). The review also summarized strategies for improving outcomes related to the four pillars of the Ending the HIV Epidemic (EHE) initiative in the United States: Diagnose, Treat, Prevent, and Respond. A comprehensive search was conducted using the Centers for Disease Control and Prevention's HIV Prevention Research Synthesis Project database, which included over 120,000 citations from routine systematic searches in CINAHL, EMBASE, Global Health, MEDLINE, PsycInfo, and Sociological Abstracts. Of 23 interventions that met inclusion criteria, 94% focused on transgender women of color and 22% focused on young transgender persons aged 15-29 years old. Most interventions focused on Treat or Prevent, few focused on Diagnosis, and none focused on Respond. Twenty interventions (87%) showed improvement in at least one EHE related outcome and a quarter of these effective interventions were tested with randomized controlled trials. Common strategies observed in effective interventions include the following: engaging the community in intervention development; pilot-testing with the focus population to ensure appropriateness and acceptability; addressing social determinants of health (e.g. stigma, discrimination, violence) through empowerment and gender-affirming approaches; increasing access to care, prevention, and services through co-location and one-stop shop models; and utilizing peer-led counseling, education, support, and navigation. Continuous effort is needed in addressing gaps, including more research for transgender men and rural settings and for how best to adopt and adapt best practices for subgroups of transgender population.

RESUMEN: Esta revisión sistemática sintetizó la literatura publicada (2000 ­ 2023) para identificar intervenciones relacionadas con el VIH diseñadas específicamente para personas transgénero en los Estados Unidos y resumió las estrategias para mejorar los resultados relacionados con los cuatro pilares de la iniciativa Poner fin a la Epidemia del VIH (EHE por sus siglas en inglés). Diagnosticar, Tratar, Prevenir y Responder. Este protocolo de estudio se registró en PROSPERO (CRD42022364101). Se realizó una búsqueda exhaustiva utilizando la base de datos del Proyecto de Síntesis de Investigación sobre Prevención del VIH de los Centros para el Control y la Prevención de Enfermedades, que incluyó más de 120.000 citas de búsquedas sistemáticas de rutina en CINAHL, EMBASE, Global Health, MEDLINE, PsycInfo y Sociological Abstracts. De las 23 intervenciones que cumplieron con los criterios de inclusión, el 94% se centró en mujeres transgénero de color y el 22% se centró en personas transgénero jóvenes de entre 15 y 29 años. La mayoría de las intervenciones se centraron en los pilares Tratar o Prevenir, pocas se centraron en el pilar de Diagnóstico y ninguna se centró en el pilar de Responder. Veinte intervenciones (87%) mostraron una mejora en al menos un resultado relacionado con la EHE; una cuarta parte de estas intervenciones efectivas se probaron con ensayos controlados aleatorios. Las intervenciones efectivas en todos los pilares compartían características comunes, como la participación de la comunidad en el desarrollo de la intervención; la realización de pruebas piloto con la población objetivo para garantizar la idoneidad y la aceptabilidad; el abordaje de los determinantes sociales de la salud (p.e., el estigma, la discriminación, la violencia, los problemas legales, la vulnerabilidad económica, la vivienda, el transporte, la alimentación) mediante enfoques de empoderamiento y afirmación de género; el aumento del acceso a la atención, la prevención y el servicio (p.e., Mediante la co-ubicación, y el sistema de ventanilla única); y el uso de asesoramiento, educación, apoyo y orientación dirigidos por pares. Se necesita un esfuerzo continuo para abordar las brechas, incluida una mayor investigación para los hombres transgénero y los entornos rurales y para determinar cuál es la mejor manera de adoptar y adaptar las mejores prácticas para los subgrupos de la población transgénero.

Executive Summary of the American Radium Society® (ARS) Appropriate Use Criteria (AUC) for Non-Small Cell Lung Cancer in a Central/Ultra-Central Location: Systematic Review and Guidelines.

INTRODUCTION: Definitive radiation therapy is considered standard therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). However, for patients with tumors located near to structures like the proximal tracheobronchial tree, esophagus, heart, spinal cord, and brachial plexus, the optimal management regimen is controversial. The objective was to develop expert multidisciplinary consensus guidelines on the management of medically inoperable NSCLC located in a central or ultra-central location relative to critical organs-at-risk. MATERIALS AND METHODS: Case variants regarding centrally and ultra-centrally located lung tumors were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel. A comprehensive review of the English medical literature was performed from 1/1/46 to 12/31/23 to inform consensus guidelines. Modified Delphi methodology was used by the panel to evaluate the variants and procedures, with ≤3 rating points from median defining agreement/consensus. The guideline was then approved by the ARS Executive Committee and released for public comment per established ARS procedures. RESULTS: The Thoracic ARS AUC Panel identified 90 relevant references and obtained consensus in all variants. Radiotherapy alone was considered appropriate, with additional immunotherapy to be considered primarily in the clinical trial setting. Hypofractionated radiotherapy in 8-18 fractions was considered appropriate for ultra-central lesions near proximal tracheobronchial tree, upper trachea, and esophagus. For other ultra-central lesions near heart, great vessels, brachial plexus, and spine, or for non-ultra-central but still central lesions, 5-fraction SBRT was also considered an appropriate option. Intensity-modulated radiotherapy was considered appropriate and 3D-conformal radiotherapy inappropriate for all variants. Other treatment planning techniques to decrease the risk of overdosing critical organs-at-risk were also considered. DISCUSSION: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of stage I NSCLC in a central or ultra-central location.

Progress Toward Achieving National HIV/AIDS Strategy Goals for Quality of Life Among Persons Aged ≥50 Years with Diagnosed HIV - Medical Monitoring Project, United States, 2017-2023.

Ensuring good quality of life (QoL) among persons with diagnosed HIV (PWH) is a priority of the National HIV/AIDS Strategy (NHAS), which established 2025 goals for improving QoL. Goals are monitored through five indicators: self-rated health, unmet needs for mental health services, unemployment, hunger or food insecurity, and unstable housing or homelessness. Among the growing population of PWH aged ≥50 years, progress toward these goals has not been assessed. Data collected during the 2017-2022 cycles of the Medical Monitoring Project, an annual complex sample survey of U.S. adults with diagnosed HIV, assessed progress toward NHAS 2025 QoL goals among PWH aged ≥50 years, overall and by age group. The recent estimated annual percentage change from baseline (2017 or 2018) to 2022 was calculated for each indicator. Among PWH aged ≥50 years, the 2025 goal of 95% PWH with good or better self-rated health is 46.2% higher than the 2022 estimate. The 2025 goals of a 50% reduction in the other indicators range from 26.3% to 56.3% lower than the 2022 estimates. Decreasing hunger or food insecurity by 50% among PWH aged ≥65 was the only goal met by 2022. If recent trends continue, other NHAS QoL 2025 goals are unlikely to be met. Multisectoral strategies to improve access to housing, employment, food, and mental health will be needed to meet NHAS 2025 goals for QoL among older PWH.

Neuropsychological outcomes of patients with haematological malignancies undergoing chimeric antigen receptor T-cell therapy: protocol for a prospective study.

Introduction: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The neurological, cognitive, psychiatric and psychosocial sequelae of ICANS are diverse and not well defined, posing a challenge for diagnosis and management. The recovery trajectory of the syndrome is uncertain. Patients are rarely examined in this population pretherapy, adding a layer of complexity to specifying symptoms pertinent solely to CAR-T treatment. We present a protocol of a prospective longitudinal research study of adult patients in a single Australian haematology service undergoing CAR-T therapy. The study will describe neurocognitive features specific to ICANS, characterise the underlying syndrome, capture recovery, identify predictors of differential postinfusion outcomes and determine a set of cognitive instruments necessary to monitor patients acutely. Methods and analysis: This is a prospective longitudinal study that comprises neuropsychological and neurological examinations occurring prior to CAR-T, during the acute post-treatment period, 28 days, 6 months and 12 months post infusion. Data will be sourced from objective psychometric measures, clinical examinations, self-report questionnaires of psychopathology and accounts of subjective cognitive complaint. Ethics and dissemination: This study aims to guide diagnosis, management and monitoring of neurocognitive features of CAR-T cell therapy. Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. All procedures involving human subjects/patients were approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (21/145).

Paternal exposure to antiseizure medications and offspring outcomes: a systematic review.

BACKGROUND: Concerns have recently been raised about risks to the fetus resulting from paternal exposure to antiseizure medications (ASMs). To address these concerns, we conducted a systematic review of the literature to assess neurodevelopmental and anatomical outcomes in offspring born to fathers taking ASMs at the time of conception. METHODS: Electronic searches of MEDLINE, PsycINFO, and Embase were conducted to identify human studies published in English that reported on outcomes, comprising neurodevelopmental disorders, major congenital malformations, small-for-gestational age or low birth weight, in offspring of fathers taking ASMs at conception. Quality analysis of included studies was undertaken using the Newcastle-Ottawa Scale. A narrative synthesis was used to report study findings. RESULTS: Of 923 studies identified by the search and screened by title and abstract, 26 underwent full-text review and 10 met eligibility criteria. There was limited evidence available, but there appeared to be no clear evidence for an adverse impact of paternal ASM use on offspring outcomes. Few isolated adverse findings were not replicated by other investigations. Several methodological limitations prevented meta-analysis, including failure by most studies to report outcomes separately for each individual ASM, heterogeneity in measurement and outcome reporting, and small numbers of monotherapy exposures. CONCLUSIONS: Although there were limited data available, this systematic review provides reassuring evidence that paternal exposure to ASMs at conception is unlikely to pose any major risk of adverse outcomes for the offspring. Further research is needed to examine the relationship between preconception ASM use in males and offspring outcomes at birth and postnatally.

Whole abdominal pencil beam scanned proton FLASH increases acute lethality.

PURPOSE: Ultra-high dose-rate FLASH radiotherapy (RT) has emerged as a modality which promises to reduce normal tissue toxicity while maintaining tumor control. Previous studies of gastrointestinal toxicity using passively scattered FLASH proton therapy (PRT) have, however, yielded mixed results, suggesting that the requirements for gastrointestinal sparing by FLASH are an open question. Furthermore, the more clinically relevant pencil beam scanned (PBS) FLASH PRT has not yet been assessed in this context, despite differences in the spatiotemporal dose-rate distributions compared to passively scattered PRT. Here, we provide the first report on the effects of PBS FLASH PRT on acute gastrointestinal injury in mice after whole abdominal irradiation. METHODS AND MATERIALS: Whole abdominal irradiation was performed on C57BL/6J mice using the entrance channel of the Bragg curve of a 250 MeV PBS proton beam at field-averaged dose-rates of 0.6 Gy/s for conventional (CONV) and 80-100 Gy/s for FLASH PRT. A 2D strip ionization chamber array was used to measure the dose and dose rate for each mouse. Survival was assessed at 14 Gy. Intestines were harvested and processed as Swiss rolls for analysis using a novel artificial intelligence (AI)-based crypt assay to quantify crypt regeneration 4 days post-irradiation. RESULTS: Survival was significantly reduced following 14 Gy FLASH PRT compared to CONV (P<0.001). Our AI-based crypt assays demonstrated no significant difference in intestinal crypts/cm or crypt depth between groups 4 days post-irradiation. Furthermore, we found no significant difference in EdU+ cells/crypt or Olfactomedin4+ intestinal stem cells with FLASH relative to CONV PRT. CONCLUSIONS: Overall, our data demonstrate significantly impaired survival following abdominal PBS FLASH PRT without apparent differences in intestinal histology 4 days post-irradiation.

American Radium Society™ Appropriate Use Criteria on Cardiac Toxicity Prevention and Management After Thoracic Radiotherapy.

PURPOSE: The multidisciplinary American Radium Society (ARS) Thoracic Committee was assigned to create Appropriate Use Criteria (AUC) on cardiac toxicity prevention and management for patients undergoing radiotherapy. METHODS AND MATERIALS: A systematic review of the current literature was conducted. Case variants of patients with thoracic malignancies undergoing radiation were created based on presence or absence cardiovascular risk factors and treatment-related risks assessed by dose exposure to the heart/cardiac substructures. Modified Delphi methodology was used by to evaluate the variants and procedures, with ≤3 rating points from median defining agreement/consensus. RESULTS: 6 variants were evaluated. The panel felt patients with cardiac comorbidities at high risk for radiation-related cardiac toxicity should undergo a prescreening cardiac focused history and physical (H&P) exam, electrocardiogram (EKG), cardiac imaging including an echocardiogram, and referral to a cardiologist/cardio-oncologist. Recommendations for those without cardiac comorbidities at low risk for cardiac toxicity were to undergo a baseline history and physical examination only. Conversely, those without cardiac comorbidities but at high risk for radiation-related cardiac toxicity were recommended to undergo a prescreening EKG, in addition to a H&P exam. For patients with cardiac comorbidities at low risk for cardiac toxicity, the panel felt prescreening and post-screening tests may be appropriate. CONCLUSIONS: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for cardiac toxicity prevention, surveillance, and management after thoracic radiotherapy based on cardiac comorbidities at presentation and risk of radiation-related cardiac toxicity.

Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs.

High solubility in water and physiological fluids is an indispensable requirement for the pharmacological efficacy of an active pharmaceutical ingredient. Indeed, it is well established that pharmaceutical substances exhibiting limited solubility in water are inclined towards diminished and inconsistent absorption following oral administration, consequently resulting in variability in therapeutic outcomes. The current advancements in combinatorial chemistry and pharmaceutical design have facilitated the creation of drug candidates characterized by increased lipophilicity, elevated molecular size, and reduced aqueous solubility. Undoubtedly, the issue of poorly water-soluble medications has been progressively escalating over recent years. Indeed, 40% of the top 200 oral medications marketed in the United States, 33% of drugs listed in the US pharmacopoeia, 75% of compounds under development and 90% of new chemical entities are insufficiently water-soluble compounds. In order to address this obstacle, formulation scientists employ a variety of approaches, encompassing both physical and chemical methods such as prodrug synthesis, salt formation, solid dispersions formation, hydrotropic substances utilization, solubilizing agents incorporation, cosolvent addition, polymorphism exploration, cocrystal creation, cyclodextrins complexation, lipid formulations, particle size reduction and nanoformulation techniques. Despite the utilization of these diverse approaches, the primary reason for the failure in new drug development persists as the poor aqueous solubility of pharmaceutical compounds. This paper, therefore, delves into the foundational principles that underpin the implementation of various formulation strategies, along with a discussion on the respective advantages and drawbacks associated with each approach. Additionally, a discourse is provided regarding methodological frameworks for making informed decisions on selecting an appropriate formulation strategy to effectively tackle the key challenges posed during the development of a poorly water-soluble drug candidate.

Self-assembled thin films as alternative surface textures in assistive aids with users who are blind.

Current tactile graphics primarily render tactile information for blind users through physical features, such as raised bumps or lines. However, the variety of distinctive physical features that can be created is effectively saturated, and alternatives to these physical features are not currently available for static tactile aids. Here, we explored the use of chemical modification through self-assembled thin films to generate distinctive textures in tactile aids. We used two silane precursors, n-butylaminopropyltrimethoxysilane and n-pentyltrichlorosilane, to coat playing card surfaces and investigated their efficacy as a tactile coating. We verified the surface coating process and examined their durability to repeated use by traditional materials characterization and custom mesoscale friction testing. Finally, we asked participants who were both congenitally blind and braille-literate to sort the cards based on touch. We found that participants were able to identify the correct coated card with 82% accuracy, which was significantly above chance, and two participants achieved 100% accuracy. This success with study participants demonstrates that surface coatings and surface modifications might augment or complement physical textures in next-generation tactile aids.

Proton Therapy for Spinal Tumors: A Consensus Statement From the Particle Therapy Cooperative Group.

PURPOSE: Proton beam therapy (PBT) plays an important role in the management of primary spine tumors. The purpose of this consensus statement was to summarize safe and optimal delivery of PBT for spinal tumors. METHODS AND MATERIALS: The Particle Therapy Cooperative Group Skull Base/Central nervous system/Sarcoma Subcommittee consisting of radiation oncologists and medical physicists with specific expertise in spinal irradiation developed expert recommendations discussing treatment planning considerations and current approaches in the treatment of primary spinal tumors. RESULTS: Computed tomography simulation: factors that require significant consideration include (1) patient comfort, (2) setup reproducibility and stability, and (3) accessibility of appropriate beam angles. SPINE STABILIZATION HARDWARE: If present, hardware should be placed with cross-links well above/below the level of the primary tumor to reduce the metal burden at the level of the tumor bed. New materials that can reduce uncertainties include polyether-ether-ketone and composite polyether-ether-ketone-carbon fiber implants. FIELD ARRANGEMENT: Appropriate beam selection is required to ensure robust target coverage and organ at risk sparing. Commonly, 2 to 4 treatment fields, typically from posterior and/or posterior-oblique directions, are used. TREATMENT PLANNING METHODOLOGY: Robust optimization is recommended for all pencil beam scanning plans (the preferred treatment modality) and should consider setup uncertainty (between 3 and 7 mm) and range uncertainty (3%-3.5%). In the presence of metal hardware, use of an increased range uncertainty up to 5% is recommended. CONCLUSIONS: The Particle Therapy Cooperative Group Skull Base/Central nervous system/Sarcoma Subcommittee has developed recommendations to enable centers to deliver PBT safely and effectively for the management of primary spinal tumors.

Learning the hierarchical organization of the frontal lobe with differential causal effects.

In this video article, accompanying the paper "An approach to learning the hierarchical organization of the frontal lobe", we discuss a data driven approach to learning brain connectivity. Hierarchical models of brain connectivity are useful to understand how the brain can process sensory information, make decisions, and perform other high-level tasks. Despite extensive research, understanding the structure of the prefrontal cortex (PFC) remains a crucial challenge. In this work, we propose an approach to studying brain signals and uncovering characteristics of the underlying neural circuity, based on the mathematics of Gaussian processes and causal strengths. For discovering causations, we propose a metric referred to as double-averaged differential causal effect, which is a variant of the recently proposed differential causal effect, and it can be used as a principled measure of the causal strength between time series. We applied this methodology to study local field potential data from the frontal lobe, where the interest was in finding the causal relationship between the medial and lateral PFC areas of the brain. Our results suggest that the medial PFC causally influences the lateral PFC.

The Accuracy of Artificial Intelligence ChatGPT in Oncology Examination Questions.

The aim of this study is to assess the accuracy of Chat Generative Pretrained Transformer (ChatGPT) in response to oncology examination questions in the setting of one-shot learning. Consecutive national radiation oncology in-service multiple-choice examinations were collected and inputted into ChatGPT 4o and ChatGPT 3.5 to determine ChatGPT's answers. ChatGPT's answers were then compared with the answer keys to determine whether ChatGPT correctly or incorrectly answered each question and to determine if improvements in responses were seen with the newer ChatGPT version. A total of 600 consecutive questions were inputted into ChatGPT. ChatGPT 4o answered 72.2% questions correctly, whereas 3.5 answered 53.8% questions correctly. There was a significant difference in performance by question category (P < .01). ChatGPT performed poorer with respect to knowledge of landmark studies and treatment recommendations and planning. ChatGPT is a promising technology, with the latest version showing marked improvement. Although it still has limitations, with further evolution, it may be considered a reliable resource for medical training and decision making in the oncology space.

Large-scale pretrained frame generative model enables real-time low-dose DSA imaging: An AI system development and multi-center validation study.

BACKGROUND: Digital subtraction angiography (DSA) devices are commonly used in numerous interventional procedures across various parts of the body, necessitating multiple scans per procedure, which results in significant radiation exposure for both doctors and patients. Inspired by generative artificial intelligence techniques, this study proposes GenDSA, a large-scale pretrained multi-frame generative model-based real-time and low-dose DSA imaging system. METHODS: GenDSA was developed to generate 1-, 2-, and 3-frame sequences following each real frame. A large-scale dataset comprising ∼3 million DSA images from 27,117 patients across 10 hospitals was constructed to pretrain, fine-tune, and validate GenDSA. Two other datasets from 25 hospitals were used for evaluation. Objective evaluations included SSIM and PSNR. Five interventional radiologists independently assessed the quality of the generated frames using the Likert scale and visual Turing test. Scoring consistency among the radiologists was measured using the Kendall coefficient of concordance (W). The Fleiss' kappa values were used for inter-rater agreement analysis for visual Turing tests. FINDINGS: Using only one-third of the clinical radiation dose, videos generated by GenDSA were perfectly consistent with real videos. Objective evaluations demonstrated that GenDSA's performance (PSNR = 36.83, SSIM = 0.911, generation time = 0.07 s/frame) surpassed state-of-the-art algorithms. Subjective ratings and statistical results from five doctors indicated no significant difference between real and generated videos. Furthermore, the generated videos were comparable to real videos in overall quality (4.905 vs. 4.935) and lesion assessment (4.825 vs. 4.860). CONCLUSIONS: With clear clinical and translational values, the developed GenDSA can significantly reduce radiation damage to both doctors and patients during DSA-guided procedures. FUNDING: This study was supported by the National Key R&D Program and the National Natural Science Foundation of China.

First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study.

BACKGROUND AND OBJECTIVE: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens. METHODS: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed. KEY FINDINGS AND LIMITATIONS: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period. CONCLUSIONS AND CLINICAL IMPLICATIONS: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy. PATIENT SUMMARY: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options.

The natural history of marginal erosions in hands with and without osteoarthritis.

INTRODUCTION/OBJECTIVES: Among people with or without hand osteoarthritis, we aimed to identify characteristics of people (e.g., age and gender) with marginal erosions (MEs). We also examined changes in MEs during 48 months. We described radiographic severity and progression among joints with MEs, changes in MEs, or central erosions (CEs). DESIGN: We studied participants from the Osteoarthritis Initiative with baseline and 48-month hand radiographs. A radiologist and rheumatologist evaluated the radiographs for disease severity (Kellgren-Lawrence grades) and erosions (central or marginal), respectively. We used descriptive statistics to characterize participants and calculated frequencies at the joint level. RESULTS: Of the 3558 participants, 89 had a ME at baseline. People with MEs were more often male, older, and ever (former and current) smokers than those without a ME. There was no difference in inflammatory biomarkers or the presence of hand pain between individuals with and without a baseline ME. Almost all hands had only one ME (80%), whereas only 50% of individuals with CEs had only one CE at baseline. Compared to CEs, MEs appeared more frequently in joints without osteoarthritis (54% vs. < 1%). Approximately 18% of joints with an ME progressed in Kellgren-Lawrence grade versus 4% without ME. Among the joints with an ME at baseline, 10% resolved by 48 months. Less than 0.1% of joints developed a new ME. CONCLUSION: MEs appear to be distinct from CEs. MEs are predominantly present in males, isolated to one specific joint without osteoarthritis within a hand, and possibly predictive of radiographic progression. Key Points • Marginal erosions appear to be distinct from central erosions. • Most marginal erosions occur in joints without radiographic osteoarthritis. • Radiographic progression but not hand pain is more common in joints with a marginal erosion than without one.

Diet, Microbiome, and Inflammation Predictors of Fecal and Plasma Short-Chain Fatty Acids in Humans.

BACKGROUND: Gut microbes produce short-chain fatty acids (SCFAs), which are associated with broad health benefits. However, it is not fully known how diet and/or the gut microbiome could be modulated to improve SCFA production. OBJECTIVES: The objective of this study was to identify dietary, inflammatory, and/or microbiome predictors of SCFAs in a cohort of healthy adults. METHODS: SCFAs were measured in fecal and plasma samples from 359 healthy adults in the United States Department of Agriculture Nutritional Phenotyping Study. Habitual and recent diet was assessed using a food frequency questionnaire and automated self-administered 24-h dietary assessment tool dietary recalls. Markers of systemic and gut inflammation were measured in fecal and plasma samples. The gut microbiome was assessed using shotgun metagenomics. Using statistics and machine learning, we determined how the abundance and composition of SCFAs varied with measures of diet, inflammation, and the gut microbiome. RESULTS: We show that fecal pH may be a good proxy for fecal SCFA abundance. A higher healthy eating index for a habitual diet was associated with a compositional increase in fecal butyrate relative to acetate and propionate. SCFAs were associated with markers of subclinical gastrointestinal (GI) inflammation. Fecal SCFA abundance was inversely related to plasma lipopolysaccharide-binding protein. When we analyzed hierarchically organized diet and microbiome data with taxonomy-aware algorithms, we observed that diet and microbiome features were far more predictive of fecal SCFA abundances compared to plasma SCFA abundances. The top diet and microbiome predictors of fecal butyrate included potatoes and the thiamine biosynthesis pathway, respectively. CONCLUSIONS: These results suggest that resistant starch in the form of potatoes and microbially produced thiamine provide a substrate and essential cofactor, respectively, for butyrate synthesis. Thiamine may be a rate-limiting nutrient for butyrate production in adults. Overall, these findings illustrate the complex biology underpinning SCFA production in the gut. This trial was registered at clinicaltrials.gov as NCT02367287.