Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

Endoscopic endonasal resection of Rathke cleft cysts: a single-institution analysis of 148 consecutive patients.

OBJECTIVE: The traditional treatment of sellar Rathke cleft cysts (RCCs) generally involves transsellar drainage; however, suprasellar RCCs present unique challenges to appropriate management and technical complexity. Reports on overall outcomes for the endoscopic endonasal approach (EEA) for this pathology are limited. The EEA for RCCs allows three surgical techniques: marsupialization, fenestration, and fenestration with cyst wall resection. METHODS: The authors performed a retrospective review of consecutive patients with RCCs that had been treated via an EEA at a single institution between January 2004 and May 2021. Marsupialization entailed the removal of cyst contents while maintaining a drainage pathway into the sphenoid sinus. Fenestration involved the removal of cyst contents, followed by separation from the sphenoid sinus, often with a free mucosal graft or vascularized nasoseptal flap. Cyst wall resection, either partial or complete, was added to select cases. RESULTS: A total of 148 patients underwent an EEA for RCC. Marsupialization or fenestration was performed in 88 cases (59.5%) and cyst wall resection in 60 (40.5%). Cysts were classified as having a purely sellar origin (43.2%), sellar origin with suprasellar extension (37.8%), and purely suprasellar origin (18.9%). Radiological recurrence was demonstrated in 22 cases (14.9%) at an average 39.7 months' follow-up (median 45 months, range 0.5-99 months), including 13 symptomatic cases (8.8%). Cases with cyst wall resection had no significantly different rate of recurrence (11.7% vs 15.9%, p = 0.48) or postoperative permanent anterior pituitary dysfunction (21.6% vs 12.5%, p = 0.29) compared to those of fenestrated and marsupialized cases. There was no significant difference in postoperative permanent posterior pituitary dysfunction based on technique, although such dysfunction tended to worsen with cyst wall resection (13.6% vs 4.0%, p = 0.09). Based on cyst location, purely suprasellar cysts were more likely to have a radiological recurrence (28.6%) than sellar cysts with suprasellar extension (12.5%) and purely sellar cysts (9.4%; p = 0.008). Most notably, of the 28 purely suprasellar cysts, selective cyst wall resection significantly improved the long-term (10-year) recurrence risk compared to fenestration alone (17.4% vs 80.0%, p = 0.0005) without any significant added risk of endocrinopathy. CONCLUSIONS: Endoscopic endonasal marsupialization or fenestration of sellar RCCs may be the ideal treatment strategy, whereas purely suprasellar cysts benefit from partial cyst wall resection to prevent recurrence. Selective cyst wall resection reduced long-term recurrence rates without significantly increasing rates of hypopituitarism.

The utility of inflammatory biomarkers in predicting overall survival and recurrence in skull base chordoma.

OBJECTIVE: Numerous studies have investigated the impact of inflammatory factors in cancer, yet few attempts have been made to investigate these markers in skull base chordoma (SBC). Inflammatory values including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) can serve as prognostic markers in various cancers. This study aimed to determine whether these inflammatory factors influence overall survival (OS) or progression-free survival (PFS) in patients with primary SBC. METHODS: The electronic medical records of patients with primary SBC who underwent resection from 2001 to 2020 were retrospectively reviewed for the associations of sex, age at diagnosis, preoperative steroid use, tumor volume, extent of resection, adjuvant radiation after surgery, tumor metastasis, Ki-67 index, percent homozygous deletion of 9p23 and percent 1p36 loss, and potential prognostic inflammatory markers of NLR, PLR, LMR, SII, and SIRI with the primary outcome measures of OS and PFS. Maximum log-rank statistical tests were used to determine inflammatory marker thresholds for grouping prior to Kaplan-Meier and Cox proportional hazards analysis for OS and PFS of the elucidated groups. RESULTS: The cohort included 115 primary SBC patients. The mean ± SD tumor volume was 23.0 ± 28.0 cm3, 73% of patients received gross-total resection, 40% received postoperative radiation, 25% had local recurrence, and 6% had subsequent metastatic disease (mean follow-up 47.2 months). Univariable Cox analysis revealed that NLR (p < 0.01), PLR (p = 0.04), LMR (p = 0.04), SII (p < 0.01), and SIRI (p < 0.01) were independently associated with PFS. Additionally, NLR (p = 0.05) and SII (p = 0.03) were significant in multivariable Cox analysis of PFS. However, both univariable and multivariable Cox analysis revealed no correlations with OS. CONCLUSIONS: The routine assessment of inflammatory biomarkers such as NLR and SIRI could have prognostic value in postresection SBC patients.

Preoperative stereotactic radiosurgery for cerebral metastases: safe, effective, and decreases steroid dependency.

OBJECTIVE: Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. METHODS: Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. RESULTS: Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). CONCLUSIONS: Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.

Engineered IgM and IgG cleaving enzymes for mitigating antibody neutralization and complement activation in AAV gene transfer.

Systemic dosing of adeno-associated viral (AAV) vectors poses potential risk of adverse side effects including complement activation triggered by anti-capsid immunity. Due to the multifactorial nature of toxicities observed in this setting, a wide spectrum of immune modulatory regimens are being investigated in the clinic. Here, we discover an IgM cleaving enzyme (IceM) that degrades human IgM, a key trigger in the anti-AAV immune cascade. We then engineer a fusion enzyme (IceMG) with dual proteolytic activity against human IgM and IgG. IceMG cleaves B cell surface antigen receptors and inactivates phospholipase gamma signaling in vitro. Importantly, IceMG is more effective at inhibiting complement activation compared with an IgG cleaving enzyme alone. Upon IV dosing, IceMG rapidly and reversibly clears circulating IgM and IgG in macaques. Antisera from these animals treated with IceMG shows decreased ability to neutralize AAV and activate complement. Consistently, pre-conditioning with IceMG restores AAV transduction in mice passively immunized with human antisera. Thus, IgM cleaving enzymes show promise in simultaneously addressing multiple aspects of anti-AAV immunity mediated by B cells, circulating antibodies and complement. These studies have implications for improving safety of AAV gene therapies and possibly broader applications including organ transplantation and autoimmune diseases.

Nexplanonectomy-the surgical removal of an embolized implanted contraceptive device: a case report and review of the literature.

BACKGROUND: Nexplanon implants are a common hormonal contraceptive modality. Though rare, these devices can embolize into the injured wall of the basilic vein, through the right heart, and finally wedge itself into a pulmonary artery. With adherence to the arterial wall over time, it becomes less amenable to endovascular retrieval. Patients may present with symptoms mimicking a pulmonary embolism, or without any symptoms at all. In asymptomatic cases, endovascular retrieval and/or surgery is required when patients wish to begin having children prior to biological inactivity. The current literature showed as little as nine case reports detailing lung tissue removal in the aim of reversing a patient's implanted contraceptive device. CASE PRESENTATION: A 22-year-old asymptomatic active-duty Caucasian female presented for elective outpatient Nexplanon removal. The suspicion of possible implant migration arose when it was discovered to be non-palpable in her left arm. After plain film x-rays failed to localize the implant, a chest x-ray and follow-up Computed Tomography (CT) scan revealed that the Nexplanon had migrated to a distal branch of the left pulmonary artery. Due to the patient's strong desires to begin having children, the decision was made for removal. Initial endovascular retrieval failed due to Nexplanon encapsulation within the arterial wall. Ultimately, the patient underwent a left video-assisted thoracoscopic surgery (VATS) for exploration and left lower lobe basilar S7-9 segmentectomy, which successfully removed the Nexplanon. CONCLUSIONS: Implanted contraceptive devices can rarely result in migration to the pulmonary vasculature. These radiopaque devices are detectable on imaging studies if patients and clinicians are unable to palpate them. An endovascular approach should be considered first to spare lung tissue and avoid chest-wall incisions, but can be complicated by encapsulation and adherence to adjacent tissue. A VATS procedure with single-lung ventilation via a double-lumen endotracheal tube allows surgeons to safely operate on an immobilized lung while anesthesiologists facilitate single-lung ventilation. This patient's case details the uncommon phenomenon of Nexplanon migration, and the exceedingly rare treatment resolution of lung resection to remove an embolized device.

Evaluating The Effect of Arthroscopic Rotator Cuff Repair with Concomitant Subacromial Decompression on 2, 4, and 6 Year Reoperation Rates.

INTRODUCTION: The risks and benefits of including an arthroscopic subacromial decompression (ASD) during arthroscopic rotator cuff repair (RCR) are uncertain. Some studies suggest no difference in revision surgery rates, whereas others have found higher revision surgery rates associated with concomitant ASD. In this study, we compare mid-term revision surgery rates in patients undergoing arthroscopic RCR with or without concomitant ASD. METHODS: A retrospective cohort analysis was conducted using a national all-payer claims database. Current Procedural Terminology and International Classification of Disease, 10th Revision, codes were used to identify patients who underwent primary arthroscopic RCR with or without ASD in the United States. The primary study outcome was revision surgery at 2, 4, and 6 years. Univariate analysis was conducted on demographic variables (age, sex) and comorbidities in the Elixhauser Comorbidity Index using chi-square and Student t-tests. Multivariate analysis was conducted using logistic regression. RESULTS: A total of 11,188 patients were identified who underwent RCR and met the inclusion criteria. Of those, 8,994 (80%) underwent concomitant ASD. Concomitant ASD was associated with lower odds of all-cause revision surgery to the ipsilateral shoulder at 2 years (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.51 to 0.73), 4 years (OR, 0.60; 95% CI, 0.51 to 0.70), and 6 years (OR, 0.59; 95% CI, 0.51 to 0.69). Concomitant ASD was also associated with lower odds of revision RCR at 2 years (OR, 0.68; 95% CI, 0.53 to 0.86), 4 years (OR, 0.63; 95% CI, 0.50 to 0.78), and 6 years (OR, 0.61; 95% CI, 0.49 to 0.76). DISCUSSION: Arthroscopic RCR with concomitant ASD is associated with lower odds of all-cause revision surgery in the ipsilateral shoulder at 2, 4, and 6 years. The lower mid-term revision surgery rates suggest benefits to performing concomitant ASD with primary arthroscopic RCR. Continued research on the mid to long-term benefits of ASD is needed to determine which patient populations benefit most from this procedure. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.

The Impact of Bundled Payment Initiatives in Orthopedic Surgery Access to Care: Cherry Picking and Lemon Dropping.

This editorial explores the impact of bundled payment initiatives, specifically in the context of orthopedic surgery, on access to care. We examine the phenomenon of "cherry picking" healthier patients and "lemon dropping" higher-risk patients, potentially leading to disparities in access and healthcare outcomes. We discuss recent studies investigating these concerns and highlight the need for more in-depth research to better understand the groups these policies may marginalize. Policymakers are urged to consider measures to protect disadvantaged patients and ensure equitable access to care, aligning with the principles of equality and diversity in healthcare.

Natural History of Opioid Use in Naive and Tolerant Patients in Revision Total Hip Arthroplasty.

BACKGROUND: Opioid use after revision total hip arthroplasty (rTHA) has not been well characterized. The purpose of this study was to characterize preoperative, perioperative, and postoperative opioid use during rTHA. METHODS: Patients undergoing revision THA from 2010 to 2018 were screened for opioid use 3 months before revision surgery and tracked 24 months postoperatively. Patients were categorized as naïve or tolerant. Opioid prescriptions and average morphine milligram equivalents (MME) were compared between the two groups. RESULTS: One hundred twenty-four of 247 patients (50%) in the tolerant group averaged a preoperative MME of 23.7 mg/day. Postoperatively, tolerant patients received significantly higher daily MME at all time points, including at 3 months 31.4 versus 18.1 mg/day (P < 0.001), 6 months 19.9 versus 2.95 mg/day (P < 0.001), 12 months 14.3 versus 3.5 mg/day (P < 0.001), and 24 months 10.7 versus 2.17 mg/day (P < 0.001). Tolerant patients were more likely to have a prescription at 6 months (44% versus 22%), 12 months (41.4% versus 24%), and 24 months (38% versus 19.3%) (P < 0.001, P = 0.002, P < 0.001, respectively). DISCUSSION: Opioid-tolerant patients had higher postoperative MME requirements for longer recovery duration. Both groups reduced opioid use at 3 months and plateaued at 6 months. These findings can help the revision surgeon counsel patients and expectations.

Trends in Orthopaedic Surgery Workforce Diversity: Analyzing Changes Over Time.

INTRODUCTION: There are many reasons why orthopaedic surgeons move or change careers. We asked the questions: (1) What is the geographic distribution of orthopaedic surgeons with respect to age, sex, and race and ethnicity? (2) How has our workforce changed over time with regard to these factors? (3) Are there any patterns or trends detected regarding policy or regulatory events that coincide with these differences? METHODS: The American Academy of Orthopaedic Surgeons surveys over 30,000 members, collecting data on demographics, age, race sex, and practice statistics. We calculated geographic distributions and evaluated these differences over time-potential influences from malpractice suits or tort reform were investigated. RESULTS: Overall surgeon density increased over time. The largest negative changes were noted in District of Columbia, Wyoming, and North Dakota and positive changes in Colorado, South Dakota, and West Virginia. Age across all states increased (mean 1.7 years). Number of female surgeons increased in most states (4.6% to 5.7%). Number of African Americans increased from 1.6% to 1.8%, Hispanic/LatinX from 1.8% to 2.2%, Asian from 5.5% to 6.7%, and multiracial from 0.8% to 1.2%. No change was noted in the percentage of Native American surgeons. DISCUSSION: Surgeon density increased from 2012 to 2018; the cause for this change was not evident. Small increases in surgeon population, female surgeons, and in some underrepresented minorities were seen.

Non-target analysis of crude oil photooxidation products at high latitudes and their biological effects.

With new oil and gas lease sales in high-latitude regions, there exists a need to better understand the chemical fate of spilled oil and its effects on biological life. To address this need, laboratory simulations of crude oil spills under sub-Arctic conditions were conducted using artificial seawater and exposure to solar irradiation to create Hydrocarbon Oxidation Products (HOPs). HOPs characterization and their biological effects were assessed using ultra high-performance liquid chromatography (UHPLC) with high resolution mass Orbitrap spectrometry and the aryl hydrocarbon receptor (AhR) chemically activated luciferase gene expression (CALUX) assay. Non-target UHPLC-Orbitrap mass spectrometry analysis identified 251 HOPs that were in greater abundance in light-exposed samples than dark controls. Oxidized polycyclic aromatic hydrocarbons were also detected, including phenanthrene quinone, anthraquinone, hydroxyanthraquinone, and 9-fluoreneone. The composition of HOPs were consistent with photo-products of alkylated two to four ring PAHs, primarily compounds between 1 and 3 aromatic rings and 1-3 oxygens. The HOP mixture formed during photochemical weathering of Cook Inlet crude oil induced greater AhR activity than parent petroleum products solubilized in dark controls, indicating that HOPs, as a complex mixture, may contribute to petroleum toxicity more than the parent petroleum compounds. These non-targeted approaches provide the most comprehensive analysis of hydrocarbon oxidation products to date, highlighting the diversity of the complex mixture resulting from the photooxidation of crude oil and the limitations of targeted analyses for adequately monitoring HOPs in the environment. Taken together, these data identify a critical "blind spot" in environmental monitoring and spill clean-up strategies as there is a diverse pool of HOPs that may negatively impact human and ecosystem health.

Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent "NoGlow" Mice.

The ability to temporally regulate gene expression and track labeled cells makes animal models powerful biomedical tools. However, sudden expression of xenobiotic genes [e.g., GFP, luciferase (Luc), or rtTA3] can trigger inadvertent immunity that suppresses foreign protein expression or results in complete rejection of transplanted cells. Germline exposure to foreign antigens somewhat addresses these challenges; however, native fluorescence and bioluminescence abrogates the utility of reporter proteins and highly spatiotemporally restricted expression can lead to suboptimal xenoantigen tolerance. To overcome these unwanted immune responses and enable reliable cell tracking/gene regulation, we developed a novel mouse model that selectively expresses antigen-intact but nonfunctional forms of GFP and Luc, as well as rtTA3, after CRE-mediated recombination. Using tissue-specific CREs, we observed model and sex-based differences in immune tolerance to the encoded xenoantigens, illustrating the obstacles of tolerizing animals to foreign genes and validating the utility of these "NoGlow" mice to dissect mechanisms of central and peripheral tolerance. Critically, tissue unrestricted NoGlow mice possess no detectable background fluorescence or luminescence and exhibit limited adaptive immunity against encoded transgenic xenoantigens after vaccination. Moreover, we demonstrate that NoGlow mice allow tracking and tetracycline-inducible gene regulation of triple-transgenic cells expressing GFP/Luc/rtTA3, in contrast to transgene-negative immune-competent mice that eliminate these cells or prohibit metastatic seeding. Notably, this model enables de novo metastasis from orthotopically implanted, triple-transgenic tumor cells, despite high xenoantigen expression. Altogether, the NoGlow model provides a critical resource for in vivo studies across disciplines, including oncology, developmental biology, infectious disease, autoimmunity, and transplantation. SIGNIFICANCE: Multitolerant NoGlow mice enable tracking and gene manipulation of transplanted tumor cells without immune-mediated rejection, thus providing a platform to investigate novel mechanisms of adaptive immunity related to metastasis, immunotherapy, and tolerance.

Complications and visual outcomes following surgical resection of pediatric optic pathway/hypothalamic gliomas: a systematic review and meta-analysis.

Pediatric optic pathway/hypothalamic gliomas (OPHG) pose challenges in treatment due to their location and proximity to vital structures. Surgical resection plays a key role in the management of OPHG especially when the tumor exhibits mass effect and causes symptoms. However, data regarding outcomes and complications of surgical resection for OPHG remains heterogenous. The authors performed a systematic review on pediatric OPHG in four databases: PubMed, EMBASE, Cochrane Library, and Google Scholar. We included studies that reported on the visual outcomes and complications of OPHG resection. A meta-analysis was performed and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 26 retrospective studies were included. Seven hundred ninety-seven pediatric patients with OPHG undergoing surgical resection were examined. A diagnosis of NF1 was confirmed in 9.7%. Gross total resection was achieved in 36.7%. Intraorbital optic pathway gliomas showed a significantly higher gross total resection rate compared to those located in the chiasmatic/hypothalamic region (75.8% vs. 9.6%). Postoperatively, visual acuity improved in 24.6%, remained unchanged in 68.2%, and worsened in 18.2%. Complications included hydrocephalus (35.4%), anterior pituitary dysfunction (19.6%), and transient diabetes insipidus (29%). Tumor progression post-resection occurred in 12.8%, through a mean follow-up of 53.5 months. Surgical resection remains an essential strategy for treating symptomatic and large pediatric OPHG and can result in favorable vision outcomes in most patients. Careful patient selection is critical. Patients should be monitored for hydrocephalus development postoperatively and followed up to assess for tumor progression and adjuvant treatment necessity.

Generative Artificial Intelligence Performs at a Second-Year Orthopedic Resident Level.

Introduction Artificial intelligence (AI) models using large language models (LLMs) and non-specific domains have gained attention for their innovative information processing. As AI advances, it's essential to regularly evaluate these tools' competency to maintain high standards, prevent errors or biases, and avoid flawed reasoning or misinformation that could harm patients or spread inaccuracies. Our study aimed to determine the performance of Chat Generative Pre-trained Transformer (ChatGPT) by OpenAI and Google BARD (BARD) in orthopedic surgery, assess performance based on question types, contrast performance between different AIs and compare AI performance to orthopedic residents. Methods We administered ChatGPT and BARD 757 Orthopedic In-Training Examination (OITE) questions. After excluding image-related questions, the AIs answered 390 multiple choice questions, all categorized within 10 sub-specialties (basic science, trauma, sports medicine, spine, hip and knee, pediatrics, oncology, shoulder and elbow, hand, and food and ankle) and three taxonomy classes (recall, interpretation, and application of knowledge). Statistical analysis was performed to analyze the number of questions answered correctly by each AI model, the performance returned by each AI model within the categorized question sub-specialty designation, and the performance of each AI model in comparison to the results returned by orthopedic residents classified by their respective post-graduate year (PGY) level. Results BARD answered more overall questions correctly (58% vs 54%, p<0.001). ChatGPT performed better in sports medicine and basic science and worse in hand surgery, while BARD performed better in basic science (p<0.05). The AIs performed better in recall questions compared to the application of knowledge (p<0.05). Based on previous data, it ranked in the 42nd-96th percentile for post-graduate year ones (PGY1s), 27th-58th for PGY2s, 3rd-29th for PGY3s, 1st-21st for PGY4s, and 1st-17th for PGY5s. Discussion ChatGPT excelled in sports medicine but fell short in hand surgery, while both AIs performed well in the basic science sub-specialty but performed poorly in the application of knowledge-based taxonomy questions. BARD performed better than ChatGPT overall. Although the AI reached the second-year PGY orthopedic resident level, it fell short of passing the American Board of Orthopedic Surgery (ABOS). Its strengths in recall-based inquiries highlight its potential as an orthopedic learning and educational tool.

Endoscopic and histologic utility of transnasal endoscopy in pediatric eosinophilic esophagitis.

Unsedated transnasal endoscopy (TNE) is an alternative method of examining the esophageal mucosa in pediatric patients with eosinophilic esophagitis (EoE), reducing cost, time, and risk associated with frequent surveillance esophagogastroduodenoscopies (EGD). Adequacy of transnasal esophageal biopsies for the evaluation of eosinophilic esophagitis histologic scoring system (EoEHSS) has not yet been evaluated. We compared procedure times, endoscopic findings, and EoEHSS scoring for EoE patients undergoing TNE versus standard EGD. Sixty-six TNE patients and 132 EGD controls matched for age (mean age 14.0 years) and disease status (29.3% active) were included. Compared to patients undergoing standard EGD, patients undergoing TNE spent 1.94 h less in the GI suite (p < 0.0001), with comparable occurrence rates of all visual endoscopic findings and most EoEHSS components. TNE serves as a useful tool for long-term disease surveillance, and consideration should be given to its use in clinical trials for EoE.

The Effect of Concomitant Biceps Tenodesis on Revision Surgery Rates After Primary Rotator Cuff Repair.

INTRODUCTION: We aimed to use a national database to compare the 4-year revision surgery rates after rotator cuff repair (RCR) in patients with concomitant biceps tenodesis (BT) versus those without BT. METHODS: A retrospective cohort analysis was conducted using the PearlDiver database from 2015 to 2017. Patients undergoing primary open and arthroscopic RCR with and without BT were identified. Demographic variables, 90-day complications, and 2- and 4-year revision surgery rates were analyzed, and a multivariable logistic regression was conducted. RESULTS: Of the 131,155 patients undergoing RCR, 24,487 (18.7%) underwent concomitant BT and 106,668 (81.3%) did not. After controlling for comorbidities and demographics, patients with concomitant BT were associated with lower odds of all-cause revision (OR; P-value [0.77; P < 0.001]), revision BT (0.65; P < 0.001), revision RCR (0.72; P < 0.001), and shoulder arthroplasty (0.81; P = 0.001) within 4 years when compared with those without concomitant BT. DISCUSSION: In our analysis, patients undergoing primary RCR with concomitant BT had 35% reduced odds of revision BT and 23% reduced odds of any all-cause revision within 4 years when compared with those without concomitant BT. This suggests that tenodesis at the time of primary RCR may be associated with a reduction in the utilization of ipsilateral shoulder revision surgery rates.

Beyond guesswork: how accurate are surgeons at determining the degree of glenoid bone loss in instability surgery?

Background: Accurate measurement of glenoid bone loss (GBL) is critical to preoperative planning in cases of recurrent shoulder instability. The concept of critical bone loss has been established with a value of GBL >13.5% being associated with higher failure rate following arthroscopic Bankart Repair. Advanced imaging, such as magnetic resonance imaging (MRI) scans, can be used to quantify GBL prior to surgery using the best-fit circle technique. Surgeons have traditionally relied on visual inspection of the MRI scan preoperatively or on visual inspection of the glenoid at the time of arthroscopy to determine whether GBL is present. The purpose of this study is to determine if 3 fellowship-trained shoulder surgeons could adequately quantify GBL without using best-fit circle measurements on MRI. Methods: A retrospective review was performed which included 122 patients over an 8-year period that had an arthroscopic Bankart repair performed by 3 fellowship-trained surgeons. In all patients, preoperative MRI scans were retrospectively measured using best-fit circle technique to determine true GBL and compare that to the surgeons' preoperative and intraoperative estimation of GBL. Results: GBL was correctly identified in only 36% (18/50) of patients when the preoperative best-fit circle measurements were not made. Critical bone loss was missed in 9.8% (12/122) of patients in the study group. The estimated mean bone loss in that group by visual inspection was 11.3% compared to 16% true bone loss measured on MRI. Even in the 18 patients with some identified bone loss prior to surgery, critical bone loss was missed in 6 patients when using visual inspection of the MRI or intraoperative inspection alone. Conclusion: Simple visual inspection of glenoid images on MRI scan and visual inspection of the glenoid at the time of surgery are inaccurate in determining the true extent of GBL especially in cases of subtle bone deficiency. Preoperative planning is dependent on the exact degree of bone deficiency and measurement on the MRI scan using the best-fit circle technique is recommended in all cases of instability surgery.

Capsid-mediated control of adeno-associated viral transcription determines host range.

Adeno-associated virus (AAV) is a member of the genus Dependoparvovirus, which infects a wide range of vertebrate species. Here, we observe that, unlike most primate AAV isolates, avian AAV is transcriptionally silenced in human cells. By swapping the VP1 N terminus from primate AAVs (e.g., AAV8) onto non-mammalian isolates (e.g., avian AAV), we identify a minimal component of the AAV capsid that controls viral transcription and unlocks robust transduction in both human cells and mouse tissue. This effect is accompanied by increased AAV genome chromatin accessibility and altered histone methylation. Proximity ligation analysis reveals that host factors are selectively recruited by the VP1 N terminus of AAV8 but not avian AAV. Notably, these include AAV essential factors implicated in the nuclear factor κB pathway, chromatin condensation, and histone methylation. We postulate that the AAV capsid has evolved mechanisms to recruit host factors to its genome, allowing transcriptional activation in a species-specific manner.

How low can we go? A randomized controlled trial of low-quantity initial opioid prescriptions for shoulder surgery.

BACKGROUND: Orthopedic surgeons are the third most frequent prescribers of opioid medications. Given the current opioid addiction crisis, it is critical to limit opioid prescriptions to the lowest effective dose. In this study, we investigated how the initial opioid prescription after shoulder surgery affects maximum possible opioid consumption. We hypothesized that fewer pills in the initial opioid prescription would lead to less opioid consumption, a lower refill request rate, and fewer post-surgery office contacts for pain. METHODS: In this single-center, prospective, randomized controlled clinical trial, 74 adults who underwent shoulder arthroplasty, rotator cuff repair, or other arthroscopic shoulder procedures were enrolled from December 2020 to July 2022. Follow-up was completed by February 2023. Participants were randomly assigned to receive postoperative prescriptions of seven 5-mg oxycodone pills (n = 20), 15 pills (n = 29), or 23 pills (n = 25). The primary outcome was maximum possible opioid consumption within 2 weeks after surgery, calculated by assuming consumption of all pills in the initial prescription, as well as any refills. Secondary outcomes were the opioid prescription refill request rates, post-surgery pain-related telephone calls or messages to the provider's office ("office contacts") within 2 weeks after surgery, and American Shoulder and Elbow Surgeons pain scores 2 weeks after surgery. Baseline characteristics did not differ among groups except for mean age, which was younger in the 7-pill group (P = .047). RESULTS: Maximum possible opioid consumption increased with the number of pills initially prescribed, with means of 78 morphine milligram equivalents (MME) for the 7-pill group, 118 MME for the 15-pill group, and 199 MME for the 23-pill group (P < .001). None of the secondary outcome measures differed among groups. Refill request rates were 20% for the 7-pill group, 3.4% for the 15-pill group, and 12% for the 23-pill group (P = .20). The proportions of patients with at least 1 office contact were 35% in the 7-pill group, 45% in the 15-pill group, and 28% in the 23-pill group (P = .43). Mean American Shoulder and Elbow Surgeons pain scores were 49 in the 7-pill group, 44 in the 15-pill group, and 40 in the 23-pill group (P = .20). CONCLUSION: After shoulder surgery, an initial prescription of fewer opioid pills was associated with less maximum possible opioid consumption without an increase in the percentage of patients requesting opioid refills or contacting the provider's office for pain-related concerns. An initial postoperative prescription of fewer 5-mg oxycodone pills may be equally or more effective compared with larger quantities for most patients.

Vaccines targeting ESR1 activating mutations elicit anti-tumor immune responses and suppress estrogen signaling in therapy resistant ER+ breast cancer.

ER+ breast cancers (BC) are characterized by the elevated expression and signaling of estrogen receptor alpha (ESR1), which renders them sensitive to anti-endocrine therapy. While these therapies are clinically effective, prolonged treatment inevitably results in therapeutic resistance, which can occur through the emergence of gain-of-function mutations in ESR1. The central importance of ESR1 and development of mutated forms of ESR1 suggest that vaccines targeting these proteins could potentially be effective in preventing or treating endocrine resistance. To explore the potential of this approach, we developed several recombinant vaccines encoding different mutant forms of ESR1 (ESR1mut) and validated their ability to elicit ESR1-specific T cell responses. We then developed novel ESR1mut-expressing murine mammary cancer models to test the anti-tumor potential of ESR1mut vaccines. We found that these vaccines could suppress tumor growth, ESR1mut expression and estrogen signaling in vivo. To illustrate the applicability of these findings, we utilize HPLC to demonstrate the presentation of ESR1 and ESR1mut peptides on human ER+ BC cell MHC complexes. We then show the presence of human T cells reactive to ESR1mut epitopes in an ER+ BC patient. These findings support the development of ESR1mut vaccines, which we are testing in a Phase I clinical trial.