Citations

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease affecting women. Sirolimus has been shown to stabilize lung function in women with LAM, but real-world data on long-term safety and efficacy are limited. Methods The NIH Multicenter Safety and Durability of Sirolimus for LAM (MIDAS, NCT02432560) observational registry was launched in 2015. All adult (≥18 years) women with LAM (treated or untreated) were eligible to enroll at any of the 20 U.S. sites and followed longitudinally with serial assessments of lung function, health-related quality of life, and treatment related adverse event (TRAEs). Baseline cohort characteristics and TRAEs are summarized using descriptive analyses. Marginal structural models (MSMs) with inverse probability of treatment weighting estimated the causal effect of sirolimus on annualized forced expiratory volume in one-second (FEV1) decline, adjusting for age at LAM diagnosis, prior treatment with sirolimus, menopausal status, race, presence of angiomyolipomas, supplemental oxygen use; time-varying covariates included diffusing capacity for carbon monoxide (DLCO) and serum vascular endothelial growth factor-D (VEGF-D) levels. Results Longitudinal data was available in 350 LAM patients, most of whom (246, 70.3%) had sporadic LAM. The median age at the baseline pulmonary function test (PFT) measurement was 46 years (range: 19 - 74) and the median (IQR) number of serial PFTs obtained per patient was 3 (1 - 5). The average follow-up duration per patient was 2.8 years. Over half of the patients (196, 56%) were treated with sirolimus during the MIDAS observation period for a median (IQR) treatment duration of 4.9 (2.4 - 7.5) years. MSM analysis demonstrated that sirolimus treatment was durably effective and reduced FEV₁ decline by 74.36 mL/year (95% CI: 15.87 - 132.85) compared with no treatment (-85.31 mL/year for the untreated group vs. -10.95 mL/year for the treated group, p = 0.01). Sirolimus was generally well tolerated; treatment interruption ≥3 months was observed in 38 (19.4%) of the 196 sirolimus treated patients. Logistic regression analysis showed that higher levels of FEV1 (odds ratio: OR = 3.12 [1.45 - 7.11], p = 0.005), VEGF-D (OR = 1.0007 [1.0004 - 1.001], p < 0.001), and DLCO (OR = 1.023 [1.0053 - 1.0413, p = 0.01]), were associated with treatment interruption. Conclusions In the MIDAS cohort, sirolimus treatment resulted in durable stabilization of lung function with a favorable safety profile over a 5-year period. These real-world data support sirolimus as a chronic suppressive therapy for LAM, demonstrating durable efficacy in slowing lung disease progression and tolerability with long-term use. This abstract is funded by: National Institutes of Health

Background: We aimed to develop automated data extraction pipelines with large language models (LLMs) to extract registry data from total hip arthroplasty (THA) operative notes and compare the performance with that of existing natural language processing (NLP) algorithms. Methods: We randomly sampled 1,000 primary THA cases from our institutional registry. Two human annotators manually reviewed each operative note for 3 data points: surgical approach, bearing surface, and fixation technique. All labeled THA notes were split into the development set (n = 239) and the testing set (n = 719). We developed a custom data extraction pipeline for each data point by combining an iteratively customized prompt with an LLM. The performance was compared with that of existing rules-based NLP algorithms. Results: The accuracy of LLMs was superior to that of NLP algorithms for all data points: surgical approach (96% compared with 94%), bearing surface (89% compared with 74%), and fixation technique (96% compared with 95%). Furthermore, the LLM accurately inferred the bearing surface for 80% of the notes that were ambiguous about the bearing surface. Conclusions: We developed LLM pipelines for extracting 3 registry-relevant data points from THA operative notes, demonstrating superior performance to existing NLP algorithms. Clinical Relevance: LLMs have the potential to impact clinical care, including the evaluation of electronic medical record free-text data. As registries serve as a cornerstone of orthopaedic evidence, this work demonstrates promise for LLMs to simplify, improve, and democratize the construction of registry databases from operative notes.

ABSTRACT Beyond the arboviruses they transmit to humans and animals, mosquitoes harbour diverse viral communities that shape infection and immunity dynamics. Understanding how these communities shift within mosquito populations across time and space has important implications for how we anticipate and manage arboviral disease epidemics. Here, we examined the viromes of rural and sylvatic mosquito species sampled longitudinally across two years from countries representing South America, Africa, and Southeast Asian geographies to quantify the relative contributions of host and ecological factors in shaping their virome dynamics. We found that virus diversity and virome composition are strongly influenced by host phylogeny and spatial factors and show limited temporal variation. By examining virus similarity networks across mosquito species and biogeographies, we observed frequent instances of within- and cross-genus Culex - Anopheles virus sharing in Madagascar. Taken together, these findings inform the development and implementation strategies of any virome-based vector control technology and raise new evolutionary questions on how host generalism shapes the spatial prevalence of viruses and their potential for disease emergence.

As artificial intelligence (AI) advances in healthcare, encompassing robust applications for the diagnosis and prognostication of musculoskeletal diseases, clinicians must increasingly understand the implications of machine learning and deep learning in their practice. This review article explores computer vision algorithms and patient-specific, multimodal prediction models; provides a simple framework to guide discussion on the limitations of AI model development; and introduces the field of generative AI.

Abstract Background: Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm that can lead to progressive diffuse cystic lung disease. Pregnancy has been associated with accelerated disease progression and increased risk of spontaneous pneumothoraces in women with LAM. Sirolimus is the current first line treatment for LAM and has demonstrated benefit in stabilizing lung function decline and reducing the risk of spontaneous pneumothoraces; however, there is unclear evidence regarding the risk benefit ratio of the use of sirolimus during pregnancy. Methods: We queried physicians across the LAM Clinic Network and obtained information regarding demographics, baseline characteristics, LAM related complications, lung function, sirolimus dosing, and pregnancy outcomes in women with LAM who took sirolimus during pregnancy. Results: We identified 9 women with LAM who had used sirolimus during pregnancy for a total of 12 pregnancies. All women had sporadic LAM with moderate lung function impairment prior to pregnancy: median FEV1 56% predicted, median DLCO 43% predicted, and 2 patients on supplemental oxygen. Sirolimus was used throughout pregnancy in most instances (10/12 (83.3%)). Sirolimus was held prior to pregnancy in 2 patients; both these patients experienced a spontaneous pneumothorax in the first trimester and resumed sirolimus in the second trimester with no further pneumothoraces during the rest of the pregnancy. The median sirolimus dose during pregnancy was 1 (range 1-2) mg daily with a median trough level of 2.95 (range: 1 – 6.7) ng/ml. Ten pregnancies (83.3%) resulted in live births, 1 pregnancy was terminated due to molar pregnancy, and 1 pregnancy resulted in miscarriage. Spirometry and DLCO were available in 8 pregnancies and tended to be stable (Figure 1). None of the 10 pregnancies that resulted in live births reported any fetal health issues. Seven out of these 10 children (70%) were breastfed with continued sirolimus use. At the time of submission of this report, the median age of these children is 3.5 years (range: 1 – 6.5 years) with no reported adverse health outcomes from sirolimus exposure during pregnancy. Conclusions: The use of sirolimus during pregnancy in women with LAM appears to be safe for both mother and fetus and might help reduce the pregnancy associated risks of accelerated lung function decline and spontaneous pneumothoraces.

Abstract Morphological hip abnormalities (MHAs) significantly influence lifelong prognosis of the hip, contributing to early-onset osteoarthritis and impaired functionality. Developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI) represent key pathologies, resulting from insufficient or excessive femoral head coverage, respectively. These abnormalities alter hip biomechanics, leading to structural damage, pain, and accelerated joint degeneration. Advances in genetic research have illuminated the interplay between genetics and mechanical loading in shaping hip morphology. Genes associated with osteoarthritis, DDH, and FAI include COL1A1, MMP13, and IL-6. Genes associated with FAI and osteoarthritis include ADAMTS4. Genes associated with DDH and osteoarthritis include FRZB, CX3CR1, ASPN, DKK1, PDRG1, GDF5, UQCC1, and TGF-β1. The mechanisms linking morphological derangements to symptomatic osteoarthritis remain incompletely understood. Multimodal approaches integrating imaging, biomechanics, and genetics may uncover distinct disease subtypes, enabling personalized interventions. Early detection of MHAs is critical in preventing early-onset osteoarthritis. Incorporating advanced imaging techniques, such as statistical shape modelling, can enhance the understanding of complex 3D hip morphologies and their progression to osteoarthritis. Future research should explore the genetic underpinnings of other morphologic hip conditions, including Slipped Capital Femoral Epiphysis and Legg–Calvé–Perthes disease, to refine preventive and therapeutic strategies. A comprehensive approach combining genetics, imaging, and clinical insights holds promise for mitigating the lifelong impact of MHAs.

Introduction : Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare hereditary multisystem vascular disease of disordered angiogenesis. Pathologic elevations in vascular endothelial growth factor (VEGF) result in fragile, abnormal vessels in nasal and gastrointestinal (GI) mucosa causing recurrent epistaxis, chronic GI bleeding, and anemia that is often transfusion-dependent. Bevacizumab is a monoclonal IgG1 antibody that neutralizes circulating VEGF and is a potential targeted anti-angiogenic treatment in HHT, which has no FDA-approved therapy. Data for use of intravenous (IV) bevacizumab in HHT is currently limited to case reports and small single-center retrospective case series. The International HHT Intravenous Bevacizumab Investigative Team study of Bleeding (InHIBIT-Bleed) is an international collaboration of HHT Centers seeking to more definitively describe the safety and effectiveness of systemic bevacizumab to treat chronic bleeding and anemia in HHT. Methods : The following data was retrospectively collected at each participating center for all HHT patients treated for at least 3 months with off-label systemic bevacizumab for chronic bleeding: demographics, baseline HHT characteristics, epistaxis severity score (ESS, a validated 10-point scale to evaluate epistaxis in HHT), bevacizumab dosing, treatment-emergent adverse events (TEAEs), hemoglobin (Hgb), red blood cell (RBC) transfusions, and IV iron infusions. Hgb and ESS at baseline were compared with post-bevacizumab values at 3, 6, 9, and 12 months with the paired t-test. RBC transfusion and iron infusion requirements before and after bevacizumab treatment were compared with the Wilcoxon signed rank test. Results : 140 HHT patients were treated with IV bevacizumab for chronic bleeding for a median of 23 (range, 3-96) months with a median of 12 (range, 2-74) total infusions. Bevacizumab was dosed at 5 mg/kg every 2 weeks for the first 2 months, then monthly for 4 months; following this, maintenance dosing practices varied depending on center. Baseline patient characteristics are given in Table 1. After bevacizumab initiation, patients with baseline anemia (Hgb<11, N=104) had an increase in mean Hgb from 8.6 g/dL to 11.9 g/dL at 3 months (P<0.0001) up to 12.5 g/dL at 12 months (P<0.0001) (Table 2, Figure 1). For patients with epistaxis as an indication for treatment (N=119), mean ESS dropped from 6.8 at baseline to ≤3.5 on treatment (P<0.0001) (Table 2, Figure 2). In patients requiring RBC transfusion prior to bevacizumab (N=81), transfusion requirements decreased from a median of 8 units in the 6 months before treatment to a median of 0 units in the first 6 months after treatment (P<0.0001); similarly, in patients requiring iron infusion prior to bevacizumab (N=99), requirements decreased from a median of 4 infusions to 2 infusions (P<0.0001) (Table 2). RBC transfusion and iron infusion requirements continued to improve with ongoing bevacizumab treatment (Table 2) and improvement occurred regardless of baseline bleeding severity; Figure 3 illustrates the dramatic reduction in RBC transfusion and iron infusion requirements in a severe patient sub-cohort. Overall, compared with pretreatment, RBC transfusion and iron infusion requirements decreased by 86% and 66%, respectively, on bevacizumab. On subgroup analysis by underlying mutation (ENG vs. ACVRL1), there were no significant differences in baseline parameters or bevacizumab response. Bevacizumab was well-tolerated; TEAEs felt to be likely or possibly related to bevacizumab occurred in 36% of patients (Table 3), with new or worsened hypertension (16%) and fatigue (9%) most common. No patient developed venous thromboembolism on bevacizumab. Only 5 patients (4%) discontinued bevacizumab for TEAEs and only 3 patients (2%) discontinued bevacizumab for lack of effectiveness. Conclusions : We present results of IV bevacizumab treatment of chronic bleeding and anemia in a large cohort of 140 HHT patients, demonstrating that bevacizumab was highly effective, with an improvement in mean Hgb of 3.9 g/dL, dramatic reduction in ESS, and decrease in RBC transfusion and iron infusion requirements by 86% and 66%, respectively. Effectiveness was maintained over time. Safety analysis included a total of 194 patient-years of IV bevacizumab administration to HHT patients and had low TEAE rates with only 4% discontinuing treatment due to TEAEs. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Kuter:Caremark: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Agios: Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Shire: Consultancy, Honoraria; Kezar: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Momenta: Consultancy, Honoraria. OffLabel Disclosure: The presentation will discuss off-label use of systemic bevacizumab for the treatment of chronic bleeding and anemia in hereditary hemorrhagic telangiectasia.