Antigen-presenting innate lymphoid cells orchestrate neuroinflammation.

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases1-6, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.

A Quantitative Analysis of Publication Trends in Vascular Surgery and a Comparative Analysis with Interventional Radiology.

BACKGROUND: Since its recognition as an independent surgical subspecialty, vascular surgery has experienced rapid growth in both surgical volume and research productivity. Trends in vascular surgery research have not been well characterized. Understanding how research in the field has evolved in comparison to interventional radiology can offer insights into evolving interests and discrepancies between the specialties. METHODS: Primary and secondary research publications indexed in the MEDLINE database from 1992 to 2023 were analyzed using a novel text mining algorithm. Eight high-impact vascular surgery journals and 6 interventional radiology journals were included. Articles were categorized based on treatment modalities, pathologies, and other subgroup analyses. Temporal trends were assessed using linear regression and correlation analysis. A comparative analysis was performed assessing publication trends by broad pathology groups between vascular surgery and interventional radiology journals. A further subgroup analysis was conducted comparing publication trends by endovascular treatment modality for peripheral arterial disease (PAD). RESULTS: 28,931 vascular surgery publications and 13,094 interventional radiology publications met the inclusion criteria. Publication volume grew exponentially, with over 50% emerging in the last decade. Publications exploring endovascular interventions have increasingly exceeded those focused on exclusively open interventions in research volume since 2006. Aortic pathology, carotid disease, PAD, and venous pathology represented the vast majority of vascular surgery research output, with PAD exhibiting the fastest growth. Comparative analysis revealed a number of key differences in research focus and treatment modalities between vascular surgery and interventional radiology, including a greater emphasis on venous pathology in interventional radiology journals and fewer relative publications on carotid artery pathology (P < 0.001). When comparing endovascular treatments for PAD, interventional radiology journals published more frequently on endovascular brachytherapy (8.73% vs 1.02%, P < 0.001) and less frequently on atherectomy (4.29% vs 6.50%, P = 0.035) as compared to the vascular surgery journals. CONCLUSIONS: Our findings demonstrate increasing emphasis on endovascular interventions and specific pathologies in vascular surgery research. Despite some key differences, there is notable overlap in interests between vascular surgery and interventional radiology, which may represent promising opportunities for collaboration in advancing endovascular procedures. Differences in research focus may stem from specialty perspectives and be perpetuated by differences in training.

The Large Language Model ChatGPT-4 Exhibits Excellent Triage Capabilities and Diagnostic Performance for Patients Presenting With Various Causes of Knee Pain.

PURPOSE: To provide a proof-of-concept analysis of the appropriateness and performance of ChatGPT-4 to triage, synthesize differential diagnoses, and generate treatment plans concerning common presentations of knee pain. METHODS: Twenty knee complaints warranting triage and expanded scenarios were input into ChatGPT-4, with memory cleared prior to each new input to mitigate bias. For the 10 triage complaints, ChatGPT-4 was asked to generate a differential diagnosis that was graded for accuracy and suitability in comparison to a differential created by 2 orthopaedic sports medicine physicians. For the 10 clinical scenarios, ChatGPT-4 was prompted to provide treatment guidance for the patient, which was again graded. To test the higher-order capabilities of ChatGPT-4, further inquiry into these specific management recommendations was performed and graded. RESULTS: All ChatGPT-4 diagnoses were deemed appropriate within the spectrum of potential pathologies on a differential. The top diagnosis on the differential was identical between surgeons and ChatGPT-4 for 70% of scenarios, and the top diagnosis provided by the surgeon appeared as either the first or second diagnosis in 90% of scenarios. Overall, 16 of 30 diagnoses (53.3%) in the differential were identical. When provided with 10 expanded vignettes with a single diagnosis, the accuracy of ChatGPT-4 increased to 100%, with the suitability of management graded as appropriate in 90% of cases. Specific information pertaining to conservative management, surgical approaches, and related treatments was appropriate and accurate in 100% of cases. CONCLUSIONS: ChatGPT-4 provided clinically reasonable diagnoses to triage patient complaints of knee pain due to various underlying conditions that were generally consistent with differentials provided by sports medicine physicians. Diagnostic performance was enhanced when providing additional information, allowing ChatGPT-4 to reach high predictive accuracy for recommendations concerning management and treatment options. However, ChatGPT-4 may show clinically important error rates for diagnosis depending on prompting strategy and information provided; therefore, further refinements are necessary prior to implementation into clinical workflows. CLINICAL RELEVANCE: Although ChatGPT-4 is increasingly being used by patients for health information, the potential for ChatGPT-4 to serve as a clinical support tool is unclear. In this study, we found that ChatGPT-4 was frequently able to diagnose and triage knee complaints appropriately as rated by sports medicine surgeons, suggesting that it may eventually be a useful clinical support tool.

ChatGPT-4 Performs Clinical Information Retrieval Tasks Using Consistently More Trustworthy Resources Than Does Google Search for Queries Concerning the Latarjet Procedure.

PURPOSE: To assess the ability of ChatGPT-4, an automated Chatbot powered by artificial intelligence, to answer common patient questions concerning the Latarjet procedure for patients with anterior shoulder instability and compare this performance with Google Search Engine. METHODS: Using previously validated methods, a Google search was first performed using the query "Latarjet." Subsequently, the top 10 frequently asked questions (FAQs) and associated sources were extracted. ChatGPT-4 was then prompted to provide the top 10 FAQs and answers concerning the procedure. This process was repeated to identify additional FAQs requiring discrete-numeric answers to allow for a comparison between ChatGPT-4 and Google. Discrete, numeric answers were subsequently assessed for accuracy on the basis of the clinical judgment of 2 fellowship-trained sports medicine surgeons who were blinded to search platform. RESULTS: Mean (± standard deviation) accuracy to numeric-based answers was 2.9 ± 0.9 for ChatGPT-4 versus 2.5 ± 1.4 for Google (P = .65). ChatGPT-4 derived information for answers only from academic sources, which was significantly different from Google Search Engine (P = .003), which used only 30% academic sources and websites from individual surgeons (50%) and larger medical practices (20%). For general FAQs, 40% of FAQs were found to be identical when comparing ChatGPT-4 and Google Search Engine. In terms of sources used to answer these questions, ChatGPT-4 again used 100% academic resources, whereas Google Search Engine used 60% academic resources, 20% surgeon personal websites, and 20% medical practices (P = .087). CONCLUSIONS: ChatGPT-4 demonstrated the ability to provide accurate and reliable information about the Latarjet procedure in response to patient queries, using multiple academic sources in all cases. This was in contrast to Google Search Engine, which more frequently used single-surgeon and large medical practice websites. Despite differences in the resources accessed to perform information retrieval tasks, the clinical relevance and accuracy of information provided did not significantly differ between ChatGPT-4 and Google Search Engine. CLINICAL RELEVANCE: Commercially available large language models (LLMs), such as ChatGPT-4, can perform diverse information retrieval tasks on-demand. An important medical information retrieval application for LLMs consists of the ability to provide comprehensive, relevant, and accurate information for various use cases such as investigation about a recently diagnosed medical condition or procedure. Understanding the performance and abilities of LLMs for use cases has important implications for deployment within health care settings.

The Reverse Fragility Index for Mortality End Points in Randomized Trials Comparing Uncemented and Cemented Hemiarthroplasty for Intracapsular Hip Fractures.

BACKGROUND: Interpreting clinical relevance of randomized clinical trials (RCTs) is challenging when P-values are marginally above or below the P = .05 threshold. This study examined the robustness of statistically insignificant mortality events from RCTs comparing hemiarthroplasty femoral fixation for displaced intracapsular hip fractures through the reverse fragility index (RFI). METHODS: RCTs were identified using Pubmed, OVID/Medline, and Cochrane databases. Mortality endpoints were stratified into 3 categories: (1) within 30-days, (2) within 90-days, and (3) at latest follow-up. The RFI was derived by manipulating reported mortality events utilizing a contingency table while maintaining a constant number of participants. The reverse fragility quotient (RFQ) was quantified by dividing the RFI by the study sample. RESULTS: Eight RCTs (2,494 participants) were included. The median RFI and RFQ within 30-days was 3.0 (interquartile range [IQR]: 3.0 to 6.0) and 0.016 (IQR: 0.015 to 0.021), suggesting nonsignificant findings were contingent on 1.6 mortality events/100 participants. The median RFI and RFQ within 90-days was 6.0 (IQR: 4.0 to 7.0) and 0.028 (IQR: 0.024 to 0.038), suggesting nonsignificant findings were contingent on 2.8 mortality events/100 participants. At latest follow-up, the median RFI and RFQ was 7.0 (IQR: 6.0 to 12.0) and 0.038 (IQR: 0.029 to 0.054), suggesting nonsignificant findings were contingent on only 3.8 mortality events/100 participants. Median loss to follow-up was 16.0 (IQR: 11.0 to 58.0; 228% greater than RFI), and exceeded the RFI in 6/7(85.7%) studies. CONCLUSIONS: A small number of events (median of 7) was required to convert a statistically nonsignificant finding to one that is significant for the endpoint of mortality. The median loss to follow-up exceeded the median RFI by greater than 200%, suggesting methodological limitations such as patient allocation could alter conclusions.

Chordoma arising from the coccygeal disc and mimicking a pilonidal cyst.

Chordomas are rare, low-grade malignant tumors often found in the sacrococcygeal region and prone to local recurrence. We report an atypical presentation of a 40-year-old patient with a symptomatic midline retrococcygeal lesion that was presumptively treated as a pilonidal cyst due to its clinical and imaging features. After surgical pathology rendered the diagnosis of chordoma, the patient required salvage surgery in the form of partial sacrectomy with soft tissue flap coverage. In addition to the unusually predominant retrococcygeal location, surgical pathology identified an intervertebral disc origin rather than the typical osseous origin. To our knowledge, this presentation of chordoma with coccygeal intervertebral origin and a large subcutaneous mass at imaging has rarely been reported in the literature. We describe this case to raise awareness of atypical presentations of sacrococcygeal chordoma that may lead to erroneous presumptive diagnosis and treatment.

Understanding How ChatGPT May Become a Clinical Administrative Tool Through an Investigation on the Ability to Answer Common Patient Questions Concerning Ulnar Collateral Ligament Injuries.

Background: The consumer availability and automated response functions of chat generator pretrained transformer (ChatGPT-4), a large language model, poise this application to be utilized for patient health queries and may have a role in serving as an adjunct to minimize administrative and clinical burden. Purpose: To evaluate the ability of ChatGPT-4 to respond to patient inquiries concerning ulnar collateral ligament (UCL) injuries and compare these results with the performance of Google. Study Design: Cross-sectional study. Methods: Google Web Search was used as a benchmark, as it is the most widely used search engine worldwide and the only search engine that generates frequently asked questions (FAQs) when prompted with a query, allowing comparisons through a systematic approach. The query "ulnar collateral ligament reconstruction" was entered into Google, and the top 10 FAQs, answers, and their sources were recorded. ChatGPT-4 was prompted to perform a Google search of FAQs with the same query and to record the sources of answers for comparison. This process was again replicated to obtain 10 new questions requiring numeric instead of open-ended responses. Finally, responses were graded independently for clinical accuracy (grade 0 = inaccurate, grade 1 = somewhat accurate, grade 2 = accurate) by 2 fellowship-trained sports medicine surgeons (D.W.A, J.S.D.) blinded to the search engine and answer source. Results: ChatGPT-4 used a greater proportion of academic sources than Google to provide answers to the top 10 FAQs, although this was not statistically significant (90% vs 50%; P = .14). In terms of question overlap, 40% of the most common questions on Google and ChatGPT-4 were the same. When comparing FAQs with numeric responses, 20% of answers were completely overlapping, 30% demonstrated partial overlap, and the remaining 50% did not demonstrate any overlap. All sources used by ChatGPT-4 to answer these FAQs were academic, while only 20% of sources used by Google were academic (P = .0007). The remaining Google sources included social media (40%), medical practices (20%), single-surgeon websites (10%), and commercial websites (10%). The mean (± standard deviation) accuracy for answers given by ChatGPT-4 was significantly greater compared with Google for the top 10 FAQs (1.9 ± 0.2 vs 1.2 ± 0.6; P = .001) and top 10 questions with numeric answers (1.8 ± 0.4 vs 1 ± 0.8; P = .013). Conclusion: ChatGPT-4 is capable of providing responses with clinically relevant content concerning UCL injuries and reconstruction. ChatGPT-4 utilized a greater proportion of academic websites to provide responses to FAQs representative of patient inquiries compared with Google Web Search and provided significantly more accurate answers. Moving forward, ChatGPT has the potential to be used as a clinical adjunct when answering queries about UCL injuries and reconstruction, but further validation is warranted before integrated or autonomous use in clinical settings.

Preoperative Physical Therapy is Associated with Decreased Length of Stay and Improved Postoperative Mobility in Patients with Sarcopenia Undergoing Adult Spinal Deformity Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the relationship between preoperative physical therapy (PT) and postoperative mobility, adverse events (AEs), and length of stay (LOS) among patients with low normalized total psoas area (NTPA) undergoing ASD surgery. SUMMARY OF BACKGROUND DATA: Sarcopenia as defined by low NTPA has been shown to predict poor perioperative outcomes following adult spinal deformity (ASD) surgery. However, there is limited evidence correlating the benefits of PT within the sarcopenic patient population. METHODS: NTPA was analyzed at the L3 and L4 mid-vertebral body on preoperative magnetic resonance imaging (MRI). Receiver operating characteristic (ROC) curve analysis was used to determine gender-specific NTPA cut-off values for predicting perioperative AEs. Patients were categorized as having low NTPA if both L3 and L4 NTPA were below these cut-off values. Perioperative outcomes were compared between patients with low NTPA that underwent documented formal PT within 6 months prior to ASD surgery with those that did not. RESULTS: 103 patients (42 males, 61 females) met criteria for low NTPA for inclusion in the study, of which 42 underwent preoperative PT and 61 did not. The preoperative PT group had a shorter LOS (111.2±37.5 vs. 162.1±97.0 h, P<0.001), higher ambulation distances (feet) on postoperative day (POD) 1 (61.7±50.3 vs. 26.1±69.0, P<0.001), POD 2 (113.2±81.8 vs. 62.1±73.1, P=0.003), and POD 3 (126.0±61.2 vs. 91.2±72.6, P=0.029), and lower rates of total AEs (31.0% vs. 54.1%, P=0.003) when excluding anemia requiring transfusion. Multivariable analysis found preoperative PT to be the most significant predictor of decreased LOS (OR 0.32, P=0.013). CONCLUSION: Sarcopenic patients may benefit from formal preoperative PT prior to undergoing ASD surgery to improve early postoperative mobility, decrease AEs, and decrease LOS. LEVEL OF EVIDENCE: 3.

Clostridium perfringens Epsilon Toxin Binds to and Kills Primary Human Lymphocytes.

Clostridium perfringens epsilon toxin (ETX) is the third most lethal bacterial toxin and has been suggested to be an environmental trigger of multiple sclerosis, an immune-mediated disease of the human central nervous system. However, ETX cytotoxicity on primary human cells has not been investigated. In this article, we demonstrate that ETX preferentially binds to and kills human lymphocytes expressing increased levels of the myelin and lymphocyte protein MAL. Using flow cytometry, ETX binding was determined to be time and dose dependent and was highest for CD4+ cells, followed by CD8+ and then CD19+ cells. Similar results were seen with ETX-induced cytotoxicity. To determine if ETX preference for CD4+ cells was related to MAL expression, MAL gene expression was determined by RT-qPCR. CD4+ cells had the highest amount of Mal gene expression followed by CD8+ and CD19+ cells. These data indicate that primary human cells are susceptible to ETX and support the hypothesis that MAL is a main receptor for ETX. Interestingly, ETX bindings to human lymphocytes suggest that ETX may influence immune response in multiple sclerosis.

Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege.

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

CNS endothelial derived extracellular vesicles are biomarkers of active disease in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a complex, heterogenous disease characterized by inflammation, demyelination, and blood-brain barrier (BBB) permeability. Currently, active disease is determined by physician confirmed relapse or detection of contrast enhancing lesions via MRI indicative of BBB permeability. However, clinical confirmation of active disease can be cumbersome. As such, disease monitoring in MS could benefit from identification of an easily accessible biomarker of active disease. We believe extracellular vesicles (EV) isolated from plasma are excellent candidates to fulfill this need. Because of the critical role BBB permeability plays in MS pathogenesis and identification of active disease, we sought to identify EV originating from central nervous system (CNS) endothelial as biomarkers of active MS. Because endothelial cells secrete more EV when stimulated or injured, we hypothesized that circulating concentrations of CNS endothelial derived EV will be increased in MS patients with active disease. METHODS: To test this, we developed a novel method to identify EV originating from CNS endothelial cells isolated from patient plasma using flow cytometry. Endothelial derived EV were identified by the absence of lymphocyte or platelet markers CD3 and CD41, respectively, and positive expression of pan-endothelial markers CD31, CD105, or CD144. To determine if endothelial derived EV originated from CNS endothelial cells, EV expressing CD31, CD105, or CD144 were evaluated for expression of the myelin and lymphocyte protein MAL, a protein specifically expressed by CNS endothelial cells compared to endothelial cells of peripheral organs. RESULTS: Quality control experiments indicate that EV detected using our flow cytometry method are 0.2 to 1 micron in size. Flow cytometry analysis of EV isolated from 20 healthy controls, 16 relapsing-remitting MS (RRMS) patients with active disease not receiving disease modifying therapy, 14 RRMS patients with stable disease not receiving disease modifying therapy, 17 relapsing-RRMS patients with stable disease receiving natalizumab, and 14 RRMS patients with stable disease receiving ocrelizumab revealed a significant increase in the plasma concentration of CNS endothelial derived EV in patients with active disease compared to all other groups (p = 0.001). CONCLUSIONS: For the first time, we have identified a method to identify CNS endothelial derived EV in circulation from human blood samples. Results from our pilot study indicate that increased levels of CNS endothelial derived EV may be a biomarker of BBB permeability and active disease in MS.

In vivo Blood-brain Barrier Permeability Assays Using Clostridium perfringens Epsilon Toxin.

In order for the brain to function properly, a carefully orchestrated homeostasis must be maintained. To help regulate this delicate balance, the brain has developed a highly selective blood-brain barrier (BBB). Under normal conditions, the BBB excludes harmful blood-borne material from the brain parenchyma. However, numerous neuropathological conditions can disrupt this barrier, causing BBB permeability and subsequent CNS dysfunction. Understanding the mechanisms involved in BBB permeability are essential to elucidating the pathology of various neurological disorders as well as identifying methods for drug delivery to the CNS. Here, we describe several in vivo methods to measure BBB permeability in mice using an array of diverse sized tracers including exogenous 376 Da fluorescein salt, 66.5 kDa bovine serum albumin, and 70 kDa dextran as well as endogenous 160 kDa mouse IgG. When administered intravenously, these substances are excluded from a healthy brain by the BBB. However, BBB dysfunction can allow entry of these tracers into the brain and this accumulation can be measured using spectrophotometry, fluorescent microscopy, and immunohistochemistry. We also describe a method to induce BBB permeability using Clostridium perfringens epsilon toxin. Finally, we include a short discussion about the advantages and disadvantages of each method and their appropriate downstream applications.