Citations

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

BACKGROUND AND OBJECTIVES: Myelomeningocele is defined by the presence of a fluid-filled sac that contains the neural placode and cerebrospinal fluid (CSF) at the level of the spinal defect. Alternatively, the term myeloschisis is used when the neural placode is not contained within a CSF-filled sac. While both are eligible for prenatal closure, few studies have characterized the impact of the type of lesion on postnatal outcomes. This study compares the outcomes of these 2 types of open spinal dysraphism using data from the Fetal Myelomeningocele Consortium registry sponsored by the North American Fetal Therapy Network. METHODS: The prospective observational Fetal Myelomeningocele Consortium registry was used to extract deidentified data corresponding to patients who underwent fetal closure of myelomeningocele vs myeloschisis. Demographics, operative characteristics, perioperative complications, and postnatal outcomes were collected. RESULTS: A total of 1327 patients were identified, including 991 (74.7%) with myelomeningocele and 336 (25.3%) with myeloschisis. Compared with myelomeningocele, myeloschisis was associated with lower rates of prenatal talipes (11% vs 24%, P < .001) and higher rates of favorable prenatal movement (94% vs 86%, P < .001). Postnatally, myeloschisis conferred higher rates of leg movement (97% vs 90%, P = .002) and an increased likelihood of ambulation in the household (10.4% vs 4.1%, P = .009) and outside (7.2% vs 1.9%, P = .004) at 1 year. However, myeloschisis was also linked to greater use of skin patches during closure (49% vs 27%, P < .001), higher CSF leak rates among those with wound dehiscence (26% vs 8%, P = .014), and more frequent CSF diversion and tethered cord surgeries at follow-up. CONCLUSION: Myeloschisis and myelomeningocele demonstrate distinct clinical profiles. Although patients with myeloschisis may have favorable motor outcomes, they are also characterized by higher rates of CSF leakage, CSF diversion, and tethered cord surgery. These findings highlight the need for lesion-specific prognostication and may inform surgical planning and parental counseling in the context of prenatal spina bifida closure.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Abstract Older adults with dementia account over 15% of intensive care unit (ICU) admissions and face higher risks of functional decline and complications. We systematically evaluated the difference in ICU-related outcomes in patients with and without dementia, (e.g., mortality, resuscitation and code status decisions, complications, duration of life support and hospital stay). Searches were performed in MEDLINE, EMBASE, SCOPUS, and Web of Science between 2003 and 2024. A random-effects meta-analysis was done of odds ratios (OR) and mean differences (MD) and their corresponding 95% confidence intervals (CI) were calculated. Fifteen studies, including 1,231,037 patients (12% with dementia), met the inclusion criteria. Adjusted analysis showed that patients with dementia had a higher risk of ICU mortality (OR = 1.05, 95% CI 1.00–1.11), 30-day mortality (OR = 1.54, 95% CI 1.47–1.62) and 12-month mortality (OR = 1.95, 95% CI 1.88–2.02). They were less likely to receive mechanical ventilation (OR = 0.73, 95% CI 0.62–0.85, I2 0.0%) and more likely to develop delirium (OR = 4.80, 95% CI 1.81–12.72). In patients with dementia, ICU stays were slightly shorter (MD = –1 day, 95% CI –1.7 to –0.4), and discharge home was less common (OR = 0.40, 95% CI 0.39–0.42). Older adults with dementia experienced greater risk of mortality and delirium, alongside less aggressive intervention use and healthcare utilization (i.e., shorter ICU stays). These findings underscore the need for prospective studies to optimize ICU decision-making and post-discharge care for this vulnerable population.

Abstract Background Plasma biomarkers offer improved accessibility compared to established diagnostic modalities for Alzheimer's disease (AD). However, current plasma biomarker candidates have not been tested comprehensively in diverse populations, and represent only a fraction of pathways dysregulated in AD. This study seeks to address these knowledge gaps through untargeted plasma biomarker discovery in African Americans (AA), an underrepresented group in AD research despite having a higher risk of developing dementia compared to non‐Hispanic Whites (NHW). Method Untargeted proteomics were generated using the SomaScan 7k platform on plasma samples from AA study participants clinically diagnosed as AD dementia ( n = 181) or cognitively unimpaired (CU; n = 142). Machine learning was implemented to identify a set of plasma proteins to distinguish between AD dementia and CU. Predictive models were constructed by elastic net regression optimized with nested cross‐validation on 6,853 proteins and evaluated by receiver operating characteristic analysis. The generalizability of plasma protein predictors was evaluated in an external Alzheimer's Disease Research Center cohort of 369 NHW and AA study participants diagnosed as AD dementia or CU. Result Thirty‐six proteins were selected as predictors. Proteins selected by machine learning were enriched for processes previously associated with AD including synaptic dysfunction, inflammation, vascular dysfunction, and amyloid processing. The 36 plasma proteins alone achieved an area under the curve (AUC) of 0.94 to classify AD dementia in the discovery cohort, representing a 22% improvement over a model including age and sex. The 36 proteins were validated in an external cohort also achieving AUC=0.94, a 35% improvement over age and sex. Conclusion Biomarker discovery combining untargeted proteomics and machine learning identified a set of plasma proteins that could serve as a novel and highly accurate diagnostic plasma biomarker panel for AD. Work is underway to assess the association of the predictive panel with p ‐tau217, medical comorbidities, and social/structural determinants of health.

Abstract Background Femoral version plays a critical role in pre-arthritic hip pain, particularly in femoroacetabular impingement (FAI). Variations in femoral version may contribute to hip instability or impingement. This study examines the outcomes of hip arthroscopy for FAI across different femoral version groups. Methods A prospective multicenter cohort of 677 FAI patients undergoing primary hip arthroscopy was collected, with 603 patients in this study based on recorded femoral version. Inclusion criteria were patients aged 14-45 years with idiopathic FAI, while previous ipsilateral hip procedures, associated disorders, or Tönnis 2 or greater osteoarthritis were excluded. Femoral version was measured on low-dose computed tomography (CT) utilizing the Yoshioka oblique method and categorized into five subgroups: &lt;5°, 6°-15°, 16°-25°, 26°-35°, 35°+. Patient-reported outcomes (PROs) were obtained at minimum one-year follow-up. The modified Harris hip score (mHHS) was assessed relative to minimal clinically important difference (MCID) of 8 and patient acceptable symptom state (PASS) of 74. Additional PROs included HOOS Pain and Sports/Recreation subscores and iHOT-12 score. Composite failure was defined as reoperation for persistent symptoms or failure to achieve either the mHHS MCID or PASS. Results Males had statistically lower femoral version than females (14.0 vs 18.0; p&lt;0.001). In females, 38.0% had a femoral version of 16°-25°, 17.9% between 26°-35°, and 3.6% greater than 35°, compared to 27.6%, 9.2%, and 1.8% in males, respectively (all p&lt;0.001). Increased or decreased femoral versions appear to have similar outcomes to normal version. The mildly increased femoral anteversion groups of 16°-25° and 26°-35° demonstrated the best outcomes with changes in HOOS pain and sports subscores being significantly higher. Severely increased femoral anteversion, &gt;35°, only present in 2.8% of patients, demonstrated a higher composite failure rate (15.4%) compared to moderately increased, 26°-35°, femoral version (3.1%). The decreased femoral version group, ≤5°, had a composite failure of 10.4% compared to normal femoral version, 16°-25° (10.2%). Conclusions The general anatomy differences between males and females lends males to be more in retroversion while females tend to be more anteverted. Overall, outcomes did not seem to differ between increased or decreased femoral versions but were superior at mildly increased femoral versions.

Abstract Background To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). Methods A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. Results Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). Conclusions This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. Clinical Trial Information NCT00592748.