Citations

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

Abstract Purpose Medical student education in geriatrics is a critical need for every doctor-in-training as the population ages, with fewer than 7,000 geriatricians, and older patients, who now approach 20% of the U.S. population, having unique health care needs. This study presents the updated competencies in geriatrics for graduating medical students, framed by the Geriatrics 5Ms (Mind, Mobility, Medications, Multicomplexity, and What Matters Most). Method From 2019–2022, a working group of the American Geriatrics Society (AGS) drafted the updated medical student geriatrics education competencies, using a modified Delphi approach. The working group reviewed the literature, conducted an initial survey of working group members, and drafted and refined proposed updates to the competencies. The 27 resulting competencies were disseminated as a national survey to geriatrics experts and medical school education deans. Following the national survey, the competencies were updated and presented at the 2021 AGS Annual Scientific Meeting and open to public comment before they were finalized. Results The 27 updated geriatrics competencies for medical students included several new competencies, such as a focus on health equity, frailty, deprescribing, and patient priorities. A total of 211 respondents completed the national survey, including geriatrics experts (187/398, response rate: 47.0%) and education deans (24/191, response rate: 12.6%). All 27 proposed competencies met the predetermined threshold of 70% cumulative agreement, with a range of 93.0% (174/187) to 100% (187/187) among geriatrics experts and 87.5% (21/24) to 100% (24/24) among education deans. Conclusions The updated Geriatrics Competencies for Graduating Medical Students met with broad agreement among the geriatrics experts and medical school education deans who responded to the national survey. By focusing on the Geriatrics 5Ms, the competencies highlight key knowledge and skills graduating medical students need for the first day of internship to be prepared to deliver age-friendly care to older adults under their care.

Objective: Pulmonary involvement is commonly observed in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), presenting with manifestations such as diffuse alveolar hemorrhage, inflammatory infiltrates, pulmonary nodules, and tracheobronchial disease. We aimed to identify distinct subgroups of tracheobronchial disease patterns in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using latent class analysis (LCA), and to evaluate their clinical characteristics and outcomes. Methods: We conducted a retrospective cohort study using electronic medical records of patients aged >18 years diagnosed with AAV and tracheobronchial disease between 1 January 2002 and 6 September 2022. Patients with follow-up <6 months were excluded. LCA was employed to identify disease subtypes based on 10 pre-defined indicators. Maximum likelihood estimation with 10 repetitions per model ensured robustness in model selection, guided by the Akaike information criterion (AIC). Patient and disease characteristics were summarized and compared across predicted classes. Statistical analyses included Kruskal–Wallis and Fisher’s exact tests for continuous and categorical variables, respectively. The primary outcome was time to relapse of the tracheobronchial inflammation after starting immunosuppressive medication, analyzed using the Kaplan–Meier method and log-rank tests. Secondary outcomes included severity of pulmonary disease on pulmonary function tests, endoscopic interventions, tracheostomy, or mortality during follow-up. Results: Among 136 identified AAV patients assessed for tracheobronchial involvement, 111 (81.6%) were included after excluding 25 without tracheal or bronchial disease. Predominant findings included subglottic stenosis (91.0%), lower tracheal stenosis (16.2%), and bronchial stenosis (17.1%). LCA identified a three-class model as optimal: tracheal predominant (n = 94), tracheobronchial (n = 12), and bronchial predominant (n = 5). Tracheal predominant patients showed reduced risk of ear, eye, and lower respiratory manifestations, with milder obstruction on pulmonary function testing (PFT). Tracheobronchial-class patients were prone to saddle nose deformity (50%), extensive lower respiratory involvement (91.7%), and renal disease (66.7%). Bronchial predominant patients exhibited severe obstructive disease (median forced expiratory volume in 1 s (FEV1)% predicted: 58, IQR 34–66; FEV1/forced vital capacity (FVC) ratio: 56.9, interquartile range (IQR) 43–63.3) but lacked systemic AAV manifestations. LCA classes did not predict outcomes such as endoscopic intervention, tracheostomy, recurrent tracheobronchial narrowing, or mortality. Conclusion: LCA shows promise in subtype stratification of AAV patients, yet its utility in predicting outcomes and guiding treatment remains limited based on our analysis. Future studies with enhanced phenotypic data and larger cohorts are warranted to improve predictive accuracy.

Artificial intelligence (AI) is revolutionizing healthcare by offering innovative solutions for diagnosis, treatment, and patient management. Only recently has the field of pediatric cardiology begun to explore the use of deep learning methods to analyze electrocardiogram (ECG) data, aiming to enhance diagnostic accuracy, expedite workflows, and improve patient outcomes. This review examines the current state of AI-enhanced ECG interpretation in pediatric cardiology applications, drawing insights from adult AI-ECG research given the progress in this field. It describes a broad range of AI methodologies, investigates the unique challenges inherent in pediatric ECG analysis, reviews the current state of the literature in pediatric AI-ECG, and discusses potential future directions for research and clinical practice. While AI-ECG applications have demonstrated considerable promise, widespread clinical adoption necessitates further research, rigorous validation, and careful consideration of equity, ethical, legal, and practical challenges.

OBJECTIVE To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring. RESEARCH DESIGN AND METHODS At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks. RESULTS Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI −0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by &gt;0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by &gt;0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects. CONCLUSIONS In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia.

Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset autoinflammatory disorder defined by somatic UBA1 mutations in hematopoietic cells. VEXAS is associated with a high frequency of clonal hematopoiesis (CH- 60%); with the clonal landscape being dominated by DNMT3A mutations. In our prior study (Gutierrez-Rodrigues Blood 2023), we showed that DNMT3A mutations in VEXAS associated with increased mortality, but without a higher risk of MDS/AML. As DNMT3A is a critical epigenetic regulator, we conducted this study to define the epigenetic deregulation and impact on mortality of DNMT3Amt (mutant) CH in VEXAS. Methods: After IRB approval, 88 VEXAS patients from the Mayo Clinic and the NIH were retrospectively assessed, including 81 screened for CH by error-corrected DNA sequencing (ECS). DNA methylation changes were identified using the Illumina Infinium MethylationEPIC BeadChip on peripheral blood samples (PB). Cellular indexing of transcriptomes and epitopes (CITE)-seq was performed using the 10x Chromium 3' GEX platform; 16,600 pooled cells were subjected to UMAP dimensionality reduction, followed by Azimuth based cell identification. Genotyping of targeted loci with chromatin accessibility (GoTChA) was conducted on two PB DNMT3Amt samples from CCUS individuals (Izzo et al Nature 2024). Results: Patients' median age was 70 years (range: 56 - 89); 95% were white. Twelve out of 81 patients screened by ECS were found with a DNMT3Amt (15%), with a median variant allele fraction (VAF) of 42% (range: 6-46%). In this cohort, while the presence of any CH mutation did not impact survival, DNMT3Amt CH had an age-independent negative impact on mortality (5.5 years vs 8.7 years, p =0.005), without an increase in risk for MDS/AML. Changes in DNA methylation were profiled in 19 and 9 VEXAS patients without CH (Median Age: 68) or with DNMT3Amt CH (Median Age: 74), respectively. VEXAS samples with DNMT3Amt CH had &gt;4,000 differentially methylated CpGs with 95% of the CpGs being hypomethylated compared to those without CH. Using the Roadmap Epigenomics project, we found that this hypomethylation was enriched at enhancer (Enh) sites and actively transcribed states (TxWk). Pathway analysis revealed that the hypomethylated sites were in or near genes involved in the development and differentiation of leukocytes, with IL-13 and IL-15 being identified as upstream regulators of the methylation changes. Bulk RNA-seq performed on PB of 2 and 3 VEXAS patients with and without DNMT3Amt, respectively, identified &gt;1,500 differentially expressed genes in DNMT3Amt samples, 78% of these being overexpressed. Pathway analysis was enriched in gene pathways involved in the development of leukocytes, with IL-13 and IL-15 once again being identified as upstream regulators. Integration of methylation and transcriptomic data identified upregulation of several genes within the IL-13 and IL-15 pathways, with these regions correlating with a decrease in methylation. To assess if the epigenetic dysregulation is linked to DNMT3A mutations, we performed GoTChA-seq on two DNMT3Amt clonal cytopenia samples (CCUS). The comparison of the number of cutsites in DNMT3A wild type vs mt cells from the same individual demonstrated increased open chromatin within the IL-13 and IL-15 pathways in mt cells, both globally and in a genomic locus specific manner. CITE-seq performed on 3 VEXAS samples (2 DNMT3Amt CH vs 1 no CH) further showed that expression of genes involved in IL-13 and IL-15 pathway is significantly increased in CD4+ and CD8+ T cells from DNMT3Amt samples, suggesting a paracrine regulatory effect of T lymphocytes (mostly UBA1 and DNMT3A wild-type) in VEXAS. Pathway analysis of DEGs in these cells also revealed an enrichment of genes involved in inflammation and lymphocyte proliferation. Conclusions: Our study validates the age-independent, negative prognostic impact of DNMT3Amt CH on survival in VEXAS syndrome. DNMT3Amt mediates epigenetic and transcriptional priming associated with upregulation of IL-13/15 pathway in CD4/CD8 T cells, which are mostly DNMT3A and UBA1 wild-type, suggesting that the contribution of T lymphocytes to inflammation may be secondary to CH in the myeloid compartment.

Background: Because of growing concerns regarding repeated head trauma, in 2016, the United States Soccer Federation (USSF) banned headers for athletes aged ≤10 years and limited athletes aged 11 to 13 years to practicing headers for 30 minutes per week. Purpose: To assess whether the USSF header policy was associated with fewer soccer-related concussions after the 2015 season. Study Design: Descriptive epidemiology study. Methods: A retrospective cohort from the National Electronic Injury Surveillance System database was assessed. Age, sex, and injury type were extracted for all soccer-related emergency department visits between January 1, 2012, and December 31, 2023. Univariate and multiple regression analyses were used to assess concussions as a percentage of all soccer-related injuries based on sex, age group (6-9, 10-13, and 14-17 years), and year. The following time frames were assessed: 2012-2015, 2016-2019, and 2020-2023. Results: The proportion of concussions decreased from 8.2% of all soccer-related injuries in 2012-2015 to 6.1% in 2020-2023 ( P < .01). The relative risk reduction for soccer-related concussions presenting to an emergency department in 2020-2023 compared with 2012-2015 was 25.6%. Overall, the proportion of concussions among 10- to 13-year-old and 14- to 17-year-old players was higher than for 6- to 9-year-old players (6.6% and 8.9% vs 4.9%, respectively; P < .01). Despite having a lower frequency of soccer-related injuries overall, female players had a greater proportion of concussions than male players (9.6% vs 6.2% of all soccer-related injuries; P < .01). In the multiple regression analysis, injuries that occurred in 2020-2023 were associated with lower odds of concussion compared with 2012-2015 (odds ratio [OR], 0.75 [95% CI, 0.69-0.81]). Compared with 6- to 9-year-old and male players, the 10- to 13-year-old (OR, 1.30 [95% CI, 1.16-1.45]), 14- to 17-year-old (OR, 1.79 [95% CI, 1.61-1.99]), and female players (OR, 1.53 [95% CI, 1.43-1.63]) were associated with higher odds of concussion. Conclusion: A 25.6% reduction in the relative risk of presenting to the emergency department with a soccer-related concussion was found when comparing 2020-2023 (after USSF header policy implementation) with 2012-2015 (before policy implementation). The USSF youth soccer header policy may improve player safety by reducing head impacts in the pediatric population.

ABSTRACT Background Flat bone chondrosarcomas have worse outcomes than extremity tumors, but there is no data directly comparing the different flat bones. The aim of this study was to examine differences in recurrence and survival between pelvic and scapular chondrosarcoma. Methods One hundred and sixty‐nine (42 scapula, 127 pelvic) patients with chondrosarcoma who underwent surgical resection were reviewed. High‐grade tumors were defined as lesions that were Grade 3 or dedifferentiated on surgical pathology. Results Patients with low‐intermediate grade lesions of the scapula were more likely to have positive margins during definitive surgical management (14% vs. 3%, OR 5, 95% CI [1.15, 22.6], p = 0.02), however, this did not translate to differences in recurrence or survival ( p > 0.05). The presence of an associated soft tissue mass in low‐intermediate grade lesions was not associated with increased recurrence. Among high‐grade tumors, patients with scapular lesions had worse DSS (HR 2.99, 95% CI [1.05, 8.51], p = 0.04). One‐ and 2‐year DSS for high‐grade pelvic tumors was 75% and 57%, respectively, and 50% and 33% for scapular tumors. Conclusion Survival for high‐grade chondrosarcoma of the flat bones is poor, particularly for those of the scapula. Despite a higher rate of positive margins for low‐intermediate grade lesions of the scapula, there was no significant difference in survival compared to low‐intermediate grade lesions of the pelvis. Additional studies with larger sample sizes are needed to further elucidate differences between these locations.

Recent literature has emphasized the role of hand surgeons in screening patients with carpal tunnel syndrome (CTS) for amyloidosis by performing a carpal tunnel synovial biopsy during open carpal tunnel release (CTR). This has led to misconceptions about the diagnostic utility of synovial biopsy and the clinical evaluation of suspected amyloidosis. Controversy over carpal tunnel biopsy is exacerbated by minimally invasive advances in CTR procedures. This current perspective aims to determine the role of carpal tunnel synovial biopsy in amyloidosis and provide an update for hand surgeons regarding the nuances of amyloidosis. We conclude that carpal tunnel synovial biopsy should not be performed without CTS symptoms but only in patients meeting criteria for open CTR such as in those with severe symptoms which have failed nonoperative treatment and minimally invasive procedures are contraindicated. A screening approach for amyloidosis is proposed in patients presenting with CTS symptoms. Despite advances in the understanding, treatment, and diagnosis of amyloidosis, there remains a need for accurate, specific, and sensitive diagnostic tests.