Citations

Abstract DDX3X dysfunction causes an X-linked multisystem disorder with high penetrance and variable expressivity. The phenotypic spectrum spans from learning disability without somatic involvement to profound intellectual disability with severe impairments in the central nervous system and other organs. A few multicenter studies and single case reports have previously highlighted some common phenotypic patterns but were unable to delineate correlations between underlying DDX3X variants and phenotypic findings.From the second largest patient cohort published to date, we analysed clinical, psychometric and diagnostic findings of 52 female and 7 male individuals, harbouring de novo and inherited DDX3X variants. These female patients revealed previously unknown quantitative correlations between variant type and localization and specific phenotypic findings (growth features, epilepsy, brain anomalies, dysmorphisms, motor-focused neurological findings). Moreover, by analysing the in silico folding and RNA binding capability of mutant DDX3X monomers, we were able to delineate novel correlations between DDX3X monomer misfolding grade and phenotypic severity.

Abstract INTRODUCTION Hydrocephalus in pediatric patients is commonly treated with endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunting (VPS). When primary ETV fails, clinicians must decide between repeat ETV (Re-ETV) and VPS placement. However, the optimal secondary intervention remains debated. Objective: To compare the efficacy and outcomes of Re-ETV versus VPS placement following failed primary ETV in pediatric hydrocephalus. METHODS We conducted a systematic review following PRISMA guidelines. Searches of PubMed, Embase, and the Cochrane Library identified English-language studies (2001–2023) reporting on Re-ETV or VPS after failed primary ETV in patients aged 0–18 years. Comparative studies, including randomized controlled trials, cohort studies, and prospective designs were eligible. Two independent reviewers screened titles, abstracts, and full texts; extracted data on sample size, intervention rates, failure rates, and complications; and assessed study quality using RoB 2.0 and CASP tools. Pooled descriptive statistics and odds ratios (OR) were calculated for secondary intervention failure. RESULTS Nine studies (n = 663) met inclusion criteria. Re-ETV was performed in 220 patients (33.2%) and VPS in 443 (66.8%). Primary ETV failure rates ranged from 16.6% to 60.9% (mean 40.6%). Re-ETV exhibited a pooled failure rate of 74.98%, whereas VPS failure was 22.26% (OR 4.86; 95% CI 3.21–7.38; p < 0.05). Hemorrhagic etiology during primary ETV significantly favored VPS over Re-ETV (p < 0.05). Time to secondary failure averaged 15.8 ± 21.7 months, with broad inter-study variability. CONCLUSION VPS placement demonstrates a substantially lower failure rate than Re-ETV as a secondary intervention after primary ETV failure in pediatric hydrocephalus. Nevertheless, variability in patient age, etiology, and follow-up underscores the necessity of individualized decision-making. Prospective trials with standardized outcome measures are warranted to refine secondary treatment guidelines.

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Abstract Background Central nervous system (CNS) tumors are a significant cause of morbidity and mortality in sub-Saharan Africa (SSA). To date, no large-scale efforts have focused on brain tumor genetics within this region. This study aimed to assess and map the current neuro-oncology capacity in SSA, including workforce availability and existing services for brain tumor registries and biobanks. The results represent the final analysis representing respondents from 70 healthcare institutions. Methods This cross-sectional study utilized an online survey to collect data from healthcare professionals involved in CNS tumor care across SSA through the Society for Neuro-Oncology SSA (SNOSSA). The survey gathered information on the availability of neuro-oncology practitioners, neuropathology and molecular diagnostic capacity, brain tumor management, cancer registries, and biobanking of specimens. Purposive sampling was used to identify participants, with the questionnaire provided in English, French, and Swahili. Results A total of 145 respondents from 22 countries and 70 healthcare institutions participated. Among the 70 institutions, neurosurgery was available in 89%, anatomic pathology in 74%, and medical oncology in 71%. For radiologic evaluation, 64% of institutions reported having both CT and MRI, while 17% had CT only. Molecular testing through IHC or NGS was available in 46% of institutions. Multidisciplinary tumor boards for CNS cases were present in 86% of institutions. General cancer registries were available in 66% of institutions, while 29% had brain tumor-specific registries, and 10% maintained brain tumor biorepositories. Conclusion This study provides a comprehensive summary of the neuro-oncology capacity in SSA. Next steps are to reach out to institutions who have registries and determine what data are being collected, with the hopes of defining a set of common elements to expand registry efforts across SSA. Similarly, to reach out to institutions that have ongoing brain tumor biobanks and CT/MRI capacity to determine what infrastructure exists.

Introduction: Peripheral Arterial Disease (PAD) is a prevalent condition associated with considerable morbidity and mortality, a burden that is further intensified by the frequent co-occurrence of hypertension. The coexistence of these conditions not only amplifies cardiovascular risks but also complicates clinical management, thereby contributing to elevated mortality rates. Although their correlation is well understood, mortality trends in United States have not been studied. Methods: This study utilized International Classification of Diseases, 10th Revision (ICD-10) codes to extract age-adjusted mortality data for individuals with PAD and hypertension from the CDC WONDER (Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) cohort. The overall sample and subgroups defined by demographics (age, sex, race/ethnicity) and region (state, census and urban-rural status) were analyzed. Trends in mortality were quantified by computing associated annual percentage changes (APC) using Joinpoint Regression Program Version 4.9.0.0 trend analysis software. Results: A total of 540954 deaths were observed, of which 260517 were men (48.2%). Overall, the age-adjusted mortality rates (AAMR) exhibited a sharp increase from 1999 to 2001 (APC:25.3; 95% CI: -0.36,56.2), followed by a sustained decrease until 2017 (APC: -2.16; 95% CI: -11.1, -1.52), after which a notable upward trend was observed (APC:9.38; 95% CI: -0.38,24.1). A similar AAMR trend was seen on gender-based subgroup analysis with male patients showing the highest AAMR 13.5 (95% CI: 13.1,13.7) in 2020. Amongst all racial groups, Black or African American showed the highest 14.9 (95% CI: 14.8-15) while Asian or Pacific Islander showed the lowest 5.8 (95% CI: 5.7-5.9) AAMR over 2 decades. The West region had the highest overall age-adjusted mortality rate (AAMR) of 10.2 (95% CI: 10.2-10.3). Among individual states, Vermont displayed the highest AAMR, reaching 15.8 (95% CI: 15.1-16.5). Conclusion: Healthcare disparities are evident. The unprecedented recent increase in mortality rates, following years of successful decline, necessitates a thorough evaluation of healthcare policies and PAD treatment advancements to identify the causative factors behind this trend reversal.

Introduction: As the global elderly population grows, so does the incidence of acute coronary syndrome (ACS) requiring urgent intervention. Emergency coronary artery bypass grafting (CABG) may offer a survival benefit, but concerns remain about its feasibility and safety in critically ill elderly patients with multiple comorbidities. Description of Case: This single-surgeon case series includes eight patients >65 years old who underwent emergency CABG for ACS between September 2023 and September 2024. Comorbidities included diabetes, hypertension, CKD, COPD, and previous stroke. All patients were critically ill, requiring combinations of inotropes, intra-aortic balloon pump (IABP), and mechanical ventilation. Ejection fractions ranged from 20–45%, and EuroSCOREs ranged from 10.86 to 30.45. Standard cardiopulmonary bypass with moderate hypothermia and a single aortic cross-clamp was used. Postoperatively, complications included transient ischemic attacks, dialysis-requiring renal dysfunction, atrial fibrillation, and infections. All patients survived; extubation times ranged from 7 to 70 hours, and hospital stays from 5 to 12 days. Discussion: This case series examines outcomes of CABG in elderly patients, emphasizing that despite multiple comorbidities, through physiological assessment, CABG can safely be performed in critically ill patients Although the LVEF was low and multiple comorbidities like diabetes and chronic kidney disease, signify the importance of a comprehensive assessment of physiology beyond standard biomarkers is necessary to determine readiness for surgery. Ventilation times variations highlighted the consequences of pulmonary and hematological challenges encountered in these patients. Recent advances in surgical techniques and perioperative care have improved outcomes, and most patients showed enhanced quality of life and physical function within a year post-surgery. Conclusion: Emergency CABG can be a lifesaving therapy in critically ill elderly ACS patients. With careful perioperative management, advanced age and comorbidity burden should not preclude surgical intervention.

Background: In patients with paradoxical low-gradient severe aortic stenosis (AS) based on aortic valve area (AVA) at rest (<1cm2) and normal left ventricular ejection fraction (LVEF >50%), the role of dobutamine stress echocardiography (DSE) is unclear. While current guidelines recommend assessing aortic valve calcium score in this context, DSE may still offer clinical value. Methods: We conducted a retrospective study on patients with paradoxical low gradient AS (LVEF >50% AVA <1cm 2 , MG < 40 mmHg) at rest who underwent DSE after Institutional Review Board approval. Data was extracted using an internal database. Patients > 18 yrs old with LVEF >50%, mean gradient (MG) < 40 mmHg, and valve area < 1 cm 2 at rest were included. Kruskal-Wallis test was used to identify which resting variables were associated with severe AS (MG >40 mm Hg and Valve area <1 cm 2 ) with DSE. Results: A total of 42 patients were included in the study and variables were reported as means (±SD). The mean age of patients was 78 years (±10) and 60% were female. The mean resting LVEF was 60% (±5%), MG at rest was 28 mmHg (±7) while it was 40 mmHg (±14) with DSE, and mean aortic valve area at rest was 0.9 cm 2 (±0.09) while it was 1.1 cm 2 (±0.23) with DSE. Of the 42 patients, 11 (26%) were found to have severe AS during DSE, defined by a MG >40 mmHg and AVA <1.0 cm 2 . Baseline AVA and MG at rest were significantly associated with severe AS on DSE (p=0.008 and p=0.024, respectively), while age, stroke volume index, and baseline LVEF were not. Univariate regression analysis showed that the area under the curve (AUC) for predicting severe AS was 0.73 for resting MG and 0.77 for resting AVA. A resting AVA cutoff of 0.78 cm 2 provided optimal sensitivity (0.63) and specificity (0.90). For resting MG, a cutoff of 29 mmHg gave a sensitivity of 0.91 and specificity of 0.68 for identifying patients with severe AS. Conclusion: Our study indicated that DSE remains useful in identifying severe AS in substantial number of patients (26%) who exhibit paradoxical low gradient severe AS. Additionally, AVA at rest and baseline mean gradient were statistically the reliable parameters to determine those who may benefit significantly from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite “paradoxical low gradient severe AS” at rest. Further research is warranted to validate our findings.

Background: Chronic kidney disease (CKD) has been linked to elevated inflammatory biomarkers, yet few studies have evaluated these associations using iothalamate-based measures of kidney function, highlighting the need for further research. Research question: Is CKD associated with elevated inflammatory markers when defined by measured glomerular filtration rate (mGFR) and urinary albumin-to-creatinine ratio (UACR)? Methods: Participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort were included if they had data available for at least one inflammatory marker at visit 2. 17 inflammatory markers were assessed, including C-reactive protein (CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), serum amyloid A, intercellular and vascular adhesion molecules (ICAM, VCAM), E-selectin, P-selectin, monocyte chemoattractant protein (MCP), myeloperoxidase (MPO), receptor for advanced glycation end products (RAGE), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Kindey function was assessed using the urinary clearance of iothalamate. CKD was defined as mGFR < 60 mL/min/1.73 m 2 or UACR ≥ 30 mg/g. To further assess whether associations persisted without albuminuria, we also defined CKD solely by mGFR < 60 mL/min/1.73 m 2 . Generalized estimating equations (GEE) were used to assess associations between CKD status and inflammatory markers, accounting for familial clustering. Exponentiated beta coefficients from GEE models were used to present geometric mean (GM) ratios of each biomarker by CKD status, adjusted for demographics, lifestyle factors, cardiovascular risk factors, and medication use. Results: Among 1,010 participants (mean age 61 ± 10 years; 67% women; 48% Black adults), 207 were classified as having CKD. After adjusting for potential confounders, individuals with CKD had significantly higher levels of hsCRP, VCAM, TNFR1, and TNFR2 compared to those without CKD (GM ratios > 1; p < 0.05), while the remaining inflammatory markers showed no significant differences ( Figure 1 ). Importantly, these elevations remained significant when CKD was defined by mGFR alone ( Figure 2 ). Conclusion: Our findings suggest that CKD, defined by mGFR, is associated with specific inflammatory biomarkers, underscoring the need for mechanistic studies to investigate these associations.

Background: Susceptibility to cardiometabolic diseases (CDs) is shaped by genetic, socio-environmental, and lifestyle factors. We evaluated the associations of disease-specific polysocial risk scores (PSSs)— derived from social determinants of health (SDOH) and lifestyle factors—and genetic risk factors with six CDs, across self-identified race/ethnicity (SIRE) groups in the eMERGE IV cohort. Methods: The six CDs included: atrial fibrillation, coronary heart disease, chronic kidney disease, hyperlipidemia, obesity, and type 2 diabetes. Disease-specific PSSs were developed using machine-learning models based on 65 SDOH and lifestyle factors. Participants were grouped based on their SIRE as Asian, Black, Hispanic/Latino, and White. We evaluated PSS distributions across SIRE groups. Genetic risk was assessed through disease-specific polygenic risk scores (PRSs), monogenic etiologies, and family history (FamHx). High PSS and high PRS were defined as the top 5th percentile. Associations were tested using multivariable logistic regression; model performance was assessed using the C-statistic. Results: Among 20178 participants (50±15 years, 68% female, 40% non-White), the most frequently associated PSS components were physical activity, sleep, self-perceived health, and income. PSS distributions varied across SIRE groups, with Whites having the lowest and Black and Hispanic/Latinos the highest scores for most CDs (Figure 1). All PSSs were significantly associated with their respective CDs, independent of confounders (OR per 1 SD increase: 1.19–2.68; Figure 2-A). No significant interactions were observed between PSSs and PRSs or monogenic etiologies. However, significant interactions were noted between PSSs and FamHx for CKD and obesity. PSS and PRS effects on the odds of CDs were independent (Figure 2-B) and additive (Figure 2-C). Incorporating PSSs into models that included clinical and genetic risk factors improved predictive performance of risk prediction models (Figure 3). Conclusion: PSSs, reflecting socio-environmental and lifestyle disadvantage, varied significantly across SIRE groups and were associated with risk of six CDs, independent of and additive to PRS. Given the substantial variation in socio-environmental and lifestyle risks across SIRE groups, integrating these factors into risk prediction models for CDs may help address health disparities and enhance preventive efforts, especially in marginalized populations.

Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), familial hypercholesterolemia (FH), and family history (FamHx)- on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults -eMERGE IV (eIV) and All of Us (AoU). Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS CHD , PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS CHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P -diff=9.1×10 -3 , Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3). Conclusion: PRS CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.