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Importance With the availability of multiple classes of advanced therapies for the treatment of Crohn disease (CD), understanding the comparative safety of different therapies can inform treatment positioning. Objective To compare the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with CD. Design, Setting, and Participants This retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean (SD) follow-up of 26.9 (2.4) months until July 1, 2024. Using an administrative claims database (OptumLabs Data Warehouse), commercially insured patients with CD, who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents (vedolizumab), interleukin (IL)-12/23p40 antagonists (ustekinumab), IL-23p19 antagonists (primarily risankizumab), or Janus kinase inhibitors (upadacitinib) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation, were included. Exposure TNF antagonists vs anti-integrin agents (vedolizumab) vs IL-12/23p40 antagonists (ustekinumab) vs IL-23p19 antagonists (risankizumab) vs Janus kinase inhibitors (upadacitinib). Main Outcomes and Measures The risk of serious infections, VTE, and MACE was compared with various advanced therapies through multinomial propensity score-based inverse probability treatment weighting, with propensity scores estimated through generalized boosted models, accounting for disease characteristics, health care utilization, comorbidities, and prior and concomitant medications, and through competing risk of mortality. Cause-specific hazard ratios (HRs) and 95% CIs for multiple treatment comparisons were calculated. Results This study included 12 245 patients with CD (mean [SD] age, 46.5 [17.5] years; 6642 females [54.2%]), who were treated with TNF antagonists (n = 5274), vedolizumab (n = 2716), ustekinumab (n = 3544), risankizumab (n = 559), or upadacitinib (n = 152). Serious infection incidence rates ranged from 5.46 (95% CI, 4.86-6.07) to 9.02 (95% CI, 6.38-11.89) per 100 person-years across therapies. After adjusting for confounding variables, there were no statistically significant differences in the risk of serious infections across different agents, including between risankizumab and ustekinumab (HR, 1.14 [95% CI, 0.78-1.67]), risankizumab and TNF antagonists (HR, 1.00 [95% CI, 0.68-1.47]), or ustekinumab and TNF antagonists (HR, 0.88 [95% CI, 0.74-1.04]). The incidence of VTE (incidence rate, 0.90 [95% CI, 0.71-1.10] to 2.33 [95% CI, 1.06-3.82] per 100 person-years) and MACE (0.68 [95% CI, 0.51-0.85] to 1.49 [95% CI, 0.43-2.76] per 100 person-years) was low, without any significant differences across agents. Conclusions and Relevance In this comparative effectiveness research study of patients with CD, no significant differences in the risks of serious infections, VTE, or MACE across various advanced therapies were found. These findings support clinical decision-making on choice of advanced therapies for most individual patients with CD to be driven primarily by comparative treatment effectiveness rather than driven by concerns of serious adverse events.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.

BACKGROUND: Lipodermatosclerosis (LDS) is a type of sclerosing panniculitis that predominantly involves the lower extremities and is characterized by erythema, hemosiderin pigmentation, and sclerotic skin lesions. LDS is a common reason for specialty consultations across clinical settings, including dermatology, vascular medicine, and occasionally the emergency department or internal medicine services. METHODS: To further evaluate the prevalence of venous hypertension in patients with LDS at the authors’ institution, they retrospectively reviewed the findings of lower extremity Doppler ultrasonography with or without segmental pressure (ie, venous ultrasonography) performed for adult patients with biopsy-confirmed LDS who were treated at the Clinic from January 1, 2000, through September 30, 2022. RESULTS: A total of 430 patients were included in the study. Venous ultrasonography findings were abnormal for 327 (76.0%) patients, whereas the other 103 (23.9%) patients had normal findings. Venous hemodynamics studies, including air plethysmography and continuous-wave Doppler ultrasonography, were performed for 33 patients with normal venous ultrasonography findings. Of these patients, 7 had mild valvular incompetence, 12 had abnormal calf muscle pump function, and 2 had pulsatility (backflow in the peripheral vein with elevated right atrial pressure) evident on continuous-wave Doppler ultrasonography. CONCLUSIONS: Overall, the findings extend previous observations that venous abnormalities are commonly present in patients with LDS and may contribute to its pathogenesis. However, a few patients with LDS have normal venous hemodynamics, which suggests that other factors also contribute to LDS pathogenesis.

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited disorder characterized by the progressive enlargement of fluid-filled cysts in the kidneys and liver. Since the cystic fibrosis transmembrane conductance regulator (CFTR) Cl– channel may mediate the secretion of Cl– and fluid into the cysts, it is conceivable that coexisting cystic fibrosis (CF) in patients with ADPKD could attenuate their development. We previously reported that two patients with ADPKD coexisting with cystic fibrosis (CF) had a milder cystic phenotype than that of kindred without CFTR mutations. A subsequent report failed to confirm this protective effect. We now have identified another family with coexisting type 1 ADPKD and CF. The kidney volumes and the number and size of renal and hepatic cysts were markedly less in a member of this family with ADPKD (PKD1 mutation C508R) and CF (homozygous ΔF508 mutation) than in her sister with ADPKD alone at comparable ages.

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

BACKGROUND: Stoma-free survival represents a key quality-of-life outcome after surgery for locally advanced rectal cancer. Despite advances in neoadjuvant and surgical management, up to 30% of patients ultimately require a permanent fecal diversion. OBJECTIVE: To evaluate stoma-free survival and identify factors associated with permanent stoma formation in patients with locally advanced rectal cancer undergoing coloanal anastomosis. DESIGN: Retrospective cohort study. SETTINGS: Single tertiary referral center (2017–2021). PATIENTS: A total of 126 patients with clinical stage II and III rectal adenocarcinoma who received neoadjuvant therapy and underwent curative-intent resection with coloanal anastomosis were included. INTERVENTION: Curative-intent resection with coloanal anastomosis. MAIN OUTCOME MEASURES: The primary outcome was stoma-free survival. Secondary analyses examined factors associated with permanent fecal diversion. RESULTS: The medical records of 126 patients were analyzed, comprising 62.5% men, with a mean age of 54 ± 10 years and a median BMI of 27.7 (interquartile range 24.5–31.4). At a median follow-up of 53.0 months, the 5-year stoma-free survival rate was 88.9%. Univariate Cox regression analysis showed that BMI ≥35 (HR 3.80; 95% CI, 1.04–13.91, p = 0.044) and handsewn coloanal anastomosis with mucosectomy compared to stapled coloanal anastomosis without mucosectomy (HR 5.58; 95% CI, 1.71–18.14, p = 0.004), as well as local recurrence (HR 6.51; 95% CI, 1.44–29.46), were associated with worse stoma-free survival. The 30-day major morbidity rate was 7.9% after the index surgery. Sixteen patients required permanent fecal diversion due to bowel dysfunction (n = 11), disease recurrence (n = 4), or bowel obstruction (n = 1). LIMITATIONS: Retrospective, single-institution design with limited generalizability. CONCLUSIONS: Coloanal anastomosis in the era of total neoadjuvant therapy resulted in favorable 5-year stoma-free survival. BMI ≥35, handsewn coloanal anastomosis with mucosectomy, and local recurrence were associated with worse stoma-free survival. See Video Abstract . SUPERVIVENCIA SIN ESTOMA TRAS UNA RESECCIÓN ANTERIOR BAJA CON ANASTOMOSIS COLOANAL PARA EL CÁNCER RECTAL EN ESTADIO II-III ANTECEDENTES: La supervivencia sin estoma representa un resultado clave para la calidad de vida tras la cirugía de cáncer rectal localmente avanzado. A pesar de los avances en el tratamiento neoadyuvante y quirúrgico, hasta un 30 % de los pacientes requieren finalmente una derivación fecal permanente. OBJETIVO: Evaluar la supervivencia sin estoma e identificar los factores asociados con la formación de un estoma permanente en pacientes con cáncer rectal localmente avanzado sometidos a anastomosis coloanal. DISEÑO: Estudio de cohorte retrospectivo. ENTORNO: Centro terciario de referencia único, 2017-2021. PACIENTES: Se incluyó a un total de 126 pacientes con adenocarcinoma rectal en estadio clínico II-III que recibieron terapia neoadyuvante y se sometieron a una resección con intención curativa con anastomosis coloanal. INTERVENCIÓN: Resección con intención curativa con anastomosis coloanal. PRINCIPALES MEDIDAS DE RESULTADO: El resultado principal fue la supervivencia sin estoma. Los análisis secundarios examinaron los factores asociados con la derivación fecal permanente. RESULTADOS: Se analizaron 126 pacientes, de los cuales el 62,5 % eran hombres, con una edad media de 54 ± 10 años y un índice de masa corporal medio de 27,7 kg/m 2 (rango intercuartílico: 24,5-31,4 kg/m 2 ). Con una mediana de seguimiento de 53,0 meses, la tasa de supervivencia sin estoma a 5 años fue del 88,9 %. El análisis de regresión de Cox univariante mostró que el índice de masa corporal ≥ 35 kg/m 2 (razón de riesgo = 3,80, intervalo de confianza del 95 %: 1,04-13,91, p = 0,044) y la anastomosis coloanal cosida a mano con mucosectomía, en comparación con la anastomosis coloanal grapada sin mucosectomía (razón de riesgo = 5,58, intervalo de confianza del 95 %: 1,71-18,14, p = 0,004), así como la recurrencia local (razón de riesgo = 6,51, intervalo de confianza del 95 %: 1,44-29,46) se asociaron con una peor supervivencia sin estoma. La tasa de morbilidad grave a los 30 días fue del 7,9 % tras la cirugía índice. Dieciséis pacientes requirieron una derivación fecal permanente debido a disfunción intestinal (n = 11), recurrencia de la enfermedad (n = 4) u obstrucción intestinal (n = 1). LIMITACIONES: Diseño retrospectivo, de una sola institución, con una generalización limitada. CONCLUSIONES: La anastomosis coloanal en la era de la terapia neoadyuvante total dio lugar a una supervivencia sin estoma favorable a los 5 años. El índice de masa corporal ≥ 35 kg/m2, la anastomosis coloanal cosida a mano con mucosectomía y la recurrencia local se asociaron con una peor supervivencia sin estoma. (AI-generated translation )

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been observed in HR+HER2-positive (HER2+) MBC, with significant progression-free survival (PFS) benefits. Cyclin-dependent kinases 4/6 (CDK4/6) are downstream of HER2 and pathways driving resistance to HER2-targeted therapies. However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody–drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium. The observation that luminal disease defined by a predictive analysis of microarray 50 (PAM50) was independently associated with a significantly longer PFS versus nonluminal disease was important, with researchers inferring that intrinsic molecular subtypes could be used to identify patients most suitable for ET + CDK4/6i + HER2-targeted treatment. Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.