Citations

Introduction: Procedural competence is essential to clinical practice, yet assessment of technical skills such as suturing remains highly variable and often relies on subjective evaluations. While tools with limited validity evidence exist in surgical specialties, their use in family medicine is limited. This study evaluated the interrater reliability of a suture assessment tool developed by Sundhagen et al when used by family medicine faculty to evaluate the simple interrupted suturing skills of family medicine residents. Methods: In this cross-sectional reliability study, 15 core faculty members from four family medicine residency programs were recruited to evaluate the simple interrupted suturing skills of 20 family medicine residents using a modified suture assessment tool developed by Sundhagen et al. Intraclass correlation coefficients were used to evaluate interrater reliability. Light’s κ was calculated for each question. Results: A total of 15 evaluators assessed 20 videos of resident suturing performance. The Light’s κ estimates ranged from 0.11 to 0.50, indicating slight to moderate agreement. None of the items reached the threshold for substantial agreement (κ≥0.61). Conclusions: The modified Sundhagen suture assessment tool demonstrated fair to moderate reliability when used to evaluate family medicine residents. While the level of agreement limits the tool’s effectiveness for standardized summative assessment, the tool may still offer value as a structured framework for formative feedback. Future studies may improve reliability through refined rater training, behaviorally anchored scoring criteria, and the use of visual exemplars.

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Abstract BACKGROUND Children exposed to poverty during frontline therapy for B-lymphoblastic leukemia (B-ALL) experience inferior overall survival (OS), higher relapse rates, and earlier relapse than their peers. Real-world data describing treatment patterns and survival after relapse of B-ALL are lacking and, as a result, the impact of poverty following relapse remains poorly understood. This study evaluated the association of poverty exposure, proxied by insurance status, with post-relapse survival and explored potential explanatory mechanisms, including disease biology and therapy utilization. METHODS Data from Retrospective Study of Contemporary Approaches to First Relapse in B-ALL (ReCALL-1), a multicenter retrospective cohort study of patients &lt; 30 years old with first relapse of B-ALL from 2018-2022, were used. The primary exposure was poverty, proxied by insurance status at relapse, categorized as any private insurance (poverty unexposed), public-only insurance (poverty exposed), no insurance, or unknown; the latter two were not included in comparative analyses due to low numbers. The primary outcome was OS. Secondary outcomes included measurable residual disease (MRD)-negative second complete remission (CR2), relapse after CR2, non-relapse mortality (NRM), with relapse treated as a competing risk, and receipt of cellular and immunotherapies. RESULTS Among 462 patients from 31 U.S. institutions, 41% had private insurance, 47% public-only insurance, 2% no insurance, and 10% unknown. Compared to privately insured patients, those with public insurance were more likely to be Hispanic (56% vs 19%, p&lt;0.001) and have non-English preferred language (30% vs 6%, p&lt;0.001). Non-Hispanic Black patients comprised 9% of those with public insurance and 5% of those with private insurance. Disease characteristics that differed by insurance status at relapse included: Ph-like cytogenetics, more common in publicly insured (23% vs 11%, p=0.002), and infant ALL, more common in privately insured patients (10% vs 5%, p=0.06). Publicly insured patients were more likely to have experienced major organ toxicity during frontline therapy (32% vs 18%, p=0.002) and very early relapse (&lt;18m from diagnosis: 43% vs 32%, p=0.07). Other demographic and disease characteristics, including relapse site and cytomolecular features, were similar by insurance status. With a median follow-up of 51 months from relapse, 4-year OS differed by insurance (log-rank p=0.02): 72% for private vs 56% for public insurance. After adjusting for race/ethnicity and language, public insurance increased the hazard of death by 65% (aHR 1.65 95% CI 1.13-2.42, p=0.004). The association remained, but was attenuated, when unbalanced disease characteristics (time to relapse, infant ALL, Ph-like cytogenetics, prior organ dysfunction) were included (aHR 1.47, 95% CI 1.00-2.16, p=0.05). Rates of MRD-negative CR2 were similar (85% public vs 87% private). However, point estimates suggested publicly insured patients had more relapse after CR2 (44% vs 37%, p=0.42) and higher 4-year NRM (16% vs 10%, Gray's test p=0.12), though neither were significant. Treatment choices for first relapse did not differ by insurance status. Utilization of intensive reinduction (91% vs 95% for public vs private, p=0.18) and clinical trial enrollment (22% for both) were similar. Receipt of cellular therapies did not significantly differ by public vs private insurance: Chimeric Antigen Receptor-T cells (CAR-T: 38% vs 34%, p=0.41), hematopoietic cell transplant (HCT: 42% vs 47%, p=0.32). Use of blinatumomab trended higher in those with private insurance (36% vs 45%, p=0.07), and inotuzumab was similar (11% for both, p=0.87). Median time from relapse to CAR-T or HCT was comparable (to CAR-T 102 vs 100 days, to HCT 117 vs 114 days). CONCLUSION This is the first study to demonstrate differential survival by insurance type, a proxy for poverty exposure, after first relapse of B-ALL. In this large multicenter, real-world cohort, patients with public insurance had worse OS after relapse than those with private insurance. The survival disparity existed independent of other SDOH factors. Adjustment for known high-risk disease features only partially accounted for the observed differences in OS. In contrast, rates of MRD-negative CR2 and receipt of CAR-T and HCT were comparable across insurance types. These findings highlight the urgent need to identify effective interventions that will ensure equitable outcomes after relapse.

Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients &lt;30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary &lt;36m; isolated extramedullary &lt;18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p&lt;0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised &gt;40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients &lt;30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (&lt;18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (&lt;0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed &lt;18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p&lt;.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses &lt;18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.

Background Patients with single-ventricle physiology are often palliated with the Fontan operation, which may involve the creation of a fenestration. We aimed to evaluate differences in cardiopulmonary exercise test (CPET) performance between patients with fenestrated and non-fenestrated Fontan circulation. Methods Patients with a Fontan circulation referred to CPET between 2006 and 2024 were included and were categorised based on their fenestration status at the time of CPET. Logistic regression analyses were performed to assess the impact of fenestration on peak oxygen consumption (VO 2 ), and Cox proportional hazard to evaluate the impact of fenestration on cardiovascular outcomes (death, heart transplant and Fontan-related hospitalisation). Results Of the 184 patients, 141 were classified as non-fenestrated and 43 as fenestrated. The minute ventilation-carbon dioxide production (V E /VCO 2 slope) was higher in the fenestrated (36.9±7.9) versus (33.2±6.2; p=0.009) in the non-fenestrated group. There was no significant difference in predicted VO 2 between groups (non-fenestrated 51.9%±14.4 vs 51.3%±15.6; p=0.7). Resting oxygen saturation was higher in the non-fenestrated group (93%±4.7 compared with fenestrated group 90.1%±5; p<0.001). Fontan fenestration was not significantly associated with the composite outcome; older patient age at the time of the CPET, cirrhosis and ventricular ejection fraction <40% were significantly associated with higher risk, while higher resting systolic blood pressure, left ventricular morphology and higher predicted peak VO 2 were protective. Conclusions The increased hypoxia and reduced ventilatory efficiency associated with Fontan fenestration offset any potential benefits, resulting in similar exercise performance between the groups. Fontan fenestration was not significantly associated with cardiovascular outcomes.

Importance Accurate classification and reliability in assessment for lesions of hidradenitis suppurativa (HS) by investigators is critical to the determination of responder status and to overall data quality in clinical trials. Objective To establish consensus-based morphological definitions of HS lesions and guidance statements that standardize investigator lesion assessments for implementation in clinical trials. Evidence Review Health professionals (primarily dermatologists) with expertise in the measurement of HS disease activity as well as novice raters completed a preliminary questionnaire in which participants were asked to assess images of HS lesions and provide qualitative feedback on their decision making. Based on this feedback, detailed morphologic definitions for lesions and guidance statements that standardize lesion assessments were formulated and presented for consensus voting in 2 electronic Delphi surveys. A virtual group discussion after round 1 supported participants in round 2 voting. Findings Response rates were 84.7% (50 of 59), 86.0% (43 of 50), and 90.9% (40 of 44) in the preliminary, electronic Delphi round 1, and electronic Delphi round 2 surveys, respectively. Morphological definitions for 11 lesion types achieved the prespecified 70% consensus threshold, with 9 definitions reaching at least 90% agreement. After 2 electronic Delphi rounds, 16 of 18 guidance statements achieved the prespecified consensus threshold, with 13 statements receiving endorsement from more than 80% of participants. Two guidance statements related to assessment of tunneled plaques with multiple openings and assessment of scalp lesions failed to reach consensus. Conclusions and Relevance Common morphologic definitions and guidance that standardize assessment of HS lesions can be implemented in clinical trial protocols and investigator trainings with the goals of improving accuracy and reliability of investigator ratings.

Background: The potential long-term effects of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection on the brain structure have not yet been fully elucidated. Even though existing studies have reported structural changes in the post-COVID-19 period, the results remain highly inconsistent and controversial. As such, identifying an imaging biomarker for post-COVID brains is still under investigation. This review aims to comprehensively summarize the structural MRI (sMRI) studies that focus on volumetric brain changes at least two weeks following COVID-19 infection. Methods: A systematic literature search was conducted on PubMed, SCOPUS, Web of Science, EMBASE, and Google Scholar up to 9 September 2025. Studies that utilized sMRI to assess volumetric brain changes post-COVID at greater than two weeks following infection were included. Exclusion criteria encompassed research involving pediatric or adolescent populations and imaging modalities other than sMRI. Preprints, reviews, case reports, case series and post-mortem studies were also excluded. Results: Forty-one studies satisfied the inclusion criteria and consisted of 2895 patients and 1729 healthy controls. Despite the wide variability in image acquisition protocols, data processing methods, and comorbidities between studies, multiple studies reported statistically significant volumetric reductions in the hippocampus, amygdala, thalamus, basal ganglia, nucleus accumbens and the cerebellum months to years after infection, especially in older hospitalized patients with severe COVID-19. Conclusions: The emerging literature reports long-term volume changes across various brain regions in individuals previously infected with COVID-19; however, the evidence is inconsistent. Specific imaging biomarkers following exposure to SARS-CoV-2 infection and the underlying mechanisms of these changes are yet to be identified. Future studies with harmonized imaging protocols, longitudinal designs, and integrated biomarker and clinical data are needed to define robust biomarkers and elucidate the pathophysiology of these findings.