Citations

Background: A growing body of research has connected electronic health record (EHR) workload to physician burnout. In orthopedic surgery, burn-out rates are rising. This study analyzed orthopedic surgeons' EHR use by sex and practice experience. Materials and Methods: EHR activity was analyzed among attending orthopedic surgeons at a single institution from May 2022 to May 2023. Demographic information included self-reported sex and practice years. Outcomes included time spent in notes, orders, clinical review, and in-basket daily; time spent outside of scheduled clinical responsibilities; volume of in-basket messages received daily; and proportion of orders with team contributions. Multivariable linear regression compared outcomes by sex and practice years. Results: A total of 105 orthopedic surgeons were included (91% male; mean 15.5 ± 9.8 practice years). Female surgeons logged 31% more time in the EHR overall (62.2 vs 47.4 minutes daily; P = .05) and on unscheduled days (10.1 additional daily minutes; P = .03), and received more messages from patients (2.4 vs 1.0 messages daily; P = .002) compared to male surgeons. Senior surgeons spent significantly less time on documentation and orders ( P ≤ .048) and on unscheduled days (3.3 less minutes daily per practice decade; P = .013), and had more support with placing orders ( P < .001). Conclusion: Female sex and fewer practice years were associated with increased EHR use. Female orthopedic surgeons tended to have higher patient message volumes, whereas junior surgeons tended to have less team support, spending more time on orders and documentation. Given known factors contributing to burnout, these findings warrant further investigation into targeted interventions to improve physician EHR use.

Background: Gender-based reimbursement disparities in orthopedic surgery remain poorly understood, particularly when accounting for practice composition and setting. The purpose of this study was to compare and evaluate gender-based differences in Medicare reimbursement and practice patterns among female and male orthopedic surgeons. Methods: A cross sectional analysis of public Medicare data from 2013 to 2021 was performed. Outcomes included annual Medicare payments, submitted charges, total services, service categories, and beneficiaries treated by orthopedic surgeons who bill Medicare. Univariate and multivariable analyses quantified differences in payment, practice volume and composition, geographic adjustment, and Current Procedural Terminology (CPT)-matched reimbursements. Results: A total of 29,357 orthopedic surgeons (27,442 men and 1,919 women) billed Medicare fee-for-service during the study period. Female surgeons, on average, submitted 48.3% fewer total charges and received 44.1% lower annual Medicare payments per surgeon compared with male surgeons. These differences persisted after multivariable regression adjusted for practice metrics and excluded top and bottom earners. Female surgeons also billed fewer services, treated fewer beneficiaries, and submitted fewer unique CPT codes. However, payment disparities persisted even after matching surgeons by volume of services, beneficiaries, and years in practice. Male surgeons performed higher volumes of all 10 highest-paying orthopedic CPT codes. In CPT matched analyses, female surgeons received lower reimbursement per service than male surgeons performing identical procedures. Conclusion: These findings suggest that the observed gender-based disparities in orthopedic surgery Medicare reimbursement cannot be explained by differences in volume, procedural mix, or geographic practice cost. Instead, they likely reflect a combination of structural and behavioral mechanisms described in prior literature that may influence how access to clinical opportunities, referrals, and reimbursement practices unfold in surgical practices. Variations in coding practices may represent an important focus for future investigation and targeted educational initiatives. Level of Evidence: Level III , Retrospective Cohort Study. See Instructions for Authors for a complete description of levels of evidence.

Abstract Metabolic reprogramming is a fundamental determinant of immune cell fate and effector function during inflammation, yet how distinct metabolic pathways regulate pathogenic lung macrophage activity and contribute to fibrotic remodeling remains incompletely understood. Here, we integrated single-cell RNA sequencing, lineage-specific genetic mouse models, and fate-mapping approaches to define the metabolic pathways that regulate the pro-fibrotic activity of lung macrophages. We found that such cells undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis. Myeloid cell-specific depletion of lactate dehydrogenase A (Ldha), but not of mitochondrial pyruvate carrier (Mpc), markedly attenuated lung fibrosis and improved survival. Mechanistically, enhanced glycolytic flux increased lactate production, which promoted histone lysine lactylation and facilitated Arginase 1 (Arg1) expression in lung macrophages, thereby driving fibrotic progression. Using monocyte fate-mapping, we further demonstrated that Arg1 expression is largely restricted to recruited monocyte-derived macrophages rather than lung-resident macrophages. Notably, selective deletion of Ldha in granulocyte-monocyte progenitors and their progeny was sufficient to suppress Arg1 expression and reduce fibrosis severity. In human lung samples, we observed significantly elevated expression of ARG1 and key glycolytic enzymes in patients with idiopathic pulmonary fibrosis, despite species-specific differences in the immune cell types expressing ARG1. Together, these findings identify an aerobic glycolysis–lactate–histone lactylation axis that regulates pro-fibrotic myeloid cell function and represents a potential therapeutic target in pulmonary fibrosis.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p&gt;0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=&lt;0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

Abstract Background The RefleXion X1 is a novel PET/CT‐guided ring gantry linac that introduces unique geometry and workflow compared to conventional systems. Existing QA guidelines (AAPM TG‐142, 148, 306) cover standard linacs and tomotherapy but do not address this platform's needs. Therefore, an automated daily QA solution is required to ensure accurate output, imaging guidance, and couch positioning, which motivated the development and evaluation of the workflow presented in this study. Purpose To develop and evaluate an automated, efficient, and comprehensive daily quality assurance (QA) workflow for a novel PET/CT‐guided ring gantry linear accelerator (RefleXion X1), incorporating tests for dosimetry, imaging guidance, and couch positioning accuracy. Methods An IMRT QA plan was designed following the CT scan of the TomoDose 2D diode detector array (Sun Nuclear, Melbourne, FL) within the RefleXion treatment planning system (TPS). Several spherical targets of varying sizes were contoured to conform the dose distribution to these targets and evaluate beam output, laser localization, profile constancy, and CT‐MV isocenter coincidence. Linear models correlating spatial location of dose peak with intentional shifts in different directions were developed and integrated into an in‐house analysis software, iQA, written in C#. The software was validated for robustness and successfully implemented in clinical practice. Results Validation with 42 intentional shifts showed submillimeter accuracy, with mean deviations of 0.2 mm (X), 0.1 mm (Y), and 0.79 mm (Z), and R 2 values ≥ 0.98. Over 1 year, daily QA data showed stable output constancy (1.006 ± 0.016), left/right target dose constancy (1.007 ± 0.005 and 0.996 ± 0.004), and consistent CT‐MV isocenter offsets (–0.335 ± 0.23 mm in X, 0.19 ± 0.19 mm in Y, and –0.544 ± 0.36 mm in Z). The software also detected a gradual output drift in between, prompting a timely linac adjustment. Conclusion This fully automated, single‐delivery QA workflow enables efficient and robust evaluation of multiple IGRT performance parameters. It improves standardization, reduces human error, and reliably monitors long‐term machine stability. The tools and methodology may be adopted by other clinics seeking a practical and automated daily QA solution. Future developments will focus on incorporating PET QA and rotational couch validations to further enhance the system's comprehensiveness and adaptability.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1) are approved for type 2 diabetes treatment. Given the link between diabetes-associated metabolic inflammation and increased carpal tunnel syndrome (CTS) risk, the aim of this study was to investigate development of CTS in diabetic patients who both were and were not taking GLP-1 therapy using a large claims database. Methods: A retrospective cohort study used a national claims database to identify diabetic patients. Those prescribed GLP-1 therapy were matched to controls by age, sex, comorbidity index, tobacco use, and obesity. Multivariable logistic regression evaluated the 2-year CTS incidence, controlling for various health conditions and socioeconomic factors. Secondary analysis also evaluated the rate of carpal tunnel release (CTR) after being diagnosed with CTS. Results: Glucagon-like peptide-1 therapy significantly reduced 2-year CTS diagnosis risk (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.46-0.52; P < .001). Independent risk factors for increased CTS incidence included chronic obstructive pulmonary disease, osteoarthritis, coronary artery disease, depression, hypothyroidism, and rheumatoid arthritis (RA). Of patients who developed CTS, GLP-1 therapy was associated with increased odds of undergoing CTR (OR 1.23; 95% CI: 1.08-1.41; P = .002). Conclusions: Glucagon-like peptide-1 therapy is associated with decreased CTS risk in diabetic patients—potentially due to improved metabolic health—and increased odds of undergoing CTR once diagnosed. Further research is needed to clarify GLP-1 therapy’s role in reducing nervous system and musculoskeletal disease burden.

Abstract Rationale Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT)-deficient Pi*MZ heterozygotes is largely missing. Objectives We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared with the Pi*MM genotype. Methods We identified 1,856 Pi*MM and 79 Pi*MZ participants with ⩾20 pack-years tobacco smoking history from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. Results Adjusted for age, sex, race, smoking pack-year history, and smoking status, Pi*MZ participants had a lower baseline percent predicted forced expiratory volume in 1 second (FEV1) (65.4% vs. 75.1%; difference 95% confidence interval [CI], −15.4% to −3.9%), more radiographic emphysema (&lt;−950 Hounsfield units%, 12.9% vs. 7.8%; difference 95% CI, 2.8% to 7.5%), and nonsignificantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (−34.5 ml/yr vs. −34.6 ml/yr for Pi*MZ and Pi*MM; difference 95% CI, −16.9 to 17.1 ml/yr). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations, or survival. The proportion with faster FEV1 decline (annual loss ⩾40 ml) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/μl; difference 95% CI, 30 to 140 cells/μl). In the subgroup analysis limited to a small number of currently smoking participants, no significant differences in longitudinal outcomes were found. Conclusions Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared with Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow-up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared with Pi*MM tobacco-exposed individuals.

484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.