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Hip morphology‐based osteoarthritis risk prediction models: development and external validation using individual participant data from the World COACH Consortium
Get PDFOBJECTIVES: This study aims to develop hip morphology-based radiographic hip osteoarthritis (RHOA) risk prediction models and investigates the added predictive value of hip morphology measurements and the generalizability to different populations. METHODS: We combined data from nine prospective cohort studies participating in the World COACH consortium. RHOA grades were harmonized, and incident RHOA was defined as hips without definite RHOA at baseline that developed definite RHOA within 4-8 years. Baseline hip morphology was quantified with automatically and uniformly determined lateral center edge angle and alpha angle measurements on anteroposterior radiographs. Discriminative performance of generalized linear mixed model (GLMM) definitions with and without hip morphology measurements was determined with stratified cross-validation. With leave-one-cohort-out cross-validation, the generalizability to unseen populations of hip morphology-based GLMMs and Random Forest (RF) models was evaluated. RESULTS: From the included 35,984 hips without definite RHOA at baseline, 4.7% developed incident RHOA within 4-8 years. The GLMM with cohort-specific intercept, considering baseline demographics, RHOA grade, and hip morphology measurements, showed a mean AUC of 0.80 (±0.01) in stratified cross-validation. Using a marginal intercept decreased performance by 0.1 in AUC. Similar results were found for a GLMM without hip morphology measurements. Leave-one-cohort-out cross-validation showed comparable discrimination (AUC between 0.56-0.88) and calibration performance for hip morphology-based GLMMs and RF models. CONCLUSIONS: In hips free of definite RHOA, our AUCs for the incident RHOA models showed good predictive performance in similar populations. However, the added predictive value of the morphology measurements was small, and model performance was heterogeneous in leave-one-cohort-out cross-validation
Mechanistic computational modeling of sFLT1 secretion dynamics.
Get PDFConstitutively secreted by endothelial cells, soluble FLT1 (sFLT1 or sVEGFR1) binds and sequesters extracellular vascular endothelial growth factors (VEGF), thereby reducing VEGF binding to VEGF receptor tyrosine kinases and their downstream signaling. In doing so, sFLT1 plays an important role in vascular development and in the patterning of new blood vessels in angiogenesis. Here, we develop multiple mechanistic models of sFLT1 secretion and identify a minimal mechanistic model that recapitulates key qualitative and quantitative features of temporal experimental datasets of sFLT1 secretion from multiple studies. We show that the experimental data on sFLT1 secretion is best represented by a delay differential equation (DDE) system including a maturation term, reflecting the time required between synthesis and secretion. Using optimization to identify appropriate values for the key mechanistic parameters in the model, we show that two model parameters (extracellular degradation rate constant and maturation time) are very strongly constrained by the experimental data, and that the remaining parameters are related by two strongly constrained constants. Thus, only one degree of freedom remains, and measurements of the intracellular levels of sFLT1 would fix the remaining parameters. Comparison between simulation predictions and additional experimental data of the outcomes of chemical inhibitors and genetic perturbations suggest that intermediate values of the secretion rate constant best match the simulation with experiments, which would completely constrain the model. However, some of the inhibitors tested produce results that cannot be reproduced by the model simulations, suggesting that additional mechanisms not included here are required to explain those inhibitors. Overall, the model reproduces most available experimental data and suggests targets for further quantitative investigation of the sFLT1 system
GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer
Get PDFAlterations in neurotransmitter signaling can influence colorectal cancer (CRC). In a large, randomized Phase III clinical trial (CALGB/SWOG 80405) involving patients with metastatic CRC, high expression of gamma-aminobutyric acid (GABA) pathway gene GAD1 and low expression of ABAT, indicative of a GABAergic environment, were associated with worse progression-free survival and overall survival outcomes. A metastasis map of human cancer cell lines (MetMap) and functional studies using a microfluidic tumor-on-chip platform demonstrated that high GAD1 expression correlates with increased metastatic potential. Knockdown and pharmacological inhibition of GAD1 reduced tumor invasion, while exogenous GABA promoted invasion. Tumor-derived GABA was elevated in Ras-altered tumors. Furthermore, analysis of publicly available data confirmed that higher GAD1 expression is associated with worse outcomes in Ras-mutant tumors. These findings establish a role for GABA signaling in tumor invasiveness, particularly in Ras-altered CRC. This study demonstrates using clinical data to inform new discoveries and highlights the need for advanced preclinical model systems that more accurately reflect human physiology to explore these findings
Intuitive virtual reality based frontal-midline theta neurofeedback: a feasibility study in young ages
Get PDFBackground Neurofeedback is a method to modulate neural activity, such as frontal-midline theta oscillations. Given the emerging role of pathologically disrupted neuronal oscillations in psychiatric disorders, neurofeedback has potential as a novel therapeutic intervention. Participant immersion in the neurofeedback paradigm is critical to its efficacy. Here, we tested whether virtual reality enabled immersion and rapid acquisition of the ability to intentionally modulate frontal-midline theta oscillations. Methods We developed a neurofeedback task in which participants were instructed to clean up trash in a virtual underwater environment with their own thoughts. Unbeknownst to the participant, the amount of trash was updated as a function of frontal-midline theta power estimated from real-time electroencephalography recording. The neurofeedback blocks were interleaved with a working memory task, which is known to increase frontal-midline theta oscillations. Results The study involved 29 participants (Mean age = 24.62 years, SD = 9.31). By the end of the first block, 70% of participants successfully increased and sustained their frontal-midline theta oscillations. The amplitude of frontal-midline theta during neurofeedback was greater than rest but not as strong as during the working memory task. Conclusion We suggest that virtual-reality-based neurofeedback is highly immersive, causes minimal discomfort and increases theta oscillations with a brief learning period. Neurofeedback is a feasible method of increasing neural activity similar to working memory tasks and a promising method for training individuals to increase endogenous theta oscillations. Future research should investigate potential transfer effects into cognitive domains to increase cognitive control and top-down control
Precision Oncology Insights into WNT Pathway Alterations in FOLFOX-Treated Early-Onset Colorectal Cancer in High-Risk Populations
Get PDFBackground/Objectives: Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, is rising rapidly and disproportionately affects Hispanic/Latino (H/L) populations. While FOLFOX is a standard first-line chemotherapy, its impact on tumor genomics in EOCRC remains poorly understood. Given the central role of WNT signaling in colorectal cancer (CRC), we aimed to characterize WNT pathway alterations in EOCRC across diverse populations and assess their associations with FOLFOX treatment and clinical outcomes. Methods: Somatic mutation data from 2515 CRC patients (266 H/L, 2249 Non-Hispanic White [NHW]) were analyzed. Patients were stratified by age (EOCRC vs. late-onset colorectal cancer), ancestry (H/L vs. NHW), and FOLFOX treatment status. Mutation frequencies in WNT pathway genes were compared, and Kaplan–Meier analysis evaluated overall survival. Results: WNT pathway alterations were pervasive across groups, with APC mutations dominating. Notably, non-canonical WNT mutations (e.g., CTNNB1, RNF43) were significantly less frequent in FOLFOX-treated H/L EOCRC patients compared to untreated individuals, suggesting potential chemotherapy-driven selection. In NHW patients, FOLFOX treatment was associated with reduced mutation frequencies across multiple WNT regulators, which correlated with improved overall survival. Conclusions: Our findings reveal that WNT pathway dysregulation in EOCRC is shaped by ancestry, treatment status, and age. FOLFOX appears to reduce specific WNT alterations in H/L patients and broader WNT disruptions in NHW patients, with survival benefits observed primarily in the latter. These results underscore ancestry-specific molecular responses to chemotherapy and the need for precision oncology strategies tailored to high-risk populations
Practice Patterns in Pediatric Cardiothoracic Presurgical Conferences: A Multicenter Survey Study
Get PDFPediatric cardiothoracic surgeries are high-stakes, complex procedures, typically undergoing prior review at multidisciplinary conferences. This study evaluates practice patterns of conferences throughout the United States (US). Surveys were distributed to fellowship program directors or division directors in 124 US pediatric cardiology centers seeking information on conference logistics, fellow roles, quality improvement (QI), and satisfaction. All 47 responding centers (response rate 38%) conduct presurgical conferences, mostly on a weekly basis (92%) lasting 60–120 min (79%). The conferences are solely virtual (19%) or hybrid (81%). High-volume centers (> 300 surgical cases/year) are more likely to hold multiple conferences (13/20 vs 7/27, p < 0.01) and less likely to designate a moderator (11/20 vs 22/26, p = 0.027). Categorical pediatric cardiology fellows at 33 centers present clinical data (97%), echocardiograms (85%), catheterizations (82%), and cross-sectional imaging (39%), typically beginning in their first year. Most centers report that minor (98%) or major changes (51%) are made to patient management at least “sometimes.” Responders rate conferences as very important (median 10/10 on a 10-point Likert scale, IQR 9–10), but satisfaction is more modest (median 7/10, IQR 7–9). Only 17% of centers have a formal QI process. Comments from 42 centers reveal positive themes of collaboration (68%) but also concerns about lengthy (30%) or inefficient (36%) discussion. Conclusions: This survey highlights common practices for pediatric cardiothoracic presurgical conferences. Conferences are collaborative and seen as highly impactful. However, satisfaction varies, and QI efforts are infrequent. These findings highlight opportunities for process improvement and standardization
Identification of Interleukin‐1β in Whole Blood as a Candidate Biomarker for Alcohol Use Disorder Risk Based on AUDIT Scores
Get PDFAlcohol use disorder (AUD) is associated with chronic inflammation and immune dysregulation, yet no validated immune-based markers exist to support assessment or monitoring. This study identifies interleukin-1 beta (IL-1β) in whole blood as a promising candidate biomarker of AUD risk, based on Alcohol Use Disorders Identification Test (AUDIT) scores. Twenty-eight non-treatment-seeking adults, with AUDIT scores between 2 and 22, provided whole blood samples. We aimed to identify biomarkers that signal immune changes associated with early AUDIT score risk, where interventions may be most effective. Luminex multiplex immunoassays quantified 14 immune-related mediators in combined cell lysates and supernatants. IL-1β, IL-18, IL-7 and CCL11 were significantly elevated in individuals with higher AUDIT scores. IL-1β showed the largest effect size (Cohen's d) and was the most consistent predictor of both AUDIT and AUDIT-Consumption (AUDIT-C) scores across random forest and linear regression analyses. Moderated multiple regression (MMR) confirmed that IL-1β predicted both scores independent of other immune mediators. Receiver operating characteristic (ROC) analyses demonstrated discriminative potential, with IL-1β achieving an AUC of 0.81 (good discrimination) for AUDIT ≥ 6 (true positive rate [TPR] = 0.71; false positive rate [FPR] = 0.14) and an AUC of 0.94 (excellent discrimination) for AUDIT-C thresholds (TPR = 0.80; FPR = 0.00). Principal component analysis (PCA) revealed greater immune variability in the high-risk group, particularly among proinflammatory mediators, suggesting immune dysregulation. This study demonstrates the utility of integrating whole blood immune profiling with high-sensitivity multiplex immunoassays, and applying both traditional statistical methods and machine learning to explore potential biomarkers for AUD risk. IL-1β is a statistically robust and clinically relevant candidate biomarker of AUD risk assessed by AUDIT scores. These findings require replication in larger, independent samples to determine their translational potential in addiction medicine
Heart Rate Variability Responses in Children With Medical Complexity Across Sensory Domains
Get PDFPurpose: Heart rate variability (HRV) is a physiologic marker of autonomic nervous system (ANS) health. Because of multisystem impairments, children with medical complexity (CMC) can be challenging to evaluate and assess. They commonly display ANS dysfunction and subsequently reduced HRV. One purpose of this study was to report respiratory sinus arrhythmia (RSA) values derived from HRV, which may provide a reference and a future method to assess CMC and related treatments. Methods: Then, 36 CMC between the ages of 5–21 years were assessed within school‐based settings. All children demonstrated severe brain impairment, functional limitations, participatory restrictions in life, and high healthcare needs and utilization. A subset of 20 children with cerebral palsy (CP) was identified within the study sample. Each child was assessed by the same assessor for 5 days within a 10‐day period. Using Firstbeat Bodyguard 2 monitors, cardiac data were collected prior to and during the administration of the newly developed Pediatric Assessment of Sensory Motor Awareness. CardioEdit and CardioBatch software were used to edit cardiac data and calculate RSA values. Descriptive, repeated measures, and modeling statistics were used to analyze data. Results: Descriptive RSA values for baseline and across five sensory domains are reported for the total CMC group and its subsets of children with CP and non‐CP. Significant differences in RSA values were noted for the gustatory domain as compared to baseline and other sensory domains. Significant differences from statistical modeling were demonstrated between the CP and non‐CP groups. Conclusions and Recommendations for Clinical Practice: This study’s HRV findings provide preliminary reference RSA values in CMC. Then, 20 children considered to be CMC with primary diagnoses of CP experienced less autonomic dysfunction than other CMC diagnostic groups at baseline and across the five sensory domains. The gustatory domain significantly reduced RSA. Modeling across days indicated that CMC experience a learning effect by Day 3 or 4. The measurement of HRV may provide a method to assess health and behavioral responses in CMC and associated treatments. Replication of these study findings will be necessary
Cultural Adaptation of Together+, a Status-Neutral mHealth Intervention to Improve HIV Prevention and Care for Adolescent and Young Men Who Have Sex With Men in Vietnam: Protocol for a Co-Design Study
Get PDFAdolescent and young men who have sex with men (AYMSM) are experiencing an ongoing epidemic in Vietnam. HIV testing and preexposure prophylaxis uptake among AYMSM remain low in Vietnam, especially compared to older men. AYMSM living with HIV are also less likely to initiate HIV care. M-Cubed is a status-neutral mobile intervention developed in the United States focusing on HIV prevention and care among men who have sex with men. The app has the potential to significantly contribute to improving the HIV prevention and care continuum for AYMSM. We propose to adapt the M-Cubed app for AYMSM in Vietnam to create Together+, a status-neutral app that promotes HIV testing, preexposure prophylaxis use, and HIV care. Adaptation will focus on ensuring that the content, features, and design of the app are culturally relevant to AYMSM in Vietnam. The adaptation process will comprise five phases: (1) adaptation and creation of videos and messages in Vietnamese, (2) in-depth interviews to further inform app adaptation, (3) app prototype development, (4) app theater testing, and (5) beta testing of the adapted app. AYMSM aged between 15 and 19 years and health care staff in Hanoi, Vietnam, will be recruited for in-depth interviews in phase 1 and focus group discussions in phase 4. Qualitative data will be analyzed thematically, and results will be generated after reviewing memos, code reports, and the matrix. To evaluate the feasibility and usability of the Together+ app, we will provide access to 30 AYMSM and encourage them to use the app for 30 days. We will assess observed use and collect quantitative and qualitative data from test users. After 30 days, we will evaluate the usability and feasibility of the Together+ app through in-app analytics as well as online quantitative surveys and individual exit interviews with participants. As of September 2025, we are in the process of adapting the set of 15 videos for Vietnamese AYMSM (phase 1) and analyzing qualitative data from in-depth interviews (phase 2). Data collection for the pilot phase will be completed by August 2026. Adaptations of proven effective interventions are a promising and efficient way to develop interventions for new service populations but require formal adaptation and evaluation in the new service population. Once culturally adapted for AYMSM in Vietnam, the Together+ app has the potential to significantly contribute to improving the HIV prevention and care continuum for this population. The findings of the adaptation process will document the level of usability and feasibility of the Together+ app and shed light on the perceptions of AYMSM and other stakeholders in Vietnam regarding status-neutral mobile health interventions. PRR1-10.2196/7389
Closed Loop Simulation as a Human Created Replay of History
Get PDFThis paper presents a conceptual thought experiment exploring the possibility that humanity might one day create a closed loop simulation to replay its own history. In this scenario, an advanced future civilization constructs a high fidelity simulation of the past and re-enters it, with participants’ memories of the outside reality suppressed to ensure authenticity. We examine this idea from technical, physical, and philosophical perspectives. Potential mechanisms for such a simulation are discussed, including the use of quantum computing and nanoparticle-based “computronium” matter to achieve the enormous computational power required. We consider how known physics phenomena; quantum indeterminacy, relativistic limits, and information theory; could manifest in or even enable a simulated universe. Possible observable indicators of living in such a simulation are reviewed, alongside the broader implications for free will, ethics, and the nature of reality. Counterarguments and limitations of the closed loop simulation hypothesis are also addressed. While firmly theoretical, this exploration connects advances in quantum mechanics and nanotechnology with enduring questions about consciousness and cosmology, offering a rigorous framework for contemplating the ultimate origins of our perceived reality