Citations

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Objective This study aims to better characterize the long‐term neurological quality of life (QOL) outcomes (using the Neuro‐QOL scale) in survivors of new onset refractory status epilepticus (NORSE), including its subtype febrile infection‐related epilepsy syndrome (FIRES), and provide guidance for psychological and social support strategies. Methods Utilizing data from a multicenter prospective study of NORSE/FIRES led by Yale University, we enrolled patients who completed the validated, patient‐reported Neuro‐QOL scale at least once at 3–6 months ( n = 37), 12 months ( n = 29), 24 months ( n = 23), or ≥36 months ( n = 9) following discharge. The Neuro‐QOL scale assesses physical, mental, and social health in patients with neurological disorders. QOL impairment (QOL‐I) scores were calculated, with higher scores indicating greater impairment. T ‐scores enabled comparisons with reference populations. Results In adults, median QOL‐I improved from 44.1% at 3–6 months to 37.6% at 36+ months. Paired analysis showed significant improvement in QOL‐I between 3–6 and 24 months ( p = .016), with specific improvements in communication, satisfaction with social roles, fatigue, and mobility. Greater improvement was also observed for participation in social roles (5.5‐point T ‐score gain) compared to the reference population, suggesting meaningful change. A gradual improvement in overall QOL‐I scores was also observed in pediatric participants, despite a modest sample size ( n = 5 with data at 3–6 and 12 months). Measures of fatigue and anxiety persisted in adults, and cognitive difficulties persisted in both adults and children. In adults, longer status epilepticus duration and intensive care unit stay were associated with poorer QOL. Additionally, a higher number of antiseizure medications was associated with more depression, cognitive impairments, and perceived stigma. Significance These findings highlight the potential for recovery following an acute episode of NORSE, although many patients continue to face challenges requiring ongoing support, and the clinical meaning of the reported QOL improvement remains unclear. Furthermore, the findings underscore the importance of strategic multidisciplinary support systems in the years following discharge.

Abstract Background: Black or African Americans (AA) with Parkinson’s disease (PD) are underrepresented in both care and research and experience significant health disparities. The existing literature provides limited guidance on how to enhance the engagement of AA individuals in PD care and research, particularly from the perspectives of AA patients, care partners, and healthcare providers. This project aimed to (1) describe the use of Community Engagement (CE) Studios as a community-engaged research approach to inform culturally appropriate and inclusive research and (2) examine factors influencing AA engagement in PD-related activities. Methods: We conducted three CE Studios: one with AA with PD and care partners (N = 6), one with healthcare providers of AA with PD (N = 8), and one with AA with PD, care partners, and healthcare providers (N = 4). Results: The CE Studios informed the design (e.g., cultural appropriateness) and conduct (e.g., accessibility) of the planned PD project, as well as identifying stakeholders to engage with, improving alignment between research and the AA community. We highlighted the importance of multifaceted factors, including environmental (e.g., segregation), biological (e.g., symptoms), sociocultural (e.g., not being invited), and behavioral (e.g., empowerment) domains, which influence AA engagement. Conclusions: The CE Studios method is a feasible and useful approach for understanding the perspectives of AA in PD. It is possible to conduct an in-depth exploration of community perspectives by synthesizing comprehensive analyses and leveraging additional frameworks. These efforts include identifying barriers to engagement, recognizing locally relevant individuals, and refining PD-related care to enhance cultural appropriateness.

Background: Treatment decisions in patients with anterior cruciate ligament (ACL) injuries are influenced by multiple factors, such as the desire to return to sports or symptomatic instability. Identifying the differential treatment effect of ACL reconstruction (ACLR) compared with nonoperative management on a patient-specific level can inform surgical decision-making. Hypothesis: Unsupervised machine learning can identify distinct patient subgroups based on outcome achievement after ACL injury, and ACLR will exert a protective effect on the development of posttraumatic osteoarthritis (PTOA) over nonoperative management. Study Design: Cohort study; Level of evidence, 3. Methods: A longitudinal populational registry identified patients with ACL injuries from 1990 to 2016 with a minimum 7.5-year follow-up. An unsupervised random forest algorithm was utilized to develop and validate patient subgroups. Treatment effects of ACLR on outcomes were analyzed using a machine learning causal inference estimator. Patient subgroup membership was incorporated into a multivariable logistic regression to identify factors predictive of optimal outcomes. Results: A total of 923 patients (785 primary ACLR, 138 nonoperative) were included. The random forest algorithm arrived at an optimal partition of 2 subgroups, with 653 patients in the optimal outcome subgroup (368 male [56.4%]; mean age, 26.0 ± 10.2 years; mean body mass index [BMI], 26.5 ± 4.30) and 270 patients in the suboptimal outcome subgroup (152 male [56.3%]; mean age, 35.0 ± 10.1 years; mean BMI, 30.5 ± 5.54). The latter group demonstrated significantly increased rates of secondary meniscal injury, development of symptomatic PTOA, and progression to total knee arthroplasty (TKA) at the final follow-up (all P < .01). In the optimal outcome subgroup, ACLR had significantly protective treatment effects on the risk of secondary meniscal injury (average treatment effect [ATE], 61%), contralateral ACL injury (ATE, 8%), symptomatic PTOA (ATE, 16%), and progression to TKA (ATE, 6%) (all P < .01). Conversely, in the suboptimal outcome subgroup, ACLR only protected against symptomatic PTOA (ATE, 11%) and progression to TKA (ATE, 8%) (both P < .01). Conclusion: Two clinically meaningful subgroups were identified from retrospectively collected data and found to experience differential treatment responses after ACL injuries. ACLR decreased the rate of development of PTOA and TKA in both subgroups but was not as effective in preventing secondary meniscal injuries or contralateral ACL injuries in patients who were older, heavier, or had concomitant medial meniscus injuries.

Abstract Background Flow‐related ghost artifact from a 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence results from unsaturated magnetization of incoming arterial flow. This is especially common on MR scanners equipped with smaller radiofrequency (RF) transmit coils. A high‐performance compact 3T (C3T) scanner features a smaller RF‐transmit coil (inner diameter 37 cm, length 40 cm), leading to a rapid fall‐off of the B1 field below the neck. This configuration results in more intense flow‐related ghost artifacts, especially in younger patients. Purpose The C3T scanner's smaller RF‐transmit coil provides RF field coverage over the brain region, causing bright in‐flow arterial signals and flow‐related artifacts in the conventional 3D‐MPRAGE scans. The purpose of this study is to suppress these artifacts by adding a RF saturation band (RFSB) pulses to the 3D‐MPRAGE sequence. Methods The RFSB was added to the 3D‐MPRAGE sequence as a preparation pulse option. To test the effectiveness, 37 subjects were scanned on the C3T under an IRB‐approved protocol using 3D‐MPRAGE with and without RFSB. Ten of those subjects underwent repeated scans with and without RFSB to evaluate test‐retest reliability. A consensus evaluation by two neuroradiologists was performed on all data to compare signal to noise ratio, image contrast, presence of artifacts, and diagnostic confidence. Quantitative analysis included calculating test‐retest differences by image subtraction and evaluating the variance in flow‐artifact‐induced image intensity between the scans with and without RFSB. Additionally, one subject was scanned on a whole‐body 3T scanner using a transmit/receive (T/R) head coil to demonstrate the method's applicability across different MRI platforms as a proof of concept. Results The Wilcoxon signed‐rank test of the neuroradiologist evaluations showed a significant reduction in artifacts and an improvement in diagnostic confidence in the posterior fossa region with and without RFSB ( p < 0.0001). Test–retest analysis showed that adding RFSB significantly reduced image intensity variability in the cerebellum, even among subjects without visible flow artifacts. The normalized difference decreased from 8.71% to 6.41% ( p = 0.0059), suggesting improved image reliability in regions prone to flow‐related artifacts. Additionally, similar findings were observed in scans on a whole‐body 3T with a T/R head coil, demonstrating the broader applicability of this method. Conclusion Incorporating RFSB into 3D‐MPRAGE scans effectively reduces flow‐related ghost artifact on the C3T scanner, improving image quality and diagnostic confidence. These findings suggest that the proposed method could be widely implemented across MRI systems utilizing a smaller RF‐transmit coil.

Abstract Background Dose‐driven continuous scanning (DDCS) is a type of beam delivery in Hitachi pencil beam scanning (PBS) particle therapy system. Particle beam is irradiated continuously between spots to achieve a higher effective dose rate and a shorter beam delivery time. The beam is only turned off at break spots, the end of a treatment layer and during spill change. The break spot is a unique feature of the DDCS introduced by the treatment planning system (TPS) to interrupt continuous scanning. DDCS separates the dose delivery of a spot into a move dose and stop dose components. The move dose is controlled by the scanning speed and beam current, while the stop dose delivers the remaining monitor units (MUs). Hence, rigorous quality assurance (QA) of the scanning speed and functionality of break spot are required to ensure safe and successful DDCS delivery. Purpose We aim to report for the first time the QA methodology and result for DDCS, focusing on the scanning speed and break spot validation. Methods A rectangular spiral irradiation pattern with different degree of break spots were irradiated on a 2D strip ionization chamber (CROSSmini) detector using 50 time resolution to validate the break spots. Four methods of measuring scanning speeds were proposed. Using a spiral irradiation pattern, methods one and two applied linear regression to the scanning time measured by the CROSSmini for different inter‐spot distances, with measurements taken at sampling rates of 5 and 20 kHz, respectively. Methods three and four measured the scanning time of single inter‐spot distances in the X and Y directions. Method three measured the scanning time with the CROSSmini while method four measured the rise and fall time of the scanning magnet (SCM) current. All measurements were performed with 70.2, 150.2 and 228.7 MeV proton beam energies and three different beam currents of 8, 14 and 20 MU/s. Lastly, the scanning speed tolerance limit was calculated analytically under the requirement of avoiding a beam abort when the stop dose was less than zero. Results The data recorded by the CROSSmini under the spiral irradiation patterns with break spots was reconstructed into a 2D dose, and the break spots’ operations were visually validated for all the energies and beam currents. There were no statistically significant difference in the measured X and Y scanning speeds across the four methods. However, the last method involving the SCM current yielded the largest type A uncertainty of up to 25% () due to the noisy signal. The first method with the linear regression and 5 kHz acquisition rate was preferred due to a smaller type A uncertainty of up to 2.0% and a lower false negative rate in detecting the rising and falling edges during scanning. The calculated tolerance limit based on our current DDCS setting was found to be 0.50 times of the expected scanning speed. Conclusion We have introduced QA protocols for DDCS, designed to ensure complete and safe beam delivery without interruptions caused by move doses exceeding planned spot doses.

ABSTRACTBackgroundCalcium hydroxylapatite (CaHA) is a biostimulatory filler frequently used in a hyperdilute form to improve skin quality. While generally safe, nodule formation is the most common adverse event, particularly in dynamic areas.AimsTo describe a case of delayed‐onset CaHA nodules in the neck and review anatomical and procedural factors contributing to this complication, as well as prevention and management strategies.PatientA 72‐year‐old woman underwent three sessions of hyperdilute CaHA injections to the neck, with recent or concurrent onabotulinumtoxinA injections. After the third treatment, which followed a longer interval since her last botulinum toxin injection, she developed multiple firm, non‐tender nodules. A stepwise approach with intralesional saline injections—initially using needles and later a cannula—was implemented.ResultsInitial saline injections with small‐gauge needles yielded minimal improvement. Transitioning to a 22G cannula enabled both saline delivery and mechanical disruption, resulting in complete resolution after five total treatments. The patient has remained recurrence‐free for over 2 years.ConclusionsNodule formation following CaHA injection is most often due to product aggregation, and is particularly common in dynamic areas with thin overlying skin. Combining treatment with botulinum toxin may reduce this risk by limiting movement. Other preventive strategies include using higher dilutions of CaHA, avoiding high‐risk areas, and optimizing injection depth. When nodules do occur, mechanical disruption with a cannula combined with saline injection is a safe, effective, and minimally invasive first‐line treatment.

Abstract The external globus pallidus (GPe) has traditionally been viewed as a relay nucleus within the basal ganglia (BG), but accumulating evidence indicates a more dynamic role in reinforcement learning (RL). One key characteristic of GPe activity—transient pauses in high-frequency discharge (HFD) neurons—is preserved across species, yet its potential implications in RL remains unclear. Here, we developed a neurophysiologically grounded computational model to investigate the origin and role of GPe pauses in RL. Our model successfully replicated a range of empirical observations, including pause dynamics during learning and cue-related activity modulation. We demonstrated that the GPe-subthalamic nucleus (STN) circuit functions analogously to a denoising autoencoder, modulating baseline excitability in downstream BG circuits and that GPe pauses emerge as circuit-level consequences of strong, convergent inhibition from the GPe to STN. Simulations and in vivo recordings revealed that the activity of GPe-STN projecting neurons increases following sudden environmental changes, promoting adaptive exploration by disrupting action value contrast. Intriguingly, this same configuration impairs performance with extended training, suggesting that habitual behavior may benefit from weakened GPe-to-STN projections. These findings provide a unifying framework for understanding GPe pause dynamics and highlight circuit-level distinctions supporting the balance between flexibility and proficiency in RL.

Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment. Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials.

ABSTRACT Objectives Multicenter research of geriatric emergency department (GED) care remains limited. Our objectives were to: 1. Prospectively collect data prioritized by the Geriatric Emergency care Applied Research (GEAR) network, a transdisciplinary taskforce for GED care, and create a multicenter GED research repository of prospective and electronic health record (EHR) data, 2. Assess concordance between prospective and EHR data. Methods The GEAR Standardization Study (GEARSS) is a multicenter, prospective study of older emergency department (ED) patients (65+) focusing on the 4Ms of age‐friendly care (mobility, medication safety, mentation, what matters) and elder mistreatment. Demographic and clinical data were collected via interviews by trained research assistants (RA) on Days 0, 4, 30, and 90 and linked to EHR. Prevalence of chronic comorbidities and incident delirium were measured and reported using descriptive statistics. Prospective and EHR data concordance was assessed with Cohen's Kappa. Results 999 participants were recruited from 5 EDs (3/25/2021–6/30/2022) across 3 institutions: Grady Health System, Northwestern Memorial Hospital, and Yale New Haven Health. The cohort was 57.0% female, 55.2% White, 39.1% Black, and 3.4% Hispanic, and the mean age was 75.1 years. For rheumatologic disease, peptic ulcer disease, diabetes, renal disease, and cancer, prevalence differed between prospective and EHR data by > 10%. About two‐thirds of participants were at risk for falls. Concordance between prospective and EHR data was good for ethnicity ( K = 0.73); excellent for sex ( K = 1.00), age ( K = 1.00), and race ( K = 0.98); fair for disposition ( K = 0.53); slight for ED observation status ( K = 0.33) and dementia diagnosis ( K = 0.24); poor for delirium presence ( K = 0.07). Conclusion In GEARSS, demographic variables aligned strongly between prospective and EHR data, while diagnosis, disposition, and mentation factors did not. This multicenter data source provides preliminary findings for common geriatric syndromes and conditions. Choice of measures using these data should be driven by GED research questions.