Citations

Objectives: The goals of this study are to assess primary care provider (PCP) knowledge of and attitudes toward pediatric obstructive sleep apnea (OSA), and to identify variations in practice patterns. Design: A cross-sectional survey including the Obstructive Sleep Apnea Knowledge and Attitudes in Children (OSAKA-KIDS) questionnaire was administered to PCPs from August to December 2021. Univariable analyses and multivariable linear regressions were performed to analyze associations between demographics and knowledge, attitudes, and screening frequency. Results: Eighty-two PCPs completed the survey (age 43.4 ± 9.6 years, 69.6% female, 90.2% non-Hispanic White). Specialties included Pediatrics (65.9%) and Family Medicine (32.9%). Respondents answered a mean 84.9 ± 10.7% questions correctly on the knowledge portion. Years in practice, provider training, and academic affiliation were not associated with knowledge scores. Less than half (45.1%) of respondents screened for OSA “most of the time” (32.9%) or “always” (12.2%). Higher screening frequency was associated with clinics with higher Medicaid beneficiaries ( P = .002) and a lower proportion of Black patients ( P = .033). Providers who felt more confident in managing OSA were more likely to screen “most of the time” ( B = 0.532, 95% CI [0.120-0.926], P = .012), or “always” ( B = 0.708, 95% CI [0.129-1.29], P = .017). Conclusion: these results suggest guideline-recommended screening for OSA is low among PCPs. Higher confidence in OSA management was associated with higher screening rates. Further studies on interventions aimed to increase screening and confidence may improve equitable care.

Abstract Description We used C57BL/6 mice bearing B16-F10 tumors expressing EGFRviii, treated with anti-EGFRviii CAR T cells and the oncolytic virus vesicular stomatitis virus (VSV). TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation over time using an unstable fluorescent protein reporter of Nr4a3. We further investigated CAR T phenotypes using CyTOF and scRNA-Seq. Using an MHC I tetramer for the dominant VSV epitope VSV-N52-59, we found that 20-50% of transfused CAR T adopted TCR specificity against VSV-N (TCR-primed), far above the predicted frequency in a naïve T cell repertoire. Ex vivo, these TCR-primed CAR T produced increased levels of Granzyme B and IFNγ over tetramer negative CAR T against either TCR or CAR targets. TCR-primed CAR had decreased levels of T cell activation as compared to non-TCR-primed CAR. CyTOF and scRNA-Seq analyses demonstrated a hyper-effector phenotype among TCR-primed CAR, with increased expression of T-bet, CD44, Granzyme B, IFNγ, and perforin. TCR sequencing revealed hyper-expansion of VSV N-specific CAR T cells and little overlap in clonotypes between CAR T co-treated with PBS versus VSV. Overall, CAR T cells that undergo endogenous anti-viral TCR priming and signaling appear to adopt a unique phenotype that promotes their cytotoxic function. These data suggest that engineering anti-viral TCRs into CAR T could be used to improve efficacy with OV boosting. Funding Sources Supported by NIH T32GM145408 and NIH R01CA269384. Topic Categories Vaccines and Immunotherapy (VAC)

Abstract Description Evidence consistent with immunoediting in human cancer has been identified through associative studies. To provide direct evidence that differences in the neoantigen profile are immune-mediated, we compared the neoantigen profiles of cutaneous squamous cell carcinoma (cSCC) from immunocompetent and immunosuppressed patients. Despite consistency in the overall mutational burden and signature, immunocompetent patients have a lower clonal mutational burden compared to immunosuppressed patients. Furthermore, clonal mutations in cSCC from immunocompetent patients have a lower proportion of neoantigens predicted to bind MHC class I, supporting the role of the immune system in shaping the neoantigen profile. In single-cell RNA sequencing of intratumoral CD8+ T cells from a separate cohort of cSCC from immunocompetent and immunosuppressed patients, we observe an increase in exhausted CD8+ T cells in tumors from immunocompetent patients, suggesting an explanation for the persistence of binding neoantigens subclonally. Finally, we compare clonal and subclonal neoantigens as an unbiased screen for characteristics associated with neoantigen immunogenicity. Neoantigens with a large increase in predicted MHC class I binding relative to the normal peptide are enriched in subclonal neoantigens in immunocompetent patients. Overall, this work supports the immune system’s role in sculpting the neoantigen profile of cSCC. Funding Sources Supported by American Cancer Society - Simone Charitable Foundation - Discovery Boost Grant, AZ-DBG-23-1151311-01-IBCD; NIH F30CA281056; R35GM149235 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description Background Castration-resistant prostate cancers (CRPC) do not respond to immunotherapy.1,2 Prostate cancer-derived immune factors (IF) like sPD-L1 drive immunosuppression and resistance.3 Circulating tumor-reactive T cells (TTR; CD8+CD11ahigh) and other immune subsets predict progression-free survival in oligometastatic CRPC after radiotherapy.4 A better understanding of the levels and changes in IF in CRPC—a tumor immune “circulome”—may lead to better immunotherapeutic approaches. Methods 79 men with oligometastatic castration-resistant prostate cancer were treated with radiation and blood was collected before and after treatment (NCT02816983). Peripheral blood mononuclear cells (PBMC) were subjected to immunophenotyping, and plasma was subjected to the Olink Explore panel assay measuring levels of 5,416 IFs using a proximity extension assay technology. Results High baseline soluble levels of PD-L1, PD-L2, TIM-3, and other selected immunotherapy-related IFs predicted inferior outcomes, including overall survival. Conversely, high soluble CTLA-4 levels strongly predicted superior outcomes (p < 0.0001). These results additionally correlated with changes in circulating tumor-reactive (TTR) T cells in these patients. Discussion IF influence systemic immunity in CRPC. These results suggest a multifactorial mechanism by which prostate cancers drive systemic immunosuppression and resistance to immunotherapy. Ongoing efforts to address IFs may help overcome CRPC immunotherapy resistance.5 Funding Sources Department of Defense HT9425-24-1-0622, An Atlas of the Tumor Immune Circulome (PI: Orme) Prostate Cancer Foundation Young Investigator Award (PI: Orme) National Cancer Institute K12 CA90628-23 (PI: Orme) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Background Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN , MAPT , or C9orf72 , and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results Mutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n ( GRN ) = 298, n( MAPT ) = 187, n ( C9orf72 ) = 417) were compared to familial non-carriers (age = 48.0 ± 12.9 years, sex = 58% female, n ( GRN ) = 201, n( MAPT ) = 114), n ( C9orf72 ) = 217). Consistent with prior findings in young adults, GRN carriers showed larger TIV, on average by 20531 mm 3 , compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η 2 p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r (295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm 3 (95% CI [–58248, −1545], p = 0.039, η 2 p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.

Abstract Background Distinguishing physiological cardiac adaptation from pathological remodeling in endurance athletes is challenging. While the athletic heart typically demonstrates balanced biventricular enlargement, extreme exercise may rarely trigger disproportionate right ventricular (RV) changes that challenge diagnostic classification. Case Summary A 47-year-old male ultra-endurance athlete presented with exertional symptoms three months after recovery from a pulmonary embolism (PE). Initial post-PE echocardiography was normal. After resuming extreme training, he developed severe RV dilation (basal diameter 5.7 cm on echocardiography; RV volume index 92 cc/m² on cardiac magnetic resonance imaging) disproportionate to the left ventricle, with preserved systolic function and no late gadolinium enhancement. Cardiopulmonary exercise testing revealed significant chronotropic incompetence with below-expected peak oxygen uptake for his elite training status. Symptoms and ventricular ectopy improved with detraining, but severe RV dilation persisted. Evaluation excluded arrhythmogenic cardiomyopathy and significant pulmonary vascular sequelae. Discussion This case illustrates disproportionate RV remodeling precipitated by the resumption of extreme exercise in a susceptible athlete post-PE. The temporal dissociation from the PE and absence of residual clot burden implicate exercise-related hemodynamic stress as the primary driver, challenging the boundary between physiological adaptation and maladaptation. These findings highlight a potential maladaptive response to extreme exercise, possibly potentiated by a prior vascular insult, and underscore the value of integrated functional assessment and monitored detraining in athletes with borderline findings.

Background α‐Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10‐year survival. Methods In this retrospective cohort, blinded clinicians scored calcification on computed tomography (0–10 scale: aorta 6 points, iliac 4 points). Plasma klotho was measured by ELISA; endothelial progenitor cell subsets were quantified via flow cytometry. Mortality data were obtained from the Minnesota Death Registry. Results This study included 148 participants (mean age 72.4±9.6 years; 41% female). Median calcification score was 3 (interquartile range, 1–5). Patients with low calcification had higher Klotho levels (669 [567–841] versus 556 [457–678] pg/mL; P <0.01), with Klotho inversely correlated with calcification (r=−0.315, P <0.01). Stratified by calcification location and severity, the highest Klotho levels were seen in patients without aortic or iliac calcification ( P =0.015). Over 10 years, low Klotho was independently associated with higher mortality (hazard ratio [HR], 3.056 [95% CI 1.288–7.878]; P =0.014). Klotho inversely correlated with mature osteocalcin‐positive EPCs; B=−0.16 (95% CI, −0.29 to −0.02; P =0.027). Immunohistochemistry and immunofluorescence confirmed endothelial Klotho expression in internal mammary artery. Conclusions Lower circulating Klotho levels are associated with increased aortoiliac calcification and higher 10‐year mortality, supporting a role for Klotho in vascular aging.

Background: Acquired and congenital limb length discrepancies often coexist with deformities of the distal femur. Lengthening of the femur along its anatomic axis changes the limb's mechanical alignment. Angular correction and lengthening can be achieved at the same site if a retrograde lengthening nail is used with a specific preoperative planning method (“reverse planning”) which permits patient-specific selection of the final mechanical axis. Methods: A consecutive cohort series of children, adolescents, and young adults (mean 15.6 ± 4.8 years) undergoing retrograde implantable femoral lengthening between the years 2011 and 2024 were analyzed. Surgical details, lengthening parameters, Limb Lengthening and Reconstruction Society (LLRS)–AIM index, accuracy of final correction, and complications were reviewed and classified. Patients were eligible only if the distal femoral physis was closed. Results: Seventy-three lengthening were eligible in the study period. Average lengthening was 4.2 ± 1.4 cm (range 2.0-8.0 cm), and consolidation index was 39.4 ± 21.9 days/cm. Deformities and length discrepancies were moderately complex, with a mean LLRS AIM score of 6 (range 1-13). Complication rates were similar to previous reports of intramedullary femoral lengthening, comparable between congenital (12 of 31, 39%) and acquired etiologies (16 of 42, 38%). Preoperative coronal alignment ranged from 14° varus to 20° valgus, while final coronal alignment was 0.4° ± 3.4° of neutral (range 7° valgus to 13° varus). Coronal deformities up to 20° and sagittal deformities up to 23° were corrected acutely at the lengthening site. Conclusions: Retrograde intramedullary femoral lengthening with acute deformity correction at the same site is an alternative to antegrade lengthening with separate osteotomy of the distal femur in children and adolescents. The reverse planning method allows reproducible length and deformity correction at the same location. Specific intraoperative technical adjuncts are used to achieve and maintain the desired alignment. Level of Evidence: Diagnostic Level IV . See Instructions for Authors for a complete description of levels of evidence.