VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.

von Hippel-Lindau (VHL), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, VHL mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, VHL loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage. In addition, the function of VHL in regulating immune response is still not well established. In this study, we demonstrate that VHL loss enhances the efficacy of anti-programmed death 1 (PD1) treatment in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α/2α induced by VHL loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA, which triggered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation and induced type I interferons. Our study thus provided mechanistic insights into the role of VHL gene loss in boosting antitumor immunity.

Racial Disparities in Sports Cardiology: A Review.

Importance: Racial disparities in cardiovascular health, including sudden cardiac death (SCD), exist among both the general and athlete populations. Among competitive athletes, disparities in health outcomes potentially influenced by social determinants of health (SDOH) and structural racism remain inadequately understood. This narrative review centers on race in sports cardiology, addressing racial disparities in SCD risk, false-positive cardiac screening rates among athletes, and the prevalence of left ventricular hypertrophy, and encourages a reexamination of race-based practices in sports cardiology, such as the interpretation of screening 12-lead electrocardiogram findings. Observations: Drawing from an array of sources, including epidemiological data and broader medical literature, this narrative review discusses racial disparities in sports cardiology and calls for a paradigm shift in approach that encompasses 3 key principles: race-conscious awareness, clinical inclusivity, and research-driven refinement of clinical practice. These proposed principles call for a shift away from race-based assumptions towards individualized, health-focused care in sports cardiology. This shift would include fostering awareness of sociopolitical constructs, diversifying the medical team workforce, and conducting diverse, evidence-based research to better understand disparities and address inequities in sports cardiology care. Conclusions and Relevance: In sports cardiology, inadequate consideration of the impact of structural racism and SDOH on racial disparities in health outcomes among athletes has resulted in potential biases in current normative standards and in the clinical approach to the cardiovascular care of athletes. An evidence-based approach to successfully address disparities requires pivoting from outdated race-based practices to a race-conscious framework to better understand and improve health care outcomes for diverse athletic populations.

Simulation-based Inference of Developmental EEG Maturation with the Spectral Graph Model.

The spectral content of macroscopic neural activity evolves throughout development, yet how this maturation relates to underlying brain network formation and dynamics remains unknown. Here, we assess the developmental maturation of electroencephalogram spectra via Bayesian model inversion of the spectral graph model, a parsimonious whole-brain model of spatiospectral neural activity derived from linearized neural field models coupled by the structural connectome. Simulation-based inference was used to estimate age-varying spectral graph model parameter posterior distributions from electroencephalogram spectra spanning the developmental period. This model-fitting approach accurately captures observed developmental electroencephalogram spectral maturation via a neurobiologically consistent progression of key neural parameters: long-range coupling, axonal conduction speed, and excitatory:inhibitory balance. These results suggest that the spectral maturation of macroscopic neural activity observed during typical development is supported by age-dependent functional adaptations in localized neural dynamics and their long-range coupling across the macroscopic structural network.

Triamcinolone acetonide has minimal effect on short- and long-term metabolic activities of cartilage.

Intra-articular corticosteroid injections, such as triamcinolone acetonide (TA), are commonly used by clinicians to manage joint synovial inflammation. However, due to conflicting evidence in literature, there is a fear among clinicians that the injections may be harmful to otherwise healthy cartilage in young patients. The purpose of this study was to evaluate the effects of TA on young, healthy chondrocytes. Articular cartilage samples were harvested from bovine knee joints (1-2 months old). In both healthy and inflammatory (interleukin-1ß) challenged cartilage, samples were treated with TA at doses ranging from 1 nM to 200 µM. Following a short- (2 days) or long-term (10-14 days) treatment, chondrocyte viability, proliferation, and extracellular matrix (ECM) synthesis and degradation were evaluated with a click chemistry-based technique. Chondrocyte viability, proliferation, and anabolic activity were all minimally affected by short-term and long-term TA treatment. After both acute and sustained inflammatory challenges, TA reduced the catabolic activities in cartilage, reducing nascent glycosaminoglycan loss and maintaining cartilage mechanical properties. Overall, at physiologically relevant doses, TA had minimal negative impact on chondrocytes when maintained within their native ECM. Clinical significance: The findings provide new insight for current clinical practices concerning the use of TA in intra-articular injections, especially in young patients, and established a foundation for future investigations into the impact of corticosteroids on joint homeostasis.

Vitamin D Deficiency, Inflammation, and Diminished Endogenous Regenerative Capacity in Coronary Heart Disease.

Background: Vitamin D deficiency (VDD) is associated with coronary heart disease (CHD) and poor outcomes, but supplementation does not improve prognosis. VDD has been implicated in and may promote greater risk through inflammation and impaired progenitor cell function. Objectives: The authors examined VDD, high-sensitivity C-reactive protein (hsCRP), circulating progenitor cell (CPC) counts, and outcomes in patients with CHD. They hypothesized that the higher risk with VDD is mediated by inflammation and impaired regenerative capacity. Methods: A total of 5,452 individuals with CHD in the Emory Cardiovascular Biobank had measurement of 25-hydroxyvitamin D, subsets of whom had hsCRP measurements and CPCs estimated as CD34-expressing mononuclear cell counts. Findings were validated in an independent cohort. 25-hydroxyvitamin D <20 ng/mL was considered VDD. Cox and Fine-Gray models determined associations between marker levels and: 1) all-cause mortality; 2) cardiovascular mortality; and 3) major adverse cardiovascular events, a composite of adverse CHD outcomes. Results: VDD (43.6% of individuals) was associated with higher adjusted cardiovascular mortality (HR: 1.57, 95% CI: 1.09-2.28). There were significant interactions between VDD and hsCRP and CPC counts in predicting cardiovascular mortality. Individuals with both VDD and elevated hsCRP had the greatest risk (HR: 2.82, 95% CI: 2.16-3.67). Only individuals with both VDD and low CPC counts were at high risk (HR: 2.25, 95% CI: 1.46-3.46). These findings were reproduced in the validation cohort. Conclusions: VDD predicts adverse outcomes in CHD. Those with VDD, inflammation and/or diminished regenerative capacity are at a significantly greater risk of cardiovascular mortality. Whether targeted supplementation in these high-risk groups improves risk warrants further study.

Electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD): A modified study protocol.

OBJECTIVE: This study began as a single-blind randomized controlled trial (RCT) to investigate the efficacy and safety of electroconvulsive therapy (ECT) for severe treatment-refractory agitation in advanced dementia. The aims are to assess agitation reduction using the Cohen-Mansfield Agitation Inventory (CMAI), evaluate tolerability and safety outcomes, and explore the long-term stability of agitation reduction and global functioning. Due to challenges encountered during implementation, including recruitment obstacles and operational difficulties, the study design was modified to an open-label format and other protocol amendments were implemented. METHODS: Initially, the RCT randomized participants 1:1 to either ECT plus usual care or simulated ECT plus usual care (S-ECT) groups. As patients were enrolled, data were collected from both ECT and simulated ECT (S-ECT) patients. The study now continues in an open-label study design where all patients receive actual ECT, reducing the targeted sample size from 200 to 50 participants. RESULTS: Study is ongoing and open to enrollment. CONCLUSION: The transition of the ECT-AD study design from an RCT to open-label design exemplifies adaptive research methodologies in response to real-world challenges. Data from both the RCT and open-label phases of the study will provide a unique perspective on the role of ECT in managing severe treatment-refractory agitation in dementia, potentially influencing future clinical practices and research approaches.

A Review of Eales' Disease and Mycobacterium tuberculosis.

Eales' Disease is an idiopathic peripheral retinal vasculopathy first described by British ophthalmologist Henry Eales in 1880. Most prevalent in healthy young males, Eales' Disease often presents with symptoms of sudden blurry or decreased vision and floaters. Although no clear, standardized stage of the disease exists, it progresses through three overlapping phases-peripheral periphlebitis, ischemic capillary ischemia, and retinal neovascularization. The etiology of Eales' Disease is unknown and appears to be multifactorial, but post-TB hypersensitivity to tuberculoprotein and M. tuberculosis DNA is the most potential cause in the etiology of Eales' Disease. With a thorough examination of the clinical presentation and diagnosis of Eales' Disease-incorporating the latest clinical findings related to the condition-the investigation for Eales' Disease extends to explore recent potential connections with other ocular conditions or possible cofactors, such as glaucoma, uncontrolled diabetes, drug abuse, or inherited medical conditions. Moreover, focusing on critical insights into the treatment of Eales' Disease across its various stages of progression, the overarching goal of the paper is to refine and suggest possible future diagnostic and therapeutic strategies. Widening our understanding of pathophysiology and utilizing various treatment options for individual patients holds immense potential for advancing ocular medicine and optimizing patient care for people with this disease with unknown pathophysiology.

Google Trends Analysis of Otologic Symptom Searches Following COVID-19.

Introduction: COVID-19 infection was accompanied by otologic symptoms, a pattern that was captured early by Google Trends. The objective of this study is to investigate searches for otologic symptoms and identify correlations with the pandemic onset. Materials and Methods: Search interest for otologic symptoms was gathered using Google Trends from two years before and two years following the pandemic start date. A two-tailed Mann-Whitney U test was used to identify significant changes and effect size. Results: In total, search interest for 14 terms was collected, with significant changes identified in 11. Six terms showed increased search interest, with the most significant rises observed for headache (r=0.589, p<0.001), dizziness (r=0.554, p<0.001), and tinnitus (r=0.410, p<0.001). Search interest decreased for five terms, with the most notable declines found in searches for migraine headache (r=0.35, p<0.001) and phonophobia (r=0.22, p=0.002). No significant changes were seen in ear pressure (p=0.142), neck pain (p=0.935), and sudden hearing loss (p=0.863) searches. Conclusion: COVID-19 infection is often accompanied otologic symptoms and holds a diagnostic role. Fluctuating search interest may be attributed to a true increase in cases, media trends, or people's desires to stay informed. Google Trends robustly captured trends in search interest and presented itself as a valuable epidemiological tool.

Stimulus Selection Based on Gender Ratios: Gender Ratios are Indicative of Both Stereotypical and Conceptual Gender.

This paper explores how the use of gender ratios to inform stimulus selection affects the activation of gendered social information. It investigates if stimuli selected this way can activate gender stereotype knowledge and/or conceptual gender knowledge. This was tested through attribute naming (Study 1) and rating (Study 2) tasks, with component and regression analysis allowing for examination of the nature of gender ratios at both attribute and component levels. The results provide rich information about the nature of gender ratio information as a means of stimulus selection, and in doing so support both conceptualisations as long as researchers acknowledge their overlap. The results also indicate that these roles elicited both positive/prescriptive (i.e., the role is appropriate for a given gender) and negative/proscriptive beliefs (i.e., the role is not appropriate for a given gender). These findings hold important implications for future research using gender ratios.

The Dawn and Advancement of the Knowledge of the Genetics of Migraine.

Background: Migraine is a prevalent episodic brain disorder known for recurrent attacks of unilateral headaches, accompanied by complaints of photophobia, phonophobia, nausea, and vomiting. Two main categories of migraine are migraine with aura (MA) and migraine without aura (MO). Main body: Early twin and population studies have shown a genetic basis for these disorders, and efforts have been invested since to discern the genes involved. Many techniques, including candidate-gene association studies, loci linkage studies, genome-wide association, and transcription studies, have been used for this goal. As a result, several genes were pinned with concurrent and conflicting data among studies. It is important to understand the evolution of techniques and their findings. Conclusions: This review provides a chronological understanding of the different techniques used from the dawn of migraine genetic investigations and the genes linked with the migraine subtypes.

International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death Tool.

BACKGROUND: Studies reporting on the incidence of sudden cardiac arrest and/or death (SCA/D) in athletes commonly lack methodological and reporting rigor, which has implications for screening and preventative policy in sport. To date, there are no tools designed for assessing study quality in studies investigating the incidence of SCA/D in athletes. METHODS AND RESULTS: The International Criteria for Reporting Study Quality for Sudden Cardiac Arrest/Death tool (IQ-SCA/D) was developed following a Delphi process. Sixteen international experts in sports cardiology were identified and invited. Experts voted on each domain with subsequent moderated discussion for successive rounds until consensus was reached for a final tool. Interobserver agreement between a novice, intermediate, and expert observer was then assessed from the scoring of 22 relevant studies using weighted and unweighted κ analyses. The final IQ-SCA/D tool comprises 8 domains with a summated score of a possible 22. Studies are categorized as low, intermediate, and high quality with summated IQ-SCA/D scores of ≤11, 12 to 16, and ≥17, respectively. Interrater agreement was "substantial" between all 3 observers for summated IQ-SCA/D scores and study categorization. CONCLUSIONS: The IQ-SCA/D is an expert consensus tool for assessing the study quality of research reporting the incidence of SCA/D in athletes. This tool may be used to assist researchers, reviewers, journal editors, and readers in contextualizing the methodological quality of different studies with varying athlete SCA/D incidence estimates. Importantly, the IQ-SCA/D also provides an expert-informed framework to support and guide appropriate design and reporting practices in future SCA/D incidence trials.

Concussion burden and later-life cardiovascular risk factors in former professional American-style football players.

OBJECTIVE: Mid-life cardiovascular risk factors are associated with later cognitive decline. Whether repetitive head injury among professional athletes impacts cardiovascular risk is unknown. We investigated associations between concussion burden and postcareer hypertension, high cholesterol, and diabetes among former professional American-style football (ASF) players. METHODS: In a cross-sectional study of 4080 professional ASF players conducted between January 2015 and March 2022, we used an mulitsymptom concussion symptom score (CSS) and the number of loss-of-consciousness (LOC) episodes as a single severe symptom to quantify football-related concussion exposure. Primary outcomes were hypertension, dyslipidemia, and diabetes, defined by current or recommended prescription medication use. RESULTS: The prevalence of hypertension, high cholesterol, and diabetes among former players (52 ± 14 years of age) was 37%, 34%, and 9%. Concussion burden was significantly associated with hypertension (lowest vs. highest CSS quartile, odds ratio (OR) = 1.99; 95%CI: 1.33-2.98; p < 0.01) and high cholesterol (lowest vs. moderate CSS, OR = 1.46, 95%CI, 1.11-1.91; p < 0.01), but not diabetes. In fully adjusted models, the prevalence of multiple CVD was associated with CSS. These results were driven by younger former players (≤ 40 year of age) in which the odds of hypertension were over three times higher in those in the highest CSS quartile (OR = 3.29, 95%CI: 1.39-7.61; p = 0.01). Results were similar for LOC analyses. INTERPRETATION: Prior concussion burden is associated with postcareer atherogenic cardiovascular risk profiles among former professional American football players.

2024 HRS expert consensus statement on arrhythmias in the athlete: Evaluation, treatment, and return to play.

Youth and adult participation in sports continues to increase, and athletes may be diagnosed with potentially arrhythmogenic cardiac conditions. This international multidisciplinary document is intended to guide electrophysiologists, sports cardiologists, and associated health care team members in the diagnosis, treatment, and management of arrhythmic conditions in the athlete with the goal of facilitating return to sport and avoiding the harm caused by restriction. Expert, disease-specific risk assessment in the context of athlete symptoms and diagnoses is emphasized throughout the document. After appropriate risk assessment, management of arrhythmias geared toward return to play when possible is addressed. Other topics include shared decision-making and emergency action planning. The goal of this document is to provide evidence-based recommendations impacting all areas in the care of athletes with arrhythmic conditions. Areas in need of further study are also discussed.

Physicians approach shared decision-making for sports eligibility decisions heterogeneously.

Background: There is limited data regarding how clinicians operationalize shared decision-making (SDM) with athletes with cardiovascular diagnoses. This study was designed to explore sports cardiologists' conceptions of SDM and approaches to sports eligibility decisions. Methods: 20 sports cardiologists were interviewed by telephone or video conference from October 2022 to May 2023. Qualitative descriptive analysis was conducted with the transcripts. Results: All participants endorsed SDM for eligibility decisions, however, SDM was defined and operationalized heterogeneously. Only 6 participants specifically referenced eliciting patient preferences during SDM. Participants described variable roles for the physician in SDM and variable views on athletes' understanding, perception, and tolerance of risk. Participants thresholds for prohibitive annual risk of sudden cardiac death ranged from <1 % to >10 %. Conclusions: These findings reinforce the general acceptance of SDM for sports eligibility decisions and highlight the need to better understand this process and identify the most effective approach for operationalization.

Online ratings and narrative comments of American Head and Neck Society surgeons.

BACKGROUND: We analyzed online rating scores and comments of head and neck surgeons to understand factors that contribute to higher ratings. METHODS: Numerical ratings and comments for American Head and Neck Society physicians were extracted from Healthgrades, Vitals, RateMDs, and Yelp, with narrative comments categorized based on content. Physician practice location, education, and residency training were also compiled. RESULTS: Patient ratings were significantly higher with supportive staff and affable physician demeanor but showed significant drops with longer wait times and difficulties scheduling appointments or follow-ups. Physician education and postgraduate training did not significantly affect ratings. CONCLUSION: Online ratings and comments correlated to modifiable factors in clinical practice and may be informative in understanding patient needs.

Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake.

Epidermal growth factor receptor (EGFR) is a transmembrane protein commonly targeted by tyrosine kinase inhibitors (TKIs) as a front-line therapy for patients with many cancers including nonsmall cell lung cancer (NSCLC). Effective treatment requires efficient intracellular drug uptake and target binding. However, despite the recent success in the development of new TKI drugs, the mechanisms of uptake for many TKIs are still poorly understood due to the difficulty in imaging and measuring nonfluorescent drug molecules at a subcellular resolution. It has previously been shown that weakly basic TKI drugs are sequestered in lysosomes. Leveraging this property, we apply hyperspectral stimulated Raman scattering imaging to directly visualize and quantify two Food and Drug Administration-approved EGFR inhibitor drugs (lapatinib and afatinib) inside living cells and the changes in their cellular uptake upon the addition of organic cation transporter inhibitors. These single-cell quantitative measurements provide new insight into the role of membrane transporters in the uptake of TKI drugs in living cells.