medRxiv : the preprint server for health sciences最新文献

Purpose: Germline deletions affecting the Y-chromosomal gr/gr region were reported in 2005 as associated with susceptibility to testicular germ cell tumor (TGCT), a highly heritable tumor type that is the most common cancer type affecting adult men under the age of 45. Attempts to replicate this association have been equivocal, primarily due to limited power.

Methods: Here, we compare and validate two computational approaches to gr/gr deletion calling in high-, low- and ultra-low-coverage whole genome sequencing data, applying these to two datasets from UK Biobank and the TECAC consortium. We generate dataset-specific effect size estimates for the gr/gr deletion-TGCT association using Firth's bias-reduced logistic regression across a total of 198,306 men of European-like ancestry (2231 with and 196,075 without TGCT).

Results: Upon random-effects meta-analysis of estimated effect sizes in the two datasets, we found no significant association between gr/gr deletion status and TGCT risk (combined odds ratio=1.24, 95% CI=0.74-2.07, p=0.42), nor upon stratification of seminoma and non-seminoma/mixed histological subtypes.

Conclusion: Our analysis suggests gr/gr deletion status alone is likely not predictive of TGCT risk in population-scale analyses of European-like individuals; however, the importance of other proposed determinants of gr/gr deletion impact, including Y-haplogroups and semen phenotype, remains unexplored at scale.

Background: Oculomotor dysfunction is common in parkinsonian syndromes and ataxias, but its impact on patient-reported vision-related quality of life (VQoL) remains insufficiently understood.

Objectives: To characterize VQoL across parkinsonian syndromes and ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias.

Methods: Participants were recruited at Massachusetts General Hospital ( n =231): 104 with Parkinson's disease (PD), 10 with progressive supranuclear palsy (PSP), 56 with genetically defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 healthy controls. VQoL was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed.

Results: All disease groups reported significantly worse VQoL than controls, with the largest deficits in visual processing speed. PSP showed the greatest impairment across all domains, while PD was less affected. Individuals with SCA3 and SCA6 had significantly lower VQoL across all subcategories. In ataxias, VQoL correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced VQoL.

Conclusions: Parkinsonian syndromes and ataxias are associated with substantial VQoL impairment, particularly in visual processing speed. Gaze-evoked nystagmus is a key predictor of reduced VQoL in ataxias, highlighting the functional relevance of fixation instability. Patient-reported outcomes and oculomotor assessments are essential for capturing visual disability in clinical care and trials.

Background: Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])-and late-life vascular brain injury, AD-related atrophy, and APOE -ε4 modification.

Methods and findings: We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by APOE -ε4. Longer reproductive span (OR=0.90 [95%CI 0.83-0.98]) and MHT use (OR=0.43 [95% CI 0.20-0.92]) were linked to lower SVD burden, particularly fewer perivascular spaces and microbleeds. OC and MHT were associated with greater white matter integrity, with additive use throughout life showing the highest fractional anisotropy (OR=0.45 [95% CI 0.12-0.78]). MHT use was associated with greater thickness in areas often affected in AD among APOE -ε4 carriers (β=0.38 [95% CI 0.01-0.76]) but not in non-carriers. Longer estrogen exposure was linked to stable cortical thickness and WMH trajectories over time.

Conclusions: Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's long-term impact on brain health and cognition to inform personalized medicine.

Objective: To characterize the clinical and administrative concerns communicated through secure ophthalmology messaging and to assess differences in message content across patient sociodemographic groups.

Design: Cross-sectional study of de-identified, patient-initiated secure messages sent between June 2014 and July 2024.

Participants: Patients with ophthalmic conditions who initiated secure electronic health record portal messages. Of 48 516 extracted message threads, 30 390 patient medical advice request messages from 4 817 unique patients were included after exclusion of questionnaires, courtesy messages, and clinician responses. Participants were 55.5% female, 56.9% aged 50 years or older, 48.7% White, and 85.7% non-Hispanic.

Methods: Natural language processing and large language model-assisted topic classification were used to categorize message content. Differences in message frequency by demographic subgroup were assessed using 2-proportion z tests.

Main outcomes and measures: Distribution of message topics and frequency of clinical concerns stratified by age, sex, race, ethnicity, and marital status.

Results: Nearly half of all messages addressed administrative issues, including scheduling, medication refills, and insurance. Among clinical concerns, vision disturbances (20.8%), glaucoma-related symptoms (8.7%), imaging or tumor-related questions (7.5%), and postoperative concerns (7.4%) were most common. Message content differed significantly by demographic characteristics. Non-White patients more frequently raised issues related to pharmacy refills, insurance, glaucoma, and disability documentation, whereas White patients more often reported surgical concerns. Older patients more frequently messaged about glaucoma, surgery, and tumor-related issues, while female patients more often reported complications and swelling or infection.

Conclusions: Secure patient messages frequently include clinically relevant symptoms with potential triage implications and demonstrate demographic differences in care-seeking behavior. Systematic analysis of message content may support safer triage, improved workflow efficiency, and more equitable delivery of ophthalmic care.

Background: Quantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic value in cardiac PET, but their widespread use is limited by the technical demands of dynamic imaging protocols. We evaluated the feasibility of using artificial intelligence (AI) to predict MBF and MFR from static and gated PET images, without the need for dynamic acquisition.

Methods: A machine learning (XGBoost) model was trained on 82Rb PET multi-center dataset using static perfusion imaging, injected dose, hemodynamic measures, clinical data and CT-derived features (including body composition) from the hybrid CT attenuation scan. Model performance was evaluated externally in an independent cohort.

Results: In total, 10,566 (derivation-cohort) and 7,842 (external-cohort) patients were included in this multi-center study. On the external-cohort, AI approach achieved an Area under the curve (AUC) of 0.92 (0.92-0.93) for abnormal stress MBF and 0.91 (0.90-0.92) for abnormal MFR; Intra-class correlation (ICC) 0.80 (0.78-0.82) and 0.78 (0.76-0.79), respectively. AI MFR closely mirrored the prognostic performance of measured MFR, showing nearly identical Kaplan-Meier risk stratification (both p<0.0001) and maintaining strong, and independently significant associations with all-cause mortality (HR 3.4 [2.8-4.2] vs. 4.6 [3.6-5.8]; both p<0.001), and demonstrated similar added value to perfusion for mortality prediction.

Conclusion: AI-predicted virtual stress MBF and MFR assessment using static and gated PET data is feasible and generalizable across cohorts. By removing the dependency on dynamic acquisitions, this approach has the potential to broaden the clinical adoption of flow quantification. Key Question: Can machine learning models trained on dynamic PET datasets accurately predict regional stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) from static image features, physiological parameters, and CT-based anatomical measures? Key Finding: Artificial intelligence can accurately estimate MBF and MFR from non-dynamic PET data, with strong agreement to reference standards. Take-home Message: By eliminating reliance on dynamic PET acquisitions, machine-learning has the potential to broaden clinical adoption of quantitative flow assessment.

Background: American Indian/Alaska Native individuals are disproportionately affected by end-stage kidney disease. Once diagnosed, treatment options include receiving a kidney transplant or starting dialysis. Disparities in treatment options are linked to social determinants of health, and in rural areas, dialysis is often the preferred treatment due to limited access to transplant. A recent nationwide analysis of survival differences showed a survival advantage after starting dialysis but also found that patients in these populations are less likely to receive hospice care before death. They face early diagnosis, leading to more years on dialysis and reduced quality of life. Using a predictive model can help identify factors that affect hospice use among patients. This study proposes a predictive model to estimate the likelihood of hospice use before death among patients who received a kidney transplant.

Methods: Using the 2022 USRDS Standard Analysis Files, adults who fit inclusion criteria were retrospectively identified. Area Deprivation Index (ADI) data, used for this analysis, includes 17 variables from US Census data, such as income, education, housing security, employment, and healthcare access, to generate the standardized ranking. This study employed regression tree, random forest, boosting, and support vector machine techniques to predict hospice use among participants. The covariates used in this study are race, IHS region, age, sex, mean ADI, comorbidities, and transplant status. Models are assessed based on their predictive performance using accuracy, sensitivity, and specificity.

Results: The random forest model outperforms others in accuracy, boosting offers the best sensitivity, and support vector machine and random forest excel in specificity. Overall, random forest and boosting are top models, with logistic regression as second-best. Logistic regression provides more interpretable results. The results, however, suggest a nonlinear relationship between covariates and the response that logistic regression might not capture. Based on both metrics, IHS region, age, and ADI are the most important features.

Conclusions: Including measures like the ADI in predictive models highlights geographic disparities that are often overlooked and can guide interventions toward communities that have been historically underserved. Researchers and healthcare systems should improve access to hospice and palliative care for those who face these disparities.

Psychotic-like experiences (PLEs) are common in youth and predict later mental health problems. Bullying victimization is a robust environmental risk factor for psychopathology including PLEs, but whether its association with PLEs reflects shared genetic liability, individual-specific putatively causal effects, or reciprocal processes is unclear. We analyzed seven waves of longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study, examining associations across the sample in addition to leveraging within-family comparisons among twin and sibling pairs who were concordant or discordant for exposure to bullying victimization. Using linear mixed-effects and cross-lagged models, we found that youth reporting bullying victimization were more likely to endorse significantly distressing PLEs than non-victimized youth (caregiver-reported odds ratio=2.35; youth-reported odds ratio=4.10). Longitudinal analyses revealed bidirectional associations: prior bullying predicted subsequent increases in distressing PLEs, and prior PLEs predicted elevated risk of later bullying victimization. Genetically-informed within-family analyses indicated that both shared genetic influences and individual-specific factors contributed to these associations; critically, bullied youth exhibited higher odds of distressing PLEs than their non-exposed siblings (youth-reported odds ratio=6.67; 95%CI:4.96-8.96), consistent with an individual-specific effect of victimization. Together, these findings suggest that bullying and PLEs are linked through reciprocal developmental processes that are not fully explained by familial confounding. More broadly, our results highlight bullying prevention as a plausible leverage point for reducing early psychosis-spectrum risk and illustrate the value of integrating within-family designs to help disentangle genetic and environmental contributions to mental health outcomes in adolescence.

Significance statement: Understanding how early adversity shapes mental health trajectories is important for science and public policy. Using nationally representative, longitudinal twin and sibling data, analyses show that bullying victimization and psychotic-like experiences in youth are linked through reciprocal processes that cannot be fully explained by shared genetics or family background. Bullied youth were more likely to endorse distressing psychotic-like experiences than their own non-bullied siblings, providing rare evidence for individual-specific effects of bullying victimization. Early psychotic-like experiences also increased subsequent risk of being bullied, suggesting a potential feedback loop that may compound risk. These findings demonstrate how social environments and mental health dynamically interact and point to bullying prevention as a population-level strategy with potential to reduce early psychopathology risk.

Purpose: Endovascular therapy is preferred over open surgery due to its minimally invasive nature, faster recovery, and lower perioperative risk; however, fluoroscopy guided procedures are limited by radiation exposure, high equipment costs, and reliance on highly skilled operators. This study aims to develop and evaluate a lightweight, portable robotic system for autonomous guidewire navigation to improve safety, accessibility, and operator independence.

Methods: A compact 400 g robotic device was designed with millimeter scale positioning accuracy, servo current based real-time haptic feedback, precise axial rotation, automated retraction advance control, and compatibility with standard endovascular tools. Miniature linear actuated servomotors replicate skilled manual maneuvers using impedance control. Upon tip contact, the system advances the guidewire by 1 mm, measures current changes, classifies lesion stiffness (soft, medium, stiff), and adapts virtual mass-spring-damper gains to regulate push speed and applied force. Bench experiments were conducted using flexible tubing with inserts simulating 20-80% stenosis and two current thresholds (75 mA and 94 mA).

Results: Retraction frequency increased with stenosis severity, validating the autonomous control strategy. Lesion stiffness classification achieved F-scores of 0.83, 0.77, and 0.95 for soft, medium, and stiff conditions, respectively, demonstrating reliable discrimination and adaptive force modulation.

Conclusions: The proposed system enables autonomous and adaptive guidewire advancement with high classification accuracy using low-cost, current based sensing and impedance control. Its lightweight and portable design reduces dependence on continuous manual operation and specialized imaging infrastructure, supporting safer and faster interventions and potential deployment in prehospital or resource-limited settings. This prototype advances the development of more accessible and operator-independent endovascular therapy.