Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption.

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac239-infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8+ T cells in lymph nodes and reduced expression of BCL-2 in CD4+ T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4+ and CD8+ T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.

Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence.

Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8+ T cell functions, which requires a deeper understanding of CD8+ T cells promoting HIV control. Here we identifiy an antigen-responsive TOXhiTCF1+CD39+CD8+ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8+ T cells and proteomic analysis of purified CD8+ T cell subsets identified TOXhiTCF1+CD39+CD8+ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOXhiTCF1+CD39+CD8+ T cells were found at higher frequency than TCF1-CD39+CD8+ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA+ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOXhiTCF1+CD39+CD8+ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8+ T cells contributes to limiting SIV and HIV persistence.

Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.

SARS-CoV-2 infection perturbs the gastrointestinal tract and induces modest microbial translocation across the intestinal barrier.

SARS-CoV-2 infects via the respiratory tract, but COVID-19 includes an array of non-respiratory symptoms, among them gastrointestinal (GI) manifestations such as vomiting and diarrhea. Here we investigated the GI pathology of SARS-CoV-2 infections in rhesus macaques and humans. Macaques experienced mild infection with USA-WA1/2020 and shed viral RNA in the respiratory tract and stool, including subgenomic RNA indicative of replication in the GI tract. Intestinal immune cell populations were disturbed, with significantly fewer proliferating (Ki67+) jejunal B cells in SARS-CoV-2-infected macaques than uninfected ones. Modest translocation of bacteria/bacterial antigen was observed across the colonic epithelium, with a corresponding significant increase in plasma soluble CD14 (sCD14) that may be induced by LPS. Human plasma demonstrated significant decreases in interleukin (IL)-6 and sCD14 upon recovery from COVID-19, suggesting resolution of inflammation and response to translocated bacteria. sCD14 significantly positively correlated with zonulin, an indicator of gut barrier integrity, and IL-6. These results demonstrate that GI perturbations such as microbial translocation can occur in even mild SARS-CoV-2 infections and may contribute to the COVID-19 inflammatory state.IMPORTANCEThis study investigates gastrointestinal (GI) barrier disruption in SARS-CoV-2 infections and how it may contribute to disease. We observed bacteria or bacterial products crossing from the colon interior (the lumen) to the lamina propria during SARS-CoV-2 infection in macaques. Bacteria/bacterial products are tolerated in the lumen but may induce immune responses if they translocate to the lamina propria. We also observed a significant increase in soluble CD14, which is associated with an immune response to bacterial products. In addition, we observed that humans recovering from COVID-19 experienced a significant decrease in soluble CD14, as well as the inflammatory marker interleukin (IL)-6. IL-6 and sCD14 correlated significantly across macaque and human samples. These findings suggest that SARS-CoV-2 infection results in GI barrier disruption that permits microbial translocation and a corresponding immune response. These findings could aid in developing interventions to improve COVID-19 patient outcomes.

The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence.

Despite the advent of effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) continues to pose major challenges, with extensive pathogenesis during acute and chronic infection prior to ART initiation and continued persistence in a reservoir of infected CD4 T cells during long-term ART. CD101 has recently been characterized to play an important role in CD4 Treg potency. Using the simian immunodeficiency virus (SIV) model of HIV infection in rhesus macaques, we characterized the role and kinetics of CD101+ CD4 T cells in longitudinal SIV infection. Phenotypic analyses and single-cell RNAseq profiling revealed that CD101 marked CD4 Tregs with high immunosuppressive potential, distinct from CD101- Tregs, and these cells also were ideal target cells for HIV/SIV infection, with higher expression of CCR5 and α4ß7 in the gut mucosa. Notably, during acute SIV infection, CD101+ CD4 T cells were preferentially depleted across all CD4 subsets when compared with their CD101- counterpart, with a pronounced reduction within the Treg compartment, as well as significant depletion in mucosal tissue. Depletion of CD101+ CD4 was associated with increased viral burden in plasma and gut and elevated levels of inflammatory cytokines. While restored during long-term ART, the reconstituted CD101+ CD4 T cells display a phenotypic profile with high expression of inhibitory receptors (including PD-1 and CTLA-4), immunsuppressive cytokine production, and high levels of Ki-67, consistent with potential for homeostatic proliferation. Both the depletion of CD101+ cells and phenotypic profile of these cells found in the SIV model were confirmed in people with HIV on ART. Overall, these data suggest an important role for CD101-expressing CD4 T cells at all stages of HIV/SIV infection and a potential rationale for targeting CD101 to limit HIV pathogenesis and persistence, particularly at mucosal sites.

ChatGPT versus NASS clinical guidelines for degenerative spondylolisthesis: a comparative analysis.

BACKGROUND CONTEXT: Clinical guidelines, developed in concordance with the literature, are often used to guide surgeons' clinical decision making. Recent advancements of large language models and artificial intelligence (AI) in the medical field come with exciting potential. OpenAI's generative AI model, known as ChatGPT, can quickly synthesize information and generate responses grounded in medical literature, which may prove to be a useful tool in clinical decision-making for spine care. The current literature has yet to investigate the ability of ChatGPT to assist clinical decision making with regard to degenerative spondylolisthesis. PURPOSE: The study aimed to compare ChatGPT's concordance with the recommendations set forth by The North American Spine Society (NASS) Clinical Guideline for the Diagnosis and Treatment of Degenerative Spondylolisthesis and assess ChatGPT's accuracy within the context of the most recent literature. METHODS: ChatGPT-3.5 and 4.0 was prompted with questions from the NASS Clinical Guideline for the Diagnosis and Treatment of Degenerative Spondylolisthesis and graded its recommendations as "concordant" or "nonconcordant" relative to those put forth by NASS. A response was considered "concordant" when ChatGPT generated a recommendation that accurately reproduced all major points made in the NASS recommendation. Any responses with a grading of "nonconcordant" were further stratified into two subcategories: "Insufficient" or "Over-conclusive," to provide further insight into grading rationale. Responses between GPT-3.5 and 4.0 were compared using Chi-squared tests. RESULTS: ChatGPT-3.5 answered 13 of NASS's 28 total clinical questions in concordance with NASS's guidelines (46.4%). Categorical breakdown is as follows: Definitions and Natural History (1/1, 100%), Diagnosis and Imaging (1/4, 25%), Outcome Measures for Medical Intervention and Surgical Treatment (0/1, 0%), Medical and Interventional Treatment (4/6, 66.7%), Surgical Treatment (7/14, 50%), and Value of Spine Care (0/2, 0%). When NASS indicated there was sufficient evidence to offer a clear recommendation, ChatGPT-3.5 generated a concordant response 66.7% of the time (6/9). However, ChatGPT-3.5's concordance dropped to 36.8% when asked clinical questions that NASS did not provide a clear recommendation on (7/19). A further breakdown of ChatGPT-3.5's nonconcordance with the guidelines revealed that a vast majority of its inaccurate recommendations were due to them being "over-conclusive" (12/15, 80%), rather than "insufficient" (3/15, 20%). ChatGPT-4.0 answered 19 (67.9%) of the 28 total questions in concordance with NASS guidelines (P = 0.177). When NASS indicated there was sufficient evidence to offer a clear recommendation, ChatGPT-4.0 generated a concordant response 66.7% of the time (6/9). ChatGPT-4.0's concordance held up at 68.4% when asked clinical questions that NASS did not provide a clear recommendation on (13/19, P = 0.104). CONCLUSIONS: This study sheds light on the duality of LLM applications within clinical settings: one of accuracy and utility in some contexts versus inaccuracy and risk in others. ChatGPT was concordant for most clinical questions NASS offered recommendations for. However, for questions NASS did not offer best practices, ChatGPT generated answers that were either too general or inconsistent with the literature, and even fabricated data/citations. Thus, clinicians should exercise extreme caution when attempting to consult ChatGPT for clinical recommendations, taking care to ensure its reliability within the context of recent literature.

Ambulatory Surgery Centers Reduce Patient Out-of-Pocket Expenditures for Isolated Arthroscopic Rotator Cuff Repair, but Patient Out-of-Pocket Expenditures Are Increasing at a Faster Rate Than Total Healthcare Utilization Reimbursement From Payers.

PURPOSE: To categorize and trend annual out-of-pocket expenditures for arthroscopic rotator cuff repair (RCR) patients relative to total healthcare utilization (THU) reimbursement and compare drivers of patient out-of-pocket expenditures (POPE) in a granular fashion via analyses by insurance type and surgical setting. METHODS: Patients who underwent outpatient arthroscopic RCR in the United States from 2013 to 2018 were identified from the IBM MarketScan Database. Primary outcome variables were total POPE and THU reimbursement, which were calculated for all claims in the 9-month perioperative period. Trends in outcome variables over time and differences across insurance types were analyzed. Multivariable analysis was performed to investigate drivers of POPE. RESULTS: A total of 52,330 arthroscopic RCR patients were identified. Between 2013 and 2018, median POPE increased by 47.5% ($917 to $1,353), and median THU increased by 9.3% ($11,964 to $13,076). Patients with high deductible insurance plans paid $1,910 toward their THU, 52.5% more than patients with preferred provider plans ($1,253, P = .001) and 280.5% more than patients with managed care plans ($502, P = .001). All components of POPE increased over the study period, with the largest observed increase being POPE for the immediate procedure (P = .001). On multivariable analysis, out-of-network facility, out-of-network surgeon, and high-deductible insurance most significantly increased POPE. CONCLUSIONS: POPE for arthroscopic RCR increased at a higher rate than THU over the study period, demonstrating that patients are paying an increasing proportion of RCR costs. A large percentage of this increase comes from increasing POPE for the immediate procedure. Out-of-network facility status increased POPE 3 times more than out-of-network surgeon status, and future cost-optimization strategies should focus on facility-specific reimbursements in particular. Last, ambulatory surgery centers (ASCs) significantly reduced POPE, so performing arthroscopic RCRs at ASCs is beneficial to cost-minimization efforts. CLINICAL RELEVANCE: This study highlights that although payers have increased reimbursement for RCR, patient out-of-pocket expenditures have increased at a much higher rate. Furthermore, this study elucidates trends in and drivers of patient out-of-pocket payments for RCR, providing evidence for development of cost-optimization strategies and counseling of patients undergoing RCR.

Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix.

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.

Use of Glycoprotein IIb-IIIa Inhibitors in Patients Undergoing Carotid Artery Stenting in the Vascular Quality Initiative.

BACKGROUND: Antiplatelet therapies with thromboxane inhibitors and adenosine 5'-diphosphate antagonists have been widely used following carotid artery stenting (CAS). However, these therapies may not apply to patients who are intolerant or present acutely. Glycoprotein IIb/IIIa inhibitors (GPI) are a proposed alternative therapy in these patients; however, their use has been limited due to concerns of increased risk for intracranial bleeding. Thus, this study aims to assess the safety profile of GPI in patients undergoing CAS. METHODS: All patients undergoing CAS in the Society of Vascular Surgery - Vascular Quality Initiative database from 2012 to 2021 was included and grouped into GPI versus non-GPI therapy (control). The primary outcome was in-hospital stroke or death, and secondary outcomes included in-hospital stroke/transient ischemic attack (TIA), death, myocardial infarction, and intracranial hemorrhage (ICH)/seizure. Patients were stratified by surgical approach (Transcarotid artery revascularization using flow reversal (TCAR) and transfemoral carotid artery stenting), and stepwise backward logistic regression analysis was conducted to evaluate major primary and secondary outcomes. RESULTS: A total of 50,628 patients underwent carotid revascularization. Of these, 4.4% of the patients received GPI. Mean age was similar between control versus GPI (71.35(9.67) vs. 71.36(10.20) years). Compared to the control group, patients who receive GPI are less likely to be on optimal medical therapy, including aspirin (83.0% vs. 88.1%), P2Y12 inhibitor (73.0% vs. 82.7%), and statin (82.3% vs. 86.0%) (All P < 0.05). In addition, patients in the GPI group were more likely to undergo TCAR for carotid revascularization (52.2% vs. 48.4%) for emergent/urgent (29.4% vs. 16.8%) and symptomatic indications (55.5% vs. 49.7%) (All P < 0.001). After stratifying by surgical approach, if patients underwent TFCAS and received a GPI, they were at increased odds of developing stroke/death (1.77(1.25-2.51)), death (odds ratio (OR) (95% CI): 1.67(1.07-2.61)), stroke/TIA (OR (95% confidence interval (CI)): 1.65(1.09-2.51)), and ICH/seizure (OR (95% CI): 2.13(1.23-3.68)) (All P < 0.05). No difference was seen in outcomes between the 2 groups if undergoing TCAR. CONCLUSIONS: Patients who receive GPI were more likely to be symptomatic at presentation and less likely to be medically optimized before their carotid revascularization. Transfemoral access in patients receiving GPI was associated with increased odds of morbidity and mortality. However, this was not observed if undergoing TCAR. TCAR can be considered for its overall favorable results in high-risk patients who are not medically optimized.

Ambulatory Surgery Centers Reduce Patient Out-of-Pocket Expenditures (POPE) for Isolated Arthroscopic Rotator Cuff Repair, but POPE Are Increasing at a Faster Rate than Total Healthcare Utilization Reimbursement from Payers.

PURPOSE: The purpose of this study is to categorize and trend annual out-of-pocket expenditures for arthroscopic RCR patients relative to total healthcare utilization (THU) reimbursement and compare drivers of patient out-of-pocket expenditures (POPE) in a granular fashion via analyses by insurance type and surgical setting. METHODS: Patients who underwent outpatient arthroscopic RCR in the U.S. from 2013 to 2018 were identified from the IBM MarketScan Database. Primary outcome variables were total POPE and THU reimbursement, which were calculated for all claims in the 9-month perioperative period. Trends in outcome variables over time and differences across insurance types were analyzed. Multivariable analysis was performed to investigate drivers of POPE. RESULTS: 52,330 arthroscopic RCR patients were identified. Between 2013 and 2018, median POPE increased by 47.5% ($917 to $1,353) and median THU increased by 9.3% ($11,964 to $13,076). Patients with high deductible insurance plans paid $1,910 toward their THU, 52.5% more than patients with preferred provider plans ($1,253, p=0.001) and 280.5% more than patients with managed care plans ($502, p=0.001). All components of POPE increased over the study period with the largest observed increase being POPE for the immediate procedure (p=0.001). On multivariable analysis, out-of-network facility, out-of-network surgeon, and high deductible insurance most significantly increased POPE. CONCLUSION: POPE for arthroscopic RCR increased at a higher rate than THU over the study period, demonstrating that patients are paying an increasing proportion of RCR costs. A large percentage of this increase comes from increasing POPE for the immediate procedure. Out-of-network facility status increased POPE three times more than out-of-network surgeon status, and future cost-optimization strategies should focus on facility-specific reimbursements in particular. Lastly, ASCs significantly reduced POPE, so performing arthroscopic RCRs at ASCs is beneficial to cost-minimization efforts.

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.

Bone Marrow-Derived CD4+ T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir.

The bone marrow (BM) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature T cells. However, very little is known on the phenotype of BM-derived CD4+ T cells, their fate during simian immunodeficiency virus (SIV) infection, and their contribution to viral persistence during antiretroviral therapy (ART). In this study, we characterized the immunologic and virologic status of BM-derived CD4+ T cells in rhesus macaques prior to SIV infection, during the early chronic phase of infection, and during ART. We found that BM memory CD4+ T cells are significantly depleted following SIV infection, at levels that are similar to those measured in the peripheral blood (PB). In addition, BM-derived memory CD4+ T cells include a high frequency of cells that express the coinhibitory receptors CTLA-4 and PD-1, two subsets previously shown to be enriched in the viral reservoir; these cells express Ki-67 at levels similar to or higher than the same cells in PB. Finally, when we analyzed SIV-infected RMs in which viral replication was effectively suppressed by 12 months of ART, we found that BM CD4+ T cells harbor SIV DNA and SIV RNA at levels comparable to those of PB CD4+ T cells, including replication-competent SIV. Thus, BM is a largely understudied anatomic site of the latent reservoir which contributes to viral persistence during ART and needs to be further characterized and targeted when designing therapies for a functional or sterilizing cure to HIV.IMPORTANCE The latent viral reservoir is one of the major obstacles in purging the immune system of HIV. It is paramount that we elucidate which anatomic compartments harbor replication-competent virus, which upon ART interruption results in viral rebound and pathogenesis. In this study, using the rhesus macaque model of SIV infection and ART, we examined the immunologic status of the BM and its role as a potential sanctuary for latent virus. We found that the BM compartment undergoes a similar depletion of memory CD4+ T cells as PB, and during ART treatment the BM-derived memory CD4+ T cells contain high levels of cells expressing CTLA-4 and PD-1, as well as amounts of cell-associated SIV DNA, SIV RNA, and replication-competent virus comparable to those in PB. These results enrich our understanding of which anatomic compartments harbor replication virus and suggest that BM-derived CD4+ T cells need to be targeted by therapeutic strategies aimed at achieving an HIV cure.

Inhibition during response preparation is sensitive to response complexity.

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors.

Sclerotherapy of the Post renal Transplant Lymphoceles: A Meta-Analysis.

PURPOSE: This study evaluated the effectiveness of sclerotherapy in treating lymphoceles after kidney transplantation, focusing on factors such as recurrence rates and procedural success. MATERIALS AND METHODS: Retrospective studies using sclerotherapy as the only form of treatment for postrenal transplant lymphoceles were included. All studies used percutaneous transcatheter sclerotherapy as treatment, and the success rate of the intervention was recorded. Sixty-one references were obtained by manually searching the MEDLINE (n = 20), Embase (n = 41), and Cochrane Library databases (n = 0) for retrospective research studies that included the keywords "sclerotherapy post renal transplant lymphoceles." After removing 3 duplicates, 50 of the remaining articles were excluded after the screening, and the remaining studies were extracted for demographic data and our primary outcome of the success rate of sclerotherapy. RESULTS: A descriptive analysis of the outcomes and complication rates associated with sclerotherapy interventions for lymphoceles is provided. A high degree of variation across the different studies was observed. According to the Kruskal-Wallis test, there was no correlation between the sclerosant used and the sclerotherapy complication rate (P = .472) or the success rate (P = .591). There was also no correlation between the gender of the patient and the success rate; however, there was a significant difference in the complication rate by gender (P < .005). CONCLUSIONS: In conclusion, different sclerosant products have been used for therapy with no consensus on the most efficacious product because the success rate has been variable. In addition, the gender of the patient may influence the complication rates associated with sclerotherapy for lymphoceles in patients post-kidney transplant.

Increased rate of out-of-network surgeon selection for hip arthroscopy compared to more common orthopedic sports procedures.

Background: Demand for hip arthroscopy (HA) has increased, but shortfalls in HA training may create disparities in care access. This analysis aimed to (1) compare out-of-network (OON) surgeon utilization for HA with that of more common orthopedics sports procedures, including rotator cuff repair (RCR), partial meniscectomy (PM), and anterior cruciate ligament reconstruction (ACLR), (2) compare the HA OON surgeon rate with another less commonly performed procedure, meniscus allograft transplant (MAT), and (3) analyze trends and predictors of OON surgeon utilization. Methods: The 2013-2017 IBM MarketScan database identified patients under 65 who underwent HA, RCR, PM, ACLR, or MAT. Demographic differences were determined using standardized differences. Cochran-Armitage tests analyzed trends in OON surgeon utilization. Multivariable logistic regression identified predictors of OON surgeon utilization. Statistical significance was set to p < 0.05 and significant standardized differences were >0.1. Results: 410,487 patients were identified, of which 12,636 patients underwent HA, 87,607 RCR, 233,241 PM, 76,700 ACLR, and 303 MAT. OON surgeon utilization increased for HA, rising from 7.98 % in 2013 to 9.37 % in 2017 (p = 0.026). Compared to RCR, PM, and ACLR, HA was associated with higher likelihood of OON surgeon utilization. Usage of ambulatory surgery centers (ASCs) was predictive of higher OON surgeon rates along with procedure year, insurance plan type, and geographic region. HA performed in an ASC was 13 % less likely to have an OON surgeon (p = 0.047). Conclusion: OON surgeon utilization generally declined but increased for HA. HA was a predictor of OON surgeon status, possibly because HA is a technically complicated procedure with fewer trained in-network providers. Other predictors of OON surgeon status included ASC usage, PPO/EPO plan type, and Northeast geographic region. There is a need to improve access to experienced HA providers-perhaps with prioritization of HA training in residency and fellowship programs-in order to address rising OON surgeon utilization.

An analysis of ChatGPT recommendations for the diagnosis and treatment of cervical radiculopathy.

OBJECTIVE: The objective of this study was to assess the safety and accuracy of ChatGPT recommendations in comparison to the evidence-based guidelines from the North American Spine Society (NASS) for the diagnosis and treatment of cervical radiculopathy. METHODS: ChatGPT was prompted with questions from the 2011 NASS clinical guidelines for cervical radiculopathy and evaluated for concordance. Selected key phrases within the NASS guidelines were identified. Completeness was measured as the number of overlapping key phrases between ChatGPT responses and NASS guidelines divided by the total number of key phrases. A senior spine surgeon evaluated the ChatGPT responses for safety and accuracy. ChatGPT responses were further evaluated on their readability, similarity, and consistency. Flesch Reading Ease scores and Flesch-Kincaid reading levels were measured to assess readability. The Jaccard Similarity Index was used to assess agreement between ChatGPT responses and NASS clinical guidelines. RESULTS: A total of 100 key phrases were identified across 14 NASS clinical guidelines. The mean completeness of ChatGPT-4 was 46%. ChatGPT-3.5 yielded a completeness of 34%. ChatGPT-4 outperformed ChatGPT-3.5 by a margin of 12%. ChatGPT-4.0 outputs had a mean Flesch reading score of 15.24, which is very difficult to read, requiring a college graduate education to understand. ChatGPT-3.5 outputs had a lower mean Flesch reading score of 8.73, indicating that they are even more difficult to read and require a professional education level to do so. However, both versions of ChatGPT were more accessible than NASS guidelines, which had a mean Flesch reading score of 4.58. Furthermore, with NASS guidelines as a reference, ChatGPT-3.5 registered a mean ± SD Jaccard Similarity Index score of 0.20 ± 0.078 while ChatGPT-4 had a mean of 0.18 ± 0.068. Based on physician evaluation, outputs from ChatGPT-3.5 and ChatGPT-4.0 were safe 100% of the time. Thirteen of 14 (92.8%) ChatGPT-3.5 responses and 14 of 14 (100%) ChatGPT-4.0 responses were in agreement with current best clinical practices for cervical radiculopathy according to a senior spine surgeon. CONCLUSIONS: ChatGPT models were able to provide safe and accurate but incomplete responses to NASS clinical guideline questions about cervical radiculopathy. Although the authors' results suggest that improvements are required before ChatGPT can be reliably deployed in a clinical setting, future versions of the LLM hold promise as an updated reference for guidelines on cervical radiculopathy. Future versions must prioritize accessibility and comprehensibility for a diverse audience.

Performance of a Large Language Model in the Generation of Clinical Guidelines for Antibiotic Prophylaxis in Spine Surgery.

OBJECTIVE: Large language models, such as chat generative pre-trained transformer (ChatGPT), have great potential for streamlining medical processes and assisting physicians in clinical decision-making. This study aimed to assess the potential of ChatGPT's 2 models (GPT-3.5 and GPT-4.0) to support clinical decision-making by comparing its responses for antibiotic prophylaxis in spine surgery to accepted clinical guidelines. METHODS: ChatGPT models were prompted with questions from the North American Spine Society (NASS) Evidence-based Clinical Guidelines for Multidisciplinary Spine Care for Antibiotic Prophylaxis in Spine Surgery (2013). Its responses were then compared and assessed for accuracy. RESULTS: Of the 16 NASS guideline questions concerning antibiotic prophylaxis, 10 responses (62.5%) were accurate in ChatGPT's GPT-3.5 model and 13 (81%) were accurate in GPT-4.0. Twenty-five percent of GPT-3.5 answers were deemed as overly confident while 62.5% of GPT-4.0 answers directly used the NASS guideline as evidence for its response. CONCLUSION: ChatGPT demonstrated an impressive ability to accurately answer clinical questions. GPT-3.5 model's performance was limited by its tendency to give overly confident responses and its inability to identify the most significant elements in its responses. GPT-4.0 model's responses had higher accuracy and cited the NASS guideline as direct evidence many times. While GPT-4.0 is still far from perfect, it has shown an exceptional ability to extract the most relevant research available compared to GPT-3.5. Thus, while ChatGPT has shown far-reaching potential, scrutiny should still be exercised regarding its clinical use at this time.

The Effect of Intraoperative Overdistraction on Subsidence Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to evaluate the effect of overdistraction on interbody cage subsidence. BACKGROUND: Vertebral overdistraction due to the use of large intervertebral cage sizes may increase the risk of postoperative subsidence. METHODS: Patients who underwent anterior cervical discectomy and fusion between 2016 and 2021 were included. All measurements were performed using lateral cervical radiographs at 3 time points - preoperative, immediate postoperative, and final follow-up >6 months postoperatively. Anterior and posterior distraction were calculated by subtracting the preoperative disc height from the immediate postoperative disc height. Cage subsidence was calculated by subtracting the final follow-up postoperative disc height from the immediate postoperative disc height. Associations between anterior and posterior subsidence and distraction were determined using multivariable linear regression models. The analyses controlled for cage type, cervical level, sex, age, smoking status, and osteopenia. RESULTS: Sixty-eight patients and 125 fused levels were included in the study. Of the 68 fusions, 22 were single-level fusions, 35 were 2-level, and 11 were 3-level. The median final follow-up interval was 368 days (range: 181-1257 d). Anterior disc space subsidence was positively associated with anterior distraction (beta = 0.23; 95% CI: 0.08, 0.38; P = 0.004), and posterior disc space subsidence was positively associated with posterior distraction (beta = 0.29; 95% CI: 0.13, 0.45; P < 0.001). No significant associations between anterior distraction and posterior subsidence (beta = 0.07; 95% CI: -0.06, 0.20; P = 0.270) or posterior distraction and anterior subsidence (beta = 0.06; 95% CI: -0.14, 0.27; P = 0.541) were observed. CONCLUSIONS: We found that overdistraction of the disc space was associated with increased postoperative subsidence after anterior cervical discectomy and fusion. Surgeons should consider choosing a smaller cage size to avoid overdistraction and minimize postoperative subsidence.

Comparison of postoperative complications and outcomes following primary versus revision discectomy: A national database analysis.

Background: Lumbar microdiscectomy is a surgical procedure that is frequently used in the treatment of symptomatic lumbar herniation. Differences in outcomes following primary and revision lumbar microdiscectomy have been previously studied, with reports of comparably satisfactory results from the Spine Patient Outcomes Research Trial. In this study, we further investigate these outcomes, including length of stay, bleeding events, and durotomy. We hypothesized that length of stay, incidence of bleeding events, and dural tear would be greater in the revision cohort. Methods: The ACS-National Surgical Quality Improvement Program database was queried for patients undergoing single-level primary and revision lumbar microdiscectomy between 2019 and 2022. Eligibility for inclusion was determined by age >18 years and current procedural terminology codes 63030 and 63042. Patients with preoperative sepsis or cancer were excluded. Length of stay, wound infection, bleeding events requiring transfusion, cerebrospinal fluid leak, dural tear, and neurological injury were compared between the cohorts. Multivariable Poisson regression adjusted for demographics and comorbidities, including age, sex, race, body mass index, diabetes, smoking, and hypertension, was used to determine if revision was predictive of complications. Results: A total of 37,669 patients were included, of whom 3,635 (9.6%) required revision surgery. Patients in the revision cohort were older (54.25 ± 15.7 vs. 50.85 ± 16.0 years, P < 0.001) and had higher proportions of male (59.0% vs. 55.7%, P < 0.001) and non-Hispanic White patients (82.0% vs. 77.4%, P < 0.001). Length of stay (1.11 ± 2.5 vs. 1.58 ± 2.7, P < 0.001) and rates of wound infection (2.1% vs. 1.4%, P = 0.002) and bleeding events requiring transfusion (1.3% vs. 0.7%, P < 0.001) were greater in the revision cohort compared to primary patients. Differences in cerebrospinal fluid leak (0.2% vs. 0.1%, P = 0.116), dural tear complication (0.01% vs. 0.01%, P = 0.092), and neurological injury (0.008% vs. 0.006%, P = 0.691) between the revision and primary cohorts were nonsignificant. Poisson log-linear regression adjusted for demographics and comorbidities demonstrated revision as a significant predictor for length of stay (χ 2 = 462.95, P < 0.001), wound infection (χ 2 = 9.22, P = 0.002), and bleeding events (χ 2 = 9.74, P = 0.002), while it was a nonsignificant predictor of cerebrospinal fluid leak (χ 2 = 2.61, P = 0.106), dural tear (χ 2 = 2.37, P = 0.123), and neurological injury (χ 2 = 0.229, P = 0.632). Conclusion: Revision surgery was a significant predictor of increased length of stay, wound infection, and bleeding events requiring transfusion. Surgeons and patients alike should be aware of increased risk for complications following revision lumbar microdiscectomy compared to primary discectomy.